miladalsh/processed_scinews_dataset · Datasets at Hugging Face

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hyoliths are abundant and globally distributed ‘shelly’ fossils that appear early in the Cambrian period and can be found throughout the 280 million year span of Palaeozoic strata 1 , 2 . The ecological and evolutionary importance of this group has remained unresolved, largely because of their poorly constrained soft anatomy and idiosyncratic scleritome, which comprises an operculum, a conical shell and, in some taxa, a pair of lateral spines (helens) 3 , 4 , 5 . Since their first description over 175 years ago, hyoliths have most often been regarded as incertae sedis 4 , 6 , related to molluscs 7 , 8 or assigned to their own phylum 1 , 2 . Here we examine over 1,500 specimens of the mid-Cambrian hyolith Haplophrentis from the Burgess Shale and Spence Shale Lagerstätten. We reconstruct Haplophrentis as a semi-sessile, epibenthic suspension feeder that could use its helens to elevate its tubular body above the sea floor 3 , 9 , 10 , 11 , 12 . Exceptionally preserved soft tissues include an extendable, gullwing-shaped, tentacle-bearing organ surrounding a central mouth, which we interpret as a lophophore, and a U-shaped digestive tract ending in a dorsolateral anus. Together with opposing bilateral sclerites and a deep ventral visceral cavity, these features indicate an affinity with the lophophorates (brachiopods, phoronids and tommotiids), substantially increasing the morphological disparity of this prominent group. Main The radiation of biomineralized skeletons ranks among the most notable and conspicuous records of the Cambrian explosion. Fossils of shelly elements track the evolution of animal body plans, but many have proven difficult to interpret from a biological perspective 6 . Among these are the hyoliths, which are particularly widespread and diverse in early Palaeozoic sediments. Orthothecid hyoliths possess a conical shell (previously referred to as a ‘conch’) and a cap-like operculum, each of which were putatively aragonitic and grew by basal–marginal accretion 1 . Hyolithid hyoliths are additionally characterized by a pair of logarithmically curving lateral spines (helens) and a non-planar operculum with a more extensive array of internally directed processes and muscle scars 13 , 14 . Hyoliths have generally been considered to be close relatives of molluscs owing to the presence of a bulb-shaped larval ‘protoconch’ 15 and purported mineralogical and microstructural similarities between their shells 7 , although recent studies have questioned both the validity and the importance of these observations 1 , 16 . Beyond this, the peculiar hyolith scleritome affords few opportunities for comparison with extant organisms. The only abundant evidence of non-mineralized anatomy comes from putative muscle scars, but these do little to constrain the affinities of hyoliths 11 , 14 . Rarer traces of U-shaped guts 3 , 4 , 5 are also phylogenetically uninformative owing to their widespread occurrence among lophotrochozoans 17 . Here we reanalyse the systematic affinity of the hyolithid Haplophrentis based on over 1,500 specimens, 254 of which have preserved soft tissues ( Supplementary Discussion and Supplementary Tables 1, 2 ). The specimens include Haplophrentis carinatus from the Burgess Shale (principally from the Stanley Glacier 18 and Marble Canyon 19 localities, British Columbia, Canada) and Haplophrentis reesei 5 from the Spence Shale (Utah, USA), which are kept at the Royal Ontario Museum and the University of Kansas Natural History Museum, respectively. Soft tissue characteristics include a gullwing-shaped band below the operculum. From this band protrude as many as 12 ( H. carinatus ) to 16 ( H. reesei ) elongate elements that exhibit variable orientation and curvature (hereafter named ‘tentacles’; Figs 1b , 2 and Extended Data Figs 1 , 2 , 3 , 4 ). The lateral regions of the band may curve slightly posteriad or anteriad. The flared basal portion of each tentacle is followed by a longer, gently tapering section, which can be up to half the length of the operculum and is about 7% as wide as it is long. Two shorter medial tentacles attach proximally around a centrally located mouth. We interpret this tentaculate band as a lophophore. Figure 1: Haplophrentis carinatus from the Burgess Shale. Specimens oriented with operculum to the top. Fossil images in top row correspond to line drawings in bottom row. a , Royal Ontario Museum (ROM) specimen ROM62928.5 from Marble Canyon, dorsal view with partially broken operculum, showing the gut and paired visceral organs within the conical shell. b , Specimen ROM63981.1 from Stanley Glacier, dorsal view (composite image of part and counterpart) showing the lophophore attached to the pharynx, and most of the gut. c , Specimen ROM63982.1 from Stanley Glacier, showing a ventral view of the U-shaped gut and anus. Scale bars, 2 mm. Abbreviations: a, anus; ag, anal branch of the gut; c, conical shell; cl, clavicle; cp, cardinal process; lh, left helen; m, mouth; o, operculum; og, oral branch of the gut; p, pharynx; rh, right helen; t, tentacle; vo, visceral organ. PowerPoint slide Full size image Figure 2: Soft tissues associated with the Haplophrentis operculum. Dorsal views of specimens, oriented with operculum to the top. a , Specimen ROM63983.1 ( H. carinatus ) from Stanley Glacier, showing lophophore in retracted position, with at least six tentacles on the left side, and muscle scars. b , University of Kansas Natural History Museum (KUMIP) specimen KUMIP366447 ( H. reesei ) from the Spence Shale, showing retracted lophophore with 16 tentacles. c , Specimen ROM59943.1 ( H. carinatus ) from Stanley Glacier, showing a partially extended lophophore with tentacles beyond the operculum margin. d , Specimen KUMIP204340 ( H. reesei ) from the Spence Shale, with a fully extended pharynx and lophophore. Scale bars, 2 mm. Abbreviations: ct, connective tissue; g, gut; ms, muscle scar; mt, medial tentacle; pl, pharynx lumen; other abbreviations as in Fig. 1 . PowerPoint slide Full size image The lophophore connects to a wide, medially situated structure that expands anteriorly from a narrow central tube with the mouth at the distal end. We interpret this tube as a pharynx with muscular walls. Variations in the length and width of this pharyngeal", "role": "user" }, { "content": "One branch on the tree of life is a bit more crowded today. A team of scientists led by 20-year-old University of Toronto (U of T) undergraduate student Joseph Moysiuk has finally determined what a bizarre group of extinct cone-shaped animals actually are. Known as hyoliths, these marine creatures evolved over 530 million years ago during the Cambrian period and are among the first animals known to have produced mineralized external skeletons. Long believed to belong to the same family as snails, squid and other molluscs, a study published today in the prestigious scientific journal Nature shows that hyoliths are instead more closely related to brachiopods - a group of animals which has a rich fossil record, although few living species remain today. Brachiopods have a soft body enclosed between upper and lower shells (valves), unlike the left and right arrangement of valves in bivalve molluscs. Brachiopods open their valves at the front when feeding, but otherwise keep them closed to protect their feeding apparatus and other body parts. Although the skeletal remains of hyoliths are abundant in the fossil record, key diagnostic aspects of their soft-anatomy remained critically absent until now. \"Our most important and surprising discovery is the hyolith feeding structure, which is a row of flexible tentacles extending away from the mouth, contained within the cavity between the lower conical shell and upper cap-like shell,\" said Moysiuk. \"Only one group of living animals - the brachiopods - has a comparable feeding structure enclosed by a pair of valves. This finding demonstrates that brachiopods, and not molluscs, are the closest surviving relatives of hyoliths. Dorsal view of specimens, anterior to the top. Detail and whole specimen. ROM59943.1, H. carinatus from Stanley Glacier (Kootenay National Park, B. C.), showing partially extended lophophore, with tentacles beyond the operculum margin. Credit: © Royal Ontario Museum \"It suggests that these hyoliths fed on organic material suspended in water as living brachiopods do today, sweeping food into their mouths with their tentacles,\" Moysiuk said. Moysiuk, who studies Earth sciences and ecology & evolutionary biology, completed this project as part of the Research Opportunity Program at U of T, a special undergraduate research program in the Faculty of Arts & Science. The distinctive appearance and structure of the hyolith skeleton has obstructed previous attempts to classify these animals. All hyoliths had an elongated, bilaterally symmetrical cone-shaped shell and a smaller cap-like shell which covered the opening of the conical shell (known as an operculum). Some species also bore a pair of rigid, curved spines (known as helens) that protruded from between the conical shell and operculum - structures with no equivalents in any other group of animals. Examination of the orientation of the helens in multiple hyolith specimens from the Burgess Shale suggests that these spines may have been used like stilts to lift the body of the animal above the sediment, elevating the feeding apparatus to enhance feeding. Moysiuk and coauthors Martin Smith at Durham University in the United Kingdom, and Jean-Bernard Caron at the Royal Ontario Museum (ROM) and U of T were able to complete the descriptions based mainly on newly discovered fossils from the renowned Cambrian Burgess Shale in British Columbia. \"Burgess Shale fossils are exceptional because they show preservation of soft tissues which are not usually preserved in normal conditions,\" said Caron, Moysiuk's research supervisor, who is the senior curator of invertebrate palaeontology at the ROM and an associate professor in U of T's Departments of Earth Sciences and Ecology & Evolutionary Biology. University of Toronto student Joseph Moysiuk showing matching halves of a fossil slab while in Kootenay National Park on a Royal Ontario Museum field expedition in 2014. Credit: © Joseph Moysiuk \"Although a molluscan affinity was proposed by some authors, this hypothesis remained based on insufficient evidence. Hyoliths became an orphaned branch on the tree of life, an embarrassment to paleontologists. Our most recent field discoveries were key in finally cracking their story, around 175 years after the first description of a hyolith.\" Caron led recent fieldwork activities to the Burgess Shale which resulted in the discovery of many specimens that form the basis of this study. The key specimens came from recently discovered deposits near Stanley Glacier and Marble Canyon in Kootenay National Park, about 40 kilometres southeast of the original Burgess Shale site in Yoho National Park. The Burgess Shale is one of the most important fossil deposits for studying the origin and early evolution of animals that took place during the Cambrian period, starting about 542 million years ago. Hyoliths are just one of the profusion of animal groups that characterize the fauna of the 'Cambrian Explosion'. They became a diverse component of marine ecosystems around the globe for more than 280 million years, only to go extinct 252 million years ago, prior to the evolution of the first dinosaurs. \"Resolving the debate over the hyoliths adds to our understanding of the Cambrian Explosion, the period of rapid evolutionary development when most major animal groups emerge in the fossil record,\" said Smith, who started this research at the University of Cambridge and who is now a lecturer in paleontology at Durham University. \"Our study reiterates the importance of soft tissue preservation from Burgess Shale-type deposits in illuminating the evolutionary history of creatures about which we still know very little.\" The Burgess Shale, from which the specimens were recovered from several locations, is part of the Canadian Rocky Mountain Parks World Heritage Site. It is one of the most important fossil deposits for understanding the origin and early evolution of animals that took place during the Cambrian Explosion starting about 542 million years ago. Parks Canada protects this globally significant site, and supports peer-reviewed scientific research that continues to enhance our understanding of these rich paleontological deposits. This discovery adds another element to the dramatic story of early animal evolution that Parks Canada guides share enthusiastically with hundreds of park visitors every year. The findings are described in the paper \"Hyoliths are Palaeozoic lophophorates\". Funding for the research was provided primarily by the Royal Ontario Museum and a Natural Sciences and Engineering Research Council of Canada Discovery Grant to Caron. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Hyoliths are abundant and globally distributed ‘shelly’ fossils that appear early in the Cambrian period and can be found throughout the 280 million year span of Palaeozoic strata 1 , 2 . The ecological and evolutionary importance of this group has remained unresolved, largely because of their poorly constrained soft anatomy and idiosyncratic scleritome, which comprises an operculum, a conical shell and, in some taxa, a pair of lateral spines (helens) 3 , 4 , 5 . Since their first description over 175 years ago, hyoliths have most often been regarded as incertae sedis 4 , 6 , related to molluscs 7 , 8 or assigned to their own phylum 1 , 2 . Here we examine over 1,500 specimens of the mid-Cambrian hyolith Haplophrentis from the Burgess Shale and Spence Shale Lagerstätten. We reconstruct Haplophrentis as a semi-sessile, epibenthic suspension feeder that could use its helens to elevate its tubular body above the sea floor 3 , 9 , 10 , 11 , 12 . Exceptionally preserved soft tissues include an extendable, gullwing-shaped, tentacle-bearing organ surrounding a central mouth, which we interpret as a lophophore, and a U-shaped digestive tract ending in a dorsolateral anus. Together with opposing bilateral sclerites and a deep ventral visceral cavity, these features indicate an affinity with the lophophorates (brachiopods, phoronids and tommotiids), substantially increasing the morphological disparity of this prominent group. Main The radiation of biomineralized skeletons ranks among the most notable and conspicuous records of the Cambrian explosion. Fossils of shelly elements track the evolution of animal body plans, but many have proven difficult to interpret from a biological perspective 6 . Among these are the hyoliths, which are particularly widespread and diverse in early Palaeozoic sediments. Orthothecid hyoliths possess a conical shell (previously referred to as a ‘conch’) and a cap-like operculum, each of which were putatively aragonitic and grew by basal–marginal accretion 1 . Hyolithid hyoliths are additionally characterized by a pair of logarithmically curving lateral spines (helens) and a non-planar operculum with a more extensive array of internally directed processes and muscle scars 13 , 14 . Hyoliths have generally been considered to be close relatives of molluscs owing to the presence of a bulb-shaped larval ‘protoconch’ 15 and purported mineralogical and microstructural similarities between their shells 7 , although recent studies have questioned both the validity and the importance of these observations 1 , 16 . Beyond this, the peculiar hyolith scleritome affords few opportunities for comparison with extant organisms. The only abundant evidence of non-mineralized anatomy comes from putative muscle scars, but these do little to constrain the affinities of hyoliths 11 , 14 . Rarer traces of U-shaped guts 3 , 4 , 5 are also phylogenetically uninformative owing to their widespread occurrence among lophotrochozoans 17 . Here we reanalyse the systematic affinity of the hyolithid Haplophrentis based on over 1,500 specimens, 254 of which have preserved soft tissues ( Supplementary Discussion and Supplementary Tables 1, 2 ). The specimens include Haplophrentis carinatus from the Burgess Shale (principally from the Stanley Glacier 18 and Marble Canyon 19 localities, British Columbia, Canada) and Haplophrentis reesei 5 from the Spence Shale (Utah, USA), which are kept at the Royal Ontario Museum and the University of Kansas Natural History Museum, respectively. Soft tissue characteristics include a gullwing-shaped band below the operculum. From this band protrude as many as 12 ( H. carinatus ) to 16 ( H. reesei ) elongate elements that exhibit variable orientation and curvature (hereafter named ‘tentacles’; Figs 1b , 2 and Extended Data Figs 1 , 2 , 3 , 4 ). The lateral regions of the band may curve slightly posteriad or anteriad. The flared basal portion of each tentacle is followed by a longer, gently tapering section, which can be up to half the length of the operculum and is about 7% as wide as it is long. Two shorter medial tentacles attach proximally around a centrally located mouth. We interpret this tentaculate band as a lophophore. Figure 1: Haplophrentis carinatus from the Burgess Shale. Specimens oriented with operculum to the top. Fossil images in top row correspond to line drawings in bottom row. a , Royal Ontario Museum (ROM) specimen ROM62928.5 from Marble Canyon, dorsal view with partially broken operculum, showing the gut and paired visceral organs within the conical shell. b , Specimen ROM63981.1 from Stanley Glacier, dorsal view (composite image of part and counterpart) showing the lophophore attached to the pharynx, and most of the gut. c , Specimen ROM63982.1 from Stanley Glacier, showing a ventral view of the U-shaped gut and anus. Scale bars, 2 mm. Abbreviations: a, anus; ag, anal branch of the gut; c, conical shell; cl, clavicle; cp, cardinal process; lh, left helen; m, mouth; o, operculum; og, oral branch of the gut; p, pharynx; rh, right helen; t, tentacle; vo, visceral organ. PowerPoint slide Full size image Figure 2: Soft tissues associated with the Haplophrentis operculum. Dorsal views of specimens, oriented with operculum to the top. a , Specimen ROM63983.1 ( H. carinatus ) from Stanley Glacier, showing lophophore in retracted position, with at least six tentacles on the left side, and muscle scars. b , University of Kansas Natural History Museum (KUMIP) specimen KUMIP366447 ( H. reesei ) from the Spence Shale, showing retracted lophophore with 16 tentacles. c , Specimen ROM59943.1 ( H. carinatus ) from Stanley Glacier, showing a partially extended lophophore with tentacles beyond the operculum margin. d , Specimen KUMIP204340 ( H. reesei ) from the Spence Shale, with a fully extended pharynx and lophophore. Scale bars, 2 mm. Abbreviations: ct, connective tissue; g, gut; ms, muscle scar; mt, medial tentacle; pl, pharynx lumen; other abbreviations as in Fig. 1 . PowerPoint slide Full size image The lophophore connects to a wide, medially situated structure that expands anteriorly from a narrow central tube with the mouth at the distal end. We interpret this tube as a pharynx with muscular walls. Variations in the length and width of this pharyngeal<|im_end|> <|im_start|>assistant One branch on the tree of life is a bit more crowded today. A team of scientists led by 20-year-old University of Toronto (U of T) undergraduate student Joseph Moysiuk has finally determined what a bizarre group of extinct cone-shaped animals actually are. Known as hyoliths, these marine creatures evolved over 530 million years ago during the Cambrian period and are among the first animals known to have produced mineralized external skeletons. Long believed to belong to the same family as snails, squid and other molluscs, a study published today in the prestigious scientific journal Nature shows that hyoliths are instead more closely related to brachiopods - a group of animals which has a rich fossil record, although few living species remain today. Brachiopods have a soft body enclosed between upper and lower shells (valves), unlike the left and right arrangement of valves in bivalve molluscs. Brachiopods open their valves at the front when feeding, but otherwise keep them closed to protect their feeding apparatus and other body parts. Although the skeletal remains of hyoliths are abundant in the fossil record, key diagnostic aspects of their soft-anatomy remained critically absent until now. "Our most important and surprising discovery is the hyolith feeding structure, which is a row of flexible tentacles extending away from the mouth, contained within the cavity between the lower conical shell and upper cap-like shell," said Moysiuk. "Only one group of living animals - the brachiopods - has a comparable feeding structure enclosed by a pair of valves. This finding demonstrates that brachiopods, and not molluscs, are the closest surviving relatives of hyoliths. Dorsal view of specimens, anterior to the top. Detail and whole specimen. ROM59943.1, H. carinatus from Stanley Glacier (Kootenay National Park, B. C.), showing partially extended lophophore, with tentacles beyond the operculum margin. Credit: © Royal Ontario Museum "It suggests that these hyoliths fed on organic material suspended in water as living brachiopods do today, sweeping food into their mouths with their tentacles," Moysiuk said. Moysiuk, who studies Earth sciences and ecology & evolutionary biology, completed this project as part of the Research Opportunity Program at U of T, a special undergraduate research program in the Faculty of Arts & Science. The distinctive appearance and structure of the hyolith skeleton has obstructed previous attempts to classify these animals. All hyoliths had an elongated, bilaterally symmetrical cone-shaped shell and a smaller cap-like shell which covered the opening of the conical shell (known as an operculum). Some species also bore a pair of rigid, curved spines (known as helens) that protruded from between the conical shell and operculum - structures with no equivalents in any other group of animals. Examination of the orientation of the helens in multiple hyolith specimens from the Burgess Shale suggests that these spines may have been used like stilts to lift the body of the animal above the sediment, elevating the feeding apparatus to enhance feeding. Moysiuk and coauthors Martin Smith at Durham University in the United Kingdom, and Jean-Bernard Caron at the Royal Ontario Museum (ROM) and U of T were able to complete the descriptions based mainly on newly discovered fossils from the renowned Cambrian Burgess Shale in British Columbia. "Burgess Shale fossils are exceptional because they show preservation of soft tissues which are not usually preserved in normal conditions," said Caron, Moysiuk's research supervisor, who is the senior curator of invertebrate palaeontology at the ROM and an associate professor in U of T's Departments of Earth Sciences and Ecology & Evolutionary Biology. University of Toronto student Joseph Moysiuk showing matching halves of a fossil slab while in Kootenay National Park on a Royal Ontario Museum field expedition in 2014. Credit: © Joseph Moysiuk "Although a molluscan affinity was proposed by some authors, this hypothesis remained based on insufficient evidence. Hyoliths became an orphaned branch on the tree of life, an embarrassment to paleontologists. Our most recent field discoveries were key in finally cracking their story, around 175 years after the first description of a hyolith." Caron led recent fieldwork activities to the Burgess Shale which resulted in the discovery of many specimens that form the basis of this study. The key specimens came from recently discovered deposits near Stanley Glacier and Marble Canyon in Kootenay National Park, about 40 kilometres southeast of the original Burgess Shale site in Yoho National Park. The Burgess Shale is one of the most important fossil deposits for studying the origin and early evolution of animals that took place during the Cambrian period, starting about 542 million years ago. Hyoliths are just one of the profusion of animal groups that characterize the fauna of the 'Cambrian Explosion'. They became a diverse component of marine ecosystems around the globe for more than 280 million years, only to go extinct 252 million years ago, prior to the evolution of the first dinosaurs. "Resolving the debate over the hyoliths adds to our understanding of the Cambrian Explosion, the period of rapid evolutionary development when most major animal groups emerge in the fossil record," said Smith, who started this research at the University of Cambridge and who is now a lecturer in paleontology at Durham University. "Our study reiterates the importance of soft tissue preservation from Burgess Shale-type deposits in illuminating the evolutionary history of creatures about which we still know very little." The Burgess Shale, from which the specimens were recovered from several locations, is part of the Canadian Rocky Mountain Parks World Heritage Site. It is one of the most important fossil deposits for understanding the origin and early evolution of animals that took place during the Cambrian Explosion starting about 542 million years ago. Parks Canada protects this globally significant site, and supports peer-reviewed scientific research that continues to enhance our understanding of these rich paleontological deposits. This discovery adds another element to the dramatic story of early animal evolution that Parks Canada guides share enthusiastically with hundreds of park visitors every year. The findings are described in the paper "Hyoliths are Palaeozoic lophophorates". Funding for the research was provided primarily by the Royal Ontario Museum and a Natural Sciences and Engineering Research Council of Canada Discovery Grant to Caron. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction 1 . Exposure to indoor allergens is a risk factor for asthma, but this disease is also associated with high household levels of total and particularly Gram-negative bacteria 2 . The ability of bacterial products to act as adjuvants 3 suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen-presenting dendritic cells (DCs) in vitro and promote allergic sensitization to inhaled innocuous proteins in vivo 4 . It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen for adjuvant activity of microbial products revealed that the bacterial protein flagellin (FLA) stimulated strong allergic airway responses to an innocuous inhaled protein, ovalbumin (OVA). Moreover, Toll-like receptor 5 (TLR5), the mammalian receptor for FLA 5 , 6 , was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, individuals with asthma have higher serum levels of FLA-specific antibodies as compared to nonasthmatic individuals. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens. Main To investigate the ability of microbial products to promote asthma-like responses in mice, we separately instilled individual products into the airway together with the innocuous protein, chicken ovalbumin (OVA). Control mice receiving either OVA alone or microbial products alone did not become sensitized and failed to develop airway inflammation after subsequent challenge with OVA ( Fig. 1a–c and Supplementary Fig. 1a ). However, instillation of some microbial products together with OVA caused the mice to become sensitized to this protein because after a subsequent OVA challenge, inflammatory leukocytes accumulated in the airway ( Fig. 1c ). Some mice displayed an allergic form of inflammation, as evidenced by large numbers of eosinophils in the airway ( Fig. 1c ). We observed strong allergic responses in mice receiving OVA together with standard FLA (sFLA) from Salmonella typhimurium , a partially purified product that contains lipopolysaccharide (LPS), or a highly purified recombinant FLA (rFLA) produced in insect cells and lacking detectable LPS (see Online Methods for details). Ultrapure LPS, which signals through TLR4, was similar to rFLA in its ability to promote allergic responses ( Supplementary Fig. 1b ), suggesting that impurities in crude preparations of LPS can reduce its potency as an adjuvant. Figure 1: Adjuvant activity of microbial products in the airways of C57BL/6 mice. ( a ) Timeline for sensitizations and challenges. ( b ) Microbial products used and the TLRs that mediate signaling responses to each product. ( c ) Airway inflammation in sensitized and challenged mice: total leukocytes (left), eosinophils (middle) and neutrophils (right) in the presence of increasing amounts (25 ng, 125 ng and 625 ng) of microbial products used during sensitizations; sFLA also includes 1,250 ng. n = 5–8 mice per group. Numbers reflect cell number ± s.e.m. in bronchoalveolar lavage fluid (BALF). ( d ) Pulmonary cytokine concentrations (mean values ± s.e.m.) in BALF for IL-4, IL-5 and IL-17, or in supernatants from OVA-stimulated, cultured whole lungs for IL-13. ( e ) Total serum IgE concentration ± s.e.m. Data are from one of three similar experiments. n = 5–8 mice per group. Full size image The clinical features of asthma stem largely from the actions of CD4 + T helper type 2 (T H 2) cells that produce the cytokines interleukin-4 (IL-4), IL-5 and IL-13 and promote IgE synthesis, eosinophilic inflammation and mucus and airway hyperresponsiveness (AHR), respectively. IL-17 production by T H 17 cells also contributes to asthma severity by promoting neutrophil accumulation and AHR 7 , 8 , 9 . We found that pulmonary IL-4, IL-5, IL-13 and IL-17 ( Fig. 1d ) and serum IgE ( Fig. 1e ) were all elevated in OVA-challenged mice previously sensitized with sFLA plus OVA or rFLA plus OVA. Mucus was present in the lungs of most mice that showed eosinophilic responses, but it was generally restricted to the large airways. However, mice sensitized with sFLA plus OVA also had mucus in preterminal and terminal bronchioles ( Fig. 2a,b ). Invasive measurements of airway resistance revealed that mice sensitized with either sFLA plus OVA ( Fig. 2c ) or rFLA plus OVA ( Fig. 2d ) developed strong AHR after a single OVA challenge, whereas mice sensitized to LPS plus OVA developed only modest AHR ( Fig. 2c ). Mice sensitized with OVA together with either sFLA or rFLA also displayed inflammation and AHR after OVA challenge on seven consecutive days ( Supplementary Fig. 2a,b ). T cells from lung-draining lymph nodes of these mice produced the Th2 cytokines IL-4, IL-5 and IL-13, as well as the Th17 cytokine IL-17, after restimulation with OVA ex vivo ( Fig. 2e ). Also, intracellular staining of CD4 + T cells from the lung revealed that they contain IL-13 and IL-17 ( Fig. 2f and Supplementary Fig. 2c ), confirming that inhaled FLA promotes T H 2 and T H 17 cell differentiation in adult mice. Figure 2: FLA promotes asthma-like responses to OVA. ( a ) Periodic acid-Schiff and Alcian blue staining of mucus-producing cells in the airway. Representative low-magnification images are shown (scale bars, 50 μm). Insets show expanded images of the indicated regions (scale bars, 10 μm). L, large airway; P, preterminal bronchioles. ( b ) Percentage of mice with mucus staining in the indicated regions of the lung. n = 8–10 mice per group. ( c , d ) Mean values ± s.e.m. of airway resistance (R) for intubated mice inhaling air (baseline) or aerosols of PBS containing the indicated concentrations of methacholine. n ≥ 8 mice per group. ( e ) Cytokine concentrations (mean values ± s.e.m.) in cultures of total cell suspensions from lymph nodes excised from mice sensitized with PBS ( n = 1) or OVA + rFLA ( n = 5). Cells were", "role": "user" }, { "content": "A bacterial protein in common house dust may worsen allergic responses to indoor allergens, according to research conducted by the National Institutes of Health and Duke University. The finding is the first to document the presence of the protein flagellin in house dust, bolstering the link between allergic asthma and the environment. Scientists from the NIH's National Institute of Environmental Health Sciences (NIEHS) and Duke University Medical Center published their findings in people and mice online Oct. 14 in the journal Nature Medicine. \"Most people with asthma have allergic asthma, resulting largely from allergic responses to inhaled substances,\" said the paper's corresponding author Donald Cook, Ph.D., an NIEHS scientist. His research team began the study to identify environmental factors that amplify the allergic responses. \"Although flagellin is not an allergen, it can boost allergic responses to true allergens.\" After inhaling house dust, mice that were able to respond to flagellin displayed all of the common symptoms of allergic asthma, including more mucous production, airway obstruction, and airway inflammation. However, mice lacking a gene that detects the presence of flagellin had reduced levels of these symptoms. \"More work will be required to confirm our conclusions, but it's possible that cleaning can reduce the amount of house dust in general, and flagellated bacteria in particular, to reduce the incidence of allergic asthma,\" Cook said. In addition to the mouse study, the research team also determined that people with asthma have higher levels of antibodies against flagellin in their blood than do non-asthmatic subjects, which provides more evidence of a link between environmental factors and allergic asthma in humans. \"More than 20 million Americans have asthma, with 4,000 deaths from the disease occurring each year,\" added Darryl Zeldin, M.D., NIEHS scientific director and paper co-author. \"All of these data suggest that flagellin in common house dust can promote allergic asthma by priming allergic responses to common indoor allergens.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction 1 . Exposure to indoor allergens is a risk factor for asthma, but this disease is also associated with high household levels of total and particularly Gram-negative bacteria 2 . The ability of bacterial products to act as adjuvants 3 suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen-presenting dendritic cells (DCs) in vitro and promote allergic sensitization to inhaled innocuous proteins in vivo 4 . It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen for adjuvant activity of microbial products revealed that the bacterial protein flagellin (FLA) stimulated strong allergic airway responses to an innocuous inhaled protein, ovalbumin (OVA). Moreover, Toll-like receptor 5 (TLR5), the mammalian receptor for FLA 5 , 6 , was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, individuals with asthma have higher serum levels of FLA-specific antibodies as compared to nonasthmatic individuals. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens. Main To investigate the ability of microbial products to promote asthma-like responses in mice, we separately instilled individual products into the airway together with the innocuous protein, chicken ovalbumin (OVA). Control mice receiving either OVA alone or microbial products alone did not become sensitized and failed to develop airway inflammation after subsequent challenge with OVA ( Fig. 1a–c and Supplementary Fig. 1a ). However, instillation of some microbial products together with OVA caused the mice to become sensitized to this protein because after a subsequent OVA challenge, inflammatory leukocytes accumulated in the airway ( Fig. 1c ). Some mice displayed an allergic form of inflammation, as evidenced by large numbers of eosinophils in the airway ( Fig. 1c ). We observed strong allergic responses in mice receiving OVA together with standard FLA (sFLA) from Salmonella typhimurium , a partially purified product that contains lipopolysaccharide (LPS), or a highly purified recombinant FLA (rFLA) produced in insect cells and lacking detectable LPS (see Online Methods for details). Ultrapure LPS, which signals through TLR4, was similar to rFLA in its ability to promote allergic responses ( Supplementary Fig. 1b ), suggesting that impurities in crude preparations of LPS can reduce its potency as an adjuvant. Figure 1: Adjuvant activity of microbial products in the airways of C57BL/6 mice. ( a ) Timeline for sensitizations and challenges. ( b ) Microbial products used and the TLRs that mediate signaling responses to each product. ( c ) Airway inflammation in sensitized and challenged mice: total leukocytes (left), eosinophils (middle) and neutrophils (right) in the presence of increasing amounts (25 ng, 125 ng and 625 ng) of microbial products used during sensitizations; sFLA also includes 1,250 ng. n = 5–8 mice per group. Numbers reflect cell number ± s.e.m. in bronchoalveolar lavage fluid (BALF). ( d ) Pulmonary cytokine concentrations (mean values ± s.e.m.) in BALF for IL-4, IL-5 and IL-17, or in supernatants from OVA-stimulated, cultured whole lungs for IL-13. ( e ) Total serum IgE concentration ± s.e.m. Data are from one of three similar experiments. n = 5–8 mice per group. Full size image The clinical features of asthma stem largely from the actions of CD4 + T helper type 2 (T H 2) cells that produce the cytokines interleukin-4 (IL-4), IL-5 and IL-13 and promote IgE synthesis, eosinophilic inflammation and mucus and airway hyperresponsiveness (AHR), respectively. IL-17 production by T H 17 cells also contributes to asthma severity by promoting neutrophil accumulation and AHR 7 , 8 , 9 . We found that pulmonary IL-4, IL-5, IL-13 and IL-17 ( Fig. 1d ) and serum IgE ( Fig. 1e ) were all elevated in OVA-challenged mice previously sensitized with sFLA plus OVA or rFLA plus OVA. Mucus was present in the lungs of most mice that showed eosinophilic responses, but it was generally restricted to the large airways. However, mice sensitized with sFLA plus OVA also had mucus in preterminal and terminal bronchioles ( Fig. 2a,b ). Invasive measurements of airway resistance revealed that mice sensitized with either sFLA plus OVA ( Fig. 2c ) or rFLA plus OVA ( Fig. 2d ) developed strong AHR after a single OVA challenge, whereas mice sensitized to LPS plus OVA developed only modest AHR ( Fig. 2c ). Mice sensitized with OVA together with either sFLA or rFLA also displayed inflammation and AHR after OVA challenge on seven consecutive days ( Supplementary Fig. 2a,b ). T cells from lung-draining lymph nodes of these mice produced the Th2 cytokines IL-4, IL-5 and IL-13, as well as the Th17 cytokine IL-17, after restimulation with OVA ex vivo ( Fig. 2e ). Also, intracellular staining of CD4 + T cells from the lung revealed that they contain IL-13 and IL-17 ( Fig. 2f and Supplementary Fig. 2c ), confirming that inhaled FLA promotes T H 2 and T H 17 cell differentiation in adult mice. Figure 2: FLA promotes asthma-like responses to OVA. ( a ) Periodic acid-Schiff and Alcian blue staining of mucus-producing cells in the airway. Representative low-magnification images are shown (scale bars, 50 μm). Insets show expanded images of the indicated regions (scale bars, 10 μm). L, large airway; P, preterminal bronchioles. ( b ) Percentage of mice with mucus staining in the indicated regions of the lung. n = 8–10 mice per group. ( c , d ) Mean values ± s.e.m. of airway resistance (R) for intubated mice inhaling air (baseline) or aerosols of PBS containing the indicated concentrations of methacholine. n ≥ 8 mice per group. ( e ) Cytokine concentrations (mean values ± s.e.m.) in cultures of total cell suspensions from lymph nodes excised from mice sensitized with PBS ( n = 1) or OVA + rFLA ( n = 5). Cells were<|im_end|> <|im_start|>assistant A bacterial protein in common house dust may worsen allergic responses to indoor allergens, according to research conducted by the National Institutes of Health and Duke University. The finding is the first to document the presence of the protein flagellin in house dust, bolstering the link between allergic asthma and the environment. Scientists from the NIH's National Institute of Environmental Health Sciences (NIEHS) and Duke University Medical Center published their findings in people and mice online Oct. 14 in the journal Nature Medicine. "Most people with asthma have allergic asthma, resulting largely from allergic responses to inhaled substances," said the paper's corresponding author Donald Cook, Ph.D., an NIEHS scientist. His research team began the study to identify environmental factors that amplify the allergic responses. "Although flagellin is not an allergen, it can boost allergic responses to true allergens." After inhaling house dust, mice that were able to respond to flagellin displayed all of the common symptoms of allergic asthma, including more mucous production, airway obstruction, and airway inflammation. However, mice lacking a gene that detects the presence of flagellin had reduced levels of these symptoms. "More work will be required to confirm our conclusions, but it's possible that cleaning can reduce the amount of house dust in general, and flagellated bacteria in particular, to reduce the incidence of allergic asthma," Cook said. In addition to the mouse study, the research team also determined that people with asthma have higher levels of antibodies against flagellin in their blood than do non-asthmatic subjects, which provides more evidence of a link between environmental factors and allergic asthma in humans. "More than 20 million Americans have asthma, with 4,000 deaths from the disease occurring each year," added Darryl Zeldin, M.D., NIEHS scientific director and paper co-author. "All of these data suggest that flagellin in common house dust can promote allergic asthma by priming allergic responses to common indoor allergens." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Predictive coding theories propose that the brain creates internal models of the environment to predict upcoming sensory input. Hierarchical predictive coding models of vision postulate that higher visual areas generate predictions of sensory inputs and feed them back to early visual cortex. In V1, sensory inputs that do not match the predictions lead to amplified brain activation, but does this amplification process dynamically update to new retinotopic locations with eye-movements? We investigated the effect of eye-movements in predictive feedback using functional brain imaging and eye-tracking whilst presenting an apparent motion illusion. Apparent motion induces an internal model of motion, during which sensory predictions of the illusory motion feed back to V1. We observed attenuated BOLD responses to predicted stimuli at the new post-saccadic location in V1. Therefore, pre-saccadic predictions update their retinotopic location in time for post-saccadic input, validating dynamic predictive coding theories in V1. Introduction Predictive coding accounts of vision propose that higher cortical areas use internal models of the world to predict sensory inputs 1 , 2 , 3 , 4 , 5 . Cortical feedback carries these predictions back to V1 where a neural mechanism compares them to the actual sensory inputs 6 . However, a central tenet of predictive coding remains to be tested. Humans saccade approximately three times per second, changing the retinotopic pattern of sensory inputs to V1 7 . Therefore, for cortical predictive feedback to be functional, it must update to new retinotopic locations in V1 in time to meet post-saccadic input 8 , 9 . Central to our study is the creation of an internal model in the brain, during which feedback carries sensory predictions from higher areas down to V1. The apparent motion illusion offers a paradigm for investigating such a model. Apparent motion is an illusion of a moving token between two alternating flashing stimuli 10 , 11 . Apparent motion is integrated in V5 12 , 13 , 14 , 15 , 16 , which feeds back a retinotopically-specific spatiotemporal prediction of a moving token to V1, inducing activation along the non-stimulated illusory motion trace 6 , 14 , 17 , 18 , 19 . The spatio-temporal prediction on the apparent motion trace can be probed with targets presented either in-time with the motion illusion (predicted), or out-of-time (unpredicted). In-time targets are detected more accurately than out-of-time targets 15 , 20 , 21 , 22 but lead to less (i.e. dis-amplified) BOLD activation in V1 compared with amplified activation for out-of-time targets 6 . According to predictive coding theories, the amplified BOLD activation for out-of-time targets is indicative of an error signal because they are less predictable in the context of the illusory moving token. Likewise, dis-amplified BOLD activity for in-time targets is consistent with the successful prediction (or ‘explaining away’) of sensory input. Here, we tested if pre-saccadic predictions feed back to new retinotopic locations in V1 in time for post-saccadic target processing. To this end, we presented the apparent motion illusion to one visual hemifield and then prompted a saccade, transferring motion-related feedback to the opposite hemisphere. Our data confirms that cortical feedback dynamically updates to new predicted retinotopic coordinates in V1. Results We first induced an apparent motion illusion, which creates a spatio-temporally precise prediction of apparent motion along the illusory motion trace in V1. We then instructed subjects to perform a right-to-left saccade across the apparent motion stimulus. When the saccade landed left of the apparent motion illusion, a target was presented either in-time or out-of-time during the last cycle of apparent motion (Fig. 1a–d ). After the saccade, the stimulus was in the right visual field, and processed by post-saccadic left V1. The post-saccadic left V1 processed only one apparent motion inducer after the target appeared, thus illusion-related activity is present even though the post-saccadic left V1 was not stimulated with a full apparent motion cycle. Without prior expectation from the contralateral hemisphere, both target stimuli are equally predictable by the surrounding stimulation. We tested for the presence of post-saccadic predictions by comparing the BOLD activity to in-time and out-of-time targets, in a test region on the illusory motion trace in post-saccadic left V1 (Fig. 2 ). This test region corresponds to the new retinotopic location at which the cortex processes the target stimulus after the saccade. We examined this test region in three apparent motion conditions: no target, in-time target, and out-of-time target. Subjects were instructed to report if they perceived a target presented immediately after saccade. We ran four functional magnetic resonance imaging (fMRI) experiments. Our pilot fMRI experiment led us to use high-resolution eye-tracking data for trial exclusion in the main apparent motion experiment. In the pilot experiment, we found consistent results with the main experiment in the subjects with valid eye movement data (see supplemental material and Figure S1 ). To confirm that our results are due to predictions created by the internal model of apparent motion, we also ran a flicker control fMRI experiment. Here, we presented the two flashing inducer stimuli simultaneously, instead of in alternating rhythm as in the apparent motion stimulation (Fig. 1e ). In the context of the flicker stimulation, neither target had a temporal predictability but for simplicity we kept the conditions labeled as “in-time” and “out-of-time” as the targets were presented at the same stimulus onset time in relation to the lower apparent motion inducer stimulus as in the main fMRI experiment. Finally, we ran a replication of our main apparent motion and flicker experiments. The design of the replication was identical to the main and flicker experiment except for two variations: (1) we ran the replication as a within- group design and (2) we used the same hardware throughout the replication (32-channel head coil) while in the original experiment we switched between experiments using the 12-channel head coil for the main and the 32-channel for the flicker control. The replication supported and strengthened our original findings. Figure 1 Apparent Motion Stimuli. (a) Stimulation before saccade: Subjects fixated on the red cross.", "role": "user" }, { "content": "Neuroscientists at the University of Glasgow have shown how the human brain can predict what our eyes will see next, using functional magnetic resonance imaging (fMRI). In a new study published in the Nature journal Scientific Reports, researchers have gained a greater understanding of visual mechanisms, and how seeing is a constant two-way dialogue between the brain and the eyes. The research, led by Professor Lars Muckli of the University of Glasgow, used fMRI and a visual illusion to show that the brain anticipates the information it will see when the eyes next move. The illusion involves two stationary flashing squares that look to the observer as one square moving between the two locations because the brain predicts motion. During these flashes, the authors instructed participants to move their eyes. The researchers imaged the visual cortex and found that the prediction of motion updated to a new spatial position in cortex with the eye movement. We move our eyes approximately 4 times per second, meaning our brains have to process new visual information every 250 milliseconds. Nevertheless, the world appears stable. If you were to move your video camera so frequently, the film would appear jumpy. The reason we still perceive the world as stable is because our brains think ahead. In other words, the brain predicts what it is going to see after you have moved your eyes. Professor Lars Muckli, of the Institute of Neuroscience & Psychology, said: \"This study is important because it demonstrates how fMRI can contribute to this area of neuroscience research. Further to that, finding a feasible mechanism for brain function will contribute to brain-inspired computing and artificial intelligence, as well as aid our investigation into mental disorders.\" The study also reveals the potential for fMRI to contribute to this area of neuroscience research, as the authors are able to detect a difference in processing of only 32ms, much faster than is typically thought possible with fMRI. Scientist Dr Gracie Edwards:\" Visual information is received from the eyes and processed by the visual system in the brain. We call visual information \"feedforward\" input. At the same time, the brain also sends information to the visual system, this information is called \"feedback\". \"Feedback information influences our perception of the feedforward input using expectations based on our memories of similar perceptual events. Feedforward and feedback information interact with one another to produce the visual scenes we perceive every day.\" The study, \"Predictive feedback to V1 dynamically updates with sensory input\" is published in Scientific Reports. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Predictive coding theories propose that the brain creates internal models of the environment to predict upcoming sensory input. Hierarchical predictive coding models of vision postulate that higher visual areas generate predictions of sensory inputs and feed them back to early visual cortex. In V1, sensory inputs that do not match the predictions lead to amplified brain activation, but does this amplification process dynamically update to new retinotopic locations with eye-movements? We investigated the effect of eye-movements in predictive feedback using functional brain imaging and eye-tracking whilst presenting an apparent motion illusion. Apparent motion induces an internal model of motion, during which sensory predictions of the illusory motion feed back to V1. We observed attenuated BOLD responses to predicted stimuli at the new post-saccadic location in V1. Therefore, pre-saccadic predictions update their retinotopic location in time for post-saccadic input, validating dynamic predictive coding theories in V1. Introduction Predictive coding accounts of vision propose that higher cortical areas use internal models of the world to predict sensory inputs 1 , 2 , 3 , 4 , 5 . Cortical feedback carries these predictions back to V1 where a neural mechanism compares them to the actual sensory inputs 6 . However, a central tenet of predictive coding remains to be tested. Humans saccade approximately three times per second, changing the retinotopic pattern of sensory inputs to V1 7 . Therefore, for cortical predictive feedback to be functional, it must update to new retinotopic locations in V1 in time to meet post-saccadic input 8 , 9 . Central to our study is the creation of an internal model in the brain, during which feedback carries sensory predictions from higher areas down to V1. The apparent motion illusion offers a paradigm for investigating such a model. Apparent motion is an illusion of a moving token between two alternating flashing stimuli 10 , 11 . Apparent motion is integrated in V5 12 , 13 , 14 , 15 , 16 , which feeds back a retinotopically-specific spatiotemporal prediction of a moving token to V1, inducing activation along the non-stimulated illusory motion trace 6 , 14 , 17 , 18 , 19 . The spatio-temporal prediction on the apparent motion trace can be probed with targets presented either in-time with the motion illusion (predicted), or out-of-time (unpredicted). In-time targets are detected more accurately than out-of-time targets 15 , 20 , 21 , 22 but lead to less (i.e. dis-amplified) BOLD activation in V1 compared with amplified activation for out-of-time targets 6 . According to predictive coding theories, the amplified BOLD activation for out-of-time targets is indicative of an error signal because they are less predictable in the context of the illusory moving token. Likewise, dis-amplified BOLD activity for in-time targets is consistent with the successful prediction (or ‘explaining away’) of sensory input. Here, we tested if pre-saccadic predictions feed back to new retinotopic locations in V1 in time for post-saccadic target processing. To this end, we presented the apparent motion illusion to one visual hemifield and then prompted a saccade, transferring motion-related feedback to the opposite hemisphere. Our data confirms that cortical feedback dynamically updates to new predicted retinotopic coordinates in V1. Results We first induced an apparent motion illusion, which creates a spatio-temporally precise prediction of apparent motion along the illusory motion trace in V1. We then instructed subjects to perform a right-to-left saccade across the apparent motion stimulus. When the saccade landed left of the apparent motion illusion, a target was presented either in-time or out-of-time during the last cycle of apparent motion (Fig. 1a–d ). After the saccade, the stimulus was in the right visual field, and processed by post-saccadic left V1. The post-saccadic left V1 processed only one apparent motion inducer after the target appeared, thus illusion-related activity is present even though the post-saccadic left V1 was not stimulated with a full apparent motion cycle. Without prior expectation from the contralateral hemisphere, both target stimuli are equally predictable by the surrounding stimulation. We tested for the presence of post-saccadic predictions by comparing the BOLD activity to in-time and out-of-time targets, in a test region on the illusory motion trace in post-saccadic left V1 (Fig. 2 ). This test region corresponds to the new retinotopic location at which the cortex processes the target stimulus after the saccade. We examined this test region in three apparent motion conditions: no target, in-time target, and out-of-time target. Subjects were instructed to report if they perceived a target presented immediately after saccade. We ran four functional magnetic resonance imaging (fMRI) experiments. Our pilot fMRI experiment led us to use high-resolution eye-tracking data for trial exclusion in the main apparent motion experiment. In the pilot experiment, we found consistent results with the main experiment in the subjects with valid eye movement data (see supplemental material and Figure S1 ). To confirm that our results are due to predictions created by the internal model of apparent motion, we also ran a flicker control fMRI experiment. Here, we presented the two flashing inducer stimuli simultaneously, instead of in alternating rhythm as in the apparent motion stimulation (Fig. 1e ). In the context of the flicker stimulation, neither target had a temporal predictability but for simplicity we kept the conditions labeled as “in-time” and “out-of-time” as the targets were presented at the same stimulus onset time in relation to the lower apparent motion inducer stimulus as in the main fMRI experiment. Finally, we ran a replication of our main apparent motion and flicker experiments. The design of the replication was identical to the main and flicker experiment except for two variations: (1) we ran the replication as a within- group design and (2) we used the same hardware throughout the replication (32-channel head coil) while in the original experiment we switched between experiments using the 12-channel head coil for the main and the 32-channel for the flicker control. The replication supported and strengthened our original findings. Figure 1 Apparent Motion Stimuli. (a) Stimulation before saccade: Subjects fixated on the red cross.<|im_end|> <|im_start|>assistant Neuroscientists at the University of Glasgow have shown how the human brain can predict what our eyes will see next, using functional magnetic resonance imaging (fMRI). In a new study published in the Nature journal Scientific Reports, researchers have gained a greater understanding of visual mechanisms, and how seeing is a constant two-way dialogue between the brain and the eyes. The research, led by Professor Lars Muckli of the University of Glasgow, used fMRI and a visual illusion to show that the brain anticipates the information it will see when the eyes next move. The illusion involves two stationary flashing squares that look to the observer as one square moving between the two locations because the brain predicts motion. During these flashes, the authors instructed participants to move their eyes. The researchers imaged the visual cortex and found that the prediction of motion updated to a new spatial position in cortex with the eye movement. We move our eyes approximately 4 times per second, meaning our brains have to process new visual information every 250 milliseconds. Nevertheless, the world appears stable. If you were to move your video camera so frequently, the film would appear jumpy. The reason we still perceive the world as stable is because our brains think ahead. In other words, the brain predicts what it is going to see after you have moved your eyes. Professor Lars Muckli, of the Institute of Neuroscience & Psychology, said: "This study is important because it demonstrates how fMRI can contribute to this area of neuroscience research. Further to that, finding a feasible mechanism for brain function will contribute to brain-inspired computing and artificial intelligence, as well as aid our investigation into mental disorders." The study also reveals the potential for fMRI to contribute to this area of neuroscience research, as the authors are able to detect a difference in processing of only 32ms, much faster than is typically thought possible with fMRI. Scientist Dr Gracie Edwards:" Visual information is received from the eyes and processed by the visual system in the brain. We call visual information "feedforward" input. At the same time, the brain also sends information to the visual system, this information is called "feedback". "Feedback information influences our perception of the feedforward input using expectations based on our memories of similar perceptual events. Feedforward and feedback information interact with one another to produce the visual scenes we perceive every day." The study, "Predictive feedback to V1 dynamically updates with sensory input" is published in Scientific Reports. <|im_end|>

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1,875

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Materials research is key to enable synthetic membranes for large-scale, energy-efficient molecular separations. Materials with rigid, engineered pore structures add an additional degree of freedom to create advanced membranes by providing entropically moderated selectivities. Scalability — the capability to efficiently and economically pack membranes into practical modules — is a critical yet often neglected factor to take into account for membrane materials screening. In this Progress Article, we highlight continuing developments and identify future opportunities in scalable membrane materials based on these rigid features, for both gas and liquid phase applications. These advanced materials open the door to a new generation of membrane processes beyond existing materials and approaches. Main Membranes are key components in systems as diverse as batteries, fuel cells, barrier packages, controlled delivery devices, solar cells and, of course, large-scale energy-efficient separation and purification systems. Here, we focus on this last category, where an engineered barrier controls the sorting of components by selective passage between feed and permeate streams 1 . Such membranes rely on materials with optimized structures to reduce costs and environmental impacts of production of vital commodities at a fraction of the energy requirements associated with traditional approaches 2 . With increasingly broad applications, membrane processes are change agents that promote a more sustainable and higher global standard of living 3 , 4 . This Progress Article focuses on molecular-scale discriminations between similarly sized molecules in gas and liquid mixtures by attending to the most detailed features of membrane materials. Such materials are crucial for maintaining clean air and water, and for efficient use of energy 2 , 5 . Hydrodynamic discrimination of suspended entities from a micromolecular medium is properly referred to as filtration, and is not the focus of this discussion. In both filtration and molecular separations, a pressure difference acting between the two faces of a supported membrane provides the most economical separation driving force. In filtrations, however, a mechanical pressure gradient within the membrane motivates fluid movement through pores, while in molecular separations a chemical potential gradient drives flux through the membrane. This significant difference causes thermodynamic partitioning (sorption coefficients) and kinetic mobility (diffusion coefficients) to control molecular separation — not primarily hydrodynamic sieving, as in simpler filtration cases 6 . This mechanistic difference opens the door to a rich area of materials science for separations in which the chemical nature and morphology of the membrane can be engineered to tailor complementary molecular diffusion and sorption selectivity 7 , 8 , 9 . Gas separation membranes Important gas separations require sorting of molecules with similar physical properties, and often similar sizes. For example, separation of O 2 molecules from N 2 molecules benefits to some extent from the slightly higher O 2 critical temperature, and hence sorption coefficient of O 2 versus N 2 in most media. In any case, it is primarily the higher O 2 diffusion coefficient in most membranes that enables their utility. Flux of component i , normalized by the applied transmembrane partial pressure difference, Δ p i (a surrogate for chemical potential difference, or fugacity difference), and selective membrane thickness, ℓ , is referred to as the permeability coefficient, P i . This coefficient characterizes the intrinsic membrane material productivity and, as the process is controlled by a coupled sorption–diffusion process, the permeability equals the product of the sorption ( i ) and diffusion ( i ) coefficient in the membrane 10 , so: The symbol is used for the sorption coefficient to avoid confusion with entropy, which is discussed later. For typical negligible downstream pressures relative to the upstream, i simply equals the sorbed concentration in the membrane at the upstream side divided by the upstream partial pressure. The i can be roughly equated to f i λ i 2 /6, where f i and λ i are the random walk jumping frequency and jump length of component i , respectively 11 . The intrinsic separation efficiency of a membrane material for equals the ratio of the respective permeabilities and, by extension, the product of sorption selectivity, and diffusion selectivity, [ , so: Engineering sorption selectivity of a particular member of a gas pair (for example, O 2 ) using strong affinity for the membrane is technically workable, but has not yet proved successful under long-term practical conditions. Instability of groups providing such affinity has been the problem with these approaches, and whether this instability can be overcome remains an open question. Fortunately, O 2 has a slimmer minimum projected diameter of 2.82 Å versus 3.01 Å for N 2 , and a slightly shorter length of 3.72 Å versus 3.87 Å for N 2 , which leads to a that is greater than unity 12 . The transition state theory of diffusion explains the importance of the respective dimensions of an A/B pair like O 2 /N 2 noted above. Specifically, as shown in equation (3), diffusion selectivity is moderated by a quadratic ratio of jump lengths multiplied by the exponential difference in free energies of activation 12 , 13 , : In equation (3), , with and equal to the respective differences in diffusion transition state enthalpy, H *, and entropy, S *, for component A versus B, where R and T are the universal gas constant and absolute temperature, respectively. Figure 1 is useful for discussing basic differences in factors determining diffusion coefficients, i = f i λ i 2 /6, in molecularly selective synthetic membrane materials. Flexible polymers. For type III ( Fig. 1 ) materials at one end of the spectrum, comprising flexible polymers, a distribution of pentrant-scale gaps occurs constantly within the material due to segmental motions. Jump lengths are similar for similarly sized penetrants of interest here, and the entropic factor offers a negligible advantage. This lack of entropic selectivity reflects difficulties in controlling penetrant rotational and vibrational modes in the diffusion transition state, due to imprecisely controlled segmental motions in the zone of activation. Effectively, the exponentially weighted difference in activation energies (or enthalpies) responsible", "role": "user" }, { "content": "Chemical separation processes account for as much as 15 percent of the world's total energy consumption. Development of next-generation molecularly-selective synthetic membranes will be among the drivers for more efficient, large-scale separation processes that could dramatically reduce that number. In a paper published this week in the journal Nature Materials, researchers from the Georgia Institute of Technology identified the opportunities they see ahead for scalable membrane materials based on rigid, engineered pore structures. They say the most promising materials are scalable for use in compact modules and take advantage of entropy at the molecular level to moderate the separation selectivity of membranes. \"It's all about energy and carbon dioxide,\" said William Koros, professor and Roberto C. Goizueta Chair in Georgia Tech's School of Chemical and Biomolecular Engineering. \"Chemical separations now consume half as much energy as the entire transportation sector – land, sea and air. Our goal is to assist industry to cut that by a factor of ten, which also means cutting the CO2 emissions. That's not going to happen right away, but we have shown that the fundamentals of this technology work.\" A membrane is an engineered barrier that controls the sorting of components by selectively allowing molecules of a certain size to pass between the incoming feed stream and an outgoing permeate stream. Because they don't require large inputs of energy – which usually would come from combustion of fuels – use of these membranes can dramatically reduce both energy consumed and carbon dioxide produced. The membranes are made from advanced polymers, hybrid materials and molecular sieves, with pore sizes tailored for the intended use. The success of aqueous membranes used to produce purified water demonstrates the potential for lowering energy consumption. Spiral-wound module membranes dramatically reduced the cost of producing clean water, though large size differences between water molecules and contaminants made those processes technically easier than gas and liquid organics separations. Photo shows the manufacture of polymer hollow fiber membranes, which are precursors to more advanced carbon molecular sieve hollow fiber membranes. Credit: Rob Felt, Georgia Tech Koros' lab focuses on gas separations, but the article also addresses liquid separation processes. For both applications, he and co-author Chen Zhang point out that to be practical, new materials must be scalable – able to be packed tightly to provide large amounts of surface area inside small modules. That is best done using hollow-fiber membranes produced using advanced versions of processes that were originally developed to make ordinary textile fibers. \"You've got to have something that is both high performance and able to be processed on the scale of acres per day,\" said Koros, who is also a Georgia Research Alliance eminent scholar in membrane technology. \"Scalability is every bit as important as the capability to do the separation. Exciting materials that are the size of a postage stamp won't make a contribution.\" The two authors also argue for entropic separation techniques that are enabled by limiting the ability of molecules to diffuse through pores, depending on their molecular geometry. A molecule whose geometry makes it difficult to diffuse through a narrow opening may be excluded, while a molecule of approximately the same size but different geometry may diffuse through. \"You may ultimately be able to get the first molecule to go through, but it pays a price in entropy,\" said Koros. \"If a molecule has many options for passing through the membrane, it is actually in a lower energy state. When you reduce the number of options, you are raising the free energy.\" Research in the Koros lab has been supported for more than 20 years by the U.S. Department of Energy's Office of Energy Science. Koros also has research projects with major energy producers and chemical companies, as well as the Georgia Research Alliance. Carbon molecular sieve hollow fiber membranes are among the options for advanced separation technologies. Credit: John Toon, Georgia Tech In their paper, Koros and Zhang, a research engineer in the School of Chemical and Biomolecular Engineering, identified five materials technologies with potential for improving gas separation processes. These include: Flexible polymersMolecular sievesSemi-rigid polymersHybrid materialsCMS materials Liquid separation processes also have significant opportunities for improvement based on new materials being developed. These processes include: PervaporationOsmotically moderated aqueous separationOrganic solvent nanofiltration (OSN)Organic solvent reverse osmosis (OSRO) The Nature Materials article focused on progress that had been made in the technology and future potential, with highlights on recent advances in Koros lab at Georgia Tech. The goal was to encourage development of new materials and make membrane scientists aware of the most promising paths. \"We want everybody to see this next-generation of materials and understand the processes that help attain the goals of reducing energy consumption and carbon dioxide production,\" Koros added. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Materials research is key to enable synthetic membranes for large-scale, energy-efficient molecular separations. Materials with rigid, engineered pore structures add an additional degree of freedom to create advanced membranes by providing entropically moderated selectivities. Scalability — the capability to efficiently and economically pack membranes into practical modules — is a critical yet often neglected factor to take into account for membrane materials screening. In this Progress Article, we highlight continuing developments and identify future opportunities in scalable membrane materials based on these rigid features, for both gas and liquid phase applications. These advanced materials open the door to a new generation of membrane processes beyond existing materials and approaches. Main Membranes are key components in systems as diverse as batteries, fuel cells, barrier packages, controlled delivery devices, solar cells and, of course, large-scale energy-efficient separation and purification systems. Here, we focus on this last category, where an engineered barrier controls the sorting of components by selective passage between feed and permeate streams 1 . Such membranes rely on materials with optimized structures to reduce costs and environmental impacts of production of vital commodities at a fraction of the energy requirements associated with traditional approaches 2 . With increasingly broad applications, membrane processes are change agents that promote a more sustainable and higher global standard of living 3 , 4 . This Progress Article focuses on molecular-scale discriminations between similarly sized molecules in gas and liquid mixtures by attending to the most detailed features of membrane materials. Such materials are crucial for maintaining clean air and water, and for efficient use of energy 2 , 5 . Hydrodynamic discrimination of suspended entities from a micromolecular medium is properly referred to as filtration, and is not the focus of this discussion. In both filtration and molecular separations, a pressure difference acting between the two faces of a supported membrane provides the most economical separation driving force. In filtrations, however, a mechanical pressure gradient within the membrane motivates fluid movement through pores, while in molecular separations a chemical potential gradient drives flux through the membrane. This significant difference causes thermodynamic partitioning (sorption coefficients) and kinetic mobility (diffusion coefficients) to control molecular separation — not primarily hydrodynamic sieving, as in simpler filtration cases 6 . This mechanistic difference opens the door to a rich area of materials science for separations in which the chemical nature and morphology of the membrane can be engineered to tailor complementary molecular diffusion and sorption selectivity 7 , 8 , 9 . Gas separation membranes Important gas separations require sorting of molecules with similar physical properties, and often similar sizes. For example, separation of O 2 molecules from N 2 molecules benefits to some extent from the slightly higher O 2 critical temperature, and hence sorption coefficient of O 2 versus N 2 in most media. In any case, it is primarily the higher O 2 diffusion coefficient in most membranes that enables their utility. Flux of component i , normalized by the applied transmembrane partial pressure difference, Δ p i (a surrogate for chemical potential difference, or fugacity difference), and selective membrane thickness, ℓ , is referred to as the permeability coefficient, P i . This coefficient characterizes the intrinsic membrane material productivity and, as the process is controlled by a coupled sorption–diffusion process, the permeability equals the product of the sorption ( i ) and diffusion ( i ) coefficient in the membrane 10 , so: The symbol is used for the sorption coefficient to avoid confusion with entropy, which is discussed later. For typical negligible downstream pressures relative to the upstream, i simply equals the sorbed concentration in the membrane at the upstream side divided by the upstream partial pressure. The i can be roughly equated to f i λ i 2 /6, where f i and λ i are the random walk jumping frequency and jump length of component i , respectively 11 . The intrinsic separation efficiency of a membrane material for equals the ratio of the respective permeabilities and, by extension, the product of sorption selectivity, and diffusion selectivity, [ , so: Engineering sorption selectivity of a particular member of a gas pair (for example, O 2 ) using strong affinity for the membrane is technically workable, but has not yet proved successful under long-term practical conditions. Instability of groups providing such affinity has been the problem with these approaches, and whether this instability can be overcome remains an open question. Fortunately, O 2 has a slimmer minimum projected diameter of 2.82 Å versus 3.01 Å for N 2 , and a slightly shorter length of 3.72 Å versus 3.87 Å for N 2 , which leads to a that is greater than unity 12 . The transition state theory of diffusion explains the importance of the respective dimensions of an A/B pair like O 2 /N 2 noted above. Specifically, as shown in equation (3), diffusion selectivity is moderated by a quadratic ratio of jump lengths multiplied by the exponential difference in free energies of activation 12 , 13 , : In equation (3), , with and equal to the respective differences in diffusion transition state enthalpy, H *, and entropy, S *, for component A versus B, where R and T are the universal gas constant and absolute temperature, respectively. Figure 1 is useful for discussing basic differences in factors determining diffusion coefficients, i = f i λ i 2 /6, in molecularly selective synthetic membrane materials. Flexible polymers. For type III ( Fig. 1 ) materials at one end of the spectrum, comprising flexible polymers, a distribution of pentrant-scale gaps occurs constantly within the material due to segmental motions. Jump lengths are similar for similarly sized penetrants of interest here, and the entropic factor offers a negligible advantage. This lack of entropic selectivity reflects difficulties in controlling penetrant rotational and vibrational modes in the diffusion transition state, due to imprecisely controlled segmental motions in the zone of activation. Effectively, the exponentially weighted difference in activation energies (or enthalpies) responsible<|im_end|> <|im_start|>assistant Chemical separation processes account for as much as 15 percent of the world's total energy consumption. Development of next-generation molecularly-selective synthetic membranes will be among the drivers for more efficient, large-scale separation processes that could dramatically reduce that number. In a paper published this week in the journal Nature Materials, researchers from the Georgia Institute of Technology identified the opportunities they see ahead for scalable membrane materials based on rigid, engineered pore structures. They say the most promising materials are scalable for use in compact modules and take advantage of entropy at the molecular level to moderate the separation selectivity of membranes. "It's all about energy and carbon dioxide," said William Koros, professor and Roberto C. Goizueta Chair in Georgia Tech's School of Chemical and Biomolecular Engineering. "Chemical separations now consume half as much energy as the entire transportation sector – land, sea and air. Our goal is to assist industry to cut that by a factor of ten, which also means cutting the CO2 emissions. That's not going to happen right away, but we have shown that the fundamentals of this technology work." A membrane is an engineered barrier that controls the sorting of components by selectively allowing molecules of a certain size to pass between the incoming feed stream and an outgoing permeate stream. Because they don't require large inputs of energy – which usually would come from combustion of fuels – use of these membranes can dramatically reduce both energy consumed and carbon dioxide produced. The membranes are made from advanced polymers, hybrid materials and molecular sieves, with pore sizes tailored for the intended use. The success of aqueous membranes used to produce purified water demonstrates the potential for lowering energy consumption. Spiral-wound module membranes dramatically reduced the cost of producing clean water, though large size differences between water molecules and contaminants made those processes technically easier than gas and liquid organics separations. Photo shows the manufacture of polymer hollow fiber membranes, which are precursors to more advanced carbon molecular sieve hollow fiber membranes. Credit: Rob Felt, Georgia Tech Koros' lab focuses on gas separations, but the article also addresses liquid separation processes. For both applications, he and co-author Chen Zhang point out that to be practical, new materials must be scalable – able to be packed tightly to provide large amounts of surface area inside small modules. That is best done using hollow-fiber membranes produced using advanced versions of processes that were originally developed to make ordinary textile fibers. "You've got to have something that is both high performance and able to be processed on the scale of acres per day," said Koros, who is also a Georgia Research Alliance eminent scholar in membrane technology. "Scalability is every bit as important as the capability to do the separation. Exciting materials that are the size of a postage stamp won't make a contribution." The two authors also argue for entropic separation techniques that are enabled by limiting the ability of molecules to diffuse through pores, depending on their molecular geometry. A molecule whose geometry makes it difficult to diffuse through a narrow opening may be excluded, while a molecule of approximately the same size but different geometry may diffuse through. "You may ultimately be able to get the first molecule to go through, but it pays a price in entropy," said Koros. "If a molecule has many options for passing through the membrane, it is actually in a lower energy state. When you reduce the number of options, you are raising the free energy." Research in the Koros lab has been supported for more than 20 years by the U.S. Department of Energy's Office of Energy Science. Koros also has research projects with major energy producers and chemical companies, as well as the Georgia Research Alliance. Carbon molecular sieve hollow fiber membranes are among the options for advanced separation technologies. Credit: John Toon, Georgia Tech In their paper, Koros and Zhang, a research engineer in the School of Chemical and Biomolecular Engineering, identified five materials technologies with potential for improving gas separation processes. These include: Flexible polymersMolecular sievesSemi-rigid polymersHybrid materialsCMS materials Liquid separation processes also have significant opportunities for improvement based on new materials being developed. These processes include: PervaporationOsmotically moderated aqueous separationOrganic solvent nanofiltration (OSN)Organic solvent reverse osmosis (OSRO) The Nature Materials article focused on progress that had been made in the technology and future potential, with highlights on recent advances in Koros lab at Georgia Tech. The goal was to encourage development of new materials and make membrane scientists aware of the most promising paths. "We want everybody to see this next-generation of materials and understand the processes that help attain the goals of reducing energy consumption and carbon dioxide production," Koros added. <|im_end|>

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279, 55424, 2968, 17239, 279, 2027, 315, 279, 25551, 562, 320, 602, 883, 323, 58430, 320, 602, 883, 36706, 304, 279, 39654, 220, 605, 1174, 779, 25, 578, 7891, 374, 1511, 369, 279, 25551, 562, 36706, 311, 5766, 22047, 449, 48602, 11, 902, 374, 14407, 3010, 13, 1789, 14595, 82802, 52452, 40850, 8844, 311, 279, 42830, 11, 602, 5042, 17239, 279, 25551, 2788, 20545, 304, 279, 39654, 520, 279, 42830, 3185, 18255, 555, 279, 42830, 7276, 7410, 13, 578, 602, 649, 387, 17715, 3312, 660, 311, 282, 602, 49438, 602, 220, 17, 611, 21, 11, 1405, 282, 602, 323, 49438, 602, 527, 279, 4288, 4321, 30102, 11900, 323, 7940, 3160, 315, 3777, 602, 1174, 15947, 220, 806, 662, 578, 47701, 25768, 15374, 315, 264, 39654, 3769, 369, 17239, 279, 11595, 315, 279, 20081, 55424, 8623, 323, 11, 555, 9070, 11, 279, 2027, 315, 25551, 562, 3373, 1968, 11, 323, 58430, 3373, 1968, 11, 510, 1174, 779, 25, 17005, 25551, 562, 3373, 1968, 315, 264, 4040, 4562, 315, 264, 6962, 6857, 320, 2000, 3187, 11, 507, 220, 17, 883, 1701, 3831, 51552, 369, 279, 39654, 374, 32654, 990, 481, 11, 719, 706, 539, 3686, 19168, 6992, 1234, 1317, 9860, 15325, 4787, 13, 6112, 2968, 315, 5315, 8405, 1778, 51552, 706, 1027, 279, 3575, 449, 1521, 20414, 11, 323, 3508, 420, 56399, 649, 387, 23075, 8625, 459, 1825, 3488, 13, 42536, 11, 507, 220, 17, 706, 264, 1776, 19519, 8187, 28448, 23899, 315, 220, 17, 13, 6086, 80352, 19579, 220, 18, 13, 1721, 80352, 369, 452, 220, 17, 1174, 323, 264, 10284, 24210, 3160, 315, 220, 18, 13, 5332, 80352, 19579, 220, 18, 13, 4044, 80352, 369, 452, 220, 17, 1174, 902, 11767, 311, 264, 430, 374, 7191, 1109, 31426, 220, 717, 662, 578, 9320, 1614, 10334, 315, 58430, 15100, 279, 12939, 315, 279, 20081, 15696, 315, 459, 362, 16675, 6857, 1093, 507, 220, 17, 611, 45, 220, 17, 10555, 3485, 13, 45863, 11, 439, 6982, 304, 24524, 320, 18, 705, 58430, 3373, 1968, 374, 87316, 555, 264, 80251, 11595, 315, 7940, 29416, 56016, 555, 279, 59855, 6811, 304, 1949, 49969, 315, 15449, 220, 717, 1174, 220, 1032, 1174, 551, 763, 24524, 320, 18, 705, 1174, 449, 323, 6273, 311, 279, 20081, 12062, 304, 58430, 9320, 1614, 1218, 12130, 3368, 11, 473, 12039, 323, 48602, 11, 328, 12039, 369, 3777, 362, 19579, 426, 11, 1405, 432, 323, 350, 527, 279, 20789, 6962, 6926, 323, 10973, 9499, 11, 15947, 13, 19575, 220, 16, 374, 5505, 369, 25394, 6913, 12062, 304, 9547, 26679, 58430, 37929, 11, 602, 284, 282, 602, 49438, 602, 220, 17, 611, 21, 11, 304, 31206, 398, 44010, 28367, 39654, 7384, 13, 53411, 46033, 388, 13, 1789, 955, 14767, 320, 23966, 13, 220, 16, 883, 7384, 520, 832, 842, 315, 279, 20326, 11, 46338, 19303, 46033, 388, 11, 264, 8141, 315, 20801, 35534, 13230, 33251, 13980, 15320, 2949, 279, 3769, 4245, 311, 10449, 278, 54245, 13, 29888, 29416, 527, 4528, 369, 30293, 30387, 44805, 1821, 315, 2802, 1618, 11, 323, 279, 1218, 45036, 8331, 6209, 264, 82802, 9610, 13, 1115, 6996, 315, 1218, 45036, 3373, 1968, 27053, 27129, 304, 26991, 44805, 519, 92371, 323, 17358, 1697, 20362, 304, 279, 58430, 9320, 1614, 11, 4245, 311, 737, 10872, 285, 989, 14400, 10449, 278, 54245, 304, 279, 10353, 315, 15449, 13, 13756, 3210, 11, 279, 75251, 37924, 6811, 304, 15449, 49969, 320, 269, 1218, 12130, 45752, 8, 8647, 128257, 198, 128256, 78191, 198, 64938, 950, 25768, 11618, 2759, 369, 439, 1790, 439, 220, 868, 3346, 315, 279, 1917, 596, 2860, 4907, 15652, 13, 11050, 315, 1828, 43927, 31206, 398, 21090, 535, 28367, 79348, 690, 387, 4315, 279, 12050, 369, 810, 11297, 11, 3544, 13230, 25768, 11618, 430, 1436, 29057, 8108, 430, 1396, 13, 763, 264, 5684, 4756, 420, 2046, 304, 279, 8486, 22037, 32009, 11, 12074, 505, 279, 16272, 10181, 315, 12053, 11054, 279, 10708, 814, 1518, 8469, 369, 69311, 39654, 7384, 3196, 389, 33956, 11, 46036, 97551, 14726, 13, 2435, 2019, 279, 1455, 26455, 7384, 527, 69311, 369, 1005, 304, 17251, 13761, 323, 1935, 9610, 315, 48602, 520, 279, 31206, 2237, 311, 24070, 279, 25768, 3373, 1968, 315, 79348, 13, 330, 2181, 596, 682, 922, 4907, 323, 12782, 40589, 1359, 1071, 12656, 36170, 437, 11, 14561, 323, 55183, 356, 13, 6122, 92715, 1955, 16478, 304, 16272, 17829, 596, 6150, 315, 36424, 323, 91608, 43943, 17005, 13, 330, 64938, 950, 4941, 811, 1457, 25024, 4376, 439, 1790, 4907, 439, 279, 4553, 18386, 10706, 1389, 4363, 11, 9581, 323, 3805, 13, 5751, 5915, 374, 311, 7945, 5064, 311, 4018, 430, 555, 264, 8331, 315, 5899, 11, 902, 1101, 3445, 14713, 279, 7432, 17, 20748, 13, 3011, 596, 539, 2133, 311, 3621, 1314, 3201, 11, 719, 584, 617, 6982, 430, 279, 57940, 315, 420, 5557, 990, 1210, 362, 39654, 374, 459, 46036, 22881, 430, 11835, 279, 29373, 315, 6956, 555, 82775, 10923, 35715, 315, 264, 3738, 1404, 311, 1522, 1990, 279, 19957, 5510, 4365, 323, 459, 37798, 55424, 349, 4365, 13, 9393, 814, 1541, 956, 1397, 3544, 11374, 315, 4907, 1389, 902, 6118, 1053, 2586, 505, 59333, 315, 40373, 1389, 1005, 315, 1521, 79348, 649, 29057, 8108, 2225, 4907, 27073, 323, 12782, 40589, 9124, 13, 578, 79348, 527, 1903, 505, 11084, 46033, 388, 11, 26038, 7384, 323, 31206, 10112, 2396, 11, 449, 97551, 12562, 41891, 369, 279, 10825, 1005, 13, 578, 2450, 315, 66300, 788, 79348, 1511, 311, 8356, 92600, 3090, 32216, 279, 4754, 369, 46301, 4907, 15652, 13, 89888, 2695, 801, 4793, 79348, 29057, 11293, 279, 2853, 315, 17843, 4335, 3090, 11, 3582, 3544, 1404, 12062, 1990, 3090, 35715, 323, 88959, 1903, 1884, 11618, 32654, 8831, 1109, 6962, 323, 14812, 2942, 1233, 4941, 811, 13, 11064, 5039, 279, 30847, 315, 47393, 42902, 24722, 79348, 11, 902, 527, 5956, 34291, 311, 810, 11084, 12782, 31206, 75436, 42902, 24722, 79348, 13, 16666, 25, 4997, 435, 3903, 11, 16272, 17829, 36170, 437, 6, 10278, 24400, 389, 6962, 4941, 811, 11, 719, 279, 4652, 1101, 14564, 14812, 25768, 11618, 13, 1789, 2225, 8522, 11, 568, 323, 1080, 43802, 25507, 37120, 1486, 704, 430, 311, 387, 15325, 11, 502, 7384, 2011, 387, 69311, 1389, 3025, 311, 387, 19937, 40069, 311, 3493, 3544, 15055, 315, 7479, 3158, 4871, 2678, 13761, 13, 3011, 374, 1888, 2884, 1701, 42902, 2269, 8799, 79348, 9124, 1701, 11084, 11028, 315, 11618, 430, 1051, 13517, 8040, 311, 1304, 19664, 66638, 49774, 13, 330, 2675, 3077, 2751, 311, 617, 2555, 430, 374, 2225, 1579, 5178, 323, 3025, 311, 387, 15590, 389, 279, 5569, 315, 27464, 824, 1938, 1359, 1071, 36170, 437, 11, 889, 374, 1101, 264, 16272, 8483, 23590, 84629, 18640, 304, 39654, 5557, 13, 330, 3407, 278, 2968, 374, 1475, 2766, 439, 3062, 439, 279, 23099, 311, 656, 279, 25768, 13, 39995, 5977, 7384, 430, 527, 279, 1404, 315, 264, 78141, 21899, 2834, 956, 1304, 264, 19035, 1210, 578, 1403, 12283, 1101, 18046, 369, 1218, 45036, 25768, 12823, 430, 527, 9147, 555, 33994, 279, 5845, 315, 35715, 311, 55517, 1555, 72028, 11, 11911, 389, 872, 31206, 17484, 13, 362, 43030, 6832, 17484, 3727, 433, 5107, 311, 55517, 1555, 264, 15376, 8736, 1253, 387, 28544, 11, 1418, 264, 43030, 315, 13489, 279, 1890, 1404, 719, 2204, 17484, 1253, 55517, 1555, 13, 330, 2675, 1253, 13967, 387, 3025, 311, 636, 279, 1176, 43030, 311, 733, 1555, 11, 719, 433, 21935, 264, 3430, 304, 48602, 1359, 1071, 36170, 437, 13, 330, 2746, 264, 43030, 706, 1690, 2671, 369, 12579, 1555, 279, 39654, 11, 433, 374, 3604, 304, 264, 4827, 4907, 1614, 13, 3277, 499, 8108, 279, 1396, 315, 2671, 11, 499, 527, 19054, 279, 1949, 4907, 1210, 8483, 304, 279, 36170, 437, 10278, 706, 1027, 7396, 369, 810, 1109, 220, 508, 1667, 555, 279, 549, 815, 13, 6011, 315, 12634, 596, 8410, 315, 12634, 10170, 13, 36170, 437, 1101, 706, 3495, 7224, 449, 3682, 4907, 24190, 323, 11742, 5220, 11, 439, 1664, 439, 279, 16272, 8483, 23590, 13, 22208, 31206, 75436, 42902, 24722, 79348, 527, 4315, 279, 2671, 369, 11084, 25768, 14645, 13, 16666, 25, 3842, 2057, 263, 11, 16272, 17829, 763, 872, 5684, 11, 36170, 437, 323, 37120, 11, 264, 3495, 24490, 304, 279, 6150, 315, 36424, 323, 91608, 43943, 17005, 11, 11054, 4330, 7384, 14645, 449, 4754, 369, 18899, 6962, 25768, 11618, 13, 4314, 2997, 25, 53411, 46033, 388, 44, 43943, 10112, 2396, 50, 22530, 3880, 21596, 46033, 388, 31916, 16621, 7384, 54357, 7384, 42358, 25768, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Metal–organic frameworks (MOFs) are a family of chemically diverse materials, with applications in a wide range of fields, covering engineering, physics, chemistry, biology and medicine. Until recently, research has focused almost entirely on crystalline structures, yet now a clear trend is emerging, shifting the emphasis onto disordered states, including ‘defective by design’ crystals, as well as amorphous phases such as glasses and gels. Here we introduce a strongly associated MOF liquid, obtained by melting a zeolitic imidazolate framework. We combine in situ variable temperature X-ray, ex situ neutron pair distribution function experiments, and first-principles molecular dynamics simulations to study the melting phenomenon and the nature of the liquid obtained. We demonstrate from structural, dynamical, and thermodynamical information that the chemical configuration, coordinative bonding, and porosity of the parent crystalline framework survive upon formation of the MOF liquid. Main Crystalline metal–organic frameworks (MOFs) have been proposed for application in a variety of situations which take advantage of their highly ordered and nanoporous structures—for example, gas sorption and separation 1 , 2 , 3 , catalysis 4 and ion transport 5 . Inherent defects 6 , structural disorder 7 and near-ubiquitous flexibility 8 present significant challenges in the development of highly robust, selective systems from perfect crystals. However, they also present opportunities, in creating functional ‘defective by design’ materials 9 , 10 . Non-crystalline, or amorphous MOF systems are formed by avoidance of crystallization, or induced collapse of crystalline systems by pressure, temperature, or ball-milling 11 . In the case of the zeolitic imidazolate framework (ZIF) family 12 , 13 , which adopt similar structures to inorganic zeolites and are formed from M n + (M n + = for example, Li + , B + , Zn 2+ ) inorganic nodes connected by Im-based (Im = imidazolate, C 3 H 3 N 2 − ) ligands, such amorphous systems resemble the continuous random network of amorphous SiO 2 . Recently, the formation of a molten ZIF state from a crystalline phase was observed in an inert argon atmosphere. No mass loss was observed during the formation of the liquid, which upon cooling yielded a melt-quenched glass, possessing an extended Zn–Im–Zn coordination network 14 . Unlike reversible solid–liquid transitions in one- or two-dimensional coordination polymers which occur below 500 K (ref. 15 ), melting processes in ZIFs have been observed only at high temperatures, that is, those exceeding 700 K. The novelty of the liquid and glass states means microscopic insight into the mechanism of melting, and the nature of the liquid produced are of great interest when considering the generality of the mechanism in the wider MOF family. However, thus far, the narrow temperature range and poorly understood kinetics-time stability of the fleeting liquid phase have precluded information on any liquid MOF state. Particularly salient and intriguing considerations pertaining to the liquid involve ‘memory’ of the crystalline framework conferred by remnant framework connectivity, coordinative framework dynamics and the proximity of structure to that of an ionic or a strongly associated liquid 16 . The ability to form hybrid ‘porous liquids’, analogous to that of the organic systems of the Cooper and James groups 17 , would present a significant advance in the field, and help shift attention away from the solid state. Motivated by the above questions and linking the MOF field to liquid, glass and polymer science, we studied the melting of ZIF-4 via experimental and computational means. The dynamic nature of the transition necessitated use of first-principles molecular dynamics (FPMD) calculations, which have previously been successfully used in ionic liquid and disordered carbonate systems 18 , 19 . Results were then combined with in situ variable temperature X-ray and ex situ neutron pair distribution function (PDF) experiments to yield a complete picture of the melting process, and, for the first time, an insight into the structure of a MOF liquid. Structural characterization upon heating and melting We first studied the evolution in structure of ZIF-4, which is composed of Zn(Im) 4 tetrahedra linked by Zn–N coordinative bonds ( Fig. 1a, b ), and forms a three-dimensional, crystalline network containing a maximum cavity diameter of 4.9 Å ( Fig. 1c ). It shares a topology with that of the mineral variscite, CaGa 2 O 4 , and a melting point of about 865 K has previously been identified, although no atomistic modelling of experimental data has to date been performed on any MOF liquid or glass. Figure 1: Structure of the ZIF-4 crystal, glass, and structural evolution upon heating. a , The construction from metal ion and linker of Zn(Im) 4 tetrahedra, the basic building unit of ZIF-4 (Im, imidazolate; Zn, green; N, blue; C, grey). b , Representation of the cag topology adopted by ZIF-4, where each polyhedra corner corresponds to one Zn(Im) 4 tetrahedron. c , Crystalline structure of ZIF-4, with free volume represented in orange. d , Atomic configuration of the melt-quenched glass, gained from modelling synchrotron and neutron total scattering data. e , Experimental neutron structure factor F ( Q ) data and the fit from the configuration shown in d . Inset: X-ray data and fit. f , Experimental glass (top) and computational ZIF-4 (bottom) X-ray structure factors upon heating. Full size image A sample of ZIF-4 was prepared and evacuated according to previous literature procedures 20 , and heated to 865 K in an argon tube furnace, before natural cooling to room temperature. The density has previously been shown to increase upon formation of a dense crystalline phase from ZIF-4 (1.24 g cm −3 to 1.582 g cm −3 ) and to 1.625 g cm −3 for the glass 21 , 22 . Neutron and X-ray total scattering data were then collected using the GEM Diffractometer at the ISIS spallation source, and the Diamond Light Source, UK, respectively. Conversion to the PDFs was performed after data corrections (see Methods ). Reverse Monte Carlo (RMC) modelling was subsequently performed, using as a starting model a previous Zn–Im–Zn continuous random network (CRN) configuration, arising from", "role": "user" }, { "content": "Known for their exceptional porosity that enables the trapping or transport of molecules, metal-organic frameworks (MOFs) take the form of a powder, which makes them difficult to format. For the first time, an international team led by scientists from the Institut de recherche de Chimie Paris (CNRS/Chimie ParisTech) has evidenced the surprising ability of a type of MOF to retain its porous properties in the liquid and then glass state. Published today in Nature Materials, these findings open the way towards new industrial applications. Metal-organic frameworks (MOFs) constitute a particularly promising class of materials. Their exceptional porosity makes it possible to store and separate large quantities of gas, or to act as a catalyst for chemical reactions. However, their crystalline structure implies that they are produced in powder form, which is difficult to store and use for industrial applications. For the first time, a team of scientists from the CNRS, Chimie ParisTech, Cambridge University, Air Liquide and the ISIS (UK) and Argonne (US) synchrotrons has shown that the properties of a zeolitic MOF were unexpectedly conserved in the liquid phase (which does not generally favor porosity). Then, after cooling and solidification, the glass obtained adopted a disordered, non-crystalline structure that also retained the same properties in terms of porosity. These results will enable the shaping and use of these materials much more efficiently than in powder form. To achieve this, the scientists used neutron diffraction and X-rays to observe the structure of the MOF after melting, once it was in the liquid phase. They correlated this data with molecular simulations that reproduced the same temperature conditions as those applied to the MOF during melting. Combination of the two methods enabled them to describe the structural changes affecting the material as it entered the liquid phase and then re-solidified. They thus succeeded in demonstrating an atypical mechanism. The MOF under study was made up of pyramidal molecular frameworks, each consisting of a zinc atom surrounded by four cyclical, organic molecules called imidazolates. At melting, the energy generated by the rise in temperature was able to break down the link between an imidazolate and zinc, thus destroying the pyramidal framework. The resulting space was then occupied by another imidazolate cycle released by a neighboring framework to recreate the original structure. It is these molecular exchanges between complex structures that gave the MOF its liquid character. Disordered structure of ZIF-4 at high temperature. Credit: F.-X. Coudert / CNRS In the case of this particular MOF, porosity resulted from the presence of gaps between the pyramidal structures that could be filled by gases. Because the MOF retained the same pyramidal structure in the liquid state, its porosity was thus maintained. As well as the ability of this MOF to retain its properties after melting, this study describes the case of a porous liquid, very few of which feature in the literature. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Metal–organic frameworks (MOFs) are a family of chemically diverse materials, with applications in a wide range of fields, covering engineering, physics, chemistry, biology and medicine. Until recently, research has focused almost entirely on crystalline structures, yet now a clear trend is emerging, shifting the emphasis onto disordered states, including ‘defective by design’ crystals, as well as amorphous phases such as glasses and gels. Here we introduce a strongly associated MOF liquid, obtained by melting a zeolitic imidazolate framework. We combine in situ variable temperature X-ray, ex situ neutron pair distribution function experiments, and first-principles molecular dynamics simulations to study the melting phenomenon and the nature of the liquid obtained. We demonstrate from structural, dynamical, and thermodynamical information that the chemical configuration, coordinative bonding, and porosity of the parent crystalline framework survive upon formation of the MOF liquid. Main Crystalline metal–organic frameworks (MOFs) have been proposed for application in a variety of situations which take advantage of their highly ordered and nanoporous structures—for example, gas sorption and separation 1 , 2 , 3 , catalysis 4 and ion transport 5 . Inherent defects 6 , structural disorder 7 and near-ubiquitous flexibility 8 present significant challenges in the development of highly robust, selective systems from perfect crystals. However, they also present opportunities, in creating functional ‘defective by design’ materials 9 , 10 . Non-crystalline, or amorphous MOF systems are formed by avoidance of crystallization, or induced collapse of crystalline systems by pressure, temperature, or ball-milling 11 . In the case of the zeolitic imidazolate framework (ZIF) family 12 , 13 , which adopt similar structures to inorganic zeolites and are formed from M n + (M n + = for example, Li + , B + , Zn 2+ ) inorganic nodes connected by Im-based (Im = imidazolate, C 3 H 3 N 2 − ) ligands, such amorphous systems resemble the continuous random network of amorphous SiO 2 . Recently, the formation of a molten ZIF state from a crystalline phase was observed in an inert argon atmosphere. No mass loss was observed during the formation of the liquid, which upon cooling yielded a melt-quenched glass, possessing an extended Zn–Im–Zn coordination network 14 . Unlike reversible solid–liquid transitions in one- or two-dimensional coordination polymers which occur below 500 K (ref. 15 ), melting processes in ZIFs have been observed only at high temperatures, that is, those exceeding 700 K. The novelty of the liquid and glass states means microscopic insight into the mechanism of melting, and the nature of the liquid produced are of great interest when considering the generality of the mechanism in the wider MOF family. However, thus far, the narrow temperature range and poorly understood kinetics-time stability of the fleeting liquid phase have precluded information on any liquid MOF state. Particularly salient and intriguing considerations pertaining to the liquid involve ‘memory’ of the crystalline framework conferred by remnant framework connectivity, coordinative framework dynamics and the proximity of structure to that of an ionic or a strongly associated liquid 16 . The ability to form hybrid ‘porous liquids’, analogous to that of the organic systems of the Cooper and James groups 17 , would present a significant advance in the field, and help shift attention away from the solid state. Motivated by the above questions and linking the MOF field to liquid, glass and polymer science, we studied the melting of ZIF-4 via experimental and computational means. The dynamic nature of the transition necessitated use of first-principles molecular dynamics (FPMD) calculations, which have previously been successfully used in ionic liquid and disordered carbonate systems 18 , 19 . Results were then combined with in situ variable temperature X-ray and ex situ neutron pair distribution function (PDF) experiments to yield a complete picture of the melting process, and, for the first time, an insight into the structure of a MOF liquid. Structural characterization upon heating and melting We first studied the evolution in structure of ZIF-4, which is composed of Zn(Im) 4 tetrahedra linked by Zn–N coordinative bonds ( Fig. 1a, b ), and forms a three-dimensional, crystalline network containing a maximum cavity diameter of 4.9 Å ( Fig. 1c ). It shares a topology with that of the mineral variscite, CaGa 2 O 4 , and a melting point of about 865 K has previously been identified, although no atomistic modelling of experimental data has to date been performed on any MOF liquid or glass. Figure 1: Structure of the ZIF-4 crystal, glass, and structural evolution upon heating. a , The construction from metal ion and linker of Zn(Im) 4 tetrahedra, the basic building unit of ZIF-4 (Im, imidazolate; Zn, green; N, blue; C, grey). b , Representation of the cag topology adopted by ZIF-4, where each polyhedra corner corresponds to one Zn(Im) 4 tetrahedron. c , Crystalline structure of ZIF-4, with free volume represented in orange. d , Atomic configuration of the melt-quenched glass, gained from modelling synchrotron and neutron total scattering data. e , Experimental neutron structure factor F ( Q ) data and the fit from the configuration shown in d . Inset: X-ray data and fit. f , Experimental glass (top) and computational ZIF-4 (bottom) X-ray structure factors upon heating. Full size image A sample of ZIF-4 was prepared and evacuated according to previous literature procedures 20 , and heated to 865 K in an argon tube furnace, before natural cooling to room temperature. The density has previously been shown to increase upon formation of a dense crystalline phase from ZIF-4 (1.24 g cm −3 to 1.582 g cm −3 ) and to 1.625 g cm −3 for the glass 21 , 22 . Neutron and X-ray total scattering data were then collected using the GEM Diffractometer at the ISIS spallation source, and the Diamond Light Source, UK, respectively. Conversion to the PDFs was performed after data corrections (see Methods ). Reverse Monte Carlo (RMC) modelling was subsequently performed, using as a starting model a previous Zn–Im–Zn continuous random network (CRN) configuration, arising from<|im_end|> <|im_start|>assistant Known for their exceptional porosity that enables the trapping or transport of molecules, metal-organic frameworks (MOFs) take the form of a powder, which makes them difficult to format. For the first time, an international team led by scientists from the Institut de recherche de Chimie Paris (CNRS/Chimie ParisTech) has evidenced the surprising ability of a type of MOF to retain its porous properties in the liquid and then glass state. Published today in Nature Materials, these findings open the way towards new industrial applications. Metal-organic frameworks (MOFs) constitute a particularly promising class of materials. Their exceptional porosity makes it possible to store and separate large quantities of gas, or to act as a catalyst for chemical reactions. However, their crystalline structure implies that they are produced in powder form, which is difficult to store and use for industrial applications. For the first time, a team of scientists from the CNRS, Chimie ParisTech, Cambridge University, Air Liquide and the ISIS (UK) and Argonne (US) synchrotrons has shown that the properties of a zeolitic MOF were unexpectedly conserved in the liquid phase (which does not generally favor porosity). Then, after cooling and solidification, the glass obtained adopted a disordered, non-crystalline structure that also retained the same properties in terms of porosity. These results will enable the shaping and use of these materials much more efficiently than in powder form. To achieve this, the scientists used neutron diffraction and X-rays to observe the structure of the MOF after melting, once it was in the liquid phase. They correlated this data with molecular simulations that reproduced the same temperature conditions as those applied to the MOF during melting. Combination of the two methods enabled them to describe the structural changes affecting the material as it entered the liquid phase and then re-solidified. They thus succeeded in demonstrating an atypical mechanism. The MOF under study was made up of pyramidal molecular frameworks, each consisting of a zinc atom surrounded by four cyclical, organic molecules called imidazolates. At melting, the energy generated by the rise in temperature was able to break down the link between an imidazolate and zinc, thus destroying the pyramidal framework. The resulting space was then occupied by another imidazolate cycle released by a neighboring framework to recreate the original structure. It is these molecular exchanges between complex structures that gave the MOF its liquid character. Disordered structure of ZIF-4 at high temperature. Credit: F.-X. Coudert / CNRS In the case of this particular MOF, porosity resulted from the presence of gaps between the pyramidal structures that could be filled by gases. Because the MOF retained the same pyramidal structure in the liquid state, its porosity was thus maintained. As well as the ability of this MOF to retain its properties after melting, this study describes the case of a porous liquid, very few of which feature in the literature. <|im_end|>

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2,047

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nodosauridae is a group of thyreophoran dinosaurs characterized by a collar of prominent osteoderms. In comparison to its sister group, the often club-tailed ankylosaurids, a different lifestyle of nodosaurids could be assumed based on their neuroanatomy and weaponry, e.g., regarding applied defensive strategies. The holotype of the nodosaurid Struthiosaurus austriacus consists of a single partial braincase from the Late Cretaceous of Austria. Since neuroanatomy is considered to be associated with ecological tendencies, we created digital models of the braincase based on micro-CT data. The cranial endocast of S. austriacus generally resembles those of its relatives. A network of vascular canals surrounding the brain cavity further supports special thermoregulatory adaptations within Ankylosauria. The horizontal orientation of the lateral semicircular canal independently confirms previous appraisals of head posture for S. austriacus and, hence, strengthens the usage of the LSC as proxy for habitual head posture in fossil tetrapods. The short anterior and angular lateral semicircular canals, combined with the relatively shortest dinosaurian cochlear duct known so far and the lack of a floccular recess suggest a rather inert lifestyle without the necessity of sophisticated senses for equilibrium and hearing in S. austriacus . These observations agree with an animal that adapted to a comparatively inactive lifestyle with limited social interactions. Introduction Thyreophora are ornithischian dinosaurs, comprising iconic taxa like Stegosaurus and Ankylosaurus 1 . Ankylosauria thrived at least since the Middle Jurassic and some of their representatives witnessed the end-Cretaceous mass extinction 1 . These globally distributed quadruped herbivores were heavily armoured living fortresses; partly either equipped with a club tail (ankylosaurids 2 ) or a collar of hypertrophied spikes on their neck and shoulders (nodosaurids 3 ). Potential palaeoenvironmental 4 and food preferences 5 , together with features of their nasal passages 6 , jaw mechanics 7 , 8 and osteoderms 9 , may indicate different lifestyles for both groups. Since the brain and associated neuroanatomical structures of vertebrates leave perceivable traces, which are possibly ecologically informative, it is worthwhile to thoroughly examine the braincase of nodosaurids in order to compare it to ankylosaurids. Whereas complete braincase material among early-diverging thyreophorans is only known from Scelidosaurus harrisoni 10 , neurocranial material of stegosaurs 11 , 12 , and ankylosaurs (e.g. 13 , 14 , 15 ) is more common. The heavily armored skull roofs of the latter likely improved their preservation potential. Struthiosaurus is a European nodosaurid with an estimated body length of up to three metres, known from cranial and postcranial material of Campanian to Maastrichtian age 16 , 17 , 18 , 19 , 20 , 21 , 22 . As currently accepted, Struthiosaurus comprises three species: S . austriacus from the early Campanian of Austria 16 , 17 , 18 , S . languedocensis from the early Campanian of France 22 , and S . transylvanicus from the Maastrichtian of Romania 23 , 24 . In addition, skeletal remains referred to Struthiosaurus sp. were reported from late Campanian to early Maastrichtian deposits of Spain 20 , 21 . The potentially oldest fossil record of Struthiosaurus is represented by a single right humerus from the Santonian of Hungary 25 . The type species of Struthiosaurus , S . austriacus , is based on fragmentary cranial and postcranial remains of at least three individuals of different ontogenetic stages that were recovered during the nineteenth century from early Campanian continental coal-bearing beds of Muthmannsdorf, Austria, referred to the Grünbach Formation (see 18 for overview). The holotype specimen of S. austriacus , a partial braincase (IPUW 2349/6; Fig. 1 ), was scanned with the aid of a micro-CT; its superficial morphology has been previously described 16 , 17 , 26 . The segmentation of the internal structures provides new insights into the neuroanatomy and behavioral capacities of this Late Cretaceous (Campanian) armoured dinosaur from Austria. Figure 1 ( A ) Outline drawing of Austria with a star marking Muthmannsdorf, the type locality of Struthiosaurus austriacus . ( B ) Silhouette of Struthiosaurus austriacus (measuring 2.7 m in length here; copyright: Fabrizio De Rossi) and a human for comparison. Photographs ( C , D , G , J ) and ambient occlusion photogrammetric models ( E , F , H , I , K ) of the holotype specimen of Struthiosaurus austriacus , IPUW 2349/6, in ( C , E ) right lateral, ( D , F ) left lateral, ( I ) anterior, ( J , K ) ventral and ( G , H ) posterior views. a, armour; bo, basioccipital; bs, basisphenoid; bt, basal tuber; ct, crista tuberalis; d, damage; fm, foramen magnum; fo/cr, fenestra ovalis/columellar recess; met, metotic foramen; pbp, posterior branching plexus; sg, stapedial groove; st/pit, sella turcica/pituitary; tov, transverso-occipital vein; uvd, uncertain vascular duct; V 3 /icg, groove for the mandibular branch of the trigeminal nerve or for the internal carotid; VI, abducens nerve; VII, facial nerve; vcm, dorsal middle cerebral vein; XII, hypoglossal nerve. Full size image Results Cranial endocast, innervation and blood supply As in most non-maniraptoriform dinosaur braincases (e.g. 27 , 28 , 29 ), features of the midbrain and hindbrain are not securely identifiable as imprints on the endocast of IPUW 2349/6 (Figs. 2 , 3 ). This suggests little correlation of the brain and respective soft tissues with the surface of the endocranial cavity in the living animal, which is similar to extant reptiles (e.g., crocodiles and turtles 30 , 31 ). Figure 2 3D model of the cranial endocast with endosseous labyrinths and neurovascular canals of the holotype specimen of Struthiosaurus austriacus , IPUW 2349/6, without ( A , C , E ) and with ( B , D , F ) a volume rendering of the braincase in ( A , B ) right lateral, ( C , D ) dorsal and ( E , F ) posterior aspects. ?cerh, possible cerebral hemisphere; dp, dural peak; fo/cr, fenestra ovalis/columellar recess; met, metotic foramen; lab, endosseous labyrinth; pbp, posterior branching plexus; pit, pituitary; tov, transverso-occipital vein; uvd, uncertain vascular duct; VI,", "role": "user" }, { "content": "German and Austrian scientists took a closer look at the braincase of a dinosaur from Austria. The group examined the fossil with a micro-CT and found surprising new details: it was sluggish and deaf. The respective study was recently published in the journal Scientific Reports. Ankylosaurs could grow up to eight meters in body length and represent a group of herbivorous dinosaurs also called 'living fortresses. Its body was cluttered with bony plates and spikes. The ankylosaurids sometimes possessed a club tail, while nodosaurids had elongated spikes on their necks and shoulders. However, some aspects of their lifestyle are still puzzling. While many dinosaurs likely lived in groups, at least some ankylosaurs seemed to prefer a lonesome life because of an inferior sense of hearing. That's what the scientists from the universities of Greifswald and Vienna concluded when they examined the braincase of the Austrian dinosaur with a high-resolution computer tomograph to produce a digital three-dimensional cast. Fossil braincases, which once housed the brain and other neurosensory tissues, are rare but important for science because these structures can provide insights into the lifestyle of a given animal. For example, the inner ears can hint to auditory capacities and skull orientation. Struthiosaurus austriacus is a comparably small nodosaurid from the Late Cretaceous (80 Ma) of Austria and comes from a locality near Muthmannsdorf, south of Vienna. The fossil remains of this dinosaur already belonged to the collection of the Institute for Paleontology in Vienna in the 19th century. For their study, Marco Schade (University of Greifswald), Cathrin Pfaff (University of Vienna) and their colleagues examined the tiny (50 mm) braincase to reveal new details of the anatomy and lifestyle of Struthiosaurus austriacus. With these data, it was possible to learn more about its sense of equilibrium and hearing. The results of this study show that Struthiosaurus' brain was very similar to the brains of its close relatives. For example, the flocculus, an evolutionary old part of the brain, was very small. The flocculus is important for the fixation of the eyes during motions of the head, neck and whole body, which can be very useful if such an animal was trying to target potential competitors or aggressors. \"In contrast to its Northamerican relative Euoplocephalus, which had a tail club and a clear flocculus on the brain cast, Struthiosaurus austriacus may have rather relied on its body armor for protection,\" says Marco Schade. Together with the form of the semicircular canals in the inner ear, this hints towards an exceptionally sluggish lifestyle of this Austrian plant eater. Furthermore, the scientists found the—so far—shortest lagena of any dinosaur. The lagena is the part of the inner ear where hearing takes place and its size can help to infer auditory capacities. This study delivers new insights into the evolutionary history of dinosaurs and their world, in which Europe was largely submerged in the ocean. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Nodosauridae is a group of thyreophoran dinosaurs characterized by a collar of prominent osteoderms. In comparison to its sister group, the often club-tailed ankylosaurids, a different lifestyle of nodosaurids could be assumed based on their neuroanatomy and weaponry, e.g., regarding applied defensive strategies. The holotype of the nodosaurid Struthiosaurus austriacus consists of a single partial braincase from the Late Cretaceous of Austria. Since neuroanatomy is considered to be associated with ecological tendencies, we created digital models of the braincase based on micro-CT data. The cranial endocast of S. austriacus generally resembles those of its relatives. A network of vascular canals surrounding the brain cavity further supports special thermoregulatory adaptations within Ankylosauria. The horizontal orientation of the lateral semicircular canal independently confirms previous appraisals of head posture for S. austriacus and, hence, strengthens the usage of the LSC as proxy for habitual head posture in fossil tetrapods. The short anterior and angular lateral semicircular canals, combined with the relatively shortest dinosaurian cochlear duct known so far and the lack of a floccular recess suggest a rather inert lifestyle without the necessity of sophisticated senses for equilibrium and hearing in S. austriacus . These observations agree with an animal that adapted to a comparatively inactive lifestyle with limited social interactions. Introduction Thyreophora are ornithischian dinosaurs, comprising iconic taxa like Stegosaurus and Ankylosaurus 1 . Ankylosauria thrived at least since the Middle Jurassic and some of their representatives witnessed the end-Cretaceous mass extinction 1 . These globally distributed quadruped herbivores were heavily armoured living fortresses; partly either equipped with a club tail (ankylosaurids 2 ) or a collar of hypertrophied spikes on their neck and shoulders (nodosaurids 3 ). Potential palaeoenvironmental 4 and food preferences 5 , together with features of their nasal passages 6 , jaw mechanics 7 , 8 and osteoderms 9 , may indicate different lifestyles for both groups. Since the brain and associated neuroanatomical structures of vertebrates leave perceivable traces, which are possibly ecologically informative, it is worthwhile to thoroughly examine the braincase of nodosaurids in order to compare it to ankylosaurids. Whereas complete braincase material among early-diverging thyreophorans is only known from Scelidosaurus harrisoni 10 , neurocranial material of stegosaurs 11 , 12 , and ankylosaurs (e.g. 13 , 14 , 15 ) is more common. The heavily armored skull roofs of the latter likely improved their preservation potential. Struthiosaurus is a European nodosaurid with an estimated body length of up to three metres, known from cranial and postcranial material of Campanian to Maastrichtian age 16 , 17 , 18 , 19 , 20 , 21 , 22 . As currently accepted, Struthiosaurus comprises three species: S . austriacus from the early Campanian of Austria 16 , 17 , 18 , S . languedocensis from the early Campanian of France 22 , and S . transylvanicus from the Maastrichtian of Romania 23 , 24 . In addition, skeletal remains referred to Struthiosaurus sp. were reported from late Campanian to early Maastrichtian deposits of Spain 20 , 21 . The potentially oldest fossil record of Struthiosaurus is represented by a single right humerus from the Santonian of Hungary 25 . The type species of Struthiosaurus , S . austriacus , is based on fragmentary cranial and postcranial remains of at least three individuals of different ontogenetic stages that were recovered during the nineteenth century from early Campanian continental coal-bearing beds of Muthmannsdorf, Austria, referred to the Grünbach Formation (see 18 for overview). The holotype specimen of S. austriacus , a partial braincase (IPUW 2349/6; Fig. 1 ), was scanned with the aid of a micro-CT; its superficial morphology has been previously described 16 , 17 , 26 . The segmentation of the internal structures provides new insights into the neuroanatomy and behavioral capacities of this Late Cretaceous (Campanian) armoured dinosaur from Austria. Figure 1 ( A ) Outline drawing of Austria with a star marking Muthmannsdorf, the type locality of Struthiosaurus austriacus . ( B ) Silhouette of Struthiosaurus austriacus (measuring 2.7 m in length here; copyright: Fabrizio De Rossi) and a human for comparison. Photographs ( C , D , G , J ) and ambient occlusion photogrammetric models ( E , F , H , I , K ) of the holotype specimen of Struthiosaurus austriacus , IPUW 2349/6, in ( C , E ) right lateral, ( D , F ) left lateral, ( I ) anterior, ( J , K ) ventral and ( G , H ) posterior views. a, armour; bo, basioccipital; bs, basisphenoid; bt, basal tuber; ct, crista tuberalis; d, damage; fm, foramen magnum; fo/cr, fenestra ovalis/columellar recess; met, metotic foramen; pbp, posterior branching plexus; sg, stapedial groove; st/pit, sella turcica/pituitary; tov, transverso-occipital vein; uvd, uncertain vascular duct; V 3 /icg, groove for the mandibular branch of the trigeminal nerve or for the internal carotid; VI, abducens nerve; VII, facial nerve; vcm, dorsal middle cerebral vein; XII, hypoglossal nerve. Full size image Results Cranial endocast, innervation and blood supply As in most non-maniraptoriform dinosaur braincases (e.g. 27 , 28 , 29 ), features of the midbrain and hindbrain are not securely identifiable as imprints on the endocast of IPUW 2349/6 (Figs. 2 , 3 ). This suggests little correlation of the brain and respective soft tissues with the surface of the endocranial cavity in the living animal, which is similar to extant reptiles (e.g., crocodiles and turtles 30 , 31 ). Figure 2 3D model of the cranial endocast with endosseous labyrinths and neurovascular canals of the holotype specimen of Struthiosaurus austriacus , IPUW 2349/6, without ( A , C , E ) and with ( B , D , F ) a volume rendering of the braincase in ( A , B ) right lateral, ( C , D ) dorsal and ( E , F ) posterior aspects. ?cerh, possible cerebral hemisphere; dp, dural peak; fo/cr, fenestra ovalis/columellar recess; met, metotic foramen; lab, endosseous labyrinth; pbp, posterior branching plexus; pit, pituitary; tov, transverso-occipital vein; uvd, uncertain vascular duct; VI,<|im_end|> <|im_start|>assistant German and Austrian scientists took a closer look at the braincase of a dinosaur from Austria. The group examined the fossil with a micro-CT and found surprising new details: it was sluggish and deaf. The respective study was recently published in the journal Scientific Reports. Ankylosaurs could grow up to eight meters in body length and represent a group of herbivorous dinosaurs also called 'living fortresses. Its body was cluttered with bony plates and spikes. The ankylosaurids sometimes possessed a club tail, while nodosaurids had elongated spikes on their necks and shoulders. However, some aspects of their lifestyle are still puzzling. While many dinosaurs likely lived in groups, at least some ankylosaurs seemed to prefer a lonesome life because of an inferior sense of hearing. That's what the scientists from the universities of Greifswald and Vienna concluded when they examined the braincase of the Austrian dinosaur with a high-resolution computer tomograph to produce a digital three-dimensional cast. Fossil braincases, which once housed the brain and other neurosensory tissues, are rare but important for science because these structures can provide insights into the lifestyle of a given animal. For example, the inner ears can hint to auditory capacities and skull orientation. Struthiosaurus austriacus is a comparably small nodosaurid from the Late Cretaceous (80 Ma) of Austria and comes from a locality near Muthmannsdorf, south of Vienna. The fossil remains of this dinosaur already belonged to the collection of the Institute for Paleontology in Vienna in the 19th century. For their study, Marco Schade (University of Greifswald), Cathrin Pfaff (University of Vienna) and their colleagues examined the tiny (50 mm) braincase to reveal new details of the anatomy and lifestyle of Struthiosaurus austriacus. With these data, it was possible to learn more about its sense of equilibrium and hearing. The results of this study show that Struthiosaurus' brain was very similar to the brains of its close relatives. For example, the flocculus, an evolutionary old part of the brain, was very small. The flocculus is important for the fixation of the eyes during motions of the head, neck and whole body, which can be very useful if such an animal was trying to target potential competitors or aggressors. "In contrast to its Northamerican relative Euoplocephalus, which had a tail club and a clear flocculus on the brain cast, Struthiosaurus austriacus may have rather relied on its body armor for protection," says Marco Schade. Together with the form of the semicircular canals in the inner ear, this hints towards an exceptionally sluggish lifestyle of this Austrian plant eater. Furthermore, the scientists found the—so far—shortest lagena of any dinosaur. The lagena is the part of the inner ear where hearing takes place and its size can help to infer auditory capacities. This study delivers new insights into the evolutionary history of dinosaurs and their world, in which Europe was largely submerged in the ocean. <|im_end|>

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5315, 11, 520, 3325, 1063, 459, 8050, 2353, 64, 1759, 9508, 311, 10932, 264, 326, 3233, 638, 2324, 1606, 315, 459, 38279, 5647, 315, 11011, 13, 3011, 596, 1148, 279, 14248, 505, 279, 23978, 315, 13842, 333, 2332, 4852, 323, 47387, 20536, 994, 814, 25078, 279, 8271, 5756, 315, 279, 58069, 63989, 449, 264, 1579, 64036, 6500, 10390, 3257, 311, 8356, 264, 7528, 2380, 33520, 6445, 13, 435, 85061, 8271, 24857, 11, 902, 3131, 52258, 279, 8271, 323, 1023, 18247, 82, 729, 683, 39881, 11, 527, 9024, 719, 3062, 369, 8198, 1606, 1521, 14726, 649, 3493, 26793, 1139, 279, 19433, 315, 264, 2728, 10065, 13, 1789, 3187, 11, 279, 9358, 25212, 649, 13310, 311, 83629, 59539, 323, 35113, 17140, 13, 4610, 952, 3614, 43613, 100206, 462, 96405, 374, 264, 7809, 2915, 2678, 16387, 59076, 307, 505, 279, 36931, 356, 2171, 77140, 320, 1490, 11583, 8, 315, 35998, 323, 4131, 505, 264, 69187, 3221, 386, 952, 18022, 13752, 33942, 11, 10007, 315, 47387, 13, 578, 31376, 8625, 315, 420, 63989, 2736, 46959, 311, 279, 4526, 315, 279, 10181, 369, 12629, 63333, 304, 47387, 304, 279, 220, 777, 339, 9478, 13, 1789, 872, 4007, 11, 35281, 5124, 1037, 320, 31272, 315, 13842, 333, 2332, 4852, 705, 12513, 26355, 43168, 2715, 320, 31272, 315, 47387, 8, 323, 872, 18105, 25078, 279, 13987, 320, 1135, 9653, 8, 8271, 5756, 311, 16805, 502, 3649, 315, 279, 62690, 323, 19433, 315, 4610, 952, 3614, 43613, 100206, 462, 96405, 13, 3161, 1521, 828, 11, 433, 574, 3284, 311, 4048, 810, 922, 1202, 5647, 315, 56411, 323, 11011, 13, 578, 3135, 315, 420, 4007, 1501, 430, 4610, 952, 3614, 43613, 6, 8271, 574, 1633, 4528, 311, 279, 35202, 315, 1202, 3345, 29658, 13, 1789, 3187, 11, 279, 9943, 641, 19990, 11, 459, 41993, 2362, 961, 315, 279, 8271, 11, 574, 1633, 2678, 13, 578, 9943, 641, 19990, 374, 3062, 369, 279, 84862, 315, 279, 6548, 2391, 54245, 315, 279, 2010, 11, 13272, 323, 4459, 2547, 11, 902, 649, 387, 1633, 5505, 422, 1778, 459, 10065, 574, 4560, 311, 2218, 4754, 28650, 477, 13632, 1105, 13, 330, 644, 13168, 311, 1202, 4892, 78818, 8844, 22730, 454, 385, 59822, 87227, 11, 902, 1047, 264, 9986, 6469, 323, 264, 2867, 9943, 641, 19990, 389, 279, 8271, 6445, 11, 4610, 952, 3614, 43613, 100206, 462, 96405, 1253, 617, 4856, 41013, 389, 1202, 2547, 20634, 369, 9313, 1359, 2795, 35281, 5124, 1037, 13, 32255, 449, 279, 1376, 315, 279, 5347, 292, 22190, 649, 1147, 304, 279, 9358, 2487, 11, 420, 31743, 7119, 459, 48298, 88046, 19433, 315, 420, 58069, 6136, 87135, 13, 24296, 11, 279, 14248, 1766, 279, 2345, 708, 3117, 2345, 8846, 478, 22171, 7304, 315, 904, 63989, 13, 578, 22171, 7304, 374, 279, 961, 315, 279, 9358, 2487, 1405, 11011, 5097, 2035, 323, 1202, 1404, 649, 1520, 311, 24499, 83629, 59539, 13, 1115, 4007, 28421, 502, 26793, 1139, 279, 41993, 3925, 315, 65375, 323, 872, 1917, 11, 304, 902, 4606, 574, 14090, 85177, 304, 279, 18435, 13, 220, 128257, 198 ]

2,255

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The extreme durability of polyethylene terephthalate (PET) debris has rendered it a long-term environmental burden. At the same time, current recycling efforts still lack sustainability. Two recently discovered bacterial enzymes that specifically degrade PET represent a promising solution. First, Ideonella sakaiensis PETase, a structurally well-characterized consensus α/β-hydrolase fold enzyme, converts PET to mono-(2-hydroxyethyl) terephthalate (MHET). MHETase, the second key enzyme, hydrolyzes MHET to the PET educts terephthalate and ethylene glycol. Here, we report the crystal structures of active ligand-free MHETase and MHETase bound to a nonhydrolyzable MHET analog. MHETase, which is reminiscent of feruloyl esterases, possesses a classic α/β-hydrolase domain and a lid domain conferring substrate specificity. In the light of structure-based mapping of the active site, activity assays, mutagenesis studies and a first structure-guided alteration of substrate specificity towards bis-(2-hydroxyethyl) terephthalate (BHET) reported here, we anticipate MHETase to be a valuable resource to further advance enzymatic plastic degradation. Introduction Appreciating its simple synthesis, robustness and durability, industrial production of PET was launched soon after its discovery and has been gradually increasing, projected to be over 70 million tons in 2020 1 , 2 . One of the biggest advantages of PET is its chemical inertness due to the hydrophobicity of the terephthalic acid (TPA) moiety, rendering it nearly resistant to environmental degradation. Although PET and other synthetic polymer plastics are considered nontoxic, larger particles and micro granules thereof are durable, omnipresent in marine or terrestrial habitats and accumulate in living organisms 3 , 4 , 5 . Often, they are also the carriers of potentially toxic colorants and additives 5 , 6 , 7 . Current recycling efforts cover only a fraction of PET waste and yield downgraded lower value products. They depend on the addition of large quantities of virgin polymer and significant consumption of energy 4 . Alternatively, several enzymes have been identified that can hydrolyze PET to TPA and ethylene glycol at elevated temperatures, albeit with low activity 8 , 9 , 10 , 11 . Enzyme optimization by biotechnology has been successful to some degree 12 , 13 , 14 , 15 , 16 , 17 , but has so far not led to enzymes, which can fully penetrate and degrade a thick layer of highly crystalline PET in a cost-effective and environmentally friendly manner. Recently, the bacterial strain Ideonella sakaiensis 201-F6 was discovered and shown to grow on low-crystallinity PET films. Two α/β-hydrolase fold enzymes (α/β-hydrolases), PETase and MHETase, work together to degrade PET in two steps via MHET, yielding TPA and ethylene glycol—the building blocks required for a new round of PET synthesis (Fig. 1a ) 10 , 18 . Recent crystal structures of PETase bound to ligands confirmed the predicted α/β-hydrolase fold, elucidated substrate binding, mode of catalysis and even permitted the enhancement of catalytic properties or alteration of substrate specificity 16 , 17 , 19 , 20 , 21 . Compared to known PET-degrading esterases, PETase from I. sakaiensis shows higher activity at ambient temperature and on highly crystalline PET 10 . In contrast, the structure of I. sakaiensis MHETase, the second enzyme—and crucial for full PET degradation—is still unknown. MHETase was initially assigned to the tannase enzyme family, which belongs to Block X of the α/β-hydrolase fold enzymes classified in the ESTHER database 10 , 22 . This family includes fungal and bacterial tannases and feruloyl esterases. Other significantly different bacterial tannases can be found in a distinct Block H (Tannases_bact) in this database. Consistently, MHETase was shown to exclusively hydrolyze MHET but not BHET, PET, p -nitrophenyl (pNP) aliphatic esters or aromatic ester compounds such as ethyl gallate and ethyl ferulate which are converted by other enzymes from the tannase family, indicating a highly restricted substrate specificity 10 . All plastic-degrading enzymes known so far display an α/β-hydrolase fold. MHETase, however, is likely to possess a scaffold unprecedented for plastic-degrading enzymes. This may be exploited in order to improve catalysis and to expand substrate specificity and thus significantly advance enzymatic plastic polymer degradation. Fig. 1 The structure of I. sakaiensis MHETase displays a bipartite domain architecture. a I. sakaiensis PETase and MHETase degrade PET to terephthalic acid and ethylene glycol. Side products are not shown. b MHETase structure with the α/β-hydrolase domain (MHETase Hyd ) colored in salmon and the lid domain (MHETase lid ) in light blue. Disulfide bonds are shown as sticks. c Close-up view of the MHETase catalytic triad, oxyanion hole and the water molecules in the substrate-binding site. d A. oryzae FaeB (PDB-ID: 3WMT 24 ), α/β-hydrolase domain (AoFaeB Hyd ) in crimson red, lid domain (AoFaeB Lid ) in cyan. e Close-up view of the AoFaeB catalytic triad, oxyanion hole and the water molecules in the substrate-binding site. Dashed lines indicate hydrogen bonds, rotation angles relate to the overview. Interacting residues are shown as sticks and colored by atom type. Carbon—as given for the respective molecule; nitrogen—blue; oxygen—red; sulfur—yellow. Water oxygens are shown as green spheres. Calcium is shown as purple sphere Full size image Here, we present the crystal structures of I. sakaiensis PETase, MHETase and MHETase bound to a nonhydrolyzable substrate analog (MHETA) or to benzoic acid. A structure-based mapping of the active site by mutations and binding studies with different substrates was used to determine the molecular basis for product inhibition and guided the development of MHETase variants with enhanced activity towards MHET or even an altered substrate specificity towards BHET. We anticipate our data to significantly advance the current understanding of enzymes degrading synthetic polyesters. Results Structure and phylogeny of I. sakaiensis MHETase We have determined crystal structures of recombinantly expressed and purified I. sakaiensis MHETase in its ligand-free form (2.05 Å resolution), MHETase bound to a nonhydrolyzable mono-(2-hydroxyethyl) terephthalamide (MHETA, 2.1 Å resolution) or to benzoic acid (BA, 2.2 Å resolution) as well as ligand-free PETase (2.0 Å resolution) (Supplementary Figs. 1 , 2a−f , Supplementary Table 1 ). The structure of PETase was solved by molecular replacement (MR) employing the structural coordinates of T. fusca cutinase TfCut2", "role": "user" }, { "content": "A research team from the University of Greifswald and Helmholtz-Zentrum-Berlin (HZB) has solved the molecular structure of the enzyme MHETase at BESSY II. MHETase was discovered in bacteria, and together with a second enzyme, PETase, is able to break down the widely used plastic PET into its basic building blocks. This 3D structure already allowed the researchers to produce a MHETase variant with optimized activity in order to use it, together with PETase, for a sustainable recycling of PET. Plastics are extremely versatile and almost eternally durable. But this is also a problem, because after only about 100 years of producing plastics, plastic particles are now found everywhere—in groundwater, in the oceans, in the air, and in the food chain. Around 50 million tonnes of the industrially important polymer PET are produced every year. Just a tiny fraction of plastic is currently recycled via expensive and energy-consuming processes that yield either downgraded products or depend in turn on adding 'fresh' crude oil. In 2016, a group of Japanese researchers discovered a bacterium that grows on PET and partially feeds on it. They found that the bacterium possesses two special enzymes, PETase and MHETase, that digest PET plastic polymers. PETase breaks down the plastic into smaller PET building blocks, primarily MHET, and MHETase splits this into the two basic precursor building blocks of PET, terephthalic acid and ethylene glycol. Both components are valuable for synthesising new PET without the addition of crude oil for a closed sustainable production and recovery cycle. In April 2018, the structure of PETase was finally solved independently by several research groups. The Diamond Light Source was also involved in the experiments. However, PETase is only part of the solution. It is equally important to characterize the structure of the second enzyme, MHETase. \"MHETase is considerably larger than PETase and even more complex. A single MHETase molecule consists of 600 amino acids, or about 4000 atoms. MHETase has a surface that is about twice as large as the surface of PETase and has therefore considerably more potential for optimization toward decomposition of PET,\" explains biochemist and structural biologist Dr. Gert Weber from Helmholtz-Zentrum Berlin and Freie Universität Berlin. During an interim professorship at the University of Greifswald, Weber contacted the biotechnologist Prof. Uwe Bornscheuer at the Institute of Biochemistry, who was already involved with plastic-degrading enzymes. Together, they developed the idea of solving the structure of MHETase and then using this insight to optimise the enzyme for applications in PET recycling. To do this, they first had to extract the enzyme from bacterial cells and purify it. Within this collaboration, the teams succeeded in obtaining the complex three-dimensional architecture of MHETase at BESSY II, the synchrotron source at HZB in Berlin. \"In order to see how MHETase binds to PET and decomposes it, you need a fragment of plastic that binds to MHETase but is not cleaved by it,\" explains Weber. A member of Weber's prior research team in Greifswald, Dr. Gottfried Palm, cut up a PET bottle, chemically decomposed the PET polymer and synthesised a small chemical fragment from it that binds to MHETase but can no longer be cleaved by it. From this 'blocked' MHETase, tiny crystals were grown for structural investigations at the HZB. \"The structural investigations enabled us to watch MHETase virtually 'at work' and develop strategies for how to optimise this enzyme,\" explains Weber. \"Thanks to the joint research group format, we have the means to offer beamtime access on the highly demanded BESSY II MX beamlines for measurements very quickly at any time,\" says Dr. Manfred Weiss, who is responsible for the BESSY II MX beamlines. The three-dimensional architecture of MHETase actually displays some special features: enzymes such as MHETase bind to their target molecule first before a chemical reaction occurs. For breakdown of a molecule you need a tailor-made enzyme: \"We can now exactly localise where the MHET molecule docks to MHETase and how MHET is then split into its two building blocks terephthalic acid and ethylene glycol,\" says Weber. However, neither PETase nor MHETase are particularly efficient. \"Plastics have only been around on this scale for a few decades—even bacteria with their rapid successions of generations and rapid adaptability have not managed to develop a perfect solution through the evolutionary process of trial and error over such a short time,\" explains Weber. \"Thanks to the clarification of the structure of this very important enzyme, we have now also been able to plan, produce and biochemically characterise variants that show significantly higher activity than natural MHETase and are even active against another intermediate product of PET degradation, BHET,\" adds Uwe Bornscheuer. In future, Uwe Bornscheuer will work on systematically optimising the enzymes PETase and MHETase for their task—the decomposition of PET. Gert Weber plans to supplement these studies with further work on biological structures in order to systematically develop plastic-digesting enzymes for environmental applications. Access to the measuring stations and the IT infrastructure of HZB is indispensable for this. Producing these kinds of enzymes in closed biotechnological cycles, for example, could be a way to really break down PET plastics and other polymers into their basic building blocks. This would also be the key to ideal recycling and a long-term solution to the plastic waste problem: production of plastic would be a closed cycle and no longer dependent on crude oil. The study is published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The extreme durability of polyethylene terephthalate (PET) debris has rendered it a long-term environmental burden. At the same time, current recycling efforts still lack sustainability. Two recently discovered bacterial enzymes that specifically degrade PET represent a promising solution. First, Ideonella sakaiensis PETase, a structurally well-characterized consensus α/β-hydrolase fold enzyme, converts PET to mono-(2-hydroxyethyl) terephthalate (MHET). MHETase, the second key enzyme, hydrolyzes MHET to the PET educts terephthalate and ethylene glycol. Here, we report the crystal structures of active ligand-free MHETase and MHETase bound to a nonhydrolyzable MHET analog. MHETase, which is reminiscent of feruloyl esterases, possesses a classic α/β-hydrolase domain and a lid domain conferring substrate specificity. In the light of structure-based mapping of the active site, activity assays, mutagenesis studies and a first structure-guided alteration of substrate specificity towards bis-(2-hydroxyethyl) terephthalate (BHET) reported here, we anticipate MHETase to be a valuable resource to further advance enzymatic plastic degradation. Introduction Appreciating its simple synthesis, robustness and durability, industrial production of PET was launched soon after its discovery and has been gradually increasing, projected to be over 70 million tons in 2020 1 , 2 . One of the biggest advantages of PET is its chemical inertness due to the hydrophobicity of the terephthalic acid (TPA) moiety, rendering it nearly resistant to environmental degradation. Although PET and other synthetic polymer plastics are considered nontoxic, larger particles and micro granules thereof are durable, omnipresent in marine or terrestrial habitats and accumulate in living organisms 3 , 4 , 5 . Often, they are also the carriers of potentially toxic colorants and additives 5 , 6 , 7 . Current recycling efforts cover only a fraction of PET waste and yield downgraded lower value products. They depend on the addition of large quantities of virgin polymer and significant consumption of energy 4 . Alternatively, several enzymes have been identified that can hydrolyze PET to TPA and ethylene glycol at elevated temperatures, albeit with low activity 8 , 9 , 10 , 11 . Enzyme optimization by biotechnology has been successful to some degree 12 , 13 , 14 , 15 , 16 , 17 , but has so far not led to enzymes, which can fully penetrate and degrade a thick layer of highly crystalline PET in a cost-effective and environmentally friendly manner. Recently, the bacterial strain Ideonella sakaiensis 201-F6 was discovered and shown to grow on low-crystallinity PET films. Two α/β-hydrolase fold enzymes (α/β-hydrolases), PETase and MHETase, work together to degrade PET in two steps via MHET, yielding TPA and ethylene glycol—the building blocks required for a new round of PET synthesis (Fig. 1a ) 10 , 18 . Recent crystal structures of PETase bound to ligands confirmed the predicted α/β-hydrolase fold, elucidated substrate binding, mode of catalysis and even permitted the enhancement of catalytic properties or alteration of substrate specificity 16 , 17 , 19 , 20 , 21 . Compared to known PET-degrading esterases, PETase from I. sakaiensis shows higher activity at ambient temperature and on highly crystalline PET 10 . In contrast, the structure of I. sakaiensis MHETase, the second enzyme—and crucial for full PET degradation—is still unknown. MHETase was initially assigned to the tannase enzyme family, which belongs to Block X of the α/β-hydrolase fold enzymes classified in the ESTHER database 10 , 22 . This family includes fungal and bacterial tannases and feruloyl esterases. Other significantly different bacterial tannases can be found in a distinct Block H (Tannases_bact) in this database. Consistently, MHETase was shown to exclusively hydrolyze MHET but not BHET, PET, p -nitrophenyl (pNP) aliphatic esters or aromatic ester compounds such as ethyl gallate and ethyl ferulate which are converted by other enzymes from the tannase family, indicating a highly restricted substrate specificity 10 . All plastic-degrading enzymes known so far display an α/β-hydrolase fold. MHETase, however, is likely to possess a scaffold unprecedented for plastic-degrading enzymes. This may be exploited in order to improve catalysis and to expand substrate specificity and thus significantly advance enzymatic plastic polymer degradation. Fig. 1 The structure of I. sakaiensis MHETase displays a bipartite domain architecture. a I. sakaiensis PETase and MHETase degrade PET to terephthalic acid and ethylene glycol. Side products are not shown. b MHETase structure with the α/β-hydrolase domain (MHETase Hyd ) colored in salmon and the lid domain (MHETase lid ) in light blue. Disulfide bonds are shown as sticks. c Close-up view of the MHETase catalytic triad, oxyanion hole and the water molecules in the substrate-binding site. d A. oryzae FaeB (PDB-ID: 3WMT 24 ), α/β-hydrolase domain (AoFaeB Hyd ) in crimson red, lid domain (AoFaeB Lid ) in cyan. e Close-up view of the AoFaeB catalytic triad, oxyanion hole and the water molecules in the substrate-binding site. Dashed lines indicate hydrogen bonds, rotation angles relate to the overview. Interacting residues are shown as sticks and colored by atom type. Carbon—as given for the respective molecule; nitrogen—blue; oxygen—red; sulfur—yellow. Water oxygens are shown as green spheres. Calcium is shown as purple sphere Full size image Here, we present the crystal structures of I. sakaiensis PETase, MHETase and MHETase bound to a nonhydrolyzable substrate analog (MHETA) or to benzoic acid. A structure-based mapping of the active site by mutations and binding studies with different substrates was used to determine the molecular basis for product inhibition and guided the development of MHETase variants with enhanced activity towards MHET or even an altered substrate specificity towards BHET. We anticipate our data to significantly advance the current understanding of enzymes degrading synthetic polyesters. Results Structure and phylogeny of I. sakaiensis MHETase We have determined crystal structures of recombinantly expressed and purified I. sakaiensis MHETase in its ligand-free form (2.05 Å resolution), MHETase bound to a nonhydrolyzable mono-(2-hydroxyethyl) terephthalamide (MHETA, 2.1 Å resolution) or to benzoic acid (BA, 2.2 Å resolution) as well as ligand-free PETase (2.0 Å resolution) (Supplementary Figs. 1 , 2a−f , Supplementary Table 1 ). The structure of PETase was solved by molecular replacement (MR) employing the structural coordinates of T. fusca cutinase TfCut2<|im_end|> <|im_start|>assistant A research team from the University of Greifswald and Helmholtz-Zentrum-Berlin (HZB) has solved the molecular structure of the enzyme MHETase at BESSY II. MHETase was discovered in bacteria, and together with a second enzyme, PETase, is able to break down the widely used plastic PET into its basic building blocks. This 3D structure already allowed the researchers to produce a MHETase variant with optimized activity in order to use it, together with PETase, for a sustainable recycling of PET. Plastics are extremely versatile and almost eternally durable. But this is also a problem, because after only about 100 years of producing plastics, plastic particles are now found everywhere—in groundwater, in the oceans, in the air, and in the food chain. Around 50 million tonnes of the industrially important polymer PET are produced every year. Just a tiny fraction of plastic is currently recycled via expensive and energy-consuming processes that yield either downgraded products or depend in turn on adding 'fresh' crude oil. In 2016, a group of Japanese researchers discovered a bacterium that grows on PET and partially feeds on it. They found that the bacterium possesses two special enzymes, PETase and MHETase, that digest PET plastic polymers. PETase breaks down the plastic into smaller PET building blocks, primarily MHET, and MHETase splits this into the two basic precursor building blocks of PET, terephthalic acid and ethylene glycol. Both components are valuable for synthesising new PET without the addition of crude oil for a closed sustainable production and recovery cycle. In April 2018, the structure of PETase was finally solved independently by several research groups. The Diamond Light Source was also involved in the experiments. However, PETase is only part of the solution. It is equally important to characterize the structure of the second enzyme, MHETase. "MHETase is considerably larger than PETase and even more complex. A single MHETase molecule consists of 600 amino acids, or about 4000 atoms. MHETase has a surface that is about twice as large as the surface of PETase and has therefore considerably more potential for optimization toward decomposition of PET," explains biochemist and structural biologist Dr. Gert Weber from Helmholtz-Zentrum Berlin and Freie Universität Berlin. During an interim professorship at the University of Greifswald, Weber contacted the biotechnologist Prof. Uwe Bornscheuer at the Institute of Biochemistry, who was already involved with plastic-degrading enzymes. Together, they developed the idea of solving the structure of MHETase and then using this insight to optimise the enzyme for applications in PET recycling. To do this, they first had to extract the enzyme from bacterial cells and purify it. Within this collaboration, the teams succeeded in obtaining the complex three-dimensional architecture of MHETase at BESSY II, the synchrotron source at HZB in Berlin. "In order to see how MHETase binds to PET and decomposes it, you need a fragment of plastic that binds to MHETase but is not cleaved by it," explains Weber. A member of Weber's prior research team in Greifswald, Dr. Gottfried Palm, cut up a PET bottle, chemically decomposed the PET polymer and synthesised a small chemical fragment from it that binds to MHETase but can no longer be cleaved by it. From this 'blocked' MHETase, tiny crystals were grown for structural investigations at the HZB. "The structural investigations enabled us to watch MHETase virtually 'at work' and develop strategies for how to optimise this enzyme," explains Weber. "Thanks to the joint research group format, we have the means to offer beamtime access on the highly demanded BESSY II MX beamlines for measurements very quickly at any time," says Dr. Manfred Weiss, who is responsible for the BESSY II MX beamlines. The three-dimensional architecture of MHETase actually displays some special features: enzymes such as MHETase bind to their target molecule first before a chemical reaction occurs. For breakdown of a molecule you need a tailor-made enzyme: "We can now exactly localise where the MHET molecule docks to MHETase and how MHET is then split into its two building blocks terephthalic acid and ethylene glycol," says Weber. However, neither PETase nor MHETase are particularly efficient. "Plastics have only been around on this scale for a few decades—even bacteria with their rapid successions of generations and rapid adaptability have not managed to develop a perfect solution through the evolutionary process of trial and error over such a short time," explains Weber. "Thanks to the clarification of the structure of this very important enzyme, we have now also been able to plan, produce and biochemically characterise variants that show significantly higher activity than natural MHETase and are even active against another intermediate product of PET degradation, BHET," adds Uwe Bornscheuer. In future, Uwe Bornscheuer will work on systematically optimising the enzymes PETase and MHETase for their task—the decomposition of PET. Gert Weber plans to supplement these studies with further work on biological structures in order to systematically develop plastic-digesting enzymes for environmental applications. Access to the measuring stations and the IT infrastructure of HZB is indispensable for this. Producing these kinds of enzymes in closed biotechnological cycles, for example, could be a way to really break down PET plastics and other polymers into their basic building blocks. This would also be the key to ideal recycling and a long-term solution to the plastic waste problem: production of plastic would be a closed cycle and no longer dependent on crude oil. The study is published in Nature Communications. <|im_end|>

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2,803

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The human eye can distinguish as many as 10,000 different colours but is far less sensitive to variations in intensity 1 , meaning that colour is highly desirable when interpreting images. However, most biological samples are essentially transparent, and nearly invisible when viewed using a standard optical microscope 2 . It is therefore highly desirable to be able to produce coloured images without needing to add any stains or dyes, which can alter the sample properties. Here we demonstrate that colorimetric histology images can be generated using full-sized plasmonically active microscope slides. These slides translate subtle changes in the dielectric constant into striking colour contrast when samples are placed upon them. We demonstrate the biomedical potential of this technique, which we term histoplasmonics, by distinguishing neoplastic cells from normal breast epithelium during the earliest stages of tumorigenesis in the mouse MMTV-PyMT mammary tumour model. We then apply this method to human diagnostic tissue and validate its utility in distinguishing normal epithelium, usual ductal hyperplasia, and early-stage breast cancer (ductal carcinoma in situ). The colorimetric output of the image pixels is compared to conventional histopathology. The results we report here support the hypothesis that histoplasmonics can be used as a novel alternative or adjunct to general staining. The widespread availability of this technique and its incorporation into standard laboratory workflows may prove transformative for applications extending well beyond tissue diagnostics. This work also highlights opportunities for improvements to digital pathology that have yet to be explored. Main Plasmonic hole arrays can support specific optical band structures that enable a range of colours to be obtained through precise control of the device geometry 3 . Colour filtering was first achieved using subwavelength gratings 4 , 5 and later via periodic arrays of nanoapertures 6 . The dynamic range of the colour palette for these structures can be extended by incorporating asymmetries in the design and exploiting the specific interactions of polarized light with the local surface plasmon resonances 7 , 8 . Particularly relevant here are techniques for fabricating these structures over large areas, which are also suitable for low-cost mass production 7 , 9 , 10 . Among the approaches that have been tried, directed self-assembly 11 , nanoimprint 12 , laser interference lithography 10 and displacement Talbot lithography 13 have been suggested as a viable means of mass production. Here, we use displacement Talbot lithography to produce devices on the scale of standard microscope slides (for example, 75 mm × 25 mm) and incorporate them into conventional bright-field imaging of histological tissue sections. We present data from the MMTV-PyMT mouse model with distinct stages of early breast cancer pathology ( N = 6) and a retrospective patient cohort ( N = 24) encompassing tissues derived from patients diagnosed with benign usual ductal hyperplasia (UDH) or ductal carcinoma in situ (DCIS), an early stage of breast cancer. Tissues from healthy patients as well as invasive cancers are included as a control. Data are scored by a human breast and murine mammary gland pathologist and the optical output quantified. Although general histopathology stains such as haematoxylin and eosin (H&E) that allow assessment of tissue morphology are a mainstay of disease diagnostics, identifying abnormal cells, which may be morphologically similar to healthy cells, can be challenging and can lead to discordance between pathologists. Using molecular targets or biomarkers for distinguishing disease states can be labour intensive and time-consuming 14 . Label-free approaches to histology offer a potential alternative or adjunct method of diagnosis that is not reliant on any specific chemical interaction with the sample yet has the potential to detect differences between a normal and a diseased cellular state. These advantages have driven the development of a wide variety of new approaches to histology in recent years, including photoacoustic and ultraviolet microscopy 15 , 16 , quantitative mass spectroscopy and bioanalytical imaging 17 , stimulated Raman scattering microscopy 18 , 19 and quantitative phase imaging 20 . Both photoacoustic and ultraviolet microscopy provide depth resolution 15 , but they require specialized equipment and data analysis. Mass spectroscopy is able to quantify protein amounts 17 but it does not yield histology-like images, which can be a critical aid or adjunct to diagnosis. Another label-free technique growing in popularity is stimulated Raman scattering microscopy 18 , 19 . This technique provides molecular specificity and has been shown to allow for imaging of DNA 16 , but it is also time-consuming and therefore may not be suitable for use in surgery or for large samples. Finally, quantitative phase imaging can be used to generate spatially resolved maps of the tissue density 20 . However, this technique does not generate colour-contrast images and may require specialized software and training for data collection. In summary, while each label-free technique has specific advantages and disadvantages for the user, in terms of analysis time, cost, ease of use and compatibility with existing pathology workflows, the technique introduced here, histoplasmonics, offers substantial advantages (see Extended Data Table 1 ). Fundamental principles Extraordinary optical contrast involves the resonant interaction of light with the collective oscillations of free electrons at a metal surface, known as surface plasmon polaritons (SPPs). The spectral change in transmitted light through an array of subwavelength apertures in contact with a thin dielectric specimen (Fig. 1a ) is a function of the wavelength shift, Δ λ , of the SPP resonant modes. When using a standard transmission bright-field microscope, a spatially resolved distribution of colours will result that relates directly to changes in the local sample thickness and/or dielectric constant. With the local dielectric constant encoded in the optical spectrum, a marked chromatic contrast effect is produced. This potentially means that difficult-to-detect features within an optically transparent sample may be clearly seen in the visible-light transmission image, via plasmon-enhanced colour contrast. This form of colorimetric full-field imaging and its potential applications are explored in the present article. Fig. 1: Conceptual design and fundamental principles. a , Top, conceptual layered design of the nanoslide; bottom, the two Ag", "role": "user" }, { "content": "When we look at biological cells under a microscope, they're usually not very colorful. Normally, to visualize them we have to artificially add color—typically by staining. By doing so, we can see their shape and arrangement in a tissue and determine whether they're healthy or not. Sometimes, though, cell structure alone isn't enough to accurately identify disease—which can lead to misdiagnosis and potentially fatal consequences for a patient. But what if there was a way to not only see the structure of cells, but also determine whether they are abnormal, simply by looking at their intrinsic color under a microscope? This was our team's goal as we developed a new medical diagnostic tool called the NanoMslide. We modified a standard microscope slide to turn it into a powerful tool for breast cancer detection. Our research is published today in Nature. Early detection is key It's estimated one in eight Australian women will be diagnosed with breast cancer by age 85. As with most cancers, catching the disease early is critical. However, an accurate diagnosis of the earliest stages of breast cancer requires identifying small numbers of diseased cells throughout a tissue, which can be incredibly challenging. The NanoMslide can manipulate light at the nanoscale, causing cells to \"light up\" with vivid color contrast. This makes it easier to recognize potentially cancerous cells (or benign abnormalities) within the tissue. By providing a way to instantly distinguish which cells could be cancerous, the tool may help to reduce current uncertainty around very early-stage breast cancer detection. With mammogram screening, distinguishing breast abnormalities from early breast cancers upon biopsy is very important, particularly as misdiagnosis rates can be as high as 15%. Human cancerous tissue, viewed through a microscope with the NanoMslide applied. Credit: Author provided Major barriers in development Incorporating nanotechnology into medical diagnostics presents a number of challenges. It took us six years of development to ensure NanoMslide would work effectively. In the end it was a combination of cutting-edge nanofabrication, a significant amount of trial-and-error and a bit of good fortune that led to our breakthrough. For decades, researchers have known cancer cells tend to interact with light in a way that's different to healthy cells. This is due to a variety of factors, such as the distribution of protein inside the cell and differences in its overall shape. The main challenge is these differences can be extremely subtle and can present in a variety of ways. Previous approaches to differentiating cancer cells (without using stains or labels) have tended to use specialized microscopy equipment, or complex techniques. But these approaches are difficult to incorporate into existing pathology workflows and can require specialist training and knowledge. So we took a radically different approach. Normal (non-cancerous) human tissue, viewed through a microscope with the NanoMslide applied. Credit: Author provided Success with human tissue Rather than focusing on developing a better microscope, we focused on improving the microscope slide instead. By developing a special nanofabricated coating, we modified the surface of an ordinary microscope slide and transformed it into one huge sensor. What's truly remarkable is the structures of the sensor are just a few hundred nanometres across, yet are repeated with amazing precision across an area of tens of centimeters, or more. Maintaining this level of precision, which is necessary for reliable fabrication at this scale, has taken advances in nanofabrication techniques that have only become commercially available in the past six years. The sensor is activated by visible light. And when an object such as a tissue or single cell comes into contact with the sensor's surface, colors are produced. It is this feature which we've been able to optimize to allow pathologists to detect cells that are likely cancerous, just by looking at them. The dyes which are currently used to stain tissues (to visualize cell shape and architecture) normally present as one or two colors. The NanoMslide renders tissues in beautiful full-color contrast, making it easier to differentiate multiple types of cell on a single slide. The NanoMslide is a large sensor fitted with cutting-edge nanotechnology capabilities. Credit: Author provided For our study, we tested the slides with expert breast-cancer pathologists, using both a mouse model and patient tissue. By starting with a well-characterized small-animal model, our team of physicists, cancer researchers and breast pathologists was able to develop the technology further. We eventually reached the point where we could be confident some of the specific colors visible were indicative of cancerous cells. This led to further pathology assessments with patient tissue, where there is more complexity to contend with in terms of diagnosis. Yet, even in this more challenging setting, the NanoMslide performed strongly. It also outperformed some commercial biomarkers, which are used as an aid for borderline diagnoses (where cancer is difficult to tell apart from benign abnormalities). Like going from black and white to color television Because the technology doesn't rely on any special function, or specific molecular interactions, it could potentially be applied to other types of cancer—even other types of disease. Another application now being worked on is to examine the results of liquid biopsies, such as cheek swabs, for immediate point-of-care analysis. In April, we were fortunate to benefit from the opening of a new instrument at the Australian National Fabrication Facility to enable the scaling-up of production. This means NanoMslide can be moved from small-scale to medium-scale manufacture, allowing us to explore a number of different applications, and produce the numbers of slides required for further clinical validation. The technology could also be hugely beneficial to the growing digital-pathology space, where the vivid colors generated by NanoMslide could help develop next-generation artificial intelligence algorithms to identify signs of disease. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The human eye can distinguish as many as 10,000 different colours but is far less sensitive to variations in intensity 1 , meaning that colour is highly desirable when interpreting images. However, most biological samples are essentially transparent, and nearly invisible when viewed using a standard optical microscope 2 . It is therefore highly desirable to be able to produce coloured images without needing to add any stains or dyes, which can alter the sample properties. Here we demonstrate that colorimetric histology images can be generated using full-sized plasmonically active microscope slides. These slides translate subtle changes in the dielectric constant into striking colour contrast when samples are placed upon them. We demonstrate the biomedical potential of this technique, which we term histoplasmonics, by distinguishing neoplastic cells from normal breast epithelium during the earliest stages of tumorigenesis in the mouse MMTV-PyMT mammary tumour model. We then apply this method to human diagnostic tissue and validate its utility in distinguishing normal epithelium, usual ductal hyperplasia, and early-stage breast cancer (ductal carcinoma in situ). The colorimetric output of the image pixels is compared to conventional histopathology. The results we report here support the hypothesis that histoplasmonics can be used as a novel alternative or adjunct to general staining. The widespread availability of this technique and its incorporation into standard laboratory workflows may prove transformative for applications extending well beyond tissue diagnostics. This work also highlights opportunities for improvements to digital pathology that have yet to be explored. Main Plasmonic hole arrays can support specific optical band structures that enable a range of colours to be obtained through precise control of the device geometry 3 . Colour filtering was first achieved using subwavelength gratings 4 , 5 and later via periodic arrays of nanoapertures 6 . The dynamic range of the colour palette for these structures can be extended by incorporating asymmetries in the design and exploiting the specific interactions of polarized light with the local surface plasmon resonances 7 , 8 . Particularly relevant here are techniques for fabricating these structures over large areas, which are also suitable for low-cost mass production 7 , 9 , 10 . Among the approaches that have been tried, directed self-assembly 11 , nanoimprint 12 , laser interference lithography 10 and displacement Talbot lithography 13 have been suggested as a viable means of mass production. Here, we use displacement Talbot lithography to produce devices on the scale of standard microscope slides (for example, 75 mm × 25 mm) and incorporate them into conventional bright-field imaging of histological tissue sections. We present data from the MMTV-PyMT mouse model with distinct stages of early breast cancer pathology ( N = 6) and a retrospective patient cohort ( N = 24) encompassing tissues derived from patients diagnosed with benign usual ductal hyperplasia (UDH) or ductal carcinoma in situ (DCIS), an early stage of breast cancer. Tissues from healthy patients as well as invasive cancers are included as a control. Data are scored by a human breast and murine mammary gland pathologist and the optical output quantified. Although general histopathology stains such as haematoxylin and eosin (H&E) that allow assessment of tissue morphology are a mainstay of disease diagnostics, identifying abnormal cells, which may be morphologically similar to healthy cells, can be challenging and can lead to discordance between pathologists. Using molecular targets or biomarkers for distinguishing disease states can be labour intensive and time-consuming 14 . Label-free approaches to histology offer a potential alternative or adjunct method of diagnosis that is not reliant on any specific chemical interaction with the sample yet has the potential to detect differences between a normal and a diseased cellular state. These advantages have driven the development of a wide variety of new approaches to histology in recent years, including photoacoustic and ultraviolet microscopy 15 , 16 , quantitative mass spectroscopy and bioanalytical imaging 17 , stimulated Raman scattering microscopy 18 , 19 and quantitative phase imaging 20 . Both photoacoustic and ultraviolet microscopy provide depth resolution 15 , but they require specialized equipment and data analysis. Mass spectroscopy is able to quantify protein amounts 17 but it does not yield histology-like images, which can be a critical aid or adjunct to diagnosis. Another label-free technique growing in popularity is stimulated Raman scattering microscopy 18 , 19 . This technique provides molecular specificity and has been shown to allow for imaging of DNA 16 , but it is also time-consuming and therefore may not be suitable for use in surgery or for large samples. Finally, quantitative phase imaging can be used to generate spatially resolved maps of the tissue density 20 . However, this technique does not generate colour-contrast images and may require specialized software and training for data collection. In summary, while each label-free technique has specific advantages and disadvantages for the user, in terms of analysis time, cost, ease of use and compatibility with existing pathology workflows, the technique introduced here, histoplasmonics, offers substantial advantages (see Extended Data Table 1 ). Fundamental principles Extraordinary optical contrast involves the resonant interaction of light with the collective oscillations of free electrons at a metal surface, known as surface plasmon polaritons (SPPs). The spectral change in transmitted light through an array of subwavelength apertures in contact with a thin dielectric specimen (Fig. 1a ) is a function of the wavelength shift, Δ λ , of the SPP resonant modes. When using a standard transmission bright-field microscope, a spatially resolved distribution of colours will result that relates directly to changes in the local sample thickness and/or dielectric constant. With the local dielectric constant encoded in the optical spectrum, a marked chromatic contrast effect is produced. This potentially means that difficult-to-detect features within an optically transparent sample may be clearly seen in the visible-light transmission image, via plasmon-enhanced colour contrast. This form of colorimetric full-field imaging and its potential applications are explored in the present article. Fig. 1: Conceptual design and fundamental principles. a , Top, conceptual layered design of the nanoslide; bottom, the two Ag<|im_end|> <|im_start|>assistant When we look at biological cells under a microscope, they're usually not very colorful. Normally, to visualize them we have to artificially add color—typically by staining. By doing so, we can see their shape and arrangement in a tissue and determine whether they're healthy or not. Sometimes, though, cell structure alone isn't enough to accurately identify disease—which can lead to misdiagnosis and potentially fatal consequences for a patient. But what if there was a way to not only see the structure of cells, but also determine whether they are abnormal, simply by looking at their intrinsic color under a microscope? This was our team's goal as we developed a new medical diagnostic tool called the NanoMslide. We modified a standard microscope slide to turn it into a powerful tool for breast cancer detection. Our research is published today in Nature. Early detection is key It's estimated one in eight Australian women will be diagnosed with breast cancer by age 85. As with most cancers, catching the disease early is critical. However, an accurate diagnosis of the earliest stages of breast cancer requires identifying small numbers of diseased cells throughout a tissue, which can be incredibly challenging. The NanoMslide can manipulate light at the nanoscale, causing cells to "light up" with vivid color contrast. This makes it easier to recognize potentially cancerous cells (or benign abnormalities) within the tissue. By providing a way to instantly distinguish which cells could be cancerous, the tool may help to reduce current uncertainty around very early-stage breast cancer detection. With mammogram screening, distinguishing breast abnormalities from early breast cancers upon biopsy is very important, particularly as misdiagnosis rates can be as high as 15%. Human cancerous tissue, viewed through a microscope with the NanoMslide applied. Credit: Author provided Major barriers in development Incorporating nanotechnology into medical diagnostics presents a number of challenges. It took us six years of development to ensure NanoMslide would work effectively. In the end it was a combination of cutting-edge nanofabrication, a significant amount of trial-and-error and a bit of good fortune that led to our breakthrough. For decades, researchers have known cancer cells tend to interact with light in a way that's different to healthy cells. This is due to a variety of factors, such as the distribution of protein inside the cell and differences in its overall shape. The main challenge is these differences can be extremely subtle and can present in a variety of ways. Previous approaches to differentiating cancer cells (without using stains or labels) have tended to use specialized microscopy equipment, or complex techniques. But these approaches are difficult to incorporate into existing pathology workflows and can require specialist training and knowledge. So we took a radically different approach. Normal (non-cancerous) human tissue, viewed through a microscope with the NanoMslide applied. Credit: Author provided Success with human tissue Rather than focusing on developing a better microscope, we focused on improving the microscope slide instead. By developing a special nanofabricated coating, we modified the surface of an ordinary microscope slide and transformed it into one huge sensor. What's truly remarkable is the structures of the sensor are just a few hundred nanometres across, yet are repeated with amazing precision across an area of tens of centimeters, or more. Maintaining this level of precision, which is necessary for reliable fabrication at this scale, has taken advances in nanofabrication techniques that have only become commercially available in the past six years. The sensor is activated by visible light. And when an object such as a tissue or single cell comes into contact with the sensor's surface, colors are produced. It is this feature which we've been able to optimize to allow pathologists to detect cells that are likely cancerous, just by looking at them. The dyes which are currently used to stain tissues (to visualize cell shape and architecture) normally present as one or two colors. The NanoMslide renders tissues in beautiful full-color contrast, making it easier to differentiate multiple types of cell on a single slide. The NanoMslide is a large sensor fitted with cutting-edge nanotechnology capabilities. Credit: Author provided For our study, we tested the slides with expert breast-cancer pathologists, using both a mouse model and patient tissue. By starting with a well-characterized small-animal model, our team of physicists, cancer researchers and breast pathologists was able to develop the technology further. We eventually reached the point where we could be confident some of the specific colors visible were indicative of cancerous cells. This led to further pathology assessments with patient tissue, where there is more complexity to contend with in terms of diagnosis. Yet, even in this more challenging setting, the NanoMslide performed strongly. It also outperformed some commercial biomarkers, which are used as an aid for borderline diagnoses (where cancer is difficult to tell apart from benign abnormalities). Like going from black and white to color television Because the technology doesn't rely on any special function, or specific molecular interactions, it could potentially be applied to other types of cancer—even other types of disease. Another application now being worked on is to examine the results of liquid biopsies, such as cheek swabs, for immediate point-of-care analysis. In April, we were fortunate to benefit from the opening of a new instrument at the Australian National Fabrication Facility to enable the scaling-up of production. This means NanoMslide can be moved from small-scale to medium-scale manufacture, allowing us to explore a number of different applications, and produce the numbers of slides required for further clinical validation. The technology could also be hugely beneficial to the growing digital-pathology space, where the vivid colors generated by NanoMslide could help develop next-generation artificial intelligence algorithms to identify signs of disease. <|im_end|>

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2,477

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Development and evaluation of new insect pest management tools is critical for overcoming over-reliance upon, and growing resistance to, synthetic, biological and plant-expressed insecticides. For transgenic crops expressing insecticidal proteins from the bacterium Bacillus thuringiensis (‘ Bt crops’) emergence of resistance is slowed by maintaining a proportion of the crop as non- Bt varieties, which produce pest insects unselected for resistance. While this strategy has been largely successful, multiple cases of Bt resistance have now been reported. One new approach to pest management is the use of genetically engineered insects to suppress populations of their own species. Models suggest that released insects carrying male-selecting (MS) transgenes would be effective agents of direct, species-specific pest management by preventing survival of female progeny, and simultaneously provide an alternative insecticide resistance management strategy by introgression of susceptibility alleles into target populations. We developed a MS strain of the diamondback moth, Plutella xylostella , a serious global pest of crucifers. MS-strain larvae are reared as normal with dietary tetracycline, but, when reared without tetracycline or on host plants, only males will survive to adulthood. We used this strain in glasshouse-cages to study the effect of MS male P. xylostella releases on target pest population size and spread of Bt resistance in these populations. Results Introductions of MS-engineered P. xylostella males into wild-type populations led to rapid pest population decline, and then elimination. In separate experiments on broccoli plants, relatively low-level releases of MS males in combination with broccoli expressing Cry1Ac ( Bt broccoli) suppressed population growth and delayed the spread of Bt resistance. Higher rates of MS male releases in the absence of Bt broccoli were also able to suppress P. xylostella populations, whereas either low-level MS male releases or Bt broccoli alone did not. Conclusions These results support theoretical modeling, indicating that MS-engineered insects can provide a powerful pest population suppressing effect, and could effectively augment current Bt resistance management strategies. We conclude that, subject to field confirmation, MS insects offer an effective and versatile control option against P. xylostella and potentially other pests, and may reduce reliance on and protect insecticide-based approaches, including Bt crops. Background Pest insects are a major threat to global food production, biodiversity conservation, and human and animal health [ 1 – 3 ]. Synthetic insecticides are widely used for control; however, potential off-target ecological damage, and the capacity of pest populations to develop resistance, has driven demand for alternative methods of pest control. Integrated pest management (IPM) approaches have been developed, utilizing multiple tools including biological insecticides (applied and expressed in transgenic crops), enhanced biological control, mating disruption, and the release of sterile insects (the sterile insect technique, SIT) to sustainably manage insect pest populations. The SIT reduces target pest populations through sustained mass-releases of radiation-sterilized insects, thus reducing the frequency of mating between fertile insects [ 4 ]. SIT relies on the mate-seeking and mating behavior of released insects, and is therefore species-specific and can be effective against pests that are difficult to control by other methods. SIT has been successful in area-wide eradication and suppression programs against numerous crop pests [ 5 ]. Wider applicability of SIT is hindered by several challenges, including the negative effects on insect performance of sterilization by irradiation [ 6 – 10 ] and difficulty in conducting large-scale sex-sorting for male-only releases [ 11 – 13 ]. We have previously developed a male-selecting (MS) transgenic system to overcome these obstacles [ 14 , 15 ]. In this system, pest colonies are engineered with tetracycline-repressible dominant female-specific lethal transgenes. Provision of tetracycline (or suitable analogues) to larval stages suppresses transgene lethality allowing mass rearing. Once released, mating between transgenic and wild insects results in mortality of female progeny (female-specific lethality) due to the absence of suitable quantities of tetracycline in the field, thereby reducing the reproductive potential of the target population [ 15 – 20 ]. Through targeting female progeny but allowing male transgene heterozygotes to survive to reproduce, the MS system is predicted to be significantly more efficient at suppressing populations than those which target both sexes (such as SIT) [ 19 ]. Additionally, this system avoids the negative impacts of irradiation on released insect competitiveness [ 21 ] and enables large-scale (off tetracycline) production of single-sex (male) release cohorts. Male-only releases can significantly improve per-male efficiency [ 22 , 23 ] by concentrating the reproductive effort of released insects on wild females. For the Mediterranean fruit fly (medfly, Ceratitis capitata ), SIT programs have, in tandem with sterilization by radiation, relied on translocation-based sex-sorting systems in which a dominant marker is translocated to the Y chromosome [ 24 ]. However, these traits are difficult to translate to new pest species, are unstable, and compromise insect productivity in mass rearing [ 25 , 26 ]. The release of male insects carrying MS transgenes (“MS males”) has been shown to be effective in suppressing target pest populations in cage experiments against the mosquito Aedes aegypti , C. capitata , and the olive fly ( Bactrocera oleae ) [ 18 , 20 , 27 ]. However, the pest suppression potential of such a transgenic system has not yet been investigated in lepidopterans, which include many of the most destructive pests of forestry and agriculture worldwide [ 28 ]. Beyond this direct population-reducing effect, modeling suggests that releases of MS males into a target population may simultaneously provide an insecticide resistance management benefit. Mating between released males and wild females results in the survival of male transgene heterozygotes and the introgression of their background genetics into the wild pest population [ 29 , 30 ]. With an insecticide-susceptible genetic background in released insects, this introgression will increase the frequency of susceptibility alleles within the target pest population. This proposed mechanism of resistance management is analogous to that currently utilized in transgenic crops engineered to express insecticidal Cry toxin proteins from the bacterium Bacillus thuringiensis . A major advantage of these ‘ Bt crops’ is their low environmental impact, with the effects", "role": "user" }, { "content": "(Phys.org)—A team of researchers at British company Oxitec has developed a genetic approach to controlling diamondback moth caterpillars and report that trials in greenhouse conditions has gone so well that they are ready to conduct tests in the wild. In their paper published in the journal BMC Biology, the team describes their technique, how it works, how safe they believe it is and their hopes that their efforts will lead to reduced crop destruction by the caterpillars Diamondback moth caterpillars are one of the world's worst insect pests—they eat holes in the leaves of kale, cabbage, canola, broccoli and cauliflower, killing the plants and causing billions in dollars of losses for farmers around the world each year. Efforts to curb them have been mixed and the caterpillars appear to be winning—they have developed immunity to most chemicals applied to kill them. For that reason scientists have looked to other ways to tackle the problem, one of which is genetic modification. The team at Oxitec, has come up with a way to cause female offspring of the moths that parent the caterpillars to die before they can reproduce, slowly causing a drop in population when they are released into a native group. In coming up with their self-limiting gene approach the team added another piece of usefulness—an off switch. The gene only self-limits in the absence of tetracycline, such as when the moth is out in the wild. To grow a community of the moths, the team need only feed them food with the chemical added. They note that their technique allows for targeting just diamondback moths, thus other insects would not be harmed—and neither would birds or other animals if they eat the moths or caterpillars. The team at Oxitec report that greenhouse environment testing has gone very well—so well in fact they are ready to test their technique in the wild—in limited releases, of course. Officials with the Department of Agriculture in the U.S. have given the go ahead for new outdoor trials in New York State. This would not be the first testing of its kind, similar genetic engineering on mosquitoes has been tested in Panama, the Cayman Islands and Brazil—in such trials insect populations have been reduced by 90 percent. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Development and evaluation of new insect pest management tools is critical for overcoming over-reliance upon, and growing resistance to, synthetic, biological and plant-expressed insecticides. For transgenic crops expressing insecticidal proteins from the bacterium Bacillus thuringiensis (‘ Bt crops’) emergence of resistance is slowed by maintaining a proportion of the crop as non- Bt varieties, which produce pest insects unselected for resistance. While this strategy has been largely successful, multiple cases of Bt resistance have now been reported. One new approach to pest management is the use of genetically engineered insects to suppress populations of their own species. Models suggest that released insects carrying male-selecting (MS) transgenes would be effective agents of direct, species-specific pest management by preventing survival of female progeny, and simultaneously provide an alternative insecticide resistance management strategy by introgression of susceptibility alleles into target populations. We developed a MS strain of the diamondback moth, Plutella xylostella , a serious global pest of crucifers. MS-strain larvae are reared as normal with dietary tetracycline, but, when reared without tetracycline or on host plants, only males will survive to adulthood. We used this strain in glasshouse-cages to study the effect of MS male P. xylostella releases on target pest population size and spread of Bt resistance in these populations. Results Introductions of MS-engineered P. xylostella males into wild-type populations led to rapid pest population decline, and then elimination. In separate experiments on broccoli plants, relatively low-level releases of MS males in combination with broccoli expressing Cry1Ac ( Bt broccoli) suppressed population growth and delayed the spread of Bt resistance. Higher rates of MS male releases in the absence of Bt broccoli were also able to suppress P. xylostella populations, whereas either low-level MS male releases or Bt broccoli alone did not. Conclusions These results support theoretical modeling, indicating that MS-engineered insects can provide a powerful pest population suppressing effect, and could effectively augment current Bt resistance management strategies. We conclude that, subject to field confirmation, MS insects offer an effective and versatile control option against P. xylostella and potentially other pests, and may reduce reliance on and protect insecticide-based approaches, including Bt crops. Background Pest insects are a major threat to global food production, biodiversity conservation, and human and animal health [ 1 – 3 ]. Synthetic insecticides are widely used for control; however, potential off-target ecological damage, and the capacity of pest populations to develop resistance, has driven demand for alternative methods of pest control. Integrated pest management (IPM) approaches have been developed, utilizing multiple tools including biological insecticides (applied and expressed in transgenic crops), enhanced biological control, mating disruption, and the release of sterile insects (the sterile insect technique, SIT) to sustainably manage insect pest populations. The SIT reduces target pest populations through sustained mass-releases of radiation-sterilized insects, thus reducing the frequency of mating between fertile insects [ 4 ]. SIT relies on the mate-seeking and mating behavior of released insects, and is therefore species-specific and can be effective against pests that are difficult to control by other methods. SIT has been successful in area-wide eradication and suppression programs against numerous crop pests [ 5 ]. Wider applicability of SIT is hindered by several challenges, including the negative effects on insect performance of sterilization by irradiation [ 6 – 10 ] and difficulty in conducting large-scale sex-sorting for male-only releases [ 11 – 13 ]. We have previously developed a male-selecting (MS) transgenic system to overcome these obstacles [ 14 , 15 ]. In this system, pest colonies are engineered with tetracycline-repressible dominant female-specific lethal transgenes. Provision of tetracycline (or suitable analogues) to larval stages suppresses transgene lethality allowing mass rearing. Once released, mating between transgenic and wild insects results in mortality of female progeny (female-specific lethality) due to the absence of suitable quantities of tetracycline in the field, thereby reducing the reproductive potential of the target population [ 15 – 20 ]. Through targeting female progeny but allowing male transgene heterozygotes to survive to reproduce, the MS system is predicted to be significantly more efficient at suppressing populations than those which target both sexes (such as SIT) [ 19 ]. Additionally, this system avoids the negative impacts of irradiation on released insect competitiveness [ 21 ] and enables large-scale (off tetracycline) production of single-sex (male) release cohorts. Male-only releases can significantly improve per-male efficiency [ 22 , 23 ] by concentrating the reproductive effort of released insects on wild females. For the Mediterranean fruit fly (medfly, Ceratitis capitata ), SIT programs have, in tandem with sterilization by radiation, relied on translocation-based sex-sorting systems in which a dominant marker is translocated to the Y chromosome [ 24 ]. However, these traits are difficult to translate to new pest species, are unstable, and compromise insect productivity in mass rearing [ 25 , 26 ]. The release of male insects carrying MS transgenes (“MS males”) has been shown to be effective in suppressing target pest populations in cage experiments against the mosquito Aedes aegypti , C. capitata , and the olive fly ( Bactrocera oleae ) [ 18 , 20 , 27 ]. However, the pest suppression potential of such a transgenic system has not yet been investigated in lepidopterans, which include many of the most destructive pests of forestry and agriculture worldwide [ 28 ]. Beyond this direct population-reducing effect, modeling suggests that releases of MS males into a target population may simultaneously provide an insecticide resistance management benefit. Mating between released males and wild females results in the survival of male transgene heterozygotes and the introgression of their background genetics into the wild pest population [ 29 , 30 ]. With an insecticide-susceptible genetic background in released insects, this introgression will increase the frequency of susceptibility alleles within the target pest population. This proposed mechanism of resistance management is analogous to that currently utilized in transgenic crops engineered to express insecticidal Cry toxin proteins from the bacterium Bacillus thuringiensis . A major advantage of these ‘ Bt crops’ is their low environmental impact, with the effects<|im_end|> <|im_start|>assistant (Phys.org)—A team of researchers at British company Oxitec has developed a genetic approach to controlling diamondback moth caterpillars and report that trials in greenhouse conditions has gone so well that they are ready to conduct tests in the wild. In their paper published in the journal BMC Biology, the team describes their technique, how it works, how safe they believe it is and their hopes that their efforts will lead to reduced crop destruction by the caterpillars Diamondback moth caterpillars are one of the world's worst insect pests—they eat holes in the leaves of kale, cabbage, canola, broccoli and cauliflower, killing the plants and causing billions in dollars of losses for farmers around the world each year. Efforts to curb them have been mixed and the caterpillars appear to be winning—they have developed immunity to most chemicals applied to kill them. For that reason scientists have looked to other ways to tackle the problem, one of which is genetic modification. The team at Oxitec, has come up with a way to cause female offspring of the moths that parent the caterpillars to die before they can reproduce, slowly causing a drop in population when they are released into a native group. In coming up with their self-limiting gene approach the team added another piece of usefulness—an off switch. The gene only self-limits in the absence of tetracycline, such as when the moth is out in the wild. To grow a community of the moths, the team need only feed them food with the chemical added. They note that their technique allows for targeting just diamondback moths, thus other insects would not be harmed—and neither would birds or other animals if they eat the moths or caterpillars. The team at Oxitec report that greenhouse environment testing has gone very well—so well in fact they are ready to test their technique in the wild—in limited releases, of course. Officials with the Department of Agriculture in the U.S. have given the go ahead for new outdoor trials in New York State. This would not be the first testing of its kind, similar genetic engineering on mosquitoes has been tested in Panama, the Cayman Islands and Brazil—in such trials insect populations have been reduced by 90 percent. <|im_end|>

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1,820

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mitochondrial DNA (mtDNA) often exists in a state of heteroplasmy, in which mutant mtDNA co-exists in cells with wild-type mtDNA. High frequencies of pathogenic mtDNA result in maternally inherited diseases; maternally and somatically acquired mutations also accumulate over time and contribute to diseases of ageing. Reducing heteroplasmy is therefore a therapeutic goal and i n vivo models in post-mitotic tissues are needed to facilitate these studies. Here we describe a transgene-based model of a heteroplasmic lethal mtDNA deletion (mtDNA Δ ) in adult Drosophila muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway or decreased levels of mitofusin result in a selective decrease in mtDNA Δ . Decreased levels of mitofusin and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNA Δ levels. These results show that an adult post-mitotic tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved. Introduction Mitochondria are membrane-bound organelles present in many copies in most eukaryotic cells. The circular mitochondrial genome (mtDNA) encodes multiple tRNAs, rRNAs and polypeptides necessary for oxidative phosphorylation, which generates the bulk of ATP in most cells. Individual mitochondria contain multiple copies of mtDNA, each of which is packaged into a structure known as a nucleoid, with primarily a single mtDNA per nucleoid 1 . This multiplicity of genomes per cell, in conjunction with mtDNA’s high mutation rate and limited repair capacity, often results in cells carrying mtDNA of different genotypes, a condition known as heteroplasmy. Recent studies suggest that 90% of individuals have some level of heteroplasmy, with 20% harbouring heteroplasmies that are implicated in disease 2 , 3 . If the frequency of such a mutation reaches a threshold, pathology results 4 , 5 . High frequencies of deleterious mutant mtDNA result in severe maternally inherited syndromes 4 , 5 , 6 , 7 . Heteroplasmy for deleterious mtDNA can also arise in somatic tissues during development and in adulthood. It accumulates throughout life, and is thought to contribute to diseases of aging that include neurodegeneration, metabolic disorders, cancer, heart disease and sarcopenia 8 , 9 . These observations emphasize the importance of devising ways to reduce heteroplasmy in vivo . Mitochondria-targeted site-specific nucleases, such as restriction enzymes 10 , 11 , engineered zinc-finger nucleases 12 , 13 and transcription activator-like effector nucleases 14 , 15 , provide one way to decrease the levels of heteroplasmy. In this approach, a site-specific nuclease is engineered so as to bind and cleave a specific mutant version of the mtDNA genome, promoting its selective degradation. This approach has recently been used to decrease the levels of heteroplasmy in patient-derived cell lines 14 , in oocytes and in single cell embryos 15 . However, these methods are likely to be challenging to implement in the adult 11 , as the nuclease being expressed is a non-self protein; many cells must be targeted without off target cleavage effects; and individuals may be heteroplasmic for multiple deleterious mutations. Here we seek to promote cell biological processes that normally regulate mtDNA quality as an alternative approach to decreasing heteroplasmy in adults. Mitophagy serves as a form of quality control that promotes the selective removal of damaged mitochondria. In one important pathway, dysfunctional mitochondria are eliminated through a process dependent on PTEN-induced putative kinase 1 (PINK1) and Parkin, loss of which lead to familial forms of Parkinson’s disease. In this pathway, mitochondrial membrane depolarization, which occurs in response to mitochondrial dysfunction of various sorts, results in stabilization of the kinase PINK1 on the outer mitochondrial membrane 16 . PINK1 recruits multiple autophagy adaptors 17 and the cytoplasmic E3 ubiquitin ligase Parkin 18 , 19 , which ubiquitinates and promotes the degradation of Mitofusins 19 , 20 , 21 , mitochondrial outer membrane proteins essential for outer mitochondrial membrane fusion 22 , thereby inhibiting re-fusion of dysfunctional mitochondria with the network. Parkin also ubiquitinates a number of other proteins 23 , 24 . These events lead to the recruitment of autophagosomal membranes, which sequester the defective mitochondria and deliver it to the lysosome for degradation. An important question is whether mitophagy, which acts at the level of individual mitochondria, contributes to quality control at the level of mtDNA—the selective removal of mutant mtDNA within the cell as a whole. Several observations suggest that PINK1/parkin -dependent mitophagy may participate in such a process. First, the frequency of a deleterious allele in a heteroplasmic mammalian cell line can be reduced if cells are cultured for long periods of time in the presence of Parkin 25 , decreased membrane potential 25 , 26 and/or stimulation of autophagy 26 , 27 . These results are intriguing, but because the experiments occur over many cell cycles, stochastic segregation of mitochondrial genomes during division, coupled with increased survival and/or proliferation of cells with an increased fraction of wild-type mtDNA, may contribute to the decreased mutant mtDNA load. Second, in lines of Caenorhabditis elegans heteroplasmic for an mtDNA deletion mutant, loss of Parkin (but not PINK1) results in increased levels of heteroplasmy 28 . These results also support a role for Parkin in mtDNA quality control, but they leave the nature of the selection event unclear, and whether it occurs during germline transmission and/or in somatic cells, during development and/or in the adulthood. Finally, dopaminergic neurons from mice expressing a proofreading-deficient mtDNA polymerase and wild type for parkin , have a spectrum of mtDNA mutations that includes fewer predicted pathogenic variants than are observed in neurons from proofreading-defective mice that lack Parkin 29 . This also is consistent with models in which Parkin promotes the elimination of some mtDNA genotypes. However, whether these events occur during development or during adulthood, and the nature of the selection event is unknown and difficult to study in a system in which mtDNA mutations are induced through random DNA polymerase errors throughout life. Regardless, the fact that mutant mtDNA accumulates in individuals wild type for PINK1 and parkin during", "role": "user" }, { "content": "Researchers from Caltech and UCLA have developed a new approach to removing cellular damage that accumulates with age. The technique can potentially help slow or reverse an important cause of aging. Led by Nikolay Kandul, senior postdoctoral scholar in biology and biological engineering in the laboratory of Professor of Biology Bruce Hay, the team developed a technique to remove mutated DNA from mitochondria, the small organelles that produce most of the chemical energy within a cell. A paper describing the research appears in the November 14 issue of Nature Communications. There are hundreds to thousands of mitochondria per cell, each of which carries its own small circular DNA genome, called mtDNA, the products of which are required for energy production. Because mtDNA has limited repair abilities, normal and mutant versions of mtDNA are often found in the same cell, a condition known as heteroplasmy. Most people start off life with some level of heteroplasmy, and the levels of mutant mtDNA increase throughout life. When a critical threshold level of mutant mtDNA is passed, cells become nonfunctional or die. The accumulation of mutant mtDNA over a lifetime is thought to contribute to aging and degenerative diseases of aging such as Alzheimer's, Parkinson's, and sarcopenia—age-related muscle loss and frailty. Inherited defects in mtDNA are also linked to a number of conditions found in children, including autism. \"We know that increased rates of mtDNA mutation cause premature aging,\" says Hay, Caltech professor of biology and biological engineering. \"This, coupled with the fact that mutant mtDNA accumulates in key tissues such as neurons and muscle that lose function as we age, suggests that if we could reduce the amount of mutant mtDNA, we could slow or reverse important aspects of aging.\" The team—in collaboration with Ming Guo, the P. Gene and Elaine Smith Chair in Alzheimer's Disease Research and professor of neurology and pharmacology at UCLA, and UCLA graduate student Ting Zhang—genetically engineered Drosophila, the common fruit fly, so that about 75 percent of the mtDNA in muscles required for flight, one of the most energy demanding tissues in the animal kingdom, underwent mutation in early adulthood. This model recapitulates aging in young animals. Drosophila grow quickly and most human disease genes have counterparts in the fly, making it an important model in which to study human disease-related processes. The researchers chose to focus on muscle because this tissue undergoes age-dependent decline in all animals, including humans, and it is easy to see the consequences of loss of function. Unlike mutations in the DNA in the nucleus, which can be corrected through cellular repair mechanisms, mutations in mtDNA are often not repaired. However, cells can break down and remove dysfunctional mitochondria through a process called mitophagy, a form of cellular quality control. What was unclear prior to this work was whether this process could also promote the selective elimination of mutant mtDNA. The team found that when they artificially increased the activity of genes that promote mitophagy, including that of several genes implicated in familial forms of Parkinson's disease, the fraction of mutated mtDNA in the fly muscle cells was dramatically reduced. For example, overexpressing the gene parkin, which is known to specifically promote the removal of dysfunctional mitochondria and is mutated in familial forms of Parkinson's disease, reduced the fraction of mutant mtDNA from 76 percent to 5 percent, while the overexpression of the gene Atg1 reduced the fraction to 4 percent. \"Such a decrease would completely eliminate any metabolic defects in these cells, essentially restoring them to a more youthful, energy-producing state,\" notes Hay. \"The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes.\" \"Now that we know mtDNA quality control exists and can be enhanced, our goal is to work with Dr. Guo's lab to search for drugs that can achieve the same effects,\" Hay adds. \"Our goal is to create a future in which we can periodically undergo a cellular housecleaning to remove damaged mtDNA from the brain, muscle, and other tissues. This will help us maintain our intellectual abilities, mobility, and support healthy aging more generally.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mitochondrial DNA (mtDNA) often exists in a state of heteroplasmy, in which mutant mtDNA co-exists in cells with wild-type mtDNA. High frequencies of pathogenic mtDNA result in maternally inherited diseases; maternally and somatically acquired mutations also accumulate over time and contribute to diseases of ageing. Reducing heteroplasmy is therefore a therapeutic goal and i n vivo models in post-mitotic tissues are needed to facilitate these studies. Here we describe a transgene-based model of a heteroplasmic lethal mtDNA deletion (mtDNA Δ ) in adult Drosophila muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway or decreased levels of mitofusin result in a selective decrease in mtDNA Δ . Decreased levels of mitofusin and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNA Δ levels. These results show that an adult post-mitotic tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved. Introduction Mitochondria are membrane-bound organelles present in many copies in most eukaryotic cells. The circular mitochondrial genome (mtDNA) encodes multiple tRNAs, rRNAs and polypeptides necessary for oxidative phosphorylation, which generates the bulk of ATP in most cells. Individual mitochondria contain multiple copies of mtDNA, each of which is packaged into a structure known as a nucleoid, with primarily a single mtDNA per nucleoid 1 . This multiplicity of genomes per cell, in conjunction with mtDNA’s high mutation rate and limited repair capacity, often results in cells carrying mtDNA of different genotypes, a condition known as heteroplasmy. Recent studies suggest that 90% of individuals have some level of heteroplasmy, with 20% harbouring heteroplasmies that are implicated in disease 2 , 3 . If the frequency of such a mutation reaches a threshold, pathology results 4 , 5 . High frequencies of deleterious mutant mtDNA result in severe maternally inherited syndromes 4 , 5 , 6 , 7 . Heteroplasmy for deleterious mtDNA can also arise in somatic tissues during development and in adulthood. It accumulates throughout life, and is thought to contribute to diseases of aging that include neurodegeneration, metabolic disorders, cancer, heart disease and sarcopenia 8 , 9 . These observations emphasize the importance of devising ways to reduce heteroplasmy in vivo . Mitochondria-targeted site-specific nucleases, such as restriction enzymes 10 , 11 , engineered zinc-finger nucleases 12 , 13 and transcription activator-like effector nucleases 14 , 15 , provide one way to decrease the levels of heteroplasmy. In this approach, a site-specific nuclease is engineered so as to bind and cleave a specific mutant version of the mtDNA genome, promoting its selective degradation. This approach has recently been used to decrease the levels of heteroplasmy in patient-derived cell lines 14 , in oocytes and in single cell embryos 15 . However, these methods are likely to be challenging to implement in the adult 11 , as the nuclease being expressed is a non-self protein; many cells must be targeted without off target cleavage effects; and individuals may be heteroplasmic for multiple deleterious mutations. Here we seek to promote cell biological processes that normally regulate mtDNA quality as an alternative approach to decreasing heteroplasmy in adults. Mitophagy serves as a form of quality control that promotes the selective removal of damaged mitochondria. In one important pathway, dysfunctional mitochondria are eliminated through a process dependent on PTEN-induced putative kinase 1 (PINK1) and Parkin, loss of which lead to familial forms of Parkinson’s disease. In this pathway, mitochondrial membrane depolarization, which occurs in response to mitochondrial dysfunction of various sorts, results in stabilization of the kinase PINK1 on the outer mitochondrial membrane 16 . PINK1 recruits multiple autophagy adaptors 17 and the cytoplasmic E3 ubiquitin ligase Parkin 18 , 19 , which ubiquitinates and promotes the degradation of Mitofusins 19 , 20 , 21 , mitochondrial outer membrane proteins essential for outer mitochondrial membrane fusion 22 , thereby inhibiting re-fusion of dysfunctional mitochondria with the network. Parkin also ubiquitinates a number of other proteins 23 , 24 . These events lead to the recruitment of autophagosomal membranes, which sequester the defective mitochondria and deliver it to the lysosome for degradation. An important question is whether mitophagy, which acts at the level of individual mitochondria, contributes to quality control at the level of mtDNA—the selective removal of mutant mtDNA within the cell as a whole. Several observations suggest that PINK1/parkin -dependent mitophagy may participate in such a process. First, the frequency of a deleterious allele in a heteroplasmic mammalian cell line can be reduced if cells are cultured for long periods of time in the presence of Parkin 25 , decreased membrane potential 25 , 26 and/or stimulation of autophagy 26 , 27 . These results are intriguing, but because the experiments occur over many cell cycles, stochastic segregation of mitochondrial genomes during division, coupled with increased survival and/or proliferation of cells with an increased fraction of wild-type mtDNA, may contribute to the decreased mutant mtDNA load. Second, in lines of Caenorhabditis elegans heteroplasmic for an mtDNA deletion mutant, loss of Parkin (but not PINK1) results in increased levels of heteroplasmy 28 . These results also support a role for Parkin in mtDNA quality control, but they leave the nature of the selection event unclear, and whether it occurs during germline transmission and/or in somatic cells, during development and/or in the adulthood. Finally, dopaminergic neurons from mice expressing a proofreading-deficient mtDNA polymerase and wild type for parkin , have a spectrum of mtDNA mutations that includes fewer predicted pathogenic variants than are observed in neurons from proofreading-defective mice that lack Parkin 29 . This also is consistent with models in which Parkin promotes the elimination of some mtDNA genotypes. However, whether these events occur during development or during adulthood, and the nature of the selection event is unknown and difficult to study in a system in which mtDNA mutations are induced through random DNA polymerase errors throughout life. Regardless, the fact that mutant mtDNA accumulates in individuals wild type for PINK1 and parkin during<|im_end|> <|im_start|>assistant Researchers from Caltech and UCLA have developed a new approach to removing cellular damage that accumulates with age. The technique can potentially help slow or reverse an important cause of aging. Led by Nikolay Kandul, senior postdoctoral scholar in biology and biological engineering in the laboratory of Professor of Biology Bruce Hay, the team developed a technique to remove mutated DNA from mitochondria, the small organelles that produce most of the chemical energy within a cell. A paper describing the research appears in the November 14 issue of Nature Communications. There are hundreds to thousands of mitochondria per cell, each of which carries its own small circular DNA genome, called mtDNA, the products of which are required for energy production. Because mtDNA has limited repair abilities, normal and mutant versions of mtDNA are often found in the same cell, a condition known as heteroplasmy. Most people start off life with some level of heteroplasmy, and the levels of mutant mtDNA increase throughout life. When a critical threshold level of mutant mtDNA is passed, cells become nonfunctional or die. The accumulation of mutant mtDNA over a lifetime is thought to contribute to aging and degenerative diseases of aging such as Alzheimer's, Parkinson's, and sarcopenia—age-related muscle loss and frailty. Inherited defects in mtDNA are also linked to a number of conditions found in children, including autism. "We know that increased rates of mtDNA mutation cause premature aging," says Hay, Caltech professor of biology and biological engineering. "This, coupled with the fact that mutant mtDNA accumulates in key tissues such as neurons and muscle that lose function as we age, suggests that if we could reduce the amount of mutant mtDNA, we could slow or reverse important aspects of aging." The team—in collaboration with Ming Guo, the P. Gene and Elaine Smith Chair in Alzheimer's Disease Research and professor of neurology and pharmacology at UCLA, and UCLA graduate student Ting Zhang—genetically engineered Drosophila, the common fruit fly, so that about 75 percent of the mtDNA in muscles required for flight, one of the most energy demanding tissues in the animal kingdom, underwent mutation in early adulthood. This model recapitulates aging in young animals. Drosophila grow quickly and most human disease genes have counterparts in the fly, making it an important model in which to study human disease-related processes. The researchers chose to focus on muscle because this tissue undergoes age-dependent decline in all animals, including humans, and it is easy to see the consequences of loss of function. Unlike mutations in the DNA in the nucleus, which can be corrected through cellular repair mechanisms, mutations in mtDNA are often not repaired. However, cells can break down and remove dysfunctional mitochondria through a process called mitophagy, a form of cellular quality control. What was unclear prior to this work was whether this process could also promote the selective elimination of mutant mtDNA. The team found that when they artificially increased the activity of genes that promote mitophagy, including that of several genes implicated in familial forms of Parkinson's disease, the fraction of mutated mtDNA in the fly muscle cells was dramatically reduced. For example, overexpressing the gene parkin, which is known to specifically promote the removal of dysfunctional mitochondria and is mutated in familial forms of Parkinson's disease, reduced the fraction of mutant mtDNA from 76 percent to 5 percent, while the overexpression of the gene Atg1 reduced the fraction to 4 percent. "Such a decrease would completely eliminate any metabolic defects in these cells, essentially restoring them to a more youthful, energy-producing state," notes Hay. "The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes." "Now that we know mtDNA quality control exists and can be enhanced, our goal is to work with Dr. Guo's lab to search for drugs that can achieve the same effects," Hay adds. "Our goal is to create a future in which we can periodically undergo a cellular housecleaning to remove damaged mtDNA from the brain, muscle, and other tissues. This will help us maintain our intellectual abilities, mobility, and support healthy aging more generally." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype–phenotype associations and guide medical therapy in individuals with vascular anomalies. Main Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development 1 , 2 , 3 . Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes is essential to provide efficacious therapy 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ; however, genetic profiling is often limited by difficulty in obtaining affected tissues and limited sequencing depth. The lack of this information limits options and the precision of targeted therapy, especially for pCLAs, which describe four separate but overlapping disorders of lymphatic malformations. Generalized lymphatic anomaly (GLA) is characterized by lymphatic malformations in bones and organs. Kaposiform lymphangiomatosis (KLA) is a subtype of GLA in which histology of the lesion may demonstrate spindle-shaped lymphatic endothelial cells. In Gorham–Stout disease (GSD), also known as vanishing bone disease, the lymphatic malformations lead to erosion of the cortical bone, and over time, the bone ‘vanishes’ on X-ray imaging. Central conducting lymphatic anomaly (CCLA) involves malformations of the central collecting lymphatic vessels. Together, these disorders may present with chylous effusions or ascites, bone fractures, pain and various other symptoms. Clinical diagnosis is established by medical history, physical examination, imaging studies and histology. To address these limitations, we established new techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA (cfDNA), deep coverage exome sequencing, and ultra-deep targeted sequencing using unique molecular identifiers (UMIs), in the molecular profiling of these diseases. We report results from the analysis of 356 participants with complex vascular anomalies. Appropriate determination of the causative pathogenic variants can identify previously unrecognized genotype-phenotype associations and guide medical management to improve therapeutic precision in these complex medical conditions. Results Study cohort and participant demographics Based on the International Society for the Study of Vascular Anomalies (ISSVA) classification for vascular anomalies, the cohort included three major disease categories: vascular malformations ( n = 326), vascular tumors ( n = 17) and unclassified vascular anomalies ( n = 13). The study cases with vascular malformations were further divided into capillary malformation (including nonsyndromic capillary malformation, (diffuse) capillary malformation with overgrowth, reticulate capillary malformation, cutis marmorata telangiectatica congenita (CMTC), hereditary hemorrhagic telangiectasia (HHT) and capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM); n = 11; Fig. 1c ), common lymphatic malformations ( n = 36; Fig. 1c ), GLA ( n = 16; Fig. 1c ), KLA ( n = 15; Fig. 1c ), GSD ( n = 4; Fig. 1c ), CCLA ( n = 54; Fig. 1c ), CCLA with lymphatic malformation ( n = 3; Fig. 1c ), primary lymphedema ( n = 6; Fig. 1c ), CCLA with primary lymphedema ( n = 12; Fig. 1c ), other lymphatic conduction disorders (including plastic bronchitis, and protein-losing enteropathy resulting from elevated central venous pressure and/or elevated lymphatic production and inflammation secondary to congenital heart defect or Fontan procedure; n = 88; Fig. 1c ), venous malformations (including common venous malformations, glomuvenous malformation (GVM), and blue rubber bleb nevus syndrome (BRBNS); n = 48; Fig. 1c ), sporadic arteriovenous malformation (AVM, n = 12; Fig. 1c ), combined vascular malformations ( n = 5; Fig. 1c ) and overgrowth syndromes associated with vascular malformation (including Klippel-Trenaunay syndrome (KTS), Parkes Weber syndrome, megalencephaly-capillary malformation syndrome (MCAP), congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES) and generally PROS; n = 16; Fig. 1c ). Unclassified vascular anomalies included angiokeratoma, PTEN hamartoma syndrome, fibroadipose vascular anomaly (FAVA) or multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT), as well as two cases without recognizable phenotype after expert panel review and discussion ( n = 13; Fig. 1c ). Vascular tumors included one each of infantile hemangioma, tufted angioma, angiosarcoma, spindle-cell hemangioma, Dabska tumor, angiofibroma, lipoblastoma, epithelioid hemangioendothelioma, benign vascular tumor ( BRAF ) and benign lipomatous tumor, three with congenital hemangioma and four with kaposiform hemangioendothelioma ( n = 17; Fig. 1c ). Fig. 1: Clinical overview. a , b , Age and sex of participants. c , Number of samples per ISSVA diagnosis. d , Example images of different participants that show microcystic lymphatic malformation, venous malformation and KTS (top panel, left to right); and syn-macrodactyly in a participant with CLOVES, GVM, and AVM (bottom panel, left to right). e , MR image of a participant with MAP2K1 -CCLA (CLA135). Maximum intensity projection (MIP) after inguinal lymph node injection showing dilated and irregular thoracic duct (arrowheads), mediastinal lymphatic perfusion (short arrow) and retrograde flow in the liver and intestinal lymphatics (thick arrows). f , MR image of a participant with BRAF- GLA (CVA119). MIP from inguinal lymph node injection showing opacification of abdominal lymphatic malformation (short arrows), perfusion of cervical lymphatic", "role": "user" }, { "content": "Researchers from Children's Hospital of Philadelphia (CHOP) recently discovered that extremely thorough \"deep sequencing\" of the genome in tissue samples and cell-free DNA of patients with potentially life-threatening vascular anomalies captured several genetic variants related to disease that were not captured with conventional genetic sequencing methods. More than 60% of patients saw an improvement in their condition after being placed on targeted therapies related to these newly found genetic variants. The findings were published June 1, 2023, in the journal Nature Medicine. Vascular anomalies describe a variety of conditions that affect the veins, arteries and lymphatic system that can be classified as either vascular tumors (benign or malignant) or vascular malformations. While certain vascular anomalies naturally resolve over time, others can cause visible deformities, impede critical organ functions such as swallowing or breathing, or cause severe pain. Some vascular anomalies can even be life-threatening. In a prior study also published in Nature Medicine, CHOP researchers were the first to discover a genetic variant that was responsible for a vascular anomaly affecting the lymphatic system, which allowed the clinical team to repurpose an existing drug to treat a patient that improved his breathing capacity and dramatically reduced swelling of his legs, side effects of his condition. The research team suspected that other patients affected by vascular anomalies might also have mutations driving diseases that would benefit from targeted therapies. However, a lack of access to affected tissue samples or insufficient genomic sequencing information meant that the gene variants responsible for these issues may not be captured by conventional genetic testing. \"While some patients have inherited variants that you can find in a blood sample, about 90% of patients with vascular anomalies have acquired somatic mutations, or mutations that are not inherited, which are usually present in very low frequencies and only in certain cell or tissue types,\" said senior study author Hakon Hakonarson, MD, Ph.D., director of the Center for Applied Genomics and co-principal investigator of the Comprehensive Vascular Anomalies Frontier Program at CHOP. \"In many cases, the disease-causing variant in the mutated gene of interest is present in frequencies of less than 1%, which makes them hard to detect with conventional sequencing approaches.\" To better capture the underlying genetics behind these more severe vascular anomalies, researchers studied DNA from CD31+ cells or cell-free DNA isolated from lymphatic fluid or plasma from a cohort of 356 patients, including 104 with primary complex lymphatic anomalies. The isolated DNA underwent deep sequencing, which involves repeatedly sequencing certain areas of interest in the genome several times, and uncovered several somatic variants that were identified for the first time. This deep sequencing achieved a variant allele frequency of 0.15%, meaning that deep sequencing could detect variants that had a frequency as low as 0.15% in a particular specimen. By identifying these variants, the researchers and clinical team were able to provide a molecular diagnosis, including previously undescribed genetic causes, in 41% of patients with primary complex lymphatic anomalies and 72% of patients with vascular malformations. As a result, 69 patients received or planned to receive a new medical therapy, and 63% of patients experienced marked improvement in their symptoms. \"The ability to link a patient's phenotype to the causative genotype of the vascular anomaly has been critical for patients,\" said study author Denise Adams, MD, a pediatric hematologist-oncologist and Director of the Comprehensive Vascular Anomalies Program at CHOP. \"This has enabled treatment with directed medical therapy that has significantly improved the quality of life of our patients. We are fortunate to work with a wonderful interdisciplinary team that has helped to move this forward for our patients.\" \"Importantly, our study comprehensively demonstrated the bedside to bench and back approach—from the molecular studies that found the low allele frequency variants to the functional studies in organoids and zebrafish that ultimately benefited the patients by directing medical therapy,\" said study co-leader Sarah Sheppard, MD, Ph.D., a tenure track investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development and clinical geneticist for the Comprehensive Vascular Anomalies Program at CHOP. \"Our findings pave the way for future applications of cfDNA technology to be an innovative, non-invasive molecular diagnostic for all patients with vascular anomalies,\" said study co-leader Dong Li, Ph.D., an assistant professor within the Center for Applied Genomics at CHOP. \"We believe the time is right to transform the understanding of these complex diseases and identify and test new therapies for these life-threatening and life-altering conditions.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype–phenotype associations and guide medical therapy in individuals with vascular anomalies. Main Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development 1 , 2 , 3 . Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes is essential to provide efficacious therapy 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ; however, genetic profiling is often limited by difficulty in obtaining affected tissues and limited sequencing depth. The lack of this information limits options and the precision of targeted therapy, especially for pCLAs, which describe four separate but overlapping disorders of lymphatic malformations. Generalized lymphatic anomaly (GLA) is characterized by lymphatic malformations in bones and organs. Kaposiform lymphangiomatosis (KLA) is a subtype of GLA in which histology of the lesion may demonstrate spindle-shaped lymphatic endothelial cells. In Gorham–Stout disease (GSD), also known as vanishing bone disease, the lymphatic malformations lead to erosion of the cortical bone, and over time, the bone ‘vanishes’ on X-ray imaging. Central conducting lymphatic anomaly (CCLA) involves malformations of the central collecting lymphatic vessels. Together, these disorders may present with chylous effusions or ascites, bone fractures, pain and various other symptoms. Clinical diagnosis is established by medical history, physical examination, imaging studies and histology. To address these limitations, we established new techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA (cfDNA), deep coverage exome sequencing, and ultra-deep targeted sequencing using unique molecular identifiers (UMIs), in the molecular profiling of these diseases. We report results from the analysis of 356 participants with complex vascular anomalies. Appropriate determination of the causative pathogenic variants can identify previously unrecognized genotype-phenotype associations and guide medical management to improve therapeutic precision in these complex medical conditions. Results Study cohort and participant demographics Based on the International Society for the Study of Vascular Anomalies (ISSVA) classification for vascular anomalies, the cohort included three major disease categories: vascular malformations ( n = 326), vascular tumors ( n = 17) and unclassified vascular anomalies ( n = 13). The study cases with vascular malformations were further divided into capillary malformation (including nonsyndromic capillary malformation, (diffuse) capillary malformation with overgrowth, reticulate capillary malformation, cutis marmorata telangiectatica congenita (CMTC), hereditary hemorrhagic telangiectasia (HHT) and capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM); n = 11; Fig. 1c ), common lymphatic malformations ( n = 36; Fig. 1c ), GLA ( n = 16; Fig. 1c ), KLA ( n = 15; Fig. 1c ), GSD ( n = 4; Fig. 1c ), CCLA ( n = 54; Fig. 1c ), CCLA with lymphatic malformation ( n = 3; Fig. 1c ), primary lymphedema ( n = 6; Fig. 1c ), CCLA with primary lymphedema ( n = 12; Fig. 1c ), other lymphatic conduction disorders (including plastic bronchitis, and protein-losing enteropathy resulting from elevated central venous pressure and/or elevated lymphatic production and inflammation secondary to congenital heart defect or Fontan procedure; n = 88; Fig. 1c ), venous malformations (including common venous malformations, glomuvenous malformation (GVM), and blue rubber bleb nevus syndrome (BRBNS); n = 48; Fig. 1c ), sporadic arteriovenous malformation (AVM, n = 12; Fig. 1c ), combined vascular malformations ( n = 5; Fig. 1c ) and overgrowth syndromes associated with vascular malformation (including Klippel-Trenaunay syndrome (KTS), Parkes Weber syndrome, megalencephaly-capillary malformation syndrome (MCAP), congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES) and generally PROS; n = 16; Fig. 1c ). Unclassified vascular anomalies included angiokeratoma, PTEN hamartoma syndrome, fibroadipose vascular anomaly (FAVA) or multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT), as well as two cases without recognizable phenotype after expert panel review and discussion ( n = 13; Fig. 1c ). Vascular tumors included one each of infantile hemangioma, tufted angioma, angiosarcoma, spindle-cell hemangioma, Dabska tumor, angiofibroma, lipoblastoma, epithelioid hemangioendothelioma, benign vascular tumor ( BRAF ) and benign lipomatous tumor, three with congenital hemangioma and four with kaposiform hemangioendothelioma ( n = 17; Fig. 1c ). Fig. 1: Clinical overview. a , b , Age and sex of participants. c , Number of samples per ISSVA diagnosis. d , Example images of different participants that show microcystic lymphatic malformation, venous malformation and KTS (top panel, left to right); and syn-macrodactyly in a participant with CLOVES, GVM, and AVM (bottom panel, left to right). e , MR image of a participant with MAP2K1 -CCLA (CLA135). Maximum intensity projection (MIP) after inguinal lymph node injection showing dilated and irregular thoracic duct (arrowheads), mediastinal lymphatic perfusion (short arrow) and retrograde flow in the liver and intestinal lymphatics (thick arrows). f , MR image of a participant with BRAF- GLA (CVA119). MIP from inguinal lymph node injection showing opacification of abdominal lymphatic malformation (short arrows), perfusion of cervical lymphatic<|im_end|> <|im_start|>assistant Researchers from Children's Hospital of Philadelphia (CHOP) recently discovered that extremely thorough "deep sequencing" of the genome in tissue samples and cell-free DNA of patients with potentially life-threatening vascular anomalies captured several genetic variants related to disease that were not captured with conventional genetic sequencing methods. More than 60% of patients saw an improvement in their condition after being placed on targeted therapies related to these newly found genetic variants. The findings were published June 1, 2023, in the journal Nature Medicine. Vascular anomalies describe a variety of conditions that affect the veins, arteries and lymphatic system that can be classified as either vascular tumors (benign or malignant) or vascular malformations. While certain vascular anomalies naturally resolve over time, others can cause visible deformities, impede critical organ functions such as swallowing or breathing, or cause severe pain. Some vascular anomalies can even be life-threatening. In a prior study also published in Nature Medicine, CHOP researchers were the first to discover a genetic variant that was responsible for a vascular anomaly affecting the lymphatic system, which allowed the clinical team to repurpose an existing drug to treat a patient that improved his breathing capacity and dramatically reduced swelling of his legs, side effects of his condition. The research team suspected that other patients affected by vascular anomalies might also have mutations driving diseases that would benefit from targeted therapies. However, a lack of access to affected tissue samples or insufficient genomic sequencing information meant that the gene variants responsible for these issues may not be captured by conventional genetic testing. "While some patients have inherited variants that you can find in a blood sample, about 90% of patients with vascular anomalies have acquired somatic mutations, or mutations that are not inherited, which are usually present in very low frequencies and only in certain cell or tissue types," said senior study author Hakon Hakonarson, MD, Ph.D., director of the Center for Applied Genomics and co-principal investigator of the Comprehensive Vascular Anomalies Frontier Program at CHOP. "In many cases, the disease-causing variant in the mutated gene of interest is present in frequencies of less than 1%, which makes them hard to detect with conventional sequencing approaches." To better capture the underlying genetics behind these more severe vascular anomalies, researchers studied DNA from CD31+ cells or cell-free DNA isolated from lymphatic fluid or plasma from a cohort of 356 patients, including 104 with primary complex lymphatic anomalies. The isolated DNA underwent deep sequencing, which involves repeatedly sequencing certain areas of interest in the genome several times, and uncovered several somatic variants that were identified for the first time. This deep sequencing achieved a variant allele frequency of 0.15%, meaning that deep sequencing could detect variants that had a frequency as low as 0.15% in a particular specimen. By identifying these variants, the researchers and clinical team were able to provide a molecular diagnosis, including previously undescribed genetic causes, in 41% of patients with primary complex lymphatic anomalies and 72% of patients with vascular malformations. As a result, 69 patients received or planned to receive a new medical therapy, and 63% of patients experienced marked improvement in their symptoms. "The ability to link a patient's phenotype to the causative genotype of the vascular anomaly has been critical for patients," said study author Denise Adams, MD, a pediatric hematologist-oncologist and Director of the Comprehensive Vascular Anomalies Program at CHOP. "This has enabled treatment with directed medical therapy that has significantly improved the quality of life of our patients. We are fortunate to work with a wonderful interdisciplinary team that has helped to move this forward for our patients." "Importantly, our study comprehensively demonstrated the bedside to bench and back approach—from the molecular studies that found the low allele frequency variants to the functional studies in organoids and zebrafish that ultimately benefited the patients by directing medical therapy," said study co-leader Sarah Sheppard, MD, Ph.D., a tenure track investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development and clinical geneticist for the Comprehensive Vascular Anomalies Program at CHOP. "Our findings pave the way for future applications of cfDNA technology to be an innovative, non-invasive molecular diagnostic for all patients with vascular anomalies," said study co-leader Dong Li, Ph.D., an assistant professor within the Center for Applied Genomics at CHOP. "We believe the time is right to transform the understanding of these complex diseases and identify and test new therapies for these life-threatening and life-altering conditions." <|im_end|>

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2,597

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex, which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala ( BLA PC) compared to those projecting to contralateral cortex ( CC PC). These ChCs in turn receive preferential input from local and contralateral CC PCs as opposed to BLA PCs and BLA neurons (the prelimbic cortex–BLA network). Accordingly, optogenetic activation of ChCs rapidly suppresses BLA PCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks. Main In many areas of the cerebral cortex, diverse and often intermingled subsets of PCs preferentially receive inputs from and project outputs to distinct brain areas, and thus are embedded in separate local circuits as well as global networks 1 . It is not well understood how specific physiological PC ensembles emerge from the underlying anatomic scaffold and contribute to different subnetworks and information processing streams. Diverse types of GABAergic interneurons appear to specialize in their inhibitory control of various aspects of cortical circuit operations, such as balancing excitation, modulating gain, tuning dynamics and generating oscillations 2 , 3 , 4 . However, the inhibitory mechanisms that regulate the dynamic segregation of functional PC ensembles and route information flow between brain networks remain elusive. ChCs (i.e., axo-axonic cells) are among the most distinctive interneuron types. ChCs selectively innervate PCs at their axon initial segment (AIS), the site of action potential initiation 5 . A single ChC innervates hundreds of PCs 6 , 7 , and multiple ChCs can converge onto the same PC 8 , 9 . The exquisite specificity of ChC innervation at the AIS has long been speculated to exert the ultimate inhibitory control over PC spiking and population output 10 , 11 . However, it remains unclear how ChCs are recruited and whether a ChC indiscriminately innervates PCs within its dense axonal arbor or selects a specific PC subset 9 . In fact, it is even controversial whether ChCs inhibit or excite PCs 12 , 13 , 14 . Thus the problem of how ChCs control PCs represents a prominent gap as well as a unique opportunity for understanding the cellular basis of cortical organization, which entails elucidating the connectivity pattern of ChCs to PC subsets within local circuits in the context of global brain networks. Rodent prelimbic cortex (PL) integrates inputs from the amygdala and other brain structures (for example, other cortical areas, ventral hippocampus, medial-dorsal thalamus) to gate fear expression via projections back to the amygdala 15 , 16 , 17 , 18 , 19 . The superficial layers of PL contain two subsets of PCs: one projects to the BLA ( BLA PC) and another projects to contralateral cortex ( CC PC) 15 , 20 . They form two separate subnetworks: the PL–BLA network, comprising reciprocally connected BLA PCs and BLA neurons, and the bilateral PL network, comprising CC PCs from the two hemispheres 20 . Here, by combining genetic labeling of ChCs and projection-based labeling of PC subsets, we demonstrate that a subset of layer 2 (L2) ChCs preferentially receives inputs from CC PCs yet selectively innervates BLA PCs. This highly directional ChC microcircuit module is distinct from the parvalbumin fast-spiking basket cell (PVBC) module, characterized by nonselective and extensive reciprocal connectivity with BLA PCs and CC PCs. Trans-synaptic rabies tracing combined with optogenetic tagging of long-range inputs further revealed that L2 ChCs are preferentially recruited by contralateral CC PCs, but not by BLA input. Notably, optogenetic activation of ChCs resulted in rapid inhibition of PC firing in freely moving mice. Together, these results reveal that the exquisite connectivity of ChCs not only mediates directional inhibitory control between local PC ensembles but may also shape communication hierarchy and route information flow between distinct PC-associated global networks. Results A subset of L2 ChCs selectively innervates BLA PCs over CC PCs in PL We combined genetic 21 and anatomic methods to reliably label ChCs, BLA PCs and CC PCs for physiological studies. Tamoxifen induction in pregnant Nkx2.1-CreER;Rosa26-loxpSTOPloxp-TdTomato ( Ai14 ) mice (where the Nkx2.1 promoter is from Nkx2 homeobox 1, gene symbol Nkx2-1 ) at embryonic day 17.5 (E17.5) resulted in specific labeling of a subset of L2 ChCs throughout the frontal cortex, characterized by their soma positions at the L1–L2 border, prominent dendritic arborization in L1 and dense axonal plexus in L2/3 ( Fig. 1a,b and Supplementary Fig. 1 ). It should be noted that L2 ChCs are also generated at earlier embryonic times 21 ; for simplicity, the E17.5-born subset of L2 ChCs are herein referred to as L2 ChCs. Single-cell reconstruction revealed that individual L2 ChCs elaborated on average 211 ± 28 'cartridges', vertical strings of boutons targeting the AIS of PCs ( Fig. 1b and Supplementary Fig. 2 ). We distinguished subpopulations of L2/3 PCs in PL according to their projection targets by injecting a different color of retrograde tracer cholera toxin subunit B (CTB) into each target region of the same mouse: the BLA (to label BLA PCs), contralateral cortex (to label CC PCs) and dorsomedial striatum (to label ST PCs) ( Fig. 1c ). Each PC population resided at characteristic laminar depths, with some overlap: L2 ChCs occupied a similar laminar depth as BLA PCs ( Fig. 1c,d and Supplementary Fig. 3a ). Notably, there was little convergence in projection targets between BLA PCs and CC PCs ( Fig. 1e ). Figure 1: L2 ChCs preferentially innervate BLA PCs over CC PCs in prelimbic cortex. ( a ) Distribution (left) and morphology (right) of L2 ChCs in PL of an adult Nkx2.1-CreER:Ai14 mouse tamoxifen-induced at E17.5.", "role": "user" }, { "content": "The brain's astonishing anatomical complexity has been appreciated for over 100 years, when pioneers first trained microscopes on the profusion of branching structures that connect individual neurons. Even in the tiniest areas of brain tissue, the pathways are tangled, almost indescribably dense. Today, neuroscientists are trying to figure out the workings of all those cells and the networks they form, the ultimate grand-challenge problem. In a study appearing today in Nature Neuroscience, a team from Cold Spring Harbor Laboratory (CSHL) uses advanced technologies to illuminate the connectivity pattern of chandelier cells, a distinctive kind of inhibitory cell type in the mammalian brain. They reveal for the first time how this candelabra-shaped cell interacts with hundreds of excitatory cells in its neighborhood, receiving information from some, imparting information to others. In the experiments just reported, these highly specific interactions are situated in the context of a larger global network regulating the fear response in mice. Chandelier cells play analogous roles in other networks, capable of inhibiting excitatory neurons in a variety of contexts. The research therefore suggests more broadly how communication hierarchies may be shaped in the brain, as diverse and often intermingled sets of neurons in \"local\" areas both receive inputs from and send outputs to distinct brain areas, near and far. The team, led by CSHL Professor Z. Josh Huang and including researcher Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, focused on dense crowds of excitatory cells called pyramidal neurons - several hundred of which can connect with a single chandelier cell. Because each chandelier cell may control the firing of hundreds of pyramidal neurons, it has been suggested that they exert a kind of \"veto\" power over local excitatory messages. But there is more to the story. As this research shows, each chandelier cell also can receive inputs from hundreds of excitatory cells, input that influences whether or not it inhibits a circuit in which it is involved. The chandelier cell, discovered only 45 years ago, is one of the most distinctive cells int he mammalian brain. Each one can synapse with hundreds of neighboring excitatory cells, accounting for its candelabra-like shape. New research is beginning to reveal how they work. Credit: Huang Lab, CSHL The new research reveals how spatially intermixed pyramidal neurons that were associated with single chandelier cells in the mouse prelimbic cortex segregated into two groups. These were distinguished according to where in the brain they project to and their likely function. One ensemble of these pyramidal cells was shown to transmit information to the amygdala, resulting in a fear response; this ensemble can be inhibited by the chandelier cell. A second ensemble projects to cortical areas conveying information from the thalamus, a relay station that Huang speculates is sending higher-order information to the chandelier cell. This information might reflect, for example, whether the individual (whether mouse, person, or other mammal) should be afraid of something that it has sensed in its environment, given past experience. \"This circuit highlights the exquisite selectivity of neuronal wiring with respect to inhibition in the most complex and heterogeneous part of the brain,\" Huang says. \"It also illustrates the directionality of information flow in local and global brain networks. The messages move in a specific direction - the chandelier cell's overall inhibitory and information-routing role being the result of signals to it and from it by specific sets of neurons to which it is connected.\" This circuit diagram summarizes the findings of Huang and colleagues. A chandelier cell (red) can inhibit excitatory pyramidal neurons (green) in a fear circuit that leads to the amygdala (BLA). A separate set of excitatory neurons (blue) provides input to the chandelier cell, most directly from the thalamus, and possibly reflecting high-order cortical information pertaining to the fear reaction. Credit: Huang Lab, CSHL ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex, which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala ( BLA PC) compared to those projecting to contralateral cortex ( CC PC). These ChCs in turn receive preferential input from local and contralateral CC PCs as opposed to BLA PCs and BLA neurons (the prelimbic cortex–BLA network). Accordingly, optogenetic activation of ChCs rapidly suppresses BLA PCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks. Main In many areas of the cerebral cortex, diverse and often intermingled subsets of PCs preferentially receive inputs from and project outputs to distinct brain areas, and thus are embedded in separate local circuits as well as global networks 1 . It is not well understood how specific physiological PC ensembles emerge from the underlying anatomic scaffold and contribute to different subnetworks and information processing streams. Diverse types of GABAergic interneurons appear to specialize in their inhibitory control of various aspects of cortical circuit operations, such as balancing excitation, modulating gain, tuning dynamics and generating oscillations 2 , 3 , 4 . However, the inhibitory mechanisms that regulate the dynamic segregation of functional PC ensembles and route information flow between brain networks remain elusive. ChCs (i.e., axo-axonic cells) are among the most distinctive interneuron types. ChCs selectively innervate PCs at their axon initial segment (AIS), the site of action potential initiation 5 . A single ChC innervates hundreds of PCs 6 , 7 , and multiple ChCs can converge onto the same PC 8 , 9 . The exquisite specificity of ChC innervation at the AIS has long been speculated to exert the ultimate inhibitory control over PC spiking and population output 10 , 11 . However, it remains unclear how ChCs are recruited and whether a ChC indiscriminately innervates PCs within its dense axonal arbor or selects a specific PC subset 9 . In fact, it is even controversial whether ChCs inhibit or excite PCs 12 , 13 , 14 . Thus the problem of how ChCs control PCs represents a prominent gap as well as a unique opportunity for understanding the cellular basis of cortical organization, which entails elucidating the connectivity pattern of ChCs to PC subsets within local circuits in the context of global brain networks. Rodent prelimbic cortex (PL) integrates inputs from the amygdala and other brain structures (for example, other cortical areas, ventral hippocampus, medial-dorsal thalamus) to gate fear expression via projections back to the amygdala 15 , 16 , 17 , 18 , 19 . The superficial layers of PL contain two subsets of PCs: one projects to the BLA ( BLA PC) and another projects to contralateral cortex ( CC PC) 15 , 20 . They form two separate subnetworks: the PL–BLA network, comprising reciprocally connected BLA PCs and BLA neurons, and the bilateral PL network, comprising CC PCs from the two hemispheres 20 . Here, by combining genetic labeling of ChCs and projection-based labeling of PC subsets, we demonstrate that a subset of layer 2 (L2) ChCs preferentially receives inputs from CC PCs yet selectively innervates BLA PCs. This highly directional ChC microcircuit module is distinct from the parvalbumin fast-spiking basket cell (PVBC) module, characterized by nonselective and extensive reciprocal connectivity with BLA PCs and CC PCs. Trans-synaptic rabies tracing combined with optogenetic tagging of long-range inputs further revealed that L2 ChCs are preferentially recruited by contralateral CC PCs, but not by BLA input. Notably, optogenetic activation of ChCs resulted in rapid inhibition of PC firing in freely moving mice. Together, these results reveal that the exquisite connectivity of ChCs not only mediates directional inhibitory control between local PC ensembles but may also shape communication hierarchy and route information flow between distinct PC-associated global networks. Results A subset of L2 ChCs selectively innervates BLA PCs over CC PCs in PL We combined genetic 21 and anatomic methods to reliably label ChCs, BLA PCs and CC PCs for physiological studies. Tamoxifen induction in pregnant Nkx2.1-CreER;Rosa26-loxpSTOPloxp-TdTomato ( Ai14 ) mice (where the Nkx2.1 promoter is from Nkx2 homeobox 1, gene symbol Nkx2-1 ) at embryonic day 17.5 (E17.5) resulted in specific labeling of a subset of L2 ChCs throughout the frontal cortex, characterized by their soma positions at the L1–L2 border, prominent dendritic arborization in L1 and dense axonal plexus in L2/3 ( Fig. 1a,b and Supplementary Fig. 1 ). It should be noted that L2 ChCs are also generated at earlier embryonic times 21 ; for simplicity, the E17.5-born subset of L2 ChCs are herein referred to as L2 ChCs. Single-cell reconstruction revealed that individual L2 ChCs elaborated on average 211 ± 28 'cartridges', vertical strings of boutons targeting the AIS of PCs ( Fig. 1b and Supplementary Fig. 2 ). We distinguished subpopulations of L2/3 PCs in PL according to their projection targets by injecting a different color of retrograde tracer cholera toxin subunit B (CTB) into each target region of the same mouse: the BLA (to label BLA PCs), contralateral cortex (to label CC PCs) and dorsomedial striatum (to label ST PCs) ( Fig. 1c ). Each PC population resided at characteristic laminar depths, with some overlap: L2 ChCs occupied a similar laminar depth as BLA PCs ( Fig. 1c,d and Supplementary Fig. 3a ). Notably, there was little convergence in projection targets between BLA PCs and CC PCs ( Fig. 1e ). Figure 1: L2 ChCs preferentially innervate BLA PCs over CC PCs in prelimbic cortex. ( a ) Distribution (left) and morphology (right) of L2 ChCs in PL of an adult Nkx2.1-CreER:Ai14 mouse tamoxifen-induced at E17.5.<|im_end|> <|im_start|>assistant The brain's astonishing anatomical complexity has been appreciated for over 100 years, when pioneers first trained microscopes on the profusion of branching structures that connect individual neurons. Even in the tiniest areas of brain tissue, the pathways are tangled, almost indescribably dense. Today, neuroscientists are trying to figure out the workings of all those cells and the networks they form, the ultimate grand-challenge problem. In a study appearing today in Nature Neuroscience, a team from Cold Spring Harbor Laboratory (CSHL) uses advanced technologies to illuminate the connectivity pattern of chandelier cells, a distinctive kind of inhibitory cell type in the mammalian brain. They reveal for the first time how this candelabra-shaped cell interacts with hundreds of excitatory cells in its neighborhood, receiving information from some, imparting information to others. In the experiments just reported, these highly specific interactions are situated in the context of a larger global network regulating the fear response in mice. Chandelier cells play analogous roles in other networks, capable of inhibiting excitatory neurons in a variety of contexts. The research therefore suggests more broadly how communication hierarchies may be shaped in the brain, as diverse and often intermingled sets of neurons in "local" areas both receive inputs from and send outputs to distinct brain areas, near and far. The team, led by CSHL Professor Z. Josh Huang and including researcher Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, focused on dense crowds of excitatory cells called pyramidal neurons - several hundred of which can connect with a single chandelier cell. Because each chandelier cell may control the firing of hundreds of pyramidal neurons, it has been suggested that they exert a kind of "veto" power over local excitatory messages. But there is more to the story. As this research shows, each chandelier cell also can receive inputs from hundreds of excitatory cells, input that influences whether or not it inhibits a circuit in which it is involved. The chandelier cell, discovered only 45 years ago, is one of the most distinctive cells int he mammalian brain. Each one can synapse with hundreds of neighboring excitatory cells, accounting for its candelabra-like shape. New research is beginning to reveal how they work. Credit: Huang Lab, CSHL The new research reveals how spatially intermixed pyramidal neurons that were associated with single chandelier cells in the mouse prelimbic cortex segregated into two groups. These were distinguished according to where in the brain they project to and their likely function. One ensemble of these pyramidal cells was shown to transmit information to the amygdala, resulting in a fear response; this ensemble can be inhibited by the chandelier cell. A second ensemble projects to cortical areas conveying information from the thalamus, a relay station that Huang speculates is sending higher-order information to the chandelier cell. This information might reflect, for example, whether the individual (whether mouse, person, or other mammal) should be afraid of something that it has sensed in its environment, given past experience. "This circuit highlights the exquisite selectivity of neuronal wiring with respect to inhibition in the most complex and heterogeneous part of the brain," Huang says. "It also illustrates the directionality of information flow in local and global brain networks. The messages move in a specific direction - the chandelier cell's overall inhibitory and information-routing role being the result of signals to it and from it by specific sets of neurons to which it is connected." This circuit diagram summarizes the findings of Huang and colleagues. A chandelier cell (red) can inhibit excitatory pyramidal neurons (green) in a fear circuit that leads to the amygdala (BLA). A separate set of excitatory neurons (blue) provides input to the chandelier cell, most directly from the thalamus, and possibly reflecting high-order cortical information pertaining to the fear reaction. Credit: Huang Lab, CSHL <|im_end|>

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2,309

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO 2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO 2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO 2 later in the season. Introduction Climate change is affecting arctic ecosystems through temperature increase 1 , hydrological changes 2 , earlier snowmelt 3 , 4 , and the associated increase in growing season length 5 . Annual arctic air temperature has been increasing at more than double the magnitude of the global mean air temperature increase 1 , and terrestrial snow cover in June has decreased by 15.2% per decade from 1981 to 2019 4 . Warming is the main driver of the earlier start of the growing season, and the greening of the Arctic 6 , 7 , 8 . Arctic greening is associated with enhanced vegetation height, biomass, cover, and abundance 9 . However, the complexity of arctic systems reveals an intricate patchwork of landscape greening and browning 8 , 10 , 11 , with browning linked to a variety of stresses to vegetation 8 including water stress 12 , 13 . The interconnected changes in temperature, soil moisture, snowmelt timing, etc. can have important effects on the carbon sequestered by arctic ecosystems 14 . The reservoir of carbon in arctic soil and vegetation depends on the interaction of two main processes: (1) changes in net CO 2 uptake by vegetation; and (2) increased net loss of CO 2 (from vegetation and soil) to the atmosphere via respiration. Therefore, defining the response of both plant productivity and ecosystem respiration to environmental changes is needed to predict the sensitivity of the net CO 2 fluxes of arctic systems to climate change. An earlier snowmelt, and a longer growing season, do not necessarily translate into more carbon sequestered by high latitude ecosystems 5 . There is a large disagreement on the response of plant productivity and the net CO 2 uptake to early snowmelt in tundra ecosystems 15 , 16 , 17 , 18 , 19 . A warmer and longer growing season might not result in more net CO 2 uptake if CO 2 loss from respiration increases 16 , particularly later in the season, and surpasses the CO 2 sequestered by enhanced plant productivity in northern ecosystems 16 , 20 . Moreover, snowmelt timing and the growing season length greatly affect hydrologic conditions of arctic soils 21 , as well as plant productivity 22 . Longer non-frozen periods earlier in the year 23 and earlier vegetation greening can increase evapotranspiration (ET), resulting in lower summer soil moisture 24 , 25 , 26 . The complexity in the hydrology of tundra systems arises from the tight link between the water drainage and the presence and depth of permafrost. The presence of permafrost reduces vertical water losses, preventing soil drainage in northern wetlands during most of the summer despite low precipitation input 27 . Increasing rainfall 28 and increased permafrost degradation can increase soil wetness in continuous permafrost regions 2 . Further permafrost degradation (e.g. ice-wedge melting) can increase hydrologic connectivity leading to increased lateral drainage of the landscape and subsequent soil drying 2 , 29 . Given the importance of soil moisture in affecting the carbon balance of arctic ecosystems, and its links with snowmelt timing, in this study, we investigated the correlation between summer fluxes of CO 2 (i.e., net ecosystem exchange (NEE), gross primary productivity (GPP) ecosystem respiration (ER)), ET, and environmental drivers such as soil moisture and snowmelt timing, while controlling for the other most important drivers of photosynthesis and respiration (i.e. solar radiation and air temperature). We expected earlier snowmelt to be correlated with larger ET and lower soil moisture, particularly during peak and late season, consistent with drying associated with a longer growing season. The lower soil moisture with earlier snowmelt should result in a negative correlation between snowmelt timing and GPP, particularly during the peak and late season (when we expect the most water stress), and in a positive correlation between snowmelt timing and ER during the entire growing season. This soil moisture limitation to plant productivity should result in lower net cumulative CO 2 sequestration during the entire summer, because of lower plant productivity if these ecosystems are water-limited due to lower soil moisture with earlier snowmelt. Testing the impact of snowmelt timing on the carbon dynamics and hydrology of tundra ecosystems The 11 sites were selected as among the longest-running tower sites in the circumpolar Arctic (including 6 to 19 years of fluxes per site and a total of 119 site-years of summer (June to August) eddy covariance CO 2 flux data, Table S1 ). All sites lie in the zone of continuous permafrost. The sites are representative of dominant tundra vegetation classes (wetland, graminoids, and shrub tundra), together accounting for 31% of all tundra vegetation types (Fig. 1 30 and Supplementary Information ). Given the complex interactions among different variables (many covarying together), we used a variety of statistical analyses to identify the association between standardized anomalies of NEE, GPP, ER,", "role": "user" }, { "content": "Every year, when the long, dark Arctic winter begins its retreat, the tundra ecosystem comes to life. \"It goes from this kind of stark, dark, icy desert, and then all of a sudden it greens up and you hear nothing but songbirds everywhere and you see these snowy owls and sometimes caribou. It's wonderful,\" said ecology graduate student Josh Hashemi, who has witnessed the transformation while doing fieldwork in northern Alaska. Because of climate change, however, the snowmelt now occurs earlier each year. This results in a longer growing season for tough tundra plants like shrubs and sedges: the so-called \"greening\" of the Arctic. A new study led by Hashemi's advisor, San Diego State University biologist Donatella Zona, found that the shift could compromise the tundra's ability to store carbon, keeping it out of the atmosphere. Zona, Hashemi and an international team of scientists working in Alaska, Canada, Greenland and Siberia have studied the consequences of the early snowmelt for the past five years. \"Models and large-scale remote sensing have been showing this greening of the Arctic. But you don't know if it really translates to more carbon sequestration from tundra ecosystems,\" said Zona. \"Most large-scale studies use some field-level data, but not to the extent we use here. This is a fully data-driven study across the northernmost understudied tundra ecosystems across the Arctic.\". The work to obtain these data can be grueling. Hashemi, who is part of a joint doctoral program between SDSU and the University of California, Davis, served as a technician at the Alaskan field sites from 2017–21, but also doubled as a biologist, electrician and handyman. In remote Ivotuk, Alaska, he slept in a tent surrounded by an electrified bear fence. \"It can be very challenging. In general, anything that would take 'x' amount of time anywhere else will take five times longer in the Arctic,\" he said. His work involves climbing small towers in the tundra to monitor instruments that quantify CO2 exchange at the interface of soil, vegetation and air. \"We measure carbon flux. That is the amount of atmospheric carbon that goes into the system versus going out. How much CO2 the tundra's producing, and at what rates it's being emitted from the surface,\" said Hashemi. The Arctic tundra has long been considered a carbon sink. That's a good thing: the amount of carbon stored by photosynthesizing plants during the summer exceeds the amount that's lost to the atmosphere. The plants eventually decompose into the soil, and the long winters keep the soil from releasing carbon dioxide, counteracting climate change. Zona says it's important for people to appreciate just how big a role the tundra ecosystem has the potential to play in the global carbon balance. \"The total amount of carbon in the permafrost soil is roughly double the amount in the atmosphere. It's stored there because it's cold there, because the growing season is just a short amount of time. The rest of the time, everything is mostly frozen,\" Zona said. The scientific community disagrees about whether the earlier snowmelt leads to an increase in overall CO2 storage due to a longer growing season. Answering that question will help determine whether the Arctic will remain a carbon sink. The study, published in the journal Scientific Reports, found that while plant growth and carbon storage increase at the beginning of the growing season in June, and in the peak of the season in July, both start to wane near the end of it, in August. They are still trying to work out why this is happening, but one possibility is that the early snowmelt causes the plants to age and die back sooner. \"We show that the earlier snowmelt stimulates the carbon uptake and the plant productivity in earlier and midsummer periods, but actually decreases in the late season. It's a little bit like you wake up earlier, then in the evening, you are tired earlier,\" Zona said. That means the decline in photosynthesis and net carbon storage in August due to the earlier snowmelt may be hindering overall CO2 uptake during the entire summer. This could disrupt the carbon balance in the Arctic and jeopardize tundra's role as a carbon sink. \"If the plants cannot store more carbon because of something that is limiting the duration of the carbon storage, then we have something that is not decreasing climate change but something that is increasing climate change,\" Zona said. \"If our ecosystems are responding in an unexpected way by increasing carbon loss, it's a big deal, because even the things we assume are helping us out are not. If we do not start reducing carbon emitted into the atmosphere, we're going to bake.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO 2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO 2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO 2 later in the season. Introduction Climate change is affecting arctic ecosystems through temperature increase 1 , hydrological changes 2 , earlier snowmelt 3 , 4 , and the associated increase in growing season length 5 . Annual arctic air temperature has been increasing at more than double the magnitude of the global mean air temperature increase 1 , and terrestrial snow cover in June has decreased by 15.2% per decade from 1981 to 2019 4 . Warming is the main driver of the earlier start of the growing season, and the greening of the Arctic 6 , 7 , 8 . Arctic greening is associated with enhanced vegetation height, biomass, cover, and abundance 9 . However, the complexity of arctic systems reveals an intricate patchwork of landscape greening and browning 8 , 10 , 11 , with browning linked to a variety of stresses to vegetation 8 including water stress 12 , 13 . The interconnected changes in temperature, soil moisture, snowmelt timing, etc. can have important effects on the carbon sequestered by arctic ecosystems 14 . The reservoir of carbon in arctic soil and vegetation depends on the interaction of two main processes: (1) changes in net CO 2 uptake by vegetation; and (2) increased net loss of CO 2 (from vegetation and soil) to the atmosphere via respiration. Therefore, defining the response of both plant productivity and ecosystem respiration to environmental changes is needed to predict the sensitivity of the net CO 2 fluxes of arctic systems to climate change. An earlier snowmelt, and a longer growing season, do not necessarily translate into more carbon sequestered by high latitude ecosystems 5 . There is a large disagreement on the response of plant productivity and the net CO 2 uptake to early snowmelt in tundra ecosystems 15 , 16 , 17 , 18 , 19 . A warmer and longer growing season might not result in more net CO 2 uptake if CO 2 loss from respiration increases 16 , particularly later in the season, and surpasses the CO 2 sequestered by enhanced plant productivity in northern ecosystems 16 , 20 . Moreover, snowmelt timing and the growing season length greatly affect hydrologic conditions of arctic soils 21 , as well as plant productivity 22 . Longer non-frozen periods earlier in the year 23 and earlier vegetation greening can increase evapotranspiration (ET), resulting in lower summer soil moisture 24 , 25 , 26 . The complexity in the hydrology of tundra systems arises from the tight link between the water drainage and the presence and depth of permafrost. The presence of permafrost reduces vertical water losses, preventing soil drainage in northern wetlands during most of the summer despite low precipitation input 27 . Increasing rainfall 28 and increased permafrost degradation can increase soil wetness in continuous permafrost regions 2 . Further permafrost degradation (e.g. ice-wedge melting) can increase hydrologic connectivity leading to increased lateral drainage of the landscape and subsequent soil drying 2 , 29 . Given the importance of soil moisture in affecting the carbon balance of arctic ecosystems, and its links with snowmelt timing, in this study, we investigated the correlation between summer fluxes of CO 2 (i.e., net ecosystem exchange (NEE), gross primary productivity (GPP) ecosystem respiration (ER)), ET, and environmental drivers such as soil moisture and snowmelt timing, while controlling for the other most important drivers of photosynthesis and respiration (i.e. solar radiation and air temperature). We expected earlier snowmelt to be correlated with larger ET and lower soil moisture, particularly during peak and late season, consistent with drying associated with a longer growing season. The lower soil moisture with earlier snowmelt should result in a negative correlation between snowmelt timing and GPP, particularly during the peak and late season (when we expect the most water stress), and in a positive correlation between snowmelt timing and ER during the entire growing season. This soil moisture limitation to plant productivity should result in lower net cumulative CO 2 sequestration during the entire summer, because of lower plant productivity if these ecosystems are water-limited due to lower soil moisture with earlier snowmelt. Testing the impact of snowmelt timing on the carbon dynamics and hydrology of tundra ecosystems The 11 sites were selected as among the longest-running tower sites in the circumpolar Arctic (including 6 to 19 years of fluxes per site and a total of 119 site-years of summer (June to August) eddy covariance CO 2 flux data, Table S1 ). All sites lie in the zone of continuous permafrost. The sites are representative of dominant tundra vegetation classes (wetland, graminoids, and shrub tundra), together accounting for 31% of all tundra vegetation types (Fig. 1 30 and Supplementary Information ). Given the complex interactions among different variables (many covarying together), we used a variety of statistical analyses to identify the association between standardized anomalies of NEE, GPP, ER,<|im_end|> <|im_start|>assistant Every year, when the long, dark Arctic winter begins its retreat, the tundra ecosystem comes to life. "It goes from this kind of stark, dark, icy desert, and then all of a sudden it greens up and you hear nothing but songbirds everywhere and you see these snowy owls and sometimes caribou. It's wonderful," said ecology graduate student Josh Hashemi, who has witnessed the transformation while doing fieldwork in northern Alaska. Because of climate change, however, the snowmelt now occurs earlier each year. This results in a longer growing season for tough tundra plants like shrubs and sedges: the so-called "greening" of the Arctic. A new study led by Hashemi's advisor, San Diego State University biologist Donatella Zona, found that the shift could compromise the tundra's ability to store carbon, keeping it out of the atmosphere. Zona, Hashemi and an international team of scientists working in Alaska, Canada, Greenland and Siberia have studied the consequences of the early snowmelt for the past five years. "Models and large-scale remote sensing have been showing this greening of the Arctic. But you don't know if it really translates to more carbon sequestration from tundra ecosystems," said Zona. "Most large-scale studies use some field-level data, but not to the extent we use here. This is a fully data-driven study across the northernmost understudied tundra ecosystems across the Arctic.". The work to obtain these data can be grueling. Hashemi, who is part of a joint doctoral program between SDSU and the University of California, Davis, served as a technician at the Alaskan field sites from 2017–21, but also doubled as a biologist, electrician and handyman. In remote Ivotuk, Alaska, he slept in a tent surrounded by an electrified bear fence. "It can be very challenging. In general, anything that would take 'x' amount of time anywhere else will take five times longer in the Arctic," he said. His work involves climbing small towers in the tundra to monitor instruments that quantify CO2 exchange at the interface of soil, vegetation and air. "We measure carbon flux. That is the amount of atmospheric carbon that goes into the system versus going out. How much CO2 the tundra's producing, and at what rates it's being emitted from the surface," said Hashemi. The Arctic tundra has long been considered a carbon sink. That's a good thing: the amount of carbon stored by photosynthesizing plants during the summer exceeds the amount that's lost to the atmosphere. The plants eventually decompose into the soil, and the long winters keep the soil from releasing carbon dioxide, counteracting climate change. Zona says it's important for people to appreciate just how big a role the tundra ecosystem has the potential to play in the global carbon balance. "The total amount of carbon in the permafrost soil is roughly double the amount in the atmosphere. It's stored there because it's cold there, because the growing season is just a short amount of time. The rest of the time, everything is mostly frozen," Zona said. The scientific community disagrees about whether the earlier snowmelt leads to an increase in overall CO2 storage due to a longer growing season. Answering that question will help determine whether the Arctic will remain a carbon sink. The study, published in the journal Scientific Reports, found that while plant growth and carbon storage increase at the beginning of the growing season in June, and in the peak of the season in July, both start to wane near the end of it, in August. They are still trying to work out why this is happening, but one possibility is that the early snowmelt causes the plants to age and die back sooner. "We show that the earlier snowmelt stimulates the carbon uptake and the plant productivity in earlier and midsummer periods, but actually decreases in the late season. It's a little bit like you wake up earlier, then in the evening, you are tired earlier," Zona said. That means the decline in photosynthesis and net carbon storage in August due to the earlier snowmelt may be hindering overall CO2 uptake during the entire summer. This could disrupt the carbon balance in the Arctic and jeopardize tundra's role as a carbon sink. "If the plants cannot store more carbon because of something that is limiting the duration of the carbon storage, then we have something that is not decreasing climate change but something that is increasing climate change," Zona said. "If our ecosystems are responding in an unexpected way by increasing carbon loss, it's a big deal, because even the things we assume are helping us out are not. If we do not start reducing carbon emitted into the atmosphere, we're going to bake." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The evolution of novel traits can involve many mutations scattered throughout the genome 1 , 2 . Detecting and validating such a suite of alleles, particularly if they arose long ago, remains a key challenge in evolutionary genetics 1 , 2 , 3 . Here we dissect an evolutionary trade-off of unprecedented genetic complexity between long-diverged species. When cultured in 1% glucose medium supplemented with galactose, Saccharomyces cerevisiae , but not S. bayanus or other Saccharomyces species, delayed commitment to galactose metabolism until glucose was exhausted. Promoters of seven galactose ( GAL ) metabolic genes from S. cerevisiae , when introduced together into S. bayanus , largely recapitulated the delay phenotype in 1% glucose–galactose medium, and most had partial effects when tested in isolation. Variation in GAL coding regions also contributed to the delay when tested individually in 1% glucose–galactose medium. When combined, S. cerevisiae GAL coding regions gave rise to profound growth defects in the S. bayanus background. In medium containing 2.5% glucose supplemented with galactose, wild-type S. cerevisiae repressed GAL gene expression and had a robust growth advantage relative to S. bayanus ; transgenesis of S. cerevisiae GAL promoter alleles or GAL coding regions was sufficient for partial reconstruction of these phenotypes. S. cerevisiae GAL genes thus encode a regulatory program of slow induction and avid repression, and a fitness detriment during the glucose–galactose transition but a benefit when glucose is in excess. Together, these results make clear that genetic mapping of complex phenotypes is within reach, even in deeply diverged species. Main A central goal of evolutionary genetics is to understand how organisms acquire phenotypic novelties. Such traits, if they have evolved over long timescales, can have a genetic basis quite distinct from those arisen more recently 4 . In landmark cases, single genes underlying species differences have been pinpointed and validated 5 , but the polygenic architecture of ancient traits has remained a mystery. In hybrids formed by mating S. cerevisiae with other Saccharomyces species 6 , we noted a pattern of coherent cis -regulatory variation in the seven genes of the galactose metabolic pathway. During growth in medium with glucose as the sole carbon source, the S. cerevisiae allele at each GAL gene conferred low expression relative to other Saccharomyces , except for the repressor GAL80 , at which the S. cerevisiae allele drove expression up ( Fig. 1b ). Likewise, purebred S. cerevisiae expressed GAL effectors at low levels in glucose, and GAL80 at high levels, relative to other species ( Fig. 1b and ref. 7 ). S. paradoxus , the sister species to S. cerevisiae , had an intermediate expression phenotype ( Fig. 1b ). Thus, the S. cerevisiae GAL program is one of heightened glucose repression relative to other species, as a product of cis -regulatory changes at the five loci that encode the seven GAL genes. Because such a pattern is unlikely under neutrality 8 , these data raised the possibility that selective pressure on the GAL pathway had changed along the S. cerevisiae lineage. Figure 1: Polygenic cis -regulatory evolution among yeast species in galactose metabolic genes. a , Phylogenetic tree of Saccharomyces species studied here 14 . S. bay , S. bayanus ; S. mik , S. mikatae ; S. par , S. paradoxus ; S. cer , S. cerevisiae . b , Each cell reports expression, as a ratio between the indicated species and S. cerevisiae , of the indicated galactose metabolism gene during culture in glucose medium 6 . Total, expression measured in purebred species; cis , expression from the indicated species’ allele in a diploid hybrid between this species and S. cerevisiae , reflecting effects of cis -regulatory divergence. PowerPoint slide Full size image In S. cerevisiae , pre-expression of metabolic genes in glucose medium can boost fitness upon a switch to other carbon sources 9 , 10 , 11 . We therefore expected that GAL expression divergence in glucose could have phenotypic correlates in other conditions. Culturing cells in 1% glucose–galactose medium, we observed a qualitative distinction between species ( Fig. 2a ). In S. cerevisiae , growth was retarded by a diauxic lag midway through the time course, reflecting the expected delay in assembling galactose metabolic machinery once glucose is exhausted 9 , 10 , 12 . In more distantly related yeasts, we observed no lag in 1% glucose–galactose medium supplemented with galactose ( Fig. 2a, b ), although S. paradoxus had a modest lag ( Fig. 2a, b ) that echoed its intermediate regulatory phenotype ( Fig. 1b ). Glucose mixtures with maltose and raffinose engendered a lag in all members of the clade ( Extended Data Fig. 1 ). S. cerevisiae strains from distinct populations all exhibited a lag in glucose–galactose cultures ( Fig. 2c ). These data highlight S. cerevisiae as an extreme among Saccharomyces with respect to two attributes of galactose metabolism: reduced GAL gene expression during growth in pure glucose, and diauxic lag in 1% glucose–galactose. Figure 2: Diauxic lag, in 1% glucose–galactose medium, is conserved within S. cerevisiae and divergent among species. a , Growth of Saccharomyces type strains inoculated into medium containing 1% glucose and 1% galactose ( n = 6). S. cas , S. castellii . b , Each bar reports the geometric mean of the growth rate (GMR) of the indicated species from the time course in a , normalized to the analogous quantity in glucose medium. c , Growth of S. cerevisiae isolates (blue) from the indicated populations (W/E, Wine/European; WA, West African; NA, North American) and the S. bayanus type strain (black), inoculated into medium containing 1% glucose and 1% galactose ( n = 6). d , Growth (solid lines, n = 4) of S. cerevisiae and S. bayanus inoculated into medium containing 1% glucose and 1% galactose, and medium concentrations of glucose and galactose (dotted and broken lines, respectively; n = 2 biological replicates, each comprising 3 technical replicates). Error bars, s.e.m. Each set of data is representative of the results", "role": "user" }, { "content": "Since Darwin, evolutionary biologists have been fascinated by how different organisms are from one another. The ultimate goal is to understand how mutations in DNA, the genetic blueprint, shape the growth and behavior of animals, plants, and microbes around us. Standard research tools have been available for some time to study the genetics of closely related individuals—for example, the variation of lactose intolerance between humans. But understanding differences between long-separated species has remained a challenge. Publishing online in Nature, Buck Institute professor Rachel Brem and her colleagues have broken through this roadblock by focusing on distantly-related species of yeast, the single-celled organism used to make beer, wine and bread. \"Yeast is an easy system to work with and a good model for more complicated organisms,\" said Brem. \"It was a great platform for us to develop a method for discovering what makes species unique.\" The researchers first noted that some species of yeast were much better than others at deriving energy from galactose, a sugar found in plant materials. Brem and her collaborators then identified seven locations in the yeast DNA at which the species had distinct genetic information, at sites that regulated how galactose metabolism genes turned on and off as the cells grew. Ultimately, the researchers showed that these regulatory changes were the reason why yeast species used galactose differently. \"What our work shows is that research in genetics is no longer limited to surveys of close relatives,\" said Brem. \"So we can start to understand how species of malaria parasites acquired different infectious behaviors over time, and develop new species-specific treatments. And we can figure out how short-and long-grained rice developed their respective shapes in the ancient past, and make new rice varieties. We are excited about future work far beyond yeast.\" The work could have implications for research on aging, said Buck professor Gordon Lithgow. His lab studies tiny nematode worms in order to uncover genes and small molecules that prolong lifespan. As an example, Lithgow sites the Caenorhabditis family of nematodes which contains widely divergent species, some of which have significant differences in lifespan. \"These animals have incredibly different genomes, even though they look identical under the microscope,\" he said. \"Tools like this give us an opportunity to compare their DNA - what are the genes that account for their lifespan changes? It's the first step in understanding how we might exploit those differences in order to extend healthspan.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The evolution of novel traits can involve many mutations scattered throughout the genome 1 , 2 . Detecting and validating such a suite of alleles, particularly if they arose long ago, remains a key challenge in evolutionary genetics 1 , 2 , 3 . Here we dissect an evolutionary trade-off of unprecedented genetic complexity between long-diverged species. When cultured in 1% glucose medium supplemented with galactose, Saccharomyces cerevisiae , but not S. bayanus or other Saccharomyces species, delayed commitment to galactose metabolism until glucose was exhausted. Promoters of seven galactose ( GAL ) metabolic genes from S. cerevisiae , when introduced together into S. bayanus , largely recapitulated the delay phenotype in 1% glucose–galactose medium, and most had partial effects when tested in isolation. Variation in GAL coding regions also contributed to the delay when tested individually in 1% glucose–galactose medium. When combined, S. cerevisiae GAL coding regions gave rise to profound growth defects in the S. bayanus background. In medium containing 2.5% glucose supplemented with galactose, wild-type S. cerevisiae repressed GAL gene expression and had a robust growth advantage relative to S. bayanus ; transgenesis of S. cerevisiae GAL promoter alleles or GAL coding regions was sufficient for partial reconstruction of these phenotypes. S. cerevisiae GAL genes thus encode a regulatory program of slow induction and avid repression, and a fitness detriment during the glucose–galactose transition but a benefit when glucose is in excess. Together, these results make clear that genetic mapping of complex phenotypes is within reach, even in deeply diverged species. Main A central goal of evolutionary genetics is to understand how organisms acquire phenotypic novelties. Such traits, if they have evolved over long timescales, can have a genetic basis quite distinct from those arisen more recently 4 . In landmark cases, single genes underlying species differences have been pinpointed and validated 5 , but the polygenic architecture of ancient traits has remained a mystery. In hybrids formed by mating S. cerevisiae with other Saccharomyces species 6 , we noted a pattern of coherent cis -regulatory variation in the seven genes of the galactose metabolic pathway. During growth in medium with glucose as the sole carbon source, the S. cerevisiae allele at each GAL gene conferred low expression relative to other Saccharomyces , except for the repressor GAL80 , at which the S. cerevisiae allele drove expression up ( Fig. 1b ). Likewise, purebred S. cerevisiae expressed GAL effectors at low levels in glucose, and GAL80 at high levels, relative to other species ( Fig. 1b and ref. 7 ). S. paradoxus , the sister species to S. cerevisiae , had an intermediate expression phenotype ( Fig. 1b ). Thus, the S. cerevisiae GAL program is one of heightened glucose repression relative to other species, as a product of cis -regulatory changes at the five loci that encode the seven GAL genes. Because such a pattern is unlikely under neutrality 8 , these data raised the possibility that selective pressure on the GAL pathway had changed along the S. cerevisiae lineage. Figure 1: Polygenic cis -regulatory evolution among yeast species in galactose metabolic genes. a , Phylogenetic tree of Saccharomyces species studied here 14 . S. bay , S. bayanus ; S. mik , S. mikatae ; S. par , S. paradoxus ; S. cer , S. cerevisiae . b , Each cell reports expression, as a ratio between the indicated species and S. cerevisiae , of the indicated galactose metabolism gene during culture in glucose medium 6 . Total, expression measured in purebred species; cis , expression from the indicated species’ allele in a diploid hybrid between this species and S. cerevisiae , reflecting effects of cis -regulatory divergence. PowerPoint slide Full size image In S. cerevisiae , pre-expression of metabolic genes in glucose medium can boost fitness upon a switch to other carbon sources 9 , 10 , 11 . We therefore expected that GAL expression divergence in glucose could have phenotypic correlates in other conditions. Culturing cells in 1% glucose–galactose medium, we observed a qualitative distinction between species ( Fig. 2a ). In S. cerevisiae , growth was retarded by a diauxic lag midway through the time course, reflecting the expected delay in assembling galactose metabolic machinery once glucose is exhausted 9 , 10 , 12 . In more distantly related yeasts, we observed no lag in 1% glucose–galactose medium supplemented with galactose ( Fig. 2a, b ), although S. paradoxus had a modest lag ( Fig. 2a, b ) that echoed its intermediate regulatory phenotype ( Fig. 1b ). Glucose mixtures with maltose and raffinose engendered a lag in all members of the clade ( Extended Data Fig. 1 ). S. cerevisiae strains from distinct populations all exhibited a lag in glucose–galactose cultures ( Fig. 2c ). These data highlight S. cerevisiae as an extreme among Saccharomyces with respect to two attributes of galactose metabolism: reduced GAL gene expression during growth in pure glucose, and diauxic lag in 1% glucose–galactose. Figure 2: Diauxic lag, in 1% glucose–galactose medium, is conserved within S. cerevisiae and divergent among species. a , Growth of Saccharomyces type strains inoculated into medium containing 1% glucose and 1% galactose ( n = 6). S. cas , S. castellii . b , Each bar reports the geometric mean of the growth rate (GMR) of the indicated species from the time course in a , normalized to the analogous quantity in glucose medium. c , Growth of S. cerevisiae isolates (blue) from the indicated populations (W/E, Wine/European; WA, West African; NA, North American) and the S. bayanus type strain (black), inoculated into medium containing 1% glucose and 1% galactose ( n = 6). d , Growth (solid lines, n = 4) of S. cerevisiae and S. bayanus inoculated into medium containing 1% glucose and 1% galactose, and medium concentrations of glucose and galactose (dotted and broken lines, respectively; n = 2 biological replicates, each comprising 3 technical replicates). Error bars, s.e.m. Each set of data is representative of the results<|im_end|> <|im_start|>assistant Since Darwin, evolutionary biologists have been fascinated by how different organisms are from one another. The ultimate goal is to understand how mutations in DNA, the genetic blueprint, shape the growth and behavior of animals, plants, and microbes around us. Standard research tools have been available for some time to study the genetics of closely related individuals—for example, the variation of lactose intolerance between humans. But understanding differences between long-separated species has remained a challenge. Publishing online in Nature, Buck Institute professor Rachel Brem and her colleagues have broken through this roadblock by focusing on distantly-related species of yeast, the single-celled organism used to make beer, wine and bread. "Yeast is an easy system to work with and a good model for more complicated organisms," said Brem. "It was a great platform for us to develop a method for discovering what makes species unique." The researchers first noted that some species of yeast were much better than others at deriving energy from galactose, a sugar found in plant materials. Brem and her collaborators then identified seven locations in the yeast DNA at which the species had distinct genetic information, at sites that regulated how galactose metabolism genes turned on and off as the cells grew. Ultimately, the researchers showed that these regulatory changes were the reason why yeast species used galactose differently. "What our work shows is that research in genetics is no longer limited to surveys of close relatives," said Brem. "So we can start to understand how species of malaria parasites acquired different infectious behaviors over time, and develop new species-specific treatments. And we can figure out how short-and long-grained rice developed their respective shapes in the ancient past, and make new rice varieties. We are excited about future work far beyond yeast." The work could have implications for research on aging, said Buck professor Gordon Lithgow. His lab studies tiny nematode worms in order to uncover genes and small molecules that prolong lifespan. As an example, Lithgow sites the Caenorhabditis family of nematodes which contains widely divergent species, some of which have significant differences in lifespan. "These animals have incredibly different genomes, even though they look identical under the microscope," he said. "Tools like this give us an opportunity to compare their DNA - what are the genes that account for their lifespan changes? It's the first step in understanding how we might exploit those differences in order to extend healthspan." <|im_end|>

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1,945

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Triassic predatory guild evolution reflects a period of ecological flux spurred by the catastrophic end-Permian mass extinction and terminating with the global ecological dominance of dinosaurs in the early Jurassic. In responding to this dynamic ecospace, terrestrial predator diversity attained new levels, prompting unique trophic webs with a seeming overabundance of carnivorous taxa and the evolution of entirely new predatory clades. Key among these was Crocodylomorpha, the largest living reptiles and only one of two archosaurian lineages that survive to the present day. In contrast to their existing role as top, semi-aquatic predators, the earliest crocodylomorphs were generally small-bodied, terrestrial faunivores, occupying subsidiary (meso) predator roles. Here we describe Carnufex carolinensis a new, unexpectedly large-bodied taxon with a slender and ornamented skull from the Carnian Pekin Formation (~231 Ma), representing one of the oldest and earliest diverging crocodylomorphs described to date. Carnufex bridges a problematic gap in the early evolution of pseudosuchians by spanning key transitions in bauplan evolution and body mass near the origin of Crocodylomorpha. With a skull length of >50 cm, the new taxon documents a rare instance of crocodylomorphs ascending to top-tier predator guilds in the equatorial regions of Pangea prior to the dominance of dinosaurs. Introduction The composition of modern ecosystems can be traced to the dynamic recovery of life in the aftermath of the catastrophic end-Permian mass extinction 1 . During the Triassic Period, unstable biotic communities 2 and morphing ecospace 3 gave rise to extant vertebrate clades such as frogs, lizards, mammals, turtles and dinosaurs 1 , 4 , 5 and spurred seemingly unbalanced trophic assemblages dominated by an excess of predatory taxa 6 . In the Middle Triassic, terrestrial predator assemblages included the small-bodied mesopredators Gracilisuchidae 7 and top tier predator guilds dominated by poposauroids and basal loricatans (“rauisuchians”) 8 . By the Late Triassic, subsidiary predator guilds had shifted composition to newly emerging clades such as ornithosuchids 9 , early dinosaurs 4 , 5 and the oldest known crocodylomorphs 10 . Whereas apex predator guilds were thought to be more highly conserved, retaining Middle Triassic representatives and expanding to include large-bodied theropod dinosaurs and rauisuchids 8 . Here we describe a new species of crocodylomorph from the Carnian Pekin Formation, North Carolina, USA, representing one of the oldest, largest and most basal crocodylomorphs yet discovered. This new taxon adds to a growing body of evidence that Triassic crocodylomorphs were more diverse than previously appreciated and that theropod dinosaurs and crocodylomorphs exploited a wide trophic reach 11 , occupying both subsidiary and top-tier predator roles in the Late Triassic. Results Systematic paleontology Archosauria Cope, 1869. Pseudosuchia Zittel, 1887–1890. Crocodylomorpha Walker, 1968 sensu Nesbitt 2011. Carnufex carolinensis gen. et sp. nov. Etymology Carnufex (Latin) butcher; carolinensis , in reference to the region of discovery. Holotype NCSM 21558, partial skull and postcranial skeleton including: right dentigerous premaxilla, left maxilla, left lacrimal, left jugal, left articular, right angular, isolated maxillary tooth, cervical neural arch, dorsal neural arch, cervical rib, dorsal ribs and left humerus. ( Fig. 1 , S9 ). Figure 1 Three dimensional skull reconstruction and representative elements of Carnufex carolinensis (NCSM 21558). (a) reconstructed skull, clockwise from upper left, rostral, oblique and lateral views; (b) right premaxilla, lateral view; (c) left maxilla, lateral view; (d) left lacrimal, lateral view; (e) left jugal, lateral view; (f) right angular, lateral view; (g) left articular, in (clockwise from upper left) lateral, medial, dorsal, caudal views; (h) cervical neural arch, in (left to right) caudal, lateral, cranial and dorsal views; (i) dorsal neural arch, in (left to right) right lateral, cranial and caudal views. Abbreviations: apm , ascending process, maxilla; bt , bulbous tuberosity; cpa , caudal process, articular; cpj , caudal process, jugal; cpm , caudal process, maxilla; dpa , dorsal process, articular; dpl , descending process, lacrimal; emf , external mandibular fenestra; gl , glenoid, gr , groove; lra , lateral ridge, angular; lrm , lateral ridge, maxilla; maj , maxillary articulation, jugal; mpp , maxillary process, premaxilla; n , naris; pol , centropostzygapophyseal lamina; poz , postzygapophysis; ppj , postorbital process, jugal; pr , prong; prl , centroprezygapophyseal lamina; prz , prezygapophysis; sn , subnarial notch; tp , transverse process; vmp , ventromedial process. Scale bar: 10 cm. Full size image Referred materials NCSM 21623, partial right humerus. Locality and horizon Chatham County, North Carolina, USA; Pekin Formation, Chatham Group, Newark Supergroup, ~231 Ma 12 , Carnian, Late Triassic (SI–II). Diagnosis Large-bodied (~3 m) crocodylomorph distinguished by the following features (loricatan autapomorphies denoted by an asterisk): six premaxillary teeth*; horizontally directed maxillary process of premaxilla; elongate, subtriangular antorbital fenestra (length to height ratio ~2.3); caudodorsally trending lateral ridge on maxilla terminates at margin of antorbital fenestra*; caudal process of maxilla rostrally pinched, minimum dorsoventral height at rostralmost corner of antorbital fenestra*; jugal with ornamented lateral boss*; caudally deep antorbital fossa, with anteriorly directed flange extending from rostral margin of lacrimal*; caudal margin of antorbital fossa vertically oriented (caudodorsal corner directly dorsal to caudoventral corner)*; antorbital fossa more than twice the estimated area of the orbit*; bifurcated caudal process of jugal bearing a small caudodorsally directed flange*; small, sub-conical, medial process of articular; pronounced crainocaudally oriented ridge on caudal aspect of lateral surface of angular; ectepicondylar crest proximal to the radial condyle of the humerus. Description All neurocentral sutures remain open in NCSM 21558 indicating a skeletally immature individual 13 . The skull is rostrally elongate (estimated minimum length > 50 cm) and lightly built ( Fig. 1a ). The maxillary process of the premaxilla projects horizontally; it is subequal in length and parallel with, the alveolar margin ( Fig. 1b ). The premaxilla bears six premaxillary teeth ( Fig. S9b ) and a subnarial notch along the caudoventral margin of the tooth row ( Fig. 1b , S1 ) as in Dromicosuchus 14 NCSM 13733 (formerly UNC 15574) and the early crocodylomorph CM 29894. The palatal process exhibits a rostral palatal foramen (for the fourth dentary tooth 15 ). The antorbital fenestra is", "role": "user" }, { "content": "A newly discovered crocodilian ancestor may have filled one of North America's top predator roles before dinosaurs arrived on the continent. Carnufex carolinensis, or the \"Carolina Butcher,\" was a 9-foot long, land-dwelling crocodylomorph that walked on its hind legs and likely preyed upon smaller inhabitants of North Carolina ecosystems such as armored reptiles and early mammal relatives. Paleontologists from North Carolina State University and the North Carolina Museum of Natural Sciences recovered parts of Carnufex's skull, spine and upper forelimb from the Pekin Formation in Chatham County, North Carolina. Because the skull of Carnufex was preserved in pieces, it was difficult to visualize what the complete skull would have looked like in life. To get a fuller picture of Carnufex's skull the researchers scanned the individual bones with the latest imaging technology - a high-resolution surface scanner. Then they created a three-dimensional model of the reconstructed skull, using the more complete skulls of close relatives to fill in the missing pieces. The Pekin Formation contains sediments deposited 231 million years ago in the beginning of the Late Triassic (the Carnian), when what is now North Carolina was a wet, warm equatorial region beginning to break apart from the supercontinent Pangea. \"Fossils from this time period are extremely important to scientists because they record the earliest appearance of crocodylomorphs and theropod dinosaurs, two groups that first evolved in the Triassic period, yet managed to survive to the present day in the form of crocodiles and birds,\" says Lindsay Zanno, assistant research professor at NC State, director of the Paleontology and Geology lab at the museum, and lead author of a paper describing the find. \"The discovery of Carnufex, one of the world's earliest and largest crocodylomorphs, adds new information to the push and pull of top terrestrial predators across Pangea.\" Typical predators roaming Pangea included large-bodied rauisuchids and poposauroids, fearsome cousins of ancient crocodiles that went extinct in the Triassic Period. In the Southern Hemisphere, \"these animals hunted alongside the earliest theropod dinosaurs, creating a predator pile-up,\" says Zanno. However, the discovery of Carnufex indicates that in the north, large-bodied crocodylomorphs, not dinosaurs, were adding to the diversity of top predator niches. \"We knew that there were too many top performers on the proverbial stage in the Late Triassic,\" Zanno adds. \"Yet, until we deciphered the story behind Carnufex, it wasn't clear that early crocodile ancestors were among those vying for top predator roles prior to the reign of dinosaurs in North America.\" Reconstructed skull of Carnufex carolinensis. 3-D surface models of skull bones are shown in white. Grey areas are missing elements reconstructed from close relatives of Carnufex. Credit: Lindsay Zanno As the Triassic drew to a close, extinction decimated this panoply of predators and only small-bodied crocodylomorphs and theropods survived. \"Theropods were ready understudies for vacant top predator niches when large-bodied crocs and their relatives bowed out,\" says Zanno. \"Predatory dinosaurs went on to fill these roles exclusively for the next 135 million years.\" Still, ancient crocodiles found success in other places. \"As theropod dinosaurs started to make it big, the ancestors of modern crocs initially took on a role similar to foxes or jackals, with small, sleek bodies and long limbs,\" says Susan Drymala, graduate student at NC State and co-author of the paper. \"If you want to picture these animals, just think of a modern day fox, but with alligator skin instead of fur.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Triassic predatory guild evolution reflects a period of ecological flux spurred by the catastrophic end-Permian mass extinction and terminating with the global ecological dominance of dinosaurs in the early Jurassic. In responding to this dynamic ecospace, terrestrial predator diversity attained new levels, prompting unique trophic webs with a seeming overabundance of carnivorous taxa and the evolution of entirely new predatory clades. Key among these was Crocodylomorpha, the largest living reptiles and only one of two archosaurian lineages that survive to the present day. In contrast to their existing role as top, semi-aquatic predators, the earliest crocodylomorphs were generally small-bodied, terrestrial faunivores, occupying subsidiary (meso) predator roles. Here we describe Carnufex carolinensis a new, unexpectedly large-bodied taxon with a slender and ornamented skull from the Carnian Pekin Formation (~231 Ma), representing one of the oldest and earliest diverging crocodylomorphs described to date. Carnufex bridges a problematic gap in the early evolution of pseudosuchians by spanning key transitions in bauplan evolution and body mass near the origin of Crocodylomorpha. With a skull length of >50 cm, the new taxon documents a rare instance of crocodylomorphs ascending to top-tier predator guilds in the equatorial regions of Pangea prior to the dominance of dinosaurs. Introduction The composition of modern ecosystems can be traced to the dynamic recovery of life in the aftermath of the catastrophic end-Permian mass extinction 1 . During the Triassic Period, unstable biotic communities 2 and morphing ecospace 3 gave rise to extant vertebrate clades such as frogs, lizards, mammals, turtles and dinosaurs 1 , 4 , 5 and spurred seemingly unbalanced trophic assemblages dominated by an excess of predatory taxa 6 . In the Middle Triassic, terrestrial predator assemblages included the small-bodied mesopredators Gracilisuchidae 7 and top tier predator guilds dominated by poposauroids and basal loricatans (“rauisuchians”) 8 . By the Late Triassic, subsidiary predator guilds had shifted composition to newly emerging clades such as ornithosuchids 9 , early dinosaurs 4 , 5 and the oldest known crocodylomorphs 10 . Whereas apex predator guilds were thought to be more highly conserved, retaining Middle Triassic representatives and expanding to include large-bodied theropod dinosaurs and rauisuchids 8 . Here we describe a new species of crocodylomorph from the Carnian Pekin Formation, North Carolina, USA, representing one of the oldest, largest and most basal crocodylomorphs yet discovered. This new taxon adds to a growing body of evidence that Triassic crocodylomorphs were more diverse than previously appreciated and that theropod dinosaurs and crocodylomorphs exploited a wide trophic reach 11 , occupying both subsidiary and top-tier predator roles in the Late Triassic. Results Systematic paleontology Archosauria Cope, 1869. Pseudosuchia Zittel, 1887–1890. Crocodylomorpha Walker, 1968 sensu Nesbitt 2011. Carnufex carolinensis gen. et sp. nov. Etymology Carnufex (Latin) butcher; carolinensis , in reference to the region of discovery. Holotype NCSM 21558, partial skull and postcranial skeleton including: right dentigerous premaxilla, left maxilla, left lacrimal, left jugal, left articular, right angular, isolated maxillary tooth, cervical neural arch, dorsal neural arch, cervical rib, dorsal ribs and left humerus. ( Fig. 1 , S9 ). Figure 1 Three dimensional skull reconstruction and representative elements of Carnufex carolinensis (NCSM 21558). (a) reconstructed skull, clockwise from upper left, rostral, oblique and lateral views; (b) right premaxilla, lateral view; (c) left maxilla, lateral view; (d) left lacrimal, lateral view; (e) left jugal, lateral view; (f) right angular, lateral view; (g) left articular, in (clockwise from upper left) lateral, medial, dorsal, caudal views; (h) cervical neural arch, in (left to right) caudal, lateral, cranial and dorsal views; (i) dorsal neural arch, in (left to right) right lateral, cranial and caudal views. Abbreviations: apm , ascending process, maxilla; bt , bulbous tuberosity; cpa , caudal process, articular; cpj , caudal process, jugal; cpm , caudal process, maxilla; dpa , dorsal process, articular; dpl , descending process, lacrimal; emf , external mandibular fenestra; gl , glenoid, gr , groove; lra , lateral ridge, angular; lrm , lateral ridge, maxilla; maj , maxillary articulation, jugal; mpp , maxillary process, premaxilla; n , naris; pol , centropostzygapophyseal lamina; poz , postzygapophysis; ppj , postorbital process, jugal; pr , prong; prl , centroprezygapophyseal lamina; prz , prezygapophysis; sn , subnarial notch; tp , transverse process; vmp , ventromedial process. Scale bar: 10 cm. Full size image Referred materials NCSM 21623, partial right humerus. Locality and horizon Chatham County, North Carolina, USA; Pekin Formation, Chatham Group, Newark Supergroup, ~231 Ma 12 , Carnian, Late Triassic (SI–II). Diagnosis Large-bodied (~3 m) crocodylomorph distinguished by the following features (loricatan autapomorphies denoted by an asterisk): six premaxillary teeth*; horizontally directed maxillary process of premaxilla; elongate, subtriangular antorbital fenestra (length to height ratio ~2.3); caudodorsally trending lateral ridge on maxilla terminates at margin of antorbital fenestra*; caudal process of maxilla rostrally pinched, minimum dorsoventral height at rostralmost corner of antorbital fenestra*; jugal with ornamented lateral boss*; caudally deep antorbital fossa, with anteriorly directed flange extending from rostral margin of lacrimal*; caudal margin of antorbital fossa vertically oriented (caudodorsal corner directly dorsal to caudoventral corner)*; antorbital fossa more than twice the estimated area of the orbit*; bifurcated caudal process of jugal bearing a small caudodorsally directed flange*; small, sub-conical, medial process of articular; pronounced crainocaudally oriented ridge on caudal aspect of lateral surface of angular; ectepicondylar crest proximal to the radial condyle of the humerus. Description All neurocentral sutures remain open in NCSM 21558 indicating a skeletally immature individual 13 . The skull is rostrally elongate (estimated minimum length > 50 cm) and lightly built ( Fig. 1a ). The maxillary process of the premaxilla projects horizontally; it is subequal in length and parallel with, the alveolar margin ( Fig. 1b ). The premaxilla bears six premaxillary teeth ( Fig. S9b ) and a subnarial notch along the caudoventral margin of the tooth row ( Fig. 1b , S1 ) as in Dromicosuchus 14 NCSM 13733 (formerly UNC 15574) and the early crocodylomorph CM 29894. The palatal process exhibits a rostral palatal foramen (for the fourth dentary tooth 15 ). The antorbital fenestra is<|im_end|> <|im_start|>assistant A newly discovered crocodilian ancestor may have filled one of North America's top predator roles before dinosaurs arrived on the continent. Carnufex carolinensis, or the "Carolina Butcher," was a 9-foot long, land-dwelling crocodylomorph that walked on its hind legs and likely preyed upon smaller inhabitants of North Carolina ecosystems such as armored reptiles and early mammal relatives. Paleontologists from North Carolina State University and the North Carolina Museum of Natural Sciences recovered parts of Carnufex's skull, spine and upper forelimb from the Pekin Formation in Chatham County, North Carolina. Because the skull of Carnufex was preserved in pieces, it was difficult to visualize what the complete skull would have looked like in life. To get a fuller picture of Carnufex's skull the researchers scanned the individual bones with the latest imaging technology - a high-resolution surface scanner. Then they created a three-dimensional model of the reconstructed skull, using the more complete skulls of close relatives to fill in the missing pieces. The Pekin Formation contains sediments deposited 231 million years ago in the beginning of the Late Triassic (the Carnian), when what is now North Carolina was a wet, warm equatorial region beginning to break apart from the supercontinent Pangea. "Fossils from this time period are extremely important to scientists because they record the earliest appearance of crocodylomorphs and theropod dinosaurs, two groups that first evolved in the Triassic period, yet managed to survive to the present day in the form of crocodiles and birds," says Lindsay Zanno, assistant research professor at NC State, director of the Paleontology and Geology lab at the museum, and lead author of a paper describing the find. "The discovery of Carnufex, one of the world's earliest and largest crocodylomorphs, adds new information to the push and pull of top terrestrial predators across Pangea." Typical predators roaming Pangea included large-bodied rauisuchids and poposauroids, fearsome cousins of ancient crocodiles that went extinct in the Triassic Period. In the Southern Hemisphere, "these animals hunted alongside the earliest theropod dinosaurs, creating a predator pile-up," says Zanno. However, the discovery of Carnufex indicates that in the north, large-bodied crocodylomorphs, not dinosaurs, were adding to the diversity of top predator niches. "We knew that there were too many top performers on the proverbial stage in the Late Triassic," Zanno adds. "Yet, until we deciphered the story behind Carnufex, it wasn't clear that early crocodile ancestors were among those vying for top predator roles prior to the reign of dinosaurs in North America." Reconstructed skull of Carnufex carolinensis. 3-D surface models of skull bones are shown in white. Grey areas are missing elements reconstructed from close relatives of Carnufex. Credit: Lindsay Zanno As the Triassic drew to a close, extinction decimated this panoply of predators and only small-bodied crocodylomorphs and theropods survived. "Theropods were ready understudies for vacant top predator niches when large-bodied crocs and their relatives bowed out," says Zanno. "Predatory dinosaurs went on to fill these roles exclusively for the next 135 million years." Still, ancient crocodiles found success in other places. "As theropod dinosaurs started to make it big, the ancestors of modern crocs initially took on a role similar to foxes or jackals, with small, sleek bodies and long limbs," says Susan Drymala, graduate student at NC State and co-author of the paper. "If you want to picture these animals, just think of a modern day fox, but with alligator skin instead of fur." <|im_end|>

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2,567

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract How quasars powered by supermassive black holes formed less than a billion years after the Big Bang is still one of the outstanding problems in astrophysics, 20 years after their discovery 1 , 2 , 3 , 4 . Cosmological simulations suggest that rare cold flows converging on primordial haloes in low-shear environments could have created these quasars if they were 10 4 –10 5 solar masses at birth, but could not resolve their formation 5 , 6 , 7 , 8 . Semi-analytical studies of the progenitor halo of a primordial quasar found that it favours the formation of such seeds, but could not verify if one actually appeared 9 . Here we show that a halo at the rare convergence of strong, cold accretion flows creates massive black holes seeds without the need for ultraviolet backgrounds, supersonic streaming motions or even atomic cooling. Cold flows drive violent, supersonic turbulence in the halo, which prevents star formation until it reaches a mass that triggers sudden, catastrophic baryon collapse that forms 31,000 and 40,000 solar-mass stars. This simple, robust process ensures that haloes capable of forming quasars by a redshift of z > 6 produce massive seeds. The first quasars were thus a natural consequence of structure formation in cold dark matter cosmologies, and not exotic, finely tuned environments as previously thought 10 , 11 , 12 , 13 , 14 . Main We investigated supermassive black hole (SMBH) seed formation during the earliest stages of collapse of the progenitor halo of a z > 6 quasar with the Enzo cosmology code. This halo grows to 1.4 × 10 12 M ⊙ ( M ⊙ , solar mass) by a redshift of z = 6 mostly by cold flow accretion 15 , 16 , 17 rather than by major mergers with other gas-rich haloes 18 , and it is not in close proximity to any external sources of Lyman–Werner (LW) ultraviolet (UV) flux or in any LW backgrounds when it first collapses. Our simulation resolves the halo when it reaches a mass of 3.9 × 10 5 M ⊙ at z = 35, the approximate minimum mass at which it could form Population III (Pop III) stars. However, highly supersonic turbulence driven by the cold flows from large scales prevents gas in the halo from collapsing into stars at this mass. As shown at z = 29 in Fig. 1 , turbulent velocities are 30–40 km s −1 , a factor of a few higher than the infall velocities, and more than an order of magnitude greater than the sound speed of the gas. Fig. 1: Spherically averaged velocity profiles of the halo. The infall velocities (solid), turbulent velocities (dashed) and sound speeds (dotted) are at just before collapse ( z = 29, green), the onset of collapse ( z = 25.74, blue) and well into collapse ( z = 25.73, red). Enclosed gas masses of 10 4 M ⊙ and 10 6 M ⊙ correspond to radii of about 1 pc and 100 pc, respectively. Full size image Over the next 45 Myr the halo grows by two orders of magnitude in mass, to 4 × 10 7 M ⊙ by z = 25.7, at an average rate of about 0.9 M ⊙ yr −1 . Although this is roughly four times the mass at which atomic cooling normally begins 19 (2.2 × 10 7 M ⊙ [(1 + z )/16] −3/2 ), the gas does not collapse by Lyα emission because temperatures in the halo never exceed 2,000 K. Collapse is instead triggered when infall velocities finally exceed turbulent velocities because the halo has grown so much in mass, as shown in Fig. 1 , and gravitational compression overcomes turbulent pressure support. We show density and temperature projections of the halo at the onset of collapse in Fig. 2 . The four cold accretion streams seen in the 100 pc image carry gas at densities of 10 3 –10 4 cm −3 deep into the halo and create the highly turbulent core visible in the 10 pc panel. Energy transfer from scales of tens of kpc down to pc scales drives this turbulence. A dense clump appears in the core 5 kyr after the onset of collapse, as shown in the 0.1 pc image. It forms a small self-gravitating disk with two prominent spiral arms and a mass of about 1,000 M ⊙ , as shown in the 0.02 pc panel. Analysis indicates that it is stable to fragmentation, and it rotates at nearly the Keplerian velocity with influx rates of about 1 M ⊙ yr −1 . However, before this clump can form a star it becomes part of a much larger clump that forms a supermassive star later on (C2, as discussed below). Fig. 2: Catastrophic baryon collapse in the halo at z = 25.7. a – h , Densities (left) and temperatures (right) at the onset of collapse ( a , e ), at 4.5 kyr ( b , f ), at 5.5 kyr ( c , g ) and at 11 kyr ( d , h ). Full size image Unlike collapse in normal Pop III star-forming haloes, which creates quasi-static settling flows 20 , or in atomically cooled haloes in which there is at most transonic turbulence, collapse in this halo proceeds on two scales via two distinct physical processes. As shown in Fig. 3 , it begins on scales of 20–200 pc when cold flows finally overcome the turbulent pressure that they originally created and settle onto the core of the halo at influx rates of up to 40 M ⊙ yr −1 . The pile up of gas at the outer layers of the core is visible in the peaks in the density and infall velocity profiles at 20 pc. Collapse on these scales is driven mostly by dynamics. Infall at larger scales compresses gas to densities of 10 −16 g cm −3 at radii below 0.01 pc, activating rapid", "role": "user" }, { "content": "The mystery of how the first quasars in the universe formed—something that has baffled scientists for nearly 20 years—has now been solved by a team of astrophysicists whose findings are published in Nature. The existence of more than 200 quasars powered by supermassive black holes less than a billion years after the Big Bang had remained one of the outstanding problems in astrophysics because it was never fully understood how they formed so early. The team of experts led by Dr. Daniel Whalen from the University of Portsmouth have found that the first quasars naturally formed in the violent, turbulent conditions of rare reservoirs of gas in the early universe. Dr. Whalen, from the University's Institute of Cosmology and Gravitation, said: \"This discovery is particularly exciting because it has overturned 20 years of thought on the origin of the first supermassive black holes in the universe. This video shows a supercomputer simulation of the birth of a primordial quasar. Credit: University of Portsmouth \"We find supermassive black holes at the centers of most massive galaxies today, which can be millions or billions of times the mass of the sun. But back in 2003 we began finding quasars—highly luminous, actively-accreting supermassive black holes that are like cosmic lighthouses in the early universe—that existed less than a billion years after the Big Bang. And no one understood how they formed by such early times.\" A few years ago, supercomputer simulations showed that early quasars could form at the junctions of rare, cold, powerful streams of gas. Only a dozen of these existed in a volume of space a billion light-years across, but the black hole had to be 100,000 solar masses at birth. Black holes today form when massive stars run out of fuel and collapse, but they are usually only 10–100 solar masses. Astrophysicists had long theorized that 10,000–100,000 solar-mass stars formed in the early universe but only in exotic, finely-tuned environments like strong ultraviolet backgrounds or supersonic flows between gas and dark matter that had no resemblance to the turbulent clouds in which the first quasars formed. Dr. Whalen said: \"We think of these stars as a bit like dinosaurs on earth, they were enormous and primitive. And they had short lives, living for just a quarter of a million years before collapsing to black holes. \"Our supercomputer models went back to very early times and found that the cold, dense streams of gas capable of growing a billion solar-mass black hole in just a few hundred million years created their own supermassive stars without any need for unusual environments. The cold streams drove turbulence in the cloud that prevented normal stars from forming until the cloud became so massive it collapsed catastrophically under its own weight, forming two gigantic primordial stars—one which was 30,000 solar masses and another which was 40,000. \"Consequently, the only primordial clouds that could form a quasar just after cosmic dawn -when the first stars in the universe formed—also conveniently created their own massive seeds. This simple, beautiful result not only explains the origin of the first quasars but also their demographics—their numbers at early times. \"The first supermassive black holes were simply a natural consequence of structure formation in cold dark matter cosmologies—children of the cosmic web.\" The paper \"The Turbulent Origins of the First Quasars\" is published in Nature. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract How quasars powered by supermassive black holes formed less than a billion years after the Big Bang is still one of the outstanding problems in astrophysics, 20 years after their discovery 1 , 2 , 3 , 4 . Cosmological simulations suggest that rare cold flows converging on primordial haloes in low-shear environments could have created these quasars if they were 10 4 –10 5 solar masses at birth, but could not resolve their formation 5 , 6 , 7 , 8 . Semi-analytical studies of the progenitor halo of a primordial quasar found that it favours the formation of such seeds, but could not verify if one actually appeared 9 . Here we show that a halo at the rare convergence of strong, cold accretion flows creates massive black holes seeds without the need for ultraviolet backgrounds, supersonic streaming motions or even atomic cooling. Cold flows drive violent, supersonic turbulence in the halo, which prevents star formation until it reaches a mass that triggers sudden, catastrophic baryon collapse that forms 31,000 and 40,000 solar-mass stars. This simple, robust process ensures that haloes capable of forming quasars by a redshift of z > 6 produce massive seeds. The first quasars were thus a natural consequence of structure formation in cold dark matter cosmologies, and not exotic, finely tuned environments as previously thought 10 , 11 , 12 , 13 , 14 . Main We investigated supermassive black hole (SMBH) seed formation during the earliest stages of collapse of the progenitor halo of a z > 6 quasar with the Enzo cosmology code. This halo grows to 1.4 × 10 12 M ⊙ ( M ⊙ , solar mass) by a redshift of z = 6 mostly by cold flow accretion 15 , 16 , 17 rather than by major mergers with other gas-rich haloes 18 , and it is not in close proximity to any external sources of Lyman–Werner (LW) ultraviolet (UV) flux or in any LW backgrounds when it first collapses. Our simulation resolves the halo when it reaches a mass of 3.9 × 10 5 M ⊙ at z = 35, the approximate minimum mass at which it could form Population III (Pop III) stars. However, highly supersonic turbulence driven by the cold flows from large scales prevents gas in the halo from collapsing into stars at this mass. As shown at z = 29 in Fig. 1 , turbulent velocities are 30–40 km s −1 , a factor of a few higher than the infall velocities, and more than an order of magnitude greater than the sound speed of the gas. Fig. 1: Spherically averaged velocity profiles of the halo. The infall velocities (solid), turbulent velocities (dashed) and sound speeds (dotted) are at just before collapse ( z = 29, green), the onset of collapse ( z = 25.74, blue) and well into collapse ( z = 25.73, red). Enclosed gas masses of 10 4 M ⊙ and 10 6 M ⊙ correspond to radii of about 1 pc and 100 pc, respectively. Full size image Over the next 45 Myr the halo grows by two orders of magnitude in mass, to 4 × 10 7 M ⊙ by z = 25.7, at an average rate of about 0.9 M ⊙ yr −1 . Although this is roughly four times the mass at which atomic cooling normally begins 19 (2.2 × 10 7 M ⊙ [(1 + z )/16] −3/2 ), the gas does not collapse by Lyα emission because temperatures in the halo never exceed 2,000 K. Collapse is instead triggered when infall velocities finally exceed turbulent velocities because the halo has grown so much in mass, as shown in Fig. 1 , and gravitational compression overcomes turbulent pressure support. We show density and temperature projections of the halo at the onset of collapse in Fig. 2 . The four cold accretion streams seen in the 100 pc image carry gas at densities of 10 3 –10 4 cm −3 deep into the halo and create the highly turbulent core visible in the 10 pc panel. Energy transfer from scales of tens of kpc down to pc scales drives this turbulence. A dense clump appears in the core 5 kyr after the onset of collapse, as shown in the 0.1 pc image. It forms a small self-gravitating disk with two prominent spiral arms and a mass of about 1,000 M ⊙ , as shown in the 0.02 pc panel. Analysis indicates that it is stable to fragmentation, and it rotates at nearly the Keplerian velocity with influx rates of about 1 M ⊙ yr −1 . However, before this clump can form a star it becomes part of a much larger clump that forms a supermassive star later on (C2, as discussed below). Fig. 2: Catastrophic baryon collapse in the halo at z = 25.7. a – h , Densities (left) and temperatures (right) at the onset of collapse ( a , e ), at 4.5 kyr ( b , f ), at 5.5 kyr ( c , g ) and at 11 kyr ( d , h ). Full size image Unlike collapse in normal Pop III star-forming haloes, which creates quasi-static settling flows 20 , or in atomically cooled haloes in which there is at most transonic turbulence, collapse in this halo proceeds on two scales via two distinct physical processes. As shown in Fig. 3 , it begins on scales of 20–200 pc when cold flows finally overcome the turbulent pressure that they originally created and settle onto the core of the halo at influx rates of up to 40 M ⊙ yr −1 . The pile up of gas at the outer layers of the core is visible in the peaks in the density and infall velocity profiles at 20 pc. Collapse on these scales is driven mostly by dynamics. Infall at larger scales compresses gas to densities of 10 −16 g cm −3 at radii below 0.01 pc, activating rapid<|im_end|> <|im_start|>assistant The mystery of how the first quasars in the universe formed—something that has baffled scientists for nearly 20 years—has now been solved by a team of astrophysicists whose findings are published in Nature. The existence of more than 200 quasars powered by supermassive black holes less than a billion years after the Big Bang had remained one of the outstanding problems in astrophysics because it was never fully understood how they formed so early. The team of experts led by Dr. Daniel Whalen from the University of Portsmouth have found that the first quasars naturally formed in the violent, turbulent conditions of rare reservoirs of gas in the early universe. Dr. Whalen, from the University's Institute of Cosmology and Gravitation, said: "This discovery is particularly exciting because it has overturned 20 years of thought on the origin of the first supermassive black holes in the universe. This video shows a supercomputer simulation of the birth of a primordial quasar. Credit: University of Portsmouth "We find supermassive black holes at the centers of most massive galaxies today, which can be millions or billions of times the mass of the sun. But back in 2003 we began finding quasars—highly luminous, actively-accreting supermassive black holes that are like cosmic lighthouses in the early universe—that existed less than a billion years after the Big Bang. And no one understood how they formed by such early times." A few years ago, supercomputer simulations showed that early quasars could form at the junctions of rare, cold, powerful streams of gas. Only a dozen of these existed in a volume of space a billion light-years across, but the black hole had to be 100,000 solar masses at birth. Black holes today form when massive stars run out of fuel and collapse, but they are usually only 10–100 solar masses. Astrophysicists had long theorized that 10,000–100,000 solar-mass stars formed in the early universe but only in exotic, finely-tuned environments like strong ultraviolet backgrounds or supersonic flows between gas and dark matter that had no resemblance to the turbulent clouds in which the first quasars formed. Dr. Whalen said: "We think of these stars as a bit like dinosaurs on earth, they were enormous and primitive. And they had short lives, living for just a quarter of a million years before collapsing to black holes. "Our supercomputer models went back to very early times and found that the cold, dense streams of gas capable of growing a billion solar-mass black hole in just a few hundred million years created their own supermassive stars without any need for unusual environments. The cold streams drove turbulence in the cloud that prevented normal stars from forming until the cloud became so massive it collapsed catastrophically under its own weight, forming two gigantic primordial stars—one which was 30,000 solar masses and another which was 40,000. "Consequently, the only primordial clouds that could form a quasar just after cosmic dawn -when the first stars in the universe formed—also conveniently created their own massive seeds. This simple, beautiful result not only explains the origin of the first quasars but also their demographics—their numbers at early times. "The first supermassive black holes were simply a natural consequence of structure formation in cold dark matter cosmologies—children of the cosmic web." The paper "The Turbulent Origins of the First Quasars" is published in Nature. <|im_end|>

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315, 279, 71812, 520, 279, 42080, 315, 18678, 304, 23966, 13, 220, 17, 662, 578, 3116, 9439, 1046, 2171, 290, 23914, 3970, 304, 279, 220, 1041, 13615, 2217, 6920, 6962, 520, 90816, 315, 220, 605, 220, 18, 1389, 605, 220, 19, 10166, 25173, 18, 5655, 1139, 279, 71812, 323, 1893, 279, 7701, 83321, 6332, 9621, 304, 279, 220, 605, 13615, 7090, 13, 12634, 8481, 505, 29505, 315, 22781, 315, 597, 4080, 1523, 311, 13615, 29505, 20722, 420, 95167, 13, 362, 29050, 1206, 1538, 8111, 304, 279, 6332, 220, 20, 597, 11160, 1306, 279, 42080, 315, 18678, 11, 439, 6982, 304, 279, 220, 15, 13, 16, 13615, 2217, 13, 1102, 7739, 264, 2678, 659, 25313, 44210, 1113, 13668, 449, 1403, 21102, 42197, 11977, 323, 264, 3148, 315, 922, 220, 16, 11, 931, 386, 54125, 247, 1174, 439, 6982, 304, 279, 220, 15, 13, 2437, 13615, 7090, 13, 18825, 15151, 430, 433, 374, 15528, 311, 88452, 11, 323, 433, 90159, 520, 7154, 279, 98843, 1122, 15798, 449, 53952, 7969, 315, 922, 220, 16, 386, 54125, 247, 43438, 25173, 16, 662, 4452, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Supercapacitors represent an important strategy for electrochemical energy storage, but are usually limited by relatively low energy density. Here we report a three-dimensional holey graphene framework with a hierarchical porous structure as a high-performance binder-free supercapacitor electrode. With large ion-accessible surface area, efficient electron and ion transport pathways as well as a high packing density, the holey graphene framework electrode can deliver a gravimetric capacitance of 298 F g −1 and a volumetric capacitance of 212 F cm −3 in organic electrolyte. Furthermore, we show that a fully packaged device stack can deliver gravimetric and volumetric energy densities of 35 Wh kg −1 and 49 Wh l −1 , respectively, approaching those of lead acid batteries. The achievement of such high energy density bridges the gap between traditional supercapacitors and batteries, and can open up exciting opportunities for mobile power supply in diverse applications. Introduction Electrochemical capacitors (ECs), also known as supercapacitors, represent an attractive technology for energy storage and mobile power supply. ECs typically exhibit superior power density and cycle life, but with relatively poor energy density at least one order of magnitude lower than those of traditional batteries 1 , 2 , 3 . The electrode material is the central component of an EC and largely dictates its ultimate performance. Considerable efforts have been focused on developing new electrode materials that can greatly increase the energy density without sacrificing the power density or cycle life 3 , 4 , 5 , 6 . In general, a high-performance EC electrode requires high electrical conductivity, high ion-accessible surface area, high ionic transport rate and high electrochemical stability. To this end, carbon-based porous materials represent the most attractive class of EC electrode materials. The state-of-the-art ECs available today are mainly constructed using porous activated carbon electrodes typically with a gravimetric capacitance of 80–120 F g − 1 and a stack energy density of 4–5 Wh kg − 1 (ref. 4 ), much lower than that of lead acid batteries (25–35 Wh kg −1 ) (ref. 1 ). Graphene has recently received intensive interest as a new EC electrode material because of its high intrinsic electrical conductivity, excellent mechanical flexibility, exceptionally large theoretical surface area of 2,630 m 2 g −1 and theoretical gravimetric capacitance of about 550 F g −1 (refs 7 , 8 ). However, due to the strong π – π interaction between graphene sheets, the graphene flakes tend to restack to form graphite-like powders or films, which can severely decrease the accessible surface area and reduce the ion diffusion rate, resulting in unsatisfactory gravimetric capacitances (typically <180 F g −1 in organic electrolytes) and relatively low charge/discharge rates 7 , 8 , 9 , 10 , 11 . A traditional activation method was recently employed to prepare activated graphene with abundant ultrasmall micropores and ultrahigh specific surface area up to 2,400–3,100 m 2 g −1 (ref. 12 ), but only with a gravimetric capacitance of 165 F g −1 because of the difficulty for the electrolyte ions to efficiently access the micropore surfaces 3 . More recently, it has been shown that laser-scribed graphene with open porous structure can be used to mitigate these challenges to increase the accessible surface area and boost the gravimetric capacitance up to 276 F g −1 (ref. 13 ). Although gravimetric capacitance was traditionally used as the figure-of-merit to evaluate an EC electrode, the volumetric performance is becoming an increasingly important metric to consider for many practical applications with limited space such as portable electronic products 14 , 15 , 16 , 17 , 18 , 19 , 20 . However, there is usually a trade-off relationship between the gravimetric and volumetric capacitances for most electrode design. On one hand, a highly porous electrode can offer large specific surface area and favour ion diffusion for high gravimetric capacitance, but usually results in a lower volumetric capacitance due to its relatively low packing density. In addition, an EC electrode made from low-packing-density materials usually have abundant empty spaces that could be flooded by the electrolyte, which could increase the total mass of the device and lower the overall energy density normalized by the total mass of the entire device 14 , 15 . On the other hand, a more compact electrode may boost the volumetric capacitance but decrease the ion-accessible surface area and ion diffusion rate to result in a lower gravimetric capacitance and poor rate performance. For example, for the EC electrodes made from laser-scribed porous graphene aforementioned, they typically exhibit a rather low packing density of ~0.05 g cm −3 , and consequently a relatively low volumetric capacitance in spite of their excellent gravimetric performance 13 . By creating a highly compact graphene film using vacuum filtration and capillary compression, a recent study has reported a greatly improved volumetric capacitance exceeding 200 F cm −3 , yet with a modest gravimetric capacitance of 167 F g −1 (ref. 16 ). Together, it remains a considerable challenge to simultaneously achieve high gravimetric and high volumetric capacitances while retaining excellent rate capability. Here, we report a free-standing holey graphene framework (HGF) with a high packing density and efficient ion transport pathway to enable high-performance EC electrodes simultaneously with the highest gravimetric capacitance (298 F g −1 ) and the highest volumetric capacitance (212 F cm −3 ) achieved in organic electrolyte to date. We further show that a fully packaged HGF EC can deliver gravimetric and volumetric energy densities of 35 Wh kg −1 and 49 Wh l −1 , approaching those of lead acid batteries. Results Structural features of HGFs for supercapacitors The HGFs are formed by conjugating holey graphene sheets into a free-standing three-dimensional (3D) network. The unique structure of the HGFs satisfies several critical requirements for an ideal EC electrode ( Fig. 1 ). First, the graphene sheets in 3D network are highly interconnected and interlocked together to prevent them from restacking and to maintain a highly porous monolithic graphene framework (GF) ( Fig. 1a ) with large specific", "role": "user" }, { "content": "(Phys.org) —Researchers at the California NanoSystems Institute (CNSI) at UCLA have set the stage for a watershed in mobile energy storage by using a special graphene material to significantly boost the energy density of electrochemical capacitors, putting them on a par with lead acid batteries. The material, called a holey graphene framework, has a three-dimensional, perforated structure characterized by tiny holes; it not only increases energy density (the amount of energy stored and ready for use) but allows electrochemical capacitors to maintain their high power density (the amount of power per unit of mass or volume), according to Xiangfeng Duan, a UCLA professor of chemistry and biochemistry who led the research. Electrochemical capacitors, also known as ECs or supercapacitors, are an important technology for the future of energy storage and mobile power supplies, but they have been limited by low energy density. Compared with traditional batteries, ECs typically have superior power density and cycle life—the number of complete charge–discharge cycles an energy source can support before it decreases to 80 percent of its original capacity and is considered \"worn out.\" But they have had energy density of at least one order of magnitude below batteries. Because the main component of an EC is its electrode material, which is responsible for the EC's overall performance, recent research has focused on efficient new materials that are able to increase energy density without sacrificing power density or cycle life. A high-performance EC electrode must have high electrical conductivity, a high ion-accessible surface area, a high ionic transport rate and high electrochemical stability. Current state-of-the-art ECs generally use porous activated carbon electrodes with energy densities much lower than lead acid batteries—4 to 5 watt hours per kilogram vs. 25 to 35 watt hours per kilogram (5 to 7 watt hours per liter vs. 50 to 90 watt hours per liter). In their study, published online August 8 in the journal Nature Communications, the CNSI researchers led by Duan used a highly interconnected 3D holey graphene framework as the electrode material to create an EC with unprecedented performance. The electrode demonstrates superior electrical conductivity, exceptional mechanical flexibility and unique hierarchical porosity, ensuring the efficient transport of electrons and ions and enabling the highest gravimetric energy densities of 127 watt hours per kilogram and volumetric energy density of 90 watt hours per liter. Furthermore, the team has shown that a fully packaged EC exhibits unparalleled energy densities of 35 watt hours per kilogram (49 watt hours per liter)—about five to 10 times higher than current commercial supercapacitors and on a par with acid batteries. \"The holey grahene EC bridges the energy density gap between traditional capacitors and batteries, yet with vastly higher power density,\" Duan said. \"It creates exciting opportunities for mobile power supplies for many applications from cell phones to electric vehicles.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Supercapacitors represent an important strategy for electrochemical energy storage, but are usually limited by relatively low energy density. Here we report a three-dimensional holey graphene framework with a hierarchical porous structure as a high-performance binder-free supercapacitor electrode. With large ion-accessible surface area, efficient electron and ion transport pathways as well as a high packing density, the holey graphene framework electrode can deliver a gravimetric capacitance of 298 F g −1 and a volumetric capacitance of 212 F cm −3 in organic electrolyte. Furthermore, we show that a fully packaged device stack can deliver gravimetric and volumetric energy densities of 35 Wh kg −1 and 49 Wh l −1 , respectively, approaching those of lead acid batteries. The achievement of such high energy density bridges the gap between traditional supercapacitors and batteries, and can open up exciting opportunities for mobile power supply in diverse applications. Introduction Electrochemical capacitors (ECs), also known as supercapacitors, represent an attractive technology for energy storage and mobile power supply. ECs typically exhibit superior power density and cycle life, but with relatively poor energy density at least one order of magnitude lower than those of traditional batteries 1 , 2 , 3 . The electrode material is the central component of an EC and largely dictates its ultimate performance. Considerable efforts have been focused on developing new electrode materials that can greatly increase the energy density without sacrificing the power density or cycle life 3 , 4 , 5 , 6 . In general, a high-performance EC electrode requires high electrical conductivity, high ion-accessible surface area, high ionic transport rate and high electrochemical stability. To this end, carbon-based porous materials represent the most attractive class of EC electrode materials. The state-of-the-art ECs available today are mainly constructed using porous activated carbon electrodes typically with a gravimetric capacitance of 80–120 F g − 1 and a stack energy density of 4–5 Wh kg − 1 (ref. 4 ), much lower than that of lead acid batteries (25–35 Wh kg −1 ) (ref. 1 ). Graphene has recently received intensive interest as a new EC electrode material because of its high intrinsic electrical conductivity, excellent mechanical flexibility, exceptionally large theoretical surface area of 2,630 m 2 g −1 and theoretical gravimetric capacitance of about 550 F g −1 (refs 7 , 8 ). However, due to the strong π – π interaction between graphene sheets, the graphene flakes tend to restack to form graphite-like powders or films, which can severely decrease the accessible surface area and reduce the ion diffusion rate, resulting in unsatisfactory gravimetric capacitances (typically <180 F g −1 in organic electrolytes) and relatively low charge/discharge rates 7 , 8 , 9 , 10 , 11 . A traditional activation method was recently employed to prepare activated graphene with abundant ultrasmall micropores and ultrahigh specific surface area up to 2,400–3,100 m 2 g −1 (ref. 12 ), but only with a gravimetric capacitance of 165 F g −1 because of the difficulty for the electrolyte ions to efficiently access the micropore surfaces 3 . More recently, it has been shown that laser-scribed graphene with open porous structure can be used to mitigate these challenges to increase the accessible surface area and boost the gravimetric capacitance up to 276 F g −1 (ref. 13 ). Although gravimetric capacitance was traditionally used as the figure-of-merit to evaluate an EC electrode, the volumetric performance is becoming an increasingly important metric to consider for many practical applications with limited space such as portable electronic products 14 , 15 , 16 , 17 , 18 , 19 , 20 . However, there is usually a trade-off relationship between the gravimetric and volumetric capacitances for most electrode design. On one hand, a highly porous electrode can offer large specific surface area and favour ion diffusion for high gravimetric capacitance, but usually results in a lower volumetric capacitance due to its relatively low packing density. In addition, an EC electrode made from low-packing-density materials usually have abundant empty spaces that could be flooded by the electrolyte, which could increase the total mass of the device and lower the overall energy density normalized by the total mass of the entire device 14 , 15 . On the other hand, a more compact electrode may boost the volumetric capacitance but decrease the ion-accessible surface area and ion diffusion rate to result in a lower gravimetric capacitance and poor rate performance. For example, for the EC electrodes made from laser-scribed porous graphene aforementioned, they typically exhibit a rather low packing density of ~0.05 g cm −3 , and consequently a relatively low volumetric capacitance in spite of their excellent gravimetric performance 13 . By creating a highly compact graphene film using vacuum filtration and capillary compression, a recent study has reported a greatly improved volumetric capacitance exceeding 200 F cm −3 , yet with a modest gravimetric capacitance of 167 F g −1 (ref. 16 ). Together, it remains a considerable challenge to simultaneously achieve high gravimetric and high volumetric capacitances while retaining excellent rate capability. Here, we report a free-standing holey graphene framework (HGF) with a high packing density and efficient ion transport pathway to enable high-performance EC electrodes simultaneously with the highest gravimetric capacitance (298 F g −1 ) and the highest volumetric capacitance (212 F cm −3 ) achieved in organic electrolyte to date. We further show that a fully packaged HGF EC can deliver gravimetric and volumetric energy densities of 35 Wh kg −1 and 49 Wh l −1 , approaching those of lead acid batteries. Results Structural features of HGFs for supercapacitors The HGFs are formed by conjugating holey graphene sheets into a free-standing three-dimensional (3D) network. The unique structure of the HGFs satisfies several critical requirements for an ideal EC electrode ( Fig. 1 ). First, the graphene sheets in 3D network are highly interconnected and interlocked together to prevent them from restacking and to maintain a highly porous monolithic graphene framework (GF) ( Fig. 1a ) with large specific<|im_end|> <|im_start|>assistant (Phys.org) —Researchers at the California NanoSystems Institute (CNSI) at UCLA have set the stage for a watershed in mobile energy storage by using a special graphene material to significantly boost the energy density of electrochemical capacitors, putting them on a par with lead acid batteries. The material, called a holey graphene framework, has a three-dimensional, perforated structure characterized by tiny holes; it not only increases energy density (the amount of energy stored and ready for use) but allows electrochemical capacitors to maintain their high power density (the amount of power per unit of mass or volume), according to Xiangfeng Duan, a UCLA professor of chemistry and biochemistry who led the research. Electrochemical capacitors, also known as ECs or supercapacitors, are an important technology for the future of energy storage and mobile power supplies, but they have been limited by low energy density. Compared with traditional batteries, ECs typically have superior power density and cycle life—the number of complete charge–discharge cycles an energy source can support before it decreases to 80 percent of its original capacity and is considered "worn out." But they have had energy density of at least one order of magnitude below batteries. Because the main component of an EC is its electrode material, which is responsible for the EC's overall performance, recent research has focused on efficient new materials that are able to increase energy density without sacrificing power density or cycle life. A high-performance EC electrode must have high electrical conductivity, a high ion-accessible surface area, a high ionic transport rate and high electrochemical stability. Current state-of-the-art ECs generally use porous activated carbon electrodes with energy densities much lower than lead acid batteries—4 to 5 watt hours per kilogram vs. 25 to 35 watt hours per kilogram (5 to 7 watt hours per liter vs. 50 to 90 watt hours per liter). In their study, published online August 8 in the journal Nature Communications, the CNSI researchers led by Duan used a highly interconnected 3D holey graphene framework as the electrode material to create an EC with unprecedented performance. The electrode demonstrates superior electrical conductivity, exceptional mechanical flexibility and unique hierarchical porosity, ensuring the efficient transport of electrons and ions and enabling the highest gravimetric energy densities of 127 watt hours per kilogram and volumetric energy density of 90 watt hours per liter. Furthermore, the team has shown that a fully packaged EC exhibits unparalleled energy densities of 35 watt hours per kilogram (49 watt hours per liter)—about five to 10 times higher than current commercial supercapacitors and on a par with acid batteries. "The holey grahene EC bridges the energy density gap between traditional capacitors and batteries, yet with vastly higher power density," Duan said. "It creates exciting opportunities for mobile power supplies for many applications from cell phones to electric vehicles." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury, surgery and infection. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Arthrofibrosis affects people of all ages, with published rates varying. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. The process begins when stress signals stimulate immune cells. The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts, which secrete fibrillar collagens and transforming growth factor-β (TGF-β). Positive feedback networks then dysregulate processes that normally terminate healing processes. We propose two subtypes of arthrofibrosis occur: active arthrofibrosis and residual arthrofibrosis. In the latter the fibrogenic processes have resolved but the joint remains stiff. The best therapeutic approach for each subtype may differ significantly. Treatment typically involves surgery, however, a pharmacological approach to correct dysregulated cell signalling could be more effective. Recent research shows that myofibroblasts are capable of reversing differentiation, and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments. Therapies with significant promise are currently available, with more in development, including those that inhibit TGF-β signalling and epigenetic modifications. This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments. Introduction Arthrofibrosis is a fibrotic joint disorder characterised by excessive collagen production and adhesions that result in restricted joint motion and pain. It can occur in most joints, 1 and is referred to by a number of names including frozen shoulder, adhesive capsulitis, joint contracture, stiff knee and stiff elbow. Sterile arthrofibrosis is typically caused by chronic or repetitive injury or surgery that leads to a dysregulated immune reaction and fibrosis in and/or around a joint 2 to varying degrees. The fibrotic scar tissue that forms in the joint is known as extracellular matrix (ECM), and is primarily composed of collagen. Although the term ECM includes a wide variety of biological components we use this established terminology when discussing fibrotic scar tissue. This forms adhesions within joint capsules and contracts tendons and bursa around the joint, 3 causing the loss of joint flexion and/or extension. In addition, scarred bursa may impinge into the joint causing more inflammation. Together with reduced range of motion (ROM), pain and varying amounts of swelling are commonly reported by patients. Arthrofibrosis affects people of all ages, although it is rare in children. 4 Arthrofibrosis frequently causes significant disability; however, the nature of the disability depends on the joint affected and disease severity. When arthrofibrosis affects the knee symptoms become intensified during walking and standing, and the condition is frequently more debilitating than the original injury or degenerative condition. 5 Even a small loss of knee extension of 5° creates difficulties in walking while a loss of flexion creates problems with stair climbing, sitting, getting in and out of chairs 6 and cars and driving. Papers sometimes state that arthrofibrosis is a “frustrating” or “disappointing” problem for both surgeon and patient, 7 , 8 , 9 , 10 , 11 however, these descriptions do not adequately describe the effects that arthrofibrosis has on patients’ lives. Patients frequently suffer constant pain, severe limitations on physical activity and difficulty sleeping, sitting and weight bearing. 12 These symptoms may lead to the loss of job/career and difficulty socialising and performing daily living tasks, negatively impacting physical and emotional well-being. On a cellular level arthrofibrosis is characterised by upregulated myofibroblast proliferation with reduced apoptosis, adhesions, aggressive synthesis of ECM that can fill and contract joint pouches and tissues and often also heterotrophic ossification. 1 , 13 , 14 Although ECM is necessary for healing and wound repair, dysregulation of production and degradation leads to pathologic fibrosis. 1 , 15 While there are relatively few studies into the pathogenesis and molecular biology of arthrofibrosis compared to other fibrotic diseases, 1 there are common pathogenic pathways. 16 , 17 , 18 This review highlights current progress in understanding the pathogenesis of sterile arthrofibrosis, focusing on arthrofibrosis of the knee to illustrate the condition. The regulation of inflammation, myofibroblast proliferation and survival and ECM production involves a highly complex array of mediators, cell types, receptors and interactions. A detailed explanation of all of these factors is beyond the scope of this review; therefore, we present a summary of the important cytokines and mediators involved in the condition. In addition this review examines currently available medications and developing pharmacological therapies that hold significant promise in the treatment of arthrofibrosis. Characterisation and classification of arthrofibrosis Although arthrofibrosis is often attributed to surgery, it can be caused by injury alone. 19 This may be particularly true for shoulder arthrofibrosis (frozen shoulder), where the cause is often not known, 20 but which may result from repeated small injuries over time, or damaged structures that place ongoing stress on the joint. 21 The extent of involvement of the joint varies greatly. The formation of ECM may be localised, for example, cyclops lesions on tendons or generalised to involve much of the joint 6 , 12 (Fig. 1 ). In knees the suprapatellar pouch, anterior interval, intercondylar notch, medial and lateral gutters, posterior capsule and infrapatellar fat pad (IFP or Hoffa’s fat pad), may all be affected, 6 with symptoms varying depending on the location and extent of the ECM and adhesions, but typically involving loss of flexion and/or extension (see above). Fig. 1 a Side view cross-section showing a healthy knee. b A knee with generalised arthrofibrosis. Major areas that are affected by arthrofibrosis are indicated. Black arrow = suprapatellar pouch. In “ b ” adhesions have pulled the walls of the pouch together with extracellular matrix (ECM) contracting the space and preventing normal movement. Green arrows = posterior capsule. In “ b ” scar tissue has contracted", "role": "user" }, { "content": "A new collaborative study led by The University of Western Australia has found that a painful joint condition called arthrofibrosis that can result from traumatic injury or surgery may come in two forms which should be treated separately. The research, published in Nature, also involved researchers from Edith Cowan University, China's Wenzhou Medical University and Guangxi Medical University and the Hospital for Special Surgery in New York. Lead researcher Dr. Kayley Usher, from UWA's School of Biomedical Sciences, said 'stiff knee', 'frozen shoulder' and 'stiff elbow' were all the same painful joint condition often caused by traumatic injury such as anterior cruciate ligament (ACL) or knee replacement surgery. \"This condition, which is known as arthrofibrosis, restricts motion and can destroy careers and cause significant suffering and disability,\" Dr. Usher said. \"For the first time, we propose that arthrofibrosis may come in two forms – active and residual – and the best treatment option may be different depending on which form it is.\" Dr. Usher said although arthrofibrosis was a common disease that affected between five and 15 per cent of people who had suffered joint trauma, awareness of the condition remained poor, even among medical and sporting professionals. \"ACL injuries appear to be particularly prone and it appears that over-aggressive exercise during rehabilitation can cause or even worsen arthrofibrosis, making it a permanent condition.\" Dr. Usher said there was an urgent need for biomarkers to identify those at risk of developing arthrofibrosis, as well as new drugs to treat the condition. \"Biomarkers could be used before surgery takes place to determine who would be at higher risk of developing the condition post-operation and also to determine how well a particular therapy was working,\" she said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury, surgery and infection. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Arthrofibrosis affects people of all ages, with published rates varying. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. The process begins when stress signals stimulate immune cells. The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts, which secrete fibrillar collagens and transforming growth factor-β (TGF-β). Positive feedback networks then dysregulate processes that normally terminate healing processes. We propose two subtypes of arthrofibrosis occur: active arthrofibrosis and residual arthrofibrosis. In the latter the fibrogenic processes have resolved but the joint remains stiff. The best therapeutic approach for each subtype may differ significantly. Treatment typically involves surgery, however, a pharmacological approach to correct dysregulated cell signalling could be more effective. Recent research shows that myofibroblasts are capable of reversing differentiation, and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments. Therapies with significant promise are currently available, with more in development, including those that inhibit TGF-β signalling and epigenetic modifications. This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments. Introduction Arthrofibrosis is a fibrotic joint disorder characterised by excessive collagen production and adhesions that result in restricted joint motion and pain. It can occur in most joints, 1 and is referred to by a number of names including frozen shoulder, adhesive capsulitis, joint contracture, stiff knee and stiff elbow. Sterile arthrofibrosis is typically caused by chronic or repetitive injury or surgery that leads to a dysregulated immune reaction and fibrosis in and/or around a joint 2 to varying degrees. The fibrotic scar tissue that forms in the joint is known as extracellular matrix (ECM), and is primarily composed of collagen. Although the term ECM includes a wide variety of biological components we use this established terminology when discussing fibrotic scar tissue. This forms adhesions within joint capsules and contracts tendons and bursa around the joint, 3 causing the loss of joint flexion and/or extension. In addition, scarred bursa may impinge into the joint causing more inflammation. Together with reduced range of motion (ROM), pain and varying amounts of swelling are commonly reported by patients. Arthrofibrosis affects people of all ages, although it is rare in children. 4 Arthrofibrosis frequently causes significant disability; however, the nature of the disability depends on the joint affected and disease severity. When arthrofibrosis affects the knee symptoms become intensified during walking and standing, and the condition is frequently more debilitating than the original injury or degenerative condition. 5 Even a small loss of knee extension of 5° creates difficulties in walking while a loss of flexion creates problems with stair climbing, sitting, getting in and out of chairs 6 and cars and driving. Papers sometimes state that arthrofibrosis is a “frustrating” or “disappointing” problem for both surgeon and patient, 7 , 8 , 9 , 10 , 11 however, these descriptions do not adequately describe the effects that arthrofibrosis has on patients’ lives. Patients frequently suffer constant pain, severe limitations on physical activity and difficulty sleeping, sitting and weight bearing. 12 These symptoms may lead to the loss of job/career and difficulty socialising and performing daily living tasks, negatively impacting physical and emotional well-being. On a cellular level arthrofibrosis is characterised by upregulated myofibroblast proliferation with reduced apoptosis, adhesions, aggressive synthesis of ECM that can fill and contract joint pouches and tissues and often also heterotrophic ossification. 1 , 13 , 14 Although ECM is necessary for healing and wound repair, dysregulation of production and degradation leads to pathologic fibrosis. 1 , 15 While there are relatively few studies into the pathogenesis and molecular biology of arthrofibrosis compared to other fibrotic diseases, 1 there are common pathogenic pathways. 16 , 17 , 18 This review highlights current progress in understanding the pathogenesis of sterile arthrofibrosis, focusing on arthrofibrosis of the knee to illustrate the condition. The regulation of inflammation, myofibroblast proliferation and survival and ECM production involves a highly complex array of mediators, cell types, receptors and interactions. A detailed explanation of all of these factors is beyond the scope of this review; therefore, we present a summary of the important cytokines and mediators involved in the condition. In addition this review examines currently available medications and developing pharmacological therapies that hold significant promise in the treatment of arthrofibrosis. Characterisation and classification of arthrofibrosis Although arthrofibrosis is often attributed to surgery, it can be caused by injury alone. 19 This may be particularly true for shoulder arthrofibrosis (frozen shoulder), where the cause is often not known, 20 but which may result from repeated small injuries over time, or damaged structures that place ongoing stress on the joint. 21 The extent of involvement of the joint varies greatly. The formation of ECM may be localised, for example, cyclops lesions on tendons or generalised to involve much of the joint 6 , 12 (Fig. 1 ). In knees the suprapatellar pouch, anterior interval, intercondylar notch, medial and lateral gutters, posterior capsule and infrapatellar fat pad (IFP or Hoffa’s fat pad), may all be affected, 6 with symptoms varying depending on the location and extent of the ECM and adhesions, but typically involving loss of flexion and/or extension (see above). Fig. 1 a Side view cross-section showing a healthy knee. b A knee with generalised arthrofibrosis. Major areas that are affected by arthrofibrosis are indicated. Black arrow = suprapatellar pouch. In “ b ” adhesions have pulled the walls of the pouch together with extracellular matrix (ECM) contracting the space and preventing normal movement. Green arrows = posterior capsule. In “ b ” scar tissue has contracted<|im_end|> <|im_start|>assistant A new collaborative study led by The University of Western Australia has found that a painful joint condition called arthrofibrosis that can result from traumatic injury or surgery may come in two forms which should be treated separately. The research, published in Nature, also involved researchers from Edith Cowan University, China's Wenzhou Medical University and Guangxi Medical University and the Hospital for Special Surgery in New York. Lead researcher Dr. Kayley Usher, from UWA's School of Biomedical Sciences, said 'stiff knee', 'frozen shoulder' and 'stiff elbow' were all the same painful joint condition often caused by traumatic injury such as anterior cruciate ligament (ACL) or knee replacement surgery. "This condition, which is known as arthrofibrosis, restricts motion and can destroy careers and cause significant suffering and disability," Dr. Usher said. "For the first time, we propose that arthrofibrosis may come in two forms – active and residual – and the best treatment option may be different depending on which form it is." Dr. Usher said although arthrofibrosis was a common disease that affected between five and 15 per cent of people who had suffered joint trauma, awareness of the condition remained poor, even among medical and sporting professionals. "ACL injuries appear to be particularly prone and it appears that over-aggressive exercise during rehabilitation can cause or even worsen arthrofibrosis, making it a permanent condition." Dr. Usher said there was an urgent need for biomarkers to identify those at risk of developing arthrofibrosis, as well as new drugs to treat the condition. "Biomarkers could be used before surgery takes place to determine who would be at higher risk of developing the condition post-operation and also to determine how well a particular therapy was working," she said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation 1 , 2 , 3 , 4 , 5 , 6 . Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease 3 , 4 , 5 , 6 , 7 , 8 , 9 , it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (T H 17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans -secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin. Main Deep-sequencing-based surveys of the gut mycobiome in several disease cohorts provide consistent evidence for ‘fungal dysbiosis’ as a hallmark 3 , 4 , 5 , 6 , 7 , 8 , 9 of inflammatory bowel disease (IBD)—the most prevalent forms of which are Crohn’s disease (CD) and ulcerative colitis (UC), which affect millions of individuals globally 10 . Antibodies against fungal mannan (anti- Saccharomyces cerevisiae antibodies (ASCA)), define IBD subtypes, further linking fungi to intestinal inflammation 11 . Candida is the most prevalent fungal genus that is consistently increased in several IBD cohorts based on faecal sequencing 3 , 6 , 12 . Notably, gut C. albicans induces an array of antifungal antibodies and acts as an immunogen for ASCA 13 , 14 , 15 . Candida species associated with the intestinal mucosa are sensed by gut-resident macrophages and therefore have the potential to induce protective immunity or trigger inflammation in a context-dependent manner experimentally 15 , 16 . Despite this evidence, it is currently unknown whether fungi detected by deep-sequencing technologies in the human intestinal mucosa have an essential role in directing mucosal immunity or disease outcomes in individual patients. Consistently, a lack of association between changes in mycobiota composition and disease severity has been observed in IBD cohorts, despite a consistent increase in Candida species 3 , 5 , 6 , 12 . Thus, we hypothesized that niche-specific strain functional diversity among Candida spp. dictates the host–fungal relationship in the human intestinal mucosa. C. albicans expands in the inflamed gut We first focused our analysis on UC, which targets the colon—a site in which commensal fungi are highly abundant and interact with host immunity 5 , 7 , 17 . To enrich for mucosa-associated immunoreactive mycobiota, we obtained colonic mucosa lavage samples from 38 individuals without IBD and 40 patients with UC undergoing colon cleansing—a process that removes faecal and other luminal contents in preparation for colonoscopy, and performed internal transcribed spacer (ITS) sequencing of fungal ribosomal DNA. This analysis revealed a distinct clustering between individuals without IBD and patients with UC, whereas alpha diversity remained similar within each group (Fig. 1a and Extended Data Fig. 1a, b ). An analysis at the genus level revealed the presence of 18 highly prevalent fungal genera with an average relative abundance of >0.2% across all of the samples (Fig. 1b and Supplementary Table 1 ). Among those, Candida and Saccharomyces represented the most abundant genera (Fig. 1b ), with an increase in Candida and a pronounced reduction in Saccharomyces in the mucosa-enriched mycobiome of patients with UC compared with individuals without IBD (Fig. 1c and Extended Data Fig. 1c ). By contrast, other fungal genera 8 , 9 , such as rare abundances of Debaromyces, Galactomyces and Malassezia spp., were not altered with UC disease status (Fig. 1c and Extended Data Fig. 1c ). C. albicans was consistently over-represented in the mucosa of patients with UC as confirmed by a culture-dependent approach (Fig. 1d ). To experimentally determine whether an increased presence of C. albicans influences intestinal inflammation, we orally gavaged wild-type (WT) C57BL/6 specific pathogen free (SPF) mice with C. albicans SC5314, a laboratory strain, and determined its effect on a dextran sulfate sodium (DSS)-induced model of colitis. Although intestinal inflammation provided a niche for C. albicans overgrowth (Extended Data Fig. 2a ), disease severity was not affected by C. albicans in this model (Extended Data Fig. 2b–e ), consistent with previous studies 8 , 16 . Furthermore, C. albicans did not cause spontaneous colitis following a prolonged colonization (up to 4 months; Extended Data Fig. 2f, g ). Thus, although Candida spp. are a disease-contributing factor in hosts with genetic deficiencies targeting antifungal immunity pathways 16 , C. albicans does not cause spontaneous intestinal inflammation in a host with intact antifungal immunity, albeit inflammation appeared to be a driver of C. albicans intestinal expansion. Fig. 1: C. albicans expands in the colonic mucosa of patients with UC and promotes inflammation in a mouse model of colitis. a , Principal coordinate analysis plot of distance ordination for fungal ITS1 operational taxonomic units (OTUs) in colonic mucosa (MUC) samples from individuals without IBD or individuals with UC. Statistical analysis was performed using analysis of similarities statistics. b , The relative abundance of detected fungal genera. c , The relative abundance of Candida spp., Saccharomyces spp. and other less represented fungal", "role": "user" }, { "content": "Individual Candida albicans yeast strains in the human gut are as different from each other as the humans that carry them, and some C. albicans strains may damage the gut of patients with inflammatory bowel disease (IBD), according to a new study from researchers at Weill Cornell Medicine. The findings suggest a possible way to tailor treatments to individual patients in the future. The researchers, who report their findings March 16 in Nature, used an array of techniques to study strains, or genetic variants, of Candida from the colons of people with or without ulcerative colitis, a chronic, relapsing and remitting inflammatory disorder of the colon and rectum and one of the main forms of IBD. They found that certain strains, which they call \"high-damaging,\" produce a potent toxin called candidalysin that damages immune cells. \"Such strains retained their 'high-damaging' properties when they were removed from the patient's gut and triggered pro-inflammatory immunity when colonized in mice, replicating certain disease hallmarks,\" said senior author Dr. Iliyan Iliev, an associate professor of immunology in medicine in the Division of Gastroenterology and Hepatology and a scientist in the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. IBD affects approximately 3.1 million people in the United States and can greatly impair patients' quality of life. Such patients rely on a handful of available therapies, but treatments may not always be effective. The new study has suggested one reason steroids, a commonly used treatment, may not work: Treating mice with the drug to suppress intestinal inflammation failed in the presence of \"high-damaging\" C. albicans strains. \"Our findings suggest that C. albicans strains do not cause spontaneous intestinal inflammation in a host with intact immunity,\" Dr. Iliev said. \"But they do expand in the intestines when inflammation is present and can be a factor that influences response to therapy in our models and perhaps in patients.\" Most studies of the human microbiome in healthy individuals and those with IBD have focused on bacteria and viruses, but recent research by Dr. Iliev and others has illuminated the contributions of fungi to the effects of microbes on humans and mice. They have found that intestinal fungi play an important role in regulating immunity at surfaces exposed to the outside, such as the intestines and lungs, due to their potent immune-stimulating characteristics. While the collective community of fungi in the body, known as the mycobiota, has been linked to several diseases, including IBD, researchers previously had not understood the mechanisms by which the mycobiota contribute to inflammation in the gut. In the new study, the investigators initially found that Candida strains, while highly diverse in the intestines of both patients with and without colitis, were on average more abundant in the patients with IBD. But that did not explain disease outcomes in individual patients. So, the investigators set out to identify the characteristics of these strains that cause damage and how they relate to individual patients. The researchers observed that in the patients with ulcerative colitis, severe disease was associated with the presence of \"high-damaging\" Candida strains, which turned out to have a key factor in common: All produce the candidalysin toxin. The scientists showed that the toxin damages immune cells called macrophages, prompting a storm of the pro-inflammatory cytokine IL-1β. To underscore this strain-specific effect, the researchers grew macrophages in the presence of Candida strains and found that the ability of the strains to induce IL-1β corresponded closely to the severity of colitis in the patients. \"Our finding shows that a cell-damaging toxin candidalysin released by \"high damaging\" C. albicans strains during the yeast-hyphae morphogenesis triggers pathogenic immunological responses in the gut,\" said the first author Dr. Xin Li, who was a Charles H. Revson Postdoctoral Fellow in the Iliev laboratory at the time of the study. Experiments in mice delineated that candidalysin-producing \"high-damaging\" strains induced the expansion of a population of T cells called Th17 cells and other immune cells associated with inflammation, such as neutrophils. \"Neutrophils contribute to tissue damage and their accumulation is a hallmark of active IBD,\" said Dr. Ellen Scherl, the Jill Roberts Professor of Inflammatory Bowel Disease at Weill Cornell Medicine and a gastroenterologist at NewYork-Presbyterian/Weill Cornell Medical Center. \"The indication that these processes might in part be driven by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches.\" Consistent with this finding, blocking IL-1β signaling had a dramatic effect in reducing colitis signs in mice that harbored these highly pro-inflammatory strains. The researchers noted that other recent studies have linked IBD to IL-1β in a general way, prompting ongoing investigations of drugs targeting related pathways as potential IBD therapies. \"We do not know whether specific strains are acquired by specific patients during the course of disease or whether they have been always there and become a problem during episodes of active disease,\" Dr. Iliev said. \"Nevertheless, our findings highlight a mechanism by which commensal fungal strains can turn against their host and overdrive inflammation.\" The team is following up with studies of the mechanisms that drive the persistence of candidalysin-producing strains in the inflamed colon of specific IBD patients, as well as ways to choose patients for therapy targeting the mycobiome. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation 1 , 2 , 3 , 4 , 5 , 6 . Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease 3 , 4 , 5 , 6 , 7 , 8 , 9 , it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (T H 17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans -secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin. Main Deep-sequencing-based surveys of the gut mycobiome in several disease cohorts provide consistent evidence for ‘fungal dysbiosis’ as a hallmark 3 , 4 , 5 , 6 , 7 , 8 , 9 of inflammatory bowel disease (IBD)—the most prevalent forms of which are Crohn’s disease (CD) and ulcerative colitis (UC), which affect millions of individuals globally 10 . Antibodies against fungal mannan (anti- Saccharomyces cerevisiae antibodies (ASCA)), define IBD subtypes, further linking fungi to intestinal inflammation 11 . Candida is the most prevalent fungal genus that is consistently increased in several IBD cohorts based on faecal sequencing 3 , 6 , 12 . Notably, gut C. albicans induces an array of antifungal antibodies and acts as an immunogen for ASCA 13 , 14 , 15 . Candida species associated with the intestinal mucosa are sensed by gut-resident macrophages and therefore have the potential to induce protective immunity or trigger inflammation in a context-dependent manner experimentally 15 , 16 . Despite this evidence, it is currently unknown whether fungi detected by deep-sequencing technologies in the human intestinal mucosa have an essential role in directing mucosal immunity or disease outcomes in individual patients. Consistently, a lack of association between changes in mycobiota composition and disease severity has been observed in IBD cohorts, despite a consistent increase in Candida species 3 , 5 , 6 , 12 . Thus, we hypothesized that niche-specific strain functional diversity among Candida spp. dictates the host–fungal relationship in the human intestinal mucosa. C. albicans expands in the inflamed gut We first focused our analysis on UC, which targets the colon—a site in which commensal fungi are highly abundant and interact with host immunity 5 , 7 , 17 . To enrich for mucosa-associated immunoreactive mycobiota, we obtained colonic mucosa lavage samples from 38 individuals without IBD and 40 patients with UC undergoing colon cleansing—a process that removes faecal and other luminal contents in preparation for colonoscopy, and performed internal transcribed spacer (ITS) sequencing of fungal ribosomal DNA. This analysis revealed a distinct clustering between individuals without IBD and patients with UC, whereas alpha diversity remained similar within each group (Fig. 1a and Extended Data Fig. 1a, b ). An analysis at the genus level revealed the presence of 18 highly prevalent fungal genera with an average relative abundance of >0.2% across all of the samples (Fig. 1b and Supplementary Table 1 ). Among those, Candida and Saccharomyces represented the most abundant genera (Fig. 1b ), with an increase in Candida and a pronounced reduction in Saccharomyces in the mucosa-enriched mycobiome of patients with UC compared with individuals without IBD (Fig. 1c and Extended Data Fig. 1c ). By contrast, other fungal genera 8 , 9 , such as rare abundances of Debaromyces, Galactomyces and Malassezia spp., were not altered with UC disease status (Fig. 1c and Extended Data Fig. 1c ). C. albicans was consistently over-represented in the mucosa of patients with UC as confirmed by a culture-dependent approach (Fig. 1d ). To experimentally determine whether an increased presence of C. albicans influences intestinal inflammation, we orally gavaged wild-type (WT) C57BL/6 specific pathogen free (SPF) mice with C. albicans SC5314, a laboratory strain, and determined its effect on a dextran sulfate sodium (DSS)-induced model of colitis. Although intestinal inflammation provided a niche for C. albicans overgrowth (Extended Data Fig. 2a ), disease severity was not affected by C. albicans in this model (Extended Data Fig. 2b–e ), consistent with previous studies 8 , 16 . Furthermore, C. albicans did not cause spontaneous colitis following a prolonged colonization (up to 4 months; Extended Data Fig. 2f, g ). Thus, although Candida spp. are a disease-contributing factor in hosts with genetic deficiencies targeting antifungal immunity pathways 16 , C. albicans does not cause spontaneous intestinal inflammation in a host with intact antifungal immunity, albeit inflammation appeared to be a driver of C. albicans intestinal expansion. Fig. 1: C. albicans expands in the colonic mucosa of patients with UC and promotes inflammation in a mouse model of colitis. a , Principal coordinate analysis plot of distance ordination for fungal ITS1 operational taxonomic units (OTUs) in colonic mucosa (MUC) samples from individuals without IBD or individuals with UC. Statistical analysis was performed using analysis of similarities statistics. b , The relative abundance of detected fungal genera. c , The relative abundance of Candida spp., Saccharomyces spp. and other less represented fungal<|im_end|> <|im_start|>assistant Individual Candida albicans yeast strains in the human gut are as different from each other as the humans that carry them, and some C. albicans strains may damage the gut of patients with inflammatory bowel disease (IBD), according to a new study from researchers at Weill Cornell Medicine. The findings suggest a possible way to tailor treatments to individual patients in the future. The researchers, who report their findings March 16 in Nature, used an array of techniques to study strains, or genetic variants, of Candida from the colons of people with or without ulcerative colitis, a chronic, relapsing and remitting inflammatory disorder of the colon and rectum and one of the main forms of IBD. They found that certain strains, which they call "high-damaging," produce a potent toxin called candidalysin that damages immune cells. "Such strains retained their 'high-damaging' properties when they were removed from the patient's gut and triggered pro-inflammatory immunity when colonized in mice, replicating certain disease hallmarks," said senior author Dr. Iliyan Iliev, an associate professor of immunology in medicine in the Division of Gastroenterology and Hepatology and a scientist in the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. IBD affects approximately 3.1 million people in the United States and can greatly impair patients' quality of life. Such patients rely on a handful of available therapies, but treatments may not always be effective. The new study has suggested one reason steroids, a commonly used treatment, may not work: Treating mice with the drug to suppress intestinal inflammation failed in the presence of "high-damaging" C. albicans strains. "Our findings suggest that C. albicans strains do not cause spontaneous intestinal inflammation in a host with intact immunity," Dr. Iliev said. "But they do expand in the intestines when inflammation is present and can be a factor that influences response to therapy in our models and perhaps in patients." Most studies of the human microbiome in healthy individuals and those with IBD have focused on bacteria and viruses, but recent research by Dr. Iliev and others has illuminated the contributions of fungi to the effects of microbes on humans and mice. They have found that intestinal fungi play an important role in regulating immunity at surfaces exposed to the outside, such as the intestines and lungs, due to their potent immune-stimulating characteristics. While the collective community of fungi in the body, known as the mycobiota, has been linked to several diseases, including IBD, researchers previously had not understood the mechanisms by which the mycobiota contribute to inflammation in the gut. In the new study, the investigators initially found that Candida strains, while highly diverse in the intestines of both patients with and without colitis, were on average more abundant in the patients with IBD. But that did not explain disease outcomes in individual patients. So, the investigators set out to identify the characteristics of these strains that cause damage and how they relate to individual patients. The researchers observed that in the patients with ulcerative colitis, severe disease was associated with the presence of "high-damaging" Candida strains, which turned out to have a key factor in common: All produce the candidalysin toxin. The scientists showed that the toxin damages immune cells called macrophages, prompting a storm of the pro-inflammatory cytokine IL-1β. To underscore this strain-specific effect, the researchers grew macrophages in the presence of Candida strains and found that the ability of the strains to induce IL-1β corresponded closely to the severity of colitis in the patients. "Our finding shows that a cell-damaging toxin candidalysin released by "high damaging" C. albicans strains during the yeast-hyphae morphogenesis triggers pathogenic immunological responses in the gut," said the first author Dr. Xin Li, who was a Charles H. Revson Postdoctoral Fellow in the Iliev laboratory at the time of the study. Experiments in mice delineated that candidalysin-producing "high-damaging" strains induced the expansion of a population of T cells called Th17 cells and other immune cells associated with inflammation, such as neutrophils. "Neutrophils contribute to tissue damage and their accumulation is a hallmark of active IBD," said Dr. Ellen Scherl, the Jill Roberts Professor of Inflammatory Bowel Disease at Weill Cornell Medicine and a gastroenterologist at NewYork-Presbyterian/Weill Cornell Medical Center. "The indication that these processes might in part be driven by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches." Consistent with this finding, blocking IL-1β signaling had a dramatic effect in reducing colitis signs in mice that harbored these highly pro-inflammatory strains. The researchers noted that other recent studies have linked IBD to IL-1β in a general way, prompting ongoing investigations of drugs targeting related pathways as potential IBD therapies. "We do not know whether specific strains are acquired by specific patients during the course of disease or whether they have been always there and become a problem during episodes of active disease," Dr. Iliev said. "Nevertheless, our findings highlight a mechanism by which commensal fungal strains can turn against their host and overdrive inflammation." The team is following up with studies of the mechanisms that drive the persistence of candidalysin-producing strains in the inflamed colon of specific IBD patients, as well as ways to choose patients for therapy targeting the mycobiome. <|im_end|>

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2,632

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Assessing functional diversity from space can help predict productivity and stability of forest ecosystems at global scale using biodiversity–ecosystem functioning relationships. We present a new spatially continuous method to map regional patterns of tree functional diversity using combined laser scanning and imaging spectroscopy. The method does not require prior taxonomic information and integrates variation in plant functional traits between and within plant species. We compare our method with leaf-level field measurements and species-level plot inventory data and find reasonable agreement. Morphological and physiological diversity show consistent change with topography and soil, with low functional richness at a mountain ridge under specific environmental conditions. Overall, functional richness follows a logarithmic increase with area, whereas divergence and evenness are scale invariant. By mapping diversity at scales of individual trees to whole communities we demonstrate the potential of assessing functional diversity from space, providing a pathway only limited by technological advances and not by methodology. Introduction Understanding community structure and the impact of changing biodiversity on ecosystem functioning are key tasks in ecology. Progress has been made on a wide variety of taxa, including plants 1 , fish 2 , birds 3 and insects 4 , amongst others. In plant ecology, biodiversity research has focused on the distribution of species based on taxonomic identity 5 . More recently, with the emergence of functional biogeography 6 , tree species or individuals of a community are described in relation to their functional identity and distribution in space. Functional traits are of particular interest due to their response to environmental conditions and direct link to growth, reproduction and survival 7 , 8 . Trait-based approaches are emerging rapidly in plant ecology, underpinning community assembly and structure, species interactions and interlinkages between vegetation and biogeochemical cycles 9 . The assessment of plant functional traits and plant functional diversity is of particular relevance when predicting ecosystem productivity and stability. A multitude of experimental studies demonstrated positive relationships between plant diversity and ecosystem functioning 10 , 11 , 12 and increasingly such positive relationships are also found in comparative observational studies 13 , 14 . A positive relationship over extended time scales is mainly driven by functional diversity due to an increased resource use efficiency and utilization as well as sampling effects in a changing environment, allowing plant communities to sustain high productivity over time 15 , 16 , 17 . Besides productivity, higher functional diversity has been linked to enhanced tree growth and ecosystem stability due to complementarity effects, better adaptability to changing environmental conditions and lower vulnerability to diseases, insect attacks, fire and storms 18 , 19 , 20 . However, to make use of the increasing knowledge about biodiversity–ecosystem functioning relationships in forest ecosystems, it would be necessary to develop methods to assess plant functional diversity efficiently over large continuous areas. Our first aim is therefore to develop such a method for a regional test area, see Fig. 1 , as a base for larger scale biodiversity scoping studies. Fig. 1 Laegern mountain temperate mixed forest site in Switzerland. The test site is located near Zurich and covers about 2 × 6 km. The mountain range is divided by a ridge running from east to west, separating the forested area in north facing (blue) and south facing (orange) slopes. Flat areas are defined with a slope <10 ° (green). Areas not covered by forest (agriculture, grassland, urban areas) are shown in grey Full size image Spatial variation in plant functional traits and diversity depend on community structure 21 and thus represent a potential signal of community assembly processes. However, plant traits and functional diversity do not only depend on community structure represented by particular species abundance distributions within a specific geographical unit, but may vary as much within species as they do between species 22 . Different species can also be redundant in terms of their functional traits, and thus not contribute to functional diversity 16 , 23 . Therefore, functional diversity is best derived from a given set of traits including their intra-specific variability 24 , 25 . By incorporating individual-level functional traits, functional diversity may better predict ecosystem functioning than species-level means 16 . A multitude of forest monitoring networks exist 26 as well as trait-based studies in forested ecosystems 27 , fostered by standardized measurement procedures 28 and global trait databases 29 . However, these procedures usually require taxonomic information about tree individuals and indirectly assess trait variation and functional diversity combining information about species abundances and mean traits, thus ignoring variation in tree functional traits within species, which can be large even within individuals 30 . In addition, there is a global bias in the distribution of forest plots, leading to large data gaps particularly in remote areas 31 . Furthermore, trait measurements in forests are typically limited in extent and magnitude due to the complexity of destructive crown-level measurements, as well as associated georeferencing challenges and plot representativeness 32 . Consequently, continuous spatial data of traits and especially on trait diversity are still very sparse. Recent advances in remote sensing provide the opportunity to map traits and trait diversity, thus filling the existing data gaps 33 , 34 , 35 . Here, we use three morphological and three physiological functional traits that we assess directly, i.e. without reference to taxonomic information, to provide a spatially continuous description of functional diversity in a forest at local scale (≈925 ha), with the potential to scale up to regional and to the global level. The selected morphological and physiological traits can be assessed with high-resolution airborne remote sensing methods 33 , 36 and are relevant for plant and ecosystem function. Three morphological traits, namely canopy height (CH, vertical distance between canopy top and ground), plant area index (PAI, projected plant area per horizontal ground area) and foliage height diversity (FHD, measure of variation and number of canopy layers), are essential to describe canopy architecture, encompassing the horizontal and vertical structure of forests and influencing light availability, thus affecting competitive and complementary light use", "role": "user" }, { "content": "Productivity and stability of forest ecosystems strongly depend on the functional diversity of plant communities. University of Zurich researchers have developed a new method to measure and map functional diversity of forests at different scales—from individual trees to whole communities—using remote sensing by aircraft. Their work paves the way for future airborne and satellite missions to monitor global plant functional diversity. Ecological studies have demonstrated positive relationships between plant diversity and ecosystem functioning. Forests with higher functional diversity are generally more productive and stable over long timescales than less diverse forests. Diverse plant communities show increased resource use efficiency and utilization, enhanced ecosystem productivity and stability and can better cope with changing environmental conditions - an insurance effect of biodiversity. They are also less vulnerable to diseases, insect attacks, fire and storms. New method to study whole forest ecosystems from above Plant functional diversity can directly be measured by mapping selected morphological and physiological traits of a forest from above. In the past, functional traits of plants had to be measured by very labor-intensive fieldwork on the ground. This fieldwork was either limited to very few measurable traits on larger plots or many traits on very small plots or single trees. Researchers from the UZH and the California Institute of Technology / NASA Jet Propulsion Laboratory have now developed a new remote-sensing method to map functional diversity of forests from small to large scales, independent of any predefined vegetation units or species information and without the need for ground-based calibration. The research team applied their methods on the Laegern mountain, a temperate mixed forest ecosystem located near Zurich, Switzerland. \"With remote sensing, we have the unique opportunity to study whole forest ecosystems by continuously mapping their functional traits looking from above on the leaves of the forest canopy over very large areas,\" says Michael Schaepman from the Remote Sensing Laboratories of the Department of Geography. Spatial composition of the physiological traits leaf chlorophyll, carotenoids and water content. The color composite shows the relative abundance of the three traits at each pixel of 6x6 m. Credit: University of Zurich Functional traits indicate activity and health status of trees With airborne laser scanning, the scientists measured morphological characteristics of the forest canopy such as canopy height, foliage and branch densities. These measurements indicate how the sunlight is taken up by the canopy to assimilate carbon dioxide from the air and use the carbon to grow. In a canopy with a more diverse structure, light can better spread between different vertical canopy layers and among individual tree crowns, allowing for a more efficient capture of light. The researchers also characterized the forest with regards to its biochemical properties using airborne imaging spectroscopy. By measuring how leaves reflect the light in many spectral bands, they were able to derive physiological traits such as the content of leaf pigments (chlorophylls, carotenoids) and leaf water content. \"These physiological traits provide information about the activity and health status of the trees. We can see, for example, if a tree is suffering water stress, and what resource allocation strategy a tree is following or how it adapts to the environment,\" Schaepman adds. Observed diversity patterns consistent with topography and soil The researchers validated their method by comparing the results with leaf-level field measurements, species-level plot inventory data and databases providing functional trait values. Using computer modelling, they were able to assess diversity patterns of morphological and physiological traits at a whole range of scales, from local diversity between individual trees to large-scale patterns of plant communities following environmental gradients. The team found a strong relationship between the observed functional diversity patterns and environmental factors such as soil and topography, with lower diversity on the mountain ridge under harsher environmental conditions, where the trees adapted to the dry, steep, shallow and rocky soils. Potential to assess functional diversity from space \"With remote sensing, we are now able to measure and monitor the diversity of forests, allowing us to observe changes at large scales and providing spatial information for nature conservation and climate change mitigation strategies,\" Michael Schaepman emphasizes. Since the methodology is only limited by the availability of advanced technological sensors, this work paves the way for future airborne and satellite missions aiming at monitoring global plant functional diversity from space. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Assessing functional diversity from space can help predict productivity and stability of forest ecosystems at global scale using biodiversity–ecosystem functioning relationships. We present a new spatially continuous method to map regional patterns of tree functional diversity using combined laser scanning and imaging spectroscopy. The method does not require prior taxonomic information and integrates variation in plant functional traits between and within plant species. We compare our method with leaf-level field measurements and species-level plot inventory data and find reasonable agreement. Morphological and physiological diversity show consistent change with topography and soil, with low functional richness at a mountain ridge under specific environmental conditions. Overall, functional richness follows a logarithmic increase with area, whereas divergence and evenness are scale invariant. By mapping diversity at scales of individual trees to whole communities we demonstrate the potential of assessing functional diversity from space, providing a pathway only limited by technological advances and not by methodology. Introduction Understanding community structure and the impact of changing biodiversity on ecosystem functioning are key tasks in ecology. Progress has been made on a wide variety of taxa, including plants 1 , fish 2 , birds 3 and insects 4 , amongst others. In plant ecology, biodiversity research has focused on the distribution of species based on taxonomic identity 5 . More recently, with the emergence of functional biogeography 6 , tree species or individuals of a community are described in relation to their functional identity and distribution in space. Functional traits are of particular interest due to their response to environmental conditions and direct link to growth, reproduction and survival 7 , 8 . Trait-based approaches are emerging rapidly in plant ecology, underpinning community assembly and structure, species interactions and interlinkages between vegetation and biogeochemical cycles 9 . The assessment of plant functional traits and plant functional diversity is of particular relevance when predicting ecosystem productivity and stability. A multitude of experimental studies demonstrated positive relationships between plant diversity and ecosystem functioning 10 , 11 , 12 and increasingly such positive relationships are also found in comparative observational studies 13 , 14 . A positive relationship over extended time scales is mainly driven by functional diversity due to an increased resource use efficiency and utilization as well as sampling effects in a changing environment, allowing plant communities to sustain high productivity over time 15 , 16 , 17 . Besides productivity, higher functional diversity has been linked to enhanced tree growth and ecosystem stability due to complementarity effects, better adaptability to changing environmental conditions and lower vulnerability to diseases, insect attacks, fire and storms 18 , 19 , 20 . However, to make use of the increasing knowledge about biodiversity–ecosystem functioning relationships in forest ecosystems, it would be necessary to develop methods to assess plant functional diversity efficiently over large continuous areas. Our first aim is therefore to develop such a method for a regional test area, see Fig. 1 , as a base for larger scale biodiversity scoping studies. Fig. 1 Laegern mountain temperate mixed forest site in Switzerland. The test site is located near Zurich and covers about 2 × 6 km. The mountain range is divided by a ridge running from east to west, separating the forested area in north facing (blue) and south facing (orange) slopes. Flat areas are defined with a slope <10 ° (green). Areas not covered by forest (agriculture, grassland, urban areas) are shown in grey Full size image Spatial variation in plant functional traits and diversity depend on community structure 21 and thus represent a potential signal of community assembly processes. However, plant traits and functional diversity do not only depend on community structure represented by particular species abundance distributions within a specific geographical unit, but may vary as much within species as they do between species 22 . Different species can also be redundant in terms of their functional traits, and thus not contribute to functional diversity 16 , 23 . Therefore, functional diversity is best derived from a given set of traits including their intra-specific variability 24 , 25 . By incorporating individual-level functional traits, functional diversity may better predict ecosystem functioning than species-level means 16 . A multitude of forest monitoring networks exist 26 as well as trait-based studies in forested ecosystems 27 , fostered by standardized measurement procedures 28 and global trait databases 29 . However, these procedures usually require taxonomic information about tree individuals and indirectly assess trait variation and functional diversity combining information about species abundances and mean traits, thus ignoring variation in tree functional traits within species, which can be large even within individuals 30 . In addition, there is a global bias in the distribution of forest plots, leading to large data gaps particularly in remote areas 31 . Furthermore, trait measurements in forests are typically limited in extent and magnitude due to the complexity of destructive crown-level measurements, as well as associated georeferencing challenges and plot representativeness 32 . Consequently, continuous spatial data of traits and especially on trait diversity are still very sparse. Recent advances in remote sensing provide the opportunity to map traits and trait diversity, thus filling the existing data gaps 33 , 34 , 35 . Here, we use three morphological and three physiological functional traits that we assess directly, i.e. without reference to taxonomic information, to provide a spatially continuous description of functional diversity in a forest at local scale (≈925 ha), with the potential to scale up to regional and to the global level. The selected morphological and physiological traits can be assessed with high-resolution airborne remote sensing methods 33 , 36 and are relevant for plant and ecosystem function. Three morphological traits, namely canopy height (CH, vertical distance between canopy top and ground), plant area index (PAI, projected plant area per horizontal ground area) and foliage height diversity (FHD, measure of variation and number of canopy layers), are essential to describe canopy architecture, encompassing the horizontal and vertical structure of forests and influencing light availability, thus affecting competitive and complementary light use<|im_end|> <|im_start|>assistant Productivity and stability of forest ecosystems strongly depend on the functional diversity of plant communities. University of Zurich researchers have developed a new method to measure and map functional diversity of forests at different scales—from individual trees to whole communities—using remote sensing by aircraft. Their work paves the way for future airborne and satellite missions to monitor global plant functional diversity. Ecological studies have demonstrated positive relationships between plant diversity and ecosystem functioning. Forests with higher functional diversity are generally more productive and stable over long timescales than less diverse forests. Diverse plant communities show increased resource use efficiency and utilization, enhanced ecosystem productivity and stability and can better cope with changing environmental conditions - an insurance effect of biodiversity. They are also less vulnerable to diseases, insect attacks, fire and storms. New method to study whole forest ecosystems from above Plant functional diversity can directly be measured by mapping selected morphological and physiological traits of a forest from above. In the past, functional traits of plants had to be measured by very labor-intensive fieldwork on the ground. This fieldwork was either limited to very few measurable traits on larger plots or many traits on very small plots or single trees. Researchers from the UZH and the California Institute of Technology / NASA Jet Propulsion Laboratory have now developed a new remote-sensing method to map functional diversity of forests from small to large scales, independent of any predefined vegetation units or species information and without the need for ground-based calibration. The research team applied their methods on the Laegern mountain, a temperate mixed forest ecosystem located near Zurich, Switzerland. "With remote sensing, we have the unique opportunity to study whole forest ecosystems by continuously mapping their functional traits looking from above on the leaves of the forest canopy over very large areas," says Michael Schaepman from the Remote Sensing Laboratories of the Department of Geography. Spatial composition of the physiological traits leaf chlorophyll, carotenoids and water content. The color composite shows the relative abundance of the three traits at each pixel of 6x6 m. Credit: University of Zurich Functional traits indicate activity and health status of trees With airborne laser scanning, the scientists measured morphological characteristics of the forest canopy such as canopy height, foliage and branch densities. These measurements indicate how the sunlight is taken up by the canopy to assimilate carbon dioxide from the air and use the carbon to grow. In a canopy with a more diverse structure, light can better spread between different vertical canopy layers and among individual tree crowns, allowing for a more efficient capture of light. The researchers also characterized the forest with regards to its biochemical properties using airborne imaging spectroscopy. By measuring how leaves reflect the light in many spectral bands, they were able to derive physiological traits such as the content of leaf pigments (chlorophylls, carotenoids) and leaf water content. "These physiological traits provide information about the activity and health status of the trees. We can see, for example, if a tree is suffering water stress, and what resource allocation strategy a tree is following or how it adapts to the environment," Schaepman adds. Observed diversity patterns consistent with topography and soil The researchers validated their method by comparing the results with leaf-level field measurements, species-level plot inventory data and databases providing functional trait values. Using computer modelling, they were able to assess diversity patterns of morphological and physiological traits at a whole range of scales, from local diversity between individual trees to large-scale patterns of plant communities following environmental gradients. The team found a strong relationship between the observed functional diversity patterns and environmental factors such as soil and topography, with lower diversity on the mountain ridge under harsher environmental conditions, where the trees adapted to the dry, steep, shallow and rocky soils. Potential to assess functional diversity from space "With remote sensing, we are now able to measure and monitor the diversity of forests, allowing us to observe changes at large scales and providing spatial information for nature conservation and climate change mitigation strategies," Michael Schaepman emphasizes. Since the methodology is only limited by the availability of advanced technological sensors, this work paves the way for future airborne and satellite missions aiming at monitoring global plant functional diversity from space. <|im_end|>

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2,064

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Changes in the Earth’s water cycle can be estimated by analyzing sea surface salinity. This variable reflects the balance between precipitation and evaporation over the ocean, since the upper layers of the ocean are the most sensitive to atmosphere–ocean interactions. In situ measurements lack spatial and temporal synopticity and are typically acquired at few meters below the surface. Satellite measurements, on the contrary, are synoptic, repetitive and acquired at the surface. Here we show that the satellite-derived sea surface salinity measurements evidence an intensification of the water cycle (the freshest waters become fresher and vice-versa) which is not observed at the in-situ near-surface salinity measurements. The largest positive differences between surface and near-surface salinity trends are located over regions characterized by a decrease in the mixed layer depth and the sea surface wind speed, and an increase in sea surface temperature, which is consistent with an increased stratification of the water column due to global warming. These results highlight the crucial importance of using satellites to unveil critical changes on ocean–atmosphere fluxes. Introduction About \$85\\%\$ of the Evaporation (E) and \$77\\%\$ of the Precipitation (P) occurs over the ocean 1 , 2 . Both processes produce changes in sea surface salinity (SSS) leading to positive (evaporation) and negative (precipitation) anomalies. In a global warming scenario, the global water cycle is expected to be intensified 3 , 4 , 5 , 6 , 7 , 8 , 9 and is a cause of great concern, because of its profound socioeconomic impacts throughout the globe. Monitoring the SSS to assess the intensification of the water cycle is proposed in Yu et al. 10 and references therein, as an alternative to directly measure E and P since these components can only be estimated with limited accuracy. However, there is still some controversy as to whether the salinity is changing at the same rate as the water cycle does 11 , 12 , 13 , 14 , 15 , as the impact of the changes in E–P fluxes, meltwater runoff, and ocean warming on the salinity is not completely understood 16 , 17 , 18 . Moreover, the number of available salinity measurements has been historically scarce and limited to some specific ocean regions 19 . Since 2000, the global array of temperature and salinity floats provided by the Argo system 20 , besides other permanent or routine observation systems, have contributed to further the knowledge on ocean salinity related processes. More recently, since 2010, SSS measurements are also available from space 21 , 22 , 23 , increasing the monitoring capability of this Essential Climate Variable. One of the main differences between satellite and in situ salinity measurements is that the latter are typically acquired at a few meters depth (5–10 m), thus monitoring the near surface salinity (NSS), while the former are providing measurements at the top cm layer of the ocean, thus monitoring the actual SSS. Differences between the SSS and NSS are due to the vertical stratification of the ocean upper layers. Whereas vertical stratification in temperature has been extensively studied over the past several decades 24 , 25 , upper-ocean salinity stratification studies were only initiated in recent years, mostly motivated by the analysis of satellite-derived SSS data 26 , 27 . The ocean salinity stratification results from a complex combination of various mechanisms such as precipitation, oceanic advection and mixing conditions, as well as fresh water input from rivers runoff, melting of sea ice and removal of freshwater through evaporation. Although negative salinity anomalies have been shown and studied in cases of rainfall 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , river runoff 37 , 38 , 39 and sea-ice melting 40 , 41 , 42 , there is a limited number of studies of positive salinity anomalies due to evaporation 43 , 44 , 45 . Under absence of rainfall, continental discharge or sea ice melting, the upper ocean layer is characterized by a nearly uniform density, active vertical mixing and a high rate of turbulent dissipation 46 , 47 . In that case, vertical salinity gradients in the upper 10 m are expected to be small 29 , 35 . Here, we show that the dynamics captured by satellite SSS measurements actually differ from the dynamics shown by in situ NSS measurements. On one hand, satellite SSS data present a clear intensification of the water cycle which is not so clearly present in the NSS data. On the other hand, we find significant differences between SSS and NSS trends, which suggest that global warming is inducing an increasing stratification over wide open ocean areas. Results Satellite versus in situ salinity measurements Since the year 2000, the observation system of free drifting Argo profiling floats has been increasing, reaching close to 4000 buoys that are nowadays available. The Argo system not only provides the capability for monitoring the salinity dynamics, but also represents the main source of data used for validating satellite measurements and a very valuable input for improving ocean models. However, the distribution of these measurements is not homogeneous over the global ocean. Particularly, coastal and polar regions are under-sampled. Moreover, far from the coast and the poles, the ocean currents drive the locations of the floats, and, thus, the locations of the Argo acquisitions. Over wide oceanic areas, as that comprised between \$60^\\circ\$ S and \$60^\\circ\$ N, the averaged salinity at the Argo locations in a 9-day window evolves with time and it is very different from the temporal evolution of the mean salinity in the entire region, as observed in Fig. 1 . In this region, the temporal evolution of the average of the salinity provided by the Argo floats at their sampling locations and collocated satellite data is very similar (see top plot of Fig. 1 ), which indicates consistency between in situ and satellite measurements. Curiously, the temporal evolution of the averaged salinity over the Argo locations provided by the", "role": "user" }, { "content": "Researchers at the Institut de Ciències del Mar (ICM-CSIC) in Barcelona have found that global warming is accelerating the water cycle, which could have significant consequences on the global climate system, according to an article published recently in the journal Scientific Reports. This acceleration of the water cycle is caused by an increase in the evaporation of water from the seas and oceans resulting from the rise in temperature. As a result, more water is circulating in the atmosphere in its vapor form, 90% of which will eventually precipitate back into the sea, while the remaining 10% will precipitate over the continent. \"The acceleration of the water cycle has implications both at the ocean and on the continent, where storms could become increasingly intense. This higher amount of water circulating in the atmosphere could also explain the increase in rainfall that is being detected in some polar areas, where the fact that it is raining instead of snowing is speeding up the melting,\" explains Estrella Olmedo, the leading author of the study. The work also shows that the decrease in the wind in some areas of the ocean, which favors stratification of the water column, i.e. water not mixing in the vertical direction, could also be contributing to the acceleration of the water cycle. \"Where the wind is no longer so strong, the surface water warms up, but does not exchange heat with the water below, allowing the surface to become more saline than the lower layers and enabling the effect of evaporation to be observed with satellite measurements,\" points out Antonio Turiel, also an author of the study. In this sense, Turiel adds that \"this tells us that the atmosphere and the ocean interact in a stronger way than we imagined, with important consequences for the continental and polar areas.\" Satellites are key for oceanographic studies To carry out the study, researchers analyzed ocean surface salinity data—which is measured by satellites. Unlike subsurface salinity data—obtained with in situ instruments—the satellite data allowed them to detect this acceleration of the water cycle and, for the first time, the effect of stratification over very large regions in the ocean. According to them, this is due to the ability of satellites to measure data continuously, regardless of environmental conditions and the accessibility of different areas of the ocean. \"We have been able to see that surface salinity is showing an intensification of the water cycle that subsurface salinity does not. Specifically, in the Pacific we have seen that surface salinity decreases more slowly than subsurface salinity and, in this same region, we have observed an increase in sea surface temperature and a decrease in the intensity of winds and the depth of the mixing layer,\" details Olmedo. These findings are the result of the use of algorithms and other data analysis products that the Barcelona Expert Center (BEC), attached to the ICM-CSIC, has been generating in the recent years from the SMOS space mission of the European Space Agency (ESA), designed to acquire observations of ocean salinity, which is essential for understanding ocean circulation, one of the key factors in understanding global climate. This circulation basically depends on the water density, which is determined by its temperature and salinity. Therefore, changes in these two parameters, however small they may be, can end up having important consequences on the global climate, which makes it key to monitor them closely. For this, Turiel concludes that \"ocean models must standardize the assimilation of satellite salinity data, since the information they provide complements in situ data, and this is crucial, especially at the current time of climate crisis, where changes are occurring much faster than before.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Changes in the Earth’s water cycle can be estimated by analyzing sea surface salinity. This variable reflects the balance between precipitation and evaporation over the ocean, since the upper layers of the ocean are the most sensitive to atmosphere–ocean interactions. In situ measurements lack spatial and temporal synopticity and are typically acquired at few meters below the surface. Satellite measurements, on the contrary, are synoptic, repetitive and acquired at the surface. Here we show that the satellite-derived sea surface salinity measurements evidence an intensification of the water cycle (the freshest waters become fresher and vice-versa) which is not observed at the in-situ near-surface salinity measurements. The largest positive differences between surface and near-surface salinity trends are located over regions characterized by a decrease in the mixed layer depth and the sea surface wind speed, and an increase in sea surface temperature, which is consistent with an increased stratification of the water column due to global warming. These results highlight the crucial importance of using satellites to unveil critical changes on ocean–atmosphere fluxes. Introduction About $85\%$ of the Evaporation (E) and $77\%$ of the Precipitation (P) occurs over the ocean 1 , 2 . Both processes produce changes in sea surface salinity (SSS) leading to positive (evaporation) and negative (precipitation) anomalies. In a global warming scenario, the global water cycle is expected to be intensified 3 , 4 , 5 , 6 , 7 , 8 , 9 and is a cause of great concern, because of its profound socioeconomic impacts throughout the globe. Monitoring the SSS to assess the intensification of the water cycle is proposed in Yu et al. 10 and references therein, as an alternative to directly measure E and P since these components can only be estimated with limited accuracy. However, there is still some controversy as to whether the salinity is changing at the same rate as the water cycle does 11 , 12 , 13 , 14 , 15 , as the impact of the changes in E–P fluxes, meltwater runoff, and ocean warming on the salinity is not completely understood 16 , 17 , 18 . Moreover, the number of available salinity measurements has been historically scarce and limited to some specific ocean regions 19 . Since 2000, the global array of temperature and salinity floats provided by the Argo system 20 , besides other permanent or routine observation systems, have contributed to further the knowledge on ocean salinity related processes. More recently, since 2010, SSS measurements are also available from space 21 , 22 , 23 , increasing the monitoring capability of this Essential Climate Variable. One of the main differences between satellite and in situ salinity measurements is that the latter are typically acquired at a few meters depth (5–10 m), thus monitoring the near surface salinity (NSS), while the former are providing measurements at the top cm layer of the ocean, thus monitoring the actual SSS. Differences between the SSS and NSS are due to the vertical stratification of the ocean upper layers. Whereas vertical stratification in temperature has been extensively studied over the past several decades 24 , 25 , upper-ocean salinity stratification studies were only initiated in recent years, mostly motivated by the analysis of satellite-derived SSS data 26 , 27 . The ocean salinity stratification results from a complex combination of various mechanisms such as precipitation, oceanic advection and mixing conditions, as well as fresh water input from rivers runoff, melting of sea ice and removal of freshwater through evaporation. Although negative salinity anomalies have been shown and studied in cases of rainfall 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , river runoff 37 , 38 , 39 and sea-ice melting 40 , 41 , 42 , there is a limited number of studies of positive salinity anomalies due to evaporation 43 , 44 , 45 . Under absence of rainfall, continental discharge or sea ice melting, the upper ocean layer is characterized by a nearly uniform density, active vertical mixing and a high rate of turbulent dissipation 46 , 47 . In that case, vertical salinity gradients in the upper 10 m are expected to be small 29 , 35 . Here, we show that the dynamics captured by satellite SSS measurements actually differ from the dynamics shown by in situ NSS measurements. On one hand, satellite SSS data present a clear intensification of the water cycle which is not so clearly present in the NSS data. On the other hand, we find significant differences between SSS and NSS trends, which suggest that global warming is inducing an increasing stratification over wide open ocean areas. Results Satellite versus in situ salinity measurements Since the year 2000, the observation system of free drifting Argo profiling floats has been increasing, reaching close to 4000 buoys that are nowadays available. The Argo system not only provides the capability for monitoring the salinity dynamics, but also represents the main source of data used for validating satellite measurements and a very valuable input for improving ocean models. However, the distribution of these measurements is not homogeneous over the global ocean. Particularly, coastal and polar regions are under-sampled. Moreover, far from the coast and the poles, the ocean currents drive the locations of the floats, and, thus, the locations of the Argo acquisitions. Over wide oceanic areas, as that comprised between $60^\circ$ S and $60^\circ$ N, the averaged salinity at the Argo locations in a 9-day window evolves with time and it is very different from the temporal evolution of the mean salinity in the entire region, as observed in Fig. 1 . In this region, the temporal evolution of the average of the salinity provided by the Argo floats at their sampling locations and collocated satellite data is very similar (see top plot of Fig. 1 ), which indicates consistency between in situ and satellite measurements. Curiously, the temporal evolution of the averaged salinity over the Argo locations provided by the<|im_end|> <|im_start|>assistant Researchers at the Institut de Ciències del Mar (ICM-CSIC) in Barcelona have found that global warming is accelerating the water cycle, which could have significant consequences on the global climate system, according to an article published recently in the journal Scientific Reports. This acceleration of the water cycle is caused by an increase in the evaporation of water from the seas and oceans resulting from the rise in temperature. As a result, more water is circulating in the atmosphere in its vapor form, 90% of which will eventually precipitate back into the sea, while the remaining 10% will precipitate over the continent. "The acceleration of the water cycle has implications both at the ocean and on the continent, where storms could become increasingly intense. This higher amount of water circulating in the atmosphere could also explain the increase in rainfall that is being detected in some polar areas, where the fact that it is raining instead of snowing is speeding up the melting," explains Estrella Olmedo, the leading author of the study. The work also shows that the decrease in the wind in some areas of the ocean, which favors stratification of the water column, i.e. water not mixing in the vertical direction, could also be contributing to the acceleration of the water cycle. "Where the wind is no longer so strong, the surface water warms up, but does not exchange heat with the water below, allowing the surface to become more saline than the lower layers and enabling the effect of evaporation to be observed with satellite measurements," points out Antonio Turiel, also an author of the study. In this sense, Turiel adds that "this tells us that the atmosphere and the ocean interact in a stronger way than we imagined, with important consequences for the continental and polar areas." Satellites are key for oceanographic studies To carry out the study, researchers analyzed ocean surface salinity data—which is measured by satellites. Unlike subsurface salinity data—obtained with in situ instruments—the satellite data allowed them to detect this acceleration of the water cycle and, for the first time, the effect of stratification over very large regions in the ocean. According to them, this is due to the ability of satellites to measure data continuously, regardless of environmental conditions and the accessibility of different areas of the ocean. "We have been able to see that surface salinity is showing an intensification of the water cycle that subsurface salinity does not. Specifically, in the Pacific we have seen that surface salinity decreases more slowly than subsurface salinity and, in this same region, we have observed an increase in sea surface temperature and a decrease in the intensity of winds and the depth of the mixing layer," details Olmedo. These findings are the result of the use of algorithms and other data analysis products that the Barcelona Expert Center (BEC), attached to the ICM-CSIC, has been generating in the recent years from the SMOS space mission of the European Space Agency (ESA), designed to acquire observations of ocean salinity, which is essential for understanding ocean circulation, one of the key factors in understanding global climate. This circulation basically depends on the water density, which is determined by its temperature and salinity. Therefore, changes in these two parameters, however small they may be, can end up having important consequences on the global climate, which makes it key to monitor them closely. For this, Turiel concludes that "ocean models must standardize the assimilation of satellite salinity data, since the information they provide complements in situ data, and this is crucial, especially at the current time of climate crisis, where changes are occurring much faster than before." <|im_end|>

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2,049

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Constraining the response time of the climate system to changes in North Atlantic Deep Water (NADW) formation is fundamental to improving climate and Atlantic Meridional Overturning Circulation predictability. Here we report a new synchronization of terrestrial, marine, and ice-core records, which allows the first quantitative determination of the response time of North Atlantic climate to changes in high-latitude NADW formation rate during the last deglaciation. Using a continuous record of deep water ventilation from the Nordic Seas, we identify a ∼ 400-year lead of changes in high-latitude NADW formation ahead of abrupt climate changes recorded in Greenland ice cores at the onset and end of the Younger Dryas stadial, which likely occurred in response to gradual changes in temperature- and wind-driven freshwater transport. We suggest that variations in Nordic Seas deep-water circulation are precursors to abrupt climate changes and that future model studies should address this phasing. Introduction Precise reconstructions that resolve the relative timing of changes in North Atlantic Ocean circulation, climate, and carbon cycling are necessary to anticipate the mechanisms initiating and propagating abrupt global climate changes. During the last deglaciation ( ∼ 18,000-11,000-years ago), the climate system underwent numerous abrupt changes that have been attributed to variations in the strength of the Atlantic Meridional Overturning Circulation (AMOC) 1 , 2 . Through changes in high-latitude North Atlantic Deep Water (NADW) formation and export, AMOC exerts an important control on the global climate system by redistributing heat near the surface and regulating carbon storage at depth. In particular, the partitioning of carbon between the surface and deep ocean is thought to play a critical role in centennial-to-millennial-scale variations of atmospheric CO 2 (refs 3 , 4 , 5 ). However, reconciling the deglacial history of changes in overturning circulation as recorded in marine records with North Atlantic climate and p CO 2 as inferred by Greenlandic and Antarctic ice cores, respectively, remains challenging. First, highly resolved records from deep convection sites sensitive to NADW that monitor the descending branch of AMOC are still lacking. Secondly, large uncertainties in high-latitude marine reservoir ages 6 limit the precision of marine 14 C-based chronologies. Thirdly, direct alignment of marine records to far afield Greenland ice-core stratigraphies hinders testing hypotheses of synchronicity. Lastly, precise comparisons between marine and ice-core climate records are hampered by inconsistencies between the radiocarbon and ice-core timescales 7 , 8 . Here we present a new synchronization of high-latitude NADW, climate, and p CO 2 records for the last deglaciation based on new marine and ice core data that allows us to conclude for the first time that changes in deep-water circulation in the Nordic Seas led rapid shifts in North Atlantic climate and changes in carbon cycling. Results Site location, 14 C ventilation and chronology We generated a continuous record of deep/intermediate- and surface-water 14 C ventilation age from 14 C measurements on planktic and benthic foraminifera (Methods) in sediment core MD99-2284 (62° 22.48 N, 0° 58.81 W, 1500 m water depth) from the Norwegian Sea (Fig. 1 ). Fig. 1 Site location. a Location of core MD99-2284 (star), NGRIP ice cores (black circle) 101 , and other sediment cores (yellow circles) and deep-sea corals (yellow triangles) discussed in this study. The white areas indicate the extent of Northern Hemisphere ice sheets at 12500 years BP 102 . Red and white arrows show warm Atlantic inflow to the Nordic Seas and main bottom current pathways in the northern North Atlantic. Simulated winter (March, purple) and summer (September, orange) 50% sea-ice cover fraction during GS-1 (12,500 years BP) 103 is also shown. b Meridional section of radiocarbon concentration within the Atlantic Ocean (averaged over 0–40°W) from a pre-industrial control simulation using a coupled climate-biogeochemical model 104 Full size image Site MD99-2284, which is characterised by exceptionally high sedimentation rates (>400 cm kyr -1 ), is located at the gateway of the Faroe-Shetland Channel (FSC), where warm surface Atlantic water flows into the Nordic Seas and cold dense water overflows into the North Atlantic. Critically, this overflow water is one of two main NADW pathways flowing into the deep North Atlantic and a key constituent of the AMOC 9 . During the last glacial period and deglaciation, overflow through the FSC remained a continuous source of NADW 10 , 11 . Hence, because deep-water 14 C activity reflects the circulation-driven exchange of carbon between the atmosphere and deep-ocean reservoir, bottom-surface water 14 C age differences of the FSC directly inform past changes in Nordic Seas deep convection, NADW production, and its southward export 12 , 13 . The age model for the core was established using a combination of tephrochronology and alignment between sea-surface temperature records from core MD99-2284 and a high-resolution hydroclimate reconstruction from a relatively closely located terrestrial sequence in southern Scandinavia (Methods; Supplementary Figs. 1 – 5 and Note 1 – 2 ). The approach enables us to precisely place our marine proxies on the IntCal13 timescale 14 and to use the foraminiferal radiocarbon data (Methods) to calculate the marine 14 C ventilation age. Our estimate was determined using a random walk model (RWM) (Methods and Supplementary Methods ) fitted via Markov chain Monte Carlo (MCMC) that took into account uncertainty structures in both calendar age modelling and 14 C measurements. To allow detailed comparison with Greenlandic and Antarctic ice-core records, we synchronized the ice-core GICC05 (ref. 15 ) and WD2014 (ref. 16 ), and 14 C timescales using previously published and new 10 Be records from GRIP 17 and WAIS Divide ice cores, respectively (Methods; Supplementary Fig. 6 ). Ages are hereafter reported as IntCal13 years before 1950 AD ± 1σ (BP). Deglacial ventilation history of the deep Nordic Seas Surface and bottom water mass reconstructions at our site are consistent with existing paleoceanographic records of water properties, transport and exchange between the Norwegian Sea and the northern North Atlantic (Supplementary Figs. 7 – 8 ), indicating that our reconstructions are representative of regional oceanographic conditions. Benthic-planktic (B-P) ventilation ages in MD99-2284 decreased by", "role": "user" }, { "content": "The warm waters of the Gulf Stream flow up along the east coast of North America, moderating the climate of vast areas of northern and western Europe. Once the Gulf Stream gets far enough north, the warm waters cool. As they cool, they sink and start flowing south, forming what scientists call the North Atlantic Deep Water. Nick Balascio explained that the Gulf Stream/Deep Water system is known as the AMOC, or Atlantic Meridional Overturning Circulation. Balascio, an assistant professor in William & Mary's Department of Geology, is a member of a group of scientists that found evidence that changes in the strength of AMOC can serve as an precursor to massive future climate changes. Their findings were published in the journal Nature Communications in a paper \"Deep-water circulation changes lead North Atlantic climate during deglaciation.\" Deglaciation, or the widespread melting of glaciers, have triggered massive shifts in climate. Balascio explains that the team's evidence shows that a strengthening in the AMOC flow was a precursor to a sudden warming trend about 11,000 years ago. Conversely, a weakening AMOC was followed by what is known as the Younger Dryas stadial, a major cooling period about 13,000 years ago. Balascio pointed out that each shift in AMOC strength preceded the climactic shift by the same amount of time—around 400 years. He also noted that the AMOC has been weakening once again for the past century or so. The paper indicates that once the Younger Dryas settled in, air temperatures in Greenland dropped by about six degrees. \"These results suggest that changes in ocean circulation precede major global climate events,\" he said. \"So we should therefore take seriously the evidence that suggests the AMOC has been slowing down over the past century or more.\" The team recorded the relative strength of the AMOC and the development of the Deep Water Formation through comparison of various coring samples of ice and sediment from various points across the North Atlantic, including sites from the land, ocean and lakes. \"Each record provides one piece of the puzzle,\" Balascio said. \"So each record provides information on a different aspect of the climate system such as past atmospheric temperatures and surface ocean conditions.\" The team was led by Francesco Muschitiello, who is associated with the University of Cambridge and Columbia University's Lamont-Doherty Earth Observatory. Other members of the team were from the Norwegian Research Centre & Bjerknes Centre for Climate Research, Oregon State University, the University of Sheffield and Purdue University. Balascio's contribution was to conduct tephra analysis, or examination of key volcanic ash layers to establish the chronology in the marine sediment record that generated much of the data for the study. \"In order to address questions about leads-and-lags of climate and ocean circulation, we had to establish how old sections of the core were with precision,\" he said. Balascio acknowledges that the ocean and climate conditions of today are quite different from the days when the Younger Dryas was getting a toehold on the world's climate. \"But these results provide insight into the mechanisms for how the systems respond and interact,\" he said. \"If we use them, we can better model and predict future changes.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Constraining the response time of the climate system to changes in North Atlantic Deep Water (NADW) formation is fundamental to improving climate and Atlantic Meridional Overturning Circulation predictability. Here we report a new synchronization of terrestrial, marine, and ice-core records, which allows the first quantitative determination of the response time of North Atlantic climate to changes in high-latitude NADW formation rate during the last deglaciation. Using a continuous record of deep water ventilation from the Nordic Seas, we identify a ∼ 400-year lead of changes in high-latitude NADW formation ahead of abrupt climate changes recorded in Greenland ice cores at the onset and end of the Younger Dryas stadial, which likely occurred in response to gradual changes in temperature- and wind-driven freshwater transport. We suggest that variations in Nordic Seas deep-water circulation are precursors to abrupt climate changes and that future model studies should address this phasing. Introduction Precise reconstructions that resolve the relative timing of changes in North Atlantic Ocean circulation, climate, and carbon cycling are necessary to anticipate the mechanisms initiating and propagating abrupt global climate changes. During the last deglaciation ( ∼ 18,000-11,000-years ago), the climate system underwent numerous abrupt changes that have been attributed to variations in the strength of the Atlantic Meridional Overturning Circulation (AMOC) 1 , 2 . Through changes in high-latitude North Atlantic Deep Water (NADW) formation and export, AMOC exerts an important control on the global climate system by redistributing heat near the surface and regulating carbon storage at depth. In particular, the partitioning of carbon between the surface and deep ocean is thought to play a critical role in centennial-to-millennial-scale variations of atmospheric CO 2 (refs 3 , 4 , 5 ). However, reconciling the deglacial history of changes in overturning circulation as recorded in marine records with North Atlantic climate and p CO 2 as inferred by Greenlandic and Antarctic ice cores, respectively, remains challenging. First, highly resolved records from deep convection sites sensitive to NADW that monitor the descending branch of AMOC are still lacking. Secondly, large uncertainties in high-latitude marine reservoir ages 6 limit the precision of marine 14 C-based chronologies. Thirdly, direct alignment of marine records to far afield Greenland ice-core stratigraphies hinders testing hypotheses of synchronicity. Lastly, precise comparisons between marine and ice-core climate records are hampered by inconsistencies between the radiocarbon and ice-core timescales 7 , 8 . Here we present a new synchronization of high-latitude NADW, climate, and p CO 2 records for the last deglaciation based on new marine and ice core data that allows us to conclude for the first time that changes in deep-water circulation in the Nordic Seas led rapid shifts in North Atlantic climate and changes in carbon cycling. Results Site location, 14 C ventilation and chronology We generated a continuous record of deep/intermediate- and surface-water 14 C ventilation age from 14 C measurements on planktic and benthic foraminifera (Methods) in sediment core MD99-2284 (62° 22.48 N, 0° 58.81 W, 1500 m water depth) from the Norwegian Sea (Fig. 1 ). Fig. 1 Site location. a Location of core MD99-2284 (star), NGRIP ice cores (black circle) 101 , and other sediment cores (yellow circles) and deep-sea corals (yellow triangles) discussed in this study. The white areas indicate the extent of Northern Hemisphere ice sheets at 12500 years BP 102 . Red and white arrows show warm Atlantic inflow to the Nordic Seas and main bottom current pathways in the northern North Atlantic. Simulated winter (March, purple) and summer (September, orange) 50% sea-ice cover fraction during GS-1 (12,500 years BP) 103 is also shown. b Meridional section of radiocarbon concentration within the Atlantic Ocean (averaged over 0–40°W) from a pre-industrial control simulation using a coupled climate-biogeochemical model 104 Full size image Site MD99-2284, which is characterised by exceptionally high sedimentation rates (>400 cm kyr -1 ), is located at the gateway of the Faroe-Shetland Channel (FSC), where warm surface Atlantic water flows into the Nordic Seas and cold dense water overflows into the North Atlantic. Critically, this overflow water is one of two main NADW pathways flowing into the deep North Atlantic and a key constituent of the AMOC 9 . During the last glacial period and deglaciation, overflow through the FSC remained a continuous source of NADW 10 , 11 . Hence, because deep-water 14 C activity reflects the circulation-driven exchange of carbon between the atmosphere and deep-ocean reservoir, bottom-surface water 14 C age differences of the FSC directly inform past changes in Nordic Seas deep convection, NADW production, and its southward export 12 , 13 . The age model for the core was established using a combination of tephrochronology and alignment between sea-surface temperature records from core MD99-2284 and a high-resolution hydroclimate reconstruction from a relatively closely located terrestrial sequence in southern Scandinavia (Methods; Supplementary Figs. 1 – 5 and Note 1 – 2 ). The approach enables us to precisely place our marine proxies on the IntCal13 timescale 14 and to use the foraminiferal radiocarbon data (Methods) to calculate the marine 14 C ventilation age. Our estimate was determined using a random walk model (RWM) (Methods and Supplementary Methods ) fitted via Markov chain Monte Carlo (MCMC) that took into account uncertainty structures in both calendar age modelling and 14 C measurements. To allow detailed comparison with Greenlandic and Antarctic ice-core records, we synchronized the ice-core GICC05 (ref. 15 ) and WD2014 (ref. 16 ), and 14 C timescales using previously published and new 10 Be records from GRIP 17 and WAIS Divide ice cores, respectively (Methods; Supplementary Fig. 6 ). Ages are hereafter reported as IntCal13 years before 1950 AD ± 1σ (BP). Deglacial ventilation history of the deep Nordic Seas Surface and bottom water mass reconstructions at our site are consistent with existing paleoceanographic records of water properties, transport and exchange between the Norwegian Sea and the northern North Atlantic (Supplementary Figs. 7 – 8 ), indicating that our reconstructions are representative of regional oceanographic conditions. Benthic-planktic (B-P) ventilation ages in MD99-2284 decreased by<|im_end|> <|im_start|>assistant The warm waters of the Gulf Stream flow up along the east coast of North America, moderating the climate of vast areas of northern and western Europe. Once the Gulf Stream gets far enough north, the warm waters cool. As they cool, they sink and start flowing south, forming what scientists call the North Atlantic Deep Water. Nick Balascio explained that the Gulf Stream/Deep Water system is known as the AMOC, or Atlantic Meridional Overturning Circulation. Balascio, an assistant professor in William & Mary's Department of Geology, is a member of a group of scientists that found evidence that changes in the strength of AMOC can serve as an precursor to massive future climate changes. Their findings were published in the journal Nature Communications in a paper "Deep-water circulation changes lead North Atlantic climate during deglaciation." Deglaciation, or the widespread melting of glaciers, have triggered massive shifts in climate. Balascio explains that the team's evidence shows that a strengthening in the AMOC flow was a precursor to a sudden warming trend about 11,000 years ago. Conversely, a weakening AMOC was followed by what is known as the Younger Dryas stadial, a major cooling period about 13,000 years ago. Balascio pointed out that each shift in AMOC strength preceded the climactic shift by the same amount of time—around 400 years. He also noted that the AMOC has been weakening once again for the past century or so. The paper indicates that once the Younger Dryas settled in, air temperatures in Greenland dropped by about six degrees. "These results suggest that changes in ocean circulation precede major global climate events," he said. "So we should therefore take seriously the evidence that suggests the AMOC has been slowing down over the past century or more." The team recorded the relative strength of the AMOC and the development of the Deep Water Formation through comparison of various coring samples of ice and sediment from various points across the North Atlantic, including sites from the land, ocean and lakes. "Each record provides one piece of the puzzle," Balascio said. "So each record provides information on a different aspect of the climate system such as past atmospheric temperatures and surface ocean conditions." The team was led by Francesco Muschitiello, who is associated with the University of Cambridge and Columbia University's Lamont-Doherty Earth Observatory. Other members of the team were from the Norwegian Research Centre & Bjerknes Centre for Climate Research, Oregon State University, the University of Sheffield and Purdue University. Balascio's contribution was to conduct tephra analysis, or examination of key volcanic ash layers to establish the chronology in the marine sediment record that generated much of the data for the study. "In order to address questions about leads-and-lags of climate and ocean circulation, we had to establish how old sections of the core were with precision," he said. Balascio acknowledges that the ocean and climate conditions of today are quite different from the days when the Younger Dryas was getting a toehold on the world's climate. "But these results provide insight into the mechanisms for how the systems respond and interact," he said. "If we use them, we can better model and predict future changes." <|im_end|>

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279, 45721, 15379, 323, 279, 18671, 4892, 23179, 320, 10254, 67082, 435, 14801, 13, 220, 22, 1389, 220, 23, 7026, 19392, 430, 1057, 16456, 20232, 527, 18740, 315, 15481, 18435, 12968, 4787, 13, 426, 21341, 292, 33207, 1201, 29150, 320, 33, 9483, 8, 56234, 17051, 304, 14306, 1484, 12, 14261, 19, 25983, 555, 128257, 198, 128256, 78191, 198, 791, 8369, 21160, 315, 279, 27945, 9384, 6530, 709, 3235, 279, 11226, 13962, 315, 4892, 5270, 11, 13606, 1113, 279, 10182, 315, 13057, 5789, 315, 18671, 323, 19001, 4606, 13, 9843, 279, 27945, 9384, 5334, 3117, 3403, 10411, 11, 279, 8369, 21160, 7155, 13, 1666, 814, 7155, 11, 814, 19868, 323, 1212, 36612, 10007, 11, 30164, 1148, 14248, 1650, 279, 4892, 23179, 18682, 10164, 13, 15341, 19984, 5171, 822, 11497, 430, 279, 27945, 9384, 14, 34564, 10164, 1887, 374, 3967, 439, 279, 6912, 7767, 11, 477, 23179, 8930, 307, 4001, 6193, 413, 287, 16741, 2987, 13, 19984, 5171, 822, 11, 459, 18328, 14561, 304, 12656, 612, 10455, 596, 6011, 315, 4323, 2508, 11, 374, 264, 4562, 315, 264, 1912, 315, 14248, 430, 1766, 6029, 430, 4442, 304, 279, 8333, 315, 6912, 7767, 649, 8854, 439, 459, 71261, 311, 11191, 3938, 10182, 4442, 13, 11205, 14955, 1051, 4756, 304, 279, 8486, 22037, 26545, 304, 264, 5684, 330, 34564, 55051, 35855, 4442, 3063, 4892, 23179, 10182, 2391, 5367, 93529, 7246, 1210, 58337, 93529, 7246, 11, 477, 279, 24716, 50684, 315, 95790, 11, 617, 22900, 11191, 29735, 304, 10182, 13, 19984, 5171, 822, 15100, 430, 279, 2128, 596, 6029, 5039, 430, 264, 48513, 304, 279, 6912, 7767, 6530, 574, 264, 71261, 311, 264, 11210, 24808, 9327, 922, 220, 806, 11, 931, 1667, 4227, 13, 82671, 11, 264, 83526, 6912, 7767, 574, 8272, 555, 1148, 374, 3967, 439, 279, 13566, 261, 31941, 300, 87223, 532, 11, 264, 3682, 28015, 4261, 922, 220, 1032, 11, 931, 1667, 4227, 13, 19984, 5171, 822, 14618, 704, 430, 1855, 6541, 304, 6912, 7767, 8333, 53580, 279, 11323, 24045, 6541, 555, 279, 1890, 3392, 315, 892, 2345, 20019, 220, 3443, 1667, 13, 1283, 1101, 10555, 430, 279, 6912, 7767, 706, 1027, 83526, 3131, 1578, 369, 279, 3347, 9478, 477, 779, 13, 578, 5684, 15151, 430, 3131, 279, 13566, 261, 31941, 300, 23183, 304, 11, 3805, 20472, 304, 73778, 12504, 555, 922, 4848, 12628, 13, 330, 9673, 3135, 4284, 430, 4442, 304, 18435, 35855, 16599, 68, 3682, 3728, 10182, 4455, 1359, 568, 1071, 13, 330, 4516, 584, 1288, 9093, 1935, 14243, 279, 6029, 430, 13533, 279, 6912, 7767, 706, 1027, 48408, 1523, 927, 279, 3347, 9478, 477, 810, 1210, 578, 2128, 12715, 279, 8844, 8333, 315, 279, 6912, 7767, 323, 279, 4500, 315, 279, 18682, 10164, 72466, 1555, 12593, 315, 5370, 1867, 287, 10688, 315, 10054, 323, 59132, 505, 5370, 3585, 4028, 279, 4892, 23179, 11, 2737, 6732, 505, 279, 4363, 11, 18435, 323, 44236, 13, 330, 4959, 3335, 5825, 832, 6710, 315, 279, 25649, 1359, 19984, 5171, 822, 1071, 13, 330, 4516, 1855, 3335, 5825, 2038, 389, 264, 2204, 13189, 315, 279, 10182, 1887, 1778, 439, 3347, 45475, 20472, 323, 7479, 18435, 4787, 1210, 578, 2128, 574, 6197, 555, 89699, 5444, 331, 12583, 4896, 11, 889, 374, 5938, 449, 279, 3907, 315, 24562, 323, 19326, 3907, 596, 33794, 546, 9607, 2319, 1368, 9420, 58974, 13, 7089, 3697, 315, 279, 2128, 1051, 505, 279, 45721, 8483, 14821, 612, 69841, 17172, 4978, 14821, 369, 31636, 8483, 11, 19313, 3314, 3907, 11, 279, 3907, 315, 61125, 323, 73334, 3907, 13, 19984, 5171, 822, 596, 19035, 574, 311, 6929, 259, 24453, 969, 6492, 11, 477, 24481, 315, 1401, 67164, 24767, 13931, 311, 5813, 279, 27076, 2508, 304, 279, 29691, 59132, 3335, 430, 8066, 1790, 315, 279, 828, 369, 279, 4007, 13, 330, 644, 2015, 311, 2686, 4860, 922, 11767, 9976, 2922, 2076, 315, 10182, 323, 18435, 35855, 11, 584, 1047, 311, 5813, 1268, 2362, 14491, 315, 279, 6332, 1051, 449, 16437, 1359, 568, 1071, 13, 19984, 5171, 822, 56030, 430, 279, 18435, 323, 10182, 4787, 315, 3432, 527, 5115, 2204, 505, 279, 2919, 994, 279, 13566, 261, 31941, 300, 574, 3794, 264, 311, 2701, 820, 389, 279, 1917, 596, 10182, 13, 330, 4071, 1521, 3135, 3493, 20616, 1139, 279, 24717, 369, 1268, 279, 6067, 6013, 323, 16681, 1359, 568, 1071, 13, 330, 2746, 584, 1005, 1124, 11, 584, 649, 2731, 1646, 323, 7168, 3938, 4442, 1210, 220, 128257, 198 ]

2,117

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Plate subduction and delamination, two key processes driving plate tectonics, are thought to be controlled by the buoyancy of the lithospheric mantle relative to the underlying asthenosphere. Most mantle delamination models consider a lithospheric density higher than the asthenosphere to ensure negative buoyancy (slab pull). However, mineral physics show that the continental lithospheric mantle density is lighter than the asthenosphere, and that only its pressure-temperature-composition dependence makes it become denser and unstable when sinking adiabatically. Here, we explore the controls on buoyancy using a 2D thermal-diffusive model of plate convergence, considering five chemical compositions and tectonothermal ages, namely Archon (>2.5 Ga), Proton (2.5–1.0 Ga), Tecton (<1.0 Ga), and two oceanic lithospheric plates of 30 Ma and 120 Ma. While the advection of colder rock in oceanic-like plates always results in negative buoyancy, Protons and Tectons exhibit an ability to slowly flip from negative to positive buoyancy at low convergence rates: they first favour the sinking due to advection and then become more buoyant because they are thinner and heat up faster during subduction. In contrast, the lighter density of cratons overprints this effect and hinders delamination or subduction, regardless of the convergence rate. This may explain why Archons are more stable during the Wilson cycle. Introduction Plate tectonics is thought to be mainly driven by the negative buoyancy of the lithospheric mantle relative to the asthenosphere, the driving force for both oceanic plate subduction and mantle delamination (the peeling off of the subcontinental lithospheric mantle from the crust and its sinking). The lithosphere interacts differently with the underlying asthenosphere in oceanic and continental domains. Oceanic lithosphere is formed at mid-ocean ridges and is soon (generally in less than 200 Ma) reworked back into the deeper mantle through subduction. In contrast, continental lithosphere is an order of magnitude older and has grown through accretion over longer time-scales, modifying its chemical composition. The continental lithosphere is believed to be recycled back into the asthenosphere at collision zones through the removal of parts of the lithospheric mantle by delaminating from the overlying crust. Geophysical and geological observations support mantle delamination in regions such as the Tibet 1 , 2 ; Alboran domain 3 , 4 , 5 ; the Apennines 6 , 7 , 8 ; Eastern Anatolia 9 , 10 , 11 , 12 ; and Sierra Nevada 13 , 14 , some of which are shown in Fig. 1 . Numerical models suggest that this process is initiated by a conduit connecting the sublithospheric mantle with the weak lower crust and the negative buoyancy of the lithospheric mantle 15 . Figure 1 Geographic overview of regions with continental collision. Three regions within continental collisions that can be related to our study according to their convergence-rate and lithospheric mantle thickness. Full size image Whereas most geodynamic studies have focused on the role of the viscosity contrast between the lower crust and the lithospheric mantle in the development of delamination 4 , 15 , 16 , 17 , 18 , 19 , or on the role of composition and thickness of the crust on the lithospheric subductability 20 , only few of them have scrutinized the influence of the density contrast between the lithospheric mantle and the asthenosphere 4 , 11 , 14 , 21 , 22 , 23 , 24 ). These geodynamic models generally adopt densities that are either constant over time and space or temperature-dependent only, predefining a density for the subcontinental lithospheric mantle (SCLM) about 50 kg m −3 higher than of the asthenosphere. More recently, the role of pressure, temperature, and composition has been incorporated in calculating the buoyancy of the descending lithospheric mantle forced by plate convergence 24 , 25 . Global geochemical analyses on mantle xenoliths, xenocrysts, and outcrops show that the mean composition of the SCLM is mainly related to the tectonothermal age of the overlying crust 26 , 27 . As the continental lithosphere undergoes cycles of melting, it gradually depletes in incompatible elements, such as Ca, Al, and Fe, relative to the primary source. The lithospheric mantle in Archean cratons (Archons), corresponding to tectonothermal ages >2.5 Ga, is generally highly depleted, while most lithospheric mantle beneath Neo-proterozoic/Phanerozoic mobile belts (Tectons, <1 Ga) is closer to the composition of the Primitive Upper Mantle (PUM). The SCLM beneath Meso- and Paleo-proterozoic shields and mobile belts (Protons), with tectonothermal ages of 2.5–1.0 Ga, is typically intermediate in composition. These compositional variations affect the bulk density of the SCLM and the greater the degree of depletion, the lower the density 27 . In contrast, the composition of the oceanic lithospheric mantle corresponds to that of PUM after melt extraction at mid-ocean ridges (MOR), being relatively homogeneous except beneath large oceanic plateaus. Petrological and geochemical studies show that at identical P-T conditions as at the LAB, the density of the SCLM is lower than that of the PUM 27 (see Supplementary Fig. S1 ), which is at odds with the aforementioned density distribution adopted in most geodynamic and static models 20 . In fact, the density of the sinking SCLM increases with pressure and decreases with temperature, thus P and T having competing effects on the depth-dependence of density. Whether mantle delamination or subduction are promoted by a negative buoyancy forced by plate convergence depends on the gradients of density relative to both parameters (Table 1 ). Table 1 Physical parameters of all of the lithosphere types used in this study, together with those of the Primitive Upper Mantle (PUM). Full size table Here we explore the idea that, whenever the lithosphere is incipiently forced to sink into the asthenosphere, it can become positively or negatively buoyant depending on its composition and on how the pressure-temperature evolution, imposed by plate convergence, affects its density evolution. This may explain why the older regions of the continental lithosphere (Archons) become tectonically more stable, self-prolonging their life span and favoring the Wilson cycle. To this purpose, we calculate the buoyancy of the sinking mantle in a kinematic model that accounts", "role": "user" }, { "content": "A fast collision rate between tectonic plates and a young age (millions of years) are two factors that favour the sinking of the lithosphere in the mantle, according to a new study made by researchers at the Institute of Earth Sciences Jaume Almera of the Spanish National Research Council (ICTJA-CSIC). The study has been published recently in Scientific Reports. The authors of the study developed a new numerical model to study the effects of the convergence rate between tectonic plates and its composition on the lithospheric mantle density promoting or avoiding its sinking during subduction or delaminating processes. \"The model designed in this study provides a methodological framework for understanding the stability of the lithosphere during the convergence of the tectonic plates,\" said Kittiphon Boonma, Ph.D. student of the SUBITOP project at ICTJA-CSIC and first author of the study. The lithosphere is the Earth's rigid outermost layer that comprises the crust and uppermost mantle, forming the tectonic plates. These plates float and move over the asthenosphere, a denser and more viscous layer of the sublithospheric mantle. In the areas where plates converge, one of the plates sinks below the other, thrusting into the sublithospheric mantle. This would be the typical case of the oceanic lithosphere subduction zones. Another possibility is that, in continental collision zones, the lithospheric mantle of one of the plates separates from (\"peels off\") the crust and sinks into the asthenosphere in a process known as delamination. Both processes are sensitive to the lithospheric mantle density which, at the same time, depends on the pressure, temperature and chemical composition or, which is the same, of the convergence rate and the age of the lithosphere. \"Our simulations combine lithospheric composition for different plate ages with a wide spectrum of plate collision rates to understand what determines the positive or negative buoyancy of the lithosphere,\" said Daniel García-Castellanos, researcher at ICTJA-CSIC and co-author of the study. \"The main advance of our work is the analysis of the dependence of lithospheric mantle buoyancy on density variations resulting from the advection-diffusion balance considering a wide range of tectonic convergence rates and different lithospheric mantle chemical compositions,\" said Kittiphon Boonma. Researchers performed several simulations with the new model considering three different types of continental lithosphere, with an age range between 2.5 Ga and 1 Ga year, and two oceanic lithospheres aged 120 and 30 milion year old. They considered six different convergence rates between 1 and 80 mm/year. Simulations were aimed to observe the effect of the different collision rates and compositions on the lithospheric mantle density. \"In subduction or continental collision processes, there are two opposite effects that affect the mantle density. Density increases due to pressure increases but, at the same time, it tends to decrease due to the temperature increase produced by the depth. The predominance of one of these two effects will depend on the convergence velocity. Moreover, the mantle density depends also on its own chemical composition and it has been observed that it decreases with the age,\" explains Manel Fernández, co-author of the study. The model outcomes showed that the oldest and thickest continental lithospheric mantle (Archon) was less dense than the asthenosphere and avoided the sinking. At low and moderate convergence rates, researchers found that the two other types of continental lithospheric mantle shifted from sinking to stay stables due to their thinner thicknesses and to the loss of density induced by the temperature increases due to the depth. Last, the two different types oceanic lithosphere always sank, whatever the applied convergence rate was, due to their bigger density derived from it composition. \"According to these results, the faster the convergence rate between two continents, the bigger the probability that one of them delaminates or sinks towards the mantle,\" explains Daniel García-Castellanos. \"Results suggest an explanation on why the young plates often sinks easily into the mantle, being recycled in the mantle while cratons (oldest continental regions) seem to resist better the changes in tectonic forces during Earth's evolution and they are less prone to subduct or delaminate,\" said García-Castellanos. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Plate subduction and delamination, two key processes driving plate tectonics, are thought to be controlled by the buoyancy of the lithospheric mantle relative to the underlying asthenosphere. Most mantle delamination models consider a lithospheric density higher than the asthenosphere to ensure negative buoyancy (slab pull). However, mineral physics show that the continental lithospheric mantle density is lighter than the asthenosphere, and that only its pressure-temperature-composition dependence makes it become denser and unstable when sinking adiabatically. Here, we explore the controls on buoyancy using a 2D thermal-diffusive model of plate convergence, considering five chemical compositions and tectonothermal ages, namely Archon (>2.5 Ga), Proton (2.5–1.0 Ga), Tecton (<1.0 Ga), and two oceanic lithospheric plates of 30 Ma and 120 Ma. While the advection of colder rock in oceanic-like plates always results in negative buoyancy, Protons and Tectons exhibit an ability to slowly flip from negative to positive buoyancy at low convergence rates: they first favour the sinking due to advection and then become more buoyant because they are thinner and heat up faster during subduction. In contrast, the lighter density of cratons overprints this effect and hinders delamination or subduction, regardless of the convergence rate. This may explain why Archons are more stable during the Wilson cycle. Introduction Plate tectonics is thought to be mainly driven by the negative buoyancy of the lithospheric mantle relative to the asthenosphere, the driving force for both oceanic plate subduction and mantle delamination (the peeling off of the subcontinental lithospheric mantle from the crust and its sinking). The lithosphere interacts differently with the underlying asthenosphere in oceanic and continental domains. Oceanic lithosphere is formed at mid-ocean ridges and is soon (generally in less than 200 Ma) reworked back into the deeper mantle through subduction. In contrast, continental lithosphere is an order of magnitude older and has grown through accretion over longer time-scales, modifying its chemical composition. The continental lithosphere is believed to be recycled back into the asthenosphere at collision zones through the removal of parts of the lithospheric mantle by delaminating from the overlying crust. Geophysical and geological observations support mantle delamination in regions such as the Tibet 1 , 2 ; Alboran domain 3 , 4 , 5 ; the Apennines 6 , 7 , 8 ; Eastern Anatolia 9 , 10 , 11 , 12 ; and Sierra Nevada 13 , 14 , some of which are shown in Fig. 1 . Numerical models suggest that this process is initiated by a conduit connecting the sublithospheric mantle with the weak lower crust and the negative buoyancy of the lithospheric mantle 15 . Figure 1 Geographic overview of regions with continental collision. Three regions within continental collisions that can be related to our study according to their convergence-rate and lithospheric mantle thickness. Full size image Whereas most geodynamic studies have focused on the role of the viscosity contrast between the lower crust and the lithospheric mantle in the development of delamination 4 , 15 , 16 , 17 , 18 , 19 , or on the role of composition and thickness of the crust on the lithospheric subductability 20 , only few of them have scrutinized the influence of the density contrast between the lithospheric mantle and the asthenosphere 4 , 11 , 14 , 21 , 22 , 23 , 24 ). These geodynamic models generally adopt densities that are either constant over time and space or temperature-dependent only, predefining a density for the subcontinental lithospheric mantle (SCLM) about 50 kg m −3 higher than of the asthenosphere. More recently, the role of pressure, temperature, and composition has been incorporated in calculating the buoyancy of the descending lithospheric mantle forced by plate convergence 24 , 25 . Global geochemical analyses on mantle xenoliths, xenocrysts, and outcrops show that the mean composition of the SCLM is mainly related to the tectonothermal age of the overlying crust 26 , 27 . As the continental lithosphere undergoes cycles of melting, it gradually depletes in incompatible elements, such as Ca, Al, and Fe, relative to the primary source. The lithospheric mantle in Archean cratons (Archons), corresponding to tectonothermal ages >2.5 Ga, is generally highly depleted, while most lithospheric mantle beneath Neo-proterozoic/Phanerozoic mobile belts (Tectons, <1 Ga) is closer to the composition of the Primitive Upper Mantle (PUM). The SCLM beneath Meso- and Paleo-proterozoic shields and mobile belts (Protons), with tectonothermal ages of 2.5–1.0 Ga, is typically intermediate in composition. These compositional variations affect the bulk density of the SCLM and the greater the degree of depletion, the lower the density 27 . In contrast, the composition of the oceanic lithospheric mantle corresponds to that of PUM after melt extraction at mid-ocean ridges (MOR), being relatively homogeneous except beneath large oceanic plateaus. Petrological and geochemical studies show that at identical P-T conditions as at the LAB, the density of the SCLM is lower than that of the PUM 27 (see Supplementary Fig. S1 ), which is at odds with the aforementioned density distribution adopted in most geodynamic and static models 20 . In fact, the density of the sinking SCLM increases with pressure and decreases with temperature, thus P and T having competing effects on the depth-dependence of density. Whether mantle delamination or subduction are promoted by a negative buoyancy forced by plate convergence depends on the gradients of density relative to both parameters (Table 1 ). Table 1 Physical parameters of all of the lithosphere types used in this study, together with those of the Primitive Upper Mantle (PUM). Full size table Here we explore the idea that, whenever the lithosphere is incipiently forced to sink into the asthenosphere, it can become positively or negatively buoyant depending on its composition and on how the pressure-temperature evolution, imposed by plate convergence, affects its density evolution. This may explain why the older regions of the continental lithosphere (Archons) become tectonically more stable, self-prolonging their life span and favoring the Wilson cycle. To this purpose, we calculate the buoyancy of the sinking mantle in a kinematic model that accounts<|im_end|> <|im_start|>assistant A fast collision rate between tectonic plates and a young age (millions of years) are two factors that favour the sinking of the lithosphere in the mantle, according to a new study made by researchers at the Institute of Earth Sciences Jaume Almera of the Spanish National Research Council (ICTJA-CSIC). The study has been published recently in Scientific Reports. The authors of the study developed a new numerical model to study the effects of the convergence rate between tectonic plates and its composition on the lithospheric mantle density promoting or avoiding its sinking during subduction or delaminating processes. "The model designed in this study provides a methodological framework for understanding the stability of the lithosphere during the convergence of the tectonic plates," said Kittiphon Boonma, Ph.D. student of the SUBITOP project at ICTJA-CSIC and first author of the study. The lithosphere is the Earth's rigid outermost layer that comprises the crust and uppermost mantle, forming the tectonic plates. These plates float and move over the asthenosphere, a denser and more viscous layer of the sublithospheric mantle. In the areas where plates converge, one of the plates sinks below the other, thrusting into the sublithospheric mantle. This would be the typical case of the oceanic lithosphere subduction zones. Another possibility is that, in continental collision zones, the lithospheric mantle of one of the plates separates from ("peels off") the crust and sinks into the asthenosphere in a process known as delamination. Both processes are sensitive to the lithospheric mantle density which, at the same time, depends on the pressure, temperature and chemical composition or, which is the same, of the convergence rate and the age of the lithosphere. "Our simulations combine lithospheric composition for different plate ages with a wide spectrum of plate collision rates to understand what determines the positive or negative buoyancy of the lithosphere," said Daniel García-Castellanos, researcher at ICTJA-CSIC and co-author of the study. "The main advance of our work is the analysis of the dependence of lithospheric mantle buoyancy on density variations resulting from the advection-diffusion balance considering a wide range of tectonic convergence rates and different lithospheric mantle chemical compositions," said Kittiphon Boonma. Researchers performed several simulations with the new model considering three different types of continental lithosphere, with an age range between 2.5 Ga and 1 Ga year, and two oceanic lithospheres aged 120 and 30 milion year old. They considered six different convergence rates between 1 and 80 mm/year. Simulations were aimed to observe the effect of the different collision rates and compositions on the lithospheric mantle density. "In subduction or continental collision processes, there are two opposite effects that affect the mantle density. Density increases due to pressure increases but, at the same time, it tends to decrease due to the temperature increase produced by the depth. The predominance of one of these two effects will depend on the convergence velocity. Moreover, the mantle density depends also on its own chemical composition and it has been observed that it decreases with the age," explains Manel Fernández, co-author of the study. The model outcomes showed that the oldest and thickest continental lithospheric mantle (Archon) was less dense than the asthenosphere and avoided the sinking. At low and moderate convergence rates, researchers found that the two other types of continental lithospheric mantle shifted from sinking to stay stables due to their thinner thicknesses and to the loss of density induced by the temperature increases due to the depth. Last, the two different types oceanic lithosphere always sank, whatever the applied convergence rate was, due to their bigger density derived from it composition. "According to these results, the faster the convergence rate between two continents, the bigger the probability that one of them delaminates or sinks towards the mantle," explains Daniel García-Castellanos. "Results suggest an explanation on why the young plates often sinks easily into the mantle, being recycled in the mantle while cratons (oldest continental regions) seem to resist better the changes in tectonic forces during Earth's evolution and they are less prone to subduct or delaminate," said García-Castellanos. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years 1 . Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners 2 , 3 , 4 , 5 . In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8 + T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders. Main Sucralose is a commonly used, calorie-free sweetener that is about 600 times sweeter than sucrose 6 . Despite its limited absorption 7 , circulating sucralose can be detected in humans following consumption of sucralose-containing food or drinks 8 , with consumption of 250 mg sucralose resulting in plasma sucralose levels of around 1 μM within 90–120 min (ref. 8 ). The maximum acceptable daily intake (ADI) of sucralose for humans has been established as 15 mg per kg (body weight) by the European Food Safety Authority (EFSA) or 5 mg per kg (body weight) by the US Food and Drug Administration (FDA). Allometric scaling on the basis of body surface area (BSA) equivalents can be used to convert human doses of drugs to mouse doses by adjusting for the increased metabolic rate in mice 9 . By allowing mice ad libitum access to water containing 0.72 mg ml −1 or 0.17 mg ml −1 of sucralose, we calculated—using BSA equivalents—that the consumption of sucralose over 10 weeks was near the equivalent of the ADI recommended by either EFSA (at the 0.72 mg ml −1 dose) or FDA (at the 0.17 mg ml −1 dose) (Fig. 1a ). As expected, we were able to detect increasing amounts of circulating sucralose corresponding with increased consumption in mice (Fig. 1b and Extended Data Fig. 1a ), reaching a plasma concentration of around 1 µM at the highest dose of sucralose, consistent with the levels that can be achieved in humans 8 . Fig. 1: Sucralose impairs T cell proliferation and differentiation. a , Sucralose (Scrl) intake in mice given 0.72 mg ml −1 (blue; n = 6) or 0.17 mg ml −1 (aquamarine; n = 6) Scrl. In box plots, whiskers show the minimum and maximum values, box margins represent the first and third quartile and the central line is the median value. Dashed lines indicate the BSA-adjusted EFSA (black) and FDA (purple) maximum ADI. Scrl concentrations are indicated in mg ml −1 throughout. b , Circulating Scrl levels in mice given water containing different Scrl concentrations for 2 weeks. n = 4 individual mice per condition. c , Schematic of the experimental design. CFSE, carboxyfluorescein succinimidyl ester. d , Homeostatic proliferation of CD8 + and CD4 + donor T cells in individual Rag2 −/− recipient mice given plain water ( n = 6) or Scrl ( n = 5). e , Histograms of CD8 + T cell proliferation in the presence of Scrl, AceK, NaS or control medium (Ctrl). f , Human CD8 + T cell proliferation in the presence of Scrl, AceK, NaS or control medium. g , Paired comparison of the percentage of proliferated CD8 + T cells in f . n = 3 independent donors. h , Representative flow cytometry plot of in vitro polarized CD4 + T H 1 cells expressing IFNγ and TBET (also known as TBX21). i , The percentage of T H 1 cells in h . n = 3 technical replicates per condition. j , Representative flow cytometry plot of CD8 + T cells expressing CD8 and IFNγ. k , Quantification of CD8 + IFNγ + cells in j . n = 3 (Ctrl) or n = 4 (Scrl, AceK and NaS) technical replicates per condition. l , m , Mice were given plain water ( n = 9) or 0.72 mg ml −1 of either Scrl ( n = 12) or NaS ( n = 11). l , Body composition (lean versus fat mass). m , Average energy expenditure measured continuously during night (grey area) and day (white area). n , Multidimensional scaling of the faecal gut microbiome from mice given water ( n = 5), 0.72 mg ml −1 Scrl ( n = 5), 0.17 mg ml −1 Scrl ( n = 5) or 10% (w/v) glucose ( n = 5) for 2 (left) or 12 (right) weeks. Data are mean ± s.d. ( b , i , k ) or mean ± s.e.m. ( d , l , m ). Significance was tested using unpaired ( d ) or paired ( g ) two-tailed Student’s t -test; one-way ANOVA with Tukey’s ( i , k ) or Dunnet’s multiple comparison test for lean and fat mass independently ( l ) or two-way ANOVA ( m ). Data are representative of two ( d ) or three ( e , h – k ) independent experiments. Source data Full size image Effect on T cell proliferation and differentiation Previous reports using different models have suggested that high doses of sucralose can have either pro-inflammatory or anti-inflammatory activities 2 , 3 , 4 . To test a possible effect of sucralose on the immune system, we profiled various immune compartments in mice given 0.17 or 0.72 mg ml −1 sucralose or the chemically unrelated sweetener sodium saccharin (NaS). In these studies, neither dose of sucralose or NaS had any detectable effect on the homeostatic levels of CD11b + myeloid cells (including monocytes and neutrophils), B220 + B cells, CD8", "role": "user" }, { "content": "Scientists at the Francis Crick Institute have found that high consumption of a common artificial sweetener, sucralose, lowers activation of T-cells, an important component of the immune system, in mice. If found to have similar effects in humans, one day it could be used therapeutically to help dampen T-cell responses. For example, in patients with autoimmune diseases who suffer from uncontrolled T cell activation. Sucralose is an artificial sweetener, about 600 times sweeter than sugar, that is commonly used in drinks and food. Like many other artificial sweeteners, the effects of sucralose on the body are not yet fully understood, although recent studies have shown that sucralose can impact human health by affecting the microbiome. In the new study, published in Nature today (March 15), the researchers tested the impact of sucralose on the immune system in mice. Mice were fed sucralose at levels equivalent to the acceptable daily intake recommended by the European and American food safety authorities. Importantly, while these doses are achievable, they would not normally be reached by people simply consuming food or drinks containing sweeteners as part of a normal diet. The mice fed diets containing high doses of sucralose were less able to activate T cells in response to cancer or infection. No effect was seen on other types of immune cells. By studying T cells in more detail, the researchers found that a high-dose of sucralose impacted intracellular calcium release in response to stimulation, and therefore dampened T -cell function. This research should not sound alarm bells for those wanting to ensure they have a healthy immune system or recover from disease, as humans consuming normal or even moderately elevated levels of sucralose would not be exposed to the levels achieved in this study. Instead, the researchers hope the findings could lead to a new way of using much higher therapeutic doses of sucralose in patients, building on the observation that when mice with T cell mediated autoimmune disease were given a high-dose sucralose diet, this helped to mitigate the harmful effects of their over active T cells. Karen Vousden, senior author and principal group leader at the Crick, says, \"We're hoping to piece together a bigger picture of the effects of diet on health and disease, so that one day we can advise on diets that are best suited to individual patients, or find elements of our diet that doctors can exploit for treatment. \"More research and studies are needed to see whether these effects of sucralose in mice can be reproduced in humans. If these initial findings hold up in people, they could one day offer a way to limit some of the harmful effects of autoimmune conditions.\" Fabio Zani, co-first author and postdoctoral training fellow at the Crick, adds, \"We do not want people to take away the message that sucralose is harmful if consumed in the course of a normal balanced diet, as the doses we used in mice would be very hard to achieve without medical intervention. \"The impact on the immune system we observed seems reversible and we believe it may be worth studying if sucralose could be used to ameliorate conditions such as autoimmunity, especially in combinational therapies.\" Julianna Blagih, co-first author and former postdoctoral training fellow at the Crick (now Assistant Professor at the Maisonneuve-Rosemont Hospital Research Center, University of Montreal), explains, \"We've shown that a commonly used sweetener, sucralose, is not a completely inert molecule and we have uncovered an unexpected effect on the immune system. We are keen to explore whether there are other cell types or processes that are similarly affected by this sweetener.\" Karis Betts, senior health information manager at Cancer Research UK, said, \"This study begins to explore how high doses of sucralose could potentially be used in new treatment options for patients, but it's still early days. \"The results of this study don't show harmful effects of sucralose for humans so you don't need to think about changing your diet to avoid it.\" The researchers are continuing this work and are hoping to run trials to test if sucralose has a similar effect in humans. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years 1 . Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners 2 , 3 , 4 , 5 . In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8 + T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders. Main Sucralose is a commonly used, calorie-free sweetener that is about 600 times sweeter than sucrose 6 . Despite its limited absorption 7 , circulating sucralose can be detected in humans following consumption of sucralose-containing food or drinks 8 , with consumption of 250 mg sucralose resulting in plasma sucralose levels of around 1 μM within 90–120 min (ref. 8 ). The maximum acceptable daily intake (ADI) of sucralose for humans has been established as 15 mg per kg (body weight) by the European Food Safety Authority (EFSA) or 5 mg per kg (body weight) by the US Food and Drug Administration (FDA). Allometric scaling on the basis of body surface area (BSA) equivalents can be used to convert human doses of drugs to mouse doses by adjusting for the increased metabolic rate in mice 9 . By allowing mice ad libitum access to water containing 0.72 mg ml −1 or 0.17 mg ml −1 of sucralose, we calculated—using BSA equivalents—that the consumption of sucralose over 10 weeks was near the equivalent of the ADI recommended by either EFSA (at the 0.72 mg ml −1 dose) or FDA (at the 0.17 mg ml −1 dose) (Fig. 1a ). As expected, we were able to detect increasing amounts of circulating sucralose corresponding with increased consumption in mice (Fig. 1b and Extended Data Fig. 1a ), reaching a plasma concentration of around 1 µM at the highest dose of sucralose, consistent with the levels that can be achieved in humans 8 . Fig. 1: Sucralose impairs T cell proliferation and differentiation. a , Sucralose (Scrl) intake in mice given 0.72 mg ml −1 (blue; n = 6) or 0.17 mg ml −1 (aquamarine; n = 6) Scrl. In box plots, whiskers show the minimum and maximum values, box margins represent the first and third quartile and the central line is the median value. Dashed lines indicate the BSA-adjusted EFSA (black) and FDA (purple) maximum ADI. Scrl concentrations are indicated in mg ml −1 throughout. b , Circulating Scrl levels in mice given water containing different Scrl concentrations for 2 weeks. n = 4 individual mice per condition. c , Schematic of the experimental design. CFSE, carboxyfluorescein succinimidyl ester. d , Homeostatic proliferation of CD8 + and CD4 + donor T cells in individual Rag2 −/− recipient mice given plain water ( n = 6) or Scrl ( n = 5). e , Histograms of CD8 + T cell proliferation in the presence of Scrl, AceK, NaS or control medium (Ctrl). f , Human CD8 + T cell proliferation in the presence of Scrl, AceK, NaS or control medium. g , Paired comparison of the percentage of proliferated CD8 + T cells in f . n = 3 independent donors. h , Representative flow cytometry plot of in vitro polarized CD4 + T H 1 cells expressing IFNγ and TBET (also known as TBX21). i , The percentage of T H 1 cells in h . n = 3 technical replicates per condition. j , Representative flow cytometry plot of CD8 + T cells expressing CD8 and IFNγ. k , Quantification of CD8 + IFNγ + cells in j . n = 3 (Ctrl) or n = 4 (Scrl, AceK and NaS) technical replicates per condition. l , m , Mice were given plain water ( n = 9) or 0.72 mg ml −1 of either Scrl ( n = 12) or NaS ( n = 11). l , Body composition (lean versus fat mass). m , Average energy expenditure measured continuously during night (grey area) and day (white area). n , Multidimensional scaling of the faecal gut microbiome from mice given water ( n = 5), 0.72 mg ml −1 Scrl ( n = 5), 0.17 mg ml −1 Scrl ( n = 5) or 10% (w/v) glucose ( n = 5) for 2 (left) or 12 (right) weeks. Data are mean ± s.d. ( b , i , k ) or mean ± s.e.m. ( d , l , m ). Significance was tested using unpaired ( d ) or paired ( g ) two-tailed Student’s t -test; one-way ANOVA with Tukey’s ( i , k ) or Dunnet’s multiple comparison test for lean and fat mass independently ( l ) or two-way ANOVA ( m ). Data are representative of two ( d ) or three ( e , h – k ) independent experiments. Source data Full size image Effect on T cell proliferation and differentiation Previous reports using different models have suggested that high doses of sucralose can have either pro-inflammatory or anti-inflammatory activities 2 , 3 , 4 . To test a possible effect of sucralose on the immune system, we profiled various immune compartments in mice given 0.17 or 0.72 mg ml −1 sucralose or the chemically unrelated sweetener sodium saccharin (NaS). In these studies, neither dose of sucralose or NaS had any detectable effect on the homeostatic levels of CD11b + myeloid cells (including monocytes and neutrophils), B220 + B cells, CD8<|im_end|> <|im_start|>assistant Scientists at the Francis Crick Institute have found that high consumption of a common artificial sweetener, sucralose, lowers activation of T-cells, an important component of the immune system, in mice. If found to have similar effects in humans, one day it could be used therapeutically to help dampen T-cell responses. For example, in patients with autoimmune diseases who suffer from uncontrolled T cell activation. Sucralose is an artificial sweetener, about 600 times sweeter than sugar, that is commonly used in drinks and food. Like many other artificial sweeteners, the effects of sucralose on the body are not yet fully understood, although recent studies have shown that sucralose can impact human health by affecting the microbiome. In the new study, published in Nature today (March 15), the researchers tested the impact of sucralose on the immune system in mice. Mice were fed sucralose at levels equivalent to the acceptable daily intake recommended by the European and American food safety authorities. Importantly, while these doses are achievable, they would not normally be reached by people simply consuming food or drinks containing sweeteners as part of a normal diet. The mice fed diets containing high doses of sucralose were less able to activate T cells in response to cancer or infection. No effect was seen on other types of immune cells. By studying T cells in more detail, the researchers found that a high-dose of sucralose impacted intracellular calcium release in response to stimulation, and therefore dampened T -cell function. This research should not sound alarm bells for those wanting to ensure they have a healthy immune system or recover from disease, as humans consuming normal or even moderately elevated levels of sucralose would not be exposed to the levels achieved in this study. Instead, the researchers hope the findings could lead to a new way of using much higher therapeutic doses of sucralose in patients, building on the observation that when mice with T cell mediated autoimmune disease were given a high-dose sucralose diet, this helped to mitigate the harmful effects of their over active T cells. Karen Vousden, senior author and principal group leader at the Crick, says, "We're hoping to piece together a bigger picture of the effects of diet on health and disease, so that one day we can advise on diets that are best suited to individual patients, or find elements of our diet that doctors can exploit for treatment. "More research and studies are needed to see whether these effects of sucralose in mice can be reproduced in humans. If these initial findings hold up in people, they could one day offer a way to limit some of the harmful effects of autoimmune conditions." Fabio Zani, co-first author and postdoctoral training fellow at the Crick, adds, "We do not want people to take away the message that sucralose is harmful if consumed in the course of a normal balanced diet, as the doses we used in mice would be very hard to achieve without medical intervention. "The impact on the immune system we observed seems reversible and we believe it may be worth studying if sucralose could be used to ameliorate conditions such as autoimmunity, especially in combinational therapies." Julianna Blagih, co-first author and former postdoctoral training fellow at the Crick (now Assistant Professor at the Maisonneuve-Rosemont Hospital Research Center, University of Montreal), explains, "We've shown that a commonly used sweetener, sucralose, is not a completely inert molecule and we have uncovered an unexpected effect on the immune system. We are keen to explore whether there are other cell types or processes that are similarly affected by this sweetener." Karis Betts, senior health information manager at Cancer Research UK, said, "This study begins to explore how high doses of sucralose could potentially be used in new treatment options for patients, but it's still early days. "The results of this study don't show harmful effects of sucralose for humans so you don't need to think about changing your diet to avoid it." The researchers are continuing this work and are hoping to run trials to test if sucralose has a similar effect in humans. <|im_end|>

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12966, 13, 220, 128257, 198 ]

2,308

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract With the recent developments in machine learning, Carrasquilla and Melko have proposed a paradigm that is complementary to the conventional approach for the study of spin models. As an alternative to investigating the thermal average of macroscopic physical quantities, they have used the spin configurations for the classification of the disordered and ordered phases of a phase transition through machine learning. We extend and generalize this method. We focus on the configuration of the long-range correlation function instead of the spin configuration itself, which enables us to provide the same treatment to multi-component systems and the systems with a vector order parameter. We analyze the Berezinskii-Kosterlitz-Thouless (BKT) transition with the same technique to classify three phases: the disordered, the BKT, and the ordered phases. We also present the classification of a model using the training data of a different model. Introduction Numerical simulations, such as Monte Carlo methods, have been successfully employed in the study of phase transitions and critical phenomena 1 . In spin systems, the spin configurations are sampled using a stochastic importance sampling technique, and the estimators for physical quantities, such as the order parameter and the specific heat, are evaluated for these samples. Several spin models have recently been studied through machine learning 2 , 3 , 4 , 5 , 6 . Carrasquilla and Melko 2 proposed a paradigm that is complementary to the above approach. By using large data sets of spin configurations, they classified and identified a high-temperature paramagnetic phase and a low-temperature ferromagnetic phase. It was similar to image classification using machine learning. They demonstrated the use of fully connected and convolutional neural networks for the study of the two-dimensional (2D) Ising model and an Ising lattice gauge theory. In this study, we extend and generalize the method proposed by Carrasquilla and Melko 2 . First, instead of considering the spin configuration itself, we analyze the long-range correlation configuration, which will be explained later. From this analysis, we can evaluate the multi-component systems, such as the Potts model, and the systems with a vector order parameter, such as the XY model. We can identify identical configurations with the permutational symmetry or the rotational symmetry, which results in an efficient classification of phases. Moreover, the inclusion of long-range correlation is helpful in the study of phase transition. Second, we investigate the Berezinskii-Kosterlitz-Thouless (BKT) phase 7 , 8 , 9 , 10 , described by a fixed line instead of a fixed point from the perspective of the renormalization group, using the same treatment as the paramagnetic-ferromagnetic phase transition. By studying the 2D clock model, which is a discrete version of the XY model, we classify the paramagnetic-BKT-ferromagnetic transitions through machine learning. Model We enlist the models we analyze below. We consider a 2D Ising model on the square lattice, whose Hamiltonian is given as $$H=-\\,J\\sum _{\\langle ij\\rangle }\\,{s}_{i}{s}_{j},\\,{s}_{i}=\\pm \\,1.$$ (1) The summation is realized over the nearest-neighbor pairs, and periodic boundary conditions are imposed in numerical simulations. The Hamiltonian of the q -state Potts model 11 , 12 is given by $$H=-\\,J\\sum _{\\langle ij\\rangle }\\,{\\delta }_{{s}_{i}{s}_{j}},\\,{s}_{i}=1,2,\\cdots ,q,$$ (2) where δ ab is the Kronecker delta. The 2D ferromagnetic Potts model is known to exhibit a second-order phase transition for \$q\\le 4\$ and a first-order phase transition for \$q\\ge 5\$ . The Potts model for \$q=2\$ is identical to the Ising model. The 2D spin systems with a continuous XY symmetry exhibit a unique phase transition called the BKT transition 7 , 8 , 9 , 10 . A BKT phase of a quasi long-range order (QLRO) exists, wherein the correlation function decays as a power law. Here, we consider the q -state clock model, which is a discrete version of the classical XY model. Its Hamiltonian is given by $$H=-\\,J\\sum _{\\langle ij\\rangle }\\,\\cos ({\\theta }_{i}-{\\theta }_{j}),\\,{\\theta }_{i}=2\\pi i/q,\\,i=1,2,\\cdots ,q.$$ (3) The 2D q -state clock model experiences a BKT transition for \$q\\ge 5\$ , whereas the clock model for \$q=4\$ comprises two sets of the Ising model and the 3-state clock model is equivalent to the 3-state Potts model. The clock model for \$q=2\$ is simply the Ising model. We measure temperature in units of J . Correlation Configuration The correlation function in the Ising model, with a distance r , is given by $${g}_{i}(r)={s}_{i}{s}_{i+r}.$$ (4) It clearly assumes a value of +1 or −1. In the case of the q -state Potts model, the correlation function is defined by $${g}_{i}(r)=\\frac{q{\\delta }_{{s}_{i}{s}_{i+r}}-1}{q-1}.$$ (5) It assumes a value of +1 or \$-1/(q-1)\$ . The correlation function \${g}_{i}(r)\$ of the q -state clock model is $${g}_{i}(r)=\\,\\cos ({\\theta }_{i}-{\\theta }_{i+r}).$$ (6) It assumes a value between +1 and −1. There are several types of symmetries in spin systems. A few different spin configurations are essentially identical, whereas they have the same correlation configuration. For phase transitions, it is preferable to include long-range correlations, which play an essential role in phase transitions. Because the longest distance in the finite-size systems of size L with periodic boundary conditions is L /2, we consider the average value of the x -direction and the y -direction, that is, $${g}_{i}(L/2)=({s}_{x,y}{s}_{x+L/2,y}+{s}_{x,y}{s}_{x,y+L/2})/2,$$ (7) for the Ising model. The same definitions are employed for other models. We note that this type of correlation function was used along with the generalized scheme for the probability-changing cluster algorithm 13 . Using the Swendsen-Wang multi-cluster flip algorithm 14 for updating spins, we generated the spin configurations for a given temperature T . The examples of the spin configurations { s i } and correlation configurations \$\\{{g}_{i}(L/2)\\}\$ for several models are shown in the Supplementary Information section. The plots of the 2D Ising model, the 2D 5-state Potts model, and the 2D 6-state clock model are shown in Fig. S1 , Fig. S2 , and Fig. S3 , respectively. Machine-Learning Study We have considered a fully connected neural network implemented with a standard TensorFlow library 15 using the 100-hidden unit model to classify the ordered and the disordered phases. For the input layer, we use correlation configurations", "role": "user" }, { "content": "Researchers from Tokyo Metropolitan University have used machine learning to analyze spin models, which are used in physics to study phase transitions. Previous work showed that an image/handwriting classification model could be applied to distinguish states in the simplest models. The team showed the approach is applicable to more complex models and found that an AI trained on one model and applied to another could reveal key similarities between distinct phases in different systems. Machine learning and artificial intelligence (AI) are revolutionizing how we live, work, play, and drive. Self-driving cars, the algorithm that beat a Go grandmaster and advances in finance are just the tip of the iceberg of a wide range of applications now having a significant impact on society. AI is also making waves in scientific research. A key attraction of these algorithms is that they can be trained with pre-classified data (e.g., images of handwritten letters) and be applied to classify a much wider range of data. In the field of condensed matter physics, recent work by Carrasquilla and Melko (Nature Physics (2017) 13, 431-434) has shown that neural networks, the same kind of AI used to interpret handwriting, could be used to distinguish different phases of matter (e.g., gas, liquid and solids) in simple physical models. They studied the Ising model, the simplest model for the emergence of magnetism in materials. A lattice of atoms with a spin (up or down) has an energy that depends on the relative alignment of adjacent spins. Depending on the conditions, these spins can line up into a ferromagnetic phase (like iron) or assume random directions in a paramagnetic phase. Usually, studies of this kind of system involve analyzing some averaged quantity (e.g., the sum of all the spins). The fact that an entire microscopic configuration can be used to classify a phase presented a genuine paradigm shift. Simulated low temperature (left) and high temperature (right) phase of a 2D Ising model, where blue points are spins pointing up, and the red points are spins pointing down. Notice that the spins in the low temperature phase are mostly in the same direction. This is called a ferromagnetic phase. On the other hand, at high temperature, the ratio of up to down spins is closer to 50:50. This is called a paramagnetic phase. Credit: Tokyo Metropolitan University Now, a team led by Professors Hiroyuki Mori and Yutaka Okabe of Tokyo Metropolitan University are collaborating with the Bioinformatics Institute in Singapore to take this approach to the next level. In its existing form, the method of Carrasquilla and Melko cannot be applied to more complex models than the Ising model. For instance, take the q-state Potts model, where atoms can take one of q states instead of just \"up\" or \"down.\" Though it also has a phase transition, telling the phases apart is not trivial. In fact, in the case of a five-state model, there are 120 states that are physically equivalent. To help an AI tell the phases apart, the team gave it more microscopic information, specifically, how the state of a particular atom relates to the state of another atom some distance away, or how the spins correlate over separation. Having trained the AI with many of these correlation configurations for three- and five-state Potts models, they found that it could correctly classify phases and identify the temperature where the transition took place. The researchers could also correctly account for the number of points in their lattice, the finite-size effect. The input (correlation configurations) is fed into a system of interconnected nodes known as a neural network, giving a series of outputs telling us which phase the configuration belongs to. During training, the algorithm is told whether the outputs are right or wrong, and the network is adjusted over and over again to get better agreement i.e. it learns. Credit: Tokyo Meropolitan University Having demonstrated that their method works, they tried the same approach on a q-state clock model, where spins adopt one of q orientations on a circle. When q is greater than or equal to five, there are three phases that the system can take: an ordered low-temperature phase, a high-temperature phase, and a phase in between known as the Berezinskii-Kosterlitz-Thouless (BKT) phase, the investigation of which won John M. Kosterlitz, David J. Thouless and Duncan Haldane the 2016 Nobel Prize for Physics. They successfully trained an AI to tell the three phases apart with a six-state clock model. When they applied it to configurations from a four-state clock model, in which only two phases are expected, they discovered that the algorithm could classify the system as being in a BKT phase near the phase transition. This demonstrates that there is a deep connection between the BKT phase and the critical phase arising at the smooth 'second-order' phase transition point in the four-state system. The method presented by the team is generally applicable to a wide range of scientific problems. A key part of physics is universality, identifying traits in seemingly unrelated systems or phenomena that give rise to unified behavior. Machine learning is uniquely suited to tease these features out of the most complex models and systems, letting scientists take a peek at the deep connections that govern nature and our universe. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract With the recent developments in machine learning, Carrasquilla and Melko have proposed a paradigm that is complementary to the conventional approach for the study of spin models. As an alternative to investigating the thermal average of macroscopic physical quantities, they have used the spin configurations for the classification of the disordered and ordered phases of a phase transition through machine learning. We extend and generalize this method. We focus on the configuration of the long-range correlation function instead of the spin configuration itself, which enables us to provide the same treatment to multi-component systems and the systems with a vector order parameter. We analyze the Berezinskii-Kosterlitz-Thouless (BKT) transition with the same technique to classify three phases: the disordered, the BKT, and the ordered phases. We also present the classification of a model using the training data of a different model. Introduction Numerical simulations, such as Monte Carlo methods, have been successfully employed in the study of phase transitions and critical phenomena 1 . In spin systems, the spin configurations are sampled using a stochastic importance sampling technique, and the estimators for physical quantities, such as the order parameter and the specific heat, are evaluated for these samples. Several spin models have recently been studied through machine learning 2 , 3 , 4 , 5 , 6 . Carrasquilla and Melko 2 proposed a paradigm that is complementary to the above approach. By using large data sets of spin configurations, they classified and identified a high-temperature paramagnetic phase and a low-temperature ferromagnetic phase. It was similar to image classification using machine learning. They demonstrated the use of fully connected and convolutional neural networks for the study of the two-dimensional (2D) Ising model and an Ising lattice gauge theory. In this study, we extend and generalize the method proposed by Carrasquilla and Melko 2 . First, instead of considering the spin configuration itself, we analyze the long-range correlation configuration, which will be explained later. From this analysis, we can evaluate the multi-component systems, such as the Potts model, and the systems with a vector order parameter, such as the XY model. We can identify identical configurations with the permutational symmetry or the rotational symmetry, which results in an efficient classification of phases. Moreover, the inclusion of long-range correlation is helpful in the study of phase transition. Second, we investigate the Berezinskii-Kosterlitz-Thouless (BKT) phase 7 , 8 , 9 , 10 , described by a fixed line instead of a fixed point from the perspective of the renormalization group, using the same treatment as the paramagnetic-ferromagnetic phase transition. By studying the 2D clock model, which is a discrete version of the XY model, we classify the paramagnetic-BKT-ferromagnetic transitions through machine learning. Model We enlist the models we analyze below. We consider a 2D Ising model on the square lattice, whose Hamiltonian is given as $$H=-\,J\sum _{\langle ij\rangle }\,{s}_{i}{s}_{j},\,{s}_{i}=\pm \,1.$$ (1) The summation is realized over the nearest-neighbor pairs, and periodic boundary conditions are imposed in numerical simulations. The Hamiltonian of the q -state Potts model 11 , 12 is given by $$H=-\,J\sum _{\langle ij\rangle }\,{\delta }_{{s}_{i}{s}_{j}},\,{s}_{i}=1,2,\cdots ,q,$$ (2) where δ ab is the Kronecker delta. The 2D ferromagnetic Potts model is known to exhibit a second-order phase transition for $q\le 4$ and a first-order phase transition for $q\ge 5$ . The Potts model for $q=2$ is identical to the Ising model. The 2D spin systems with a continuous XY symmetry exhibit a unique phase transition called the BKT transition 7 , 8 , 9 , 10 . A BKT phase of a quasi long-range order (QLRO) exists, wherein the correlation function decays as a power law. Here, we consider the q -state clock model, which is a discrete version of the classical XY model. Its Hamiltonian is given by $$H=-\,J\sum _{\langle ij\rangle }\,\cos ({\theta }_{i}-{\theta }_{j}),\,{\theta }_{i}=2\pi i/q,\,i=1,2,\cdots ,q.$$ (3) The 2D q -state clock model experiences a BKT transition for $q\ge 5$ , whereas the clock model for $q=4$ comprises two sets of the Ising model and the 3-state clock model is equivalent to the 3-state Potts model. The clock model for $q=2$ is simply the Ising model. We measure temperature in units of J . Correlation Configuration The correlation function in the Ising model, with a distance r , is given by $${g}_{i}(r)={s}_{i}{s}_{i+r}.$$ (4) It clearly assumes a value of +1 or −1. In the case of the q -state Potts model, the correlation function is defined by $${g}_{i}(r)=\frac{q{\delta }_{{s}_{i}{s}_{i+r}}-1}{q-1}.$$ (5) It assumes a value of +1 or $-1/(q-1)$ . The correlation function ${g}_{i}(r)$ of the q -state clock model is $${g}_{i}(r)=\,\cos ({\theta }_{i}-{\theta }_{i+r}).$$ (6) It assumes a value between +1 and −1. There are several types of symmetries in spin systems. A few different spin configurations are essentially identical, whereas they have the same correlation configuration. For phase transitions, it is preferable to include long-range correlations, which play an essential role in phase transitions. Because the longest distance in the finite-size systems of size L with periodic boundary conditions is L /2, we consider the average value of the x -direction and the y -direction, that is, $${g}_{i}(L/2)=({s}_{x,y}{s}_{x+L/2,y}+{s}_{x,y}{s}_{x,y+L/2})/2,$$ (7) for the Ising model. The same definitions are employed for other models. We note that this type of correlation function was used along with the generalized scheme for the probability-changing cluster algorithm 13 . Using the Swendsen-Wang multi-cluster flip algorithm 14 for updating spins, we generated the spin configurations for a given temperature T . The examples of the spin configurations { s i } and correlation configurations $\{{g}_{i}(L/2)\}$ for several models are shown in the Supplementary Information section. The plots of the 2D Ising model, the 2D 5-state Potts model, and the 2D 6-state clock model are shown in Fig. S1 , Fig. S2 , and Fig. S3 , respectively. Machine-Learning Study We have considered a fully connected neural network implemented with a standard TensorFlow library 15 using the 100-hidden unit model to classify the ordered and the disordered phases. For the input layer, we use correlation configurations<|im_end|> <|im_start|>assistant Researchers from Tokyo Metropolitan University have used machine learning to analyze spin models, which are used in physics to study phase transitions. Previous work showed that an image/handwriting classification model could be applied to distinguish states in the simplest models. The team showed the approach is applicable to more complex models and found that an AI trained on one model and applied to another could reveal key similarities between distinct phases in different systems. Machine learning and artificial intelligence (AI) are revolutionizing how we live, work, play, and drive. Self-driving cars, the algorithm that beat a Go grandmaster and advances in finance are just the tip of the iceberg of a wide range of applications now having a significant impact on society. AI is also making waves in scientific research. A key attraction of these algorithms is that they can be trained with pre-classified data (e.g., images of handwritten letters) and be applied to classify a much wider range of data. In the field of condensed matter physics, recent work by Carrasquilla and Melko (Nature Physics (2017) 13, 431-434) has shown that neural networks, the same kind of AI used to interpret handwriting, could be used to distinguish different phases of matter (e.g., gas, liquid and solids) in simple physical models. They studied the Ising model, the simplest model for the emergence of magnetism in materials. A lattice of atoms with a spin (up or down) has an energy that depends on the relative alignment of adjacent spins. Depending on the conditions, these spins can line up into a ferromagnetic phase (like iron) or assume random directions in a paramagnetic phase. Usually, studies of this kind of system involve analyzing some averaged quantity (e.g., the sum of all the spins). The fact that an entire microscopic configuration can be used to classify a phase presented a genuine paradigm shift. Simulated low temperature (left) and high temperature (right) phase of a 2D Ising model, where blue points are spins pointing up, and the red points are spins pointing down. Notice that the spins in the low temperature phase are mostly in the same direction. This is called a ferromagnetic phase. On the other hand, at high temperature, the ratio of up to down spins is closer to 50:50. This is called a paramagnetic phase. Credit: Tokyo Metropolitan University Now, a team led by Professors Hiroyuki Mori and Yutaka Okabe of Tokyo Metropolitan University are collaborating with the Bioinformatics Institute in Singapore to take this approach to the next level. In its existing form, the method of Carrasquilla and Melko cannot be applied to more complex models than the Ising model. For instance, take the q-state Potts model, where atoms can take one of q states instead of just "up" or "down." Though it also has a phase transition, telling the phases apart is not trivial. In fact, in the case of a five-state model, there are 120 states that are physically equivalent. To help an AI tell the phases apart, the team gave it more microscopic information, specifically, how the state of a particular atom relates to the state of another atom some distance away, or how the spins correlate over separation. Having trained the AI with many of these correlation configurations for three- and five-state Potts models, they found that it could correctly classify phases and identify the temperature where the transition took place. The researchers could also correctly account for the number of points in their lattice, the finite-size effect. The input (correlation configurations) is fed into a system of interconnected nodes known as a neural network, giving a series of outputs telling us which phase the configuration belongs to. During training, the algorithm is told whether the outputs are right or wrong, and the network is adjusted over and over again to get better agreement i.e. it learns. Credit: Tokyo Meropolitan University Having demonstrated that their method works, they tried the same approach on a q-state clock model, where spins adopt one of q orientations on a circle. When q is greater than or equal to five, there are three phases that the system can take: an ordered low-temperature phase, a high-temperature phase, and a phase in between known as the Berezinskii-Kosterlitz-Thouless (BKT) phase, the investigation of which won John M. Kosterlitz, David J. Thouless and Duncan Haldane the 2016 Nobel Prize for Physics. They successfully trained an AI to tell the three phases apart with a six-state clock model. When they applied it to configurations from a four-state clock model, in which only two phases are expected, they discovered that the algorithm could classify the system as being in a BKT phase near the phase transition. This demonstrates that there is a deep connection between the BKT phase and the critical phase arising at the smooth 'second-order' phase transition point in the four-state system. The method presented by the team is generally applicable to a wide range of scientific problems. A key part of physics is universality, identifying traits in seemingly unrelated systems or phenomena that give rise to unified behavior. Machine learning is uniquely suited to tease these features out of the most complex models and systems, letting scientists take a peek at the deep connections that govern nature and our universe. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mechanically interlocked molecules such as rotaxanes and catenanes have potential as components of molecular machinery. Rotaxanes consist of a dumb-bell-shaped molecule encircled by a macrocycle that can move unhindered along the axle, trapped by bulky stoppers. Previously, rotaxanes have been made from a variety of molecules, but not from DNA. Here, we report the design, assembly and characterization of rotaxanes in which both the dumb-bell-shaped molecule and the macrocycle are made of double-stranded DNA, and in which the axle of the dumb-bell is threaded through the macrocycle by base pairing. The assembly involves the formation of pseudorotaxanes, in which the macrocycle and the axle are locked together by hybridization. Ligation of stopper modules to the axle leads to the characteristic dumb-bell topology. When an oligonucleotide is added to release the macrocycle from the axle, the pseudorotaxanes are either converted to mechanically stable rotaxanes, or they disassemble by means of a slippage mechanism to yield a dumb-bell and a free macrocycle. Our DNA rotaxanes allow the fields of mechanically interlocked molecules and DNA nanotechnology to be combined, thus opening new possibilities for research into molecular machines and synthetic biology. Main Rotaxanes are a class of mechanically interlocked molecules consisting of at least one macrocycle threaded over a dumb-bell-shaped molecule, in which the macrocycle is kinetically trapped by rigid and bulky stoppers 1 , 2 . These molecules have attracted much attention as functional materials, and the so-called mechanical bond 3 is the de facto reason for the legion of examples describing the enhanced physical properties of rotaxanes when compared with their non-interlocked components, including enzymatic protection 4 , dye fluorescence 5 and electroluminescence 6 . One of the most striking features of rotaxane architectures is that their mechanically interlocked components can move relative to one another with large-amplitude motions, which has use in prototypical design features of components for nanoscale machinery 7 . In the field of organic chemistry, a number of classical supramolecular cognate motifs exist as interlocking models, which have applications in constructing molecular architectures 8 that can be used to control sub-molecular motion through the application of external stimuli 9 . Indeed, under the influence of such external stimuli the movement of components can be used to vary physical properties such as conductivity 10 , fluorescence 11 , porosity 12 and wettability 13 . Methods of extending these approaches to DNA-based nanodevices are unprecedented, but highly desirable, owing to the superiority of DNA over other construction materials. DNA is an ideal material for the bottom-up fabrication of nanometre-scale objects and nanomechanical devices because of the reliable interactions that bind complementary oligonucleotides together in a double helix 14 , 15 , 16 . Furthermore, DNA has a combination of properties that are a prerequisite for building more competent nanomechanical devices based on the high information density of DNA (one bit comprised of one base pair occupies a volume of ∼ 1 nm 3 ), the principal ability to evolve, its simplicity, and the fact that it can easily be functionalized with an array of chemical groups. Indeed, DNA nanotechnology has furnished the scientific world with a plethora of topologies in the form of designed patterns 17 , algorithmically ordered arrays 18 , 19 , logic gates 20 , 21 and geometries in both the second 22 and third dimensions 23 . Additionally, the programmable aspect 24 of DNA enables facile post-assembly modification of fabricated constructs in response to external applied stimuli 25 , 26 . Some of these designed systems allow repetitive, processive steps characteristic of bipedal molecular motors and switches that emulate certain biological motor proteins 27 , 28 , 29 , 30 . Rotaxanes made of double-stranded DNA (dsDNA) with mobile interlocked components would be attractive devices for use in nanorobotics, because they have a unique mechanical bonding motif, not available to conventional building blocks. Simple interlocked structures made of single-stranded (ss) circular DNAs have been described, but these systems are immobile, because of the different stabilizing interactions such as double- and triple-strand formation or other tertiary interactions that ssDNAs assume with the interlocked partner 31 , 32 . Recently, we described the efficient synthesis of DNA minicircles containing bespoke gap regions, which could be used as handles for the construction of higher-order nano-objects 33 , 34 , 35 . The DNA circles show hardly any ring strain because they contain repetitive, intrinsically bent AT-tracts that cooperatively result in the circular shape of the double helix with 105, 126, 147, 168 or more base pairs (bp) 36 . In the initial conception of this described research, we reasoned that the combination of the different properties of rotaxane architectures, such as mechanical interlocking and facility of construction, and those of DNA as a carrier of information, could potentially lead to an exciting hybrid structure of DNA rotaxanes. Interlocking principle and assembly of pseudorotaxanes The interlocking approach used here involves the synthesis of pseudorotaxane species as a prerequisite for the assembly of a DNA–rotaxane. To assemble a DNA–pseudorotaxane, a linear DNA rod was threaded through a dsDNA ring containing a single-strand gap of 13 nucleotides ( Supplementary Figs S1 , S2 ). As the DNA rod itself contained an 8-mer complementary single-strand region covering more than half but less than one helical turn, threading of the DNA rod occurred as a consequence of hybridization to the gap-ring ( Fig. 1 a, Supplementary Fig. S3 ). The size of the stoppers had to be at least as large as the inner diameter of a 168-bp gap-ring, which is ∼ 14–15 nm (ref. 34 ). This size is much larger than the diameter of any single protein (for comparison: the diameter of a ribosome is ∼ 18–20 nm; ref. 37 ). Therefore, in a first version, 168-bp single rings were used as stoppers ( Supplementary Fig. S3 ). They were ligated onto each side of the rod, resulting either in a dumb-bell-shaped DNA object or, in the presence of a 126-bp gap-ring, in a dsDNA–pseudorotaxane ( Supplementary Figs S1 –", "role": "user" }, { "content": "Chemists have long been tinkering with rotaxanes. The name, derived from the Greek, basically means \"wheel axle\" - and not without reason. For a rotaxane molecule consists essentially of an axle and a ring, or hoop, threaded over it. To prevent the hoop from slipping off the axle, bulky \"stoppers\" are placed at each end. These, in turn, consist of intertwined rings. The whole construction looks rather like a dumbbell with a hoop around its handle (see diagram). All previous DNA rotaxanes are products of organic chemistry. They are also much smaller in size and therefore exhibit shorter margins of mechanical movement at the nanoscale. Moreover, the new DNA alternative can easily be equipped with additional functions, so that sophisticated mechanical systems can be quickly developed. To build the new rotaxanes, the research team around Dr. Damian Ackermann and Prof. Michael Famulok from the Life & Medical Sciences (LIMES) Institute at the University of Bonn made use of a material that is normally known for constituting the building blocks of life itself: DNA. But the researchers are not primarily interested in DNA's function as a genetic carrier. Rather, their focus of interest lies in using the principles of base-pairing of DNA double-strands for constructing sophisticated architectures at the nanoscale. The double-helix forms a very stable scaffold. Moreover, a part of one strand can be removed at any chosen position to serve as a connecting point for other components of a nanomachine. \" The specificity of individual strands makes DNA highly suitable. It offers us quite a lot of possibilities,\" explains Damian Ackermann. \"DNA is like a Lego brick, It's the ideal material for nano-architecture,\" adds Professor Famulok. The Bonn-based biochemists have created a completely new kind of rotaxane. It forms a stable mechanical unit, with a freely moving inner hoop. A great deal can be done with this wheel. \"We envisage quite a few things,\" says Professor Famulok. \"Our initial aim is to construct systems in which movement can be controlled at the nano-level. The axle and wheels are now available, and we have some ideas for how to get the wheels turning.\" These nanoengines might then also be combined with other biological systems, such as proteins. The researchers now realize that, with their DNA rotaxanes, they have laid the foundations for developing all sorts of different nano-mechanical systems based on mechanically interlocked double-stranded DNA. It remains open what will finally emerge from these efforts, but the important breakthrough has been made. \"What matters is that we now have a set of novel components with which we can build things that were previously impossible,\" says Ackermann: \"The boundaries of our imagination have, in a sense, been pushed a little further.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mechanically interlocked molecules such as rotaxanes and catenanes have potential as components of molecular machinery. Rotaxanes consist of a dumb-bell-shaped molecule encircled by a macrocycle that can move unhindered along the axle, trapped by bulky stoppers. Previously, rotaxanes have been made from a variety of molecules, but not from DNA. Here, we report the design, assembly and characterization of rotaxanes in which both the dumb-bell-shaped molecule and the macrocycle are made of double-stranded DNA, and in which the axle of the dumb-bell is threaded through the macrocycle by base pairing. The assembly involves the formation of pseudorotaxanes, in which the macrocycle and the axle are locked together by hybridization. Ligation of stopper modules to the axle leads to the characteristic dumb-bell topology. When an oligonucleotide is added to release the macrocycle from the axle, the pseudorotaxanes are either converted to mechanically stable rotaxanes, or they disassemble by means of a slippage mechanism to yield a dumb-bell and a free macrocycle. Our DNA rotaxanes allow the fields of mechanically interlocked molecules and DNA nanotechnology to be combined, thus opening new possibilities for research into molecular machines and synthetic biology. Main Rotaxanes are a class of mechanically interlocked molecules consisting of at least one macrocycle threaded over a dumb-bell-shaped molecule, in which the macrocycle is kinetically trapped by rigid and bulky stoppers 1 , 2 . These molecules have attracted much attention as functional materials, and the so-called mechanical bond 3 is the de facto reason for the legion of examples describing the enhanced physical properties of rotaxanes when compared with their non-interlocked components, including enzymatic protection 4 , dye fluorescence 5 and electroluminescence 6 . One of the most striking features of rotaxane architectures is that their mechanically interlocked components can move relative to one another with large-amplitude motions, which has use in prototypical design features of components for nanoscale machinery 7 . In the field of organic chemistry, a number of classical supramolecular cognate motifs exist as interlocking models, which have applications in constructing molecular architectures 8 that can be used to control sub-molecular motion through the application of external stimuli 9 . Indeed, under the influence of such external stimuli the movement of components can be used to vary physical properties such as conductivity 10 , fluorescence 11 , porosity 12 and wettability 13 . Methods of extending these approaches to DNA-based nanodevices are unprecedented, but highly desirable, owing to the superiority of DNA over other construction materials. DNA is an ideal material for the bottom-up fabrication of nanometre-scale objects and nanomechanical devices because of the reliable interactions that bind complementary oligonucleotides together in a double helix 14 , 15 , 16 . Furthermore, DNA has a combination of properties that are a prerequisite for building more competent nanomechanical devices based on the high information density of DNA (one bit comprised of one base pair occupies a volume of ∼ 1 nm 3 ), the principal ability to evolve, its simplicity, and the fact that it can easily be functionalized with an array of chemical groups. Indeed, DNA nanotechnology has furnished the scientific world with a plethora of topologies in the form of designed patterns 17 , algorithmically ordered arrays 18 , 19 , logic gates 20 , 21 and geometries in both the second 22 and third dimensions 23 . Additionally, the programmable aspect 24 of DNA enables facile post-assembly modification of fabricated constructs in response to external applied stimuli 25 , 26 . Some of these designed systems allow repetitive, processive steps characteristic of bipedal molecular motors and switches that emulate certain biological motor proteins 27 , 28 , 29 , 30 . Rotaxanes made of double-stranded DNA (dsDNA) with mobile interlocked components would be attractive devices for use in nanorobotics, because they have a unique mechanical bonding motif, not available to conventional building blocks. Simple interlocked structures made of single-stranded (ss) circular DNAs have been described, but these systems are immobile, because of the different stabilizing interactions such as double- and triple-strand formation or other tertiary interactions that ssDNAs assume with the interlocked partner 31 , 32 . Recently, we described the efficient synthesis of DNA minicircles containing bespoke gap regions, which could be used as handles for the construction of higher-order nano-objects 33 , 34 , 35 . The DNA circles show hardly any ring strain because they contain repetitive, intrinsically bent AT-tracts that cooperatively result in the circular shape of the double helix with 105, 126, 147, 168 or more base pairs (bp) 36 . In the initial conception of this described research, we reasoned that the combination of the different properties of rotaxane architectures, such as mechanical interlocking and facility of construction, and those of DNA as a carrier of information, could potentially lead to an exciting hybrid structure of DNA rotaxanes. Interlocking principle and assembly of pseudorotaxanes The interlocking approach used here involves the synthesis of pseudorotaxane species as a prerequisite for the assembly of a DNA–rotaxane. To assemble a DNA–pseudorotaxane, a linear DNA rod was threaded through a dsDNA ring containing a single-strand gap of 13 nucleotides ( Supplementary Figs S1 , S2 ). As the DNA rod itself contained an 8-mer complementary single-strand region covering more than half but less than one helical turn, threading of the DNA rod occurred as a consequence of hybridization to the gap-ring ( Fig. 1 a, Supplementary Fig. S3 ). The size of the stoppers had to be at least as large as the inner diameter of a 168-bp gap-ring, which is ∼ 14–15 nm (ref. 34 ). This size is much larger than the diameter of any single protein (for comparison: the diameter of a ribosome is ∼ 18–20 nm; ref. 37 ). Therefore, in a first version, 168-bp single rings were used as stoppers ( Supplementary Fig. S3 ). They were ligated onto each side of the rod, resulting either in a dumb-bell-shaped DNA object or, in the presence of a 126-bp gap-ring, in a dsDNA–pseudorotaxane ( Supplementary Figs S1 –<|im_end|> <|im_start|>assistant Chemists have long been tinkering with rotaxanes. The name, derived from the Greek, basically means "wheel axle" - and not without reason. For a rotaxane molecule consists essentially of an axle and a ring, or hoop, threaded over it. To prevent the hoop from slipping off the axle, bulky "stoppers" are placed at each end. These, in turn, consist of intertwined rings. The whole construction looks rather like a dumbbell with a hoop around its handle (see diagram). All previous DNA rotaxanes are products of organic chemistry. They are also much smaller in size and therefore exhibit shorter margins of mechanical movement at the nanoscale. Moreover, the new DNA alternative can easily be equipped with additional functions, so that sophisticated mechanical systems can be quickly developed. To build the new rotaxanes, the research team around Dr. Damian Ackermann and Prof. Michael Famulok from the Life & Medical Sciences (LIMES) Institute at the University of Bonn made use of a material that is normally known for constituting the building blocks of life itself: DNA. But the researchers are not primarily interested in DNA's function as a genetic carrier. Rather, their focus of interest lies in using the principles of base-pairing of DNA double-strands for constructing sophisticated architectures at the nanoscale. The double-helix forms a very stable scaffold. Moreover, a part of one strand can be removed at any chosen position to serve as a connecting point for other components of a nanomachine. " The specificity of individual strands makes DNA highly suitable. It offers us quite a lot of possibilities," explains Damian Ackermann. "DNA is like a Lego brick, It's the ideal material for nano-architecture," adds Professor Famulok. The Bonn-based biochemists have created a completely new kind of rotaxane. It forms a stable mechanical unit, with a freely moving inner hoop. A great deal can be done with this wheel. "We envisage quite a few things," says Professor Famulok. "Our initial aim is to construct systems in which movement can be controlled at the nano-level. The axle and wheels are now available, and we have some ideas for how to get the wheels turning." These nanoengines might then also be combined with other biological systems, such as proteins. The researchers now realize that, with their DNA rotaxanes, they have laid the foundations for developing all sorts of different nano-mechanical systems based on mechanically interlocked double-stranded DNA. It remains open what will finally emerge from these efforts, but the important breakthrough has been made. "What matters is that we now have a set of novel components with which we can build things that were previously impossible," says Ackermann: "The boundaries of our imagination have, in a sense, been pushed a little further." <|im_end|>

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1,981

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels. Methods Two thousand fifty one New Zealanders (of Māori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake. Results Seventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20 % specifically mentioned tomatoes, the 4 th most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (β = 0.66 μmolL −1 increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: β = 0.84 μmolL −1 , P = 0.035; women: β = 0.59 μmolL −1 , P = 0.041). Conclusions While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis. Peer Review reports Background High serum urate levels are the major risk factor for gout [ 1 ]. Urate levels are maintained within the body through a balance between urate production (hepatic) and excretion (renal and gut), controlled by genetic and dietary factors [ 2 ]. When urate levels reach supersaturation monosodium urate crystals may deposit within the joints and elicit an immune reaction [ 3 ]. Variants in genes encoding renal and gut uric acid transporters are associated with urate levels and gout [ 4 – 8 ], while serum urate-controlling variants of weaker effect map to loci thought to be involved in glycolysis and other pathways enriched for inhibins and activins [ 5 ]. Foods and beverages positively associated with serum urate and gout are alcohol (particularly beer), purine-rich foods, red meat, seafood, and sugar-sweetened beverages [ 9 – 15 ]. Conversely, intake of coffee, dairy products and vitamin C have been associated with lowered serum urate levels and reduced risk of gout [ 11 , 16 – 20 ]. Urate is generated from breakdown of purines and as a consequence of hepatic metabolism of alcohol and sugar, with evidence that both ethanol and sugar also interfere with renal excretion of uric acid [ 9 , 21 ]. Gout is often associated with dietary triggers, commonly perceived by patients to be the most important cause of gout [ 22 ]. Demonstrated food triggers, identified using case-crossover study design, include alcohol and purine-rich foods [ 23 , 24 ]. These foods also increase serum urate levels [ 12 , 15 , 25 ], consistent with the hypothesis that they trigger acute gout attacks. People with gout also self-report food avoidances that have not been substantiated by the medical literature – these avoidances include tomatoes and tomato products [ 26 ]. This study aimed to determine the frequency of tomato consumption as a self-reported trigger of gout flares in a large gout sample set from New Zealand (including Māori and Pacific Island participants). These groups have a prevalence of gout double that of European Caucasian [ 27 ], with earlier onset, more severe gout presentation and a higher prevalence of co-morbidities [ 28 ]. We also tested the hypothesis that tomato consumption is associated with serum urate levels. Methods New Zealand men and women >17 years of age with gout ( n = 1791) (recruited as part of a study focused on the risk factors for gout) [ 29 ] were asked the question “Do certain foods/drinks trigger your gout?” Patients were prompted to specify whether alcohol or seafood triggered their gout, then given the opportunity to list other gout trigger foods/drinks in an open-question format. Responses to the same question by a separate Māori sample set from the rohe (area) of the Ngati Porou iwi (tribe), patients of the primary health care provider Ngati Porou Hauora (health) Charitable Trust, in the Tairawhiti region on the East Coast of the North Island of New Zealand were also analysed (260 people with gout). All participants had a confirmed diagnosis of gout, as defined by the 1977 American Rheumatology Association preliminary classification criteria for acute gout [ 30 ]. They were recruited from community-based settings, and primary and secondary health care. Ethical approval was given by the New Zealand Multi-Region and Northern Y Ethics Committees and all participants provided written informed consent for the collection of samples and subsequent analysis. Anthropometric, clinical and gout attack trigger information for each analysis cohort are contained in Additional file 1 : Table S1. Trigger foods were summarised into ten categories (alcohol, dairy products, fruit, poultry, red meat, seafood/fish, sugar-sweetened beverages, tomatoes, vegetables, and other) and the percentage of people who mentioned each category calculated – split also into five ancestral groups, New Zealand Māori, Ngati Porou Māori, New Zealand Pacific Island, European and Other. Multivariate logistic regression adjusted for sex, age at first attack, body mass index, and number of flares per year was conducted to determine whether ancestry influenced the reporting of acute gout attack triggers. Data from the Atherosclerosis Risk in Communities (ARIC) ( ), Cardiovascular Health Study (CHS) ( ) and Framingham Heart Study (FHS) Generation 3 ( ) cohorts were used to test the hypothesis that tomato consumption is associated with serum urate", "role": "user" }, { "content": "People who maintain that eating tomatoes can cause their gout to flare up are likely to welcome new University of Otago research that has, for the first time, found a biological basis for this belief. Gout is a painful and debilitating form of arthritis that affects approximately three times more men than women. Four to five percent of European men in New Zealand suffer from gout. Amongst Māori and Pacific Island men this figure rises to 10-15% due to a greater genetic risk in these people. Once a person has gout, eating certain foods can cause their gout to flare up in a painful attack. A group of Otago Department of Biochemistry researchers noticed that a large number of gout sufferers believe tomatoes to be one of these gout trigger foods. The researchers surveyed 2051 New Zealanders with clinically verified gout. Of these people 71% reported having one or more food triggers. Tomatoes were listed as a trigger in 20% of these cases. One of the study authors, Genetics PhD student Tanya Flynn, says that tomatoes were found to be the fourth most commonly mentioned trigger, after seafood, alcohol and red meat. \"We thought it important to find a biological reason for this to add weight to what gout patients are already saying,\" Miss Flynn says. After determining tomatoes are a commonly cited trigger food, the authors pooled and analysed data from 12,720 male and female members of three long-running US health studies. This data showed that tomato consumption is linked to higher levels of uric acid in the blood, which is the major underlying cause of gout. Miss Flynn says that while their research is not geared to prove that tomatoes trigger gout attacks, it does suggest that this food can alter uric acid levels to a degree comparable to other commonly accepted gout trigger foods. \"We found that the positive association between eating tomato and uric acid levels was on a par with that of consuming seafood, red meat, alcohol or sugar-sweetened drinks,\" she says. Miss Flynn emphasised that the most important thing that people with gout can do to prevent attacks is take a drug—such as Allopurinol—that is very effective at reducing uric acid levels. \"Avoiding tomatoes may be helpful for people who have experienced a gout attack after eating them, but with proper treatment this doesn't have to be a long-term avoidance,\" she says. The findings are published in a paper in the international journal BMC Musculoskeletal Disorders. \"Further intervention studies are needed to determine whether tomatoes should be added to the list of traditional dietary triggers of gout flares, but this research is the first step in supporting this idea,\" says Miss Flynn. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels. Methods Two thousand fifty one New Zealanders (of Māori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake. Results Seventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20 % specifically mentioned tomatoes, the 4 th most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (β = 0.66 μmolL −1 increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: β = 0.84 μmolL −1 , P = 0.035; women: β = 0.59 μmolL −1 , P = 0.041). Conclusions While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis. Peer Review reports Background High serum urate levels are the major risk factor for gout [ 1 ]. Urate levels are maintained within the body through a balance between urate production (hepatic) and excretion (renal and gut), controlled by genetic and dietary factors [ 2 ]. When urate levels reach supersaturation monosodium urate crystals may deposit within the joints and elicit an immune reaction [ 3 ]. Variants in genes encoding renal and gut uric acid transporters are associated with urate levels and gout [ 4 – 8 ], while serum urate-controlling variants of weaker effect map to loci thought to be involved in glycolysis and other pathways enriched for inhibins and activins [ 5 ]. Foods and beverages positively associated with serum urate and gout are alcohol (particularly beer), purine-rich foods, red meat, seafood, and sugar-sweetened beverages [ 9 – 15 ]. Conversely, intake of coffee, dairy products and vitamin C have been associated with lowered serum urate levels and reduced risk of gout [ 11 , 16 – 20 ]. Urate is generated from breakdown of purines and as a consequence of hepatic metabolism of alcohol and sugar, with evidence that both ethanol and sugar also interfere with renal excretion of uric acid [ 9 , 21 ]. Gout is often associated with dietary triggers, commonly perceived by patients to be the most important cause of gout [ 22 ]. Demonstrated food triggers, identified using case-crossover study design, include alcohol and purine-rich foods [ 23 , 24 ]. These foods also increase serum urate levels [ 12 , 15 , 25 ], consistent with the hypothesis that they trigger acute gout attacks. People with gout also self-report food avoidances that have not been substantiated by the medical literature – these avoidances include tomatoes and tomato products [ 26 ]. This study aimed to determine the frequency of tomato consumption as a self-reported trigger of gout flares in a large gout sample set from New Zealand (including Māori and Pacific Island participants). These groups have a prevalence of gout double that of European Caucasian [ 27 ], with earlier onset, more severe gout presentation and a higher prevalence of co-morbidities [ 28 ]. We also tested the hypothesis that tomato consumption is associated with serum urate levels. Methods New Zealand men and women >17 years of age with gout ( n = 1791) (recruited as part of a study focused on the risk factors for gout) [ 29 ] were asked the question “Do certain foods/drinks trigger your gout?” Patients were prompted to specify whether alcohol or seafood triggered their gout, then given the opportunity to list other gout trigger foods/drinks in an open-question format. Responses to the same question by a separate Māori sample set from the rohe (area) of the Ngati Porou iwi (tribe), patients of the primary health care provider Ngati Porou Hauora (health) Charitable Trust, in the Tairawhiti region on the East Coast of the North Island of New Zealand were also analysed (260 people with gout). All participants had a confirmed diagnosis of gout, as defined by the 1977 American Rheumatology Association preliminary classification criteria for acute gout [ 30 ]. They were recruited from community-based settings, and primary and secondary health care. Ethical approval was given by the New Zealand Multi-Region and Northern Y Ethics Committees and all participants provided written informed consent for the collection of samples and subsequent analysis. Anthropometric, clinical and gout attack trigger information for each analysis cohort are contained in Additional file 1 : Table S1. Trigger foods were summarised into ten categories (alcohol, dairy products, fruit, poultry, red meat, seafood/fish, sugar-sweetened beverages, tomatoes, vegetables, and other) and the percentage of people who mentioned each category calculated – split also into five ancestral groups, New Zealand Māori, Ngati Porou Māori, New Zealand Pacific Island, European and Other. Multivariate logistic regression adjusted for sex, age at first attack, body mass index, and number of flares per year was conducted to determine whether ancestry influenced the reporting of acute gout attack triggers. Data from the Atherosclerosis Risk in Communities (ARIC) ( ), Cardiovascular Health Study (CHS) ( ) and Framingham Heart Study (FHS) Generation 3 ( ) cohorts were used to test the hypothesis that tomato consumption is associated with serum urate<|im_end|> <|im_start|>assistant People who maintain that eating tomatoes can cause their gout to flare up are likely to welcome new University of Otago research that has, for the first time, found a biological basis for this belief. Gout is a painful and debilitating form of arthritis that affects approximately three times more men than women. Four to five percent of European men in New Zealand suffer from gout. Amongst Māori and Pacific Island men this figure rises to 10-15% due to a greater genetic risk in these people. Once a person has gout, eating certain foods can cause their gout to flare up in a painful attack. A group of Otago Department of Biochemistry researchers noticed that a large number of gout sufferers believe tomatoes to be one of these gout trigger foods. The researchers surveyed 2051 New Zealanders with clinically verified gout. Of these people 71% reported having one or more food triggers. Tomatoes were listed as a trigger in 20% of these cases. One of the study authors, Genetics PhD student Tanya Flynn, says that tomatoes were found to be the fourth most commonly mentioned trigger, after seafood, alcohol and red meat. "We thought it important to find a biological reason for this to add weight to what gout patients are already saying," Miss Flynn says. After determining tomatoes are a commonly cited trigger food, the authors pooled and analysed data from 12,720 male and female members of three long-running US health studies. This data showed that tomato consumption is linked to higher levels of uric acid in the blood, which is the major underlying cause of gout. Miss Flynn says that while their research is not geared to prove that tomatoes trigger gout attacks, it does suggest that this food can alter uric acid levels to a degree comparable to other commonly accepted gout trigger foods. "We found that the positive association between eating tomato and uric acid levels was on a par with that of consuming seafood, red meat, alcohol or sugar-sweetened drinks," she says. Miss Flynn emphasised that the most important thing that people with gout can do to prevent attacks is take a drug—such as Allopurinol—that is very effective at reducing uric acid levels. "Avoiding tomatoes may be helpful for people who have experienced a gout attack after eating them, but with proper treatment this doesn't have to be a long-term avoidance," she says. The findings are published in a paper in the international journal BMC Musculoskeletal Disorders. "Further intervention studies are needed to determine whether tomatoes should be added to the list of traditional dietary triggers of gout flares, but this research is the first step in supporting this idea," says Miss Flynn. <|im_end|>

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1,942

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues. However, developing tissues also undergo dynamic morphogenesis, which may produce cells with unfit morphogen signalling and consequent noisy morphogen gradients. Here we show that a cell competition-related system corrects such noisy morphogen gradients. Zebrafish imaging analyses of the Wnt/β-catenin signalling gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, identify that unfit cells with abnormal Wnt/β-catenin activity spontaneously appear and produce noise in the gradient. Communication between unfit and neighbouring fit cells via cadherin proteins stimulates apoptosis of the unfit cells by activating Smad signalling and reactive oxygen species production. This unfit cell elimination is required for proper Wnt/β-catenin gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning not only in the embryo but also in adult tissues, this system may support tissue robustness and disease prevention. Introduction Tissue patterning is a fundamental process during embryonic development and adult tissue homeostasis. To reproducibly achieve precise tissue patterning, the molecular and cellular systems controlling patterning must be robust against environmental and physiological perturbations. Activity gradients of morphogen signalling, including Wnt/β-catenin, bone morphogenetic protein (BMP), sonic hedgehog (Shh), fibroblast growth factor (FGF) and nodal signalling pattern the tissue axes 1 , 2 . In the embryonic anterior–posterior (AP) axis formation of deuterostomes (amphioxus, fish, frog and mammal), Wnt/β-catenin signalling is activated and inhibited in the presumptive posterior and anterior tissue, respectively. This bi-directional regulation forms a signalling activity gradient along the AP axis to establish embryonic AP patterning 3 . However, rapid cell proliferation and movement in developing tissues may affect morphogen diffusion and signal transduction, thereby producing cells with unfit signalling and consequent noisy morphogen gradients. It is not yet completely understood how these noises are overcome to generate robust patterning. Cell competition is an interactive process wherein cells compete for fitness in a tissue environment. Specifically, relatively higher fitness cells eliminate those with lower fitness 4 , 5 . Key features of this process include that it originates from specific interactions between two cell types leading to elimination in one, and context-dependency. For example, mosaically introduced polarity-deficient cells are apoptotically eliminated by their neighbouring wild-type cells in Drosophila imaginal disc and mammalian cultured cells 6 , 7 , 8 and in Myc-low-level cells upon communicating with Myc-high-level cells 9 , 10 , 11 . Although cell competition, which is evolutionarily conserved from insects to mammals, may assist in proper embryogenesis, tissue morphogenesis, and tumour progression and prevention 12 , its physiological relevance and detailed mechanisms, especially of unfit cell-sensing, remain unclear. Here, we identify a cell competition-related system for correcting the noise in the Wnt/β-catenin morphogen gradient, presenting a previously unidentified physiological role of cell competition and the mechanisms that mediate unfit cell sensing and elimination. Results Unfit cell elimination smoothens the Wnt/β-catenin gradient To clarify the entire morphogen gradient formation process, we visualized Wnt/β-catenin signalling activity during AP axis formation in zebrafish early embryos (Fig. 1a ) using OTM (Optimal TCF Motif):d2EGFP 13 and OTM:ELuc-CP (Supplementary Fig. 1a ) reporters. These respectively express destabilized EGFP (d2EGFP), providing high spatial resolution, and highly-destabilized Emerald luciferase (ELuc-CP), possessing high temporal resolution and suitable for quantitative analyses (Supplementary Fig. 1b–e ), upon Wnt/β-catenin signalling activation. A noisy signalling-gradient along the AP axis was detected in both transgenic zebrafish embryo types at around 8.5–12 h-post-fertilization (hpf) (Fig. 1b–d , Supplementary Movie 1 ). Abnormally low and high Wnt/β-catenin activities were spontaneously detected in the Wnt/β-catenin activity-high posterior and -low regions, respectively (Fig. 1b, d, e , Supplementary Movie 1 ). We confirmed that the endogenous Wnt/β-catenin target gene ( lef1 ) and nuclear β-catenin proteins also showed noisy expression patterns, which was reflected by the reporter activities (Supplementary Fig. 1f–i ). Abnormal Wnt/β-catenin activity gradually disappeared over time (Fig. 1d ), suggesting that zebrafish embryonic tissue may possess a system for eliminating signalling noise to smoothen the Wnt/β-catenin-gradient. As mouse embryonic tissues eliminate defective cells, including low Myc level, autophagy-deficient, and tetraploid cells in an apoptosis-dependent manner 9 , 11 , unfit Wnt/β-catenin activity-abnormal cells might also be apoptotically eliminated. To investigate the relationship between apoptosis and abnormal Wnt/β-catenin activity, we detected active caspase-3- and TUNEL-positive apoptotic cells in 8–10 hpf embryos undergoing Wnt/β-catenin-gradient-mediated AP axis patterning (Supplementary Fig. 2a–c , Supplementary Movie 2 ). Apoptotic cell number and position varied between embryos (Supplementary Fig. 2d and 2e ), suggesting that the apoptosis is not pre-programmed. In some unfit Wnt/β-catenin activity-abnormal cells, caspase-3 was activated (Fig. 1b , right; Supplementary Fig. 2f–g ), whereas apoptosis inhibition by anti-apoptotic bcl-2 or caspase inhibitor p35 overexpression reduced physiologically occurring apoptosis (Supplementary Fig. 2c – h ), enhanced the appearance of unfit cells with abnormally high or low Wnt/β-catenin activity, and severely distorted the Wnt/β-catenin activity gradient (Fig. 1f , Supplementary Fig. 2i – j ). These results suggest that apoptotic elimination of unfit cells smoothens the Wnt/β-catenin-gradient. Fig. 1 Apoptotic elimination of unfit cells smoothens the Wnt/β-catenin gradient. a Schematic illustration of Wnt/β-catenin activity gradient formation. A: anterior, P: posterior. b Caspase-3 activation in unfit cells with abnormal Wnt/β-catenin activity. Whole-mount immunostaining of d2EGFP (green) and active caspase-3 (magenta) in Tg(OTM:d2EGFP) zebrafish embryos (Dorsal view). Dotted line indicates abnormal Wnt/β-catenin-reporter activity. Scale bars, 200 μm. c OTM:ELuc-CP drives destabilized ELuc-CP expression in response to Wnt/β-catenin signalling activation in reporter embryo (dorsal view). Scale bar, 200 μm. (See also Supplementary Movie 1 ). d Time lapse images showing unfit cells with abnormal Wnt/β-catenin activity appear then disappear in OTM:ELuc-CP embryos. Scale bars, 100 μm. Pixel area length is 6.5 μm, ≤ zebrafish deep cell diameter (~10 μm). e Physiological Wnt/β-catenin-noise during zebrafish AP axis formation. Graphs show the number of pixels with unfit Wnt/β-catenin activity in the luminescence images of living OTM:ELuc-CP transgenic zebrafish embryos during AP axis formation. Schematic illustrations: pixel retaining >two-fold or <two-fold intensity compared to neighbouring pixels for ≥frames (>6 min) was defined as High or Low noise,", "role": "user" }, { "content": "Tissue patterning is an important process during embryo formation, as well in adult tissue, which ensures that groups of cells are correctly arranged to allow them to function properly. Many studies have attempted to understand how disruptive cells (arranged or signaling improperly) are removed from healthy tissues; none have provided a clear explanation, until now. In a new study published in Nature Communications, a research team led by experts from Osaka University investigated Wnt/β-catenin signaling, which constitutes a morphogen system (a system that helps to control tissue organization in developing embryos of various species, including amphioxi, fish, frogs, and mammals). Using a zebrafish model, the researchers found that aberrant Wnt/β-catenin signaling led to changes in membrane expression levels of proteins. These changes were indicators of poor cell fitness and led to cell death, which encouraged consistent tissue patterning during embryo formation. \"We found that a type of 'morphogen-gradient noise-cancelling system' senses and eliminates unhealthy cells, which are accidentally generated during embryogenesis,\" says Tohru Ishitani, corresponding author on the study. \"Our findings suggest that this system is essential for the construction of a healthy embryo with appropriate tissue patterning.\" In the study, cells with aberrant Wnt/β-catenin signaling also demonstrated changes in cadherin proteins on the cell membrane, which led to an imbalance relative to cadherin proteins on neighboring cells. In those same cells with aberrant Wnt/β-catenin signaling, the activation of TGF-β-Smad signaling led to the production of reactive oxygen species, followed by cell death via apoptosis. \"Our analyses revealed that this 'morphogen-gradient noise-cancelling system' is only activated only in cells with dramatic changes in Wnt/β-catenin signaling, or substantial noise,\" says Yuki Akieda, lead author on the study. \"We presume that this system might help to eliminate cells with severe signaling-defects related to malformation- or cancer-causing mutations.\" Because of the importance of ensuring appropriate tissue patterning, the results of this study can help to explain mechanisms involved in the formation of cancer and the occurrence of congenital diseases. In addition, the results may be useful for designing new diagnostic methods for these diseases. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues. However, developing tissues also undergo dynamic morphogenesis, which may produce cells with unfit morphogen signalling and consequent noisy morphogen gradients. Here we show that a cell competition-related system corrects such noisy morphogen gradients. Zebrafish imaging analyses of the Wnt/β-catenin signalling gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, identify that unfit cells with abnormal Wnt/β-catenin activity spontaneously appear and produce noise in the gradient. Communication between unfit and neighbouring fit cells via cadherin proteins stimulates apoptosis of the unfit cells by activating Smad signalling and reactive oxygen species production. This unfit cell elimination is required for proper Wnt/β-catenin gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning not only in the embryo but also in adult tissues, this system may support tissue robustness and disease prevention. Introduction Tissue patterning is a fundamental process during embryonic development and adult tissue homeostasis. To reproducibly achieve precise tissue patterning, the molecular and cellular systems controlling patterning must be robust against environmental and physiological perturbations. Activity gradients of morphogen signalling, including Wnt/β-catenin, bone morphogenetic protein (BMP), sonic hedgehog (Shh), fibroblast growth factor (FGF) and nodal signalling pattern the tissue axes 1 , 2 . In the embryonic anterior–posterior (AP) axis formation of deuterostomes (amphioxus, fish, frog and mammal), Wnt/β-catenin signalling is activated and inhibited in the presumptive posterior and anterior tissue, respectively. This bi-directional regulation forms a signalling activity gradient along the AP axis to establish embryonic AP patterning 3 . However, rapid cell proliferation and movement in developing tissues may affect morphogen diffusion and signal transduction, thereby producing cells with unfit signalling and consequent noisy morphogen gradients. It is not yet completely understood how these noises are overcome to generate robust patterning. Cell competition is an interactive process wherein cells compete for fitness in a tissue environment. Specifically, relatively higher fitness cells eliminate those with lower fitness 4 , 5 . Key features of this process include that it originates from specific interactions between two cell types leading to elimination in one, and context-dependency. For example, mosaically introduced polarity-deficient cells are apoptotically eliminated by their neighbouring wild-type cells in Drosophila imaginal disc and mammalian cultured cells 6 , 7 , 8 and in Myc-low-level cells upon communicating with Myc-high-level cells 9 , 10 , 11 . Although cell competition, which is evolutionarily conserved from insects to mammals, may assist in proper embryogenesis, tissue morphogenesis, and tumour progression and prevention 12 , its physiological relevance and detailed mechanisms, especially of unfit cell-sensing, remain unclear. Here, we identify a cell competition-related system for correcting the noise in the Wnt/β-catenin morphogen gradient, presenting a previously unidentified physiological role of cell competition and the mechanisms that mediate unfit cell sensing and elimination. Results Unfit cell elimination smoothens the Wnt/β-catenin gradient To clarify the entire morphogen gradient formation process, we visualized Wnt/β-catenin signalling activity during AP axis formation in zebrafish early embryos (Fig. 1a ) using OTM (Optimal TCF Motif):d2EGFP 13 and OTM:ELuc-CP (Supplementary Fig. 1a ) reporters. These respectively express destabilized EGFP (d2EGFP), providing high spatial resolution, and highly-destabilized Emerald luciferase (ELuc-CP), possessing high temporal resolution and suitable for quantitative analyses (Supplementary Fig. 1b–e ), upon Wnt/β-catenin signalling activation. A noisy signalling-gradient along the AP axis was detected in both transgenic zebrafish embryo types at around 8.5–12 h-post-fertilization (hpf) (Fig. 1b–d , Supplementary Movie 1 ). Abnormally low and high Wnt/β-catenin activities were spontaneously detected in the Wnt/β-catenin activity-high posterior and -low regions, respectively (Fig. 1b, d, e , Supplementary Movie 1 ). We confirmed that the endogenous Wnt/β-catenin target gene ( lef1 ) and nuclear β-catenin proteins also showed noisy expression patterns, which was reflected by the reporter activities (Supplementary Fig. 1f–i ). Abnormal Wnt/β-catenin activity gradually disappeared over time (Fig. 1d ), suggesting that zebrafish embryonic tissue may possess a system for eliminating signalling noise to smoothen the Wnt/β-catenin-gradient. As mouse embryonic tissues eliminate defective cells, including low Myc level, autophagy-deficient, and tetraploid cells in an apoptosis-dependent manner 9 , 11 , unfit Wnt/β-catenin activity-abnormal cells might also be apoptotically eliminated. To investigate the relationship between apoptosis and abnormal Wnt/β-catenin activity, we detected active caspase-3- and TUNEL-positive apoptotic cells in 8–10 hpf embryos undergoing Wnt/β-catenin-gradient-mediated AP axis patterning (Supplementary Fig. 2a–c , Supplementary Movie 2 ). Apoptotic cell number and position varied between embryos (Supplementary Fig. 2d and 2e ), suggesting that the apoptosis is not pre-programmed. In some unfit Wnt/β-catenin activity-abnormal cells, caspase-3 was activated (Fig. 1b , right; Supplementary Fig. 2f–g ), whereas apoptosis inhibition by anti-apoptotic bcl-2 or caspase inhibitor p35 overexpression reduced physiologically occurring apoptosis (Supplementary Fig. 2c – h ), enhanced the appearance of unfit cells with abnormally high or low Wnt/β-catenin activity, and severely distorted the Wnt/β-catenin activity gradient (Fig. 1f , Supplementary Fig. 2i – j ). These results suggest that apoptotic elimination of unfit cells smoothens the Wnt/β-catenin-gradient. Fig. 1 Apoptotic elimination of unfit cells smoothens the Wnt/β-catenin gradient. a Schematic illustration of Wnt/β-catenin activity gradient formation. A: anterior, P: posterior. b Caspase-3 activation in unfit cells with abnormal Wnt/β-catenin activity. Whole-mount immunostaining of d2EGFP (green) and active caspase-3 (magenta) in Tg(OTM:d2EGFP) zebrafish embryos (Dorsal view). Dotted line indicates abnormal Wnt/β-catenin-reporter activity. Scale bars, 200 μm. c OTM:ELuc-CP drives destabilized ELuc-CP expression in response to Wnt/β-catenin signalling activation in reporter embryo (dorsal view). Scale bar, 200 μm. (See also Supplementary Movie 1 ). d Time lapse images showing unfit cells with abnormal Wnt/β-catenin activity appear then disappear in OTM:ELuc-CP embryos. Scale bars, 100 μm. Pixel area length is 6.5 μm, ≤ zebrafish deep cell diameter (~10 μm). e Physiological Wnt/β-catenin-noise during zebrafish AP axis formation. Graphs show the number of pixels with unfit Wnt/β-catenin activity in the luminescence images of living OTM:ELuc-CP transgenic zebrafish embryos during AP axis formation. Schematic illustrations: pixel retaining >two-fold or <two-fold intensity compared to neighbouring pixels for ≥frames (>6 min) was defined as High or Low noise,<|im_end|> <|im_start|>assistant Tissue patterning is an important process during embryo formation, as well in adult tissue, which ensures that groups of cells are correctly arranged to allow them to function properly. Many studies have attempted to understand how disruptive cells (arranged or signaling improperly) are removed from healthy tissues; none have provided a clear explanation, until now. In a new study published in Nature Communications, a research team led by experts from Osaka University investigated Wnt/β-catenin signaling, which constitutes a morphogen system (a system that helps to control tissue organization in developing embryos of various species, including amphioxi, fish, frogs, and mammals). Using a zebrafish model, the researchers found that aberrant Wnt/β-catenin signaling led to changes in membrane expression levels of proteins. These changes were indicators of poor cell fitness and led to cell death, which encouraged consistent tissue patterning during embryo formation. "We found that a type of 'morphogen-gradient noise-cancelling system' senses and eliminates unhealthy cells, which are accidentally generated during embryogenesis," says Tohru Ishitani, corresponding author on the study. "Our findings suggest that this system is essential for the construction of a healthy embryo with appropriate tissue patterning." In the study, cells with aberrant Wnt/β-catenin signaling also demonstrated changes in cadherin proteins on the cell membrane, which led to an imbalance relative to cadherin proteins on neighboring cells. In those same cells with aberrant Wnt/β-catenin signaling, the activation of TGF-β-Smad signaling led to the production of reactive oxygen species, followed by cell death via apoptosis. "Our analyses revealed that this 'morphogen-gradient noise-cancelling system' is only activated only in cells with dramatic changes in Wnt/β-catenin signaling, or substantial noise," says Yuki Akieda, lead author on the study. "We presume that this system might help to eliminate cells with severe signaling-defects related to malformation- or cancer-causing mutations." Because of the importance of ensuring appropriate tissue patterning, the results of this study can help to explain mechanisms involved in the formation of cancer and the occurrence of congenital diseases. In addition, the results may be useful for designing new diagnostic methods for these diseases. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract A critical current density on stripping is identified that results in dendrite formation on plating and cell failure. When the stripping current density removes Li from the interface faster than it can be replenished, voids form in the Li at the interface and accumulate on cycling, increasing the local current density at the interface and ultimately leading to dendrite formation on plating, short circuit and cell death. This occurs even when the overall current density is considerably below the threshold for dendrite formation on plating. For the Li/Li 6 PS 5 Cl/Li cell, this is 0.2 and 1.0 mA cm −2 at 3 and 7 MPa pressure, respectively, compared with a critical current for plating of 2.0 mA cm −2 at both 3 and 7 MPa. The pressure dependence on stripping indicates that creep rather than Li diffusion is the dominant mechanism transporting Li to the interface. The critical stripping current is a major factor limiting the power density of Li anode solid-state cells. Considerable pressure may be required to achieve even modest power densities in solid-state cells. Main Solid-state cells composed of a ceramic electrolyte and Li metal anode have the potential to deliver enhanced safety along with higher specific energy and energy density compared with liquid electrolyte Li-ion batteries 1 . However, even 99% dense ceramic electrolytes suffer from failure due to short circuits arising from penetration of Li dendrites through the ceramic on plating 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . For Li 7 La 3 Zr 2 O 12 , the current density for dendrite formation can be as low as 0.6 mA cm −2 (refs. 6 , 13 , 14 , 15 ). Another problem is that contact can be lost due to void formation between the solid electrolyte (SE) and Li during stripping 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 . It is difficult to separate plating from stripping with two-electrode, Li/SE/Li cells 22 , 25 . A recent paper used two-electrode cells in which one electrode was formed under very high pressure to minimize interfacial impedance, and highlighted the role of void formation in polarization on stripping 26 . Here, we use three-electrode cells to study separately the processes of plating and stripping Li metal at the Li metal/Li 6 PS 5 Cl interface on cycling. Argyrodite, Li 6 PS 5 Cl, was chosen as the solid electrolyte. Sulfides have higher conductivity than oxides and are being pursued as the electrolyte of choice by a number of companies attempting to commercialize solid-state batteries 27 , 28 , 29 , 30 . Argyrodite has the advantage of being less brittle than the other highly conducting sulfides 31 . In addition, we show that it produces a kinetically stable interface with Li metal. By separating plating from stripping we demonstrate that each has a critical current density above which dendrite formation and short-circuiting will occur. When the current density on stripping is such that it exceeds the rate at which Li is replenished at the surface, voids form in the Li metal at the interface 18 , 22 . They are only partially eliminated on subsequent plating, and hence voids accumulate on cycling, reducing the contact area at the interface and increasing the local current density. In such circumstances, even when the overall current density is lower than the threshold for dendrite formation on plating, the local current density will rise to exceed the limit for dendrite formation on plating, resulting in dendrite formation and short-circuiting. Increasing pressure increases the threshold of current density below which dendrites do not form, demonstrating that Li metal creep is the primary mechanism of replenishing Li metal at the interface. Although voltage polarization is high on stripping, it returns rapidly to a much lower value on subsequent plating due to rapid formation of a Li film across the electrolyte surface that occludes the voids formed on the previous stripping. Critical current density on stripping can be identified through single stripping experiments, and can predict the threshold of current density below which dendrite formation will not occur and therefore at which cells can be cycled indefinitely. With a stack pressure of 3 MPa for Li/Li 6 PS 5 Cl, the maximum current for avoiding voids and subsequent dendrite formation is 0.2 mA cm −2 , rising to 1.0 mA cm −2 at 7 MPa. Li 6 PS 5 Cl (argyrodite) was synthesized as described in Methods . The composition was confirmed by powder X-ray diffraction patterns that displayed the peaks characteristic of the argyrodite structure (Supplementary Fig. 1 ) 32 . Discs were prepared by cold pressing the powder at 500 MPa, then loaded into a vacuum-sealed quartz tube (<10 −5 mbar) before undergoing sintering at 300 °C for 15 min. The sintered discs were polished with a 1,200 grit SiC abrasive disc. All manipulations were carried out in an Ar-filled glovebox with a H 2 O and O 2 content of less than 1 ppm. Two-electrode cells were constructed by sandwiching the disc between two pieces of Li metal foil of 40 μm thickness, to investigate the stability of the interface. A.c. impedance data were collected as a function of time, showing that the interfacial resistance ( R SEI + R CT ) stabilizes with time, reaching within 10% of the final value after 100 h (Supplementary Fig. 2 ). After contacting Li metal to the surface of our Li 6 PS 5 Cl disc for 250 h, the Li metal was removed and the surface of the disc investigated using phosphorus, sulfur and lithium X-ray photoemission spectroscopy (XPS) (Supplementary Fig. 3 ). The XPS data demonstrate that the interface is dominated by the presence of Li 2 S, with much smaller amounts of Li 3 P and other compounds with the XPS signature of phosphosulfides. As expected, Li 6 PS 5 Cl", "role": "user" }, { "content": "All-solid-state batteries, a battery design composed of all solid components, have gained attention as the next major advance beyond lithium ion batteries because of their potential to store more energy while being safer to operate. When capable of being produced in commercial quantities, solid-state batteries would revolutionize electric vehicles (EVs) effectively increasing drivable range or significantly decreasing volume and weight. Yet solid-state batteries can fail after cycling (repeated charging and discharging) at practical currents, which has been one of the barriers preventing their mass commercialization. In a new paper published by Nature Materials, titled \"Critical Stripping Current Leads to Dendrite Formation on Plating in Lithium Anode Solid Electrolyte Cells,\" Faraday Institution researchers at the University of Oxford have taken a step forward in understanding the mechanisms by which solid-state batteries fail—a necessary prerequisite to avoiding such failures. Dendrites are branching networks of lithium which grow through the solid, ceramic, electrolyte during charging of a battery, causing a short circuit. \"This research adds to our fundamental knowledge of why solid-state batteries behave the way they do. We believe our improved understanding will help to inform approaches to avoid some of the problems at the lithium metal anode in solid electrolyte cells,\" commented Professor Peter G. Bruce of the University of Oxford's Departments of Materials and Chemistry and Principal Investigator of the Faraday Institution's SOLBAT project, whose team led the research. Void creation at the anode of solid-state cells has long been recognized, but their role in dendrite formation has not been understood. The study uses a combination of cutting edge electrochemical and imaging techniques to form a fundamental understanding of void formation as a function of cycling and its role in dendrites and cell failure. Significantly, parameters in the failure model correlate to key physical properties that could be used as \"levers\" to suppress void formation and cell failure. \"It is key to break down the scientific barriers that prevent the progression to market of technologies that will enable our vision of the future of mobility. The study by Oxford researchers is one early example of a scientific advance that the Faraday Institution was set up to drive,\" said Tony Harper, Director of the ISCF Faraday Battery Challenge at UK Research & Innovation. The research: importance of critical current density on stripping One well-recognized challenge facing scientists studying solid-state batteries is to prevent dendrite growth as batteries are cycled between a charged and uncharged state (as they would repeatedly have to do if they to be used to power EVs). Another significant problem is void formation between the solid electrolyte and lithium anode (negatively charged electrode) during stripping (discharge of a battery), which leads to a reduced area of contact between those two parts of the battery cell. It is difficult to separate lithium plating from stripping using an experiment with a battery cell containing the usual two electrodes. In this study researchers used three-electrode cells to study separately the processes of plating and stripping lithium metal at the lithium metal / ceramic interface on battery cycling. Argyrodite, Li6PS5Cl, was chosen as the solid electrolyte. Such sulphides have higher conductivity than oxides and are being pursued as the electrolyte of choice by several companies attempting to commercialize solid-state batteries. Argyrodite has the advantage of being less brittle than other highly conducting sulphides. The researchers found that if dendrite formation is to be avoided in all-solid-state battery cells, it is vital to cycle the cells below the critical current density at which voids begin to form at the lithium metal / solid electrolyte interface during lithium stripping (CCS). This is the case even when the current density is below the threshold for dendrite formation on plating. When the current density is greater than CCS, voids accumulate on cycling, the lithium / solid electrolyte area of contact decreases correspondingly and as a result the local current density increases until it reaches a value where dendrites form on plating, leading to a short-circuit and cell failure. It may take multiple cycles, but the research demonstrates that cell failure is inevitable if the overall current density is greater than CCS. These results show that it is not just the current density for dendrite formation that is important in achieving cycling of all-solid-state cells at practical current densities; stripping currents are also important. The researchers also conclude the lithium metal creep is the primary mechanism of transporting lithium metal at the interface. The team working on this discovery included a mix of theoreticians and experimentalists, in the type of multi-disciplinary research environment that the Faraday Institution fosters. The prizes of developing a commercial all solid-state battery for electric vehicles Small, non-rechargeable, solid-state batteries are growing in commercial use, for example, in medical implants such as heart monitoring. However, there remain considerable challenges associated with both the fabrication of solid-state batteries at the scale required for use in EVs, and to ensure that such devices operate safely and to acceptable performance levels over the lifetime of the EV. Current lithium ion batteries used in EVs contain a flammable organic liquid electrolyte, through which charge-carrying lithium ions pass during the charging and discharging of the battery. This liquid presents an inherent (albeit well-managed) safety concern. The replacement of the liquid electrolyte with a solid would remove this fire risk. Worldwide, significant scientific effort is being expended to develop new battery chemistries that would achieve battery performance (power density and energy density) that would give an EV driving experience aligned with expectations from driving cars with internal combustion engines. The elimination of the need for a liquid electrolyte would be a prerequisite for developing batteries with a lithium metal anode, which could unlock significant performance improvements. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract A critical current density on stripping is identified that results in dendrite formation on plating and cell failure. When the stripping current density removes Li from the interface faster than it can be replenished, voids form in the Li at the interface and accumulate on cycling, increasing the local current density at the interface and ultimately leading to dendrite formation on plating, short circuit and cell death. This occurs even when the overall current density is considerably below the threshold for dendrite formation on plating. For the Li/Li 6 PS 5 Cl/Li cell, this is 0.2 and 1.0 mA cm −2 at 3 and 7 MPa pressure, respectively, compared with a critical current for plating of 2.0 mA cm −2 at both 3 and 7 MPa. The pressure dependence on stripping indicates that creep rather than Li diffusion is the dominant mechanism transporting Li to the interface. The critical stripping current is a major factor limiting the power density of Li anode solid-state cells. Considerable pressure may be required to achieve even modest power densities in solid-state cells. Main Solid-state cells composed of a ceramic electrolyte and Li metal anode have the potential to deliver enhanced safety along with higher specific energy and energy density compared with liquid electrolyte Li-ion batteries 1 . However, even 99% dense ceramic electrolytes suffer from failure due to short circuits arising from penetration of Li dendrites through the ceramic on plating 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . For Li 7 La 3 Zr 2 O 12 , the current density for dendrite formation can be as low as 0.6 mA cm −2 (refs. 6 , 13 , 14 , 15 ). Another problem is that contact can be lost due to void formation between the solid electrolyte (SE) and Li during stripping 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 . It is difficult to separate plating from stripping with two-electrode, Li/SE/Li cells 22 , 25 . A recent paper used two-electrode cells in which one electrode was formed under very high pressure to minimize interfacial impedance, and highlighted the role of void formation in polarization on stripping 26 . Here, we use three-electrode cells to study separately the processes of plating and stripping Li metal at the Li metal/Li 6 PS 5 Cl interface on cycling. Argyrodite, Li 6 PS 5 Cl, was chosen as the solid electrolyte. Sulfides have higher conductivity than oxides and are being pursued as the electrolyte of choice by a number of companies attempting to commercialize solid-state batteries 27 , 28 , 29 , 30 . Argyrodite has the advantage of being less brittle than the other highly conducting sulfides 31 . In addition, we show that it produces a kinetically stable interface with Li metal. By separating plating from stripping we demonstrate that each has a critical current density above which dendrite formation and short-circuiting will occur. When the current density on stripping is such that it exceeds the rate at which Li is replenished at the surface, voids form in the Li metal at the interface 18 , 22 . They are only partially eliminated on subsequent plating, and hence voids accumulate on cycling, reducing the contact area at the interface and increasing the local current density. In such circumstances, even when the overall current density is lower than the threshold for dendrite formation on plating, the local current density will rise to exceed the limit for dendrite formation on plating, resulting in dendrite formation and short-circuiting. Increasing pressure increases the threshold of current density below which dendrites do not form, demonstrating that Li metal creep is the primary mechanism of replenishing Li metal at the interface. Although voltage polarization is high on stripping, it returns rapidly to a much lower value on subsequent plating due to rapid formation of a Li film across the electrolyte surface that occludes the voids formed on the previous stripping. Critical current density on stripping can be identified through single stripping experiments, and can predict the threshold of current density below which dendrite formation will not occur and therefore at which cells can be cycled indefinitely. With a stack pressure of 3 MPa for Li/Li 6 PS 5 Cl, the maximum current for avoiding voids and subsequent dendrite formation is 0.2 mA cm −2 , rising to 1.0 mA cm −2 at 7 MPa. Li 6 PS 5 Cl (argyrodite) was synthesized as described in Methods . The composition was confirmed by powder X-ray diffraction patterns that displayed the peaks characteristic of the argyrodite structure (Supplementary Fig. 1 ) 32 . Discs were prepared by cold pressing the powder at 500 MPa, then loaded into a vacuum-sealed quartz tube (<10 −5 mbar) before undergoing sintering at 300 °C for 15 min. The sintered discs were polished with a 1,200 grit SiC abrasive disc. All manipulations were carried out in an Ar-filled glovebox with a H 2 O and O 2 content of less than 1 ppm. Two-electrode cells were constructed by sandwiching the disc between two pieces of Li metal foil of 40 μm thickness, to investigate the stability of the interface. A.c. impedance data were collected as a function of time, showing that the interfacial resistance ( R SEI + R CT ) stabilizes with time, reaching within 10% of the final value after 100 h (Supplementary Fig. 2 ). After contacting Li metal to the surface of our Li 6 PS 5 Cl disc for 250 h, the Li metal was removed and the surface of the disc investigated using phosphorus, sulfur and lithium X-ray photoemission spectroscopy (XPS) (Supplementary Fig. 3 ). The XPS data demonstrate that the interface is dominated by the presence of Li 2 S, with much smaller amounts of Li 3 P and other compounds with the XPS signature of phosphosulfides. As expected, Li 6 PS 5 Cl<|im_end|> <|im_start|>assistant All-solid-state batteries, a battery design composed of all solid components, have gained attention as the next major advance beyond lithium ion batteries because of their potential to store more energy while being safer to operate. When capable of being produced in commercial quantities, solid-state batteries would revolutionize electric vehicles (EVs) effectively increasing drivable range or significantly decreasing volume and weight. Yet solid-state batteries can fail after cycling (repeated charging and discharging) at practical currents, which has been one of the barriers preventing their mass commercialization. In a new paper published by Nature Materials, titled "Critical Stripping Current Leads to Dendrite Formation on Plating in Lithium Anode Solid Electrolyte Cells," Faraday Institution researchers at the University of Oxford have taken a step forward in understanding the mechanisms by which solid-state batteries fail—a necessary prerequisite to avoiding such failures. Dendrites are branching networks of lithium which grow through the solid, ceramic, electrolyte during charging of a battery, causing a short circuit. "This research adds to our fundamental knowledge of why solid-state batteries behave the way they do. We believe our improved understanding will help to inform approaches to avoid some of the problems at the lithium metal anode in solid electrolyte cells," commented Professor Peter G. Bruce of the University of Oxford's Departments of Materials and Chemistry and Principal Investigator of the Faraday Institution's SOLBAT project, whose team led the research. Void creation at the anode of solid-state cells has long been recognized, but their role in dendrite formation has not been understood. The study uses a combination of cutting edge electrochemical and imaging techniques to form a fundamental understanding of void formation as a function of cycling and its role in dendrites and cell failure. Significantly, parameters in the failure model correlate to key physical properties that could be used as "levers" to suppress void formation and cell failure. "It is key to break down the scientific barriers that prevent the progression to market of technologies that will enable our vision of the future of mobility. The study by Oxford researchers is one early example of a scientific advance that the Faraday Institution was set up to drive," said Tony Harper, Director of the ISCF Faraday Battery Challenge at UK Research & Innovation. The research: importance of critical current density on stripping One well-recognized challenge facing scientists studying solid-state batteries is to prevent dendrite growth as batteries are cycled between a charged and uncharged state (as they would repeatedly have to do if they to be used to power EVs). Another significant problem is void formation between the solid electrolyte and lithium anode (negatively charged electrode) during stripping (discharge of a battery), which leads to a reduced area of contact between those two parts of the battery cell. It is difficult to separate lithium plating from stripping using an experiment with a battery cell containing the usual two electrodes. In this study researchers used three-electrode cells to study separately the processes of plating and stripping lithium metal at the lithium metal / ceramic interface on battery cycling. Argyrodite, Li6PS5Cl, was chosen as the solid electrolyte. Such sulphides have higher conductivity than oxides and are being pursued as the electrolyte of choice by several companies attempting to commercialize solid-state batteries. Argyrodite has the advantage of being less brittle than other highly conducting sulphides. The researchers found that if dendrite formation is to be avoided in all-solid-state battery cells, it is vital to cycle the cells below the critical current density at which voids begin to form at the lithium metal / solid electrolyte interface during lithium stripping (CCS). This is the case even when the current density is below the threshold for dendrite formation on plating. When the current density is greater than CCS, voids accumulate on cycling, the lithium / solid electrolyte area of contact decreases correspondingly and as a result the local current density increases until it reaches a value where dendrites form on plating, leading to a short-circuit and cell failure. It may take multiple cycles, but the research demonstrates that cell failure is inevitable if the overall current density is greater than CCS. These results show that it is not just the current density for dendrite formation that is important in achieving cycling of all-solid-state cells at practical current densities; stripping currents are also important. The researchers also conclude the lithium metal creep is the primary mechanism of transporting lithium metal at the interface. The team working on this discovery included a mix of theoreticians and experimentalists, in the type of multi-disciplinary research environment that the Faraday Institution fosters. The prizes of developing a commercial all solid-state battery for electric vehicles Small, non-rechargeable, solid-state batteries are growing in commercial use, for example, in medical implants such as heart monitoring. However, there remain considerable challenges associated with both the fabrication of solid-state batteries at the scale required for use in EVs, and to ensure that such devices operate safely and to acceptable performance levels over the lifetime of the EV. Current lithium ion batteries used in EVs contain a flammable organic liquid electrolyte, through which charge-carrying lithium ions pass during the charging and discharging of the battery. This liquid presents an inherent (albeit well-managed) safety concern. The replacement of the liquid electrolyte with a solid would remove this fire risk. Worldwide, significant scientific effort is being expended to develop new battery chemistries that would achieve battery performance (power density and energy density) that would give an EV driving experience aligned with expectations from driving cars with internal combustion engines. The elimination of the need for a liquid electrolyte would be a prerequisite for developing batteries with a lithium metal anode, which could unlock significant performance improvements. <|im_end|>

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555, 26275, 12074, 374, 832, 4216, 3187, 315, 264, 12624, 12178, 430, 279, 13759, 65726, 43964, 574, 743, 709, 311, 6678, 1359, 1071, 19036, 33107, 11, 10783, 315, 279, 3507, 9847, 13759, 65726, 34712, 26323, 520, 6560, 8483, 612, 38710, 13, 578, 3495, 25, 12939, 315, 9200, 1510, 17915, 389, 67770, 3861, 1664, 12, 47167, 8815, 13176, 14248, 21630, 6573, 21395, 27360, 374, 311, 5471, 90052, 1269, 6650, 439, 27360, 527, 272, 37676, 1990, 264, 11684, 323, 653, 38061, 1614, 320, 300, 814, 1053, 19352, 617, 311, 656, 422, 814, 311, 387, 1511, 311, 2410, 15238, 82, 570, 13596, 5199, 3575, 374, 742, 18488, 1990, 279, 6573, 73396, 668, 323, 57907, 459, 536, 320, 29875, 8046, 11684, 72048, 8, 2391, 67770, 320, 4338, 14215, 315, 264, 11863, 705, 902, 11767, 311, 264, 11293, 3158, 315, 3729, 1990, 1884, 1403, 5596, 315, 279, 11863, 2849, 13, 1102, 374, 5107, 311, 8821, 57907, 628, 1113, 505, 67770, 1701, 459, 9526, 449, 264, 11863, 2849, 8649, 279, 13783, 1403, 80390, 13, 763, 420, 4007, 12074, 1511, 2380, 37081, 299, 451, 7917, 311, 4007, 26214, 279, 11618, 315, 628, 1113, 323, 67770, 57907, 9501, 520, 279, 57907, 9501, 611, 43124, 3834, 389, 11863, 33162, 13, 1676, 4680, 24409, 635, 11, 14851, 21, 5119, 20, 5176, 11, 574, 12146, 439, 279, 6573, 73396, 668, 13, 15483, 83778, 3422, 617, 5190, 98971, 1109, 19488, 3422, 323, 527, 1694, 46531, 439, 279, 73396, 668, 315, 5873, 555, 3892, 5220, 19969, 311, 8518, 553, 6573, 21395, 27360, 13, 1676, 4680, 24409, 635, 706, 279, 9610, 315, 1694, 2753, 95749, 1109, 1023, 7701, 31474, 83778, 3422, 13, 578, 12074, 1766, 430, 422, 90052, 1269, 18488, 374, 311, 387, 31890, 304, 682, 58353, 21395, 11863, 7917, 11, 433, 374, 16595, 311, 11008, 279, 7917, 3770, 279, 9200, 1510, 17915, 520, 902, 742, 82, 3240, 311, 1376, 520, 279, 57907, 9501, 611, 6573, 73396, 668, 3834, 2391, 57907, 67770, 320, 3791, 50, 570, 1115, 374, 279, 1162, 1524, 994, 279, 1510, 17915, 374, 3770, 279, 12447, 369, 90052, 1269, 18488, 389, 628, 1113, 13, 3277, 279, 1510, 17915, 374, 7191, 1109, 74192, 11, 742, 82, 47376, 389, 33162, 11, 279, 57907, 611, 6573, 73396, 668, 3158, 315, 3729, 43154, 8024, 11559, 323, 439, 264, 1121, 279, 2254, 1510, 17915, 12992, 3156, 433, 25501, 264, 907, 1405, 90052, 24143, 1376, 389, 628, 1113, 11, 6522, 311, 264, 2875, 1824, 38368, 323, 2849, 8060, 13, 1102, 1253, 1935, 5361, 25492, 11, 719, 279, 3495, 32216, 430, 2849, 8060, 374, 31352, 422, 279, 8244, 1510, 17915, 374, 7191, 1109, 74192, 13, 4314, 3135, 1501, 430, 433, 374, 539, 1120, 279, 1510, 17915, 369, 90052, 1269, 18488, 430, 374, 3062, 304, 32145, 33162, 315, 682, 58353, 21395, 7917, 520, 15325, 1510, 90816, 26, 67770, 60701, 527, 1101, 3062, 13, 578, 12074, 1101, 32194, 279, 57907, 9501, 28182, 374, 279, 6156, 17383, 315, 67757, 57907, 9501, 520, 279, 3834, 13, 578, 2128, 3318, 389, 420, 18841, 5343, 264, 6651, 315, 26188, 9818, 323, 22772, 1705, 11, 304, 279, 955, 315, 7447, 52765, 44550, 3495, 4676, 430, 279, 13759, 65726, 43964, 37413, 388, 13, 578, 38508, 315, 11469, 264, 8518, 682, 6573, 21395, 11863, 369, 9249, 11731, 15344, 11, 2536, 5621, 14215, 481, 11, 6573, 21395, 27360, 527, 7982, 304, 8518, 1005, 11, 369, 3187, 11, 304, 6593, 63284, 1778, 439, 4851, 16967, 13, 4452, 11, 1070, 7293, 24779, 11774, 5938, 449, 2225, 279, 59251, 315, 6573, 21395, 27360, 520, 279, 5569, 2631, 369, 1005, 304, 15238, 82, 11, 323, 311, 6106, 430, 1778, 7766, 14816, 21676, 323, 311, 22281, 5178, 5990, 927, 279, 19569, 315, 279, 15238, 13, 9303, 57907, 28772, 27360, 1511, 304, 15238, 82, 6782, 264, 1344, 100210, 17808, 14812, 73396, 668, 11, 1555, 902, 6900, 1824, 11687, 287, 57907, 65125, 1522, 2391, 279, 23468, 323, 834, 63459, 315, 279, 11863, 13, 1115, 14812, 18911, 459, 38088, 320, 278, 20582, 1664, 21110, 3359, 8, 7296, 4747, 13, 578, 14039, 315, 279, 14812, 73396, 668, 449, 264, 6573, 1053, 4148, 420, 4027, 5326, 13, 53035, 11, 5199, 12624, 5149, 374, 1694, 99131, 311, 2274, 502, 11863, 8590, 380, 4108, 430, 1053, 11322, 11863, 5178, 320, 13477, 17915, 323, 4907, 17915, 8, 430, 1053, 3041, 459, 15238, 10043, 3217, 27210, 449, 17078, 505, 10043, 9515, 449, 5419, 59333, 21787, 13, 578, 44032, 315, 279, 1205, 369, 264, 14812, 73396, 668, 1053, 387, 264, 80884, 369, 11469, 27360, 449, 264, 57907, 9501, 459, 536, 11, 902, 1436, 15405, 5199, 5178, 18637, 13, 220, 128257, 198 ]

2,512

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the past decades, rest-frame ultraviolet (UV) observations have provided large samples of UV luminous galaxies at redshift ( z ) greater than 6 (refs. 1 , 2 , 3 ), during the so-called epoch of reionization. While a few of these UV-identified galaxies revealed substantial dust reservoirs 4 , 5 , 6 , 7 , very heavily dust-obscured sources at these early times have remained elusive. They are limited to a rare population of extreme starburst galaxies 8 , 9 , 10 , 11 , 12 and companions of rare quasars 13 , 14 . These studies conclude that the contribution of dust-obscured galaxies to the cosmic star formation rate density at z > 6 is sub-dominant. Recent ALMA and Spitzer observations have identified a more abundant, less extreme population of obscured galaxies at z = 3−6 (refs. 15 , 16 ). However, this population has not been confirmed in the reionization epoch so far. Here, we report the discovery of two dust-obscured star-forming galaxies at z = 6.6813 ± 0.0005 and z = 7.3521 ± 0.0005. These objects are not detected in existing rest-frame UV data and were discovered only through their far-infrared [C ii ] lines and dust continuum emission as companions to typical UV-luminous galaxies at the same redshift. The two galaxies exhibit lower infrared luminosities and star-formation rates than extreme starbursts, in line with typical star-forming galaxies at z ≈ 7. This population of heavily dust-obscured galaxies appears to contribute 10–25% to the z > 6 cosmic star formation rate density. Main As part of the ongoing ALMA large program REBELS (Reionization-Era Bright Emission Line Survey), we are observing 40 UV-luminous primary targets at z > 6.5 (ref. 17 ). Among these targets are REBELS-12 and REBELS-29. When inspecting the ALMA data cube of these two sources, we identified two additional emission line neighbours. The primary targets of our ALMA observing program, REBELS-12 and REBELS-29, represent some of the most UV-luminous galaxies in this redshift range, and have M UV = −22.5 ± 0.3 and −22.2 ± 0.1. They were originally identified with a photometric redshift of \${z}_{{\\rm{phot}}}={6.82}_{-0.11}^{+0.13}\$ and \${z}_{{\\rm{phot}}}={7.40}_{-0.21}^{+0.15}\$ , respectively, based on deep ground based optical and near-infrared (NIR) data. The ALMA observations were carried out on 24 and 29 November 2019, targeting the singly ionized carbon emission line, [C ii ] 158 μm and dust continuum emission with a frequency coverage of the vast majority of the photometric redshift probability distribution. The ALMA observations reached emission line sensitivities of 0.19 mJy beam −1 and 0.16 mJy beam −1 per 100 km s –1 spectral element for REBELS-29 and REBELS-12, respectively. This resulted in clear [C ii ] emission line detections of both sources, at frequencies perfectly consistent with the photometric redshift estimations (see Fig. 1 and Extended Data Fig. 1 ). The integrated flux densities of these lines are 0.44 Jy kms −1 and 1.20 Jy kms −1 corresponding to point source detection significances of 9.2 σ and 6.3 σ , respectively. These lines yield a spectroscopic redshift of z = 6.6847 ± 0.0002 and z = 7.347 ± 0.001 for REBELS-29 and REBELS-12, respectively. Fig. 1: [C ii ] 158 μm line and dust emission detections. a , REBELS-29 field at z ≈ 6.68. b , REBELS-12 field at z ≈ 7.35. Background images are HST F140W and VIDEO J-band, respectively. Black circles show the half power beam widths of each ALMA pointing (~13 arcsec radius), and white squares indicate 6.5-arcsec-wide boxes that are shown in the middle panels. White horizontal bars correspond to 10 pkpc. Solid red and light blue contours show 2 σ to 5 σ levels (and −5 σ to −2 σ for dashed contours) for the continuum and [C ii ] moment-0 maps, respectively. The continuum subtracted [C ii ] spectra are shown at the native velocity resolution of 20 km s –1 . The two sources REBELS-29-2 and REBELS-12-2 were found serendipitously as companions to the central, UV-luminous targets, with emission lines at almost exactly the same frequencies as the central targets, accompanied with dust continuum emission at the same location. Their spatial and spectral proximity, and absence in optical/NIR images confirms these companions as unexpected, dusty star-forming sources in the epoch of reionization. Full size image The [C ii ] line integrated maps of these galaxies revealed two strong, serendipitous emission lines at ~7.4 and ~11.5 arcsec offset from the primary targets, corresponding to 40 pkpc (proper kiloparsecs) and 58 pkpc, respectively. The continuum subtracted spectra then confirmed that the additional emission lines emerge at almost exactly the same frequency as the central targets (velocity offsets of 110 km s –1 and 210 km s –1 for REBELS-29 and REBELS-12, respectively; see right panels of Fig. 1 ). Hereafter, we call these additional line sources REBELS-12-2 and REBELS-29-2. After correcting for the primary beam attenuation, these emission lines have integrated flux densities of 0.781 Jy kms −1 and 0.581 Jy kms −1 , corresponding to a detection significance of 9.7 σ and 6.8 σ in the moment-0 maps for REBELS-29-2 and REBELS-12-2, respectively. Additionally, REBELS-29-2 has a clear (9.2 σ ) dust continuum detection, while only a tentative (2.8 σ ) continuum signal is found for REBELS-12-2. These measurements correspond to flux densities of 192 ± 25 μJy and 110 ± 52 μJy after applying primary beam and cosmic microwave background (CMB) corrections, respectively (see Extended Data Table 1 ). Given the significance of the emission line detections and the number of independent beams in the moment-0 maps, the probability of a random Gaussian noise fluctuation is negligible. Furthermore, the co-spatial continuum signals confirm that these blind line detections are real. In the Methods, we estimate the probability of finding an unassociated, random emission line almost exactly at the same frequency as a primary one in an ALMA data cube to be extremely small ( p < 6 × 10 −4 ). Therefore, this strongly suggests that these serendipitous detections stem from neighbouring sources", "role": "user" }, { "content": "When astronomers peer deep into the night sky, they observe what the universe looked like a long time ago. Because the speed of light is finite, studying the most distant observable galaxies allows us to glimpse billions of years into the past when the universe was very young and galaxies had just started to form stars. Studying this \"early universe\" is one of the last frontiers in astronomy and is essential for constructing accurate and consistent astrophysics models. A key goal of scientists is to identify all the galaxies in the first billion years of cosmic history and to measure the rate at which galaxies were growing by forming new stars. Various efforts have been made over the past decades to observe distant galaxies, which are characterized by electromagnetic emissions that become strongly redshifted (shifted towards longer wavelengths) before reaching the Earth. So far, our knowledge of early galaxies has mostly relied on observations with the Hubble Space Telescope (HST) and large ground-based telescopes, which probe their ultra-violet (UV) emission. However, recently, astronomers have started to use the unique capability of the Atacama Large Millimeter/submillimeter Array (ALMA) telescope to study distant galaxies at submillimeter wavelengths. This could be particularly useful for studying dusty galaxies missed in the HST surveys due to the dust absorbing UV emission. Since ALMA observes in submillimeter wavelengths, it can detect these galaxies by observing the dust emissions instead. In an ongoing large program called REBELS (Reionization-Era Bright Emission Line Survey), astronomers are using ALMA to observe the emissions of 40 target galaxies at cosmic dawn. Using this dataset, they have recently discovered that the regions around some of these galaxies contain more than meets the eye. While analyzing the observed data for two REBELS galaxies, Dr. Yoshinobu Fudamoto of the Research Institute for Science and Engineering at Waseda University, Japan, and the National Astronomical Observatory of Japan (NAOJ), noticed strong emission by dust and singly ionized carbon in positions substantially offset from the initial targets. To his surprise, even highly sensitive equipment like the HST couldn't detect any UV emission from these locations. To understand these mysterious signals, Fudamoto and his colleagues investigated matters further. In their latest paper published in Nature, they presented a thorough analysis, revealing that these unexpected emissions came from two previously unknown galaxies located near the two original REBELS targets. These galaxies are not visible in the UV or visible wavelengths as they are almost completely obscured by cosmic dust. One of them represents the most distant dust-obscured galaxy discovered so far. Distant galaxies imaged with ALMA, the Hubble Space Telescope, and the European Southern Observatory’s VISTA telescope. Green and orange colors represent radiations from ionized carbon atoms and dust particles, respectively, observed with ALMA, and blue represents near-infrared radiation observed with VISTA and Hubble Space Telescopes. REBELS-12 and REBELS-29 detected both near-infrared radiation and radiation from ionized carbon atoms and dust. On the other hand, REBELS-12-2 and REBELS-29-2 have not been detected in the near-infrared, which suggests that these galaxies are deeply buried in dust. Credit: ALMA (ESO/NAOJ/NRAO), NASA/ESA Hubble Space Telescope, ESO, Fudamoto et al. What is most surprising about this serendipitous finding is that the newly discovered galaxies, which formed more than 13 billion years ago, are not strange at all when compared with typical galaxies at the same epoch. \"These new galaxies were missed not because they are extremely rare, but only because they are completely dust-obscured,\" explains Fudamoto. However, it is uncommon to find such \"dusty\" galaxies in the early period of the universe (less than 1 billion years after the Big Bang), suggesting that the current census of early galaxy formation is most likely incomplete, and would call for deeper, blind surveys. \"It is possible that we have been missing up to one out of every five galaxies in the early universe so far,\" Fudamoto adds. The researchers expect that the unprecedented capability of the James Webb Space Telescope (JWST) and its strong synergy with ALMA would lead to significant advances in this field in the coming years. \"Completing our census of early galaxies with the currently missing dust-obscured galaxies, like the ones we found this time, will be one of the main objectives of JWST and ALMA surveys in the near future,\" says Pascal Oesch from University of Geneva. Scientists serendipitously discover two heavily dust-enshrouded galaxies that formed when the Universe was only 5% of its present age. Credit: Waseda University Overall, this study constitutes an important step in uncovering when the very first galaxies started to form in the early universe, which in turn shall help us understand where we are standing today. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Over the past decades, rest-frame ultraviolet (UV) observations have provided large samples of UV luminous galaxies at redshift ( z ) greater than 6 (refs. 1 , 2 , 3 ), during the so-called epoch of reionization. While a few of these UV-identified galaxies revealed substantial dust reservoirs 4 , 5 , 6 , 7 , very heavily dust-obscured sources at these early times have remained elusive. They are limited to a rare population of extreme starburst galaxies 8 , 9 , 10 , 11 , 12 and companions of rare quasars 13 , 14 . These studies conclude that the contribution of dust-obscured galaxies to the cosmic star formation rate density at z > 6 is sub-dominant. Recent ALMA and Spitzer observations have identified a more abundant, less extreme population of obscured galaxies at z = 3−6 (refs. 15 , 16 ). However, this population has not been confirmed in the reionization epoch so far. Here, we report the discovery of two dust-obscured star-forming galaxies at z = 6.6813 ± 0.0005 and z = 7.3521 ± 0.0005. These objects are not detected in existing rest-frame UV data and were discovered only through their far-infrared [C ii ] lines and dust continuum emission as companions to typical UV-luminous galaxies at the same redshift. The two galaxies exhibit lower infrared luminosities and star-formation rates than extreme starbursts, in line with typical star-forming galaxies at z ≈ 7. This population of heavily dust-obscured galaxies appears to contribute 10–25% to the z > 6 cosmic star formation rate density. Main As part of the ongoing ALMA large program REBELS (Reionization-Era Bright Emission Line Survey), we are observing 40 UV-luminous primary targets at z > 6.5 (ref. 17 ). Among these targets are REBELS-12 and REBELS-29. When inspecting the ALMA data cube of these two sources, we identified two additional emission line neighbours. The primary targets of our ALMA observing program, REBELS-12 and REBELS-29, represent some of the most UV-luminous galaxies in this redshift range, and have M UV = −22.5 ± 0.3 and −22.2 ± 0.1. They were originally identified with a photometric redshift of ${z}_{{\rm{phot}}}={6.82}_{-0.11}^{+0.13}$ and ${z}_{{\rm{phot}}}={7.40}_{-0.21}^{+0.15}$ , respectively, based on deep ground based optical and near-infrared (NIR) data. The ALMA observations were carried out on 24 and 29 November 2019, targeting the singly ionized carbon emission line, [C ii ] 158 μm and dust continuum emission with a frequency coverage of the vast majority of the photometric redshift probability distribution. The ALMA observations reached emission line sensitivities of 0.19 mJy beam −1 and 0.16 mJy beam −1 per 100 km s –1 spectral element for REBELS-29 and REBELS-12, respectively. This resulted in clear [C ii ] emission line detections of both sources, at frequencies perfectly consistent with the photometric redshift estimations (see Fig. 1 and Extended Data Fig. 1 ). The integrated flux densities of these lines are 0.44 Jy kms −1 and 1.20 Jy kms −1 corresponding to point source detection significances of 9.2 σ and 6.3 σ , respectively. These lines yield a spectroscopic redshift of z = 6.6847 ± 0.0002 and z = 7.347 ± 0.001 for REBELS-29 and REBELS-12, respectively. Fig. 1: [C ii ] 158 μm line and dust emission detections. a , REBELS-29 field at z ≈ 6.68. b , REBELS-12 field at z ≈ 7.35. Background images are HST F140W and VIDEO J-band, respectively. Black circles show the half power beam widths of each ALMA pointing (~13 arcsec radius), and white squares indicate 6.5-arcsec-wide boxes that are shown in the middle panels. White horizontal bars correspond to 10 pkpc. Solid red and light blue contours show 2 σ to 5 σ levels (and −5 σ to −2 σ for dashed contours) for the continuum and [C ii ] moment-0 maps, respectively. The continuum subtracted [C ii ] spectra are shown at the native velocity resolution of 20 km s –1 . The two sources REBELS-29-2 and REBELS-12-2 were found serendipitously as companions to the central, UV-luminous targets, with emission lines at almost exactly the same frequencies as the central targets, accompanied with dust continuum emission at the same location. Their spatial and spectral proximity, and absence in optical/NIR images confirms these companions as unexpected, dusty star-forming sources in the epoch of reionization. Full size image The [C ii ] line integrated maps of these galaxies revealed two strong, serendipitous emission lines at ~7.4 and ~11.5 arcsec offset from the primary targets, corresponding to 40 pkpc (proper kiloparsecs) and 58 pkpc, respectively. The continuum subtracted spectra then confirmed that the additional emission lines emerge at almost exactly the same frequency as the central targets (velocity offsets of 110 km s –1 and 210 km s –1 for REBELS-29 and REBELS-12, respectively; see right panels of Fig. 1 ). Hereafter, we call these additional line sources REBELS-12-2 and REBELS-29-2. After correcting for the primary beam attenuation, these emission lines have integrated flux densities of 0.781 Jy kms −1 and 0.581 Jy kms −1 , corresponding to a detection significance of 9.7 σ and 6.8 σ in the moment-0 maps for REBELS-29-2 and REBELS-12-2, respectively. Additionally, REBELS-29-2 has a clear (9.2 σ ) dust continuum detection, while only a tentative (2.8 σ ) continuum signal is found for REBELS-12-2. These measurements correspond to flux densities of 192 ± 25 μJy and 110 ± 52 μJy after applying primary beam and cosmic microwave background (CMB) corrections, respectively (see Extended Data Table 1 ). Given the significance of the emission line detections and the number of independent beams in the moment-0 maps, the probability of a random Gaussian noise fluctuation is negligible. Furthermore, the co-spatial continuum signals confirm that these blind line detections are real. In the Methods, we estimate the probability of finding an unassociated, random emission line almost exactly at the same frequency as a primary one in an ALMA data cube to be extremely small ( p < 6 × 10 −4 ). Therefore, this strongly suggests that these serendipitous detections stem from neighbouring sources<|im_end|> <|im_start|>assistant When astronomers peer deep into the night sky, they observe what the universe looked like a long time ago. Because the speed of light is finite, studying the most distant observable galaxies allows us to glimpse billions of years into the past when the universe was very young and galaxies had just started to form stars. Studying this "early universe" is one of the last frontiers in astronomy and is essential for constructing accurate and consistent astrophysics models. A key goal of scientists is to identify all the galaxies in the first billion years of cosmic history and to measure the rate at which galaxies were growing by forming new stars. Various efforts have been made over the past decades to observe distant galaxies, which are characterized by electromagnetic emissions that become strongly redshifted (shifted towards longer wavelengths) before reaching the Earth. So far, our knowledge of early galaxies has mostly relied on observations with the Hubble Space Telescope (HST) and large ground-based telescopes, which probe their ultra-violet (UV) emission. However, recently, astronomers have started to use the unique capability of the Atacama Large Millimeter/submillimeter Array (ALMA) telescope to study distant galaxies at submillimeter wavelengths. This could be particularly useful for studying dusty galaxies missed in the HST surveys due to the dust absorbing UV emission. Since ALMA observes in submillimeter wavelengths, it can detect these galaxies by observing the dust emissions instead. In an ongoing large program called REBELS (Reionization-Era Bright Emission Line Survey), astronomers are using ALMA to observe the emissions of 40 target galaxies at cosmic dawn. Using this dataset, they have recently discovered that the regions around some of these galaxies contain more than meets the eye. While analyzing the observed data for two REBELS galaxies, Dr. Yoshinobu Fudamoto of the Research Institute for Science and Engineering at Waseda University, Japan, and the National Astronomical Observatory of Japan (NAOJ), noticed strong emission by dust and singly ionized carbon in positions substantially offset from the initial targets. To his surprise, even highly sensitive equipment like the HST couldn't detect any UV emission from these locations. To understand these mysterious signals, Fudamoto and his colleagues investigated matters further. In their latest paper published in Nature, they presented a thorough analysis, revealing that these unexpected emissions came from two previously unknown galaxies located near the two original REBELS targets. These galaxies are not visible in the UV or visible wavelengths as they are almost completely obscured by cosmic dust. One of them represents the most distant dust-obscured galaxy discovered so far. Distant galaxies imaged with ALMA, the Hubble Space Telescope, and the European Southern Observatory’s VISTA telescope. Green and orange colors represent radiations from ionized carbon atoms and dust particles, respectively, observed with ALMA, and blue represents near-infrared radiation observed with VISTA and Hubble Space Telescopes. REBELS-12 and REBELS-29 detected both near-infrared radiation and radiation from ionized carbon atoms and dust. On the other hand, REBELS-12-2 and REBELS-29-2 have not been detected in the near-infrared, which suggests that these galaxies are deeply buried in dust. Credit: ALMA (ESO/NAOJ/NRAO), NASA/ESA Hubble Space Telescope, ESO, Fudamoto et al. What is most surprising about this serendipitous finding is that the newly discovered galaxies, which formed more than 13 billion years ago, are not strange at all when compared with typical galaxies at the same epoch. "These new galaxies were missed not because they are extremely rare, but only because they are completely dust-obscured," explains Fudamoto. However, it is uncommon to find such "dusty" galaxies in the early period of the universe (less than 1 billion years after the Big Bang), suggesting that the current census of early galaxy formation is most likely incomplete, and would call for deeper, blind surveys. "It is possible that we have been missing up to one out of every five galaxies in the early universe so far," Fudamoto adds. The researchers expect that the unprecedented capability of the James Webb Space Telescope (JWST) and its strong synergy with ALMA would lead to significant advances in this field in the coming years. "Completing our census of early galaxies with the currently missing dust-obscured galaxies, like the ones we found this time, will be one of the main objectives of JWST and ALMA surveys in the near future," says Pascal Oesch from University of Geneva. Scientists serendipitously discover two heavily dust-enshrouded galaxies that formed when the Universe was only 5% of its present age. Credit: Waseda University Overall, this study constitutes an important step in uncovering when the very first galaxies started to form in the early universe, which in turn shall help us understand where we are standing today. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential. Main Nanomaterials designed to target cancer may hold therapeutic potential by enhancing the delivery of therapeutics 1 , 2 , 3 , 4 , but their interactions with cancer in animal models and their long-term effects on cells remain poorly understood 5 , 6 , 7 , 8 , 9 . To examine the effects of nanoparticle ingestion on cells, we used ∼ 6 nm surface-functionalized poly(ethylene glycol)-coated (PEGylated) near-infrared (NIR) fluorescent silica nanoparticles, referred to as Cornell dots (C dots), with diameters controllable down to the sub-10 nm range, as reported in detail elsewhere 10 . This FDA Investigational New Drug (IND)-approved hybrid organo-silica particle was previously shown to be a promising cancer molecular imaging agent in metastatic melanoma patients after functionalizing its surface with α v β 3 -integrin-targeting peptides and radiolabels 2 , 11 . Preferential accumulation was observed within integrin-expressing primary and/or metastatic melanomatous lesions in human subjects and animal melanoma models 11 , 12 , while at the same time demonstrating rapid renal clearance. Given its potential clinical utility and its early adaptation for drug delivery applications 13 , we initially performed detailed cell biological studies using the latest generation of C dots, synthesized in water, referred to as C′ dots 10 , surface-functionalized with a 14 mer peptide analogue, alpha-melanocyte stimulating hormone (αMSH) 14 , which targets a different surface receptor expressed on malignant melanoma cells (melanocortin-1 receptor, MC1-R). The resulting αMSH-PEG-C′ dots ( Fig. 1a ) were used here to determine whether alterations in cell survival occurred in cancer cell lines and tumour xenografts over a wide dose range relative to that seen under control conditions and whether cellular pathways were modulated by particle ingestion. Figure 1: αMSH-PEG-C′-dot particles and their localization to lysosomal networks. a , Silica-based and ultrasmall αMSH-PEG-C′ dots of 6-nm-diameter silica-based particles with a fluorescent (Cy5 encapsulated) core and polyethylene glycol (PEG) coating and alpha melanocyte-stimulating hormone (αMSH)-modified exterior. b , αMSH-PEG-C′ dots localize to lysosomal networks in cells. M21 melanoma cells expressing LAMP1-GFP (green) were treated with αMSH-PEG-C′ dots (15 µM) for 24 h. Note co-localization between nanoparticles (Cy5 fluorescence, pseudo-coloured red) and LAMP1-GFP in the merged image. Scale bar, 10 µm. Full size image αMSH-PEG-C′ dots reside in lysosomes and are well tolerated Live imaging of MC1-R-expressing human melanoma cells (M21) treated with particles for 24 h revealed co-localization of fluorescent αMSH-PEG-C′ dots with lysosomes, the latter visualized by expression of a green fluorescent protein (GFP)-tagged lysosomal-associated membrane protein 1 (LAMP1), indicating that ingested particles reside in lysosomal or late endosomal networks ( Fig. 1b ). M21 cells treated with increasing concentrations of αMSH-PEG-C′ dots up to 15 µM showed similar survival and proliferation rates to control cells ( Fig. 2a ), demonstrating that incubation at even high particle concentrations is well tolerated. We next examined if lysosomes were functioning properly within cells treated with αMSH-PEG-C′ dots. To determine this, we examined the autophagy pathway, which targets intracellular substrates for lysosomal degradation. Autophagy was examined by quantifying the basal levels and turnover rates of the autophagy protein microtubule-associated protein 1 light chain 3 (LC3), which is lipidated onto autophagosomal membranes and becomes degraded following the fusion of autophagosomes with lysosomes 15 . The accumulation of the autophagosome-associated, lipidated form of LC3, or LC3-II, identified by its faster electrophoretic mobility in SDS–polyacrylamide gel electrophoresis (PAGE) relative to the non-lipidated form, LC3-I, can be quantified as a measure of autophagy induction or flux through lysosomes 15 . Cells treated with increasing concentrations of αMSH-PEG-C′ dots for 24 h, from 0.15 to 15 µM, had similar relative LC3-II levels as control cells, suggesting that autophagy is not induced or perturbed by nanoparticle treatment ( Fig. 2b ). Importantly, the treatment of cells with a lysosomal inhibitor, concanamycin A (ConA), which inhibits lysosome function by raising pH, and blocks autophagosome degradation, resulted in a similar accumulation of LC3-II in particle-treated cells as compared to controls, demonstrating that lysosomes are functioning properly even when cells are loaded with high concentrations of αMSH-PEG-C′ dots ( Fig. 2b ). Figure 2: αMSH-PEG-C′ dot particles induce cell death in amino-acid-deprived conditions. a , Nanoparticles are well tolerated in nutrient-replete media. Images show M21 cells treated with the indicated αMSH-PEG-C′ dot concentrations and cultured for 40 h. Nanoparticles had no significant effect on cell survival (left graph) or cell proliferation (right graph), as quantified by time-lapse microscopy-based tracking of individual cell fates. Error bars indicate mean ± standard error of the mean. n = 3 biological experiments, with five independent fields of view for each. Supplementary Fig. 6a,b shows individual experimental values. Scale bar, 10 µm. b , Autophagy and lysosome function in nanoparticle-treated cells are unperturbed. Western blot shows LC3-I and -II in cells treated with increasing doses of αMSH-PEG-C′ dots for 24 h compared to untreated (Full media) and amino-acid-starved (AA-st) cells, in the presence (+) and absence (−) of the lysosome inhibitor concanamycin A (ConA, 1 h at 100 nM). Levels of LC3-II (left graph) are unaltered by nanoparticle treatment, and ConA-inducible LC3-II accumulation (right graph), a measure of autophagy flux, is similar in treated and untreated cells. Error bars indicate mean ± standard error of the mean. n = 3 biological replicates for each group. Supplementary Fig. 6c,d shows", "role": "user" }, { "content": "Nanoparticles known as Cornell dots, or C dots, have shown great promise as a therapeutic tool in the detection and treatment of cancer. Now, the ultrasmall particles – developed more than a dozen years ago by Ulrich Wiesner, the Spencer T. Olin Professor of Engineering – have shown they can do something even better: kill cancer cells without attaching a cytotoxic drug. A study led by Michelle Bradbury, director of intraoperative imaging at Memorial Sloan Kettering Cancer Center and associate professor of radiology at Weill Cornell Medicine, and Michael Overholtzer, cell biologist at MSKCC, in collaboration with Wiesner has thrown a surprising twist into the decadelong quest to bring C dots out of the lab and into use as a clinical therapy. Their paper, \"Ultrasmall Nanoparticles Induce Ferroptosis of Nutrient-Deprived Cancer Cells and Suppress Tumor Growth,\" was published Sept. 26 in Nature Nanotechnology. The work details how C dots, administered in large doses and with the tumors in a state of nutrient deprivation, trigger a type of cell death called ferroptosis. \"If you had to design a nanoparticle for killing cancer, this would be exactly the way you would do it,\" Wiesner said. \"The particle is well tolerated in normally healthy tissue, but as soon as you have a tumor, and under very specific conditions, these particles become killers.\" \"In fact,\" Bradbury said, \"this is the first time we have shown that the particle has intrinsic therapeutic properties.\" Wiesner's fluorescent silica particles, as small as 5 nanometers in diameter, were originally designed to be used as diagnostic tools, attaching to cancer cells and lighting up to show a surgeon where the tumor cells are. Potential uses also included drug delivery and environmental sensing. A first-in-human clinical trial by the Food and Drug Administration, led by Bradbury, deemed the particles safe for humans. In further testing of the particles over the last five years – including the last 13 months as a member of the Centers of Cancer Nanotechnology Excellence, a National Cancer Institute initiative established in August 2015 – Bradbury, Overholtzer, Wiesner and their collaborators made this major, unexpected finding. When incubated with cancer cells at high doses – and, importantly, with cancer cells in a state of nutrient deprivation – Wiesner's peptide-coated C dots show the ability to adsorb iron from the environment and deliver this into cancer cells. The peptide, called alpha-MSH, was developed by Thomas Quinn, professor of biochemistry at the University of Missouri. This process triggers ferroptosis, a necrotic form of cell death involving plasma membrane rupture – different from the typical cell fragmentation found during a more commonly observed form of cell death called apoptosis. \"The original purpose for studying the dots in cells was to see how well larger concentrations would be tolerated without altering cellular function,\" Overholtzer said. \"While high concentrations were well-tolerated under normal conditions, we wanted to also know how cancer cells under stress might respond.\" To the group's surprise, in 24 to 48 hours after the cancer cells were exposed to the dots, there was a \"wave of destruction\" throughout the entire cell culture, Wiesner said. Tumors also shrank when mice were administered multiple high dose injections without any adverse reactions, said Bradbury, co-director with Wiesner of the MSKCC-Cornell Center for Translation of Cancer Nanomedicines. In the ongoing fight against a disease that kills millions worldwide annually – cancer has taken several in Wiesner's family, making this also a personal crusade for him. Having another weapon can only help, Wiesner said. \"We've found another tool that people have not thought about at all so far,\" he said. \"This has changed our way of thinking about nanoparticles and what they could potentially do.\" Future work will focus on utilizing these particles in combination with other standard therapies for a given tumor type, Bradbury said, with the hope of further enhancing efficacy before testing in humans. Researchers will also look to tailor the particle to target specific cancers. \"It's a matter of designing the particles with different attachments on them, so they'll bind to the particular cancer we're after,\" Overholtzer said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential. Main Nanomaterials designed to target cancer may hold therapeutic potential by enhancing the delivery of therapeutics 1 , 2 , 3 , 4 , but their interactions with cancer in animal models and their long-term effects on cells remain poorly understood 5 , 6 , 7 , 8 , 9 . To examine the effects of nanoparticle ingestion on cells, we used ∼ 6 nm surface-functionalized poly(ethylene glycol)-coated (PEGylated) near-infrared (NIR) fluorescent silica nanoparticles, referred to as Cornell dots (C dots), with diameters controllable down to the sub-10 nm range, as reported in detail elsewhere 10 . This FDA Investigational New Drug (IND)-approved hybrid organo-silica particle was previously shown to be a promising cancer molecular imaging agent in metastatic melanoma patients after functionalizing its surface with α v β 3 -integrin-targeting peptides and radiolabels 2 , 11 . Preferential accumulation was observed within integrin-expressing primary and/or metastatic melanomatous lesions in human subjects and animal melanoma models 11 , 12 , while at the same time demonstrating rapid renal clearance. Given its potential clinical utility and its early adaptation for drug delivery applications 13 , we initially performed detailed cell biological studies using the latest generation of C dots, synthesized in water, referred to as C′ dots 10 , surface-functionalized with a 14 mer peptide analogue, alpha-melanocyte stimulating hormone (αMSH) 14 , which targets a different surface receptor expressed on malignant melanoma cells (melanocortin-1 receptor, MC1-R). The resulting αMSH-PEG-C′ dots ( Fig. 1a ) were used here to determine whether alterations in cell survival occurred in cancer cell lines and tumour xenografts over a wide dose range relative to that seen under control conditions and whether cellular pathways were modulated by particle ingestion. Figure 1: αMSH-PEG-C′-dot particles and their localization to lysosomal networks. a , Silica-based and ultrasmall αMSH-PEG-C′ dots of 6-nm-diameter silica-based particles with a fluorescent (Cy5 encapsulated) core and polyethylene glycol (PEG) coating and alpha melanocyte-stimulating hormone (αMSH)-modified exterior. b , αMSH-PEG-C′ dots localize to lysosomal networks in cells. M21 melanoma cells expressing LAMP1-GFP (green) were treated with αMSH-PEG-C′ dots (15 µM) for 24 h. Note co-localization between nanoparticles (Cy5 fluorescence, pseudo-coloured red) and LAMP1-GFP in the merged image. Scale bar, 10 µm. Full size image αMSH-PEG-C′ dots reside in lysosomes and are well tolerated Live imaging of MC1-R-expressing human melanoma cells (M21) treated with particles for 24 h revealed co-localization of fluorescent αMSH-PEG-C′ dots with lysosomes, the latter visualized by expression of a green fluorescent protein (GFP)-tagged lysosomal-associated membrane protein 1 (LAMP1), indicating that ingested particles reside in lysosomal or late endosomal networks ( Fig. 1b ). M21 cells treated with increasing concentrations of αMSH-PEG-C′ dots up to 15 µM showed similar survival and proliferation rates to control cells ( Fig. 2a ), demonstrating that incubation at even high particle concentrations is well tolerated. We next examined if lysosomes were functioning properly within cells treated with αMSH-PEG-C′ dots. To determine this, we examined the autophagy pathway, which targets intracellular substrates for lysosomal degradation. Autophagy was examined by quantifying the basal levels and turnover rates of the autophagy protein microtubule-associated protein 1 light chain 3 (LC3), which is lipidated onto autophagosomal membranes and becomes degraded following the fusion of autophagosomes with lysosomes 15 . The accumulation of the autophagosome-associated, lipidated form of LC3, or LC3-II, identified by its faster electrophoretic mobility in SDS–polyacrylamide gel electrophoresis (PAGE) relative to the non-lipidated form, LC3-I, can be quantified as a measure of autophagy induction or flux through lysosomes 15 . Cells treated with increasing concentrations of αMSH-PEG-C′ dots for 24 h, from 0.15 to 15 µM, had similar relative LC3-II levels as control cells, suggesting that autophagy is not induced or perturbed by nanoparticle treatment ( Fig. 2b ). Importantly, the treatment of cells with a lysosomal inhibitor, concanamycin A (ConA), which inhibits lysosome function by raising pH, and blocks autophagosome degradation, resulted in a similar accumulation of LC3-II in particle-treated cells as compared to controls, demonstrating that lysosomes are functioning properly even when cells are loaded with high concentrations of αMSH-PEG-C′ dots ( Fig. 2b ). Figure 2: αMSH-PEG-C′ dot particles induce cell death in amino-acid-deprived conditions. a , Nanoparticles are well tolerated in nutrient-replete media. Images show M21 cells treated with the indicated αMSH-PEG-C′ dot concentrations and cultured for 40 h. Nanoparticles had no significant effect on cell survival (left graph) or cell proliferation (right graph), as quantified by time-lapse microscopy-based tracking of individual cell fates. Error bars indicate mean ± standard error of the mean. n = 3 biological experiments, with five independent fields of view for each. Supplementary Fig. 6a,b shows individual experimental values. Scale bar, 10 µm. b , Autophagy and lysosome function in nanoparticle-treated cells are unperturbed. Western blot shows LC3-I and -II in cells treated with increasing doses of αMSH-PEG-C′ dots for 24 h compared to untreated (Full media) and amino-acid-starved (AA-st) cells, in the presence (+) and absence (−) of the lysosome inhibitor concanamycin A (ConA, 1 h at 100 nM). Levels of LC3-II (left graph) are unaltered by nanoparticle treatment, and ConA-inducible LC3-II accumulation (right graph), a measure of autophagy flux, is similar in treated and untreated cells. Error bars indicate mean ± standard error of the mean. n = 3 biological replicates for each group. Supplementary Fig. 6c,d shows<|im_end|> <|im_start|>assistant Nanoparticles known as Cornell dots, or C dots, have shown great promise as a therapeutic tool in the detection and treatment of cancer. Now, the ultrasmall particles – developed more than a dozen years ago by Ulrich Wiesner, the Spencer T. Olin Professor of Engineering – have shown they can do something even better: kill cancer cells without attaching a cytotoxic drug. A study led by Michelle Bradbury, director of intraoperative imaging at Memorial Sloan Kettering Cancer Center and associate professor of radiology at Weill Cornell Medicine, and Michael Overholtzer, cell biologist at MSKCC, in collaboration with Wiesner has thrown a surprising twist into the decadelong quest to bring C dots out of the lab and into use as a clinical therapy. Their paper, "Ultrasmall Nanoparticles Induce Ferroptosis of Nutrient-Deprived Cancer Cells and Suppress Tumor Growth," was published Sept. 26 in Nature Nanotechnology. The work details how C dots, administered in large doses and with the tumors in a state of nutrient deprivation, trigger a type of cell death called ferroptosis. "If you had to design a nanoparticle for killing cancer, this would be exactly the way you would do it," Wiesner said. "The particle is well tolerated in normally healthy tissue, but as soon as you have a tumor, and under very specific conditions, these particles become killers." "In fact," Bradbury said, "this is the first time we have shown that the particle has intrinsic therapeutic properties." Wiesner's fluorescent silica particles, as small as 5 nanometers in diameter, were originally designed to be used as diagnostic tools, attaching to cancer cells and lighting up to show a surgeon where the tumor cells are. Potential uses also included drug delivery and environmental sensing. A first-in-human clinical trial by the Food and Drug Administration, led by Bradbury, deemed the particles safe for humans. In further testing of the particles over the last five years – including the last 13 months as a member of the Centers of Cancer Nanotechnology Excellence, a National Cancer Institute initiative established in August 2015 – Bradbury, Overholtzer, Wiesner and their collaborators made this major, unexpected finding. When incubated with cancer cells at high doses – and, importantly, with cancer cells in a state of nutrient deprivation – Wiesner's peptide-coated C dots show the ability to adsorb iron from the environment and deliver this into cancer cells. The peptide, called alpha-MSH, was developed by Thomas Quinn, professor of biochemistry at the University of Missouri. This process triggers ferroptosis, a necrotic form of cell death involving plasma membrane rupture – different from the typical cell fragmentation found during a more commonly observed form of cell death called apoptosis. "The original purpose for studying the dots in cells was to see how well larger concentrations would be tolerated without altering cellular function," Overholtzer said. "While high concentrations were well-tolerated under normal conditions, we wanted to also know how cancer cells under stress might respond." To the group's surprise, in 24 to 48 hours after the cancer cells were exposed to the dots, there was a "wave of destruction" throughout the entire cell culture, Wiesner said. Tumors also shrank when mice were administered multiple high dose injections without any adverse reactions, said Bradbury, co-director with Wiesner of the MSKCC-Cornell Center for Translation of Cancer Nanomedicines. In the ongoing fight against a disease that kills millions worldwide annually – cancer has taken several in Wiesner's family, making this also a personal crusade for him. Having another weapon can only help, Wiesner said. "We've found another tool that people have not thought about at all so far," he said. "This has changed our way of thinking about nanoparticles and what they could potentially do." Future work will focus on utilizing these particles in combination with other standard therapies for a given tumor type, Bradbury said, with the hope of further enhancing efficacy before testing in humans. Researchers will also look to tailor the particle to target specific cancers. "It's a matter of designing the particles with different attachments on them, so they'll bind to the particular cancer we're after," Overholtzer said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Maternal care, including by non-biological parents, is important for offspring survival 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Oxytocin 1 , 2 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress 15 . However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin. Introduction Social interactions, such as pair bond formation and child rearing, are fundamental aspects of animal and human behaviour 1 , 2 , 3 , 4 . Parental care is especially important, and is therefore believed to be at least partially innate or induced after mating. However, maternal behaviour can also be acquired from experience. In primates, including humans, non-biological parents can learn to care for children after instruction or observation of experienced caretakers and infants 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . However, it is unclear whether alloparenting can be learned from experience in other species, and what neural mechanisms might underlie maternal learning. The evolutionarily ancient hormone oxytocin is an important molecular signal for maternal behaviour 1 , 2 , 9 , 10 . In mammals, oxytocin release from the hypothalamus is associated with childbirth and lactation 10 , 11 . Oxytocin also acts in the brain to increase the salience of social information and enable alloparenting in mice 1 , 9 , 12 , 13 , 14 . Pup-naive virgin female mice initially ignore neonates and ultrasonic distress calls emitted by isolated pups 15 . However, within days of co-housing with experienced mothers (dams) and litters, most virgin females begin expressing alloparenting behaviours, including retrieving pups to the nest. Oxytocin accelerates the onset of pup retrieval, promoting plasticity in virgin auditory cortex for recognizing pup calls 15 . However, little is known about when PVN neurons in nulliparous, non-lactating adults are activated to promote alloparenting behaviour. Continuous behaviour monitoring over days Emergence of pup retrieval in co-housed virgin females provides an opportunity to monitor neural activity during interactions with adults and infants. To examine the behavioural events and neural activity patterns that lead to maternal behaviour in virgin female mice, we built a system for days-long combined behavioural and neural activity monitoring in cages of mother, litter and co-housed virgin female mice (Fig. 1a ). This system consists of an overhead camera imaging homecages with visible (daytime) and infrared light (nighttime), synchronized with ultrasonic audio recordings and amplifiers for neural recordings. We constructed ethograms 16 and quantified the frequency and duration of specific behaviours (for example, spontaneous pup retrieval and time in nest; Fig. 1b , Extended Data Fig. 1 , Supplementary Videos 1 , 2 ). We examined daily pup retrieval offline to determine when virgins began reliably responding to infant calls (Fig. 1b, c ). Fig. 1: Dams shepherd virgins to nest. a , System for continuous monitoring of behaviour and neural activity. b , Ethogram showing activities of co-housed dam and virgin mice over a period of four days. c , Co-housing with dam and pups led to earlier retrieval by virgins. Left, individual retrieval rates. Right, mean retrieval probability. d , Day of retrieval onset was earlier in D+ virgins. e , Time in nest for dams and co-housed virgin mice. f , Correlation between virgin nest entry during day 1 and virgin retrieval at the end of day 1. g , Illustration of shepherding behaviour; arrows, movement direction; dashed circle, nest area. h , Probabilities of dam starting (yellow) and ending (orange) chasing of a co-housed virgin, relative to nest position (circle indicates the nest, radius approximately 10 cm). i , Distances from nest of dam→virgin chases. j , Frequency of shepherding events (grey, individual dyads; red, daily averages across cages) was more frequent than dam→virgin chases in the absence of pups (0.2, indicated by dashed line). k , Correlation between shepherding during day 1 and virgin retrieval at day 1 end. Data are mean ± s.e.m.; * P < 0.05, ** P < 0.01. Full size image We found that the presence of the mother accelerated the onset of alloparenting in co-housed virgins. Virgins co-housed with dams and litters (D+ virgins, n = 14) began reliably retrieving (in more than 1 out of 10 trials) on day two of co-housing, earlier than virgins co-housed with pups but without dams (D− virgins, n = 10) (Fig. 1c, d , Extended Data Fig. 2a, b , Supplementary Videos 3 , 4 ; P < 0.0001). Pup retrieval was not initially performed by virgins but was reliably performed by dams regardless of litter size (Extended Data Fig. 2c ). Virgins also began to spend time in the nest with pups (Fig. 1b, e ; P < 0.0001), and the more virgins entered the nest, the more likely it was that retrieval occurred on day 1 (Fig. 1f ; r = 0.66, P = 0.009). PVN activity when dams shepherd virgins To determine how dams influenced virgin alloparenting, we analysed four days of video per cage and observed some unusual interactions between dams and virgins. First, mothers attempted to keep virgins within the nest with pups. If the virgin left the nest, the mother would escort", "role": "user" }, { "content": "Watching a mother mouse gather her pups into the family's nest trains other female mice without pups to perform the same parenting task, a new study shows. Furthermore, these observations lead to the production of oxytocin in the brains of virgin female mice, biochemically shaping their maternal behaviors even before they have pups of their own. Led by researchers at NYU Grossman School of Medicine, the new set of experiments involved round-the-clock filming of female mice interacting with their newborns as well as with virgin mice. Simultaneous electrical readings were made in several brain regions known to produce oxytocin or thought to be responding to the hormone. The research team built on its earlier studies of the so-called pleasure hormone showing that the release of oxytocin is essential not only for the onset of nursing but also for the initiating of other maternal behaviors. Publishing in the journal Nature online Aug. 11, researchers describe what they called a never-before-seen behavior in which new mouse mothers would without prompting shepherd virgin female mice into the family's nest along with their pups. Within 24 hours, the virgins began mimicking the maternal behavior of gathering the mom's pups into the nest even if the mother was not there. Almost as quickly, virgin mice would also start to perform the pup-retrieving task without any direct contact with an experienced mouse mother and after having only \"viewed\" the mother through a clear plastic window. The research team also measured brain electrical activity in virgin mice during shepherding and later when they became mothers on their own. They found that both the sight and sound of crying pups moved outside of their nest stimulated oxytocin production in a specific region of the brain, the hypothalamic paraventricular nucleus (PVN). By contrast, chemically blocking any of the visual, auditory, or oxytocin-producing PVN nerve pathways prevented virgin mice from learning to take care of pups. Mother mouse at top corrals virgin mouse (bottom) into nest in demonstration of “shepherding” behavior. Credit: NYU Langone \"Our study shows that in mice the best way to be a mom is to watch and learn from an experienced mom,\" says study senior investigator Robert Froemke, Ph.D., a professor in the Skirball Institute of Biomolecular Medicine at NYU Langone Health. \"Given the evidence, we propose that similar mechanisms operate in human mothers.\" Froemke says the study findings in rodents add scientific evidence to the benefits observed from parenting classes in humans. He says the team next plans to examine if the same tutoring relationship exists among dad mice and virgin males. \"This work redefines oxytocin's role in brain function, broadening its impact to include formidable and complex social networking activities that force the brain to pay attention and adapt to its surroundings at the time, whether it's reacting to the sound of a pup's cries or feelings of happiness,\" says Froemke, who also serves as a professor in the departments of Otolaryngology-Head and Neck Surgery, and Neuroscience and Physiology at NYU Langone. As part of the ongoing study, researchers analyzed nearly 5,000 hours (over six months) of video footage of several dozen mother mice interacting with their pups and with virgin mice. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Maternal care, including by non-biological parents, is important for offspring survival 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Oxytocin 1 , 2 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress 15 . However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin. Introduction Social interactions, such as pair bond formation and child rearing, are fundamental aspects of animal and human behaviour 1 , 2 , 3 , 4 . Parental care is especially important, and is therefore believed to be at least partially innate or induced after mating. However, maternal behaviour can also be acquired from experience. In primates, including humans, non-biological parents can learn to care for children after instruction or observation of experienced caretakers and infants 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . However, it is unclear whether alloparenting can be learned from experience in other species, and what neural mechanisms might underlie maternal learning. The evolutionarily ancient hormone oxytocin is an important molecular signal for maternal behaviour 1 , 2 , 9 , 10 . In mammals, oxytocin release from the hypothalamus is associated with childbirth and lactation 10 , 11 . Oxytocin also acts in the brain to increase the salience of social information and enable alloparenting in mice 1 , 9 , 12 , 13 , 14 . Pup-naive virgin female mice initially ignore neonates and ultrasonic distress calls emitted by isolated pups 15 . However, within days of co-housing with experienced mothers (dams) and litters, most virgin females begin expressing alloparenting behaviours, including retrieving pups to the nest. Oxytocin accelerates the onset of pup retrieval, promoting plasticity in virgin auditory cortex for recognizing pup calls 15 . However, little is known about when PVN neurons in nulliparous, non-lactating adults are activated to promote alloparenting behaviour. Continuous behaviour monitoring over days Emergence of pup retrieval in co-housed virgin females provides an opportunity to monitor neural activity during interactions with adults and infants. To examine the behavioural events and neural activity patterns that lead to maternal behaviour in virgin female mice, we built a system for days-long combined behavioural and neural activity monitoring in cages of mother, litter and co-housed virgin female mice (Fig. 1a ). This system consists of an overhead camera imaging homecages with visible (daytime) and infrared light (nighttime), synchronized with ultrasonic audio recordings and amplifiers for neural recordings. We constructed ethograms 16 and quantified the frequency and duration of specific behaviours (for example, spontaneous pup retrieval and time in nest; Fig. 1b , Extended Data Fig. 1 , Supplementary Videos 1 , 2 ). We examined daily pup retrieval offline to determine when virgins began reliably responding to infant calls (Fig. 1b, c ). Fig. 1: Dams shepherd virgins to nest. a , System for continuous monitoring of behaviour and neural activity. b , Ethogram showing activities of co-housed dam and virgin mice over a period of four days. c , Co-housing with dam and pups led to earlier retrieval by virgins. Left, individual retrieval rates. Right, mean retrieval probability. d , Day of retrieval onset was earlier in D+ virgins. e , Time in nest for dams and co-housed virgin mice. f , Correlation between virgin nest entry during day 1 and virgin retrieval at the end of day 1. g , Illustration of shepherding behaviour; arrows, movement direction; dashed circle, nest area. h , Probabilities of dam starting (yellow) and ending (orange) chasing of a co-housed virgin, relative to nest position (circle indicates the nest, radius approximately 10 cm). i , Distances from nest of dam→virgin chases. j , Frequency of shepherding events (grey, individual dyads; red, daily averages across cages) was more frequent than dam→virgin chases in the absence of pups (0.2, indicated by dashed line). k , Correlation between shepherding during day 1 and virgin retrieval at day 1 end. Data are mean ± s.e.m.; * P < 0.05, ** P < 0.01. Full size image We found that the presence of the mother accelerated the onset of alloparenting in co-housed virgins. Virgins co-housed with dams and litters (D+ virgins, n = 14) began reliably retrieving (in more than 1 out of 10 trials) on day two of co-housing, earlier than virgins co-housed with pups but without dams (D− virgins, n = 10) (Fig. 1c, d , Extended Data Fig. 2a, b , Supplementary Videos 3 , 4 ; P < 0.0001). Pup retrieval was not initially performed by virgins but was reliably performed by dams regardless of litter size (Extended Data Fig. 2c ). Virgins also began to spend time in the nest with pups (Fig. 1b, e ; P < 0.0001), and the more virgins entered the nest, the more likely it was that retrieval occurred on day 1 (Fig. 1f ; r = 0.66, P = 0.009). PVN activity when dams shepherd virgins To determine how dams influenced virgin alloparenting, we analysed four days of video per cage and observed some unusual interactions between dams and virgins. First, mothers attempted to keep virgins within the nest with pups. If the virgin left the nest, the mother would escort<|im_end|> <|im_start|>assistant Watching a mother mouse gather her pups into the family's nest trains other female mice without pups to perform the same parenting task, a new study shows. Furthermore, these observations lead to the production of oxytocin in the brains of virgin female mice, biochemically shaping their maternal behaviors even before they have pups of their own. Led by researchers at NYU Grossman School of Medicine, the new set of experiments involved round-the-clock filming of female mice interacting with their newborns as well as with virgin mice. Simultaneous electrical readings were made in several brain regions known to produce oxytocin or thought to be responding to the hormone. The research team built on its earlier studies of the so-called pleasure hormone showing that the release of oxytocin is essential not only for the onset of nursing but also for the initiating of other maternal behaviors. Publishing in the journal Nature online Aug. 11, researchers describe what they called a never-before-seen behavior in which new mouse mothers would without prompting shepherd virgin female mice into the family's nest along with their pups. Within 24 hours, the virgins began mimicking the maternal behavior of gathering the mom's pups into the nest even if the mother was not there. Almost as quickly, virgin mice would also start to perform the pup-retrieving task without any direct contact with an experienced mouse mother and after having only "viewed" the mother through a clear plastic window. The research team also measured brain electrical activity in virgin mice during shepherding and later when they became mothers on their own. They found that both the sight and sound of crying pups moved outside of their nest stimulated oxytocin production in a specific region of the brain, the hypothalamic paraventricular nucleus (PVN). By contrast, chemically blocking any of the visual, auditory, or oxytocin-producing PVN nerve pathways prevented virgin mice from learning to take care of pups. Mother mouse at top corrals virgin mouse (bottom) into nest in demonstration of “shepherding” behavior. Credit: NYU Langone "Our study shows that in mice the best way to be a mom is to watch and learn from an experienced mom," says study senior investigator Robert Froemke, Ph.D., a professor in the Skirball Institute of Biomolecular Medicine at NYU Langone Health. "Given the evidence, we propose that similar mechanisms operate in human mothers." Froemke says the study findings in rodents add scientific evidence to the benefits observed from parenting classes in humans. He says the team next plans to examine if the same tutoring relationship exists among dad mice and virgin males. "This work redefines oxytocin's role in brain function, broadening its impact to include formidable and complex social networking activities that force the brain to pay attention and adapt to its surroundings at the time, whether it's reacting to the sound of a pup's cries or feelings of happiness," says Froemke, who also serves as a professor in the departments of Otolaryngology-Head and Neck Surgery, and Neuroscience and Physiology at NYU Langone. As part of the ongoing study, researchers analyzed nearly 5,000 hours (over six months) of video footage of several dozen mother mice interacting with their pups and with virgin mice. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1 HIGH and MAFA HIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1 HIGH and MAFA HIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca 2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function. Introduction Type 2 diabetes mellitus (T2DM) occurs when β-cells are unable to release enough insulin to compensate for insulin resistance. At the cellular level, glucose-regulated insulin secretion depends upon generation of ATP/ADP, closure of ATP-sensitive K + (K ATP ) channels, opening of voltage-dependent Ca 2+ channels (VDCC) and exocytosis of insulin granules 1 . At the multicellular level, insulin release is a tightly controlled process, requiring hundreds of β-cells throughout the islet to coordinate their activities in response to diverse stimuli including glucose, incretins and fatty acids 2 , 3 . Our current understanding of the mechanisms underlying insulin release is mainly derived from experiments in single β-cells or measures averaged across the entire β-cell complement. However, such studies, which generally view β-cells as a tightly coupled system, are difficult to reconcile with the known heterogeneous nature of β-cell identity and function. Based on transcriptomic 4 , 5 and protein signatures 6 , marker analyses 7 , 8 , 9 , glucose-responsiveness 10 , 11 , reporter imaging 12 , 13 , 14 , 15 or single molecule hybridization 16 , β-cell subpopulations have been shown to exist with altered maturity states, metabolism, electrical activity, insulin secretion and proliferative capacity (reviewed in 17 , 18 ). Of note, β-cell subpopulations are highly plastic. During aging and T2DM, β-cells with reduced maturity, metabolism and insulin secretion, but enhanced proliferative capacity, typically increase in proportion in both rodent and human 4 , 7 , 8 . At the same time, there is an increase in the number of mature, secretory β-cells that display poorer proliferative capacity 6 , 7 . Thus, the adult islet houses highly plastic mature and immature β-cell subpopulations whose co-existence might be important for balancing renewal with the need for insulin release. Mature β-cells are generally thought to contribute the most to islet function, since they comprise ~70–90% of the β-cell population, express higher levels of insulin, glucose transporter, glucokinase and maturity genes, and mount normal ATP/ADP and Ca 2+ responses to stimulus (reviewed in 19 ). By contrast, immature β-cells are in the minority, show poor glucose-responsiveness and are less secretory 4 , 7 , 8 , 14 , 19 . However, β-cell subpopulations that disproportionately influence islet responses to glucose have recently been identified in situ and in vivo 20 , 21 , 22 . One of the subpopulations, termed hubs, was found to display lowered expression of β-cell maturity markers and insulin, but increased expression of glucose-sensing enzymes, including glucokinase 21 , 22 . These studies provide the first glimpse that immature cells with similar characteristics might contribute to the regulation of insulin release across the islet. We hypothesized that transcriptionally immature β-cells (PDX1 LOW /MAFA LOW ) belong to a highly functional subpopulation, able to overcome their relative deficiencies by interacting with their more mature counterparts to drive insulin release. In this work, we use recombinant genetic and chemogenetic disruption strategies to alter the balance of PDX1 LOW /MAFA LOW :PDX1 HIGH /MAFA HIGH β-cells in the islet. An increase in the proportion of PDX1 HIGH /MAFA HIGH β-cells leads to defective ionic and metabolic fluxes, dysregulation of genes involved in metabolism, as well as impaired insulin secretion. Heterogeneity in PDX1 and MAFA is encoded at the individual β-cell level by the islet Ca 2+ signaling network, and maintaining a balance between PDX1 LOW /MAFA LOW :PDX1 HIGH /MAFA HIGH β-cells restores Ca 2+ fluxes during metabolic stress. Together, these results show that differences in PDX1 and MAFA levels, and more broadly in β-cell maturity, contribute to islet function. Results Generation of islets with proportionally more PDX HIGH /MAFA HIGH β-cells We first generated and validated an overexpression model to alter the balance between immature and mature β-cells throughout the population. Here, immature β-cells are operationally defined as expressing low levels of the transcription factors PDX1 and MAFA based upon fluorescent immunostaining. Islets were transduced with control adenovirus containing PATagRFP (β normal; B-NORM) or a polycistronic construct encoding NEUROG3/PDX1/MAFA (Ad-M3C) (β mature; B-MAT). The M3C construct is well-validated 23 , 24 , a TetO mouse possessing the same construct exists 25 , and driving multiple transcription factors using the same promoter avoids heterogeneous expression profiles. Ad-M3C was able to drive exogenous Neurog3 , Pdx1 and Mafa expression (Fig. 1a ), expected to occur predominantly in the first two layers of the islet where functional imaging takes place. Native gene expression levels remained unchanged for Neurog3 and Mafa , but ~ 25% lower for Pdx1 , consistent with the absence of positive autoregulation seen with Pdx1-fluorophore constructs 26 . Fig. 1: Generating islets with proportionally more PDX1 HIGH /MAFA HIGH β-cells. a Adenoviral Neurog3 , Pdx1 and Mafa in islets (inset, endogenous gene expression) ( n = 5 animals; paired t -test). b Islets transduced with Ad-M3C (β-cell mature; B-MAT) lose β-cells occupying the bottom 15 percentile for PDX1 compared to controls (β-cell normal; B-NORM) (inset, non-normalized polynomial-fitted B-NORM distribution) ( n = 6 islets/3 animals; two-way ANOVA, Bonferonni’s multiple comparison) (F = 18.75, DF = 20). c", "role": "user" }, { "content": "Scientists have broadened our understanding of how 'weak' cells bond with their more mature cellular counterparts to boost the body's production of insulin, improving our knowledge of the processes leading to type 2 diabetes—a significant global health problem. Type 2 diabetes mellitus occurs when β-cells cannot release enough insulin—a tightly controlled process requiring hundreds of such cells clustered together to co-ordinate their response to signals from food, such as sugar, fat and gut hormones. An international research team—led by scientists at the University of Birmingham—have discovered that immature β-cells (PDX1LOW/MAFALOW) are able to overcome their relative deficiencies by partnering with 'stronger' counterparts to drive insulin release. Publishing their findings today in Nature Communications, the researchers reveal that subtle differences in the levels of PDX1 and MAFA proteins (found only in β-cells) , and more broadly, differences in β-cell maturity, contribute to how clusters of insulin-producing cells, known as islets, function. The corresponding author David Hodson, Professor of Cellular Metabolism, at the University of Birmingham, commented: \"Our research shows that differences in β-cell maturity, defined using PDX1 and MAFA levels, are needed across the islet for proper insulin release. Unexpectedly, increases in the proportion of mature β-cells, is associated with islet failure. It seems that, rather like society, the islet needs cells with all ages to be properly functional. \"Redressing the balance between immature and mature β-cells restores islet function under conditions of metabolic stress—an excess of sugar and fat in the diet—providing evidence that both 'weak' and 'strong' β-cells could contribute to proper islet function and insulin release. \"This is the first glimpse that immature cells might contribute to the regulation of insulin release across the islet. Our study indicates a promising line of investigation that could be leveraged to make islets more resilient during type 2 diabetes or when generating new islets in a 'dish' for the purpose of transplantation.\" Normally, mature and immature β-cells co-exist within the adult islet and can be grouped into subpopulations according to differences in their levels of specific genes and proteins. Immature β-cells are generally considered to be poorly functional when viewed alone, as single cells. Researchers found that islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells showed defects in cell function (metabolism, ionic fluxes and insulin secretion). The team believes maintaining a mix of 'strong' and 'weak' β-cells is important for effective insulin production. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1 HIGH and MAFA HIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1 HIGH and MAFA HIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca 2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function. Introduction Type 2 diabetes mellitus (T2DM) occurs when β-cells are unable to release enough insulin to compensate for insulin resistance. At the cellular level, glucose-regulated insulin secretion depends upon generation of ATP/ADP, closure of ATP-sensitive K + (K ATP ) channels, opening of voltage-dependent Ca 2+ channels (VDCC) and exocytosis of insulin granules 1 . At the multicellular level, insulin release is a tightly controlled process, requiring hundreds of β-cells throughout the islet to coordinate their activities in response to diverse stimuli including glucose, incretins and fatty acids 2 , 3 . Our current understanding of the mechanisms underlying insulin release is mainly derived from experiments in single β-cells or measures averaged across the entire β-cell complement. However, such studies, which generally view β-cells as a tightly coupled system, are difficult to reconcile with the known heterogeneous nature of β-cell identity and function. Based on transcriptomic 4 , 5 and protein signatures 6 , marker analyses 7 , 8 , 9 , glucose-responsiveness 10 , 11 , reporter imaging 12 , 13 , 14 , 15 or single molecule hybridization 16 , β-cell subpopulations have been shown to exist with altered maturity states, metabolism, electrical activity, insulin secretion and proliferative capacity (reviewed in 17 , 18 ). Of note, β-cell subpopulations are highly plastic. During aging and T2DM, β-cells with reduced maturity, metabolism and insulin secretion, but enhanced proliferative capacity, typically increase in proportion in both rodent and human 4 , 7 , 8 . At the same time, there is an increase in the number of mature, secretory β-cells that display poorer proliferative capacity 6 , 7 . Thus, the adult islet houses highly plastic mature and immature β-cell subpopulations whose co-existence might be important for balancing renewal with the need for insulin release. Mature β-cells are generally thought to contribute the most to islet function, since they comprise ~70–90% of the β-cell population, express higher levels of insulin, glucose transporter, glucokinase and maturity genes, and mount normal ATP/ADP and Ca 2+ responses to stimulus (reviewed in 19 ). By contrast, immature β-cells are in the minority, show poor glucose-responsiveness and are less secretory 4 , 7 , 8 , 14 , 19 . However, β-cell subpopulations that disproportionately influence islet responses to glucose have recently been identified in situ and in vivo 20 , 21 , 22 . One of the subpopulations, termed hubs, was found to display lowered expression of β-cell maturity markers and insulin, but increased expression of glucose-sensing enzymes, including glucokinase 21 , 22 . These studies provide the first glimpse that immature cells with similar characteristics might contribute to the regulation of insulin release across the islet. We hypothesized that transcriptionally immature β-cells (PDX1 LOW /MAFA LOW ) belong to a highly functional subpopulation, able to overcome their relative deficiencies by interacting with their more mature counterparts to drive insulin release. In this work, we use recombinant genetic and chemogenetic disruption strategies to alter the balance of PDX1 LOW /MAFA LOW :PDX1 HIGH /MAFA HIGH β-cells in the islet. An increase in the proportion of PDX1 HIGH /MAFA HIGH β-cells leads to defective ionic and metabolic fluxes, dysregulation of genes involved in metabolism, as well as impaired insulin secretion. Heterogeneity in PDX1 and MAFA is encoded at the individual β-cell level by the islet Ca 2+ signaling network, and maintaining a balance between PDX1 LOW /MAFA LOW :PDX1 HIGH /MAFA HIGH β-cells restores Ca 2+ fluxes during metabolic stress. Together, these results show that differences in PDX1 and MAFA levels, and more broadly in β-cell maturity, contribute to islet function. Results Generation of islets with proportionally more PDX HIGH /MAFA HIGH β-cells We first generated and validated an overexpression model to alter the balance between immature and mature β-cells throughout the population. Here, immature β-cells are operationally defined as expressing low levels of the transcription factors PDX1 and MAFA based upon fluorescent immunostaining. Islets were transduced with control adenovirus containing PATagRFP (β normal; B-NORM) or a polycistronic construct encoding NEUROG3/PDX1/MAFA (Ad-M3C) (β mature; B-MAT). The M3C construct is well-validated 23 , 24 , a TetO mouse possessing the same construct exists 25 , and driving multiple transcription factors using the same promoter avoids heterogeneous expression profiles. Ad-M3C was able to drive exogenous Neurog3 , Pdx1 and Mafa expression (Fig. 1a ), expected to occur predominantly in the first two layers of the islet where functional imaging takes place. Native gene expression levels remained unchanged for Neurog3 and Mafa , but ~ 25% lower for Pdx1 , consistent with the absence of positive autoregulation seen with Pdx1-fluorophore constructs 26 . Fig. 1: Generating islets with proportionally more PDX1 HIGH /MAFA HIGH β-cells. a Adenoviral Neurog3 , Pdx1 and Mafa in islets (inset, endogenous gene expression) ( n = 5 animals; paired t -test). b Islets transduced with Ad-M3C (β-cell mature; B-MAT) lose β-cells occupying the bottom 15 percentile for PDX1 compared to controls (β-cell normal; B-NORM) (inset, non-normalized polynomial-fitted B-NORM distribution) ( n = 6 islets/3 animals; two-way ANOVA, Bonferonni’s multiple comparison) (F = 18.75, DF = 20). c<|im_end|> <|im_start|>assistant Scientists have broadened our understanding of how 'weak' cells bond with their more mature cellular counterparts to boost the body's production of insulin, improving our knowledge of the processes leading to type 2 diabetes—a significant global health problem. Type 2 diabetes mellitus occurs when β-cells cannot release enough insulin—a tightly controlled process requiring hundreds of such cells clustered together to co-ordinate their response to signals from food, such as sugar, fat and gut hormones. An international research team—led by scientists at the University of Birmingham—have discovered that immature β-cells (PDX1LOW/MAFALOW) are able to overcome their relative deficiencies by partnering with 'stronger' counterparts to drive insulin release. Publishing their findings today in Nature Communications, the researchers reveal that subtle differences in the levels of PDX1 and MAFA proteins (found only in β-cells) , and more broadly, differences in β-cell maturity, contribute to how clusters of insulin-producing cells, known as islets, function. The corresponding author David Hodson, Professor of Cellular Metabolism, at the University of Birmingham, commented: "Our research shows that differences in β-cell maturity, defined using PDX1 and MAFA levels, are needed across the islet for proper insulin release. Unexpectedly, increases in the proportion of mature β-cells, is associated with islet failure. It seems that, rather like society, the islet needs cells with all ages to be properly functional. "Redressing the balance between immature and mature β-cells restores islet function under conditions of metabolic stress—an excess of sugar and fat in the diet—providing evidence that both 'weak' and 'strong' β-cells could contribute to proper islet function and insulin release. "This is the first glimpse that immature cells might contribute to the regulation of insulin release across the islet. Our study indicates a promising line of investigation that could be leveraged to make islets more resilient during type 2 diabetes or when generating new islets in a 'dish' for the purpose of transplantation." Normally, mature and immature β-cells co-exist within the adult islet and can be grouped into subpopulations according to differences in their levels of specific genes and proteins. Immature β-cells are generally considered to be poorly functional when viewed alone, as single cells. Researchers found that islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells showed defects in cell function (metabolism, ionic fluxes and insulin secretion). The team believes maintaining a mix of 'strong' and 'weak' β-cells is important for effective insulin production. <|im_end|>

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2,078

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract For over 300 million years, insects have relied on symbiotic microbes for nutrition and defence. However, it is unclear whether specific ecological conditions have repeatedly favoured the evolution of symbioses, and how this has influenced insect diversification. Here, using data on 1,850 microbe–insect symbioses across 402 insect families, we found that symbionts have allowed insects to specialize on a range of nutrient-imbalanced diets, including phloem, blood and wood. Across diets, the only limiting nutrient consistently associated with the evolution of obligate symbiosis was B vitamins. The shift to new diets, facilitated by symbionts, had mixed consequences for insect diversification. In some cases, such as herbivory, it resulted in spectacular species proliferation. In other niches, such as strict blood feeding, diversification has been severely constrained. Symbioses therefore appear to solve widespread nutrient deficiencies for insects, but the consequences for insect diversification depend on the feeding niche that is invaded. Main Across the tree of life, microbial symbionts have enabled organisms to harness new forms of energy, access unobtainable nutrients and outsource critical functions such as defence 1 , 2 , 3 , 4 . So valuable are symbiotic partnerships that they have repeatedly led to organisms becoming obligately dependent on each other for survival 5 . Such interdependence between hosts and symbionts has led to the evolution of new levels of organismal complexity that have ultimately shaped the diversity of life on Earth 3 , 6 . The essential metabolic services provided by symbionts have enabled hosts to expand into previously uninhabitable environments 1 , 4 , 7 . For example, sulfur-oxidizing bacteria enable giant marine tubeworms to live in deep-sea vents, root-associated fungi helped plants colonize land and nutrient-supplementing symbionts have allowed insects to live solely on the imbalanced diets of plant sap and vertebrate blood 2 , 8 , 9 . However, it is unclear whether there are unifying factors that guide how and why symbiotic relationships evolve. Insects are an excellent system to study the evolution of obligate symbiosis. Multiple insect families have acquired microbes to perform a range of functions, including defence and nutrition 10 . Defensive symbionts protect their hosts from attack by natural enemies 11 , whereas nutritional symbioses allow insects to feed on specialized resources that lack essential nutrients, such as plant sap, blood (haematophagy) and wood (xylophagy) 2 . It is therefore widely accepted that symbiotic partnerships have opened new ecological niches and helped the incredible diversification of insects 7 . However, previous work has primarily focused on the functional role and impact of obligate symbiosis within single groups of insects. Consequently, whether we can generalize about the ecological causes and consequences of obligate symbiosis across different groups of insects is unknown. Are there consistent nutrient limitations that have repeatedly selected for the evolution of symbioses across different feeding niches? Do symbioses influence diversification in a consistent or niche-dependent way? In this article, we address these questions by examining the macro-evolutionary patterns of obligate symbiosis across 1,850 microbe-insect combinations from 402 insect families. Data were collated across bacteria, fungi and protist symbionts with nutritional and defensive functions (Supplementary Tables 1 – 4 ). First, we estimated how often insect lineages within different feeding niches have evolved obligate symbiosis, where the host cannot survive without symbionts. We are interested in cases where hosts are obligately or highly dependent (effectively obligately) on their symbionts. Obligate dependence is ideally proven experimentally, but only a limited number of such studies exist 5 . To allow comparison across a wider range of species, we used two criteria to establish putative obligate dependence, hereafter referred to as obligate dependence, both of which had to be fulfilled: (1) the symbiont is universally present in reproductive females; and (2) the insect possesses morphological structures that are predominantly associated with symbionts being required for survival (for example, bacteriocytes 10 ), or where information on symbiont housing organs was lacking, data on the impact of symbiont removal and patterns of host–symbiont co-speciation were used to determine obligate dependence (‘Insect and symbiont data’ in Methods ). Known parasitic symbionts, such as reproductive manipulators (for example, Spiroplasma , Cardinium and Wolbachia ), that have not evolved beneficial functions were excluded from our dataset. Second, we examined the composition of insect diets to determine whether specific nutrient deficiencies have consistently led to the evolution of obligate symbiosis across different feeding niches. The nutritional composition of diets was determined by collating literature on the food sources used by adults and juveniles ( n food sources = 362) and extracting information on carbohydrates, fats, proteins, essential amino acids, non-essential amino acids and vitamins A, B, C and E from as many example foods as possible (range 1–24) from nutritional databases (‘Nutrient data’ in Methods , Supplementary Table 4 and Extended Data Fig. 1 ). Data on other vitamins were collected but had >30% missing data and so were excluded from analyses (‘Nutrient data’ in Methods ). We differentiate between insect families that specialize on single plant-based resources (phloem, xylem or wood) from families that exploit various plant parts (phytophagy, referred to here as herbivores), as there were large differences in the nutrients of these diets (Supplementary Tables 1 and 4 ). Third, we tested if the acquisition of obligate symbionts has increased or decreased host species richness after radiating into different feeding niches. We circumvent the problem of poorly resolved species level phylogenies by reconstructing the evolutionary history of obligate symbioses at the family level. Evolutionary origins of obligate symbiosis We found at least 16 independent origins of obligate symbiosis spread across 89 insect families (Bayesian phylogenetic mixed model (BPMM): Fig. 1 and Supplementary Table 5 ). These origins were estimated on the time-calibrated phylogeny 12 to date back as far as 336 million years. Within insect families, there were also several more recent transitions to obligate symbiosis. For example, 15 families were found to contain species with and without obligate symbionts (Fig. 1 and Supplementary Tables 1 and 2 ) but without species phylogenies the exact", "role": "user" }, { "content": "Insects are crucial for biodiversity and among the most successful species on the planet. However, until now, it has been unclear how they could exploit such a diversity of food sources. According to a recent study published in the journal Nature Ecology and Evolution, bacteria have played a crucial role. \"Insect diets range from human blood, in the case of mosquitoes, to the wood used to build our houses, in the case of termites. The common denominator is bacteria. Our findings show that bacteria play a crucial role in providing insects with the nutrients they need to survive and thrive,\" says Charlie Cornwallis, biology researcher at Lund University. The study, which included Weevils, shows that bacteria consistently provide insects with vitamin B, a vital nutrient they cannot make themselves. Insects have become so dependent on bacteria that they have developed new organelles to house them—so called bacteria factories. \"The nutrients provided by bacteria have enabled insects to survive on highly unbalanced diets and exploit new types of food resources. Some insects, such as aphids, solely feed on phloem, essentially sugary water. Imagine being able to lead a healthy life only on sweets!\" says Charlie Cornwallis. However, the effects of bacteria on insect diversity and variation are not straightforward. In certain insect families, specialization on specific diets involving blood has halted species diversification. But in most cases, such as plant-feeding insects, dietary specialization is linked to a significant increase in species. \"Insects are all around us and influence our every walk of life. They spread diseases and even threaten food production as crop pests. Knowing how and why insects survive and diversify is important for understanding the evolution of the natural world and its influence on our own well-being,\" says Charlie Cornwallis. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract For over 300 million years, insects have relied on symbiotic microbes for nutrition and defence. However, it is unclear whether specific ecological conditions have repeatedly favoured the evolution of symbioses, and how this has influenced insect diversification. Here, using data on 1,850 microbe–insect symbioses across 402 insect families, we found that symbionts have allowed insects to specialize on a range of nutrient-imbalanced diets, including phloem, blood and wood. Across diets, the only limiting nutrient consistently associated with the evolution of obligate symbiosis was B vitamins. The shift to new diets, facilitated by symbionts, had mixed consequences for insect diversification. In some cases, such as herbivory, it resulted in spectacular species proliferation. In other niches, such as strict blood feeding, diversification has been severely constrained. Symbioses therefore appear to solve widespread nutrient deficiencies for insects, but the consequences for insect diversification depend on the feeding niche that is invaded. Main Across the tree of life, microbial symbionts have enabled organisms to harness new forms of energy, access unobtainable nutrients and outsource critical functions such as defence 1 , 2 , 3 , 4 . So valuable are symbiotic partnerships that they have repeatedly led to organisms becoming obligately dependent on each other for survival 5 . Such interdependence between hosts and symbionts has led to the evolution of new levels of organismal complexity that have ultimately shaped the diversity of life on Earth 3 , 6 . The essential metabolic services provided by symbionts have enabled hosts to expand into previously uninhabitable environments 1 , 4 , 7 . For example, sulfur-oxidizing bacteria enable giant marine tubeworms to live in deep-sea vents, root-associated fungi helped plants colonize land and nutrient-supplementing symbionts have allowed insects to live solely on the imbalanced diets of plant sap and vertebrate blood 2 , 8 , 9 . However, it is unclear whether there are unifying factors that guide how and why symbiotic relationships evolve. Insects are an excellent system to study the evolution of obligate symbiosis. Multiple insect families have acquired microbes to perform a range of functions, including defence and nutrition 10 . Defensive symbionts protect their hosts from attack by natural enemies 11 , whereas nutritional symbioses allow insects to feed on specialized resources that lack essential nutrients, such as plant sap, blood (haematophagy) and wood (xylophagy) 2 . It is therefore widely accepted that symbiotic partnerships have opened new ecological niches and helped the incredible diversification of insects 7 . However, previous work has primarily focused on the functional role and impact of obligate symbiosis within single groups of insects. Consequently, whether we can generalize about the ecological causes and consequences of obligate symbiosis across different groups of insects is unknown. Are there consistent nutrient limitations that have repeatedly selected for the evolution of symbioses across different feeding niches? Do symbioses influence diversification in a consistent or niche-dependent way? In this article, we address these questions by examining the macro-evolutionary patterns of obligate symbiosis across 1,850 microbe-insect combinations from 402 insect families. Data were collated across bacteria, fungi and protist symbionts with nutritional and defensive functions (Supplementary Tables 1 – 4 ). First, we estimated how often insect lineages within different feeding niches have evolved obligate symbiosis, where the host cannot survive without symbionts. We are interested in cases where hosts are obligately or highly dependent (effectively obligately) on their symbionts. Obligate dependence is ideally proven experimentally, but only a limited number of such studies exist 5 . To allow comparison across a wider range of species, we used two criteria to establish putative obligate dependence, hereafter referred to as obligate dependence, both of which had to be fulfilled: (1) the symbiont is universally present in reproductive females; and (2) the insect possesses morphological structures that are predominantly associated with symbionts being required for survival (for example, bacteriocytes 10 ), or where information on symbiont housing organs was lacking, data on the impact of symbiont removal and patterns of host–symbiont co-speciation were used to determine obligate dependence (‘Insect and symbiont data’ in Methods ). Known parasitic symbionts, such as reproductive manipulators (for example, Spiroplasma , Cardinium and Wolbachia ), that have not evolved beneficial functions were excluded from our dataset. Second, we examined the composition of insect diets to determine whether specific nutrient deficiencies have consistently led to the evolution of obligate symbiosis across different feeding niches. The nutritional composition of diets was determined by collating literature on the food sources used by adults and juveniles ( n food sources = 362) and extracting information on carbohydrates, fats, proteins, essential amino acids, non-essential amino acids and vitamins A, B, C and E from as many example foods as possible (range 1–24) from nutritional databases (‘Nutrient data’ in Methods , Supplementary Table 4 and Extended Data Fig. 1 ). Data on other vitamins were collected but had >30% missing data and so were excluded from analyses (‘Nutrient data’ in Methods ). We differentiate between insect families that specialize on single plant-based resources (phloem, xylem or wood) from families that exploit various plant parts (phytophagy, referred to here as herbivores), as there were large differences in the nutrients of these diets (Supplementary Tables 1 and 4 ). Third, we tested if the acquisition of obligate symbionts has increased or decreased host species richness after radiating into different feeding niches. We circumvent the problem of poorly resolved species level phylogenies by reconstructing the evolutionary history of obligate symbioses at the family level. Evolutionary origins of obligate symbiosis We found at least 16 independent origins of obligate symbiosis spread across 89 insect families (Bayesian phylogenetic mixed model (BPMM): Fig. 1 and Supplementary Table 5 ). These origins were estimated on the time-calibrated phylogeny 12 to date back as far as 336 million years. Within insect families, there were also several more recent transitions to obligate symbiosis. For example, 15 families were found to contain species with and without obligate symbionts (Fig. 1 and Supplementary Tables 1 and 2 ) but without species phylogenies the exact<|im_end|> <|im_start|>assistant Insects are crucial for biodiversity and among the most successful species on the planet. However, until now, it has been unclear how they could exploit such a diversity of food sources. According to a recent study published in the journal Nature Ecology and Evolution, bacteria have played a crucial role. "Insect diets range from human blood, in the case of mosquitoes, to the wood used to build our houses, in the case of termites. The common denominator is bacteria. Our findings show that bacteria play a crucial role in providing insects with the nutrients they need to survive and thrive," says Charlie Cornwallis, biology researcher at Lund University. The study, which included Weevils, shows that bacteria consistently provide insects with vitamin B, a vital nutrient they cannot make themselves. Insects have become so dependent on bacteria that they have developed new organelles to house them—so called bacteria factories. "The nutrients provided by bacteria have enabled insects to survive on highly unbalanced diets and exploit new types of food resources. Some insects, such as aphids, solely feed on phloem, essentially sugary water. Imagine being able to lead a healthy life only on sweets!" says Charlie Cornwallis. However, the effects of bacteria on insect diversity and variation are not straightforward. In certain insect families, specialization on specific diets involving blood has halted species diversification. But in most cases, such as plant-feeding insects, dietary specialization is linked to a significant increase in species. "Insects are all around us and influence our every walk of life. They spread diseases and even threaten food production as crop pests. Knowing how and why insects survive and diversify is important for understanding the evolution of the natural world and its influence on our own well-being," says Charlie Cornwallis. <|im_end|>

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1,762

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Edible insects are often considered a nutritious, protein-rich, environmentally sustainable alternative to traditional livestock with growing popularity among North American consumers. While the nutrient composition of several insects is characterized, all potential health impacts have not been evaluated. In addition to high protein levels, crickets contain chitin and other fibers that may influence gut health. In this study, we evaluated the effects of consuming 25 grams/day whole cricket powder on gut microbiota composition, while assessing safety and tolerability. Twenty healthy adults participated in this six-week, double-blind, crossover dietary intervention. Participants were randomized into two study arms and consumed either cricket-containing or control breakfast foods for 14 days, followed by a washout period and assignment to the opposite treatment. Blood and stool samples were collected at baseline and after each treatment period to assess liver function and microbiota changes. Results demonstrate cricket consumption is tolerable and non-toxic at the studied dose. Cricket powder supported growth of the probiotic bacterium, Bifidobacterium animalis , which increased 5.7-fold. Cricket consumption was also associated with reduced plasma TNF-α. These data suggest that eating crickets may improve gut health and reduce systemic inflammation; however, more research is needed to understand these effects and underlying mechanisms. Introduction The human gastrointestinal tract is home to a host of bacterial cells. These cells outnumber human cells by a factor of three 1 and encode at least 100 times more genes 2 , which influence human physiology, metabolism, and gene expression pertinent to immune function, energy, and even mood 3 . Extensive research demonstrates that microbiota in the gut respond to nutritional cues and generate hormone-like signals influencing normal physiology, nutritional status, metabolism, immune function, as well as disease progression and overall wellbeing 2 , 4 , 5 , 6 . Imbalances in the gut microbiota, also known as dysbiosis, and low microbial diversity are associated with metabolic and non-communicable diseases, gastrointestinal conditions, allergies, asthma, and even neuropsychiatric disorders 7 , 8 , 9 , 10 . Diet is an especially relevant factor in defining the composition of gut microbiota 11 , and even small shifts have demonstrated meaningful effects 5 , 12 . Dietary diversity is linked with a more diverse, healthy microbiota that is more adept at adjusting to perturbations 13 . Indigestible dietary carbohydrates (dietary fibers) are the primary energy sources for gut microbiota, and thus shape microbial growth 14 . Not surprisingly, dietary fiber intake has been shown to contribute to the health of the gut microbiome by increasing diversity in fecal microbiota 15 , 16 , and high fiber intake has been associated with a reduced risk of breast cancer 17 , diverticular disease 18 , coronary heart disease 19 , 20 , and metabolic syndrome 21 , 22 . Edible insects are hailed as an excellent source of protein and other nutrients, but they also provide a relatively understudied fiber source, chitin, that could influence the gut microbiota. For western consumers, edible insects are a novel food that is just now gaining traction in certain areas. Motivations to eat insects stem from their cultural and nutritional value, as well as their numerous environmental benefits. The current pressures on global food security, including climate change, population growth, and shifting dietary preferences, have ignited a search for more environmentally sustainable protein sources. Given that livestock production alone is responsible for about 14.5% of total human-induced greenhouse gas (GHG) emissions 23 there is a mounting need for more efficient animal production systems. Edible insects have been touted as one such option, as they typically emit fewer GHGs 24 and require less land, water, and feed to survive and thrive than traditional livestock 25 . The result is a significantly lower environmental impact 24 , 25 , 26 , and high desirability due in part to insects’ large edible body mass percentage 27 , high feed-conversion ratio 26 , and ectothermic thermoregulation, which limits energy expenditure on temperature regulation. Entomophagy, the practice of eating insects, is not new however; it has been recorded throughout human history across the globe 28 , 29 . Today, insects are regularly consumed by approximately 2 billion people 25 spread across 80% of the world’s populations 30 in 130 countries 31 . Edible insects are gaining traction in North America and Europe, in addition to regions that traditionally practice entomophagy. The commercial industry was valued at 33 million USD in 2015, with future growth estimated at more than 40% by 2023 32 . Insects that have been eaten historically are generally considered safe for human consumption if properly processed like other animal products, although some people are allergic to insect proteins and chitin 33 . Generally, insects are a good source of bioavailable animal protein 33 , 34 , 35 , 36 including all essential amino acids 26 , as well as B vitamins 35 , 37 , minerals 37 , 38 , and essential fatty acids 39 . Insects also contain relevant levels of crude fiber, most predominately in the form of chitin, derived from the exoskeleton 40 . A recent estimate of chitin and chitosan based on percent dry weight of whole ground crickets found values between 4.3–7.1% and 2.4–5.8%, respectively 41 . Chitin (C 8 H 13 O 5 N) n ) is a modified polysaccharide (poly-beta-1,4- N -acetylglucosamine) containing nitrogen with a structure analogous to indigestible cellulose; it is considered an insoluble fiber with potential prebiotic properties that could benefit human health by selectively promoting the growth of beneficial bacterial species in the intestines, though this relationship is not well understood. Chitin is the primary component of the exoskeleton, respiratory linings, digestive and excretory systems of arthropods 42 , and given the variation in insect anatomy chitin levels in common feeder insects vary widely 43 . Chitin has applications in health, drug delivery, agriculture, gene therapy, food technology, nano-technology, and bioenergy, among others 44 . While the nutritional value of edible insects is widely documented 25 , 33 , 45 , other potentially beneficial properties of edible insects", "role": "user" }, { "content": "A new clinical trial shows that consuming crickets can help support the growth of beneficial gut bacteria and that eating crickets is not only safe at high doses but may also reduce inflammation in the body. Valerie Stull was 12 when she ate her first insect. \"I was on a trip with my parents in Central America and we were served fried ants,\" she says. \"I remember being so grossed out initially, but when I put the ant in my mouth, I was really surprised because it tasted like food—and it was good!\" Today, Stull, a recent doctoral graduate of the University of Wisconsin-Madison Nelson Institute for Environmental Studies, is the lead author of a new pilot clinical trial published in the journal Scientific Reports that looks at what eating crickets does to the human microbiome. It shows that consuming crickets can help support the growth of beneficial gut bacteria and that eating crickets is not only safe at high doses but may also reduce inflammation in the body. \"There is a lot of interest right now in edible insects,\" Stull says. \"It's gaining traction in Europe and in the U.S. as a sustainable, environmentally friendly protein source compared to traditional livestock.\" More than 2 billion people around the world regularly consume insects, which are also a good source of protein, vitamins, minerals and healthy fats. The research team was interested in documenting for the first time via clinical trial the health effects of eating them. \"This study is important because insects represent a novel component in Western diets and their health effects in human populations haven't really been studied,\" says co-corresponding author Tiffany Weir, a professor of food science and human nutrition at Colorado State University. \"With what we now know about the gut microbiota and its relationship to human health, it's important to establish how a novel food might affect gut microbial populations. We found that cricket consumption may actually offer benefits beyond nutrition.\" Raising insects for protein not only helps protect the environment, but also offers a more healthful option than meat in many wealthy countries with high-meat diets, says co-author Jonathan Patz, director of the UW-Madison Global Health Institute, where Stull will begin a postdoctoral research position in the fall. Crickets, like other insects, contain fibers, such as chitin, that are different from the dietary fiber found in foods like fruits and vegetables. Fiber serves as a microbial food source and some fiber types promote the growth of beneficial bacteria, also known as probiotics. The small trial probed whether insect fibers might influence the bacteria found in the gastrointestinal tract. For two weeks, 20 healthy men and women between the ages of 18 and 48 ate either a control breakfast or a breakfast containing 25 grams of powdered cricket meal made into muffins and shakes. Each participant then ate a normal diet for a two-week \"washout period.\" For the following two weeks, those who started on the cricket diet consumed a control breakfast and those who started on the control diet consumed a cricket breakfast. Every participant served as their own control for the study and the researchers were blinded with respect to which diet each participant was on at any given time. The researchers collected blood samples, stool samples and answers to gastrointestinal questionnaires immediately before the study began, immediately following the first two-week diet period and immediately after the second two-week diet period. Participants' blood samples were tested for a host of health measures, like blood glucose and enzymes associated with liver function, and also for levels of a protein associated with inflammation. The fecal samples were tested for the byproducts of microbial metabolism in the human gut, inflammatory chemicals associated with the gastrointestinal tract, and the overall makeup of the microbial communities present in the stools. Participants reported no significant gastrointestinal changes or side effects and the researchers found no evidence of changes to overall microbial composition or changes to gut inflammation. They did see an increase in a metabolic enzyme associated with gut health, and a decrease in an inflammatory protein in the blood called TNF-alpha, which has been linked to other measures of well-being, like depression and cancer. Additionally, the team saw an increase in the abundance of beneficial gut bacteria like Bifidobacterium animalis, a strain that has been linked to improved gastrointestinal function and other measures of health in studies of a commercially available strain called BB-12. But, the researchers say, more and larger studies are needed to replicate these findings and determine what components of crickets may contribute to improved gut health.\"This very small study shows that this is something worth looking at in the future when promoting insects as a sustainable food source,\" says Stull. Stull is co-founder of an award-winning startup and research collaboration called MIGHTi, the Mission to Improve Global Health Through Insects. In the future, MIGHTi hopes to provide home-use insect-farming kits to communities that already consume insects, including many in southern Africa. Insects require far less water to farm than traditional livestock and can help improve food security in impoverished communities while providing economic opportunities to women. \"Most of the insects consumed around the world are wild-harvested where they are and when they are available,\" says Stull, who has eaten insects—including caterpillars, cicadas, grasshoppers and beetle larvae—all over the world. \"People love flying termites in Zambia, which come out only once or twice a year and are really good; they taste like popcorn and are a crunchy, oily snack.\" She hopes to promote insects as a more mainstream food in the United States, and though the industry is currently small, the rise of edible insect producers and companies using insects in their food products may make this possible. \"Food is very tied to culture, and 20 or 30 years ago, no one in the U.S. was eating sushi because we thought it was disgusting, but now you can get it at a gas station in Nebraska,\" she says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Edible insects are often considered a nutritious, protein-rich, environmentally sustainable alternative to traditional livestock with growing popularity among North American consumers. While the nutrient composition of several insects is characterized, all potential health impacts have not been evaluated. In addition to high protein levels, crickets contain chitin and other fibers that may influence gut health. In this study, we evaluated the effects of consuming 25 grams/day whole cricket powder on gut microbiota composition, while assessing safety and tolerability. Twenty healthy adults participated in this six-week, double-blind, crossover dietary intervention. Participants were randomized into two study arms and consumed either cricket-containing or control breakfast foods for 14 days, followed by a washout period and assignment to the opposite treatment. Blood and stool samples were collected at baseline and after each treatment period to assess liver function and microbiota changes. Results demonstrate cricket consumption is tolerable and non-toxic at the studied dose. Cricket powder supported growth of the probiotic bacterium, Bifidobacterium animalis , which increased 5.7-fold. Cricket consumption was also associated with reduced plasma TNF-α. These data suggest that eating crickets may improve gut health and reduce systemic inflammation; however, more research is needed to understand these effects and underlying mechanisms. Introduction The human gastrointestinal tract is home to a host of bacterial cells. These cells outnumber human cells by a factor of three 1 and encode at least 100 times more genes 2 , which influence human physiology, metabolism, and gene expression pertinent to immune function, energy, and even mood 3 . Extensive research demonstrates that microbiota in the gut respond to nutritional cues and generate hormone-like signals influencing normal physiology, nutritional status, metabolism, immune function, as well as disease progression and overall wellbeing 2 , 4 , 5 , 6 . Imbalances in the gut microbiota, also known as dysbiosis, and low microbial diversity are associated with metabolic and non-communicable diseases, gastrointestinal conditions, allergies, asthma, and even neuropsychiatric disorders 7 , 8 , 9 , 10 . Diet is an especially relevant factor in defining the composition of gut microbiota 11 , and even small shifts have demonstrated meaningful effects 5 , 12 . Dietary diversity is linked with a more diverse, healthy microbiota that is more adept at adjusting to perturbations 13 . Indigestible dietary carbohydrates (dietary fibers) are the primary energy sources for gut microbiota, and thus shape microbial growth 14 . Not surprisingly, dietary fiber intake has been shown to contribute to the health of the gut microbiome by increasing diversity in fecal microbiota 15 , 16 , and high fiber intake has been associated with a reduced risk of breast cancer 17 , diverticular disease 18 , coronary heart disease 19 , 20 , and metabolic syndrome 21 , 22 . Edible insects are hailed as an excellent source of protein and other nutrients, but they also provide a relatively understudied fiber source, chitin, that could influence the gut microbiota. For western consumers, edible insects are a novel food that is just now gaining traction in certain areas. Motivations to eat insects stem from their cultural and nutritional value, as well as their numerous environmental benefits. The current pressures on global food security, including climate change, population growth, and shifting dietary preferences, have ignited a search for more environmentally sustainable protein sources. Given that livestock production alone is responsible for about 14.5% of total human-induced greenhouse gas (GHG) emissions 23 there is a mounting need for more efficient animal production systems. Edible insects have been touted as one such option, as they typically emit fewer GHGs 24 and require less land, water, and feed to survive and thrive than traditional livestock 25 . The result is a significantly lower environmental impact 24 , 25 , 26 , and high desirability due in part to insects’ large edible body mass percentage 27 , high feed-conversion ratio 26 , and ectothermic thermoregulation, which limits energy expenditure on temperature regulation. Entomophagy, the practice of eating insects, is not new however; it has been recorded throughout human history across the globe 28 , 29 . Today, insects are regularly consumed by approximately 2 billion people 25 spread across 80% of the world’s populations 30 in 130 countries 31 . Edible insects are gaining traction in North America and Europe, in addition to regions that traditionally practice entomophagy. The commercial industry was valued at 33 million USD in 2015, with future growth estimated at more than 40% by 2023 32 . Insects that have been eaten historically are generally considered safe for human consumption if properly processed like other animal products, although some people are allergic to insect proteins and chitin 33 . Generally, insects are a good source of bioavailable animal protein 33 , 34 , 35 , 36 including all essential amino acids 26 , as well as B vitamins 35 , 37 , minerals 37 , 38 , and essential fatty acids 39 . Insects also contain relevant levels of crude fiber, most predominately in the form of chitin, derived from the exoskeleton 40 . A recent estimate of chitin and chitosan based on percent dry weight of whole ground crickets found values between 4.3–7.1% and 2.4–5.8%, respectively 41 . Chitin (C 8 H 13 O 5 N) n ) is a modified polysaccharide (poly-beta-1,4- N -acetylglucosamine) containing nitrogen with a structure analogous to indigestible cellulose; it is considered an insoluble fiber with potential prebiotic properties that could benefit human health by selectively promoting the growth of beneficial bacterial species in the intestines, though this relationship is not well understood. Chitin is the primary component of the exoskeleton, respiratory linings, digestive and excretory systems of arthropods 42 , and given the variation in insect anatomy chitin levels in common feeder insects vary widely 43 . Chitin has applications in health, drug delivery, agriculture, gene therapy, food technology, nano-technology, and bioenergy, among others 44 . While the nutritional value of edible insects is widely documented 25 , 33 , 45 , other potentially beneficial properties of edible insects<|im_end|> <|im_start|>assistant A new clinical trial shows that consuming crickets can help support the growth of beneficial gut bacteria and that eating crickets is not only safe at high doses but may also reduce inflammation in the body. Valerie Stull was 12 when she ate her first insect. "I was on a trip with my parents in Central America and we were served fried ants," she says. "I remember being so grossed out initially, but when I put the ant in my mouth, I was really surprised because it tasted like food—and it was good!" Today, Stull, a recent doctoral graduate of the University of Wisconsin-Madison Nelson Institute for Environmental Studies, is the lead author of a new pilot clinical trial published in the journal Scientific Reports that looks at what eating crickets does to the human microbiome. It shows that consuming crickets can help support the growth of beneficial gut bacteria and that eating crickets is not only safe at high doses but may also reduce inflammation in the body. "There is a lot of interest right now in edible insects," Stull says. "It's gaining traction in Europe and in the U.S. as a sustainable, environmentally friendly protein source compared to traditional livestock." More than 2 billion people around the world regularly consume insects, which are also a good source of protein, vitamins, minerals and healthy fats. The research team was interested in documenting for the first time via clinical trial the health effects of eating them. "This study is important because insects represent a novel component in Western diets and their health effects in human populations haven't really been studied," says co-corresponding author Tiffany Weir, a professor of food science and human nutrition at Colorado State University. "With what we now know about the gut microbiota and its relationship to human health, it's important to establish how a novel food might affect gut microbial populations. We found that cricket consumption may actually offer benefits beyond nutrition." Raising insects for protein not only helps protect the environment, but also offers a more healthful option than meat in many wealthy countries with high-meat diets, says co-author Jonathan Patz, director of the UW-Madison Global Health Institute, where Stull will begin a postdoctoral research position in the fall. Crickets, like other insects, contain fibers, such as chitin, that are different from the dietary fiber found in foods like fruits and vegetables. Fiber serves as a microbial food source and some fiber types promote the growth of beneficial bacteria, also known as probiotics. The small trial probed whether insect fibers might influence the bacteria found in the gastrointestinal tract. For two weeks, 20 healthy men and women between the ages of 18 and 48 ate either a control breakfast or a breakfast containing 25 grams of powdered cricket meal made into muffins and shakes. Each participant then ate a normal diet for a two-week "washout period." For the following two weeks, those who started on the cricket diet consumed a control breakfast and those who started on the control diet consumed a cricket breakfast. Every participant served as their own control for the study and the researchers were blinded with respect to which diet each participant was on at any given time. The researchers collected blood samples, stool samples and answers to gastrointestinal questionnaires immediately before the study began, immediately following the first two-week diet period and immediately after the second two-week diet period. Participants' blood samples were tested for a host of health measures, like blood glucose and enzymes associated with liver function, and also for levels of a protein associated with inflammation. The fecal samples were tested for the byproducts of microbial metabolism in the human gut, inflammatory chemicals associated with the gastrointestinal tract, and the overall makeup of the microbial communities present in the stools. Participants reported no significant gastrointestinal changes or side effects and the researchers found no evidence of changes to overall microbial composition or changes to gut inflammation. They did see an increase in a metabolic enzyme associated with gut health, and a decrease in an inflammatory protein in the blood called TNF-alpha, which has been linked to other measures of well-being, like depression and cancer. Additionally, the team saw an increase in the abundance of beneficial gut bacteria like Bifidobacterium animalis, a strain that has been linked to improved gastrointestinal function and other measures of health in studies of a commercially available strain called BB-12. But, the researchers say, more and larger studies are needed to replicate these findings and determine what components of crickets may contribute to improved gut health."This very small study shows that this is something worth looking at in the future when promoting insects as a sustainable food source," says Stull. Stull is co-founder of an award-winning startup and research collaboration called MIGHTi, the Mission to Improve Global Health Through Insects. In the future, MIGHTi hopes to provide home-use insect-farming kits to communities that already consume insects, including many in southern Africa. Insects require far less water to farm than traditional livestock and can help improve food security in impoverished communities while providing economic opportunities to women. "Most of the insects consumed around the world are wild-harvested where they are and when they are available," says Stull, who has eaten insects—including caterpillars, cicadas, grasshoppers and beetle larvae—all over the world. "People love flying termites in Zambia, which come out only once or twice a year and are really good; they taste like popcorn and are a crunchy, oily snack." She hopes to promote insects as a more mainstream food in the United States, and though the industry is currently small, the rise of edible insect producers and companies using insects in their food products may make this possible. "Food is very tied to culture, and 20 or 30 years ago, no one in the U.S. was eating sushi because we thought it was disgusting, but now you can get it at a gas station in Nebraska," she says. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Organic light-emitting transistors, three-terminal devices combining a thin-film transistor with a light-emitting diode, have generated increasing interest in organic electronics. However, increasing their efficiency while keeping the operating voltage low still remains a key challenge. Here, we demonstrate organic permeable base light-emitting transistors; these three-terminal vertical optoelectronic devices operate at driving voltages below 5.0 V; emit in the red, green and blue ranges; and reach, respectively, peak external quantum efficiencies of 19.6%, 24.6% and 11.8%, current efficiencies of 20.6 cd A –1 , 90.1 cd A –1 and 27.1 cd A –1 and maximum luminance values of 9,833 cd m –2 , 12,513 cd m –2 and 4,753 cd m –2 . Our simulations demonstrate that the nano-pore permeable base electrode located at the centre of the device, which forms a distinctive optical microcavity and regulates charge carrier injection and transport, is the key to the good performance obtained. Our work paves the way towards efficient and low-voltage organic light-emitting transistors, useful for power-efficient active matrix displays and solid-state lighting. Main The enormous potential of organic optoelectrical devices has been successfully proven by the industrialization of solid-state lighting and display technologies on the basis of organic light-emitting diodes (OLEDs) for mobile phones and televisions 1 , 2 , 3 . However, thin-film transistor technology in the active matrix backplane remains a primary technical challenge preventing wider commercial implementation of OLEDs. In particular, the driving transistor in an active matrix cell acting as a constant-current source for the OLED (Fig. 1a ) has to operate in the saturation regime, requiring a relatively high supply voltage. This high supply voltage would cause an unacceptably high power consumption. Overall, this leads to the unsatisfying situation that in commercial active matrix OLED displays, more than 40% of the power is lost 4 . Organic light-emitting transistors (OLETs) have been considered as an emerging class of organic semiconductor-based devices, where the light-producing capability of OLEDs and the electric-switching capability of organic thin-film transistors (TFTs) are integrated into a single stacked device, exhibiting great potential for integrated optoelectronics, smart display technology (Fig. 1b ), light communication, optical switching and solid-state lighting 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . Since the first demonstration of OLETs in 2003 (ref. 10 ), continual improvements in the performance of OLETs have been achieved. An OLET with an n-channel/emitter/p-channel trilayer device structure was developed; the trilayer devices realized a peak external quantum efficiency (EQE) of 5.0%, exceeding that of the corresponding reference OLEDs 23 . To construct high-performance OLETs using such a trilayer device structure, the energetic compatibility among the involved n-type, p-type and light-emitting organic semiconductors is an important factor that should be carefully considered 24 , 25 . A further improvement was made by optimizing the single-layer OLET and suppressing the exciton–polaron quenching, yielding a maximum current efficiency of 28.2 cd A –1 and a peak EQE of 8.16% (ref. 26 ). However, because of the low dielectric capacitance combined with the intrinsic low mobility, OLETs usually need high working voltages (>100 V) for optimal device performance 27 . To realize low-voltage OLETs below 10.0 V, the dual-layer dielectric strategy with low- k (defined as the dielectric constant) and high- k dielectrics can be applied, resulting in an EQE of 0.02% at 700 cd m –2 (ref. 28 ). Fig. 1: Fabrication of organic permeable base light-emitting transistors. a , Pixel circuit of traditional 2T1C (two thin-film transistors and one capacitor) digital drive scheme for active matrix OLED, T1 is the first transitor for selecting input signal, T2 is the second transistor for driving the OLEDs, C s is a capacitor, SEL represents the signal selection, a and b are the junction nodes, and V DD is the supply voltage. b , Circuit of OPB-LET used for active matrix OLED. c , Schematic device structure and hole/electron injection paths of OPB-LETs. For each colour device, the device architecture (the substrate, emitter, collector, base and channel layers) is the same. V B is the applied base voltage, V C is the collector voltage. The orange arrow represents the electron injection and transport, and the blue one shows the hole injection and transport. d , Chemical molecular structures of the functional materials; full names of these molecules are given in Supplementary Table 4 . Full size image To gain efficient and low-voltage OLETs, vertical-channel OLETs (VOLETs) with various structural designs and operating principles have been prepared in recent years 30 , 31 , 32 , 33 , 34 , 35 , 36 . Best-performing VOLETs with a single-wall carbon nanotube network source electrode were demonstrated in three primary colours 33 . The fabricated red, green and blue devices realized maximum luminance values of 1,000–2,000 cd m –2 at the drain and gate voltages of −7.0 V and −3.0 V. Current efficiencies of red, green and blue OLETs are 12.5 cd A –1 , 48.0 cd A –1 and 23.3 cd A –1 at the brightness of 250 cd m –2 , respectively. However, the performance of VOLETs is still unsatisfying considering the requirements for solid-state lighting and active matrix display application. Further improvements of efficiencies still remain challenging in the field of VOLETs, especially on how to maximize the exciton utilization and suppress photon loss to further enhance the efficiency while taking into account the operational stability. To meet the requirements of future large-scale industrial production, designing high-efficiency (EQE > 20%) and low-voltage ( V < 10 V) VOLETs becomes a problem that urgently needs to be solved. Here, we report a device concept of an efficient and low-voltage all-vacuum-evaporation VOLET, incorporating a vertical organic permeable base transistor (OPBT) and an OLED into", "role": "user" }, { "content": "In a new publication in the scientific journal Nature Materials, researchers of the Institute for Applied Physics at TU Dresden introduce a novel device concept towards high-efficient and low-voltage vertical organic lighting-emitting transistors. With the new device architecture and fabrication technology, the team paves the way for a broad application of efficient OLED active matrix displays. In the group of Prof. Karl Leo, physicists, material scientists and engineers are working jointly on the development of novel organic materials and devices for high performance, flexible and possibly even biocompatible electronics and optoelectronics of the future. Increasing the performance of organic devices is one of the key challenges in their research. It was only last year, when the team headed by Dr. Hans Kleemann announced an important breakthrough with the development of efficient, printable vertical organic transistors. Now Dr. Zhongbin Wu, Dr. Yuan Liu, and Ph.D. student Erjuan Guo present the first electronic device that combines a vertical organic permeable base transistor (OPBT) and an OLED. With this novel device concept of an organic permeable base light-emitting transistor (OPB-LET), the researchers succeeded in combining the function of a highly efficient switching transistor and an organic light-emitting diode as commonly employed in active matrix displays. Active matrix liquid crystal displays (AMLCD) usually contain a matrix of thin-film transistors to drive LCD pixels. Each individual pixel has a circuit with active components (mostly transistors). In this context, organic light-emitting transistors, three-terminal devices combining a thin-film transistor with a light-emitting diode, have generated increasing interest. However, increasing their efficiency while keeping the operating voltage low remains a key challenge. \"The key to construct the high performance OPB-LETs is the permeable base electrode located at the center of the device, forming a distinctive optical microcavity and regulating charge carrier injection and transport. The thus designed three-terminal vertical optoelectronic devices can simultaneously high efficiencies (up to 24.6%), high luminance (up to 12,513 cd m-2), and low driving voltages (<5.0 V),\" explains Erjuan Guo. The performance of OPB-LETs demonstrated in this work is comparable to state-of-the-art OLEDs and cutting-edge, low-voltage organic transistors. Prof. Karl Leo explains: \"We expect that this novel device principle will pave the way for highly-efficient flexible displays with a rather simple pixel design.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Organic light-emitting transistors, three-terminal devices combining a thin-film transistor with a light-emitting diode, have generated increasing interest in organic electronics. However, increasing their efficiency while keeping the operating voltage low still remains a key challenge. Here, we demonstrate organic permeable base light-emitting transistors; these three-terminal vertical optoelectronic devices operate at driving voltages below 5.0 V; emit in the red, green and blue ranges; and reach, respectively, peak external quantum efficiencies of 19.6%, 24.6% and 11.8%, current efficiencies of 20.6 cd A –1 , 90.1 cd A –1 and 27.1 cd A –1 and maximum luminance values of 9,833 cd m –2 , 12,513 cd m –2 and 4,753 cd m –2 . Our simulations demonstrate that the nano-pore permeable base electrode located at the centre of the device, which forms a distinctive optical microcavity and regulates charge carrier injection and transport, is the key to the good performance obtained. Our work paves the way towards efficient and low-voltage organic light-emitting transistors, useful for power-efficient active matrix displays and solid-state lighting. Main The enormous potential of organic optoelectrical devices has been successfully proven by the industrialization of solid-state lighting and display technologies on the basis of organic light-emitting diodes (OLEDs) for mobile phones and televisions 1 , 2 , 3 . However, thin-film transistor technology in the active matrix backplane remains a primary technical challenge preventing wider commercial implementation of OLEDs. In particular, the driving transistor in an active matrix cell acting as a constant-current source for the OLED (Fig. 1a ) has to operate in the saturation regime, requiring a relatively high supply voltage. This high supply voltage would cause an unacceptably high power consumption. Overall, this leads to the unsatisfying situation that in commercial active matrix OLED displays, more than 40% of the power is lost 4 . Organic light-emitting transistors (OLETs) have been considered as an emerging class of organic semiconductor-based devices, where the light-producing capability of OLEDs and the electric-switching capability of organic thin-film transistors (TFTs) are integrated into a single stacked device, exhibiting great potential for integrated optoelectronics, smart display technology (Fig. 1b ), light communication, optical switching and solid-state lighting 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . Since the first demonstration of OLETs in 2003 (ref. 10 ), continual improvements in the performance of OLETs have been achieved. An OLET with an n-channel/emitter/p-channel trilayer device structure was developed; the trilayer devices realized a peak external quantum efficiency (EQE) of 5.0%, exceeding that of the corresponding reference OLEDs 23 . To construct high-performance OLETs using such a trilayer device structure, the energetic compatibility among the involved n-type, p-type and light-emitting organic semiconductors is an important factor that should be carefully considered 24 , 25 . A further improvement was made by optimizing the single-layer OLET and suppressing the exciton–polaron quenching, yielding a maximum current efficiency of 28.2 cd A –1 and a peak EQE of 8.16% (ref. 26 ). However, because of the low dielectric capacitance combined with the intrinsic low mobility, OLETs usually need high working voltages (>100 V) for optimal device performance 27 . To realize low-voltage OLETs below 10.0 V, the dual-layer dielectric strategy with low- k (defined as the dielectric constant) and high- k dielectrics can be applied, resulting in an EQE of 0.02% at 700 cd m –2 (ref. 28 ). Fig. 1: Fabrication of organic permeable base light-emitting transistors. a , Pixel circuit of traditional 2T1C (two thin-film transistors and one capacitor) digital drive scheme for active matrix OLED, T1 is the first transitor for selecting input signal, T2 is the second transistor for driving the OLEDs, C s is a capacitor, SEL represents the signal selection, a and b are the junction nodes, and V DD is the supply voltage. b , Circuit of OPB-LET used for active matrix OLED. c , Schematic device structure and hole/electron injection paths of OPB-LETs. For each colour device, the device architecture (the substrate, emitter, collector, base and channel layers) is the same. V B is the applied base voltage, V C is the collector voltage. The orange arrow represents the electron injection and transport, and the blue one shows the hole injection and transport. d , Chemical molecular structures of the functional materials; full names of these molecules are given in Supplementary Table 4 . Full size image To gain efficient and low-voltage OLETs, vertical-channel OLETs (VOLETs) with various structural designs and operating principles have been prepared in recent years 30 , 31 , 32 , 33 , 34 , 35 , 36 . Best-performing VOLETs with a single-wall carbon nanotube network source electrode were demonstrated in three primary colours 33 . The fabricated red, green and blue devices realized maximum luminance values of 1,000–2,000 cd m –2 at the drain and gate voltages of −7.0 V and −3.0 V. Current efficiencies of red, green and blue OLETs are 12.5 cd A –1 , 48.0 cd A –1 and 23.3 cd A –1 at the brightness of 250 cd m –2 , respectively. However, the performance of VOLETs is still unsatisfying considering the requirements for solid-state lighting and active matrix display application. Further improvements of efficiencies still remain challenging in the field of VOLETs, especially on how to maximize the exciton utilization and suppress photon loss to further enhance the efficiency while taking into account the operational stability. To meet the requirements of future large-scale industrial production, designing high-efficiency (EQE > 20%) and low-voltage ( V < 10 V) VOLETs becomes a problem that urgently needs to be solved. Here, we report a device concept of an efficient and low-voltage all-vacuum-evaporation VOLET, incorporating a vertical organic permeable base transistor (OPBT) and an OLED into<|im_end|> <|im_start|>assistant In a new publication in the scientific journal Nature Materials, researchers of the Institute for Applied Physics at TU Dresden introduce a novel device concept towards high-efficient and low-voltage vertical organic lighting-emitting transistors. With the new device architecture and fabrication technology, the team paves the way for a broad application of efficient OLED active matrix displays. In the group of Prof. Karl Leo, physicists, material scientists and engineers are working jointly on the development of novel organic materials and devices for high performance, flexible and possibly even biocompatible electronics and optoelectronics of the future. Increasing the performance of organic devices is one of the key challenges in their research. It was only last year, when the team headed by Dr. Hans Kleemann announced an important breakthrough with the development of efficient, printable vertical organic transistors. Now Dr. Zhongbin Wu, Dr. Yuan Liu, and Ph.D. student Erjuan Guo present the first electronic device that combines a vertical organic permeable base transistor (OPBT) and an OLED. With this novel device concept of an organic permeable base light-emitting transistor (OPB-LET), the researchers succeeded in combining the function of a highly efficient switching transistor and an organic light-emitting diode as commonly employed in active matrix displays. Active matrix liquid crystal displays (AMLCD) usually contain a matrix of thin-film transistors to drive LCD pixels. Each individual pixel has a circuit with active components (mostly transistors). In this context, organic light-emitting transistors, three-terminal devices combining a thin-film transistor with a light-emitting diode, have generated increasing interest. However, increasing their efficiency while keeping the operating voltage low remains a key challenge. "The key to construct the high performance OPB-LETs is the permeable base electrode located at the center of the device, forming a distinctive optical microcavity and regulating charge carrier injection and transport. The thus designed three-terminal vertical optoelectronic devices can simultaneously high efficiencies (up to 24.6%), high luminance (up to 12,513 cd m-2), and low driving voltages (<5.0 V)," explains Erjuan Guo. The performance of OPB-LETs demonstrated in this work is comparable to state-of-the-art OLEDs and cutting-edge, low-voltage organic transistors. Prof. Karl Leo explains: "We expect that this novel device principle will pave the way for highly-efficient flexible displays with a rather simple pixel design." <|im_end|>

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2,012

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Extreme Energy Events Project is an experiment devoted to the study of cosmic ray physics. It consists in a network of about 60 detectors based on the Multigap-Resistive Plate Chamber technology, distributed in the Italian territory and at CERN. In particular, the detectors are installed in high-school buildings, and the scientific activity is carried on in strong cooperation with students and professors. In this perspective, the project relies on citizen science, since non-professional people are fully involved in the constant monitoring of the operations. Furthermore, students participate in many stages of the scientific process, from the building of the detectors at CERN to the installation and commissioning of the telescopes inside their schools, to data collection and analysis, and to publication and dissemination of results. Working on a manuscript? Avoid the common mistakes 1 Introduction In its more general definition, citizen science is the involvement of the public in scientific research. It has been recognized as a strategic initiative, whose goal is to bring scientific awareness in the society. The COVID-19 pandemic proved how important it is to have an educated society, able to properly absorb scientific concepts, as the ones encoded in the statistical information it has been exposed to during the years 2020–2021. While standard dissemination procedures served as an important tool, so far, in bringing scientific ideas to the public, and updated people on the progresses of science in the different disciplines, from medicine to physics, the question remains on how to make people not only familiar with scientific notions, but really able to practice science in their everyday life. As an example, the ability to understand basic statistical concepts as frequency, conditional probability and margin of errors would play a relevant role in defining one’s behaviours in a risky situation as the pandemic is, and properly tell between the risk of getting the COVID-19 in the most serious forms or suffer for possible collateral effects of vaccination. To reach this goal, people cannot be simply exposed to science, but have to practice it with an active involvement in professional projects. From these considerations, citizen science is acquiring a dominant role, proposing different initiatives in which people are directly involved in data analysis, data collection, etc. In this context, even more crucial than the awareness of adults is the awareness of young people. Beyond the obvious importance of educating next generations to science, they can also be more reactive to inputs coming from the scientific community, given their capability of easily develop familiarity with modern technologies. With this goal in mind, the Italian Extreme Energy Events Project was designed in the early 2000s with the two-fold ambition of bringing science into the life of high-schools students and organizing an experiment on cosmic rays with the maximum area covered by a network of detectors. In order to achieve these goals, a coarse installation of well-equipped stations, with a coordinated data-taking system and well distributed all over the Italian territory was necessary. A continuous, well-organized monitoring system that allows to check the status of the network and let promptly intervene in case of problems was also mandatory. This ideal scenario was implemented through the decision of installing the detectors inside high schools all over the Italian territory, involving in this way, for the first time ever, also students and their teachers in a modern experiment within a unique outreach program. In this perspective, the project fully relies on citizen science, since the collaboration of students and teachers plays a dominant role in assuring the operational condition of the network. They are, in fact, involved in the constant monitoring of the detectors. Furthermore, students participate in many stages of the scientific process, from the building of the detectors at CERN to the installation and commissioning of the telescopes inside their schools, to data collection and analysis, and to publication and dissemination of results. 2 A network for detecting cosmic ray showers The Extreme Energy Events (EEE) Project is an extensive experiment finalized to the detection of secondary cosmic rays [ 1 ]. The latter are particles produced by the primary radiation—fully ionized nuclei of all the known elements, mostly protons and light nuclei—when they hit the Earth atmosphere. In passing through the medium, indeed, they interact and produce different secondary particles that, travelling for many kilometers, eventually get to the ground where they can be observed by properly equipped stations. A single, primary cosmic ray can produce a shower of up to several millions of particles, and the print on the ground can shed light on the nature of the primary particle producing it. The distribution of the particle hits can cover an area of many squared kilometers, and it increases as a function of the energy of the primary particle. In view of this, in order to detect and reconstruct a shower produced by highly-energetic particles, a detector system covering a very large area is mandatory. As an example, a primary proton with an energy of \$10^{17}\$ eV hitting the atmosphere at an altitude of 15 km can produce a secondary shower completely covering a city as big as Bologna (Italy), as shown in Fig. 1 . Fig. 1 Simulation of a very high energy shower (10 \$^{17}\$ eV) perpendicularly impinging on the city of Bologna and producing 1 million secondary muons on ground shown as red dots Full size image The EEE network consists of about 60 detectors, the so-called “EEE telescopes”, spread all over the Italian territory, including the islands, and also in Switzerland (at CERN). Most of these telescopes are installed in high schools, as shown in Fig. 2 . Tens of high schools without telescopes are also involved in the EEE Project and participate in the EEE meetings and activities, as it will be described later on (Sect. 5 ). The project has been launched and funded by the “Enrico Fermi” Historical Museum of Physics and Study and Research Centre [ 2 ], and it is now operated in collaboration with the Italian", "role": "user" }, { "content": "Citizen science projects offer the general public, or segments of that public such as school students, an opportunity to take part in scientific research. The Extreme Energy Events (EEE) Project in Italy is a cooperation between particle physicists studying cosmic rays and school students, and their teachers, throughout the country. This has the twin aims of bringing cosmic ray research into schools and setting up a country-wide 'open laboratory' of particle detectors. One of the lead researchers from the EEE Project consortium, Silvia Pisano of the Italian Centro Fermi and Laboratori Nazionali di Frascati of INFN, Rome, Italy, has summarized the results from about 20 years of this project in a new paper in The European Physical Journal Plus . Cosmic rays are high-energy particles that travel through space at nearly the speed of light; when they come into contact with the earth's atmosphere they produce a variety of secondary particles that can be detected when they reach ground level. One primary cosmic ray can produce a shower of such particles that completely covers a city the size of, for instance, Bologna. \"There are still many open questions about these secondary particles, such as the full details of their energy spectra,\" explains Pisano. The EEE network consists of about 60 detectors or \"EEE telescopes\" located across Italy, mostly in high schools. Students and their teachers are involved in all aspects of the project: installation and maintenance of the equipment, data collection and analysis, and disseminating the results. \"The peculiarity of an experiment designed in this way is that it can look for correlations between events that are hundreds of kilometers apart,\" adds Pisano. She and her collaborators are now planning to extend the network to include more schools, including some outside Italy. Another ongoing development is the design of a mixture of gases for the detectors to replace the powerful greenhouse gas tetrafluoroethane; school students are involved in this and other improvements. \"This experiment provides a unique environment for educating future generations in the practice of science,\" Pisano concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Extreme Energy Events Project is an experiment devoted to the study of cosmic ray physics. It consists in a network of about 60 detectors based on the Multigap-Resistive Plate Chamber technology, distributed in the Italian territory and at CERN. In particular, the detectors are installed in high-school buildings, and the scientific activity is carried on in strong cooperation with students and professors. In this perspective, the project relies on citizen science, since non-professional people are fully involved in the constant monitoring of the operations. Furthermore, students participate in many stages of the scientific process, from the building of the detectors at CERN to the installation and commissioning of the telescopes inside their schools, to data collection and analysis, and to publication and dissemination of results. Working on a manuscript? Avoid the common mistakes 1 Introduction In its more general definition, citizen science is the involvement of the public in scientific research. It has been recognized as a strategic initiative, whose goal is to bring scientific awareness in the society. The COVID-19 pandemic proved how important it is to have an educated society, able to properly absorb scientific concepts, as the ones encoded in the statistical information it has been exposed to during the years 2020–2021. While standard dissemination procedures served as an important tool, so far, in bringing scientific ideas to the public, and updated people on the progresses of science in the different disciplines, from medicine to physics, the question remains on how to make people not only familiar with scientific notions, but really able to practice science in their everyday life. As an example, the ability to understand basic statistical concepts as frequency, conditional probability and margin of errors would play a relevant role in defining one’s behaviours in a risky situation as the pandemic is, and properly tell between the risk of getting the COVID-19 in the most serious forms or suffer for possible collateral effects of vaccination. To reach this goal, people cannot be simply exposed to science, but have to practice it with an active involvement in professional projects. From these considerations, citizen science is acquiring a dominant role, proposing different initiatives in which people are directly involved in data analysis, data collection, etc. In this context, even more crucial than the awareness of adults is the awareness of young people. Beyond the obvious importance of educating next generations to science, they can also be more reactive to inputs coming from the scientific community, given their capability of easily develop familiarity with modern technologies. With this goal in mind, the Italian Extreme Energy Events Project was designed in the early 2000s with the two-fold ambition of bringing science into the life of high-schools students and organizing an experiment on cosmic rays with the maximum area covered by a network of detectors. In order to achieve these goals, a coarse installation of well-equipped stations, with a coordinated data-taking system and well distributed all over the Italian territory was necessary. A continuous, well-organized monitoring system that allows to check the status of the network and let promptly intervene in case of problems was also mandatory. This ideal scenario was implemented through the decision of installing the detectors inside high schools all over the Italian territory, involving in this way, for the first time ever, also students and their teachers in a modern experiment within a unique outreach program. In this perspective, the project fully relies on citizen science, since the collaboration of students and teachers plays a dominant role in assuring the operational condition of the network. They are, in fact, involved in the constant monitoring of the detectors. Furthermore, students participate in many stages of the scientific process, from the building of the detectors at CERN to the installation and commissioning of the telescopes inside their schools, to data collection and analysis, and to publication and dissemination of results. 2 A network for detecting cosmic ray showers The Extreme Energy Events (EEE) Project is an extensive experiment finalized to the detection of secondary cosmic rays [ 1 ]. The latter are particles produced by the primary radiation—fully ionized nuclei of all the known elements, mostly protons and light nuclei—when they hit the Earth atmosphere. In passing through the medium, indeed, they interact and produce different secondary particles that, travelling for many kilometers, eventually get to the ground where they can be observed by properly equipped stations. A single, primary cosmic ray can produce a shower of up to several millions of particles, and the print on the ground can shed light on the nature of the primary particle producing it. The distribution of the particle hits can cover an area of many squared kilometers, and it increases as a function of the energy of the primary particle. In view of this, in order to detect and reconstruct a shower produced by highly-energetic particles, a detector system covering a very large area is mandatory. As an example, a primary proton with an energy of $10^{17}$ eV hitting the atmosphere at an altitude of 15 km can produce a secondary shower completely covering a city as big as Bologna (Italy), as shown in Fig. 1 . Fig. 1 Simulation of a very high energy shower (10 $^{17}$ eV) perpendicularly impinging on the city of Bologna and producing 1 million secondary muons on ground shown as red dots Full size image The EEE network consists of about 60 detectors, the so-called “EEE telescopes”, spread all over the Italian territory, including the islands, and also in Switzerland (at CERN). Most of these telescopes are installed in high schools, as shown in Fig. 2 . Tens of high schools without telescopes are also involved in the EEE Project and participate in the EEE meetings and activities, as it will be described later on (Sect. 5 ). The project has been launched and funded by the “Enrico Fermi” Historical Museum of Physics and Study and Research Centre [ 2 ], and it is now operated in collaboration with the Italian<|im_end|> <|im_start|>assistant Citizen science projects offer the general public, or segments of that public such as school students, an opportunity to take part in scientific research. The Extreme Energy Events (EEE) Project in Italy is a cooperation between particle physicists studying cosmic rays and school students, and their teachers, throughout the country. This has the twin aims of bringing cosmic ray research into schools and setting up a country-wide 'open laboratory' of particle detectors. One of the lead researchers from the EEE Project consortium, Silvia Pisano of the Italian Centro Fermi and Laboratori Nazionali di Frascati of INFN, Rome, Italy, has summarized the results from about 20 years of this project in a new paper in The European Physical Journal Plus . Cosmic rays are high-energy particles that travel through space at nearly the speed of light; when they come into contact with the earth's atmosphere they produce a variety of secondary particles that can be detected when they reach ground level. One primary cosmic ray can produce a shower of such particles that completely covers a city the size of, for instance, Bologna. "There are still many open questions about these secondary particles, such as the full details of their energy spectra," explains Pisano. The EEE network consists of about 60 detectors or "EEE telescopes" located across Italy, mostly in high schools. Students and their teachers are involved in all aspects of the project: installation and maintenance of the equipment, data collection and analysis, and disseminating the results. "The peculiarity of an experiment designed in this way is that it can look for correlations between events that are hundreds of kilometers apart," adds Pisano. She and her collaborators are now planning to extend the network to include more schools, including some outside Italy. Another ongoing development is the design of a mixture of gases for the detectors to replace the powerful greenhouse gas tetrafluoroethane; school students are involved in this and other improvements. "This experiment provides a unique environment for educating future generations in the practice of science," Pisano concludes. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Sex determination mechanisms evolve surprisingly rapidly, yet little is known in the large nematode phylum other than for Caenorhabditis elegans , which relies on chromosomal XX-XO sex determination and a dosage compensation mechanism. Here we analyze by sex-specific genome sequencing and genetic analysis sex determination in two fungal feeding/plant-parasitic Bursaphelenchus nematodes and find that their sex differentiation is more likely triggered by random, epigenetic regulation than by more well-known mechanisms of chromosomal or environmental sex determination. There is no detectable difference in male and female chromosomes, nor any linkage to sexual phenotype. Moreover, the protein sets of these nematodes lack genes involved in X chromosome dosage counting or compensation. By contrast, our genetic screen for sex differentiation mutants identifies a Bursaphelenchus ortholog of tra-1 , the major output of the C. elegans sex determination cascade. Nematode sex determination pathways might have evolved by “bottom-up” accretion from the most downstream regulator, tra-1 . Introduction Sexual reproduction in animals results in powerful selective forces that optimize male and female phenotypes over the course of evolution. Since sexual dimorphism likely originated from the last common ancestor of celomate bilaterians, comprising most animals 1 , the mechanism that specifies sex is expected to be highly conserved; however, sex determination mechanisms are unexpectedly diverse and rapidly evolving (e.g., Dubendorfer et al. 2 ; Bachtrog et al. 3 ). Sex-determination mechanisms have been broadly classified based on the type of switch that triggers the sex determination cascade. In the common “genetic sex determination (GSD)” sex is determined by a sex chromosome (e.g., Sry gene in mammals 4 or the X:A ratio in the fruitfly Drosophila melanogaster 5 and the nematode Caenorhabditis elegans 6 , 7 or an autosomal gene or genes (e.g., polygenic in fish 8 , and a single-sex determination locus in house flies 9 ). In “environmental sex determination (ESD)”, sex is determined by temperature (e.g., reptiles 10 ) or local sex ratio of males to females (e.g., fish 11 ). An often-overlooked sex determination mechanism is based on random factors. For example, in ciliate Tetrahymena thermophila , alleles at the MAT locus determine the distribution of probabilities with which one of seven mating types is expressed 12 . However, very little is known about how much randomness is actually involved in sex determination. Sex determination takes place not only through the initial switch but also through a cascade of interacting genes. At the bottom of the cascade are the terminal regulators of sex determination, which integrate position and development information in sexual identity and coordinate male or female development. Despite the essential nature of sex determination, the genetic cascade of it is only understood in surprisingly few animals, such as the nematode C. elegans , the fly D. melanogaster 13 , and the mouse Mus musculus 14 . Sex determination of C. elegans is one of the most well-known aspects of its biology. C. elegans has two sexes: self-fertilizing hermaphrodite and male. The hermaphrodite is a modified female whose fourth larval stage produces sperm to be used later to fertilize oocytes 15 . A C. elegans male is produced by nondisjunction of the X-chromosome. The initial switch for sex determination in C. elegans is the ratio of X chromosomes (X), to sets of autosomes (A) 6 , 7 , 16 . XX embryos develop as hermaphrodites and XO embryos as males. The set of sex chromosomes inherited determines the activity of the master regulator Transformer-1 (TRA-1), a zinc-finger transcription factor that directs sexual differentiation through acting on the intermediate factors in the sex determination cascade. High TRA-1 activity in XX animals promotes hermaphrodite (female) differentiation, whereas low TRA-1 activity in XO animals allows for male differentiation. However, there are still many questions regarding the diversity of sex determination mechanisms and their evolution among nematodes 17 , 18 , 19 . Many studied nematode species have an XX/XO system for sex determination in which females/hermaphrodites are XX and males are XO, like C. elegans , though some animal parasitic nematodes have an XX/XY mechanism 20 , 21 . Furthermore, Mermithidae and some plant-parasitic nematodes have ESD 22 , 23 , though the molecular mechanisms underlying ESD are totally unknown. In particular, a major issue that remains largely unsolved is how sex determination pathways evolved among nematodes. Here, we focus on the sex determination of the nematode genus Bursaphelenchus , containing over 100 fungal-feeding and/or plant-parasitic species and two economically relevant plant pathogens: B. xylophilus , the pathogen of pine wilt disease, and B. cocophilus , the pathogen of red ring disease. We previously reported that B. okinawaensis has self-fertilizing hermaphrodites that spontaneously produces males with low frequency (< 1% of the population) 24 , similar to C. elegans . Strikingly, the sex ratio of progeny produced from a cross fertilization between a B. okinawaensis male and a B. okinawaensis hermaphrodite is still highly skewed (0.3% of males) towards hermaphrodites. If males have an XO karyotype, then this cross-mating should yield an approximately 1:1 ratio of males to hermaphrodites in the progeny. For example, in C. elegans , approximately 50% of progeny after cross-mating between a male and hermaphrodite are male. Moreover, it has been suggested that the sex determination of the closely-related species B. xylophilus is not an XX/XO system, based on DAPI staining cytology 25 . B. xylophilus is diecious and therefore always reproduces by mating. The sex ratio of B. xylophilus is generally biased towards females, but there is a certain variation in sex ratio, with the percentage of males varying between isolates in the range of 25–55% 26 . Given the sex ratio distortion and cytological observation in the above studies, we hypothesize that Bursaphelenchus nematodes may have a strikingly distinct sex determination system from C. elegans in this work. To test this hypothesis, we investigate both the initial trigger for sex determination using a genome-wide comparative analysis, and the genetic cascade that follows that initial switch in Bursaphelenchus nematodes using forward genetic screening and genomics. We find that their", "role": "user" }, { "content": "The sex and sexual characteristics constitute key aspects of an organism's life and are determined by a biological process known as sex determination. These ever-evolving mechanisms are broadly classified based on the type of \"switch\" that triggers them. Genetic sex determination is dependent on sex chromosomes, such as the X and Y chromosomes in human beings, whereas environmental sex determination depends on factors like temperature and the local ratio between males and females. Although most sex determination mechanisms are genetic or environmental, a third type of sex determination, which depends on completely random factors, also exists. This, however, has not been explored completely. The sex determination mechanism of Caenorhabditis elegans, a species of nematode, or our common garden-variety roundworm, is one of the best understood aspects of its biology. In its case, embryos with two X chromosomes, or the XX embryos, develop into hermaphrodites, while the XO embryos, which have one sex chromosome—the X chromosome—develop into males. Several species of nematodes have a sex determination mechanism similar to that of C. elegans. Interestingly, however, some nematode species also rely on the XX/XY system for sex determination, with both X and Y types of sex chromosomes, as well on environmental factors. Unfortunately, the mechanisms that cause this variance in sex-determination between nematode species have remained a mystery thus far. Recently, a group of researchers led by Associate Professor Ryoji Shinya from Meiji University, Japan, Professor Paul Sternberg from the California Institute of Technology, U.S., and Associate Professor Taisei Kikuchi from the University of Miyazaki, Japan, conducted a study to understand sex determination in two nematode species—Bursaphelenchus xylophilus and Bursaphelenchus okinawaensis. Dr. Shinya's team have long been engaged with nematode research. In this new study, they conducted a sex-specific genome-wide comparative analysis to determine the initial trigger of sex determination in the two Bursaphelenchus species, and genetic screening to determine the genetic cascade that followed the trigger. In their study published in Nature Communications, the researchers report that there is no difference in the number of chromosomes, or the genome, between males and females in B. xylophilus and between males and hermaphrodites in B. okinawaensis. This suggests that these sexes in both nematode species have identical genomes and no sex chromosomes. Thus, sex determination in these species must be through non-genetic mechanisms. Credit: Meiji University, Tokyo, Japan To explore this further, the team conducted an analysis to find out if environmental factors such as temperature, nutrient availability, and population density influenced sex determination in these organisms. They observed that these factors had a minimal effect on sex determination in the larvae of these species, and that none of the larvae turned into males. Considering that the offspring produced through self-fertilization in B. okinawaensis are essentially isogenic clones, it is clear that genetic differences are not required for sex determination in B. okinawaensis. In addition, even under fixed environmental conditions, genetically identical individuals of B. okinawaensis differentiate into hermaphrodites and males. The team suggests that the sex of B. okinawaensis nematodes is mainly determined by stochastic expression of an unknown trigger gene and/or developmental noise. In other words, sex differentiation occurs as a result of random events during development. The team also compared the orthologs, i.e., genes related by common descent, of similar sequences in C. elegans, B. xylophilus, and B. okinawaensis. They found that only downstream genes in these three nematodes were conserved, indicating that the Bursaphelenchus genus has a different sex determination trigger than does C. elegans. In addition, they conducted genetic analyses and identified one major sex determining locus in B. okinawaensis, known as Bok-tra-1a. Using bioinformatics and RNA-sequencing, they observed a conservation of putative targets in this regulating gene, further supporting the findings that indicated the conservation of downstream functions. This implies that nematode sex differentiation might have evolved from this downstream regulator. \"Our discovery of a striking new mode of sex determination in the nematode phylum might help not only with lab studies of parasitic nematodes, but also contribute to population engineering,\" observed an excited Dr. Shinya. Indicating the importance of these findings in pest control, Dr. Shinya says, \"Damage caused by plant-parasitic nematodes is estimated at 80 billion USD per year. Conventional nematicides are harmful for the environment. Understanding the sex determination mechanisms of plant parasitic nematodes can help in developing sterile strains that are not parasitic but may help reduce nematode populations in a safe and sustainable way.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Sex determination mechanisms evolve surprisingly rapidly, yet little is known in the large nematode phylum other than for Caenorhabditis elegans , which relies on chromosomal XX-XO sex determination and a dosage compensation mechanism. Here we analyze by sex-specific genome sequencing and genetic analysis sex determination in two fungal feeding/plant-parasitic Bursaphelenchus nematodes and find that their sex differentiation is more likely triggered by random, epigenetic regulation than by more well-known mechanisms of chromosomal or environmental sex determination. There is no detectable difference in male and female chromosomes, nor any linkage to sexual phenotype. Moreover, the protein sets of these nematodes lack genes involved in X chromosome dosage counting or compensation. By contrast, our genetic screen for sex differentiation mutants identifies a Bursaphelenchus ortholog of tra-1 , the major output of the C. elegans sex determination cascade. Nematode sex determination pathways might have evolved by “bottom-up” accretion from the most downstream regulator, tra-1 . Introduction Sexual reproduction in animals results in powerful selective forces that optimize male and female phenotypes over the course of evolution. Since sexual dimorphism likely originated from the last common ancestor of celomate bilaterians, comprising most animals 1 , the mechanism that specifies sex is expected to be highly conserved; however, sex determination mechanisms are unexpectedly diverse and rapidly evolving (e.g., Dubendorfer et al. 2 ; Bachtrog et al. 3 ). Sex-determination mechanisms have been broadly classified based on the type of switch that triggers the sex determination cascade. In the common “genetic sex determination (GSD)” sex is determined by a sex chromosome (e.g., Sry gene in mammals 4 or the X:A ratio in the fruitfly Drosophila melanogaster 5 and the nematode Caenorhabditis elegans 6 , 7 or an autosomal gene or genes (e.g., polygenic in fish 8 , and a single-sex determination locus in house flies 9 ). In “environmental sex determination (ESD)”, sex is determined by temperature (e.g., reptiles 10 ) or local sex ratio of males to females (e.g., fish 11 ). An often-overlooked sex determination mechanism is based on random factors. For example, in ciliate Tetrahymena thermophila , alleles at the MAT locus determine the distribution of probabilities with which one of seven mating types is expressed 12 . However, very little is known about how much randomness is actually involved in sex determination. Sex determination takes place not only through the initial switch but also through a cascade of interacting genes. At the bottom of the cascade are the terminal regulators of sex determination, which integrate position and development information in sexual identity and coordinate male or female development. Despite the essential nature of sex determination, the genetic cascade of it is only understood in surprisingly few animals, such as the nematode C. elegans , the fly D. melanogaster 13 , and the mouse Mus musculus 14 . Sex determination of C. elegans is one of the most well-known aspects of its biology. C. elegans has two sexes: self-fertilizing hermaphrodite and male. The hermaphrodite is a modified female whose fourth larval stage produces sperm to be used later to fertilize oocytes 15 . A C. elegans male is produced by nondisjunction of the X-chromosome. The initial switch for sex determination in C. elegans is the ratio of X chromosomes (X), to sets of autosomes (A) 6 , 7 , 16 . XX embryos develop as hermaphrodites and XO embryos as males. The set of sex chromosomes inherited determines the activity of the master regulator Transformer-1 (TRA-1), a zinc-finger transcription factor that directs sexual differentiation through acting on the intermediate factors in the sex determination cascade. High TRA-1 activity in XX animals promotes hermaphrodite (female) differentiation, whereas low TRA-1 activity in XO animals allows for male differentiation. However, there are still many questions regarding the diversity of sex determination mechanisms and their evolution among nematodes 17 , 18 , 19 . Many studied nematode species have an XX/XO system for sex determination in which females/hermaphrodites are XX and males are XO, like C. elegans , though some animal parasitic nematodes have an XX/XY mechanism 20 , 21 . Furthermore, Mermithidae and some plant-parasitic nematodes have ESD 22 , 23 , though the molecular mechanisms underlying ESD are totally unknown. In particular, a major issue that remains largely unsolved is how sex determination pathways evolved among nematodes. Here, we focus on the sex determination of the nematode genus Bursaphelenchus , containing over 100 fungal-feeding and/or plant-parasitic species and two economically relevant plant pathogens: B. xylophilus , the pathogen of pine wilt disease, and B. cocophilus , the pathogen of red ring disease. We previously reported that B. okinawaensis has self-fertilizing hermaphrodites that spontaneously produces males with low frequency (< 1% of the population) 24 , similar to C. elegans . Strikingly, the sex ratio of progeny produced from a cross fertilization between a B. okinawaensis male and a B. okinawaensis hermaphrodite is still highly skewed (0.3% of males) towards hermaphrodites. If males have an XO karyotype, then this cross-mating should yield an approximately 1:1 ratio of males to hermaphrodites in the progeny. For example, in C. elegans , approximately 50% of progeny after cross-mating between a male and hermaphrodite are male. Moreover, it has been suggested that the sex determination of the closely-related species B. xylophilus is not an XX/XO system, based on DAPI staining cytology 25 . B. xylophilus is diecious and therefore always reproduces by mating. The sex ratio of B. xylophilus is generally biased towards females, but there is a certain variation in sex ratio, with the percentage of males varying between isolates in the range of 25–55% 26 . Given the sex ratio distortion and cytological observation in the above studies, we hypothesize that Bursaphelenchus nematodes may have a strikingly distinct sex determination system from C. elegans in this work. To test this hypothesis, we investigate both the initial trigger for sex determination using a genome-wide comparative analysis, and the genetic cascade that follows that initial switch in Bursaphelenchus nematodes using forward genetic screening and genomics. We find that their<|im_end|> <|im_start|>assistant The sex and sexual characteristics constitute key aspects of an organism's life and are determined by a biological process known as sex determination. These ever-evolving mechanisms are broadly classified based on the type of "switch" that triggers them. Genetic sex determination is dependent on sex chromosomes, such as the X and Y chromosomes in human beings, whereas environmental sex determination depends on factors like temperature and the local ratio between males and females. Although most sex determination mechanisms are genetic or environmental, a third type of sex determination, which depends on completely random factors, also exists. This, however, has not been explored completely. The sex determination mechanism of Caenorhabditis elegans, a species of nematode, or our common garden-variety roundworm, is one of the best understood aspects of its biology. In its case, embryos with two X chromosomes, or the XX embryos, develop into hermaphrodites, while the XO embryos, which have one sex chromosome—the X chromosome—develop into males. Several species of nematodes have a sex determination mechanism similar to that of C. elegans. Interestingly, however, some nematode species also rely on the XX/XY system for sex determination, with both X and Y types of sex chromosomes, as well on environmental factors. Unfortunately, the mechanisms that cause this variance in sex-determination between nematode species have remained a mystery thus far. Recently, a group of researchers led by Associate Professor Ryoji Shinya from Meiji University, Japan, Professor Paul Sternberg from the California Institute of Technology, U.S., and Associate Professor Taisei Kikuchi from the University of Miyazaki, Japan, conducted a study to understand sex determination in two nematode species—Bursaphelenchus xylophilus and Bursaphelenchus okinawaensis. Dr. Shinya's team have long been engaged with nematode research. In this new study, they conducted a sex-specific genome-wide comparative analysis to determine the initial trigger of sex determination in the two Bursaphelenchus species, and genetic screening to determine the genetic cascade that followed the trigger. In their study published in Nature Communications, the researchers report that there is no difference in the number of chromosomes, or the genome, between males and females in B. xylophilus and between males and hermaphrodites in B. okinawaensis. This suggests that these sexes in both nematode species have identical genomes and no sex chromosomes. Thus, sex determination in these species must be through non-genetic mechanisms. Credit: Meiji University, Tokyo, Japan To explore this further, the team conducted an analysis to find out if environmental factors such as temperature, nutrient availability, and population density influenced sex determination in these organisms. They observed that these factors had a minimal effect on sex determination in the larvae of these species, and that none of the larvae turned into males. Considering that the offspring produced through self-fertilization in B. okinawaensis are essentially isogenic clones, it is clear that genetic differences are not required for sex determination in B. okinawaensis. In addition, even under fixed environmental conditions, genetically identical individuals of B. okinawaensis differentiate into hermaphrodites and males. The team suggests that the sex of B. okinawaensis nematodes is mainly determined by stochastic expression of an unknown trigger gene and/or developmental noise. In other words, sex differentiation occurs as a result of random events during development. The team also compared the orthologs, i.e., genes related by common descent, of similar sequences in C. elegans, B. xylophilus, and B. okinawaensis. They found that only downstream genes in these three nematodes were conserved, indicating that the Bursaphelenchus genus has a different sex determination trigger than does C. elegans. In addition, they conducted genetic analyses and identified one major sex determining locus in B. okinawaensis, known as Bok-tra-1a. Using bioinformatics and RNA-sequencing, they observed a conservation of putative targets in this regulating gene, further supporting the findings that indicated the conservation of downstream functions. This implies that nematode sex differentiation might have evolved from this downstream regulator. "Our discovery of a striking new mode of sex determination in the nematode phylum might help not only with lab studies of parasitic nematodes, but also contribute to population engineering," observed an excited Dr. Shinya. Indicating the importance of these findings in pest control, Dr. Shinya says, "Damage caused by plant-parasitic nematodes is estimated at 80 billion USD per year. Conventional nematicides are harmful for the environment. Understanding the sex determination mechanisms of plant parasitic nematodes can help in developing sterile strains that are not parasitic but may help reduce nematode populations in a safe and sustainable way." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5 ), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7 ), 8q24.21 (rs4733613, telomeric to MYC ), 15q15.1 (rs937213, in EIF2AK4 , near BMF ) and 14q32.33 (rs2498796, in AKT1 , near SIVA1 ). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro , suggesting that regulation of the expression of KLF5 , a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. Main Endometrial cancer is the fourth most common cancer in women in the United States 1 and Europe 2 and the most common cancer of the female reproductive system. The familial relative risk is ∼ 2 (refs. 3 , 4 ), but highly penetrant germline mutations in mismatch-repair genes 5 and DNA polymerase genes 6 , 7 account for only a small proportion of the familial aggregation. Our previous GWAS and subsequent fine-mapping identified the only two reported genome-wide significant risk loci for endometrial cancer, tagged by rs11263763 in HNF1B (intron 1) 8 and rs727479 in CYP19A1 (intron 4) 9 . To identify additional endometrial cancer risk loci, we reanalyzed data from our previous GWAS (the Australian National Endometrial Cancer Study (ANECS) and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) data sets 10 ) and conducted a meta-analysis with two further studies ( Supplementary Fig. 1 ). The first study was an independent GWAS, the National Study of Endometrial Cancer (NSECG), including 925 endometrial cancer cases genotyped using the Illumina 660W Quad array, 1,286 cancer-free controls from the CORGI/SP1 GWAS 11 , 12 and 2,674 controls from the 1958 British Birth Cohort 13 . The second study comprised 4,330 endometrial cancer cases and 26,849 controls from Europe, the United States and Australia, genotyped using a Custom Illumina Infinium iSelect array designed by the Collaborative Oncological Gene-environment Study (COGS) initiative 14 , 15 , 16 , 17 ( Supplementary Table 1 and Supplementary Note ). We first performed genome-wide imputation using 1000 Genomes Project data, allowing us to assess up to 8.6 million variants with allele frequency ≥1% across the different studies. Per-allele odds ratios and P values for all SNPs in the GWAS and iCOGS analyses were obtained using a logistic regression model. There was little evidence of systematic overdispersion of the test statistic ( λ GC = 1.002–1.038; Supplementary Fig. 2 ). A fixed-effects meta-analysis was conducted for all 2.3 million typed and well-imputed (info score >0.90) SNPs in a total of 6,542 endometrial cancer cases and 36,393 controls. The strongest associations were with SNPs in linkage disequilibrium (LD) with previously identified risk SNPs for endometrial cancer in HNF1B 8 , 10 , 18 and CYP19A1 (refs. 9 , 19 ) ( Fig. 1 and Table 1 ). For fourteen 1.5-Mb regions containing at least one new SNP with P meta < 1 × 10 −5 , we performed regional imputation using an additional reference panel that comprised high-coverage whole-genome sequencing data for 196 UK individuals ( Supplementary Table 2 ). Figure 1: Manhattan plot from endometrial cancer meta-analysis. The Manhattan plot shows negative log 10 -transformed P values from meta-analysis over 22 autosomes. There are seven loci surpassing genome-wide significance (red horizontal line), including two known loci, 15q21 ( CYP19A1 ) and 17q12 ( HNF1B ), and five new loci, 6q22 ( NCOA7 and HEY2 ), 8q24 ( MYC ), 13q22 ( KLF5 ), 14q32 ( AKT1 and SIVA1 ) and 15q15 ( EIF2AK4 and BMF ). Full size image Table 1 Risk loci associated with endometrial cancer at P < 5 × 10 −8 in the meta-analysis Full size table We identified five new regions containing at least one endometrial cancer risk SNP with P meta < 1 × 10 −7 and genotyped the most strongly associated SNP in each region in an additional 1,195 NSECG endometrial cancer cases and 751 controls using competitive allele-specific PCR (KASPar, KBiosciences) and the Fluidigm BioMark System ( Supplementary Table 3 ). Duplicate samples displayed concordance of >98.5% between different genotyping platforms ( Supplementary Table 4 ). All five SNPs were associated with endometrial cancer at genome-wide significance ( P < 5 × 10 −8 ; Figs. 2 and 3 , and Table 1 ), and these associations remained highly significant when analysis was restricted to cases with the endometrioid subtype only. Endometrioid-only analysis did not identify any additional risk loci. Expression quantitative trait locus (eQTL) analysis (Online Methods ) in normal uterine tissue 20 and endometrial cancer tumor and adjacent normal tissue 21 did not yield any SNPs robustly associated with the expression of nearby genes at the endometrial cancer risk loci ( Supplementary Table 5 ). However, for each risk locus, bioinformatic analysis including cell-type-specific expression and histone modification data identified correlated SNPs within 500 kb of the lead SNP in likely enhancers and multiple potential regulatory targets ( Supplementary Fig. 3 and Supplementary Table 6 ). The most compelling candidates for future functional analysis are described below. Figure 2: Forest plots for new endometrial cancer risk loci. The odds ratio and 95% confidence interval (L, lower; U, upper) for the loci in each study of the meta-analysis are listed and shown in the adjacent plot. The I 2 heterogeneity scores (all <0.4) suggest that there is no marked difference in effects between studies. ( a ) rs11841589 (13q22). ( b ) rs13328298 (6q22). ( c ) rs4733613 (8q24). ( d ) rs17232730 (8q24;", "role": "user" }, { "content": "An international collaboration of researchers has identified five new gene regions that increase a woman's risk of developing endometrial cancer, one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine. Endometrial cancer affects the lining of the uterus. It is the fourth most commonly diagnosed cancer in UK women, with around 9,000 new cases being diagnosed each year. Researchers at the University of Cambridge, Oxford University and QIMR Berghofer Medical Research Institute in Brisbane studied the DNA of over 7,000 women with endometrial cancer and 37,000 women without cancer to identify genetic variants that affected a woman's risk of developing the disease. The results are published today in the journal Nature Genetics. Dr Deborah Thompson from the Department of Public Health and Primary Care at the University of Cambridge said: \"Our findings help us to paint a clearer picture of the genetic causes of endometrial cancer in women, particularly where there no strong family history of cancer. Prior to this study, we only knew of four regions of the genome in which a common genetic variant increases a woman's risk of endometrial cancer. \"In this study we have identified another five regions, bringing the total to nine. This finding doubles the number of known risk regions, and therefore makes an important contribution to our knowledge of the genetic drivers of endometrial cancer. \"Interestingly, several of the gene regions we identified in the study were already known to contribute to the risk of other common cancers such as ovarian and prostate. \"Although each individual variant only increases risk by around 10-15%, their real value will be in looking at the total number of such variants inherited by a woman, together with her other risk factors, in order to identify those women at higher risk of endometrial cancer so that they can be regularly checked and be alert to the early signs and symptoms of the disease.\" The study also looked at how the identified gene regions might be increasing the risk of cancer, and these findings have implications for the future treatment of endometrial cancer patients. \"As we develop a more comprehensive view of the genetic risk factors for endometrial cancer, we can start to work out which genes could potentially be targeted with new treatments down the track,\" said Associate Professor Amanda Spurdle from QIMR Berghofer. \"In particular, we can start looking into whether there are drugs that are already approved and available for use that can be used to target those genes.\" The study was an international collaboration involving researchers from Australia, the United Kingdom, German, Belgium, Norway, Sweden, the United States and China. The UK part of the study received funding from Cancer Research UK. Dr Emma Smith, Cancer Research UK's science information manager, said: \"The discovery of genetic changes that affect women's risk of developing endometrial – or womb – cancer could help doctors identify women at higher risk, who could benefit from being more closely monitored for signs of the disease. \"It might also provide clues into the faulty molecules that play an important role in womb cancer, leading to potential new treatments. More than a third of womb cancer cases in the UK each year could be prevented, and staying a healthy weight and keeping active are both great ways for women to reduce the risk.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5 ), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7 ), 8q24.21 (rs4733613, telomeric to MYC ), 15q15.1 (rs937213, in EIF2AK4 , near BMF ) and 14q32.33 (rs2498796, in AKT1 , near SIVA1 ). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro , suggesting that regulation of the expression of KLF5 , a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. Main Endometrial cancer is the fourth most common cancer in women in the United States 1 and Europe 2 and the most common cancer of the female reproductive system. The familial relative risk is ∼ 2 (refs. 3 , 4 ), but highly penetrant germline mutations in mismatch-repair genes 5 and DNA polymerase genes 6 , 7 account for only a small proportion of the familial aggregation. Our previous GWAS and subsequent fine-mapping identified the only two reported genome-wide significant risk loci for endometrial cancer, tagged by rs11263763 in HNF1B (intron 1) 8 and rs727479 in CYP19A1 (intron 4) 9 . To identify additional endometrial cancer risk loci, we reanalyzed data from our previous GWAS (the Australian National Endometrial Cancer Study (ANECS) and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) data sets 10 ) and conducted a meta-analysis with two further studies ( Supplementary Fig. 1 ). The first study was an independent GWAS, the National Study of Endometrial Cancer (NSECG), including 925 endometrial cancer cases genotyped using the Illumina 660W Quad array, 1,286 cancer-free controls from the CORGI/SP1 GWAS 11 , 12 and 2,674 controls from the 1958 British Birth Cohort 13 . The second study comprised 4,330 endometrial cancer cases and 26,849 controls from Europe, the United States and Australia, genotyped using a Custom Illumina Infinium iSelect array designed by the Collaborative Oncological Gene-environment Study (COGS) initiative 14 , 15 , 16 , 17 ( Supplementary Table 1 and Supplementary Note ). We first performed genome-wide imputation using 1000 Genomes Project data, allowing us to assess up to 8.6 million variants with allele frequency ≥1% across the different studies. Per-allele odds ratios and P values for all SNPs in the GWAS and iCOGS analyses were obtained using a logistic regression model. There was little evidence of systematic overdispersion of the test statistic ( λ GC = 1.002–1.038; Supplementary Fig. 2 ). A fixed-effects meta-analysis was conducted for all 2.3 million typed and well-imputed (info score >0.90) SNPs in a total of 6,542 endometrial cancer cases and 36,393 controls. The strongest associations were with SNPs in linkage disequilibrium (LD) with previously identified risk SNPs for endometrial cancer in HNF1B 8 , 10 , 18 and CYP19A1 (refs. 9 , 19 ) ( Fig. 1 and Table 1 ). For fourteen 1.5-Mb regions containing at least one new SNP with P meta < 1 × 10 −5 , we performed regional imputation using an additional reference panel that comprised high-coverage whole-genome sequencing data for 196 UK individuals ( Supplementary Table 2 ). Figure 1: Manhattan plot from endometrial cancer meta-analysis. The Manhattan plot shows negative log 10 -transformed P values from meta-analysis over 22 autosomes. There are seven loci surpassing genome-wide significance (red horizontal line), including two known loci, 15q21 ( CYP19A1 ) and 17q12 ( HNF1B ), and five new loci, 6q22 ( NCOA7 and HEY2 ), 8q24 ( MYC ), 13q22 ( KLF5 ), 14q32 ( AKT1 and SIVA1 ) and 15q15 ( EIF2AK4 and BMF ). Full size image Table 1 Risk loci associated with endometrial cancer at P < 5 × 10 −8 in the meta-analysis Full size table We identified five new regions containing at least one endometrial cancer risk SNP with P meta < 1 × 10 −7 and genotyped the most strongly associated SNP in each region in an additional 1,195 NSECG endometrial cancer cases and 751 controls using competitive allele-specific PCR (KASPar, KBiosciences) and the Fluidigm BioMark System ( Supplementary Table 3 ). Duplicate samples displayed concordance of >98.5% between different genotyping platforms ( Supplementary Table 4 ). All five SNPs were associated with endometrial cancer at genome-wide significance ( P < 5 × 10 −8 ; Figs. 2 and 3 , and Table 1 ), and these associations remained highly significant when analysis was restricted to cases with the endometrioid subtype only. Endometrioid-only analysis did not identify any additional risk loci. Expression quantitative trait locus (eQTL) analysis (Online Methods ) in normal uterine tissue 20 and endometrial cancer tumor and adjacent normal tissue 21 did not yield any SNPs robustly associated with the expression of nearby genes at the endometrial cancer risk loci ( Supplementary Table 5 ). However, for each risk locus, bioinformatic analysis including cell-type-specific expression and histone modification data identified correlated SNPs within 500 kb of the lead SNP in likely enhancers and multiple potential regulatory targets ( Supplementary Fig. 3 and Supplementary Table 6 ). The most compelling candidates for future functional analysis are described below. Figure 2: Forest plots for new endometrial cancer risk loci. The odds ratio and 95% confidence interval (L, lower; U, upper) for the loci in each study of the meta-analysis are listed and shown in the adjacent plot. The I 2 heterogeneity scores (all <0.4) suggest that there is no marked difference in effects between studies. ( a ) rs11841589 (13q22). ( b ) rs13328298 (6q22). ( c ) rs4733613 (8q24). ( d ) rs17232730 (8q24;<|im_end|> <|im_start|>assistant An international collaboration of researchers has identified five new gene regions that increase a woman's risk of developing endometrial cancer, one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine. Endometrial cancer affects the lining of the uterus. It is the fourth most commonly diagnosed cancer in UK women, with around 9,000 new cases being diagnosed each year. Researchers at the University of Cambridge, Oxford University and QIMR Berghofer Medical Research Institute in Brisbane studied the DNA of over 7,000 women with endometrial cancer and 37,000 women without cancer to identify genetic variants that affected a woman's risk of developing the disease. The results are published today in the journal Nature Genetics. Dr Deborah Thompson from the Department of Public Health and Primary Care at the University of Cambridge said: "Our findings help us to paint a clearer picture of the genetic causes of endometrial cancer in women, particularly where there no strong family history of cancer. Prior to this study, we only knew of four regions of the genome in which a common genetic variant increases a woman's risk of endometrial cancer. "In this study we have identified another five regions, bringing the total to nine. This finding doubles the number of known risk regions, and therefore makes an important contribution to our knowledge of the genetic drivers of endometrial cancer. "Interestingly, several of the gene regions we identified in the study were already known to contribute to the risk of other common cancers such as ovarian and prostate. "Although each individual variant only increases risk by around 10-15%, their real value will be in looking at the total number of such variants inherited by a woman, together with her other risk factors, in order to identify those women at higher risk of endometrial cancer so that they can be regularly checked and be alert to the early signs and symptoms of the disease." The study also looked at how the identified gene regions might be increasing the risk of cancer, and these findings have implications for the future treatment of endometrial cancer patients. "As we develop a more comprehensive view of the genetic risk factors for endometrial cancer, we can start to work out which genes could potentially be targeted with new treatments down the track," said Associate Professor Amanda Spurdle from QIMR Berghofer. "In particular, we can start looking into whether there are drugs that are already approved and available for use that can be used to target those genes." The study was an international collaboration involving researchers from Australia, the United Kingdom, German, Belgium, Norway, Sweden, the United States and China. The UK part of the study received funding from Cancer Research UK. Dr Emma Smith, Cancer Research UK's science information manager, said: "The discovery of genetic changes that affect women's risk of developing endometrial – or womb – cancer could help doctors identify women at higher risk, who could benefit from being more closely monitored for signs of the disease. "It might also provide clues into the faulty molecules that play an important role in womb cancer, leading to potential new treatments. More than a third of womb cancer cases in the UK each year could be prevented, and staying a healthy weight and keeping active are both great ways for women to reduce the risk." <|im_end|>

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2,293

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429–32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P - value =3.12 × 10 −8 ) and in the joint discovery and replication meta-analysis ( P - value =3.28 × 10 −9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 ( CADM2 ) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex ( P-value =4 × 10 −4 ). The protein encoded by CADM2 is involved in glutamate signaling ( P-value =7.22 × 10 −15 ), gamma-aminobutyric acid (GABA) transport ( P-value= 1.36 × 10 −11 ) and neuron cell-cell adhesion ( P-value =1.48 × 10 −13 ). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. Introduction Cognitive function broadly refers to multiple dissociable, but inter-correlated cognitive domains, including memory, language, executive function, processing speed and visuospatial ability. Unimpaired cognitive abilities are an important determinant of quality of life. Impairment of cognitive abilities is seen with dementia, bipolar disorder, schizophrenia and attention deficit hyperactivity disorder. 1 , 2 , 3 Among the cognitive domains, processing speed is considered a fundamental process, reflecting the speed at which cognitive operations are performed. 4 , 5 Executive function reflects higher-order cognitive capabilities, presumably mediated by the frontal lobes, including response inhibition, attention, cognitive flexibility and planning. 6 In addition to domain-specific variance, processing speed and executive function are also, in part, explained by an individual’s general cognitive ability. The same holds true for the genetic variance of performance on individual cognitive tests. 7 The estimated heritability of general cognitive ability from twin studies of intelligence ranges from approximately 50 to 80%, and appears to increase with age. 8 The general intelligence construct g has a heritability of around 29%, for example, observed in a genome-wide association study (GWAS) based on the GCTA procedure. 9 , 10 Heritability of performance on tests within individual cognitive domains has been estimated from 12 to 68% 11 , 12 , 13 , 14 for processing speed and 16–63% 13 , 15 , 16 for executive function. Of note, there is also considerable covariation between cognitive domains. 17 , 18 There is, for example, debate as to whether processing speed is merely one of the cognitive domains, or whether processing speed has a more unique role as a fundamental process underlying variation in more complex cognitive traits as well as in cognitive aging. 19 , 20 Identifying variants that influence quantitative variation in processing speed and executive function may provide insight into the normal variation in these important cognitive functions, and may ultimately increase our understanding of diseases that disrupt these cognitive domains. Although various genes have been identified as potential candidates affecting different dimensions of cognitive function, prior studies have yielded inconsistent results. 21 Candidate gene meta-analyses have shown associations of the apolipoprotein E ( APOE ) gene 22 and the DTNBP1 (dystrobrevin binding protein 1) gene 23 to general cognitive ability, although these findings do not meet the current standard of genome-wide significance ( P-value between 0.01 and 0.05 for APOE , P-value =0.003 for DTNBP1 ). Linkage analyses of executive function tasks have identified regions on chromosomes 2q, 5q, 11q, 13q and 14q. 24 , 25 , 26 To our knowledge, there are currently five published GWAS on processing speed and executive traits in adults. 5 , 27 , 28 , 29 , 30 Processing speed was suggestively associated with several loci, of which the TRIB3 (tribbles homolog 3) gene was the strongest and biologically most interesting. 5 For executive function, one study 30 identified a genome-wide significant association ( P-value =4.32 × 10 −8 ) of a single-nucleotide polymorphism (SNP) in the WDR72 gene (chromosome 15) for a cognitive test similar to the Stroop interference test. The WDR72 gene has also been associated with kidney function. 31 Prior studies of executive function and processing speed have been limited by small sample sizes (700 and 4000 subjects), resulting in limited power, and by application of lenient significance thresholds. Replication of prior findings has been lacking both across and within cognitive domains. In this study, we performed a large-scale meta-analysis to identify genetic variants associated with executive function and information processing speed combining GWAS from multiple cohorts of non-demented middle-aged and older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. 32 Materials and methods Study populations The discovery phase included 20 cohorts contributing to one or more test ( N per test=5429–32 070) ( Supplementary Table 1 ). The number of discovery cohorts and subjects varied based on the availability of each test. Each cohort had extensive phenotypic data on one or more traits, and genome-wide SNP data available. Details for each cohort are given in Supplementary Table 1 . Subjects aged 45 and older who were free of stroke and dementia and of European ancestry were eligible for the study.", "role": "user" }, { "content": "An international team of researchers, including investigators from the University of Mississippi Medical Center (UMMC), has identified a gene that underlies healthy information processing—a first step on a complicated road to understand cognitive aging and age-related diseases, such as Alzheimer's disease. The study, published online and expected to come out this fall in a print edition of the journal Molecular Psychiatry, is one of the the largest genetics study to date to link a specific genetic mutation and information processing speed. \"It is well known that genetic variation plays an important role in explaining individual differences in thinking skills such as memory and information processing speed,\" said Dr. Tom Mosley, director of the Memory Impairment and Neurodegenerative Dementia (MIND) Center at UMMC and senior scientist on the study. \"However, the genes that underlie thinking skills remain largely unknown. Our team has identified a genetic mutation that may help unravel this puzzle.\" The effort was conducted through the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, in which researchers from around the world work together to search for genetic causes of disease in the general aging population. Previous studies in families and in twins have shown genetics play an important role in cognitive functioning, but finding the specific genes or genetic regions has proved difficult, requiring a combination of large sample sizes and detailed genetic measurements. But in this case, researchers analyzed data from more than 30,000 people who were 45 or older, bringing together genetic and cognitive functioning data from participants in several studies in 12 different countries. In addition, they examined genetic variations across 2.5 million sites along each individual's DNA, looking for associations between genetic variants and performance on several different tests of cognitive function. Of the different cognitive skills examined, the strongest genetic association was related to performance on a test of information processing speed. The most associated variants were located in the CADM2 gene, also known as Syncam2. \"It seems like, through this genetic analysis, we have identified a genetic variant which partly explains the differences in information processing speed between people,\" said Dr. Carla Ibrahim-Verbaas, a resident in neurology at Erasmus University Medical Center in Rotterdam, The Netherlands, and lead author on the study. \"It confirms the likely role of CADM2 in between-cell communication, and therefore cognitive performance. It is of interest that the gene has also been suggested in other studies to be involved in autism and personality traits.\" She cautions that the results remain to be replicated by additional studies. Researchers said a protein product from CADM2 is involved in the short-term and long-term chemically mediated communication between brain cells and is specifically abundant in the frontal and cingulate cortex, which are areas of the brain known to be involved in processing speed as well as in the developing brain. \"We are finding that for complex traits, like cognitive function, not a single gene, but several genes or genetic regions come into play, with each making a relatively small contribution,\" Mosley said. \"We now have the technology to measure across the entire genome in a much more fine-grained manner compared to a few years ago, in this case 2.5 million sites, and are able to combine that genetic mapping with large sample sizes. The collaboration of leading scientists from around the world, who have agreed to pool their data and analytic resources, is significantly enhancing our ability to identify genes related to complex brain functions and disease.\" The core CHARGE cohorts include five population-based studies, including the Atherosclerosis Risk in Communities study, AGES-Reykjavik Study, Framingham Heart Study, Cardiovascular Health Study, and the Rotterdam study. Funding for the cohorts was provided by the National Institutes of Health. Mosley said the study complements two other discoveries by the CHARGE team that identified genetic variants associated with both memory performance and general cognitive functioning in older adults. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429–32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P - value =3.12 × 10 −8 ) and in the joint discovery and replication meta-analysis ( P - value =3.28 × 10 −9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 ( CADM2 ) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex ( P-value =4 × 10 −4 ). The protein encoded by CADM2 is involved in glutamate signaling ( P-value =7.22 × 10 −15 ), gamma-aminobutyric acid (GABA) transport ( P-value= 1.36 × 10 −11 ) and neuron cell-cell adhesion ( P-value =1.48 × 10 −13 ). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. Introduction Cognitive function broadly refers to multiple dissociable, but inter-correlated cognitive domains, including memory, language, executive function, processing speed and visuospatial ability. Unimpaired cognitive abilities are an important determinant of quality of life. Impairment of cognitive abilities is seen with dementia, bipolar disorder, schizophrenia and attention deficit hyperactivity disorder. 1 , 2 , 3 Among the cognitive domains, processing speed is considered a fundamental process, reflecting the speed at which cognitive operations are performed. 4 , 5 Executive function reflects higher-order cognitive capabilities, presumably mediated by the frontal lobes, including response inhibition, attention, cognitive flexibility and planning. 6 In addition to domain-specific variance, processing speed and executive function are also, in part, explained by an individual’s general cognitive ability. The same holds true for the genetic variance of performance on individual cognitive tests. 7 The estimated heritability of general cognitive ability from twin studies of intelligence ranges from approximately 50 to 80%, and appears to increase with age. 8 The general intelligence construct g has a heritability of around 29%, for example, observed in a genome-wide association study (GWAS) based on the GCTA procedure. 9 , 10 Heritability of performance on tests within individual cognitive domains has been estimated from 12 to 68% 11 , 12 , 13 , 14 for processing speed and 16–63% 13 , 15 , 16 for executive function. Of note, there is also considerable covariation between cognitive domains. 17 , 18 There is, for example, debate as to whether processing speed is merely one of the cognitive domains, or whether processing speed has a more unique role as a fundamental process underlying variation in more complex cognitive traits as well as in cognitive aging. 19 , 20 Identifying variants that influence quantitative variation in processing speed and executive function may provide insight into the normal variation in these important cognitive functions, and may ultimately increase our understanding of diseases that disrupt these cognitive domains. Although various genes have been identified as potential candidates affecting different dimensions of cognitive function, prior studies have yielded inconsistent results. 21 Candidate gene meta-analyses have shown associations of the apolipoprotein E ( APOE ) gene 22 and the DTNBP1 (dystrobrevin binding protein 1) gene 23 to general cognitive ability, although these findings do not meet the current standard of genome-wide significance ( P-value between 0.01 and 0.05 for APOE , P-value =0.003 for DTNBP1 ). Linkage analyses of executive function tasks have identified regions on chromosomes 2q, 5q, 11q, 13q and 14q. 24 , 25 , 26 To our knowledge, there are currently five published GWAS on processing speed and executive traits in adults. 5 , 27 , 28 , 29 , 30 Processing speed was suggestively associated with several loci, of which the TRIB3 (tribbles homolog 3) gene was the strongest and biologically most interesting. 5 For executive function, one study 30 identified a genome-wide significant association ( P-value =4.32 × 10 −8 ) of a single-nucleotide polymorphism (SNP) in the WDR72 gene (chromosome 15) for a cognitive test similar to the Stroop interference test. The WDR72 gene has also been associated with kidney function. 31 Prior studies of executive function and processing speed have been limited by small sample sizes (700 and 4000 subjects), resulting in limited power, and by application of lenient significance thresholds. Replication of prior findings has been lacking both across and within cognitive domains. In this study, we performed a large-scale meta-analysis to identify genetic variants associated with executive function and information processing speed combining GWAS from multiple cohorts of non-demented middle-aged and older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. 32 Materials and methods Study populations The discovery phase included 20 cohorts contributing to one or more test ( N per test=5429–32 070) ( Supplementary Table 1 ). The number of discovery cohorts and subjects varied based on the availability of each test. Each cohort had extensive phenotypic data on one or more traits, and genome-wide SNP data available. Details for each cohort are given in Supplementary Table 1 . Subjects aged 45 and older who were free of stroke and dementia and of European ancestry were eligible for the study.<|im_end|> <|im_start|>assistant An international team of researchers, including investigators from the University of Mississippi Medical Center (UMMC), has identified a gene that underlies healthy information processing—a first step on a complicated road to understand cognitive aging and age-related diseases, such as Alzheimer's disease. The study, published online and expected to come out this fall in a print edition of the journal Molecular Psychiatry, is one of the the largest genetics study to date to link a specific genetic mutation and information processing speed. "It is well known that genetic variation plays an important role in explaining individual differences in thinking skills such as memory and information processing speed," said Dr. Tom Mosley, director of the Memory Impairment and Neurodegenerative Dementia (MIND) Center at UMMC and senior scientist on the study. "However, the genes that underlie thinking skills remain largely unknown. Our team has identified a genetic mutation that may help unravel this puzzle." The effort was conducted through the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, in which researchers from around the world work together to search for genetic causes of disease in the general aging population. Previous studies in families and in twins have shown genetics play an important role in cognitive functioning, but finding the specific genes or genetic regions has proved difficult, requiring a combination of large sample sizes and detailed genetic measurements. But in this case, researchers analyzed data from more than 30,000 people who were 45 or older, bringing together genetic and cognitive functioning data from participants in several studies in 12 different countries. In addition, they examined genetic variations across 2.5 million sites along each individual's DNA, looking for associations between genetic variants and performance on several different tests of cognitive function. Of the different cognitive skills examined, the strongest genetic association was related to performance on a test of information processing speed. The most associated variants were located in the CADM2 gene, also known as Syncam2. "It seems like, through this genetic analysis, we have identified a genetic variant which partly explains the differences in information processing speed between people," said Dr. Carla Ibrahim-Verbaas, a resident in neurology at Erasmus University Medical Center in Rotterdam, The Netherlands, and lead author on the study. "It confirms the likely role of CADM2 in between-cell communication, and therefore cognitive performance. It is of interest that the gene has also been suggested in other studies to be involved in autism and personality traits." She cautions that the results remain to be replicated by additional studies. Researchers said a protein product from CADM2 is involved in the short-term and long-term chemically mediated communication between brain cells and is specifically abundant in the frontal and cingulate cortex, which are areas of the brain known to be involved in processing speed as well as in the developing brain. "We are finding that for complex traits, like cognitive function, not a single gene, but several genes or genetic regions come into play, with each making a relatively small contribution," Mosley said. "We now have the technology to measure across the entire genome in a much more fine-grained manner compared to a few years ago, in this case 2.5 million sites, and are able to combine that genetic mapping with large sample sizes. The collaboration of leading scientists from around the world, who have agreed to pool their data and analytic resources, is significantly enhancing our ability to identify genes related to complex brain functions and disease." The core CHARGE cohorts include five population-based studies, including the Atherosclerosis Risk in Communities study, AGES-Reykjavik Study, Framingham Heart Study, Cardiovascular Health Study, and the Rotterdam study. Funding for the cohorts was provided by the National Institutes of Health. Mosley said the study complements two other discoveries by the CHARGE team that identified genetic variants associated with both memory performance and general cognitive functioning in older adults. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Near-zero index (NZI) materials, i.e., materials having a phase refractive index close to zero, are known to enhance or inhibit light-matter interactions. Most theoretical derivations of fundamental radiative processes rely on energetic considerations and detailed balance equations, but not on momentum considerations. Because momentum exchange should also be incorporated into theoretical models, we investigate momentum inside the three categories of NZI materials, i.e., inside epsilon-and-mu-near-zero (EMNZ), epsilon-near-zero (ENZ) and mu-near-zero (MNZ) materials. In the context of Abraham–Minkowski debate in dispersive materials, we show that Minkowski-canonical momentum of light is zero inside all categories of NZI materials while Abraham-kinetic momentum of light is zero in ENZ and MNZ materials but nonzero inside EMNZ materials. We theoretically demonstrate that momentum recoil, transfer momentum from the field to the atom and Doppler shift are inhibited in NZI materials. Fundamental radiative processes inhibition is also explained due to those momentum considerations inside three-dimensional NZI materials. Absence of diffraction pattern in slits experiments is seen as a consequence of zero Minkowski momentum. Lastly, consequence on Heisenberg inequality, microscopy applications and on the canonical momentum as generator of translations are discussed. Those findings are appealing for a better understanding of fundamental light-matter interactions at the nanoscale as well as for lasing applications. Introduction In his seminal papers introducing fundamental radiative processes 1 , 2 , Einstein noted that, while the description of the interaction between light and matter typically only take into account energy exchange, energy and momentum are directly connected to each other, and momentum exchange is equally important. A consequence of Einstein’s theory of radiation is that the absorption/emission of a quantum of energy ħω is accompanied by a momentum transfer \$\\hbar \\omega /c = \\hbar k\$ between the field and the atom, with ħ the reduced Planck constant and k being the wavevector. When an atom absorbs radiation, the momentum transfer is in the direction of propagation of the photon, while for emission the transfer is in the opposite direction, inducing a recoil of the atom. In a medium, the momentum of electromagnetic radiation (“electromagnetic momentum”) depends on the refractive index. However, there has been a long-standing debate concerning the dependence of the electromagnetic momentum on the refractive index depending on whether one uses the Minkowski 3 or Abraham 4 , 5 formulation of the electromagnetic momentum. The electromagnetic momentum density in the Abraham ( g A ) and Minkowski ( g M ) forms are $${{{\\mathbf{g}}}}_A = {{{\\mathbf{E}}}} \\times {{{\\mathbf{H}}}}/c^2$$ (1) and $${{{\\mathbf{g}}}}_M = {{{\\mathbf{D}}}} \\times {{{\\mathbf{B}}}}$$ (2) respectively 6 , 7 . These formulations yield the following two expressions for the magnitude of the electromagnetic momentum in a dispersive medium: $$p_A = \\frac{{\\hbar \\omega }}{{n_g(\\omega )c}}$$ (3) and $$p_M = n_\\varphi (\\omega )\\frac{{\\hbar \\omega }}{c}$$ (4) for the Abraham momentum p A and the Minkowski momentum p M , respectively, and where \$n_\\varphi (\\omega ) = \\sqrt {\\varepsilon (\\omega )\\mu (\\omega )}\$ is the phase refractive index and \$n_g = c\\left( {\\frac{{d\\omega }}{{dk}}} \\right)^{ - 1}\$ the group refractive index. Note that in a non-dispersive medium, \$n_\\varphi = n_g = n\$ and consequently \$p_M = n\\frac{{\\hbar \\omega }}{c}\$ and \$p_A = \\frac{{\\hbar \\omega }}{{nc}}\$ . The difference between those two expressions for the electromagnetic momentum is at the heart of Abraham–Minkowski debate. Some experiments appear to support the Minkowski formulation 8 , 9 , 10 , while others support the Abraham formulation 11 , 12 , 13 . A resolution of this long-lasting dilemma was recently proposed 14 , 15 by attributing the difference between the Abraham and Minkowski momenta of light to the duality of light and matter 6 . For a particle, the classical (particle) momentum is given by the kinetic momentum, defined as \$p_{kin} = p_A\$ . On the other hand, the canonical momentum, \$p_C = h/\\lambda\$ , embodies the wavelike nature of the particle. It was shown that in any light-matter interaction 14 , 15 , the total momentum—a conserved quantity—is given by the sum of the kinetic momentum of the particle and the Abraham momentum of the light and is equal to the sum of the canonical momentum of the particle and the Minkowski momentum of the light: $$p_{{\\rm{kin}}}^{{\\rm{medium}}} + p_A = p_C^{{\\rm{medium}}} + p_M$$ (5) One could therefore call the Abraham momentum the “kinetic momentum of the light” and the Minkowski momentum the “canonical momentum of the light” 14 , 15 . In other words, the Abraham momentum comes into play when considering the particle nature of light and the Minkowski momentum when considering the wavelike nature of light 16 . In this paper we re-examine the difference between these two formulations in the extreme case that the index of refraction of the medium approaches zero. Results Momentum inside near-zero index materials In the past decade materials with near-zero refractive index have received a lot of attention because of their unusual optical properties, such as supercoupling 17 , 18 , enhanced nonlinearities 19 , 20 , 21 , 22 and fluorescence 23 , 24 , 25 , control of dipole-dipole interactions 26 , 27 , geometry-invariant resonant cavities 28 , photonic doping 29 and propagation of the light power flow akin to ideal fluids 30 . The refractive index of a material is near zero when at least one of the two constitutive parameters of the refractive index — the relative electric permittivity ε ( ω ) or the relative magnetic permeability μ ( ω ) — is close to zero 31 , 32 . Near-zero index materials (NZI materials) fall into three categories: epsilon-near-zero (ENZ) materials where ε approaches zero with nonzero μ ; 17 , 33 mu-near-zero (MNZ) materials with μ approaching zero with nonzero permittivity ε 34 ; or epsilon-and-mu-near-zero (EMNZ) media where both ε and μ approach zero simultaneously 28 , 32 , 35 , 36 , 37 . Phase and group indices inside NZI materials At the zero-index frequency in a NZI materials, the phase index is zero, but it is important to note that the group index for", "role": "user" }, { "content": "In physics, as in life, it's always good to look at things from different perspectives. Since the beginning of quantum physics, how light moves and interacts with matter around it has mostly been described and understood mathematically through the lens of its energy. In 1900, Max Planck used energy to explain how light is emitted by heated objects, a seminal study in the foundation of quantum mechanics. In 1905, Albert Einstein used energy when he introduced the concept of photon. But light has another equally important quality, known as momentum. And as it turns out, when you take momentum away, light starts behaving in really interesting ways. An international team of physicists led by Michaël Lobet, a research associate at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Eric Mazur, the Balkanski Professor of Physics and Applied Physics at SEAS, are re-examining the foundations of quantum physics from the perspective of momentum and exploring what happens when the momentum of light is reduced to zero. The research is published in Nature Light: Science & Applications. Any object with mass and velocity has momentum—from atoms to bullets to asteroids—and momentum can be transferred from one object to another. A gun recoils when a bullet is fired because the momentum of the bullet is transferred to the gun. At the microscopic scale, an atom recoils when it emits light because of the acquired momentum of the photon. Atomic recoil, first described by Einstein when he was writing the quantum theory of radiation, is a fundamental phenomenon that governs light emission. But a century after Planck and Einstein, a new class of metamaterials is raising questions regarding these fundamental phenomena. These metamaterials have a refractive index close to zero, meaning that when light travels through them, it doesn't travel like a wave in phases of crests and troughs. Instead, the wave is stretched out to infinity, creating a constant phase. When that happens, many of the typical processes of quantum mechanics disappear, including atomic recoil. Why? It all goes back to momentum. In these so-called near-zero index materials, the wave momentum of light becomes zero and when the wave momentum is zero, odd things happen. \"Fundamental radiative processes are inhibited in three-dimensional near-zero index materials,\" says Lobet, who is currently a lecturer at the University of Namur in Belgium. \"We realized that the momentum recoil of an atom is forbidden in near-zero index materials and that no momentum transfer is allowed between the electromagnetic field and the atom.\" If breaking one of Einstein's rules wasn't enough, the researchers also broke perhaps the most well-known experiment in quantum physics—Young's double-slit experiment. This experiment is used in classrooms across the globe to demonstrate the particle-wave duality in quantum physics—showing that light can display characteristics of both waves and particles. In a typical material, light passing through two slits produces two coherent sources of waves that interfere to form a bright spot in the center of the screen with a pattern of light and dark fringes on either side, known as diffraction fringes. \"When we modeled and numerically computed Young's double-slit experiment, it turned out that the diffraction fringes vanished when the refractive index was lowered,\" said co-author Larissa Vertchenko, of the Technical University of Denmark. \"As it can be seen, this work interrogates fundamental laws of quantum mechanics and probes the limits of wave-corpuscle duality,\" said co-author Iñigo Liberal, of the Public University of Navarre in Pamplona, Spain. While some fundamental processes are inhibited in near-zero refractive index materials, others are enhanced. Take another famous quantum phenomenon—Heisenberg's uncertainty principle, more accurately known in physics as the Heisenberg inequality. This principle states that you cannot know both the position and speed of a particle with perfect accuracy and the more you know about one, the less you know about the other. But, in near-zero index materials, you know with 100% certainty that the momentum of a particle is zero, which means you have absolutely no idea where in the material the particle is at any given moment. \"This material would make a really poor microscope, but it does enable to cloak objects quite perfectly,\" Lobet said. \"In some way, objects become invisible.\" \"These new theoretical results shed new light on near-zero refractive index photonics from a momentum perspective,\" said Mazur. \"It provides insights in the understanding of light-matter interactions in systems with a low- refraction index, which can be useful for lasing and quantum optics applications.\" The research could also shed light on other applications, including quantum computing, light sources that emit a single photon at a time, the lossless propagation of light through a waveguide and more. The team next aims to revisit other foundational quantum experiments in these materials from a momentum perspective. After all, even though Einstein didn't predict near-zero refractive index materials, he did stress the importance of momentum. In his seminal 1916 paper on fundamental radiative processes, Einstein insisted that from a theoretical point of view, energy and momentum \"should be considered on a completely equal footing since energy and momentum are linked in the closest possible way.\" \"As physicists, it's a dream to follow in the footsteps of giants like Einstein and push their ideas further,\" said Lobet. \"We hope that we can provide a new tool that physicists can use and a new perspective, which might help us understand these fundamental processes and develop new applications.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Near-zero index (NZI) materials, i.e., materials having a phase refractive index close to zero, are known to enhance or inhibit light-matter interactions. Most theoretical derivations of fundamental radiative processes rely on energetic considerations and detailed balance equations, but not on momentum considerations. Because momentum exchange should also be incorporated into theoretical models, we investigate momentum inside the three categories of NZI materials, i.e., inside epsilon-and-mu-near-zero (EMNZ), epsilon-near-zero (ENZ) and mu-near-zero (MNZ) materials. In the context of Abraham–Minkowski debate in dispersive materials, we show that Minkowski-canonical momentum of light is zero inside all categories of NZI materials while Abraham-kinetic momentum of light is zero in ENZ and MNZ materials but nonzero inside EMNZ materials. We theoretically demonstrate that momentum recoil, transfer momentum from the field to the atom and Doppler shift are inhibited in NZI materials. Fundamental radiative processes inhibition is also explained due to those momentum considerations inside three-dimensional NZI materials. Absence of diffraction pattern in slits experiments is seen as a consequence of zero Minkowski momentum. Lastly, consequence on Heisenberg inequality, microscopy applications and on the canonical momentum as generator of translations are discussed. Those findings are appealing for a better understanding of fundamental light-matter interactions at the nanoscale as well as for lasing applications. Introduction In his seminal papers introducing fundamental radiative processes 1 , 2 , Einstein noted that, while the description of the interaction between light and matter typically only take into account energy exchange, energy and momentum are directly connected to each other, and momentum exchange is equally important. A consequence of Einstein’s theory of radiation is that the absorption/emission of a quantum of energy ħω is accompanied by a momentum transfer $\hbar \omega /c = \hbar k$ between the field and the atom, with ħ the reduced Planck constant and k being the wavevector. When an atom absorbs radiation, the momentum transfer is in the direction of propagation of the photon, while for emission the transfer is in the opposite direction, inducing a recoil of the atom. In a medium, the momentum of electromagnetic radiation (“electromagnetic momentum”) depends on the refractive index. However, there has been a long-standing debate concerning the dependence of the electromagnetic momentum on the refractive index depending on whether one uses the Minkowski 3 or Abraham 4 , 5 formulation of the electromagnetic momentum. The electromagnetic momentum density in the Abraham ( g A ) and Minkowski ( g M ) forms are $${{{\mathbf{g}}}}_A = {{{\mathbf{E}}}} \times {{{\mathbf{H}}}}/c^2$$ (1) and $${{{\mathbf{g}}}}_M = {{{\mathbf{D}}}} \times {{{\mathbf{B}}}}$$ (2) respectively 6 , 7 . These formulations yield the following two expressions for the magnitude of the electromagnetic momentum in a dispersive medium: $$p_A = \frac{{\hbar \omega }}{{n_g(\omega )c}}$$ (3) and $$p_M = n_\varphi (\omega )\frac{{\hbar \omega }}{c}$$ (4) for the Abraham momentum p A and the Minkowski momentum p M , respectively, and where $n_\varphi (\omega ) = \sqrt {\varepsilon (\omega )\mu (\omega )}$ is the phase refractive index and $n_g = c\left( {\frac{{d\omega }}{{dk}}} \right)^{ - 1}$ the group refractive index. Note that in a non-dispersive medium, $n_\varphi = n_g = n$ and consequently $p_M = n\frac{{\hbar \omega }}{c}$ and $p_A = \frac{{\hbar \omega }}{{nc}}$ . The difference between those two expressions for the electromagnetic momentum is at the heart of Abraham–Minkowski debate. Some experiments appear to support the Minkowski formulation 8 , 9 , 10 , while others support the Abraham formulation 11 , 12 , 13 . A resolution of this long-lasting dilemma was recently proposed 14 , 15 by attributing the difference between the Abraham and Minkowski momenta of light to the duality of light and matter 6 . For a particle, the classical (particle) momentum is given by the kinetic momentum, defined as $p_{kin} = p_A$ . On the other hand, the canonical momentum, $p_C = h/\lambda$ , embodies the wavelike nature of the particle. It was shown that in any light-matter interaction 14 , 15 , the total momentum—a conserved quantity—is given by the sum of the kinetic momentum of the particle and the Abraham momentum of the light and is equal to the sum of the canonical momentum of the particle and the Minkowski momentum of the light: $$p_{{\rm{kin}}}^{{\rm{medium}}} + p_A = p_C^{{\rm{medium}}} + p_M$$ (5) One could therefore call the Abraham momentum the “kinetic momentum of the light” and the Minkowski momentum the “canonical momentum of the light” 14 , 15 . In other words, the Abraham momentum comes into play when considering the particle nature of light and the Minkowski momentum when considering the wavelike nature of light 16 . In this paper we re-examine the difference between these two formulations in the extreme case that the index of refraction of the medium approaches zero. Results Momentum inside near-zero index materials In the past decade materials with near-zero refractive index have received a lot of attention because of their unusual optical properties, such as supercoupling 17 , 18 , enhanced nonlinearities 19 , 20 , 21 , 22 and fluorescence 23 , 24 , 25 , control of dipole-dipole interactions 26 , 27 , geometry-invariant resonant cavities 28 , photonic doping 29 and propagation of the light power flow akin to ideal fluids 30 . The refractive index of a material is near zero when at least one of the two constitutive parameters of the refractive index — the relative electric permittivity ε ( ω ) or the relative magnetic permeability μ ( ω ) — is close to zero 31 , 32 . Near-zero index materials (NZI materials) fall into three categories: epsilon-near-zero (ENZ) materials where ε approaches zero with nonzero μ ; 17 , 33 mu-near-zero (MNZ) materials with μ approaching zero with nonzero permittivity ε 34 ; or epsilon-and-mu-near-zero (EMNZ) media where both ε and μ approach zero simultaneously 28 , 32 , 35 , 36 , 37 . Phase and group indices inside NZI materials At the zero-index frequency in a NZI materials, the phase index is zero, but it is important to note that the group index for<|im_end|> <|im_start|>assistant In physics, as in life, it's always good to look at things from different perspectives. Since the beginning of quantum physics, how light moves and interacts with matter around it has mostly been described and understood mathematically through the lens of its energy. In 1900, Max Planck used energy to explain how light is emitted by heated objects, a seminal study in the foundation of quantum mechanics. In 1905, Albert Einstein used energy when he introduced the concept of photon. But light has another equally important quality, known as momentum. And as it turns out, when you take momentum away, light starts behaving in really interesting ways. An international team of physicists led by Michaël Lobet, a research associate at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Eric Mazur, the Balkanski Professor of Physics and Applied Physics at SEAS, are re-examining the foundations of quantum physics from the perspective of momentum and exploring what happens when the momentum of light is reduced to zero. The research is published in Nature Light: Science & Applications. Any object with mass and velocity has momentum—from atoms to bullets to asteroids—and momentum can be transferred from one object to another. A gun recoils when a bullet is fired because the momentum of the bullet is transferred to the gun. At the microscopic scale, an atom recoils when it emits light because of the acquired momentum of the photon. Atomic recoil, first described by Einstein when he was writing the quantum theory of radiation, is a fundamental phenomenon that governs light emission. But a century after Planck and Einstein, a new class of metamaterials is raising questions regarding these fundamental phenomena. These metamaterials have a refractive index close to zero, meaning that when light travels through them, it doesn't travel like a wave in phases of crests and troughs. Instead, the wave is stretched out to infinity, creating a constant phase. When that happens, many of the typical processes of quantum mechanics disappear, including atomic recoil. Why? It all goes back to momentum. In these so-called near-zero index materials, the wave momentum of light becomes zero and when the wave momentum is zero, odd things happen. "Fundamental radiative processes are inhibited in three-dimensional near-zero index materials," says Lobet, who is currently a lecturer at the University of Namur in Belgium. "We realized that the momentum recoil of an atom is forbidden in near-zero index materials and that no momentum transfer is allowed between the electromagnetic field and the atom." If breaking one of Einstein's rules wasn't enough, the researchers also broke perhaps the most well-known experiment in quantum physics—Young's double-slit experiment. This experiment is used in classrooms across the globe to demonstrate the particle-wave duality in quantum physics—showing that light can display characteristics of both waves and particles. In a typical material, light passing through two slits produces two coherent sources of waves that interfere to form a bright spot in the center of the screen with a pattern of light and dark fringes on either side, known as diffraction fringes. "When we modeled and numerically computed Young's double-slit experiment, it turned out that the diffraction fringes vanished when the refractive index was lowered," said co-author Larissa Vertchenko, of the Technical University of Denmark. "As it can be seen, this work interrogates fundamental laws of quantum mechanics and probes the limits of wave-corpuscle duality," said co-author Iñigo Liberal, of the Public University of Navarre in Pamplona, Spain. While some fundamental processes are inhibited in near-zero refractive index materials, others are enhanced. Take another famous quantum phenomenon—Heisenberg's uncertainty principle, more accurately known in physics as the Heisenberg inequality. This principle states that you cannot know both the position and speed of a particle with perfect accuracy and the more you know about one, the less you know about the other. But, in near-zero index materials, you know with 100% certainty that the momentum of a particle is zero, which means you have absolutely no idea where in the material the particle is at any given moment. "This material would make a really poor microscope, but it does enable to cloak objects quite perfectly," Lobet said. "In some way, objects become invisible." "These new theoretical results shed new light on near-zero refractive index photonics from a momentum perspective," said Mazur. "It provides insights in the understanding of light-matter interactions in systems with a low- refraction index, which can be useful for lasing and quantum optics applications." The research could also shed light on other applications, including quantum computing, light sources that emit a single photon at a time, the lossless propagation of light through a waveguide and more. The team next aims to revisit other foundational quantum experiments in these materials from a momentum perspective. After all, even though Einstein didn't predict near-zero refractive index materials, he did stress the importance of momentum. In his seminal 1916 paper on fundamental radiative processes, Einstein insisted that from a theoretical point of view, energy and momentum "should be considered on a completely equal footing since energy and momentum are linked in the closest possible way." "As physicists, it's a dream to follow in the footsteps of giants like Einstein and push their ideas further," said Lobet. "We hope that we can provide a new tool that physicists can use and a new perspective, which might help us understand these fundamental processes and develop new applications." <|im_end|>

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2,658

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Severe diaphragm dysfunction can lead to respiratory failure and to the need for permanent mechanical ventilation. Yet permanent tethering to a mechanical ventilator through the mouth or via tracheostomy can hinder a patient’s speech, swallowing ability and mobility. Here we show, in a porcine model of varied respiratory insufficiency, that a contractile soft robotic actuator implanted above the diaphragm augments its motion during inspiration. Synchronized actuation of the diaphragm-assist implant with the native respiratory effort increased tidal volumes and maintained ventilation flow rates within the normal range. Robotic implants that intervene at the diaphragm rather than at the upper airway and that augment physiological metrics of ventilation may restore respiratory performance without sacrificing quality of life. Main The diaphragm is the major muscle responsible for inspiration and contributes up to 70% of the inspiratory tidal volume in a healthy individual 1 , 2 . Diaphragm dysfunction can result from a variety of etiologies including phrenic nerve trauma 3 and neuromuscular disease 4 , 5 . Owing to the degenerative nature of many of these etiologies, mechanical respiratory failure exists as a continuous spectrum of dysfunction. Severe diaphragm dysfunction or paralysis can lead to chronic respiratory failure. When disease progresses beyond the treatment capacity of non-invasive treatment, patients must make the difficult decision to opt for permanent invasive ventilation via a tracheostomy or to pursue palliative care with an understanding of the terminal nature of their disease. Invasive ventilation can interfere with many aspects of a patient’s quality of life, such as hindering speech, requiring full-time care and possibly necessitating the patient move into a care facility. There is an urgent need for therapeutic ventilation options that restore respiratory performance without sacrificing quality of life, especially for those with the most severe cases of diaphragm dysfunction. Respiration is a fundamentally mechanical process. The diaphragm is a dome-shaped muscle that drives up to 70% of respiration 1 , 6 . Soft robotic actuators are ideal for reproducing complex, repetitive muscle contractions, such as that of the diaphragm, while interfacing non-destructively with biological tissue. Previously, fully implanted soft actuators have shown the ability to augment heart function 7 , 8 , 9 , 10 , 11 and many other newly developed implantable robotics have shown utility in a broad spread of biological applications 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Due to the mechanical nature of respiratory failure, especially in the context of conditions such as muscular dystrophy, implanted soft robotic actuators applied to the diaphragm have the potential to mechanically support and augment its function. There is minimal previous work investigating soft robotics applied to the augmentation of respiration; one of the few examples reports a dielectric elastomer sheet used to completely replace an excised diaphragm and generate motion 12 , 21 . Contrastingly, the work presented here leaves the native diaphragm intact while demonstrating function in terms of augmentation of clinically relevant physiological metrics (ventilation flows, volumes and pressures) in addition to diaphragm motion in an in vivo porcine model as opposed to solely replicating diaphragm motion while excising the native diaphragm. Here we demonstrate a diaphragm-assist system that functions as an implantable ventilator by using soft robotic actuators to mechanically augment diaphragm function during inhalation, increasing inspiration. As a proof-of-concept, we simulate a range of respiratory insufficiency within each animal—specifically, we induce respiratory depression via anaesthetics and diaphragm paralysis by severing the phrenic nerve—and then demonstrate the ability of the assist system to augment respiratory flows, volumes and pressures. We also investigate specific metrics of inspiratory function, including peak inspiratory flow and transdiaphragmatic pressure 22 . We show that to achieve effective inspiration assistance, the actuation of the assist system must be synchronized to the subject’s underlying respiratory effort. To achieve this, we have built a control system in which actuation is triggered by the beginning of inspiration. Through an analysis of the respiratory waveforms, we investigate the optimal alignment of actuation with the subject’s native respiratory effort. By augmenting diaphragm function in a biomimetic fashion, we demonstrate the replication and augmentation of the native biomechanics of respiration in which a negative pleural and alveolar pressure drives airflow, as opposed to the positive pressure ventilation of standard mechanical ventilation. Results Soft robotic design strategy applied to mechanically assisting inspiration As depicted in the schematic in Fig. 1a , when the diaphragm contracts, the arclength of the diaphragm shortens, and the entire sheet of the diaphragm moves downwards, acting as a pump. The thoracic cavity volume increases and pressure decreases, ultimately driving respiration. Fig. 1: Overview of the use of implantable PAMs for augmenting respiratory muscle function. a , Schematic depicting the lateral cross-section of the native diaphragm anchored to the ribs in a relaxed (left) and contracted (right) state. b , Schematic of the components that makeup a single PAM. c , Pictures of a single PAM in an unpressurized and pressurized state. d , Lateral cross-sectional schematic of the strategy to augment diaphragm motion by placing PAMs superior to the diaphragm. The PAM conforms to the relaxed diaphragm in its unpressurized (left) state and pushes the diaphragm caudally in its pressurized (right) state. e , Visualization of the placement of PAMs (in black) superior to the diaphragm in a live pig model. f , g , Lateral fluoroscopy view of the in vivo porcine diaphragm with PAMs in an unpressurized ( f ) and pressurized ( g ) state (fluoroscopic videos available as Supplementary Video 1 ). The air-filled balloon of the actuator is outlined with a dashed line and indicated by an arrow. A and P denote the anterior and posterior direction of the animal, respectively. Full size image Our strategy aims to harness the contractile function of pneumatic artificial muscles (PAMs) to mimic and augment the native contraction of the diaphragm. We opt for a McKibben type PAM—a classical soft actuator type with a simple fabrication process and high force generation 23 , 24 that", "role": "user" }, { "content": "For many of us, the act of breathing comes naturally. Behind the scenes, our diaphragm—the dome-shaped muscle that lies just beneath the ribcage—works like a slow and steady trampoline, pushing down to create a vacuum for the lungs to expand and draw air in, then relaxing as air is pushed out. In this way, the diaphragm automatically controls our lung capacity, and is the major muscle responsible for our ability to breathe. But when the diaphragm's function is compromised, the breathing instinct becomes a laborious task. Chronic diaphragm dysfunction can occur in people with ALS, muscular dystrophy, and other neuromuscular diseases, as well as patients with paralysis, and damage to the phrenic nerve, which stimulates the diaphragm to contract. A new proof-of-concept design by MIT engineers aims to one day boost the diaphragm's life-sustaining function and improve lung capacity for people with diaphragm dysfunction. The MIT team has developed a soft, robotic, and implantable ventilator that is designed to augment the diaphragm's natural contractions. At the heart of the system are two soft, balloon-like tubes that can be implanted to lie over the diaphragm. When inflated with an external pump, the tubes act as artificial muscles to push down on the diaphragm and help the lungs expand. The tubes can be inflated at a frequency to match the diaphragm's natural rhythm. The researchers demonstrated the implantable ventilator in animal models, and showed that in cases of compromised diaphragm function, the system was able to significantly improve the amount of air that the lungs could draw in. There is still much work to be done before such an implantable system can be used to treat humans with chronic diaphragm dysfunction. But the preliminary results open a new path in assistive breathing technology that the researchers are eager to optimize. \"This is a proof of concept of a new way to ventilate,\" says Ellen Roche, associate professor of mechanical engineering and a member of the Institute for Medical Engineering and Science at MIT. \"The biomechanics of this design are closer to normal breathing, versus ventilators that push air into the lungs, where you have a mask or tracheostomy. There's a long road before this will be implanted in a human. But it's exciting that we could show we could augment ventilation with something implantable.\" Roche and her colleagues published their results December 12 in Nature Biomedical Engineering. Her co-authors at MIT include first author and former graduate student Lucy Hu, as well as Manisha Singh, and Diego Quevedo Moreno; along with Jean Bonnemain of Lausanne University Hospital in Switzerland, and Mossab Saeed and Nikolay Vasilyev of Boston Children's Hospital. A soft pressure The team's implantable ventilator design grew out of Roche's previous work on an assistive device for the heart. As a graduate student at Harvard University, Roche developed a cardiac sleeve designed to wrap around the heart to relieve pressure and provide support as the organ pumps. Now at MIT, she and her research group found that a similar soft, robotic assistance could be applied to other tissues and muscles. \"We thought, what's another big muscle that pumps cyclically and is life sustaining? The diaphragm,\" Roche says. The team began exploring designs for an implantable ventilator well before the start of the COVID-19 pandemic, when use of conventional ventilators spiked along with cases. Those ventilators create positive pressure, in which air is pushed down through a patient's central airways and forced into the lungs. Ellen Roche and her colleagues have developed a soft, robotic, and implantable ventilator that is designed to augment the diaphragm’s natural contractions. Credit: M. Scott Brauer The diaphragm, by contrast, creates negative pressure. When the muscle contracts and pushes downward, it creates a negative pressure that sucks air in to the lungs, similar to pulling the handle of a bike pump to draw in air. Roche's team looked to design a negative pressure ventilator—a system that could help augment the natural function of the diaphragm, particularly for those with long-term breathing dysfunction. \"We were really thinking of chronically ill people that have these degenerative diseases that are progressively getting worse,\" she says. 'The work of breathing' The new system reported in the paper consists of two long, soft and inflatable tubes, which take after a type of pneumatic devices known as McKibben actuators. The team adapted the tubes to lie across the diaphragm (from front to back) and attach to the ribcage at either side of the dome-shaped muscle. One end of each tube connects to a thin external airline, which runs to a small pump and control system. By analyzing the diaphragm's contractions, the team can program the pump to inflate the tubes at a similar frequency. \"We realized we don't have to fully mimic exactly how the diaphragm moves—we just have to give it an extra push downward when it naturally contracts,\" Roche says. The researchers tested the system on anesthetized pigs, implanting the tubes over the animals' diaphragm, and surgically attaching the ends of the tubes to ribs on either end of the muscle. They monitored the animals' oxygen levels and observed their diaphragm function using ultrasound imaging. The team found that in general, the implantable ventilator increased the pigs' tidal volume, or the amount of air that the lungs could draw in with every breath. The most significant improvement was seen in cases where the contractions of the diaphragm and the artificial muscles were in sync. In these cases, the ventilator helped the diaphragm draw in three times the amount of air than it would without assistance. \"We were excited to see we could get such changes in the tidal volume, and we were able to rescue ventilation,\" Roche says. The team is working to optimize various aspects of the system, with the goal of some day implementing it in patients with chronic diaphragm dysfunction. \"The vision is, we know certain parts of this system could be miniaturized,\" Roche says. \"The pump and control system could be worn on a belt or backpack, or even potentially fully implantable. There are implantable heart pumps, so we know it's doable. For now, we are learning a lot about the biomechanics and the work of breathing, and how we can augment all that with this new approach.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Severe diaphragm dysfunction can lead to respiratory failure and to the need for permanent mechanical ventilation. Yet permanent tethering to a mechanical ventilator through the mouth or via tracheostomy can hinder a patient’s speech, swallowing ability and mobility. Here we show, in a porcine model of varied respiratory insufficiency, that a contractile soft robotic actuator implanted above the diaphragm augments its motion during inspiration. Synchronized actuation of the diaphragm-assist implant with the native respiratory effort increased tidal volumes and maintained ventilation flow rates within the normal range. Robotic implants that intervene at the diaphragm rather than at the upper airway and that augment physiological metrics of ventilation may restore respiratory performance without sacrificing quality of life. Main The diaphragm is the major muscle responsible for inspiration and contributes up to 70% of the inspiratory tidal volume in a healthy individual 1 , 2 . Diaphragm dysfunction can result from a variety of etiologies including phrenic nerve trauma 3 and neuromuscular disease 4 , 5 . Owing to the degenerative nature of many of these etiologies, mechanical respiratory failure exists as a continuous spectrum of dysfunction. Severe diaphragm dysfunction or paralysis can lead to chronic respiratory failure. When disease progresses beyond the treatment capacity of non-invasive treatment, patients must make the difficult decision to opt for permanent invasive ventilation via a tracheostomy or to pursue palliative care with an understanding of the terminal nature of their disease. Invasive ventilation can interfere with many aspects of a patient’s quality of life, such as hindering speech, requiring full-time care and possibly necessitating the patient move into a care facility. There is an urgent need for therapeutic ventilation options that restore respiratory performance without sacrificing quality of life, especially for those with the most severe cases of diaphragm dysfunction. Respiration is a fundamentally mechanical process. The diaphragm is a dome-shaped muscle that drives up to 70% of respiration 1 , 6 . Soft robotic actuators are ideal for reproducing complex, repetitive muscle contractions, such as that of the diaphragm, while interfacing non-destructively with biological tissue. Previously, fully implanted soft actuators have shown the ability to augment heart function 7 , 8 , 9 , 10 , 11 and many other newly developed implantable robotics have shown utility in a broad spread of biological applications 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Due to the mechanical nature of respiratory failure, especially in the context of conditions such as muscular dystrophy, implanted soft robotic actuators applied to the diaphragm have the potential to mechanically support and augment its function. There is minimal previous work investigating soft robotics applied to the augmentation of respiration; one of the few examples reports a dielectric elastomer sheet used to completely replace an excised diaphragm and generate motion 12 , 21 . Contrastingly, the work presented here leaves the native diaphragm intact while demonstrating function in terms of augmentation of clinically relevant physiological metrics (ventilation flows, volumes and pressures) in addition to diaphragm motion in an in vivo porcine model as opposed to solely replicating diaphragm motion while excising the native diaphragm. Here we demonstrate a diaphragm-assist system that functions as an implantable ventilator by using soft robotic actuators to mechanically augment diaphragm function during inhalation, increasing inspiration. As a proof-of-concept, we simulate a range of respiratory insufficiency within each animal—specifically, we induce respiratory depression via anaesthetics and diaphragm paralysis by severing the phrenic nerve—and then demonstrate the ability of the assist system to augment respiratory flows, volumes and pressures. We also investigate specific metrics of inspiratory function, including peak inspiratory flow and transdiaphragmatic pressure 22 . We show that to achieve effective inspiration assistance, the actuation of the assist system must be synchronized to the subject’s underlying respiratory effort. To achieve this, we have built a control system in which actuation is triggered by the beginning of inspiration. Through an analysis of the respiratory waveforms, we investigate the optimal alignment of actuation with the subject’s native respiratory effort. By augmenting diaphragm function in a biomimetic fashion, we demonstrate the replication and augmentation of the native biomechanics of respiration in which a negative pleural and alveolar pressure drives airflow, as opposed to the positive pressure ventilation of standard mechanical ventilation. Results Soft robotic design strategy applied to mechanically assisting inspiration As depicted in the schematic in Fig. 1a , when the diaphragm contracts, the arclength of the diaphragm shortens, and the entire sheet of the diaphragm moves downwards, acting as a pump. The thoracic cavity volume increases and pressure decreases, ultimately driving respiration. Fig. 1: Overview of the use of implantable PAMs for augmenting respiratory muscle function. a , Schematic depicting the lateral cross-section of the native diaphragm anchored to the ribs in a relaxed (left) and contracted (right) state. b , Schematic of the components that makeup a single PAM. c , Pictures of a single PAM in an unpressurized and pressurized state. d , Lateral cross-sectional schematic of the strategy to augment diaphragm motion by placing PAMs superior to the diaphragm. The PAM conforms to the relaxed diaphragm in its unpressurized (left) state and pushes the diaphragm caudally in its pressurized (right) state. e , Visualization of the placement of PAMs (in black) superior to the diaphragm in a live pig model. f , g , Lateral fluoroscopy view of the in vivo porcine diaphragm with PAMs in an unpressurized ( f ) and pressurized ( g ) state (fluoroscopic videos available as Supplementary Video 1 ). The air-filled balloon of the actuator is outlined with a dashed line and indicated by an arrow. A and P denote the anterior and posterior direction of the animal, respectively. Full size image Our strategy aims to harness the contractile function of pneumatic artificial muscles (PAMs) to mimic and augment the native contraction of the diaphragm. We opt for a McKibben type PAM—a classical soft actuator type with a simple fabrication process and high force generation 23 , 24 that<|im_end|> <|im_start|>assistant For many of us, the act of breathing comes naturally. Behind the scenes, our diaphragm—the dome-shaped muscle that lies just beneath the ribcage—works like a slow and steady trampoline, pushing down to create a vacuum for the lungs to expand and draw air in, then relaxing as air is pushed out. In this way, the diaphragm automatically controls our lung capacity, and is the major muscle responsible for our ability to breathe. But when the diaphragm's function is compromised, the breathing instinct becomes a laborious task. Chronic diaphragm dysfunction can occur in people with ALS, muscular dystrophy, and other neuromuscular diseases, as well as patients with paralysis, and damage to the phrenic nerve, which stimulates the diaphragm to contract. A new proof-of-concept design by MIT engineers aims to one day boost the diaphragm's life-sustaining function and improve lung capacity for people with diaphragm dysfunction. The MIT team has developed a soft, robotic, and implantable ventilator that is designed to augment the diaphragm's natural contractions. At the heart of the system are two soft, balloon-like tubes that can be implanted to lie over the diaphragm. When inflated with an external pump, the tubes act as artificial muscles to push down on the diaphragm and help the lungs expand. The tubes can be inflated at a frequency to match the diaphragm's natural rhythm. The researchers demonstrated the implantable ventilator in animal models, and showed that in cases of compromised diaphragm function, the system was able to significantly improve the amount of air that the lungs could draw in. There is still much work to be done before such an implantable system can be used to treat humans with chronic diaphragm dysfunction. But the preliminary results open a new path in assistive breathing technology that the researchers are eager to optimize. "This is a proof of concept of a new way to ventilate," says Ellen Roche, associate professor of mechanical engineering and a member of the Institute for Medical Engineering and Science at MIT. "The biomechanics of this design are closer to normal breathing, versus ventilators that push air into the lungs, where you have a mask or tracheostomy. There's a long road before this will be implanted in a human. But it's exciting that we could show we could augment ventilation with something implantable." Roche and her colleagues published their results December 12 in Nature Biomedical Engineering. Her co-authors at MIT include first author and former graduate student Lucy Hu, as well as Manisha Singh, and Diego Quevedo Moreno; along with Jean Bonnemain of Lausanne University Hospital in Switzerland, and Mossab Saeed and Nikolay Vasilyev of Boston Children's Hospital. A soft pressure The team's implantable ventilator design grew out of Roche's previous work on an assistive device for the heart. As a graduate student at Harvard University, Roche developed a cardiac sleeve designed to wrap around the heart to relieve pressure and provide support as the organ pumps. Now at MIT, she and her research group found that a similar soft, robotic assistance could be applied to other tissues and muscles. "We thought, what's another big muscle that pumps cyclically and is life sustaining? The diaphragm," Roche says. The team began exploring designs for an implantable ventilator well before the start of the COVID-19 pandemic, when use of conventional ventilators spiked along with cases. Those ventilators create positive pressure, in which air is pushed down through a patient's central airways and forced into the lungs. Ellen Roche and her colleagues have developed a soft, robotic, and implantable ventilator that is designed to augment the diaphragm’s natural contractions. Credit: M. Scott Brauer The diaphragm, by contrast, creates negative pressure. When the muscle contracts and pushes downward, it creates a negative pressure that sucks air in to the lungs, similar to pulling the handle of a bike pump to draw in air. Roche's team looked to design a negative pressure ventilator—a system that could help augment the natural function of the diaphragm, particularly for those with long-term breathing dysfunction. "We were really thinking of chronically ill people that have these degenerative diseases that are progressively getting worse," she says. 'The work of breathing' The new system reported in the paper consists of two long, soft and inflatable tubes, which take after a type of pneumatic devices known as McKibben actuators. The team adapted the tubes to lie across the diaphragm (from front to back) and attach to the ribcage at either side of the dome-shaped muscle. One end of each tube connects to a thin external airline, which runs to a small pump and control system. By analyzing the diaphragm's contractions, the team can program the pump to inflate the tubes at a similar frequency. "We realized we don't have to fully mimic exactly how the diaphragm moves—we just have to give it an extra push downward when it naturally contracts," Roche says. The researchers tested the system on anesthetized pigs, implanting the tubes over the animals' diaphragm, and surgically attaching the ends of the tubes to ribs on either end of the muscle. They monitored the animals' oxygen levels and observed their diaphragm function using ultrasound imaging. The team found that in general, the implantable ventilator increased the pigs' tidal volume, or the amount of air that the lungs could draw in with every breath. The most significant improvement was seen in cases where the contractions of the diaphragm and the artificial muscles were in sync. In these cases, the ventilator helped the diaphragm draw in three times the amount of air than it would without assistance. "We were excited to see we could get such changes in the tidal volume, and we were able to rescue ventilation," Roche says. The team is working to optimize various aspects of the system, with the goal of some day implementing it in patients with chronic diaphragm dysfunction. "The vision is, we know certain parts of this system could be miniaturized," Roche says. "The pump and control system could be worn on a belt or backpack, or even potentially fully implantable. There are implantable heart pumps, so we know it's doable. For now, we are learning a lot about the biomechanics and the work of breathing, and how we can augment all that with this new approach." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the R NA E diting DA mage R esponse (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution. Introduction Cells are continuously challenged by DNA damage. Among all kinds of insults that a DNA molecule has to deal with, double-strand breaks (DSBs) are the most dangerous. Indeed, just one unrepaired DSB is enough to either kill or terminally arrest cells. For these reasons when DSBs are formed, a complex cellular response—the DNA damage response (DDR)—is triggered in order to ensure the proper repair of such a threat to genomic integrity 1 . There are several pathways that can be used in order to repair a DSB and the choice between them is highly regulated. A eukaryotic cell can repair a DSB either by the simple re-ligation of the DNA ends (a process known as Non-Homologous End-Joining, NHEJ) 2 or by a homology-driven repair event. There are different routes among the repair pathways that use homologous regions for repair, all of which are grouped in a process called homologous recombination (HR) 3 . All HR events share a first biochemical step called DNA resection, which is the key to decide the pathway that will be eventually used to repair the DSB 4 , 5 . This process consists of the nucleolytic degradation of the DNA ends of the break that produces tails of 3' ended single-stranded DNA (ssDNA), that are rapidly protected by the RPA protein complex. In recent years, the importance of RNA and RNA-related factors in DNA repair has become clear 6 , 7 , 8 , 9 . Indeed, many RNA-related proteins have been shown to be targets of the DNA damage-induced post-translational modifications 10 , 11 , 12 . Also, direct roles of specific RNA-related factors in DNA repair have been recently reported (for a review see 9 ). Moreover, the RNA molecule itself seems to impact DNA repair. Several labs have shown the formation of DNA:RNA hybrids around DSBs in different eukaryotes, either dependent on previous transcription 13 , 14 or upon de novo transcription of the broken chromatin 15 , 16 . The relevance of such RNA molecules is still under debate, with both pro- and anti-repair effects ascribed to them 9 . An important co-transcriptional RNA modification that, so far, has not been extensively studied in its putative relationship with DNA repair and the response to DNA damage is RNA editing. This process alters RNA sequences by the action of specific deaminases that convert one base into another. Every mammalian transcript can be subjected to RNA editing 17 , 18 , 19 . RNA editing can be classified into several categories 20 , including adenosine-to-inosine (A-to-I) deamination, which is accomplished by a family of RNA-specific adenosine deaminases known as ADARs 18 , 19 . This family is formed by ADAR1, ADAR2 (also known as ADARB1), and ADAR3; however, only ADAR1 and ADAR2 have been shown to present catalytic activity. A-to-I deamination is the most abundant form of RNA-editing in mammals and defects in this process are associated with human diseases, such as disorders of the central nervous system 21 or pediatric astrocytomas 22 . Only limited information has been published regarding the connection of A-to-I editing and DNA damage, albeit at least the mRNA of NEIL1, has been shown to be re-coded by ADAR1 to alter its enzymatic properties 23 . Moreover, A-to-I editing has been proposed to be involved in the pathogenesis of cancer 24 , 25 . Here, we show that the general pattern of ADAR2-mediated A-to-I editing changes upon DSB formation. Such changes depend on the DDR, specifically the ATR kinase and the resection protein CtIP. As a consequence, ADAR2 is required for the maintenance of genomic integrity and, specifically for DNA end resection and HR. Strikingly, mRNAs from either resection-related or recombination-related genes are not affected by ADAR2. Instead, ADAR2 role in resection is related to its ability to edit DNA:RNA hybrids. Not only do such structures increase when ADAR2 is depleted, but this protein physically and functionally interacts with the BRCA1-SETX complex for this role. Results RNA editing changes after DNA damage As previously mentioned, crosstalk between RNA metabolism and DNA repair has been extensively documented 9 , but a connection between DNA repair and RNA editing has not been extensively analyzed. Thus, we wanted to study whether the appearance of DNA damage had any effect on RNA editing. In order to explore this possibility, we used a previously published reporter system (RNAG) that measures levels of RNA editing using the accumulation of the fluorescent proteins GFP and RFP 26 . This system bears both the RFP and GFP ORFs in a single transcript, with a stop codon between them (Fig. 1A ). So, cells bearing such reporter express RFP constitutively, but GFP is only produced if an RNA editing event changes the A of the stop codon to an I (Fig. 1A ) 26 . Therefore, the number of red cells that are also green indicates the efficiency of RNA editing. As a control to discard other effects non-related to the editing on this system, we used the RNWG control reporter, in which the stop codon is pre-edited, so all cells bearing the construct fluoresce, indeed, in red and green 26 . In", "role": "user" }, { "content": "An organism's genome could be compared to a complex system of instructions that allows it not only to develop, but also to carry out all the activities essential to its survival. To do this, this genome needs to be expressed correctly, i.e. these instructions need to be \"read\" properly, and the information it contains must not be altered or degraded over time. The first process is known as gene expression and involves the information contained in the genes (the DNA) being properly converted into a set of valid tools (the proteins). This requires the transient formation of a messenger molecule that transmits this information (messenger RNA). Classical biology, as it appears in textbooks, describes how DNA is literally copied into an RNA molecule that is transformed in a specific way into a specific protein in a process in which the information remains unchanged. This classical view has been shown to be erroneous, as the RNA molecule itself can be altered in a regulated manner in different ways before it is converted into proteins. The second process, the maintenance of genomic stability, is possible because of a series of cellular intrinsic mechanisms that check and repair any physical or chemical alterations in the DNA to restore the original information. These processes are the DNA repair mechanisms. In a study led by Sonia Jimeno and carried out at the laboratory of Pablo Huertas (CABIMER and Department of Genetics of the University of Seville), a novel connection has been described between the repair of DNA breaks and the modifying factors of the messenger RNA molecule. Specifically, they have established that when the DNA of a cell suffers breaks, a specific mechanism is activated to alter the RNA molecules, changing the information they contain. This mechanism promotes faithful DNA repair in several ways. In particular, one way is to facilitate the removal of RNA molecules that are trapped in the DNA requiring repair. This elimination is necessary for the repair machinery to work properly and is carried out by proteins called ADARs. Taking into account that these proteins are implicated in some rare diseases and in the appearance of cancer, it is possible that these discoveries may serve in the long term to better understand how these pathologies appear. The resaerch was published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the R NA E diting DA mage R esponse (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution. Introduction Cells are continuously challenged by DNA damage. Among all kinds of insults that a DNA molecule has to deal with, double-strand breaks (DSBs) are the most dangerous. Indeed, just one unrepaired DSB is enough to either kill or terminally arrest cells. For these reasons when DSBs are formed, a complex cellular response—the DNA damage response (DDR)—is triggered in order to ensure the proper repair of such a threat to genomic integrity 1 . There are several pathways that can be used in order to repair a DSB and the choice between them is highly regulated. A eukaryotic cell can repair a DSB either by the simple re-ligation of the DNA ends (a process known as Non-Homologous End-Joining, NHEJ) 2 or by a homology-driven repair event. There are different routes among the repair pathways that use homologous regions for repair, all of which are grouped in a process called homologous recombination (HR) 3 . All HR events share a first biochemical step called DNA resection, which is the key to decide the pathway that will be eventually used to repair the DSB 4 , 5 . This process consists of the nucleolytic degradation of the DNA ends of the break that produces tails of 3' ended single-stranded DNA (ssDNA), that are rapidly protected by the RPA protein complex. In recent years, the importance of RNA and RNA-related factors in DNA repair has become clear 6 , 7 , 8 , 9 . Indeed, many RNA-related proteins have been shown to be targets of the DNA damage-induced post-translational modifications 10 , 11 , 12 . Also, direct roles of specific RNA-related factors in DNA repair have been recently reported (for a review see 9 ). Moreover, the RNA molecule itself seems to impact DNA repair. Several labs have shown the formation of DNA:RNA hybrids around DSBs in different eukaryotes, either dependent on previous transcription 13 , 14 or upon de novo transcription of the broken chromatin 15 , 16 . The relevance of such RNA molecules is still under debate, with both pro- and anti-repair effects ascribed to them 9 . An important co-transcriptional RNA modification that, so far, has not been extensively studied in its putative relationship with DNA repair and the response to DNA damage is RNA editing. This process alters RNA sequences by the action of specific deaminases that convert one base into another. Every mammalian transcript can be subjected to RNA editing 17 , 18 , 19 . RNA editing can be classified into several categories 20 , including adenosine-to-inosine (A-to-I) deamination, which is accomplished by a family of RNA-specific adenosine deaminases known as ADARs 18 , 19 . This family is formed by ADAR1, ADAR2 (also known as ADARB1), and ADAR3; however, only ADAR1 and ADAR2 have been shown to present catalytic activity. A-to-I deamination is the most abundant form of RNA-editing in mammals and defects in this process are associated with human diseases, such as disorders of the central nervous system 21 or pediatric astrocytomas 22 . Only limited information has been published regarding the connection of A-to-I editing and DNA damage, albeit at least the mRNA of NEIL1, has been shown to be re-coded by ADAR1 to alter its enzymatic properties 23 . Moreover, A-to-I editing has been proposed to be involved in the pathogenesis of cancer 24 , 25 . Here, we show that the general pattern of ADAR2-mediated A-to-I editing changes upon DSB formation. Such changes depend on the DDR, specifically the ATR kinase and the resection protein CtIP. As a consequence, ADAR2 is required for the maintenance of genomic integrity and, specifically for DNA end resection and HR. Strikingly, mRNAs from either resection-related or recombination-related genes are not affected by ADAR2. Instead, ADAR2 role in resection is related to its ability to edit DNA:RNA hybrids. Not only do such structures increase when ADAR2 is depleted, but this protein physically and functionally interacts with the BRCA1-SETX complex for this role. Results RNA editing changes after DNA damage As previously mentioned, crosstalk between RNA metabolism and DNA repair has been extensively documented 9 , but a connection between DNA repair and RNA editing has not been extensively analyzed. Thus, we wanted to study whether the appearance of DNA damage had any effect on RNA editing. In order to explore this possibility, we used a previously published reporter system (RNAG) that measures levels of RNA editing using the accumulation of the fluorescent proteins GFP and RFP 26 . This system bears both the RFP and GFP ORFs in a single transcript, with a stop codon between them (Fig. 1A ). So, cells bearing such reporter express RFP constitutively, but GFP is only produced if an RNA editing event changes the A of the stop codon to an I (Fig. 1A ) 26 . Therefore, the number of red cells that are also green indicates the efficiency of RNA editing. As a control to discard other effects non-related to the editing on this system, we used the RNWG control reporter, in which the stop codon is pre-edited, so all cells bearing the construct fluoresce, indeed, in red and green 26 . In<|im_end|> <|im_start|>assistant An organism's genome could be compared to a complex system of instructions that allows it not only to develop, but also to carry out all the activities essential to its survival. To do this, this genome needs to be expressed correctly, i.e. these instructions need to be "read" properly, and the information it contains must not be altered or degraded over time. The first process is known as gene expression and involves the information contained in the genes (the DNA) being properly converted into a set of valid tools (the proteins). This requires the transient formation of a messenger molecule that transmits this information (messenger RNA). Classical biology, as it appears in textbooks, describes how DNA is literally copied into an RNA molecule that is transformed in a specific way into a specific protein in a process in which the information remains unchanged. This classical view has been shown to be erroneous, as the RNA molecule itself can be altered in a regulated manner in different ways before it is converted into proteins. The second process, the maintenance of genomic stability, is possible because of a series of cellular intrinsic mechanisms that check and repair any physical or chemical alterations in the DNA to restore the original information. These processes are the DNA repair mechanisms. In a study led by Sonia Jimeno and carried out at the laboratory of Pablo Huertas (CABIMER and Department of Genetics of the University of Seville), a novel connection has been described between the repair of DNA breaks and the modifying factors of the messenger RNA molecule. Specifically, they have established that when the DNA of a cell suffers breaks, a specific mechanism is activated to alter the RNA molecules, changing the information they contain. This mechanism promotes faithful DNA repair in several ways. In particular, one way is to facilitate the removal of RNA molecules that are trapped in the DNA requiring repair. This elimination is necessary for the repair machinery to work properly and is carried out by proteins called ADARs. Taking into account that these proteins are implicated in some rare diseases and in the appearance of cancer, it is possible that these discoveries may serve in the long term to better understand how these pathologies appear. The resaerch was published in Nature Communications. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Newton’s third law of motion is one of the pillars of classical physics. This fundamental principle states that the forces two bodies exert on each other are equal and opposite. Had the resulting accelerations been oriented in the same direction, this would have instead led to a counterintuitive phenomenon, that of diametric drive 1 . In such a hypothetical arrangement, two interacting particles constantly accelerate each other in the same direction through a violation of the action–reaction symmetry. Although in classical mechanics any realization of this process requires one of the two particles to have a negative mass and hence is strictly forbidden, it could nevertheless be feasible in periodic structures where the effective mass can also attain a negative sign 2 , 3 , 4 , 5 , 6 , 7 . Here we report the first experimental observation of such diametric drive acceleration for pulses propagating in a nonlinear optical mesh lattice 8 , 9 , 10 , 11 , 12 , 13 , 14 . The demonstrated reversal of action–reaction symmetry could enable altogether new possibilities for frequency conversion and pulse-steering applications. Main Newton’s third law states that action–reaction forces involved in an elemental two-body interaction must be equal and opposite: F 1 = − F 2 . Combined with the second law of motion, this leads to m 1 a 1 = − m 2 a 2 , where m 1,2 represent the masses of these two particles and a 1,2 their respective accelerations. Given that mass is by nature a positive quantity, two classical bodies are expected to accelerate either towards or away from each other, but never in the same direction ( Fig. 1a ). However, this situation completely changes if hypothetically one of the masses is negative. In fact, in this regime, an intriguing scenario arises whenever m 1 = − m 2 ; under these conditions, two interacting bodies will indefinitely accelerate in the same direction while keeping a constant distance among themselves ( Fig. 1a ). Interestingly, this possibility was first speculated within the context of diametric drive that could itself provide a possible mechanism for space propulsion 1 . Of course, given that in classical mechanics the mass of a particle is always positive, no such acceleration behaviour that breaks the action–reaction symmetry has ever been reported. Figure 1: Diametric drive interaction between two particles, fibre-optic set-up and mesh lattice dispersion (effective mass) diagram. a , Two bodies of positive masses accelerate towards each other in the presence of attractive forces. In contrast, two particles with equal and opposite in sign masses tend to self-accelerate when subject to the same force (schematic illustration). b , Set-up of two time-multiplexed fibre loops with length difference Δ L , connected through a 50/50 coupler. Sequences of light pulses circulating in both loops obey the same dynamics as in a spatial mesh lattice 8 , 10 . The nonlinearity in the fibres introduces a nonlinear phase shift on each pulse that is proportional to its peak power. c , Dispersion diagram associated with two oppositely curved bands. The upper (lower) band has a positive (negative) curvature and therefore exhibits a positive (negative) effective photon mass that is inverse to the curvature. The Kerr nonlinearity tends to focus excitations in the upper band whereas the corresponding effects in the lower band are of the defocusing type. Q , wave number; θ , propagation constant. See Supplementary Methods for details. Full size image Waves on the other hand are free of such limitations. In the case of a free quantum particle governed by the Schrödinger equation, the resulting parabolic dispersion relation between energy and momentum has a positive curvature defined by the particle’s mass. Meanwhile, quasiparticles such as electrons and holes in solid-state crystals, mass–spring systems 5 or collective excitations such as Bose–Einstein condensates in lattices 6 , 7 may exhibit a dispersion relation with regions of inverted curvature where the effective mass is negative. Similarly, in photonic guiding structures, the effective photon mass can be positive or negative depending on the sign of the associated group velocity dispersion 3 , 4 . In addition, photonic lattices such as waveguide arrays 15 , 16 or mesh lattices 8 , 9 , 10 , 11 , 12 provide a versatile environment to experimentally investigate this class of phenomena, as broad light excitations of these structures are effectively governed by their respective mass that can be either positive or negative ( Fig. 1c ). The second component needed for realizing a diametric drive is an effective interaction between the two entities involved. Although in general such forces can emerge from a number of physical processes, in optics, this can be achieved only through nonlinear effects. For example in waveguide structures, optical wave packets can interact through third-order Kerr nonlinearity—in direct analogy to point-like scattering in Bose–Einstein condensates 6 , 7 , 17 . In this setting, an effective force is established between two partially overlapping light beams 2 , 18 , 19 . Therefore, nonlinear optical periodic configurations can serve as an ideal platform to observe diametric drive acceleration and to study action–reaction symmetry breaking effects. Here we experimentally demonstrate such optical self-accelerating bound states in a temporal mesh lattice. A composite beam or a wave packet is formed by a sequence of circulating optical pulses 11 , 12 propagating in two fibre loops connected by a 50/50 coupler 10 ( Fig. 1b and Supplementary Methods ). A length difference Δ L between the two loops essentially creates an effective grid of positions or time slots n that are coupled to their nearest neighbours at every propagation step or loop round-trip s . A light pulse propagating in the short loop takes a shortcut and thus advances by a fixed time amount, moving its time slot to the left from n +1 to n . In contrast, a pulse circulating in the long loop is delayed from n −1 to n . After each round trip", "role": "user" }, { "content": "(Phys.org) —A team of physicists working at the University of Erlangen-Nuernberg in Germany has built a working optical diametric drive. In their paper published in Nature Physics, the team describes how they built a two-loop structure that because one loop is longer than the other, works to create an effective mass resulting in a demonstrable optical diametric drive. A diametric drive is one where particles that run into one another are made to react by accelerating in the same direction—like balls on a pool table both accelerating in the same direction when made to run into one another—it's only theoretically possible if one of the balls has a negative mass. Scientists have toyed with the idea of diametric drives for quite some time, hoping to overcome the obvious limitation that it goes against Newton's third law of motion (every action must have an equal and opposite reaction). In this new effort, the team working in Germany hasn't violated Newton's law, but has found a way to make it appear as if they have. The team imagined an optical drive that allowed for photons running into each other to both accelerate in the same direction afterwards—a possibility because photons have no mass. Their idea relies on a property of photonics called effective mass—it comes about when photons travel through a material that slows its speed proportional to its mass. If some photons travel though such a material then join the rest of a pulse, interference will occur causing the original pulse to behave as if it has mass. The problem in creating a diametric drive using this technique is that any material used would have to be so long that it would absorb the light before the drive properties could be achieved. To overcome this problem, the team in Germany connected two fiber optic cable loops together (creating an infinitely long pathway) at a juncture point—with one longer than the other. Photons sent by a laser pulse take longer, of course, to travel around the longer loop, thus when they meet up with photons in the smaller loop, interference occurs, causing the photons to both accelerate in the same direction. The optical diametric drive doesn't have much practical purpose just yet, but further research into electronics that use fiber cables could result in faster communications, and thus faster networks. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Newton’s third law of motion is one of the pillars of classical physics. This fundamental principle states that the forces two bodies exert on each other are equal and opposite. Had the resulting accelerations been oriented in the same direction, this would have instead led to a counterintuitive phenomenon, that of diametric drive 1 . In such a hypothetical arrangement, two interacting particles constantly accelerate each other in the same direction through a violation of the action–reaction symmetry. Although in classical mechanics any realization of this process requires one of the two particles to have a negative mass and hence is strictly forbidden, it could nevertheless be feasible in periodic structures where the effective mass can also attain a negative sign 2 , 3 , 4 , 5 , 6 , 7 . Here we report the first experimental observation of such diametric drive acceleration for pulses propagating in a nonlinear optical mesh lattice 8 , 9 , 10 , 11 , 12 , 13 , 14 . The demonstrated reversal of action–reaction symmetry could enable altogether new possibilities for frequency conversion and pulse-steering applications. Main Newton’s third law states that action–reaction forces involved in an elemental two-body interaction must be equal and opposite: F 1 = − F 2 . Combined with the second law of motion, this leads to m 1 a 1 = − m 2 a 2 , where m 1,2 represent the masses of these two particles and a 1,2 their respective accelerations. Given that mass is by nature a positive quantity, two classical bodies are expected to accelerate either towards or away from each other, but never in the same direction ( Fig. 1a ). However, this situation completely changes if hypothetically one of the masses is negative. In fact, in this regime, an intriguing scenario arises whenever m 1 = − m 2 ; under these conditions, two interacting bodies will indefinitely accelerate in the same direction while keeping a constant distance among themselves ( Fig. 1a ). Interestingly, this possibility was first speculated within the context of diametric drive that could itself provide a possible mechanism for space propulsion 1 . Of course, given that in classical mechanics the mass of a particle is always positive, no such acceleration behaviour that breaks the action–reaction symmetry has ever been reported. Figure 1: Diametric drive interaction between two particles, fibre-optic set-up and mesh lattice dispersion (effective mass) diagram. a , Two bodies of positive masses accelerate towards each other in the presence of attractive forces. In contrast, two particles with equal and opposite in sign masses tend to self-accelerate when subject to the same force (schematic illustration). b , Set-up of two time-multiplexed fibre loops with length difference Δ L , connected through a 50/50 coupler. Sequences of light pulses circulating in both loops obey the same dynamics as in a spatial mesh lattice 8 , 10 . The nonlinearity in the fibres introduces a nonlinear phase shift on each pulse that is proportional to its peak power. c , Dispersion diagram associated with two oppositely curved bands. The upper (lower) band has a positive (negative) curvature and therefore exhibits a positive (negative) effective photon mass that is inverse to the curvature. The Kerr nonlinearity tends to focus excitations in the upper band whereas the corresponding effects in the lower band are of the defocusing type. Q , wave number; θ , propagation constant. See Supplementary Methods for details. Full size image Waves on the other hand are free of such limitations. In the case of a free quantum particle governed by the Schrödinger equation, the resulting parabolic dispersion relation between energy and momentum has a positive curvature defined by the particle’s mass. Meanwhile, quasiparticles such as electrons and holes in solid-state crystals, mass–spring systems 5 or collective excitations such as Bose–Einstein condensates in lattices 6 , 7 may exhibit a dispersion relation with regions of inverted curvature where the effective mass is negative. Similarly, in photonic guiding structures, the effective photon mass can be positive or negative depending on the sign of the associated group velocity dispersion 3 , 4 . In addition, photonic lattices such as waveguide arrays 15 , 16 or mesh lattices 8 , 9 , 10 , 11 , 12 provide a versatile environment to experimentally investigate this class of phenomena, as broad light excitations of these structures are effectively governed by their respective mass that can be either positive or negative ( Fig. 1c ). The second component needed for realizing a diametric drive is an effective interaction between the two entities involved. Although in general such forces can emerge from a number of physical processes, in optics, this can be achieved only through nonlinear effects. For example in waveguide structures, optical wave packets can interact through third-order Kerr nonlinearity—in direct analogy to point-like scattering in Bose–Einstein condensates 6 , 7 , 17 . In this setting, an effective force is established between two partially overlapping light beams 2 , 18 , 19 . Therefore, nonlinear optical periodic configurations can serve as an ideal platform to observe diametric drive acceleration and to study action–reaction symmetry breaking effects. Here we experimentally demonstrate such optical self-accelerating bound states in a temporal mesh lattice. A composite beam or a wave packet is formed by a sequence of circulating optical pulses 11 , 12 propagating in two fibre loops connected by a 50/50 coupler 10 ( Fig. 1b and Supplementary Methods ). A length difference Δ L between the two loops essentially creates an effective grid of positions or time slots n that are coupled to their nearest neighbours at every propagation step or loop round-trip s . A light pulse propagating in the short loop takes a shortcut and thus advances by a fixed time amount, moving its time slot to the left from n +1 to n . In contrast, a pulse circulating in the long loop is delayed from n −1 to n . After each round trip<|im_end|> <|im_start|>assistant (Phys.org) —A team of physicists working at the University of Erlangen-Nuernberg in Germany has built a working optical diametric drive. In their paper published in Nature Physics, the team describes how they built a two-loop structure that because one loop is longer than the other, works to create an effective mass resulting in a demonstrable optical diametric drive. A diametric drive is one where particles that run into one another are made to react by accelerating in the same direction—like balls on a pool table both accelerating in the same direction when made to run into one another—it's only theoretically possible if one of the balls has a negative mass. Scientists have toyed with the idea of diametric drives for quite some time, hoping to overcome the obvious limitation that it goes against Newton's third law of motion (every action must have an equal and opposite reaction). In this new effort, the team working in Germany hasn't violated Newton's law, but has found a way to make it appear as if they have. The team imagined an optical drive that allowed for photons running into each other to both accelerate in the same direction afterwards—a possibility because photons have no mass. Their idea relies on a property of photonics called effective mass—it comes about when photons travel through a material that slows its speed proportional to its mass. If some photons travel though such a material then join the rest of a pulse, interference will occur causing the original pulse to behave as if it has mass. The problem in creating a diametric drive using this technique is that any material used would have to be so long that it would absorb the light before the drive properties could be achieved. To overcome this problem, the team in Germany connected two fiber optic cable loops together (creating an infinitely long pathway) at a juncture point—with one longer than the other. Photons sent by a laser pulse take longer, of course, to travel around the longer loop, thus when they meet up with photons in the smaller loop, interference occurs, causing the photons to both accelerate in the same direction. The optical diametric drive doesn't have much practical purpose just yet, but further research into electronics that use fiber cables could result in faster communications, and thus faster networks. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The structural complexity and bioactivity of natural products often depend on enzymatic redox tailoring steps. This is exemplified by the generation of the bisbenzannulated [5,6]-spiroketal pharmacophore in the bacterial rubromycin family of aromatic polyketides, which exhibit a wide array of bioactivities such as the inhibition of HIV reverse transcriptase or DNA helicase. Here we elucidate the complex flavoenzyme-driven formation of the rubromycin pharmacophore that is markedly distinct from conventional (bio)synthetic strategies for spiroketal formation. Accordingly, a polycyclic aromatic precursor undergoes extensive enzymatic oxidative rearrangement catalyzed by two flavoprotein monooxygenases and a flavoprotein oxidase that ultimately results in a drastic distortion of the carbon skeleton. The one-pot in vitro reconstitution of the key enzymatic steps as well as the comprehensive characterization of reactive intermediates allow to unravel the intricate underlying reactions, during which four carbon-carbon bonds are broken and two CO 2 become eliminated. This work provides detailed insight into perplexing redox tailoring enzymology that sets the stage for the (chemo)enzymatic production and bioengineering of bioactive spiroketal-containing polyketides. Introduction The benastatins, pradimicins, fredericamycins, xantholipins (among others), as well as the rubromycin family belong to a growing group of biosynthetically related aromatic type II polyketide natural products with extended “pentangular” architecture that are produced by numerous actinobacterial species 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . The intensely colored rubromycins comprise various griseorhodins (e.g., griseorhodin A ( 1 )), hyaluromycin, purpuromycin, heliquinomycin, as well as the eponymous rubromycins (e.g., β-rubromycin ( 2 )) 2 , 9 , 10 , 11 , 12 . Often, these compounds act as potent enzyme inhibitors and 2 was consequently suggested as a lead structure for drug development 13 . The hallmark structural feature of the rubromycins is a bisbenzannulated [5,6]-spiroketal pharmacophore that disrupts the planarity of the polycyclic, aromatic carbon backbone (Fig. 1 ) 13 . Even though 2 was first described in 1953 11 (Fig. 1 ), it took almost half a century before the total synthesis of a rubromycin polyketide was achieved owing to their intricate structures 12 , 14 . In fact, synthetic strategies for the griseorhodins have yet to be reported, which are distinguished by even more complex, highly oxygenated pharmacophores such as the epoxyspiroketal of 1 12 . Fig. 1: Overview of the proposed biosynthesis of bacterial rubromycin-type polyketides and final pathway products. a Griseorhodin A biosynthetic gene cluster encoding, e.g., the minimal type II polyketide synthase (PKS), cyclases, and tailoring enzymes 9 . b Initial steps afford a reactive acyl-carrier protein (ACP)-bound poly-β-ketone, which is subsequently cyclized and modified to 3 . Compounds 3 and 11 were previously identified in the course of gene deletion experiments (ΔgrhO5 and ΔgrhO6, respectively, encoding flavin-dependent tailoring enzymes investigated in this work) and assigned as putative advanced intermediates 10 . The conversion of 3 into 4 via 8 and 11 (dashed box) and additional intermediates was elucidated in this work. A ketoreductase (presumably GrhO10) then converts 4 into 13 . c Examples of mature rubromycins likely formed from 13 . Full size image Moreover, details on the biosynthesis of the rubromycins and the spiroketal moiety remain scarce. First insights originated from extensive gene-inactivation studies with the griseorhodin ( grh ) A biosynthetic gene cluster of Streptomyces sp. JP95 isolated from the marine tunicate Aplidium lenticulum , which was expressed in the heterologous producer S. albus sp. J1074 9 , 10 . Initial steps resemble typical type II polyketide pathways involving a minimal polyketide synthase (PKS) that likely utilizes an acetyl-CoA starter unit and 12 malonyl-CoA extender units to generate a highly reactive acyl-carrier protein (ACP)-bound poly-β-ketone chain. Following enzyme-catalyzed regioselective ketoreduction, cyclization, aromatization and ACP elimination, further tailoring reactions modify the polyketide backbone and lead to the advanced and highly oxidized intermediate collinone ( 3 ) (previously also isolated from a heterologous producer expressing parts of the rubromycin biosynthetic gene cluster 15 ), which may serve as a direct precursor for spiroketalization 10 . This would necessitate an extensive oxidative backbone rearrangement as well as the elimination of two C 1 units, which may be mediated by mechanistically versatile flavin-dependent enzymes 16 , 17 , 18 , 19 , 20 , 21 , 22 that often facilitate redox tailoring reactions in natural product biosynthesis (Fig. 1 ) 16 , 19 . Here, we report the full in vitro reconstitution of enzymatic spiroketal formation in the biosynthesis of rubromycin-type polyketides. We elucidate the conversion of 3 into the [5,6]-spiroketal-containing 7,8-dideoxy-6-oxo-griseorhodin C ( 4 ) via various reactive intermediates by the concerted action of the flavoprotein monooxygenases GrhO5 and GrhO6, as well as the flavoprotein oxidase GrhO1 that are encoded by the grh gene cluster. This process is primarily mediated by the multifunctional monooxygenase GrhO5 that oxidatively rearranges the carbon backbone and ultimately forms a [6,6]-spiroketal and is assisted by GrhO1, before the ring-contracting GrhO6 generates the [5,6]-spiroketal pharmacophore found in mature rubromycin polyketides (Fig. 1 ). Results Flavoprotein monooxygenase GrhO5 initiates spiroketal formation by rapid collinone reduction S. albus sp. J1074 KR8 (Δ grhO5 ) was previously reported to produce 3 as major shunt metabolite, which may thus represent the native substrate of GrhO5 10 . To investigate this, 3 was isolated from the S. albus mutant, while GrhO5 (fused with an N-terminal maltose binding protein tag) was obtained from the heterologous producer Escherichia coli BL21 DE3 (see Online Methods section for details on gene cloning as well as production and purification of enzymes and compounds). GrhO5 is predicted to function as flavoprotein monooxygenase based on the amino acid sequence 10 and is homologous to the NAD(P)H- and FAD-dependent class A flavoprotein monooxygenases with “glutathione reductase type” Rossmann fold 21 . Typically, these enzymes catalyze aromatic hydroxylation reactions via an electrophilic flavin-C4a-hydroperoxide oxygenating species, while some members instead act as Baeyer–Villiger monooxygenases (BVMOs) that employ a nucleophilic flavin-C4a-peroxide anion 22 , 23 . The purified enzyme showed an intense yellow coloration indicative of a bound flavin cofactor that was further determined as flavin adenine dinucleotide (FAD;", "role": "user" }, { "content": "Plants, fungi and bacteria produce natural products that function as defenses that are deployed against predators and competitors. In medicine, these compounds have such applications as antibiotics, cancer drugs and cholesterol reducers. The team working with associate professor Dr. Robin Teufel and Dr. Britta Frensch of the Institute of Biology II of the Faculty of Biology of the University of Freiburg and researchers from the ETH Zürich in Switzerland were able to shed light on the key role of three enzymes that are involved in synthesizing a class of natural products. The researchers have published their findings in Nature Communications. Actinobacteria produce many natural products, such as those that are known as aromatic polyketides. The Freiburg researchers examined how actinobacteria—aided by enzymes—were able to synthesize such bioactive substances from simple, molecular components. Teufel and his team were able to illuminate the key roles played by three enzymes in the biosynthesis of rubromycins, which belong to the most structurally complex aromatic polyketides. The researchers discovered that the enzymes drastically restructure a chemical precursor molecule. Through this process they create the carbon backbone of the rubromycins, which is key to the diverse, pharmacological effects of these compounds. Using chemical and biochemical methods, the researchers succeeded in examining the functions of the enzymes more closely and identifying several previously unknown intermediates in the biosynthesis of the rubromycins. Teufel explains, \"We've made important findings about the ways such enzymes control the formation of complex natural products in microorganisms. These findings could play a central role in applying bioengineering to make new types of bioactive rubromycin-polyketides.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The structural complexity and bioactivity of natural products often depend on enzymatic redox tailoring steps. This is exemplified by the generation of the bisbenzannulated [5,6]-spiroketal pharmacophore in the bacterial rubromycin family of aromatic polyketides, which exhibit a wide array of bioactivities such as the inhibition of HIV reverse transcriptase or DNA helicase. Here we elucidate the complex flavoenzyme-driven formation of the rubromycin pharmacophore that is markedly distinct from conventional (bio)synthetic strategies for spiroketal formation. Accordingly, a polycyclic aromatic precursor undergoes extensive enzymatic oxidative rearrangement catalyzed by two flavoprotein monooxygenases and a flavoprotein oxidase that ultimately results in a drastic distortion of the carbon skeleton. The one-pot in vitro reconstitution of the key enzymatic steps as well as the comprehensive characterization of reactive intermediates allow to unravel the intricate underlying reactions, during which four carbon-carbon bonds are broken and two CO 2 become eliminated. This work provides detailed insight into perplexing redox tailoring enzymology that sets the stage for the (chemo)enzymatic production and bioengineering of bioactive spiroketal-containing polyketides. Introduction The benastatins, pradimicins, fredericamycins, xantholipins (among others), as well as the rubromycin family belong to a growing group of biosynthetically related aromatic type II polyketide natural products with extended “pentangular” architecture that are produced by numerous actinobacterial species 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . The intensely colored rubromycins comprise various griseorhodins (e.g., griseorhodin A ( 1 )), hyaluromycin, purpuromycin, heliquinomycin, as well as the eponymous rubromycins (e.g., β-rubromycin ( 2 )) 2 , 9 , 10 , 11 , 12 . Often, these compounds act as potent enzyme inhibitors and 2 was consequently suggested as a lead structure for drug development 13 . The hallmark structural feature of the rubromycins is a bisbenzannulated [5,6]-spiroketal pharmacophore that disrupts the planarity of the polycyclic, aromatic carbon backbone (Fig. 1 ) 13 . Even though 2 was first described in 1953 11 (Fig. 1 ), it took almost half a century before the total synthesis of a rubromycin polyketide was achieved owing to their intricate structures 12 , 14 . In fact, synthetic strategies for the griseorhodins have yet to be reported, which are distinguished by even more complex, highly oxygenated pharmacophores such as the epoxyspiroketal of 1 12 . Fig. 1: Overview of the proposed biosynthesis of bacterial rubromycin-type polyketides and final pathway products. a Griseorhodin A biosynthetic gene cluster encoding, e.g., the minimal type II polyketide synthase (PKS), cyclases, and tailoring enzymes 9 . b Initial steps afford a reactive acyl-carrier protein (ACP)-bound poly-β-ketone, which is subsequently cyclized and modified to 3 . Compounds 3 and 11 were previously identified in the course of gene deletion experiments (ΔgrhO5 and ΔgrhO6, respectively, encoding flavin-dependent tailoring enzymes investigated in this work) and assigned as putative advanced intermediates 10 . The conversion of 3 into 4 via 8 and 11 (dashed box) and additional intermediates was elucidated in this work. A ketoreductase (presumably GrhO10) then converts 4 into 13 . c Examples of mature rubromycins likely formed from 13 . Full size image Moreover, details on the biosynthesis of the rubromycins and the spiroketal moiety remain scarce. First insights originated from extensive gene-inactivation studies with the griseorhodin ( grh ) A biosynthetic gene cluster of Streptomyces sp. JP95 isolated from the marine tunicate Aplidium lenticulum , which was expressed in the heterologous producer S. albus sp. J1074 9 , 10 . Initial steps resemble typical type II polyketide pathways involving a minimal polyketide synthase (PKS) that likely utilizes an acetyl-CoA starter unit and 12 malonyl-CoA extender units to generate a highly reactive acyl-carrier protein (ACP)-bound poly-β-ketone chain. Following enzyme-catalyzed regioselective ketoreduction, cyclization, aromatization and ACP elimination, further tailoring reactions modify the polyketide backbone and lead to the advanced and highly oxidized intermediate collinone ( 3 ) (previously also isolated from a heterologous producer expressing parts of the rubromycin biosynthetic gene cluster 15 ), which may serve as a direct precursor for spiroketalization 10 . This would necessitate an extensive oxidative backbone rearrangement as well as the elimination of two C 1 units, which may be mediated by mechanistically versatile flavin-dependent enzymes 16 , 17 , 18 , 19 , 20 , 21 , 22 that often facilitate redox tailoring reactions in natural product biosynthesis (Fig. 1 ) 16 , 19 . Here, we report the full in vitro reconstitution of enzymatic spiroketal formation in the biosynthesis of rubromycin-type polyketides. We elucidate the conversion of 3 into the [5,6]-spiroketal-containing 7,8-dideoxy-6-oxo-griseorhodin C ( 4 ) via various reactive intermediates by the concerted action of the flavoprotein monooxygenases GrhO5 and GrhO6, as well as the flavoprotein oxidase GrhO1 that are encoded by the grh gene cluster. This process is primarily mediated by the multifunctional monooxygenase GrhO5 that oxidatively rearranges the carbon backbone and ultimately forms a [6,6]-spiroketal and is assisted by GrhO1, before the ring-contracting GrhO6 generates the [5,6]-spiroketal pharmacophore found in mature rubromycin polyketides (Fig. 1 ). Results Flavoprotein monooxygenase GrhO5 initiates spiroketal formation by rapid collinone reduction S. albus sp. J1074 KR8 (Δ grhO5 ) was previously reported to produce 3 as major shunt metabolite, which may thus represent the native substrate of GrhO5 10 . To investigate this, 3 was isolated from the S. albus mutant, while GrhO5 (fused with an N-terminal maltose binding protein tag) was obtained from the heterologous producer Escherichia coli BL21 DE3 (see Online Methods section for details on gene cloning as well as production and purification of enzymes and compounds). GrhO5 is predicted to function as flavoprotein monooxygenase based on the amino acid sequence 10 and is homologous to the NAD(P)H- and FAD-dependent class A flavoprotein monooxygenases with “glutathione reductase type” Rossmann fold 21 . Typically, these enzymes catalyze aromatic hydroxylation reactions via an electrophilic flavin-C4a-hydroperoxide oxygenating species, while some members instead act as Baeyer–Villiger monooxygenases (BVMOs) that employ a nucleophilic flavin-C4a-peroxide anion 22 , 23 . The purified enzyme showed an intense yellow coloration indicative of a bound flavin cofactor that was further determined as flavin adenine dinucleotide (FAD;<|im_end|> <|im_start|>assistant Plants, fungi and bacteria produce natural products that function as defenses that are deployed against predators and competitors. In medicine, these compounds have such applications as antibiotics, cancer drugs and cholesterol reducers. The team working with associate professor Dr. Robin Teufel and Dr. Britta Frensch of the Institute of Biology II of the Faculty of Biology of the University of Freiburg and researchers from the ETH Zürich in Switzerland were able to shed light on the key role of three enzymes that are involved in synthesizing a class of natural products. The researchers have published their findings in Nature Communications. Actinobacteria produce many natural products, such as those that are known as aromatic polyketides. The Freiburg researchers examined how actinobacteria—aided by enzymes—were able to synthesize such bioactive substances from simple, molecular components. Teufel and his team were able to illuminate the key roles played by three enzymes in the biosynthesis of rubromycins, which belong to the most structurally complex aromatic polyketides. The researchers discovered that the enzymes drastically restructure a chemical precursor molecule. Through this process they create the carbon backbone of the rubromycins, which is key to the diverse, pharmacological effects of these compounds. Using chemical and biochemical methods, the researchers succeeded in examining the functions of the enzymes more closely and identifying several previously unknown intermediates in the biosynthesis of the rubromycins. Teufel explains, "We've made important findings about the ways such enzymes control the formation of complex natural products in microorganisms. These findings could play a central role in applying bioengineering to make new types of bioactive rubromycin-polyketides." <|im_end|>

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2,088

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. Scrambling was proposed to occur with lipid headgroups moving between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryogenic electron microscopy structure of the nanodisc-reconstituted Ca 2+ -bound afTMEM16 scramblase showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove’s intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not require specific protein-lipid interactions with the extracellular vestibule. We find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes, despite an open pathway. Our results show afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove. Introduction Biological membranes play a fundamental role in many cellular signaling pathways as they define the physical boundaries of cellular compartments and actively modulate the function of integral and membrane-associated proteins. In eukaryotic cells, the composition and distribution of the phospholipid constituents of the membrane is tightly regulated by the activity of a variety of dedicated enzymes, flipases, flopases and scramblases 1 . The headgroup asymmetry of the plasma membrane is established by the action of ATP-driven pumps which distribute phosphatidylethanolamine (PE) and phosphatidylserine (PS) to the inner leaflet and phosphatidylcholine (PC) to the outer leaflet 1 . Activated phospholipid scramblases dissipate this asymmetry and expose PS on the extracellular leaflet. This is critical for multiple signaling pathways, ranging from apoptosis to blood coagulation, autophagy and cell-cell fusion 1 , 2 . There are five known families of scramblases, the Ca 2+ -activated TMEM16 3 , 4 , 5 , the caspase-activated Xk-related (Xkr) proteins 6 , and the more recently identified ATG9, TMEM41B and VMP1 7 , 8 , 9 . Additionally, several GPCR’s scramble lipids when reconstituted in liposomes 10 , 11 . Lipid scrambling by the TMEM16’s is of critical importance for a myriad of physiological processes, including blood coagulation, bone mineralization, membrane fusion and viral entry 2 , 4 , 12 . Dysregulation of TMEM16 scramblase activity can have disastrous consequences, as both gain- and loss- of function mutations have been associated with disorders of blood, brain, bone and muscle 3 , 13 , 14 , 15 , 16 . The TMEM16 superfamily is comprised of Cl - channels and dual function scramblases/non-selective ion channels 4 . Both subtypes share a common homodimeric architecture where each protomer is comprised of 10 transmembrane (TM) helices 17 , 18 , 19 , 20 , 21 , 22 , 23 (Fig. 1A, B ). In each protomer, the TM3-TM7 helices form a hydrophilic permeation pathway, or groove, that can adopt multiple conformations to allow passage of ions, lipids or to prevent movement of both substrates 20 , 21 , 22 , 23 , 24 . Fig. 1: Lipid-protein interactions in Ca 2+ -bound afTMEM16. A Structural model of afTMEM16 in 0.5 mM Ca 2+ in C18 lipid nanodiscs. B View of the open permeation pathway. C , D Unsharpened maps of the protein (gray) and associated lipids (red) viewed from the membrane plane ( C ) and from the extracellular side ( D ). The map showing the density of the nanodisc membrane is low-pass filtered to 10 Å and shown in transparent red. E – G Views of the lipid groove from the plane of the membrane ( E , F ) and from the extracellular solution ( G ). The unsharpened maps of the protein (gray) and lipids (red) are shown. H – J Views of the afTMEM16 dimer from the plane of the membrane ( H ), extra- ( I ) and intra-cellular ( J ) sides with modeled lipids shown in stick representation. Lipids at the dimer interface are labeled D1–9 and those at the permeation pathway are labeled P1–7. Lipids from the inner and outer leaflets are colored in yellow and blue, respectively. Lipids D4 and D5 were built as PG, while all others were built up to the phosphate atom in the head. In all views, the cytosolic domain of afTMEM16 was omitted for clarity. K Close up of the density map at the dimer interface viewed from the extracellular side showing the two afTMEM16 monomers (gray and cyan) and intercalated lipid tails (red). * denotes the symmetry axis. L The dimer interface salt bridge between TM9 and 10 (in cartoon representation) is formed by E618 and H619 (in stick representation) and is shielded from the intra- and extra-cellular solutions by lipids D3, D4, D6, and D7 (in spheres and colored as in F – H ). Full size image The scrambling mechanism has been extensively investigated at the functional, computational and structural levels 3 , 11 , 13 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . The consensus proposal is a ‘credit-card’ mechanism 37 , where the lipid headgroups penetrate and traverse the open hydrophilic groove while their tails remain embedded within the hydrocarbon core of the membrane 25 , 29 , 32 . Within this framework, lipid scrambling is enabled by specific interactions of the permeating lipids with charged and polar groove-lining residues 25 , 29 , 32 . However, TMEM16 scramblases do not discriminate among lipids such as PS, PE, PG, PC and DOTAP with headgroups differing in in charge, structure and size 18 , 26 , 28 , 30 . Further, PE lipids conjugated to cargoes of up to 5 kDa molecular weight are also efficiently scrambled 11 . These observations suggest that specific interactions between the groove and the scrambled lipids might not be necessary. The poor headgroup selectivity is also shared by other scramblases that lack", "role": "user" }, { "content": "A class of proteins known as TMEM16 scramblases permit rearrangement of lipids in the cell membrane chiefly by thinning the membrane, according to a new model by Weill Cornell Medicine investigators. The model, based on the highest-resolution images to date of a TMEM16 scramblase, challenges the prevailing theory of how these proteins play their fundamental role in biology and could lead to the first scramblase-targeted pharmaceuticals. Scramblase proteins reside in the outer membranes of virtually all eukaryotic cells and can disorganize—scramble—the normal arrangement of fat-related lipid molecules that constitute the membranes. This disruption of the normal membrane structure is a necessary part of many important biological events including blood coagulation, membrane repair and apoptosis, the programmed death of damaged cells. Dysfunctions of TMEM16 scramblases have been linked to blood and bone disorders, lower sperm motility, cancers and movement disorders, among other conditions. The researchers, whose findings were reported May 11 in Nature Communications, used cryogenic electron microscopy (cryo-EM) to image the structure of a TMEM16 scramblase at near-atomic-scale resolution in a membrane-like environment. The image data suggested strongly that what had been the consensus model of how these scramblases work needs to be revised. \"We're proposing that the TMEM16 scramblase protein works not by interacting directly with specific lipids, but instead by mechanically altering the structure of the membrane, making it generally very thin and disordered,\" said Alessio Accardi, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. The first authors of the study were Maria Falzone, a doctoral student in the Accardi lab during the study, and Zhang Feng, a postdoctoral associate in the Accardi lab. The outer membrane of a cell is composed of two tightly ordered layers of lipid molecules, where the outer and inner layers are composed of distinct sets of lipid molecule types. A TMEM16 scramblase spans these layers and has a tube or \"chute\" structure, which opens when activated by binding of calcium ions. Activation of this protein causes lipids in the cell membrane to lose their normal arrangement and to become randomly distributed between the two layers. The dominant hypothesis had been that the chute acts somewhat like the groove in a credit card-swipe reader with lipids freely moving between membrane layers by fitting into the groove head-first, thus causing the two membrane leaflets to lose their usual ordering. However, the difficulty of resolving TMEM16's structure in complex with weakly associated lipid molecules in sufficient detail with imaging methods had left the precise mechanism of lipid scrambling unclear. Accardi and his team used cryo-EM to build a 3D structural image of the TMEM16 scramblase found in a species of fungus, Aspergillus fumigatus. This version of the scramblase is very similar to the human proteins, though it is more stable for cryo-EM purposes. The resolution of the structural image was 2.4 Angstroms, or about a quarter of a billionth of a meter—the highest resolution to date for a TMEM16 scramblase structure. The structural imaging data, combined with functional analyses of different mutants of the TMEM16 scramblase, implied that the card-swipe reader model is incorrect. Instead of having specific interactions with lipids, the scramblase chute locally deforms the membrane to make it significantly thinner, disorganizing lipids in the vicinity. \"We're proposing that TMEM16 scramblase mechanically alters the structure of the membrane, making it very thin and disordered near the groove,\" Accardi said. \"This enables lipid movement without necessitating interactions with the inside of the groove, as in the credit card reader model.\" Opening of the chute, he noted, also brings in water molecules which facilitate the movement of the nearby lipid heads between the membrane layers. Accardi and his team are now working to confirm their findings in mammalian versions of TMEM16 scramblases. They are also studying how these scramblases' functions are regulated in cells, and are starting to think about how future small-molecule drugs could restore or otherwise alter scramblase function to treat diseases. \"We're trying to understand the implications, for biology and medicine, of this new model suggested by our study,\" Accardi said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. Scrambling was proposed to occur with lipid headgroups moving between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryogenic electron microscopy structure of the nanodisc-reconstituted Ca 2+ -bound afTMEM16 scramblase showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove’s intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not require specific protein-lipid interactions with the extracellular vestibule. We find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes, despite an open pathway. Our results show afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove. Introduction Biological membranes play a fundamental role in many cellular signaling pathways as they define the physical boundaries of cellular compartments and actively modulate the function of integral and membrane-associated proteins. In eukaryotic cells, the composition and distribution of the phospholipid constituents of the membrane is tightly regulated by the activity of a variety of dedicated enzymes, flipases, flopases and scramblases 1 . The headgroup asymmetry of the plasma membrane is established by the action of ATP-driven pumps which distribute phosphatidylethanolamine (PE) and phosphatidylserine (PS) to the inner leaflet and phosphatidylcholine (PC) to the outer leaflet 1 . Activated phospholipid scramblases dissipate this asymmetry and expose PS on the extracellular leaflet. This is critical for multiple signaling pathways, ranging from apoptosis to blood coagulation, autophagy and cell-cell fusion 1 , 2 . There are five known families of scramblases, the Ca 2+ -activated TMEM16 3 , 4 , 5 , the caspase-activated Xk-related (Xkr) proteins 6 , and the more recently identified ATG9, TMEM41B and VMP1 7 , 8 , 9 . Additionally, several GPCR’s scramble lipids when reconstituted in liposomes 10 , 11 . Lipid scrambling by the TMEM16’s is of critical importance for a myriad of physiological processes, including blood coagulation, bone mineralization, membrane fusion and viral entry 2 , 4 , 12 . Dysregulation of TMEM16 scramblase activity can have disastrous consequences, as both gain- and loss- of function mutations have been associated with disorders of blood, brain, bone and muscle 3 , 13 , 14 , 15 , 16 . The TMEM16 superfamily is comprised of Cl - channels and dual function scramblases/non-selective ion channels 4 . Both subtypes share a common homodimeric architecture where each protomer is comprised of 10 transmembrane (TM) helices 17 , 18 , 19 , 20 , 21 , 22 , 23 (Fig. 1A, B ). In each protomer, the TM3-TM7 helices form a hydrophilic permeation pathway, or groove, that can adopt multiple conformations to allow passage of ions, lipids or to prevent movement of both substrates 20 , 21 , 22 , 23 , 24 . Fig. 1: Lipid-protein interactions in Ca 2+ -bound afTMEM16. A Structural model of afTMEM16 in 0.5 mM Ca 2+ in C18 lipid nanodiscs. B View of the open permeation pathway. C , D Unsharpened maps of the protein (gray) and associated lipids (red) viewed from the membrane plane ( C ) and from the extracellular side ( D ). The map showing the density of the nanodisc membrane is low-pass filtered to 10 Å and shown in transparent red. E – G Views of the lipid groove from the plane of the membrane ( E , F ) and from the extracellular solution ( G ). The unsharpened maps of the protein (gray) and lipids (red) are shown. H – J Views of the afTMEM16 dimer from the plane of the membrane ( H ), extra- ( I ) and intra-cellular ( J ) sides with modeled lipids shown in stick representation. Lipids at the dimer interface are labeled D1–9 and those at the permeation pathway are labeled P1–7. Lipids from the inner and outer leaflets are colored in yellow and blue, respectively. Lipids D4 and D5 were built as PG, while all others were built up to the phosphate atom in the head. In all views, the cytosolic domain of afTMEM16 was omitted for clarity. K Close up of the density map at the dimer interface viewed from the extracellular side showing the two afTMEM16 monomers (gray and cyan) and intercalated lipid tails (red). * denotes the symmetry axis. L The dimer interface salt bridge between TM9 and 10 (in cartoon representation) is formed by E618 and H619 (in stick representation) and is shielded from the intra- and extra-cellular solutions by lipids D3, D4, D6, and D7 (in spheres and colored as in F – H ). Full size image The scrambling mechanism has been extensively investigated at the functional, computational and structural levels 3 , 11 , 13 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . The consensus proposal is a ‘credit-card’ mechanism 37 , where the lipid headgroups penetrate and traverse the open hydrophilic groove while their tails remain embedded within the hydrocarbon core of the membrane 25 , 29 , 32 . Within this framework, lipid scrambling is enabled by specific interactions of the permeating lipids with charged and polar groove-lining residues 25 , 29 , 32 . However, TMEM16 scramblases do not discriminate among lipids such as PS, PE, PG, PC and DOTAP with headgroups differing in in charge, structure and size 18 , 26 , 28 , 30 . Further, PE lipids conjugated to cargoes of up to 5 kDa molecular weight are also efficiently scrambled 11 . These observations suggest that specific interactions between the groove and the scrambled lipids might not be necessary. The poor headgroup selectivity is also shared by other scramblases that lack<|im_end|> <|im_start|>assistant A class of proteins known as TMEM16 scramblases permit rearrangement of lipids in the cell membrane chiefly by thinning the membrane, according to a new model by Weill Cornell Medicine investigators. The model, based on the highest-resolution images to date of a TMEM16 scramblase, challenges the prevailing theory of how these proteins play their fundamental role in biology and could lead to the first scramblase-targeted pharmaceuticals. Scramblase proteins reside in the outer membranes of virtually all eukaryotic cells and can disorganize—scramble—the normal arrangement of fat-related lipid molecules that constitute the membranes. This disruption of the normal membrane structure is a necessary part of many important biological events including blood coagulation, membrane repair and apoptosis, the programmed death of damaged cells. Dysfunctions of TMEM16 scramblases have been linked to blood and bone disorders, lower sperm motility, cancers and movement disorders, among other conditions. The researchers, whose findings were reported May 11 in Nature Communications, used cryogenic electron microscopy (cryo-EM) to image the structure of a TMEM16 scramblase at near-atomic-scale resolution in a membrane-like environment. The image data suggested strongly that what had been the consensus model of how these scramblases work needs to be revised. "We're proposing that the TMEM16 scramblase protein works not by interacting directly with specific lipids, but instead by mechanically altering the structure of the membrane, making it generally very thin and disordered," said Alessio Accardi, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. The first authors of the study were Maria Falzone, a doctoral student in the Accardi lab during the study, and Zhang Feng, a postdoctoral associate in the Accardi lab. The outer membrane of a cell is composed of two tightly ordered layers of lipid molecules, where the outer and inner layers are composed of distinct sets of lipid molecule types. A TMEM16 scramblase spans these layers and has a tube or "chute" structure, which opens when activated by binding of calcium ions. Activation of this protein causes lipids in the cell membrane to lose their normal arrangement and to become randomly distributed between the two layers. The dominant hypothesis had been that the chute acts somewhat like the groove in a credit card-swipe reader with lipids freely moving between membrane layers by fitting into the groove head-first, thus causing the two membrane leaflets to lose their usual ordering. However, the difficulty of resolving TMEM16's structure in complex with weakly associated lipid molecules in sufficient detail with imaging methods had left the precise mechanism of lipid scrambling unclear. Accardi and his team used cryo-EM to build a 3D structural image of the TMEM16 scramblase found in a species of fungus, Aspergillus fumigatus. This version of the scramblase is very similar to the human proteins, though it is more stable for cryo-EM purposes. The resolution of the structural image was 2.4 Angstroms, or about a quarter of a billionth of a meter—the highest resolution to date for a TMEM16 scramblase structure. The structural imaging data, combined with functional analyses of different mutants of the TMEM16 scramblase, implied that the card-swipe reader model is incorrect. Instead of having specific interactions with lipids, the scramblase chute locally deforms the membrane to make it significantly thinner, disorganizing lipids in the vicinity. "We're proposing that TMEM16 scramblase mechanically alters the structure of the membrane, making it very thin and disordered near the groove," Accardi said. "This enables lipid movement without necessitating interactions with the inside of the groove, as in the credit card reader model." Opening of the chute, he noted, also brings in water molecules which facilitate the movement of the nearby lipid heads between the membrane layers. Accardi and his team are now working to confirm their findings in mammalian versions of TMEM16 scramblases. They are also studying how these scramblases' functions are regulated in cells, and are starting to think about how future small-molecule drugs could restore or otherwise alter scramblase function to treat diseases. "We're trying to understand the implications, for biology and medicine, of this new model suggested by our study," Accardi said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Fixed orthodontic appliances are common and effective tools to treat malocclusion. Adverse effects of these appliances, such as dental caries and periodontitis, may be associated with alteration of the microbiome. This study investigated the impact of these appliances on the dynamics of the oral microbiome. Seventy-one patients were selected. Supragingival plaque samples were collected before placement (T0) and six months after placement (T1). Saliva samples were collected at T0 and T1, and then when appliance removal (T2). Microbial DNA was analyzed by 16S rRNA meta-sequencing. The diversity analysis indicated dynamic changes in the structure of the oral microbiome. Taxonomic analysis at phylum level showed a significant increase in Bacteroidetes and Saccharibacteria (formally TM7) and decrease in Proteobacteria and Actinobacteria over time, in both plaque and saliva. Genus level analysis of relative abundance indicated a significant increase in anaerobic and facultative anaerobes in both plaque and saliva. Fixed orthodontic appliances induced measurable changes in the oral microbiome. This was characterized by an increase in relative abundance of obligate anaerobes, including periodontal pathogens. It can be concluded that this dysbiosis induced by fixed orthodontic appliances is likely to represent a transitional stage in the shift in microbiome from healthy to periodontitis. Introduction The mouth harbors more than 700 bacterial species, constituting one of the most diverse bacterial communities in the human body 1 . The mouth comprises complex structures of hard and soft tissue, such as teeth, tongue, gingiva, and palate; unique variation in oral microbiome structure is observed according to the different surface properties 2 , 3 . Fixed orthodontic appliances are a common and effective tool used to treat malocclusion, but can be associated with secondary effects, such as a change of microbiome and subsequent infections. The complicated undercut shape of orthodontic appliances makes teeth cleaning more difficult and induces plaque accumulation as well as need for restorations 4 , 5 , 6 . Therefore, it has been suggested that the risk of white-spot lesions, dental caries, and periodontal complication are due to the change in oral microbiome. The incidence and prevalence rates of white-spot lesions in patients undergoing orthodontic treatment are high, but these are incipient carious lesions that can be remineralized by application of fluoride 7 . Previous studies have suggested that an increase in Streptococcus mutans bacterial counts, generally regarded as a major risk factor for dental caries, is associated with placement of fixed orthodontic appliances 8 , 9 , 10 , 11 . It is understood that anaerobic microorganisms in plaque play a key role in the initiation and acceleration of periodontal diseases. Periodontal pathogens, such as Fusobacterium, Treponema, and Porphyromonas spp., have been detected in dental plaque around orthodontic appliances 12 . Furthermore, the frequency of Tannerella forsythia, Campylobacter rectus, and Prevotella nigrescens increased after placement of orthodontic appliances 13 . Severe clinical attachment loss during orthodontic treatment has also been reported 14 . These reports suggest that fixed orthodontic appliances may change the oral microbiome and have the potential to shift the bacterial ecosystem toward a pathogenic state. However, most previous reports have focused on only specific species and very few have focused on the microbiome and its dynamics, including unculturable bacteria, following orthodontic treatment. Conventional methods of bacteriological identification, such as cultivation, present limitations to the analysis of microbial community structure and diversity, because the human bacterial flora contains many unculturable species. Emergence of Next Generation Sequencing (NGS) technology has enabled analysis and comparison of bacterial composition, including unculturable bacteria, with unprecedented depth compared to previous methodologies 15 . However, there are few reports about the relationship between orthodontic treatment and the dynamics of oral microbiome. In previous report using NGS, periodontal pathogens were highest during orthodontic treatment, but the data was confined about plaque 16 . The aim of this study was to assess the changes in oral microbiome dynamics caused by fixed orthodontic appliances using 16S rRNA gene meta-sequencing of supragingival plaque and saliva. Results Operational taxonomic unit clustering and trim report In total, 13,506,556 reads were generated from 144 samples, with an average length of 300.4. After sequence trimming, 8,284,029 high quality reads remained, with an average length of 222.5 bp. In plaque samples, 44 samples were successfully analyzed both at T0 and T1. In saliva samples, 16, 23, and 17 samples were successfully analyzed at T0, T1 and T2 respectively. We detected 983 OTUs in total, with an average of 341 OTUs per sample. The number of OTUs increased according to time course both in plaque (T0, 312 and T1, 321) and saliva samples (T0, 329; T1, 366; and T2, 376) though the difference was not significant. Alpha and beta diversity Alpha diversity, a measure of microbial community evenness and richness in each sample, was calculated and compared between time points (2 for plaque samples and 3 for saliva samples; Supplementary Fig. 1 ). The difference in number of OTUs in each sample relates to bacterial community diversity and the difference in number of reads at the end of clustering relates to diversity of sample DNA concentrations. Beta diversity, a measure of the variation of microbial communities between samples, was calculated and compared using Principal Coordinates Analysis (PCoA), based on the Jaccard index. In plaque samples, bacterial diversity at T1 (321 ± 60 OTUs; range 214–430) was slightly more diverse than at T0 (312 ± 69; range 189–465; Supplementary Fig. 1 a). There was no significant difference between upper and lower teeth at either T0 or T1. In saliva samples, there were no visible changes of bacterial community diversity between T0 (329 ± 54; range 240–409), T1 (366 ± 62; 271–481), and T2 (376 ± 60; range 214–430; appendix Supplementary Fig. 1 b). Combined analysis of the beta diversity of plaque and saliva showed that they consisted of different bacterial communities (Fig. 1 a). Comparison of T0 with T1 plaque samples indicates that these two types of sample were apart from each other (Fig. 1 b). We did not observe any obvious shifts in diversity between saliva samples", "role": "user" }, { "content": "A study that sequenced oral microbiome before, during, and after braces of Japanese patients revealed a transformed bacterial community akin to mouths at a pre-gum disease state. \"People who had undergone orthodontic treatments could get a healthy oral environment and beautiful mouth,\" said study co-author Isamu Kado from the Department of Orthodontics and Craniofacial Developmental Biology of Hiroshima University's Graduate School of Biochemical and Health Sciences. But he added that these treatments could also be associated with bacteria-related problems. Our mouth is the second most diverse microbiome in the human body, harboring over 700 bacterial species. And having braces on could make cleaning difficult and induce plaque accumulation. Previous studies have linked braces to imbalances in the oral microbiome. These studies, however, focused on specific harmful species like the tooth decay-causing Streptococcus mutans and not the bacterial community as a whole. Kado and his colleagues cataloged the whole bacterial population present in the mouths of 71 patients by running supragingival plaque and saliva samples through Next Generation Sequencing (NGS) technology. They monitored microbiome changes before the braces were put on, six months after the placement, and post-removal. They found a spike in the number of harmful anaerobic bacteria and a drop in the friendly ones comparable to oral environments at risk of gum disease. \"In our study, the oral microbiome definitely changed during orthodontic treatment. The shift represented an increase of anaerobes, a bacterium that does not require oxygen for growth, and a decrease in commensal bacteria,\" Kado explained. \"This oral condition was similar to the microbiome of the transitional stage from healthy gingiva to periodontitis.\" The researchers said their findings, published in Scientific Reports last December 2020, could support their goal of establishing a prevention system that would avert tooth decay and gingivitis from happening during orthodontic treatments. \"To achieve this goal, it is necessary to clarify the difference in dental caries risk between patients. If this can be achieved, the quality of orthodontic treatment will be further improved,\" Kado said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Fixed orthodontic appliances are common and effective tools to treat malocclusion. Adverse effects of these appliances, such as dental caries and periodontitis, may be associated with alteration of the microbiome. This study investigated the impact of these appliances on the dynamics of the oral microbiome. Seventy-one patients were selected. Supragingival plaque samples were collected before placement (T0) and six months after placement (T1). Saliva samples were collected at T0 and T1, and then when appliance removal (T2). Microbial DNA was analyzed by 16S rRNA meta-sequencing. The diversity analysis indicated dynamic changes in the structure of the oral microbiome. Taxonomic analysis at phylum level showed a significant increase in Bacteroidetes and Saccharibacteria (formally TM7) and decrease in Proteobacteria and Actinobacteria over time, in both plaque and saliva. Genus level analysis of relative abundance indicated a significant increase in anaerobic and facultative anaerobes in both plaque and saliva. Fixed orthodontic appliances induced measurable changes in the oral microbiome. This was characterized by an increase in relative abundance of obligate anaerobes, including periodontal pathogens. It can be concluded that this dysbiosis induced by fixed orthodontic appliances is likely to represent a transitional stage in the shift in microbiome from healthy to periodontitis. Introduction The mouth harbors more than 700 bacterial species, constituting one of the most diverse bacterial communities in the human body 1 . The mouth comprises complex structures of hard and soft tissue, such as teeth, tongue, gingiva, and palate; unique variation in oral microbiome structure is observed according to the different surface properties 2 , 3 . Fixed orthodontic appliances are a common and effective tool used to treat malocclusion, but can be associated with secondary effects, such as a change of microbiome and subsequent infections. The complicated undercut shape of orthodontic appliances makes teeth cleaning more difficult and induces plaque accumulation as well as need for restorations 4 , 5 , 6 . Therefore, it has been suggested that the risk of white-spot lesions, dental caries, and periodontal complication are due to the change in oral microbiome. The incidence and prevalence rates of white-spot lesions in patients undergoing orthodontic treatment are high, but these are incipient carious lesions that can be remineralized by application of fluoride 7 . Previous studies have suggested that an increase in Streptococcus mutans bacterial counts, generally regarded as a major risk factor for dental caries, is associated with placement of fixed orthodontic appliances 8 , 9 , 10 , 11 . It is understood that anaerobic microorganisms in plaque play a key role in the initiation and acceleration of periodontal diseases. Periodontal pathogens, such as Fusobacterium, Treponema, and Porphyromonas spp., have been detected in dental plaque around orthodontic appliances 12 . Furthermore, the frequency of Tannerella forsythia, Campylobacter rectus, and Prevotella nigrescens increased after placement of orthodontic appliances 13 . Severe clinical attachment loss during orthodontic treatment has also been reported 14 . These reports suggest that fixed orthodontic appliances may change the oral microbiome and have the potential to shift the bacterial ecosystem toward a pathogenic state. However, most previous reports have focused on only specific species and very few have focused on the microbiome and its dynamics, including unculturable bacteria, following orthodontic treatment. Conventional methods of bacteriological identification, such as cultivation, present limitations to the analysis of microbial community structure and diversity, because the human bacterial flora contains many unculturable species. Emergence of Next Generation Sequencing (NGS) technology has enabled analysis and comparison of bacterial composition, including unculturable bacteria, with unprecedented depth compared to previous methodologies 15 . However, there are few reports about the relationship between orthodontic treatment and the dynamics of oral microbiome. In previous report using NGS, periodontal pathogens were highest during orthodontic treatment, but the data was confined about plaque 16 . The aim of this study was to assess the changes in oral microbiome dynamics caused by fixed orthodontic appliances using 16S rRNA gene meta-sequencing of supragingival plaque and saliva. Results Operational taxonomic unit clustering and trim report In total, 13,506,556 reads were generated from 144 samples, with an average length of 300.4. After sequence trimming, 8,284,029 high quality reads remained, with an average length of 222.5 bp. In plaque samples, 44 samples were successfully analyzed both at T0 and T1. In saliva samples, 16, 23, and 17 samples were successfully analyzed at T0, T1 and T2 respectively. We detected 983 OTUs in total, with an average of 341 OTUs per sample. The number of OTUs increased according to time course both in plaque (T0, 312 and T1, 321) and saliva samples (T0, 329; T1, 366; and T2, 376) though the difference was not significant. Alpha and beta diversity Alpha diversity, a measure of microbial community evenness and richness in each sample, was calculated and compared between time points (2 for plaque samples and 3 for saliva samples; Supplementary Fig. 1 ). The difference in number of OTUs in each sample relates to bacterial community diversity and the difference in number of reads at the end of clustering relates to diversity of sample DNA concentrations. Beta diversity, a measure of the variation of microbial communities between samples, was calculated and compared using Principal Coordinates Analysis (PCoA), based on the Jaccard index. In plaque samples, bacterial diversity at T1 (321 ± 60 OTUs; range 214–430) was slightly more diverse than at T0 (312 ± 69; range 189–465; Supplementary Fig. 1 a). There was no significant difference between upper and lower teeth at either T0 or T1. In saliva samples, there were no visible changes of bacterial community diversity between T0 (329 ± 54; range 240–409), T1 (366 ± 62; 271–481), and T2 (376 ± 60; range 214–430; appendix Supplementary Fig. 1 b). Combined analysis of the beta diversity of plaque and saliva showed that they consisted of different bacterial communities (Fig. 1 a). Comparison of T0 with T1 plaque samples indicates that these two types of sample were apart from each other (Fig. 1 b). We did not observe any obvious shifts in diversity between saliva samples<|im_end|> <|im_start|>assistant A study that sequenced oral microbiome before, during, and after braces of Japanese patients revealed a transformed bacterial community akin to mouths at a pre-gum disease state. "People who had undergone orthodontic treatments could get a healthy oral environment and beautiful mouth," said study co-author Isamu Kado from the Department of Orthodontics and Craniofacial Developmental Biology of Hiroshima University's Graduate School of Biochemical and Health Sciences. But he added that these treatments could also be associated with bacteria-related problems. Our mouth is the second most diverse microbiome in the human body, harboring over 700 bacterial species. And having braces on could make cleaning difficult and induce plaque accumulation. Previous studies have linked braces to imbalances in the oral microbiome. These studies, however, focused on specific harmful species like the tooth decay-causing Streptococcus mutans and not the bacterial community as a whole. Kado and his colleagues cataloged the whole bacterial population present in the mouths of 71 patients by running supragingival plaque and saliva samples through Next Generation Sequencing (NGS) technology. They monitored microbiome changes before the braces were put on, six months after the placement, and post-removal. They found a spike in the number of harmful anaerobic bacteria and a drop in the friendly ones comparable to oral environments at risk of gum disease. "In our study, the oral microbiome definitely changed during orthodontic treatment. The shift represented an increase of anaerobes, a bacterium that does not require oxygen for growth, and a decrease in commensal bacteria," Kado explained. "This oral condition was similar to the microbiome of the transitional stage from healthy gingiva to periodontitis." The researchers said their findings, published in Scientific Reports last December 2020, could support their goal of establishing a prevention system that would avert tooth decay and gingivitis from happening during orthodontic treatments. "To achieve this goal, it is necessary to clarify the difference in dental caries risk between patients. If this can be achieved, the quality of orthodontic treatment will be further improved," Kado said. <|im_end|>

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1,886

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Isopods (woodlice, slaters and their relatives) are common crustaceans and abundant in numerous habitats. They employ a variety of lifestyles including free-living scavengers and predators but also obligate parasites. This modern-day variability of lifestyles is not reflected in isopod fossils so far, mostly as the life habits of many fossil isopods are still unclear. A rather common group of fossil isopods is Urda (190-100 million years). Although some of the specimens of different species of Urda are considered well preserved, crucial characters for the interpretation of their lifestyle (and also of their phylogenetic position), have so far not been accessible. Results Using up-to-date imaging methods, we here present morphological details of the mouthparts and the thoracopods of 168 million years old specimens of Urda rostrata . Mouthparts are of a sucking-piercing-type morphology, similar to the mouthparts of representatives of ectoparasitic isopods in groups such as Aegidae or Cymothoidae. The thoracopods bear strong, curved dactyli most likely for attaching to a host. Therefore, mouthpart and thoracopod morphology indicate a parasitic lifestyle of Urda rostrata . Based on morphological details, Urda seems deeply nested within the parasitic isopods of the group Cymothoida. Conclusions Similarities to Aegidae and Cymothoidae are interpreted as ancestral characters; Urda is more closely related to Gnathiidae, which is therefore also interpreted as an ingroup of Cymothoida. With this position Urda provides crucial information for our understanding of the evolution of parasitism within isopods. Finally, the specimens reported herein represent the oldest parasitic isopods known to date. Background Parasitism is a widespread strategy among animals (Metazoa), if not the most widespread one. Most, if not all parasites originated from free-living relatives. Still our understanding of how the evolution of a parasitic lifestyle evolved is not fully understood. It has been suggested that there are morphological, physiological, or ecological pre-adaptations to parasitism [ 1 – 4 ]. For improving our understanding of the evolution of parasitism, insects have been considered to be an especially interesting group. It seems that in various insect lineages clear pre-adaptations, such as elongated mouthparts, can be identified [ 5 ]. One model example for studying evolution of parasitism and co-evolution between the parasite and host are lice, possibly due to human medical health and livestock health interest. Chewing lice (‘Mallophaga’), specialized for a parasitic lifestyle on birds [ 6 ], have been proposed to have evolved from a free-living relative [ 7 ]. Comparable to lice, an evolutionary origin from free-living relatives, has been reconstructed for other parasitic groups, for example several worms, such as parasitic nematode worms [ 2 , 8 ], parasitic flatworms [ 9 ], acanthocephalan worms [ 10 ], but also other groups closer related to mallophagan lice, such as mites [ 11 ], or parasitic isopod crustaceans [ 12 ]. Isopod crustaceans – woodlice, slaters, pill bugs and their relatives – are very diverse and successful malacostracan crustaceans (the group containing e.g. crabs, lobsters, shrimps, krill and crayfish). Isopods inhabit various habitats, including marine, freshwater and terrestrial environments [ 12 – 18 ]. They have developed various kinds of lifestyles, among them free-living [ 19 ], scavenging [ 20 – 22 ] or predatory [ 23 ], but also parasitic forms of varying degrees of specialization [ 24 – 27 ]. This is nicely exemplified by the isopod ingroup Cymothoida sensu Wägele [ 12 ]. Within this group numerous lifestyles have evolved, some quite soon after the appearance of the group [ 28 ]. Also, as isopods have potential to be preserved as fossils this group allows a degree of estimation of the appearance of such strategies within Earth history: A scavenging lifestyle is known from representatives of Cirolanidae. Fossil representatives of this group, indirectly suggesting a similar lifestyle, have been reported from the Jurassic [ 21 ] and Cretaceous [ 22 ]. Representatives of Corallanidae and Aegidae have a lifestyle reminiscent of that of a mosquito; one may interpret this as quasi-predatory behavior, yet more precisely it is a temporary parasitic lifestyle; they attach briefly to a host, a fish, only during feeding. An aegiid fossil [ 29 ] has been reported from the Late Miocene, indicating a similar lifestyle at this time. Phylogenetic inference would suggest an older origin of a “marine mosquito” strategy. Representatives of Cymothoidae feed similarly to aegiid isopods when they are juveniles. Yet, as adults they attach to a host fish permanently. The oldest fossil indicating such a type of parasitism in Cymothoidae has been reported from the Jurassic [ 30 ]. During a specific larval phase, representatives of Gnathiidae feed in a comparable way to representatives of adult Aegidae and juvenile Cymothidae [ 20 , 31 ]. Yet, as adults gnathiid isopods are not parasitic. An ingroup position of gnathiids within Cymothoida is equivocal ([ 32 ] vs. [ 33 ]). So far no fossils of this lineage have been reported. A host change respective to their ontogenetic phase can be observed also in representatives of Epicaridea. Larval epicaridids parasitize small crustaceans, e.g. copepods. Adult epicaridids infest mainly larger crustaceans, some are even quasi-endoparasitic. Based on malformations on the host [ 24 , 27 ] or by comparing the life habits of modern relative groups [ 34 ], this lifestyle must have been present since the Jurassic. These examples illustrate not only the diversity of life styles within Cymothoida. They also illustrate different ways of inferring a specific lifestyle in fossils [ 5 ]: 1) The most direct case is finding a parasite directly associated with a host [ 30 ]. 2) A more indirect way is finding isolated specimens with specific morphologies [ 34 ]. More indirect cases are (3) findings of developmental stages with a different lifestyle [ 35 ] and (4) teratological changes in the morphology of a host [ 24 ]. For 2) functional morphology and comparison to extant relatives can support interpretations of different lifestyles. Hook-like claws at the end of thoracopods for attachment in an isopod give a clear hint to a parasitic lifestyle in", "role": "user" }, { "content": "Biologists at LMU have identified two 168-million-year-old fossils as the oldest known parasitic representatives of the crustacean group Isopoda. The study sheds new light on the evolutionary history of isopods. Isopods—of which the woodlouse is perhaps the best known representative—are crustaceans, related to shrimps and lobsters. Representatives of this crustacean group exhibit a wide variety of lifestyles and exploit a large spectrum of ecological niches. Cymothoida, an isopod ingroup, is composed of different sub-groups that evolved different feeding strategies, from free-living scavengers to host-specific and obligate parasites depending on their hosts for their survival; hence, isopods in this group show an extremely diverse morphology. A new study of the oldest fossil parasitic isopods discovered to date, carried out by LMU biologists Christina Nagler and Joachim Haug, has allowed reconstructing the evolution of parasitism within Cymothoida in detail. The findings have just appeared in the online journal BMC Evolutionary Biology. For the study, the authors chose two specimens of the fossil species Urda rostrata held in the Bavarian State Collection for Paleontology and Geology in Munich, which are unusually well preserved and amenable to three-dimensional reconstruction. Both were recovered at the same site and are 168 million years old, hence from the Jurassic period (145-200 million years ago). Representatives of Urda were widespread during the Jurassic. However, little is known about their lifestyle or phylogenetic affiliation, as morphological characters that would allow drawing reliable conclusions on these aspects have not been accessible in the fossil specimens investigated so far. \"With modern imaging techniques, especially micro-computed tomography, we were able to visualize morphological details of the mouthparts and the legs of these fossil isopods for the first time,\" Nagler says. The imaging data revealed that the fossils possess certain features that are typically found in modern parasitic isopods. The morphology of the mouthparts suggests that both specimens were specialized for piercing and sucking, while the legs on the thorax end in clearly curved hooks of the sort that modern forms use to attach themselves firmly to their hosts. These aspects of its functional morphology therefore support the inference that U. rostrata was an external parasite. Moreover, both specimens were recovered from limestone beds indicative of a tropical lagoon – an environment in which diverse present-day species of Cymothoida occur as obligate ectoparasites on fish. In addition, the fossils have a number of morphological features in common with modern isopods which follow a parasitic lifestyle only during the juvenile phase of the life-cycle. \"This finding indicates that the morphology of the mouthparts and the thoracic appendages was progressively adapted to the demands of a parasitic lifestyle,\" Nagler explains. Furthermore, the reconstruction of the phylogenetic relationships suggests that parasitism originated only once within Cymothoida, and that the transition from scavenger to parasite involved intermediate forms that began as opportunistic predators (like mosquitoes) and subsequently gave rise to stage-specific and to obligate parasites. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Isopods (woodlice, slaters and their relatives) are common crustaceans and abundant in numerous habitats. They employ a variety of lifestyles including free-living scavengers and predators but also obligate parasites. This modern-day variability of lifestyles is not reflected in isopod fossils so far, mostly as the life habits of many fossil isopods are still unclear. A rather common group of fossil isopods is Urda (190-100 million years). Although some of the specimens of different species of Urda are considered well preserved, crucial characters for the interpretation of their lifestyle (and also of their phylogenetic position), have so far not been accessible. Results Using up-to-date imaging methods, we here present morphological details of the mouthparts and the thoracopods of 168 million years old specimens of Urda rostrata . Mouthparts are of a sucking-piercing-type morphology, similar to the mouthparts of representatives of ectoparasitic isopods in groups such as Aegidae or Cymothoidae. The thoracopods bear strong, curved dactyli most likely for attaching to a host. Therefore, mouthpart and thoracopod morphology indicate a parasitic lifestyle of Urda rostrata . Based on morphological details, Urda seems deeply nested within the parasitic isopods of the group Cymothoida. Conclusions Similarities to Aegidae and Cymothoidae are interpreted as ancestral characters; Urda is more closely related to Gnathiidae, which is therefore also interpreted as an ingroup of Cymothoida. With this position Urda provides crucial information for our understanding of the evolution of parasitism within isopods. Finally, the specimens reported herein represent the oldest parasitic isopods known to date. Background Parasitism is a widespread strategy among animals (Metazoa), if not the most widespread one. Most, if not all parasites originated from free-living relatives. Still our understanding of how the evolution of a parasitic lifestyle evolved is not fully understood. It has been suggested that there are morphological, physiological, or ecological pre-adaptations to parasitism [ 1 – 4 ]. For improving our understanding of the evolution of parasitism, insects have been considered to be an especially interesting group. It seems that in various insect lineages clear pre-adaptations, such as elongated mouthparts, can be identified [ 5 ]. One model example for studying evolution of parasitism and co-evolution between the parasite and host are lice, possibly due to human medical health and livestock health interest. Chewing lice (‘Mallophaga’), specialized for a parasitic lifestyle on birds [ 6 ], have been proposed to have evolved from a free-living relative [ 7 ]. Comparable to lice, an evolutionary origin from free-living relatives, has been reconstructed for other parasitic groups, for example several worms, such as parasitic nematode worms [ 2 , 8 ], parasitic flatworms [ 9 ], acanthocephalan worms [ 10 ], but also other groups closer related to mallophagan lice, such as mites [ 11 ], or parasitic isopod crustaceans [ 12 ]. Isopod crustaceans – woodlice, slaters, pill bugs and their relatives – are very diverse and successful malacostracan crustaceans (the group containing e.g. crabs, lobsters, shrimps, krill and crayfish). Isopods inhabit various habitats, including marine, freshwater and terrestrial environments [ 12 – 18 ]. They have developed various kinds of lifestyles, among them free-living [ 19 ], scavenging [ 20 – 22 ] or predatory [ 23 ], but also parasitic forms of varying degrees of specialization [ 24 – 27 ]. This is nicely exemplified by the isopod ingroup Cymothoida sensu Wägele [ 12 ]. Within this group numerous lifestyles have evolved, some quite soon after the appearance of the group [ 28 ]. Also, as isopods have potential to be preserved as fossils this group allows a degree of estimation of the appearance of such strategies within Earth history: A scavenging lifestyle is known from representatives of Cirolanidae. Fossil representatives of this group, indirectly suggesting a similar lifestyle, have been reported from the Jurassic [ 21 ] and Cretaceous [ 22 ]. Representatives of Corallanidae and Aegidae have a lifestyle reminiscent of that of a mosquito; one may interpret this as quasi-predatory behavior, yet more precisely it is a temporary parasitic lifestyle; they attach briefly to a host, a fish, only during feeding. An aegiid fossil [ 29 ] has been reported from the Late Miocene, indicating a similar lifestyle at this time. Phylogenetic inference would suggest an older origin of a “marine mosquito” strategy. Representatives of Cymothoidae feed similarly to aegiid isopods when they are juveniles. Yet, as adults they attach to a host fish permanently. The oldest fossil indicating such a type of parasitism in Cymothoidae has been reported from the Jurassic [ 30 ]. During a specific larval phase, representatives of Gnathiidae feed in a comparable way to representatives of adult Aegidae and juvenile Cymothidae [ 20 , 31 ]. Yet, as adults gnathiid isopods are not parasitic. An ingroup position of gnathiids within Cymothoida is equivocal ([ 32 ] vs. [ 33 ]). So far no fossils of this lineage have been reported. A host change respective to their ontogenetic phase can be observed also in representatives of Epicaridea. Larval epicaridids parasitize small crustaceans, e.g. copepods. Adult epicaridids infest mainly larger crustaceans, some are even quasi-endoparasitic. Based on malformations on the host [ 24 , 27 ] or by comparing the life habits of modern relative groups [ 34 ], this lifestyle must have been present since the Jurassic. These examples illustrate not only the diversity of life styles within Cymothoida. They also illustrate different ways of inferring a specific lifestyle in fossils [ 5 ]: 1) The most direct case is finding a parasite directly associated with a host [ 30 ]. 2) A more indirect way is finding isolated specimens with specific morphologies [ 34 ]. More indirect cases are (3) findings of developmental stages with a different lifestyle [ 35 ] and (4) teratological changes in the morphology of a host [ 24 ]. For 2) functional morphology and comparison to extant relatives can support interpretations of different lifestyles. Hook-like claws at the end of thoracopods for attachment in an isopod give a clear hint to a parasitic lifestyle in<|im_end|> <|im_start|>assistant Biologists at LMU have identified two 168-million-year-old fossils as the oldest known parasitic representatives of the crustacean group Isopoda. The study sheds new light on the evolutionary history of isopods. Isopods—of which the woodlouse is perhaps the best known representative—are crustaceans, related to shrimps and lobsters. Representatives of this crustacean group exhibit a wide variety of lifestyles and exploit a large spectrum of ecological niches. Cymothoida, an isopod ingroup, is composed of different sub-groups that evolved different feeding strategies, from free-living scavengers to host-specific and obligate parasites depending on their hosts for their survival; hence, isopods in this group show an extremely diverse morphology. A new study of the oldest fossil parasitic isopods discovered to date, carried out by LMU biologists Christina Nagler and Joachim Haug, has allowed reconstructing the evolution of parasitism within Cymothoida in detail. The findings have just appeared in the online journal BMC Evolutionary Biology. For the study, the authors chose two specimens of the fossil species Urda rostrata held in the Bavarian State Collection for Paleontology and Geology in Munich, which are unusually well preserved and amenable to three-dimensional reconstruction. Both were recovered at the same site and are 168 million years old, hence from the Jurassic period (145-200 million years ago). Representatives of Urda were widespread during the Jurassic. However, little is known about their lifestyle or phylogenetic affiliation, as morphological characters that would allow drawing reliable conclusions on these aspects have not been accessible in the fossil specimens investigated so far. "With modern imaging techniques, especially micro-computed tomography, we were able to visualize morphological details of the mouthparts and the legs of these fossil isopods for the first time," Nagler says. The imaging data revealed that the fossils possess certain features that are typically found in modern parasitic isopods. The morphology of the mouthparts suggests that both specimens were specialized for piercing and sucking, while the legs on the thorax end in clearly curved hooks of the sort that modern forms use to attach themselves firmly to their hosts. These aspects of its functional morphology therefore support the inference that U. rostrata was an external parasite. Moreover, both specimens were recovered from limestone beds indicative of a tropical lagoon – an environment in which diverse present-day species of Cymothoida occur as obligate ectoparasites on fish. In addition, the fossils have a number of morphological features in common with modern isopods which follow a parasitic lifestyle only during the juvenile phase of the life-cycle. "This finding indicates that the morphology of the mouthparts and the thoracic appendages was progressively adapted to the demands of a parasitic lifestyle," Nagler explains. Furthermore, the reconstruction of the phylogenetic relationships suggests that parasitism originated only once within Cymothoida, and that the transition from scavenger to parasite involved intermediate forms that began as opportunistic predators (like mosquitoes) and subsequently gave rise to stage-specific and to obligate parasites. <|im_end|>

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2,126

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Waterbird aggregations and droughts affect nutrient and microbial dynamics in wetlands. We analysed the effects of high densities of flamingos on nutrients and microbial dynamics in a saline lake during a wet and a dry hydrological year, and explored the effects of guano on prokaryotic growth. Concentrations of dissolved organic carbon, total phosphorus and total nitrogen in the surface waters were 2–3 fold higher during the drought and were correlated with salinity. Flamingos stimulated prokaryotic heterotrophic production and triggered cascading effects on prokaryotic abundance, viruses and dissolved nitrogen. This stimulus of heterotrophic prokaryotes was associated with soluble phosphorus inputs from guano, and also from sediments. In the experiments, the specific growth rate and the carrying capacity were almost twice as high after guano addition than in the control treatments, and were coupled with soluble phosphorus assimilation. Flamingo guano was also rich in nitrogen. Dissolved N in lake water lagged behind the abundance of flamingos, but the causes of this lag are unclear. This study demonstrates that intense droughts could lead to increases in total nutrients in wetlands; however, microbial activity is likely constrained by the availability of soluble phosphorus, which appears to be more dependent on the abundance of waterbirds. Introduction Since Hutchinson’s seminal work 1 on the importance of guano on marine productivity, many studies have analyzed the inputs of nutrients associated with waterbird feces in inland waters 2 , 3 , 4 , 5 , 6 . This process is termed guanotrophication 7 and appears to be particularly important in arid regions 8 , systems with long water residence times 9 and inland waters used as roosts by non-breeding birds or as breeding sites by colonial waterbirds, where birds import nutrients from foraging areas 4 , 5 , 10 , 11 , 12 . Guanotrophication affects wetland quality and primary productivity, as shown in studies by Kitchell et al . 3 in which chlorophyll increased with the density of geese, and in experiments with phytoplankton 13 . On the other hand, large waterbirds cause sediment bioturbation with consequences for nutrient release and methane fluxes 14 , 15 . Although bacterial production and diversity are known to change under pulses of nutrients 16 , 17 , 18 , no studies have directly addressed changes in aquatic microbial communities associated with guanotrophication and sediment bioturbation by waterbirds, despite the key role of microbial processes in biogeochemical cycles and greenhouse gas fluxes in wetlands and lakes. Insights into the effects of waterbirds on microbial communities are crucial to enable integrative wetland management and the measures required to support waterbird diversity and their effects on guanotrophication, nutrient recycling, microbial-derived processes and water quality in general 9 , 19 . This is even more important given the consequences of climate change that is affecting hydrological regimes in contrasting ways in different biomes 20 . Projected changes suggest an increase in wetland areas in tropical or polar latitudes; whereas temperate and Mediterranean wetlands and lakes may reduce their hydroperiod or dry out completely 21 , 22 , with major implications for species diversity 23 . In the Mediterranean biome, extended droughts could reduce runoff and increase evaporation, causing salinization of many wetlands and lakes 22 , 24 , 25 . This reduction in wetland surface or in hydroperiod length may promote the overcrowding of waterbirds in arid or semiarid regions during breeding or wintering periods 8 , 9 , which may reduce water quality through guano inputs and sediment bioturbation 2 . Similar effects may be caused by other kinds of global change such as increasing water extraction or the increase in bird populations resulting from exploitation of anthropogenic habitats (e.g. agricultural fields or fish farms) or protection from disturbance and hunting. For example, numbers of flamingos and other wading birds have increased markedly in southern Spain in recent decades due to increased protection and exploitation of artificial habitats, such as ricefields and fish ponds 26 , 27 . Flamingos represent a major fraction of the waterbird biomass in saline lakes in Africa 28 , 29 , and have profound effects on the limnology of Andean salt lakes 30 . In the Western Mediterranean region, their abundance and movements are particularly well monitored 31 , 32 , 33 , 34 , 35 . Here, we studied the influence of flamingos on nitrogen, phosphorus, and microbial dynamics in a saline lake that holds the largest flamingo colony in the Western Mediterranean. Flamingos can increase N and P concentrations by guano inputs from mass aggregations during breeding periods, and by sediment bioturbation during feeding and trampling in the lake. We hypothesized that in this lake (i) dissolved nitrogen and phosphorus concentrations would be related with flamingo abundance due to guanotrophication and sediment bioturbation and used correlation and regression analysis to test it; (ii) dissolved nutrients from guano would boost heterotrophic prokaryotic production affecting microbial dynamics and performed two experiments and cross-correlations to test it; (iii) drought would concentrate nutrients and microbial cells by evaporation, and therefore intensify the effects of flamingos and we compared the nutrient and microbial dynamics in two well-contrasted (wet and dry) hydrological years to test it. Finally, we discuss the implications of our findings given ongoing climate change and the effects of conservation policies on waterbird densities. Material and Methods Study site, water level and flamingo abundance This study was performed in Fuente de Piedra, an athalassohaline lake located in an endorheic basin of karstic origin in the south of Spain (37° 6′ N, 4° 44′ W) (Fig. 1a ). Its hydrology is mainly linked to inputs from rainfall, two intermittent streams (Santillán and Humilladero) and ground water, and outputs mainly by evaporation 36 , 37 . This large saline lake covers a maximum area of 1350 ha and supports one of the most important breeding colonies of the greater flamingo ( Phoenicopterus roseus ) in the Western Mediterranean 34 , 38 . Breeding adults fly within a radius of 350 km to feed in other wetlands, returning to feed their", "role": "user" }, { "content": "An international group of researchers led by the University of Granada (UGR) has proven that the greater flamingo (Phoenicopterus roseus) facilitates microbial filtering of organic matter in saline wetlands, thus improving water quality and reducing nitrogen loads by promoting denitrification. This is a facilitating role which was unknown until now. UGR researchers Gema Batanero and Isabel Reche, along with their colleagues from the Doñana Biological Station-CSIC, the Nature Reserve Laguna de Fuente de Piedra, the University of Twente (Netherlands) and the University of British Columbia (Canada), have analysed the influence of flamingos in microbial processes at the Fuente de Piedra lake (Málaga, Spain) during wet and dry hydrological years. Isabel Reche says, \"Saline wetlands are extremely productive ecosystems that act as natural filters by mineralizing organic matter and reducing the load of organic nitrogen they receive. This purification function is carried out by the microorganisms present in their water column and sediments and, with it, they improve the general quality of the water and reduce the nitrogen load by promoting denitrification.\" Additionally, wetlands are the refuge and breeding sites of countless waterbirds, including the greater flamingo (Phoenicopterus roseus), which inhabit the Fuente de Piedra lake. The effects that waterbirds may have on the wetlands' microbial activity were unknown until now. In the Mediterranean biome, as a consequence of climate change, there is a reduction of wetland areas and the length of their hydroperiod. \"This fact, along with conservation policies on waterbird densities and flamingos exploiting alternative artificial habitats such as rice fields and fish ponds, has caused an increase in flamingo populations in southern Spain,\" the UGR researcher remarks. Waterbirds in general, and especially flamingos, input nitrogen and phosphorus (N and P) in wetlands by means of their feces. They also stir the sediments. \"Mass aggregations of birds may have a negative impact, promoting water eutrophization by means of their guano input (guanotrophication), since microorganisms need bioavailable N and P for the mineralization of organic matter,\" says Reche. Therefore, establishing the total load of waterbirds a wetland can accommodate without the occurrence of guanotrophication but promoting filtering' microbial activity is essential for a good management of the wetlands. \"A management that ensures the maximum number of birds recommended, depending on meteorological conditions, without negatively affecting water quality.\" The researchers, whose work has been published in Scientific Reports, have proven that flamingos promote bacterial activity triggering cascading effects on prokaryotic (bacterial) abundance and viruses. That stimulus occurs only during wet years, when both flamingo abundance and water level are high. On the contrary, during drought years, flamingo populations are greatly reduced and, even though N and P evapoconcentration occurs, the absence of bioavailable soluble phosphorus produced by flamingos has a negative effect on microbial activity at the Fuente de Piedra lake. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Waterbird aggregations and droughts affect nutrient and microbial dynamics in wetlands. We analysed the effects of high densities of flamingos on nutrients and microbial dynamics in a saline lake during a wet and a dry hydrological year, and explored the effects of guano on prokaryotic growth. Concentrations of dissolved organic carbon, total phosphorus and total nitrogen in the surface waters were 2–3 fold higher during the drought and were correlated with salinity. Flamingos stimulated prokaryotic heterotrophic production and triggered cascading effects on prokaryotic abundance, viruses and dissolved nitrogen. This stimulus of heterotrophic prokaryotes was associated with soluble phosphorus inputs from guano, and also from sediments. In the experiments, the specific growth rate and the carrying capacity were almost twice as high after guano addition than in the control treatments, and were coupled with soluble phosphorus assimilation. Flamingo guano was also rich in nitrogen. Dissolved N in lake water lagged behind the abundance of flamingos, but the causes of this lag are unclear. This study demonstrates that intense droughts could lead to increases in total nutrients in wetlands; however, microbial activity is likely constrained by the availability of soluble phosphorus, which appears to be more dependent on the abundance of waterbirds. Introduction Since Hutchinson’s seminal work 1 on the importance of guano on marine productivity, many studies have analyzed the inputs of nutrients associated with waterbird feces in inland waters 2 , 3 , 4 , 5 , 6 . This process is termed guanotrophication 7 and appears to be particularly important in arid regions 8 , systems with long water residence times 9 and inland waters used as roosts by non-breeding birds or as breeding sites by colonial waterbirds, where birds import nutrients from foraging areas 4 , 5 , 10 , 11 , 12 . Guanotrophication affects wetland quality and primary productivity, as shown in studies by Kitchell et al . 3 in which chlorophyll increased with the density of geese, and in experiments with phytoplankton 13 . On the other hand, large waterbirds cause sediment bioturbation with consequences for nutrient release and methane fluxes 14 , 15 . Although bacterial production and diversity are known to change under pulses of nutrients 16 , 17 , 18 , no studies have directly addressed changes in aquatic microbial communities associated with guanotrophication and sediment bioturbation by waterbirds, despite the key role of microbial processes in biogeochemical cycles and greenhouse gas fluxes in wetlands and lakes. Insights into the effects of waterbirds on microbial communities are crucial to enable integrative wetland management and the measures required to support waterbird diversity and their effects on guanotrophication, nutrient recycling, microbial-derived processes and water quality in general 9 , 19 . This is even more important given the consequences of climate change that is affecting hydrological regimes in contrasting ways in different biomes 20 . Projected changes suggest an increase in wetland areas in tropical or polar latitudes; whereas temperate and Mediterranean wetlands and lakes may reduce their hydroperiod or dry out completely 21 , 22 , with major implications for species diversity 23 . In the Mediterranean biome, extended droughts could reduce runoff and increase evaporation, causing salinization of many wetlands and lakes 22 , 24 , 25 . This reduction in wetland surface or in hydroperiod length may promote the overcrowding of waterbirds in arid or semiarid regions during breeding or wintering periods 8 , 9 , which may reduce water quality through guano inputs and sediment bioturbation 2 . Similar effects may be caused by other kinds of global change such as increasing water extraction or the increase in bird populations resulting from exploitation of anthropogenic habitats (e.g. agricultural fields or fish farms) or protection from disturbance and hunting. For example, numbers of flamingos and other wading birds have increased markedly in southern Spain in recent decades due to increased protection and exploitation of artificial habitats, such as ricefields and fish ponds 26 , 27 . Flamingos represent a major fraction of the waterbird biomass in saline lakes in Africa 28 , 29 , and have profound effects on the limnology of Andean salt lakes 30 . In the Western Mediterranean region, their abundance and movements are particularly well monitored 31 , 32 , 33 , 34 , 35 . Here, we studied the influence of flamingos on nitrogen, phosphorus, and microbial dynamics in a saline lake that holds the largest flamingo colony in the Western Mediterranean. Flamingos can increase N and P concentrations by guano inputs from mass aggregations during breeding periods, and by sediment bioturbation during feeding and trampling in the lake. We hypothesized that in this lake (i) dissolved nitrogen and phosphorus concentrations would be related with flamingo abundance due to guanotrophication and sediment bioturbation and used correlation and regression analysis to test it; (ii) dissolved nutrients from guano would boost heterotrophic prokaryotic production affecting microbial dynamics and performed two experiments and cross-correlations to test it; (iii) drought would concentrate nutrients and microbial cells by evaporation, and therefore intensify the effects of flamingos and we compared the nutrient and microbial dynamics in two well-contrasted (wet and dry) hydrological years to test it. Finally, we discuss the implications of our findings given ongoing climate change and the effects of conservation policies on waterbird densities. Material and Methods Study site, water level and flamingo abundance This study was performed in Fuente de Piedra, an athalassohaline lake located in an endorheic basin of karstic origin in the south of Spain (37° 6′ N, 4° 44′ W) (Fig. 1a ). Its hydrology is mainly linked to inputs from rainfall, two intermittent streams (Santillán and Humilladero) and ground water, and outputs mainly by evaporation 36 , 37 . This large saline lake covers a maximum area of 1350 ha and supports one of the most important breeding colonies of the greater flamingo ( Phoenicopterus roseus ) in the Western Mediterranean 34 , 38 . Breeding adults fly within a radius of 350 km to feed in other wetlands, returning to feed their<|im_end|> <|im_start|>assistant An international group of researchers led by the University of Granada (UGR) has proven that the greater flamingo (Phoenicopterus roseus) facilitates microbial filtering of organic matter in saline wetlands, thus improving water quality and reducing nitrogen loads by promoting denitrification. This is a facilitating role which was unknown until now. UGR researchers Gema Batanero and Isabel Reche, along with their colleagues from the Doñana Biological Station-CSIC, the Nature Reserve Laguna de Fuente de Piedra, the University of Twente (Netherlands) and the University of British Columbia (Canada), have analysed the influence of flamingos in microbial processes at the Fuente de Piedra lake (Málaga, Spain) during wet and dry hydrological years. Isabel Reche says, "Saline wetlands are extremely productive ecosystems that act as natural filters by mineralizing organic matter and reducing the load of organic nitrogen they receive. This purification function is carried out by the microorganisms present in their water column and sediments and, with it, they improve the general quality of the water and reduce the nitrogen load by promoting denitrification." Additionally, wetlands are the refuge and breeding sites of countless waterbirds, including the greater flamingo (Phoenicopterus roseus), which inhabit the Fuente de Piedra lake. The effects that waterbirds may have on the wetlands' microbial activity were unknown until now. In the Mediterranean biome, as a consequence of climate change, there is a reduction of wetland areas and the length of their hydroperiod. "This fact, along with conservation policies on waterbird densities and flamingos exploiting alternative artificial habitats such as rice fields and fish ponds, has caused an increase in flamingo populations in southern Spain," the UGR researcher remarks. Waterbirds in general, and especially flamingos, input nitrogen and phosphorus (N and P) in wetlands by means of their feces. They also stir the sediments. "Mass aggregations of birds may have a negative impact, promoting water eutrophization by means of their guano input (guanotrophication), since microorganisms need bioavailable N and P for the mineralization of organic matter," says Reche. Therefore, establishing the total load of waterbirds a wetland can accommodate without the occurrence of guanotrophication but promoting filtering' microbial activity is essential for a good management of the wetlands. "A management that ensures the maximum number of birds recommended, depending on meteorological conditions, without negatively affecting water quality." The researchers, whose work has been published in Scientific Reports, have proven that flamingos promote bacterial activity triggering cascading effects on prokaryotic (bacterial) abundance and viruses. That stimulus occurs only during wet years, when both flamingo abundance and water level are high. On the contrary, during drought years, flamingo populations are greatly reduced and, even though N and P evapoconcentration occurs, the absence of bioavailable soluble phosphorus produced by flamingos has a negative effect on microbial activity at the Fuente de Piedra lake. <|im_end|>

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845, 1174, 220, 1114, 1174, 220, 972, 1174, 912, 7978, 617, 6089, 20669, 4442, 304, 72491, 75418, 10977, 5938, 449, 1709, 276, 354, 22761, 20901, 323, 59132, 6160, 354, 65916, 555, 3090, 67461, 11, 8994, 279, 1401, 3560, 315, 75418, 11618, 304, 6160, 540, 25634, 32056, 25492, 323, 37647, 6962, 31405, 288, 304, 14739, 8329, 323, 44236, 13, 73137, 1139, 279, 6372, 315, 3090, 67461, 389, 75418, 10977, 527, 16996, 311, 7431, 8936, 1413, 14739, 1974, 6373, 323, 279, 11193, 2631, 311, 1862, 3090, 23414, 20057, 323, 872, 6372, 389, 1709, 276, 354, 22761, 20901, 11, 50123, 34978, 11, 75418, 72286, 11618, 323, 3090, 4367, 304, 4689, 220, 24, 1174, 220, 777, 662, 1115, 374, 1524, 810, 3062, 2728, 279, 16296, 315, 10182, 2349, 430, 374, 28987, 17055, 31356, 61911, 304, 75055, 5627, 304, 2204, 6160, 20969, 220, 508, 662, 5907, 291, 4442, 4284, 459, 5376, 304, 14739, 1974, 5789, 304, 35148, 477, 25685, 6987, 21237, 26, 20444, 6940, 349, 323, 38785, 14739, 8329, 323, 44236, 1253, 8108, 872, 17055, 19862, 477, 9235, 704, 6724, 220, 1691, 1174, 220, 1313, 1174, 449, 3682, 25127, 369, 9606, 20057, 220, 1419, 662, 763, 279, 38785, 84710, 11, 11838, 37846, 82, 1436, 8108, 79152, 323, 5376, 3721, 96649, 11, 14718, 4371, 258, 2065, 315, 1690, 14739, 8329, 323, 44236, 220, 1313, 1174, 220, 1187, 1174, 220, 914, 662, 1115, 14278, 304, 14739, 1974, 7479, 477, 304, 17055, 19862, 3160, 1253, 12192, 279, 88204, 7113, 315, 3090, 67461, 304, 802, 307, 477, 5347, 13884, 307, 13918, 2391, 40308, 477, 12688, 287, 18852, 220, 23, 1174, 220, 24, 1174, 902, 1253, 8108, 3090, 4367, 1555, 1709, 5770, 11374, 323, 59132, 6160, 354, 65916, 220, 17, 662, 22196, 6372, 1253, 387, 9057, 555, 1023, 13124, 315, 3728, 2349, 1778, 439, 7859, 3090, 33289, 477, 279, 5376, 304, 12224, 22673, 13239, 505, 40761, 315, 41416, 29569, 71699, 320, 68, 1326, 13, 29149, 5151, 477, 7795, 34324, 8, 477, 9313, 505, 65858, 323, 23330, 13, 1789, 3187, 11, 5219, 315, 85723, 437, 323, 1023, 289, 2277, 20229, 617, 7319, 88101, 304, 18561, 18157, 304, 3293, 11026, 4245, 311, 7319, 9313, 323, 40761, 315, 21075, 71699, 11, 1778, 439, 20228, 9184, 323, 7795, 89455, 220, 1627, 1174, 220, 1544, 662, 3061, 6605, 437, 4097, 264, 3682, 19983, 315, 279, 3090, 23414, 58758, 304, 99107, 44236, 304, 10384, 220, 1591, 1174, 220, 1682, 1174, 323, 617, 28254, 6372, 389, 279, 4671, 77, 2508, 315, 1628, 5420, 12290, 44236, 220, 966, 662, 763, 279, 11104, 38785, 5654, 11, 872, 37492, 323, 19567, 527, 8104, 1664, 41223, 220, 2148, 1174, 220, 843, 1174, 220, 1644, 1174, 220, 1958, 1174, 220, 1758, 662, 5810, 11, 584, 20041, 279, 10383, 315, 85723, 437, 389, 47503, 11, 33088, 30969, 11, 323, 75418, 30295, 304, 264, 99107, 22553, 430, 10187, 279, 7928, 85723, 78, 42036, 304, 279, 11104, 38785, 13, 3061, 6605, 437, 649, 5376, 452, 323, 393, 32466, 555, 1709, 5770, 11374, 505, 3148, 26263, 811, 2391, 40308, 18852, 11, 323, 555, 59132, 6160, 354, 65916, 2391, 26040, 323, 490, 30809, 304, 279, 22553, 13, 1226, 22601, 83979, 430, 304, 420, 22553, 320, 72, 8, 56767, 47503, 323, 33088, 30969, 32466, 1053, 387, 5552, 449, 85723, 78, 37492, 4245, 311, 1709, 276, 354, 22761, 20901, 323, 59132, 6160, 354, 65916, 323, 1511, 26670, 323, 31649, 6492, 311, 1296, 433, 26, 320, 3893, 8, 56767, 37493, 505, 1709, 5770, 1053, 7916, 30548, 354, 42810, 463, 74, 661, 14546, 5788, 28987, 75418, 30295, 323, 10887, 1403, 21896, 323, 5425, 46713, 66434, 311, 1296, 433, 26, 320, 35694, 8, 37846, 1053, 37455, 37493, 323, 75418, 7917, 555, 3721, 96649, 11, 323, 9093, 25228, 1463, 279, 6372, 315, 85723, 437, 323, 584, 7863, 279, 50123, 323, 75418, 30295, 304, 1403, 1664, 12, 8386, 15386, 320, 86, 295, 323, 9235, 8, 17055, 31356, 1667, 311, 1296, 433, 13, 17830, 11, 584, 4358, 279, 25127, 315, 1057, 14955, 2728, 14529, 10182, 2349, 323, 279, 6372, 315, 29711, 10396, 389, 3090, 23414, 90816, 13, 10441, 323, 19331, 19723, 2816, 11, 3090, 2237, 323, 85723, 78, 37492, 1115, 4007, 574, 10887, 304, 30353, 6960, 409, 84430, 969, 11, 459, 12004, 278, 395, 2319, 278, 483, 22553, 7559, 304, 459, 842, 269, 383, 292, 58309, 315, 24318, 267, 292, 6371, 304, 279, 10007, 315, 18157, 320, 1806, 11877, 220, 21, 39615, 452, 11, 220, 19, 11877, 220, 2096, 39615, 468, 8, 320, 30035, 13, 220, 16, 64, 7609, 11699, 17055, 36781, 374, 14918, 10815, 311, 11374, 505, 53958, 11, 1403, 75568, 23914, 320, 50, 519, 484, 11644, 323, 20449, 484, 74330, 8, 323, 5015, 3090, 11, 323, 16674, 14918, 555, 3721, 96649, 220, 1927, 1174, 220, 1806, 662, 1115, 3544, 99107, 22553, 14861, 264, 7340, 3158, 315, 220, 8878, 15, 6520, 323, 11815, 832, 315, 279, 1455, 3062, 40308, 49028, 315, 279, 7191, 85723, 78, 320, 2405, 16355, 24904, 46109, 16392, 355, 883, 304, 279, 11104, 38785, 220, 1958, 1174, 220, 1987, 662, 11681, 16490, 12884, 11722, 2949, 264, 10801, 315, 220, 8652, 13437, 311, 5510, 304, 1023, 14739, 8329, 11, 13758, 311, 5510, 872, 128257, 198, 128256, 78191, 198, 2127, 6625, 1912, 315, 12074, 6197, 555, 279, 3907, 315, 27622, 2649, 320, 3014, 49, 8, 706, 17033, 430, 279, 7191, 85723, 78, 320, 3438, 16355, 24904, 46109, 16392, 355, 8, 73633, 75418, 30770, 315, 17808, 5030, 304, 99107, 14739, 8329, 11, 8617, 18899, 3090, 4367, 323, 18189, 47503, 21577, 555, 22923, 3453, 22288, 2461, 13, 1115, 374, 264, 68365, 3560, 902, 574, 9987, 3156, 1457, 13, 549, 8796, 12074, 480, 9355, 16488, 276, 2382, 323, 87886, 1050, 1557, 11, 3235, 449, 872, 18105, 505, 279, 3234, 88184, 63711, 17040, 79413, 1341, 11, 279, 22037, 25820, 94198, 409, 30353, 6960, 409, 84430, 969, 11, 279, 3907, 315, 12015, 6960, 320, 45, 24530, 8, 323, 279, 3907, 315, 8013, 19326, 320, 37031, 705, 617, 67458, 279, 10383, 315, 85723, 437, 304, 75418, 11618, 520, 279, 30353, 6960, 409, 84430, 969, 22553, 320, 44, 19540, 12748, 11, 18157, 8, 2391, 14739, 323, 9235, 17055, 31356, 1667, 13, 87886, 1050, 1557, 2795, 11, 330, 17691, 483, 14739, 8329, 527, 9193, 27331, 61951, 430, 1180, 439, 5933, 13711, 555, 25107, 4954, 17808, 5030, 323, 18189, 279, 2865, 315, 17808, 47503, 814, 5371, 13, 1115, 94536, 734, 374, 11953, 704, 555, 279, 8162, 76991, 3118, 304, 872, 3090, 3330, 323, 11163, 12843, 323, 11, 449, 433, 11, 814, 7417, 279, 4689, 4367, 315, 279, 3090, 323, 8108, 279, 47503, 2865, 555, 22923, 3453, 22288, 2461, 1210, 23212, 11, 14739, 8329, 527, 279, 14850, 323, 40308, 6732, 315, 28701, 3090, 67461, 11, 2737, 279, 7191, 85723, 78, 320, 3438, 16355, 24904, 46109, 16392, 355, 705, 902, 33427, 279, 30353, 6960, 409, 84430, 969, 22553, 13, 578, 6372, 430, 3090, 67461, 1253, 617, 389, 279, 14739, 8329, 6, 75418, 5820, 1051, 9987, 3156, 1457, 13, 763, 279, 38785, 84710, 11, 439, 264, 29774, 315, 10182, 2349, 11, 1070, 374, 264, 14278, 315, 14739, 1974, 5789, 323, 279, 3160, 315, 872, 17055, 19862, 13, 330, 2028, 2144, 11, 3235, 449, 29711, 10396, 389, 3090, 23414, 90816, 323, 85723, 437, 71701, 10778, 21075, 71699, 1778, 439, 20228, 5151, 323, 7795, 89455, 11, 706, 9057, 459, 5376, 304, 85723, 78, 22673, 304, 18561, 18157, 1359, 279, 549, 8796, 32185, 24208, 13, 10164, 67461, 304, 4689, 11, 323, 5423, 85723, 437, 11, 1988, 47503, 323, 33088, 30969, 320, 45, 323, 393, 8, 304, 14739, 8329, 555, 3445, 315, 872, 55061, 288, 13, 2435, 1101, 23935, 279, 11163, 12843, 13, 330, 26909, 26263, 811, 315, 20229, 1253, 617, 264, 8389, 5536, 11, 22923, 3090, 384, 332, 22761, 2065, 555, 3445, 315, 872, 1709, 5770, 1988, 320, 8890, 276, 354, 22761, 20901, 705, 2533, 8162, 76991, 1205, 17332, 10547, 452, 323, 393, 369, 279, 25107, 2065, 315, 17808, 5030, 1359, 2795, 1050, 1557, 13, 15636, 11, 31692, 279, 2860, 2865, 315, 3090, 67461, 264, 14739, 1974, 649, 29376, 2085, 279, 32659, 315, 1709, 276, 354, 22761, 20901, 719, 22923, 30770, 6, 75418, 5820, 374, 7718, 369, 264, 1695, 6373, 315, 279, 14739, 8329, 13, 330, 32, 6373, 430, 26420, 279, 7340, 1396, 315, 20229, 11349, 11, 11911, 389, 42142, 5848, 4787, 11, 2085, 48291, 28987, 3090, 4367, 1210, 578, 12074, 11, 6832, 990, 706, 1027, 4756, 304, 38130, 29140, 11, 617, 17033, 430, 85723, 437, 12192, 45964, 5820, 52605, 76057, 2277, 6372, 389, 463, 74, 661, 14546, 320, 65, 71034, 8, 37492, 323, 42068, 13, 3011, 39535, 13980, 1193, 2391, 14739, 1667, 11, 994, 2225, 85723, 78, 37492, 323, 3090, 2237, 527, 1579, 13, 1952, 279, 26102, 11, 2391, 37846, 1667, 11, 85723, 78, 22673, 527, 19407, 11293, 323, 11, 1524, 3582, 452, 323, 393, 3721, 66652, 444, 94376, 13980, 11, 279, 19821, 315, 17332, 10547, 88045, 33088, 30969, 9124, 555, 85723, 437, 706, 264, 8389, 2515, 389, 75418, 5820, 520, 279, 30353, 6960, 409, 84430, 969, 22553, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in β-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC. Main Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer mortality in women worldwide 1 . Obesity and type 2 diabetes (T2D) are both associated with a higher BC incidence and worse cancer-related outcomes 2 , 3 , 4 , 5 . Meta-analyses show that women with diabetes (primarily T2D) have a 20–27% increased risk of BC 6 , 7 , 8 , with no identified bias for tumour subtypes 4 . Higher levels of fasting glucose and glycated haemoglobin are notably associated with premenopausal BC 9 . Hyperglycaemia is associated with elevated mortality risk in patients with BC with or without diabetes 10 . Insulin resistance (IR) has also been associated with BC incidence and poor survival 11 , 12 , 13 , 14 . However, the reported associations of circulating insulin with BC are inconsistent. While some studies suggest hyperinsulinaemia is a risk factor for BC and may partake in BC’s association with obesity 15 , 16 , 17 , 18 , 19 , others find lack of an association 13 , 20 , 21 . In sharp contrast, studies of women who are premenopausal or of younger age (≤50 years) indicate inverse associations of fasting insulin/C-peptide levels with BC incidence 22 , 23 . On the other hand, if and how BC can influence whole-body glucose or insulin metabolism remains less understood. Population-based studies show that diabetes risk begins to increase 2 years after BC diagnosis, and by 10 years post-diagnosis is ~20% higher in BC survivors compared with age-matched women without BC 24 , 25 , 26 . Among BRCA1 / 2 carriers, diagnosis of BC is associated with a twofold increase in the risk of diabetes, which is exacerbated by a high body mass index (BMI; >25.0 kg m − 2 ) (ref. 27 ). Patients with diabetes and a history of BC have more comorbidities than cancer-free individuals 28 . We hypothesize that BC cells may negatively affect glycaemic control through secreted factors such as extracellular vesicles (EVs). EVs (including exosomes of endocytic origin and microvesicles shed from cell surface) mediate the crosstalk between cancer and normal cells through local and long-range transfer of functional cargo including RNA, DNA, proteins and lipids 29 , 30 . Cancer-cell-secreted EVs contribute to tumour growth, immunomodulation and establishment of pre-metastatic niches 30 , 31 . Many of these effects are mediated by EV-encapsulated microRNAs (miRNAs) 32 , 33 , 34 . Circulating miRNAs and other EV cargo molecules have emerged as potential biomarkers for cancer 35 , 36 . In this Article, we investigate the direct effect of tumour-derived EVs on the endocrine function of pancreas and its impact on whole-body metabolism. Results EV from BC impair insulin signalling and glucose homeostasis Female NOD/SCID/IL2Rγ-null (NSG) mice were treated with EVs derived from MDA-MB-231 BC cells or MCF-10A non-cancer cells through semi-weekly intravenous injections for 5 weeks. We previously report that miR-122-5p (miR-122) is highly secreted by BC cells and predicts tumour progression and metastasis in patients with early-stage BC 33 , 36 , 37 . Therefore, here we also examined high-miR-122 EVs from engineered MCF-10A/miR-122 cells 33 . No significant differences in food intake or body weight were observed between different groups (Extended Data Fig. 1a,b ). We first compared the transcriptomes of liver, a central organ in systemic energy metabolism. Mice receiving MDA-MB-231 or MCF-10A/miR-122 EVs exhibited altered gene expression related to insulin signalling and its downstream pathways, including FOXO-mediated transcription and glycogen metabolism (Fig. 1a and Extended Data Fig. 1c,d ). Liver from these two groups had lower levels of phosphorylated insulin receptor β, AKT, FOXO1, P70S6K and eIF4G (Fig. 1b ), lower levels of glycogen (Fig. 1c,d ) and triglycerides (Extended Data Fig. 1e ), higher expression of Igfbp1 , Pck1 , G6pc and Ppargc1a (Fig. 1e ) and enhanced glycaemic excursion in response to a pyruvate tolerance test (PTT) (Fig. 1f ). These results together indicate suppression of insulin signalling and anabolic synthesis along with an induction of endogenous glucose production. Fig. 1: BC-derived EVs suppress insulin signalling in liver and enhance hepatic glucose production. a , Liver tissues were collected from mice after 5 weeks of EV/PBS treatment and analysed by RNA-seq and GSEA ( n = 6 mice per group). b , Immunoblots using the liver lysates from these mice. c , d , Liver glycogen levels determined by PAS staining ( c ; scale bar, 100 μm; representative images are shown) and phenol–sulfuric acid method ( d ; n = 9 mice per group). e , RT–qPCR showing relative mRNA levels (normalized to cyclophilin B mRNA) in the liver ( n = 10 mice per group). f , PTT showing hepatic gluconeogenesis (left) and the corresponding area under the curve (AUC) analysis (right) ( n = 8 mice for MDA-MB-231 EV group and n = 7 mice for other groups). g , h , Fasting insulin ( g ) and C-peptide ( h ) levels in the sera ( n = 9 mice per group). i , Basal (fasting) and", "role": "user" }, { "content": "Breast cancer and type 2 diabetes would seem to be distinctly different diseases, with commonality only in their commonality. Breast cancer is the second most diagnosed malignancy after some types of skin cancer; approximately 1 in eight U.S. women will develop invasive breast cancer over the course of their lifetime. More than 10 percent of the U.S. population has diabetes, with an estimated 2 in 5 Americans expected to develop the chronic disease during their lifetime. However, past research has uncovered associations between the two diseases. Women with diabetes, for example, have a 20 to 27 percent increased risk of developing breast cancer. Insulin resistance—a key characteristic of diabetes—has been associated with breast cancer incidence and poor survival. Population studies suggest diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20 percent higher in breast cancer survivors than in age-matched women without breast cancer. But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In a new paper, publishing May 30, 2022 in Nature Cell Biology, a research team led by scientists at University of California San Diego School of Medicine describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumor growth. \"No disease is an island because no cell lives alone,\" said corresponding study author Shizhen Emily Wang, Ph.D., professor of pathology at UC San Diego School of Medicine. \"In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.\" Wang said the study was inspired by early work and guidance from Jerrold Olefsky, MD, professor of medicine and associate dean for scientific affairs in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine. Olefsky is co-senior author of the study with Wang. The culprit, according to Wang and Olefsky, are extracellular vesicles (EV)—hollow spheres secreted or shed by cells that transport DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system. In this case, the cancer cells were found to be secreting microRNA-122 into the vesicles. Wang said when vesicles reach the pancreas, they can enter the islet cells responsible for insulin production, dispense their miR-122 cargo and damage the islets' critical function in maintaining a normal blood glucose level. \"Cancer cells have a sweet tooth,\" Wang said. \"They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.\" The research was conducted using mouse models, which found that slow-releasing insulin pellets or a glucose-lowering drug known as an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumor, which in turn suppressed the tumor's growth. \"These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors,\" said Wang, noting that an inhibitor of miR-122, developed by Regulus Therapeutics Inc. in San Diego, is currently in clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumor growth in mouse models of breast cancer. \"These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy,\" Wang said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in β-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC. Main Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer mortality in women worldwide 1 . Obesity and type 2 diabetes (T2D) are both associated with a higher BC incidence and worse cancer-related outcomes 2 , 3 , 4 , 5 . Meta-analyses show that women with diabetes (primarily T2D) have a 20–27% increased risk of BC 6 , 7 , 8 , with no identified bias for tumour subtypes 4 . Higher levels of fasting glucose and glycated haemoglobin are notably associated with premenopausal BC 9 . Hyperglycaemia is associated with elevated mortality risk in patients with BC with or without diabetes 10 . Insulin resistance (IR) has also been associated with BC incidence and poor survival 11 , 12 , 13 , 14 . However, the reported associations of circulating insulin with BC are inconsistent. While some studies suggest hyperinsulinaemia is a risk factor for BC and may partake in BC’s association with obesity 15 , 16 , 17 , 18 , 19 , others find lack of an association 13 , 20 , 21 . In sharp contrast, studies of women who are premenopausal or of younger age (≤50 years) indicate inverse associations of fasting insulin/C-peptide levels with BC incidence 22 , 23 . On the other hand, if and how BC can influence whole-body glucose or insulin metabolism remains less understood. Population-based studies show that diabetes risk begins to increase 2 years after BC diagnosis, and by 10 years post-diagnosis is ~20% higher in BC survivors compared with age-matched women without BC 24 , 25 , 26 . Among BRCA1 / 2 carriers, diagnosis of BC is associated with a twofold increase in the risk of diabetes, which is exacerbated by a high body mass index (BMI; >25.0 kg m − 2 ) (ref. 27 ). Patients with diabetes and a history of BC have more comorbidities than cancer-free individuals 28 . We hypothesize that BC cells may negatively affect glycaemic control through secreted factors such as extracellular vesicles (EVs). EVs (including exosomes of endocytic origin and microvesicles shed from cell surface) mediate the crosstalk between cancer and normal cells through local and long-range transfer of functional cargo including RNA, DNA, proteins and lipids 29 , 30 . Cancer-cell-secreted EVs contribute to tumour growth, immunomodulation and establishment of pre-metastatic niches 30 , 31 . Many of these effects are mediated by EV-encapsulated microRNAs (miRNAs) 32 , 33 , 34 . Circulating miRNAs and other EV cargo molecules have emerged as potential biomarkers for cancer 35 , 36 . In this Article, we investigate the direct effect of tumour-derived EVs on the endocrine function of pancreas and its impact on whole-body metabolism. Results EV from BC impair insulin signalling and glucose homeostasis Female NOD/SCID/IL2Rγ-null (NSG) mice were treated with EVs derived from MDA-MB-231 BC cells or MCF-10A non-cancer cells through semi-weekly intravenous injections for 5 weeks. We previously report that miR-122-5p (miR-122) is highly secreted by BC cells and predicts tumour progression and metastasis in patients with early-stage BC 33 , 36 , 37 . Therefore, here we also examined high-miR-122 EVs from engineered MCF-10A/miR-122 cells 33 . No significant differences in food intake or body weight were observed between different groups (Extended Data Fig. 1a,b ). We first compared the transcriptomes of liver, a central organ in systemic energy metabolism. Mice receiving MDA-MB-231 or MCF-10A/miR-122 EVs exhibited altered gene expression related to insulin signalling and its downstream pathways, including FOXO-mediated transcription and glycogen metabolism (Fig. 1a and Extended Data Fig. 1c,d ). Liver from these two groups had lower levels of phosphorylated insulin receptor β, AKT, FOXO1, P70S6K and eIF4G (Fig. 1b ), lower levels of glycogen (Fig. 1c,d ) and triglycerides (Extended Data Fig. 1e ), higher expression of Igfbp1 , Pck1 , G6pc and Ppargc1a (Fig. 1e ) and enhanced glycaemic excursion in response to a pyruvate tolerance test (PTT) (Fig. 1f ). These results together indicate suppression of insulin signalling and anabolic synthesis along with an induction of endogenous glucose production. Fig. 1: BC-derived EVs suppress insulin signalling in liver and enhance hepatic glucose production. a , Liver tissues were collected from mice after 5 weeks of EV/PBS treatment and analysed by RNA-seq and GSEA ( n = 6 mice per group). b , Immunoblots using the liver lysates from these mice. c , d , Liver glycogen levels determined by PAS staining ( c ; scale bar, 100 μm; representative images are shown) and phenol–sulfuric acid method ( d ; n = 9 mice per group). e , RT–qPCR showing relative mRNA levels (normalized to cyclophilin B mRNA) in the liver ( n = 10 mice per group). f , PTT showing hepatic gluconeogenesis (left) and the corresponding area under the curve (AUC) analysis (right) ( n = 8 mice for MDA-MB-231 EV group and n = 7 mice for other groups). g , h , Fasting insulin ( g ) and C-peptide ( h ) levels in the sera ( n = 9 mice per group). i , Basal (fasting) and<|im_end|> <|im_start|>assistant Breast cancer and type 2 diabetes would seem to be distinctly different diseases, with commonality only in their commonality. Breast cancer is the second most diagnosed malignancy after some types of skin cancer; approximately 1 in eight U.S. women will develop invasive breast cancer over the course of their lifetime. More than 10 percent of the U.S. population has diabetes, with an estimated 2 in 5 Americans expected to develop the chronic disease during their lifetime. However, past research has uncovered associations between the two diseases. Women with diabetes, for example, have a 20 to 27 percent increased risk of developing breast cancer. Insulin resistance—a key characteristic of diabetes—has been associated with breast cancer incidence and poor survival. Population studies suggest diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20 percent higher in breast cancer survivors than in age-matched women without breast cancer. But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In a new paper, publishing May 30, 2022 in Nature Cell Biology, a research team led by scientists at University of California San Diego School of Medicine describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumor growth. "No disease is an island because no cell lives alone," said corresponding study author Shizhen Emily Wang, Ph.D., professor of pathology at UC San Diego School of Medicine. "In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer." Wang said the study was inspired by early work and guidance from Jerrold Olefsky, MD, professor of medicine and associate dean for scientific affairs in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine. Olefsky is co-senior author of the study with Wang. The culprit, according to Wang and Olefsky, are extracellular vesicles (EV)—hollow spheres secreted or shed by cells that transport DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system. In this case, the cancer cells were found to be secreting microRNA-122 into the vesicles. Wang said when vesicles reach the pancreas, they can enter the islet cells responsible for insulin production, dispense their miR-122 cargo and damage the islets' critical function in maintaining a normal blood glucose level. "Cancer cells have a sweet tooth," Wang said. "They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells." The research was conducted using mouse models, which found that slow-releasing insulin pellets or a glucose-lowering drug known as an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumor, which in turn suppressed the tumor's growth. "These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors," said Wang, noting that an inhibitor of miR-122, developed by Regulus Therapeutics Inc. in San Diego, is currently in clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumor growth in mouse models of breast cancer. "These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy," Wang said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery—Arf1, IRSp53 and actin—and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route. Main Endocytosis is a vital process involving the internalization of extracellular material and cell surface receptors. This controls various functions ranging from fluid-phase nutrient uptake and spatially and temporally regulated traffic of adhesion and growth-factor receptors, to pathogen entry 1 . The predominant view is that the specificity of endocytosis is achieved through cargo-specific adaptors, as described for clathrin-mediated endocytosis (CME) 2 , 3 . This raises the possibility that as-yet unidentified cargo adaptor proteins could function as key gatekeepers for other endosomal routes. The clathrin- and dynamin-independent endocytic pathway (CG pathway) internalizes a major fraction of the extracellular fluid phase, glycosylphosphotidylinositol-anchored proteins and other cell surface receptors—including nutrient transporters, ion channels and cell adhesion receptors 4 , 5 —as well as bacterial and viral pathogens 4 , 6 . This occurs through high-capacity tubulovesicular membrane uptake carriers called clathrin-independent carriers (CLICs) 7 , 8 . CLICs are formed via the recruitment of Arf1, the actin-binding BAR-domain protein IRSp53 and Arp2/3 to the membrane, followed by Cdc42 activation of IRSp53 and Arp2/3-mediated actin polymerization, presumptively resulting in the scission of CLICs and generation of CG endosomes 9 . Although the core machinery of CG-endocytosis has been defined, no cargo-specific adaptors are known 10 . The small GTPase Rab21 binds directly to integrins to regulate endo/exosomal traffic, cytokinesis, chromosome integrity, endosomal signalling and anoikis 11 , 12 , 13 , 14 . Rab21 interacts with integrins independently of its activation state (GDP/GTP); nevertheless, integrin endocytosis requires Rab21 activity, but the exact mechanism is currently unknown 11 . In addition, very few Rab21 interactors have been identified 15 . Here we identify Swiprosin-1 (Swip1, EFHD2) as an interactor of Rab21 and a cargo-specific adaptor for CG-endocytosis. Results Swip1 interacts with Rab21 and β1-integrin To identify Rab21-interacting proteins, we performed proteomic analyses by stable isotope labelling with amino acids in cell culture (SILAC) of cells expressing wild-type (WT) Rab21, the constitutively active Rab21 Q76L mutant (CA-Rab21) or the Rab21 T31N inactive mutant 16 , 17 . This mass-spectrometry strategy identified the actin-binding protein Swip1 as a putative active Rab21 interactor (Fig. 1a , Extended Data Fig. 1a–d and Supplementary Table 1 ). Green fluorescent protein (GFP) pulldowns from the cell lysates demonstrated endogenous Swip1 preferably bound to WT and CA-Rab21, and not to the closely related Rab5 GTPase (Fig. 1b and Extended Data Fig. 1e ). Moreover, purified recombinant glutathione S -transferase (GST)–Swip1 interacted directly with GTP-analogue-loaded recombinant Rab21 (positive control: Rab21–GTP-specific interactor APPL1 (refs. 18 , 19 ); Fig. 1c ). We next validated the interaction in cells, where Swip1 localized to GFP–Rab21-containing endosomes (Fig. 2a ) and a proximity ligation assay (PLA) indicated endogenous Swip1 and Rab21 association in intact cells (Fig. 2b ). Rab21 localizes with membrane-proximal puncta and early endosomes positive for endocytosed active β1-integrins 11 , 14 , 20 . Concordantly, bimolecular fluorescence complementation (BiFC) 21 revealed an interaction between Swip1 and Rab21 in structures overlapping predominantly with EEA1, Rab5 and VPS35, and to a lesser extent with late endosome markers (Extended Data Fig. 2a–c ). Furthermore, Swip1 localized to Rab21-positive, β1-integrin-containing endosomes (Extended Data Fig. 3a ). These data indicate that Swip1 interacts with integrin-associated Rab21 in cells. Fig. 1: Swip1 interacts directly with active Rab21. a , SILAC proteomics analysis of GFP-Trap pulldowns in MDA-MB-231 cells expressing GFP-tagged CA-Rab21 versus GFP alone. The plot is representative of two independent experiments, forward and reverse; the experiments consisted of two independent affinity purifications. The plot shows the mean fold-changes from the forward and reverse experiments against absolute protein abundances (intensity-based absolute quantification, iBAQ). Abundance bins were defined by including 1,000 proteins in a subsequent order. The log 10 -transformed fold-change values of the proteins were tested for statistical significance using double-sided Significance B tests. No multiple hypothesis correction method was applied due to the small number of selected proteins for the statistical analysis. Proteins with P < 0.01 are represented by a triangle and non-significant proteins are shown as circles. P values are depicted in the figure for a selected set of proteins. The proteins in red are markedly enriched in the CA-Rab21 fraction and proteins in blue are known endosomal proteins—clathrin (CLTA, CLTB and CLTC), AP2 (AP2A1, AP2B1, AP2M1 and AP2S1), caveolin (CAV1) and dynamin II (DNM2)—that are not specifically enriched. b , Representative immunoblots of GFP-Trap pulldowns from MDA-MB-231 cells transfected with the indicated constructs and probed for GFP and endogenous Swip1. Three independent experiments were performed. GFP–DN-Rab21, Rab21 T33N dominant negative, GDP-bound/nucleotide-free; IP, immunoprecipitation. c , Coomassie-stained gel and immunoblot (IB) of GST-pulldowns with the indicated GST-tagged proteins and recombinant Rab21 (indicated by asterisks) bound to a non-hydrolysable form of GTP (GppNHP; active Rab21), GDP or no nucleotide after EDTA treatment (nuc free). The Rab21-effector GST–APPL1 was used as a positive control. Three independent experiments were performed. Unprocessed blots are provided. Source data Full size image Fig. 2: Swip1 interacts with Rab21 and β1-integrin. a , Representative MDA-MB-231 cell expressing GFP–Rab21 and immunostained for Swip1. The arrows point to regions of overlap between Swip1 and GFP–Rab21. Scale bar, 10 µm. The micrograph is representative of two independent experiments. b ,", "role": "user" }, { "content": "A research group at the University of Turku, Finland, has discovered a completely new mechanism that cells use to circulate integrins on the cell surface. Aggressive breast cancer cells exploit this mechanism to spread and metastasise to other parts of the body. Researchers have known for decades that human cells migrate by circulating cell surface adhesion receptors from one part of the cell to another. These adhesion receptors, called integrins, are important for normal cell motility, for example, during wound healing. Earlier studies have also shown that cancer cells have developed particularly efficient ways to circulate these receptors in order to spread to the surrounding tissue and to metastasise to other organs. Professor Johanna Ivaska's research group at the University of Turku, Finland, has discovered a new mechanism that highly aggressive, so-called triple-negative breast cancer cells use to circulate integrins and migrate in the tissue. \"Human cells constantly renew their surface by first absorbing parts of the cell membrane and then recycling it. This so-called CG endocytosis mechanism is like a constantly moving conveyor belt that also transports soluble nutrients into cells,\" Professor Ivaska explains. Post-doc Researcher Paulina Moreno-Layseca and Doctoral Candidate Niklas Jäntti in Professor Ivaska's research group discovered that breast cancer cells use the molecule swiprosin-1 to direct the integrin adhesion receptors onto this conveyor belt. By hijacking this conveyor belt mechanism, cancer cells can promote the circulation of integrins, thus increasing cell migration and the formation of metastases. By studying hundreds of breast cancer specimens, the researchers discovered that a high expression of the swiprosin-1 molecule in the tumor correlates significantly with the formation of metastases and with the malignancy of the breast cancer. \"Our findings open up an entirely new perspective into the function of integrins and reveal a new mechanism which cancer cells can use to spread throughout the body. These results will impact the direction of cancer studies in the future,\" says Professor Ivaska. The results were published on 6 October 2021 in the journal Nature Cell Biology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery—Arf1, IRSp53 and actin—and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route. Main Endocytosis is a vital process involving the internalization of extracellular material and cell surface receptors. This controls various functions ranging from fluid-phase nutrient uptake and spatially and temporally regulated traffic of adhesion and growth-factor receptors, to pathogen entry 1 . The predominant view is that the specificity of endocytosis is achieved through cargo-specific adaptors, as described for clathrin-mediated endocytosis (CME) 2 , 3 . This raises the possibility that as-yet unidentified cargo adaptor proteins could function as key gatekeepers for other endosomal routes. The clathrin- and dynamin-independent endocytic pathway (CG pathway) internalizes a major fraction of the extracellular fluid phase, glycosylphosphotidylinositol-anchored proteins and other cell surface receptors—including nutrient transporters, ion channels and cell adhesion receptors 4 , 5 —as well as bacterial and viral pathogens 4 , 6 . This occurs through high-capacity tubulovesicular membrane uptake carriers called clathrin-independent carriers (CLICs) 7 , 8 . CLICs are formed via the recruitment of Arf1, the actin-binding BAR-domain protein IRSp53 and Arp2/3 to the membrane, followed by Cdc42 activation of IRSp53 and Arp2/3-mediated actin polymerization, presumptively resulting in the scission of CLICs and generation of CG endosomes 9 . Although the core machinery of CG-endocytosis has been defined, no cargo-specific adaptors are known 10 . The small GTPase Rab21 binds directly to integrins to regulate endo/exosomal traffic, cytokinesis, chromosome integrity, endosomal signalling and anoikis 11 , 12 , 13 , 14 . Rab21 interacts with integrins independently of its activation state (GDP/GTP); nevertheless, integrin endocytosis requires Rab21 activity, but the exact mechanism is currently unknown 11 . In addition, very few Rab21 interactors have been identified 15 . Here we identify Swiprosin-1 (Swip1, EFHD2) as an interactor of Rab21 and a cargo-specific adaptor for CG-endocytosis. Results Swip1 interacts with Rab21 and β1-integrin To identify Rab21-interacting proteins, we performed proteomic analyses by stable isotope labelling with amino acids in cell culture (SILAC) of cells expressing wild-type (WT) Rab21, the constitutively active Rab21 Q76L mutant (CA-Rab21) or the Rab21 T31N inactive mutant 16 , 17 . This mass-spectrometry strategy identified the actin-binding protein Swip1 as a putative active Rab21 interactor (Fig. 1a , Extended Data Fig. 1a–d and Supplementary Table 1 ). Green fluorescent protein (GFP) pulldowns from the cell lysates demonstrated endogenous Swip1 preferably bound to WT and CA-Rab21, and not to the closely related Rab5 GTPase (Fig. 1b and Extended Data Fig. 1e ). Moreover, purified recombinant glutathione S -transferase (GST)–Swip1 interacted directly with GTP-analogue-loaded recombinant Rab21 (positive control: Rab21–GTP-specific interactor APPL1 (refs. 18 , 19 ); Fig. 1c ). We next validated the interaction in cells, where Swip1 localized to GFP–Rab21-containing endosomes (Fig. 2a ) and a proximity ligation assay (PLA) indicated endogenous Swip1 and Rab21 association in intact cells (Fig. 2b ). Rab21 localizes with membrane-proximal puncta and early endosomes positive for endocytosed active β1-integrins 11 , 14 , 20 . Concordantly, bimolecular fluorescence complementation (BiFC) 21 revealed an interaction between Swip1 and Rab21 in structures overlapping predominantly with EEA1, Rab5 and VPS35, and to a lesser extent with late endosome markers (Extended Data Fig. 2a–c ). Furthermore, Swip1 localized to Rab21-positive, β1-integrin-containing endosomes (Extended Data Fig. 3a ). These data indicate that Swip1 interacts with integrin-associated Rab21 in cells. Fig. 1: Swip1 interacts directly with active Rab21. a , SILAC proteomics analysis of GFP-Trap pulldowns in MDA-MB-231 cells expressing GFP-tagged CA-Rab21 versus GFP alone. The plot is representative of two independent experiments, forward and reverse; the experiments consisted of two independent affinity purifications. The plot shows the mean fold-changes from the forward and reverse experiments against absolute protein abundances (intensity-based absolute quantification, iBAQ). Abundance bins were defined by including 1,000 proteins in a subsequent order. The log 10 -transformed fold-change values of the proteins were tested for statistical significance using double-sided Significance B tests. No multiple hypothesis correction method was applied due to the small number of selected proteins for the statistical analysis. Proteins with P < 0.01 are represented by a triangle and non-significant proteins are shown as circles. P values are depicted in the figure for a selected set of proteins. The proteins in red are markedly enriched in the CA-Rab21 fraction and proteins in blue are known endosomal proteins—clathrin (CLTA, CLTB and CLTC), AP2 (AP2A1, AP2B1, AP2M1 and AP2S1), caveolin (CAV1) and dynamin II (DNM2)—that are not specifically enriched. b , Representative immunoblots of GFP-Trap pulldowns from MDA-MB-231 cells transfected with the indicated constructs and probed for GFP and endogenous Swip1. Three independent experiments were performed. GFP–DN-Rab21, Rab21 T33N dominant negative, GDP-bound/nucleotide-free; IP, immunoprecipitation. c , Coomassie-stained gel and immunoblot (IB) of GST-pulldowns with the indicated GST-tagged proteins and recombinant Rab21 (indicated by asterisks) bound to a non-hydrolysable form of GTP (GppNHP; active Rab21), GDP or no nucleotide after EDTA treatment (nuc free). The Rab21-effector GST–APPL1 was used as a positive control. Three independent experiments were performed. Unprocessed blots are provided. Source data Full size image Fig. 2: Swip1 interacts with Rab21 and β1-integrin. a , Representative MDA-MB-231 cell expressing GFP–Rab21 and immunostained for Swip1. The arrows point to regions of overlap between Swip1 and GFP–Rab21. Scale bar, 10 µm. The micrograph is representative of two independent experiments. b ,<|im_end|> <|im_start|>assistant A research group at the University of Turku, Finland, has discovered a completely new mechanism that cells use to circulate integrins on the cell surface. Aggressive breast cancer cells exploit this mechanism to spread and metastasise to other parts of the body. Researchers have known for decades that human cells migrate by circulating cell surface adhesion receptors from one part of the cell to another. These adhesion receptors, called integrins, are important for normal cell motility, for example, during wound healing. Earlier studies have also shown that cancer cells have developed particularly efficient ways to circulate these receptors in order to spread to the surrounding tissue and to metastasise to other organs. Professor Johanna Ivaska's research group at the University of Turku, Finland, has discovered a new mechanism that highly aggressive, so-called triple-negative breast cancer cells use to circulate integrins and migrate in the tissue. "Human cells constantly renew their surface by first absorbing parts of the cell membrane and then recycling it. This so-called CG endocytosis mechanism is like a constantly moving conveyor belt that also transports soluble nutrients into cells," Professor Ivaska explains. Post-doc Researcher Paulina Moreno-Layseca and Doctoral Candidate Niklas Jäntti in Professor Ivaska's research group discovered that breast cancer cells use the molecule swiprosin-1 to direct the integrin adhesion receptors onto this conveyor belt. By hijacking this conveyor belt mechanism, cancer cells can promote the circulation of integrins, thus increasing cell migration and the formation of metastases. By studying hundreds of breast cancer specimens, the researchers discovered that a high expression of the swiprosin-1 molecule in the tumor correlates significantly with the formation of metastases and with the malignancy of the breast cancer. "Our findings open up an entirely new perspective into the function of integrins and reveal a new mechanism which cancer cells can use to spread throughout the body. These results will impact the direction of cancer studies in the future," says Professor Ivaska. The results were published on 6 October 2021 in the journal Nature Cell Biology. <|im_end|>

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2,196

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Accurate representation of the viscous flow of ice is fundamental to understanding glacier dynamics and projecting sea-level rise. Ice viscosity is often described by a simple but largely untested and uncalibrated constitutive relation, Glen’s Flow Law, wherein the rate of deformation is proportional to stress raised to the power n . The value n = 3 is commonly prescribed in ice-flow models, though observations and experiments support a range of values across stresses and temperatures found on Earth. Here, we leverage recent remotely-sensed observations of Antarctic ice shelves to show that Glen’s Flow Law approximates the viscous flow of ice with n = 4.1 ± 0.4 in fast-flowing areas. The viscosity and flow rate of ice are therefore more sensitive to changes in stress than most ice-flow models allow. By calibrating the governing equation of ice deformation, our result is a pathway towards improving projections of future glacier change. Introduction Mass loss from ice sheets presents both the greatest potential contribution to future sea-level rise and the largest source of uncertainty in such estimates 1 , 2 . In Antarctica, mass loss occurs principally through fast-flowing glaciers that flow into floating ice shelves, which provide resistive buttressing stresses that impede the seaward flow of ice and stabilize marine grounding zones 3 , 4 , 5 . The rate at which glaciers flow is controlled by the shear-thinning viscous deformation of ice 6 . The most commonly adopted constitutive relation, known as Glen’s Flow Law, is often employed to quantify the viscous deformation of glacier ice by relating the rate of deformation, hereafter called strain rate, to the deviatoric stress 7 . Glen’s Flow Law is most simply expressed as $${\\dot{\\epsilon }}_{e}=A{\\tau }_{e}^{n}$$ (1) where \${\\dot{\\epsilon }}_{e}\$ is the effective strain rate, τ e the effective deviatoric stress, n the stress exponent, and A the rate factor or flow-law coefficient. Variation in parameter A can be used to represent the effects of temperature, grain size, grain orientation (fabric), impurities, and interstitial water content 8 . Glen’s Flow Law is routinely implemented in large-scale ice-flow models with the prescribed value n = 3 assumed to be constant in space and time 9 , 10 . Glen’s laboratory experiments pinpointed the power-law rheology and extrapolated his findings to flows of natural ice 7 , 8 , 11 . Shortly thereafter, Glen’s findings and supporting evidence were widely adopted in the glaciological literature, with the field converging on the canonical value of n = 3 12 , 13 , 14 . However, multiple mechanisms influence the viscous deformation of ice, each with a suggested value of n : dislocation creeps ( n = 4), grain-boundary sliding ( n ≈ 2, with slight variance dictated by the direction of motion of dislocations), and diffusion creep ( n = 1) all accommodate creep at the individual grain level and, in aggregate, describe the flow of glacier ice 15 . These mechanisms are not treated independently in Glen’s Flow Law (Eq. ( 1 )). Rather, it serves as a lumped parameterization representing the combined effect of all mechanisms. Generalized forms of the flow law have been proposed to account for multiple creep mechanisms, fabric, and grain size, but these have not been widely tested, calibrated, nor implemented 10 , 15 , 16 . The simplicity of Glen’s Flow Law has proven useful and, subject to suitable calibration under different conditions, has the potential to provide a reasonably accurate general description of the flow of glacier ice 7 , 8 , 14 , 17 . Glen’s Flow Law (Eq. ( 1 )) with n = 3 shows consistency with sparse observations of natural ice flows such as borehole deformation measurements and ice-flow velocities, as well as laboratory experiments on polycrystalline ice aggregates under conditions relevant for ice sheets 7 , 15 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . However, the broad range of conditions over which the rheological behavior of ice has been examined reveals the way in which variations in stress can influence the stress exponent and, in turn, the mechanisms of creep 10 , 26 , 27 , 28 . Nearly 70 years after its introduction, the need remains to test and rigorously calibrate the parameters n and A in the natural environment. We infer the stress exponent of Glen’s Flow Law across wide areas of Antarctic ice shelves, the floating extensions of the ice sheet. Using satellite observations, we are able to address the long-standing problem of benchmarking a flow law that can be used in ice-flow models. The abundance and extent of the data allow us to investigate the creep of glacial ice on a continental scale, assembling inferences to reveal spatial coherence and patterns with statistical constraints. To do so, we require independent estimates of strain rates and (deviatoric) stresses (Eq. 1 ). The schematic in Fig. 1 graphically illustrates the methodology, showing how we begin with independent observations of surface velocities and ice thicknesses, apply these to evaluate strain-rates \${\\dot{\\epsilon }}_{e}\$ and stresses τ e , and then conduct a regression analysis to infer the parameters in Glen’s Flow Law. This method is comparable to previously published work 21 , 22 , 26 , 29 , but applied to Antarctic ice shelves using continental-scale remote sensing observations. Our results reveal that a value of n = 4.1 ± 0.4 is the most representative flow-law exponent in fast-flowing, extensional regions, where the magnitude of deviatoric stresses are comparable to those expected in other dynamic regions of the ice sheet. Making use of continent-scale remote sensing observations on Antarctic ice shelves, we demonstrate how the viability of power-law rheology can be constrained directly using observations. Fig. 1: The premise of this study applied to validate and calibrate the flow law of glacier ice. Visual summary of our methodology. The schematic shows how we begin with publicly available satellite observations of surface velocity vector u i and ice thickness H . Using the strain-rate", "role": "user" }, { "content": "The rate of glacier ice flow is more sensitive to stress than previously calculated, according to a new study by MIT researchers that upends a decades-old equation used to describe ice flow. Stress in this case refers to the forces acting on Antarctic glaciers, which are primarily influenced by gravity that drags the ice down toward lower elevations. Viscous glacier ice flows \"really similarly to honey,\" explains Joanna Millstein, a Ph.D. student in the Glacier Dynamics and Remote Sensing Group and lead author of the study. \"If you squeeze honey in the center of a piece of toast, and it piles up there before oozing outward, that's the exact same motion that's happening for ice.\" The revision to the equation proposed by Millstein and her colleagues should improve models for making predictions about the ice flow of glaciers. This could help glaciologists predict how Antarctic ice flow might contribute to future sea level rise, although Millstein said the equation change is unlikely to raise estimates of sea level rise beyond the maximum levels already predicted under climate change models. \"Almost all our uncertainties about sea level rise coming from Antarctica have to do with the physics of ice flow, though, so this will hopefully be a constraint on that uncertainty,\" she says. Other authors on the paper, published in Nature Communications Earth and Environment, include Brent Minchew, the Cecil and Ida Green Career Development Professor in MIT's Department of Earth, Atmospheric, and Planetary Sciences, and Samuel Pegler, a university academic fellow at the University of Leeds. Benefits of big data The equation in question, called Glen's Flow Law, is the most widely used equation to describe viscous ice flow. It was developed in 1958 by British scientist J. W. Glen, one of the few glaciologists working on the physics of ice flow in the 1950s, according to Millstein. Pictured is the Juneau ice field in Alaska. Credit: Joanna Millstein With relatively few scientists working in the field until recently, along with the remoteness and inaccessibility of most large glacier ice sheets, there were few attempts to calibrate Glen's Flow Law outside the lab until recently. In the recent study, Millstein and her colleagues took advantage of a new wealth of satellite imagery over Antarctic ice shelves, the floating extensions of the continent's ice sheet, to revise the stress exponent of the flow law. \"In 2002, this major ice shelf [Larsen B] collapsed in Antarctica, and all we have from that collapse is two satellite images that are a month apart,\" she says. \"Now, over that same area we can get [imagery] every six days.\" The new analysis shows that \"the ice flow in the most dynamic, fastest-changing regions of Antarctica—the ice shelves, which basically hold back and hug the interior of the continental ice—is more sensitive to stress than commonly assumed,\" Millstein says. She's optimistic that the growing record of satellite data will help capture rapid changes on Antarctica in the future, providing insights into the underlying physical processes of glaciers. But stress isn't the only thing that affects ice flow, the researchers note. Other parts of the flow law equation represent differences in temperature, ice grain size and orientation, and impurities and water contained in the ice—all of which can alter flow velocity. Factors like temperature could be especially important in understanding how ice flow impacts sea level rise in the future, Millstein says. Cracking under strain Millstein and colleagues are also studying the mechanics of ice sheet collapse, which involves different physical models than those used to understand the ice flow problem. \"The cracking and breaking of ice is what we're working on now, using strain rate observations,\" Millstein says. The researchers use InSAR, radar images of the Earth's surface collected by satellites, to observe deformations of the ice sheets that can be used to make precise measurements of strain. By observing areas of ice with high strain rates, they hope to better understand the rate at which crevasses and rifts propagate to trigger collapse. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Accurate representation of the viscous flow of ice is fundamental to understanding glacier dynamics and projecting sea-level rise. Ice viscosity is often described by a simple but largely untested and uncalibrated constitutive relation, Glen’s Flow Law, wherein the rate of deformation is proportional to stress raised to the power n . The value n = 3 is commonly prescribed in ice-flow models, though observations and experiments support a range of values across stresses and temperatures found on Earth. Here, we leverage recent remotely-sensed observations of Antarctic ice shelves to show that Glen’s Flow Law approximates the viscous flow of ice with n = 4.1 ± 0.4 in fast-flowing areas. The viscosity and flow rate of ice are therefore more sensitive to changes in stress than most ice-flow models allow. By calibrating the governing equation of ice deformation, our result is a pathway towards improving projections of future glacier change. Introduction Mass loss from ice sheets presents both the greatest potential contribution to future sea-level rise and the largest source of uncertainty in such estimates 1 , 2 . In Antarctica, mass loss occurs principally through fast-flowing glaciers that flow into floating ice shelves, which provide resistive buttressing stresses that impede the seaward flow of ice and stabilize marine grounding zones 3 , 4 , 5 . The rate at which glaciers flow is controlled by the shear-thinning viscous deformation of ice 6 . The most commonly adopted constitutive relation, known as Glen’s Flow Law, is often employed to quantify the viscous deformation of glacier ice by relating the rate of deformation, hereafter called strain rate, to the deviatoric stress 7 . Glen’s Flow Law is most simply expressed as $${\dot{\epsilon }}_{e}=A{\tau }_{e}^{n}$$ (1) where ${\dot{\epsilon }}_{e}$ is the effective strain rate, τ e the effective deviatoric stress, n the stress exponent, and A the rate factor or flow-law coefficient. Variation in parameter A can be used to represent the effects of temperature, grain size, grain orientation (fabric), impurities, and interstitial water content 8 . Glen’s Flow Law is routinely implemented in large-scale ice-flow models with the prescribed value n = 3 assumed to be constant in space and time 9 , 10 . Glen’s laboratory experiments pinpointed the power-law rheology and extrapolated his findings to flows of natural ice 7 , 8 , 11 . Shortly thereafter, Glen’s findings and supporting evidence were widely adopted in the glaciological literature, with the field converging on the canonical value of n = 3 12 , 13 , 14 . However, multiple mechanisms influence the viscous deformation of ice, each with a suggested value of n : dislocation creeps ( n = 4), grain-boundary sliding ( n ≈ 2, with slight variance dictated by the direction of motion of dislocations), and diffusion creep ( n = 1) all accommodate creep at the individual grain level and, in aggregate, describe the flow of glacier ice 15 . These mechanisms are not treated independently in Glen’s Flow Law (Eq. ( 1 )). Rather, it serves as a lumped parameterization representing the combined effect of all mechanisms. Generalized forms of the flow law have been proposed to account for multiple creep mechanisms, fabric, and grain size, but these have not been widely tested, calibrated, nor implemented 10 , 15 , 16 . The simplicity of Glen’s Flow Law has proven useful and, subject to suitable calibration under different conditions, has the potential to provide a reasonably accurate general description of the flow of glacier ice 7 , 8 , 14 , 17 . Glen’s Flow Law (Eq. ( 1 )) with n = 3 shows consistency with sparse observations of natural ice flows such as borehole deformation measurements and ice-flow velocities, as well as laboratory experiments on polycrystalline ice aggregates under conditions relevant for ice sheets 7 , 15 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . However, the broad range of conditions over which the rheological behavior of ice has been examined reveals the way in which variations in stress can influence the stress exponent and, in turn, the mechanisms of creep 10 , 26 , 27 , 28 . Nearly 70 years after its introduction, the need remains to test and rigorously calibrate the parameters n and A in the natural environment. We infer the stress exponent of Glen’s Flow Law across wide areas of Antarctic ice shelves, the floating extensions of the ice sheet. Using satellite observations, we are able to address the long-standing problem of benchmarking a flow law that can be used in ice-flow models. The abundance and extent of the data allow us to investigate the creep of glacial ice on a continental scale, assembling inferences to reveal spatial coherence and patterns with statistical constraints. To do so, we require independent estimates of strain rates and (deviatoric) stresses (Eq. 1 ). The schematic in Fig. 1 graphically illustrates the methodology, showing how we begin with independent observations of surface velocities and ice thicknesses, apply these to evaluate strain-rates ${\dot{\epsilon }}_{e}$ and stresses τ e , and then conduct a regression analysis to infer the parameters in Glen’s Flow Law. This method is comparable to previously published work 21 , 22 , 26 , 29 , but applied to Antarctic ice shelves using continental-scale remote sensing observations. Our results reveal that a value of n = 4.1 ± 0.4 is the most representative flow-law exponent in fast-flowing, extensional regions, where the magnitude of deviatoric stresses are comparable to those expected in other dynamic regions of the ice sheet. Making use of continent-scale remote sensing observations on Antarctic ice shelves, we demonstrate how the viability of power-law rheology can be constrained directly using observations. Fig. 1: The premise of this study applied to validate and calibrate the flow law of glacier ice. Visual summary of our methodology. The schematic shows how we begin with publicly available satellite observations of surface velocity vector u i and ice thickness H . Using the strain-rate<|im_end|> <|im_start|>assistant The rate of glacier ice flow is more sensitive to stress than previously calculated, according to a new study by MIT researchers that upends a decades-old equation used to describe ice flow. Stress in this case refers to the forces acting on Antarctic glaciers, which are primarily influenced by gravity that drags the ice down toward lower elevations. Viscous glacier ice flows "really similarly to honey," explains Joanna Millstein, a Ph.D. student in the Glacier Dynamics and Remote Sensing Group and lead author of the study. "If you squeeze honey in the center of a piece of toast, and it piles up there before oozing outward, that's the exact same motion that's happening for ice." The revision to the equation proposed by Millstein and her colleagues should improve models for making predictions about the ice flow of glaciers. This could help glaciologists predict how Antarctic ice flow might contribute to future sea level rise, although Millstein said the equation change is unlikely to raise estimates of sea level rise beyond the maximum levels already predicted under climate change models. "Almost all our uncertainties about sea level rise coming from Antarctica have to do with the physics of ice flow, though, so this will hopefully be a constraint on that uncertainty," she says. Other authors on the paper, published in Nature Communications Earth and Environment, include Brent Minchew, the Cecil and Ida Green Career Development Professor in MIT's Department of Earth, Atmospheric, and Planetary Sciences, and Samuel Pegler, a university academic fellow at the University of Leeds. Benefits of big data The equation in question, called Glen's Flow Law, is the most widely used equation to describe viscous ice flow. It was developed in 1958 by British scientist J. W. Glen, one of the few glaciologists working on the physics of ice flow in the 1950s, according to Millstein. Pictured is the Juneau ice field in Alaska. Credit: Joanna Millstein With relatively few scientists working in the field until recently, along with the remoteness and inaccessibility of most large glacier ice sheets, there were few attempts to calibrate Glen's Flow Law outside the lab until recently. In the recent study, Millstein and her colleagues took advantage of a new wealth of satellite imagery over Antarctic ice shelves, the floating extensions of the continent's ice sheet, to revise the stress exponent of the flow law. "In 2002, this major ice shelf [Larsen B] collapsed in Antarctica, and all we have from that collapse is two satellite images that are a month apart," she says. "Now, over that same area we can get [imagery] every six days." The new analysis shows that "the ice flow in the most dynamic, fastest-changing regions of Antarctica—the ice shelves, which basically hold back and hug the interior of the continental ice—is more sensitive to stress than commonly assumed," Millstein says. She's optimistic that the growing record of satellite data will help capture rapid changes on Antarctica in the future, providing insights into the underlying physical processes of glaciers. But stress isn't the only thing that affects ice flow, the researchers note. Other parts of the flow law equation represent differences in temperature, ice grain size and orientation, and impurities and water contained in the ice—all of which can alter flow velocity. Factors like temperature could be especially important in understanding how ice flow impacts sea level rise in the future, Millstein says. Cracking under strain Millstein and colleagues are also studying the mechanics of ice sheet collapse, which involves different physical models than those used to understand the ice flow problem. "The cracking and breaking of ice is what we're working on now, using strain rate observations," Millstein says. The researchers use InSAR, radar images of the Earth's surface collected by satellites, to observe deformations of the ice sheets that can be used to make precise measurements of strain. By observing areas of ice with high strain rates, they hope to better understand the rate at which crevasses and rifts propagate to trigger collapse. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The genome sequences of many species of the human gut microbiome remain unknown, largely owing to challenges in cultivating microorganisms under laboratory conditions. Here we address this problem by reconstructing 60,664 draft prokaryotic genomes from 3,810 faecal metagenomes, from geographically and phenotypically diverse humans. These genomes provide reference points for 2,058 newly identified species-level operational taxonomic units (OTUs), which represents a 50% increase over the previously known phylogenetic diversity of sequenced gut bacteria. On average, the newly identified OTUs comprise 33% of richness and 28% of species abundance per individual, and are enriched in humans from rural populations. A meta-analysis of clinical gut-microbiome studies pinpointed numerous disease associations for the newly identified OTUs, which have the potential to improve predictive models. Finally, our analysis revealed that uncultured gut species have undergone genome reduction that has resulted in the loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future. Main The gut microbiome has myriad important roles in human health and disease 1 . Microbial reference genomes are essential resources for understanding the functional role of specific organisms in the microbiome, and for quantifying their abundance from metagenomes 2 . However, an estimated 40–50% of human gut species lack a reference genome 3 , 4 . Although considerable efforts have been made to culture and sequence members of the gut microbiome 5 , 6 , 7 , many microorganisms have not been grown under laboratory conditions to date and lack a sequenced genome—despite being prevalent in humans 8 . Recent advances in experimental technologies have begun to close this gap: some studies 6 , 7 have used microbial culturomics to isolate and sequence hundreds of previously uncultured organisms in the human gut, and others have performed single-cell genome sequencing 9 . In contrast to experimental approaches, metagenome binning is a computational approach that can be used to obtain genomes directly from samples without isolation or culturing. Sequencing reads are first assembled into contigs, which are then binned into metagenome-assembled genomes (MAGs) on the basis of nucleotide frequency, abundance and/or co-variation of abundance across a group of samples 10 . This process is performed either for individual metagenomes 11 or multiple co-assembled metagenomes 12 . MAGs are subsequently evaluated for various indicators of genome quality, including estimated completeness and contamination, the presence of marker genes and overall contiguity 13 , 14 , 15 . MAGs were first assembled from a low-complexity acid-mine drainage community 16 but—with advances in sequencing technology and computational methods—MAGs have now been recovered from a myriad of environments including the global ocean 17 , cow rumen 12 , aquifer systems 18 and others 11 . These uncultured genomes have expanded the tree of life by revealing novel lineages in diverse environments, as well as unusual biology 11 , 19 . Despite the growing number of publicly available human gut metagenomes, there has not been any large-scale assembly of MAGs from the gut microbiome. Nielsen et al. 20 were the first to recover MAGs from gut metagenomes, and similar concepts have been developed and applied to other individual studies 21 . We hypothesized that human gut MAGs systematically recovered from public metagenomes could substantially increase the diversity of species with a sequenced genome, and shed light on the biology of uncultivated organisms in the gut microbiome. Reconstructing genomes from global gut metagenomes To recover genomes for novel human gut lineages, we performed metagenomic assembly and binning on 3,810 globally distributed samples from phenotypically and demographically diverse human subjects, using a pipeline developed for this study (Fig. 1a, b , Supplementary Tables 1 – 5 ). MAG quality was improved further by using a pipeline that we developed to identify and remove incorrectly binned contigs (Fig. 1c , Extended Data Fig. 1 , Supplementary Tables 6 , 7 , Methods ). We performed single-sample assembly and binning (rather than co-assembly) to preserve strain variation between human hosts, and because co-assembly was not computationally feasible for our large dataset. On the basis of a subset of samples, our pipeline produced 1.8× more non-redundant high-quality MAGs compared to co-assembly, and 3.3× more than a previous study 20 that used abundance co-variation across samples (Extended Data Fig. 2 ). Fig. 1: Recovery of genomes from globally distributed gut metagenomes. a , Geographical distribution of metagenomes. Sample sizes are indicated in parentheses, and pin colour indicates the majority age group and lifestyle (infants, ≤3 years old; adults, ≥18 years old). Several locations are represented by multiple studies; several studies were conducted in multiple locations. b , Computational pipeline for assembling MAGs. c , Pipeline for identifying and removing incorrectly binned contigs. d , Quality metrics across low- ( n = 101,651), medium- (med., n = 36,319) and high-quality ( n = 24,345) MAGs. e , Barriers to MAG recovery. Single nucleotide polymorphisms (SNPs) were called for MAGs with sufficient read depth ( n = 17,671), and compared with N50. Red line is from a Spearman correlation ( ρ = −0.61). f , At least 10–20× depth is required to assemble a MAG, but assembly rates vary between taxa. AB, Actinobacteria; AR, Archaea; BD, Bacteroidetes; FR, Firmicutes; VM, Verrucomicrobia; PR, Proteobacteria; SP, Spirochaetes. Sequencing read depth was estimated using IGGsearch (see Methods ), and curves were fit using logistic regression. For box plots, the middle line denotes the median; the box denotes the interquartile range (IQR); and the whiskers denote 1.5× IQR. Full size image Our pipeline yielded 60,664 MAGs that met or exceeded the medium-quality ‘Minimum information about a metagenome-assembled genome’ (MIMAG) standard 14 which we refer to as the global human gut MAG (HGM) dataset (Fig. 1b , Supplementary Table 8 ). The MAGs form 43,737 clusters at an average-nucleotide-identity threshold of 99%, which indicates that most of the MAGs are unique. The vast majority of MAGs displayed >98% DNA identity within the same species and <98% identity between species at individual marker genes, which suggests that they are not chimeric (Extended Data Fig. 3g–l ).", "role": "user" }, { "content": "A tree's growth is dependent on nutrients from the soil and water, as well as the microbes in, on, and around the roots. Similarly, a human's health is shaped both by environmental factors and the body's interactions with the microbiome, particularly in the gut. Genome sequences are critical for characterizing individual microbes and understanding their functional roles. However, previous studies have estimated that only 50 percent of species in the gut microbiome have a sequenced genome, in part because many species have not yet been cultivated for study. Published this week in Nature, researchers from the Department of Energy's (DOE) Lawrence Berkeley National Laboratory (Berkeley Lab), the Gladstone Institutes, and the Chan-Zuckerberg Biohub presented nearly 61,000 microbial genomes that were computationally reconstructed from 3,810 publicly available human gut metagenomes, which are datasets of all the genetic material present in a microbiome sample. The metagenome-assembled genomes (MAGs) included 2,058 previously unknown species, thereby bringing the number of known human gut species to 4,558 and increasing the phylogenetic diversity of sequenced gut bacteria by 50 percent. A model community for large-scale culturing efforts This work helps answer the question of why certain microbes have not been cultivated in the lab. Scientists have previously used metagenomics and single-cell genomics to discern the specific metabolic capabilities of uncultured microbes present in environmental samples. \"However, many environmental communities are poorly studied, so it's not clear whether or not uncultivated organisms are really uncultivable,\" said Stephen Nayfach, a scientist in Berkeley Lab's Environmental Genomics and Systems Biology (EGSB) division and the study's first author. \"The human gut, in contrast, is intensely studied with many large-scale culturing efforts, which suggests that the many of the 'wild,' uncultivated species in the human gut are difficult to culture using current approaches.\" By comparing the reconstructed genomes of uncultivated species versus those that have been cultivated, the team found that uncultivated species' genomes are roughly 20 percent smaller, on average, and are missing numerous pathways for biosynthesis of fatty acids, amino acids, and vitamins. \"Genes that are commonly missing from uncultivated gut bacteria may point towards important growth factors that have been overlooked in previous culture-based studies,\" Nayfach said. Improving genomic resources for global populations With the help of a new tool called IGGsearch, the team compared the microbiomes of people with 10 different diseases to those of healthy individuals and found that nearly 40 percent of microbe-disease associations involve a species that did not previously have a genome. \"These disease links used to be invisible or hard to detect,\" said Katie Pollard, a senior investigator at the Gladstone Institutes and Biohub, and contributing author on the study. One new species in the Negativicutes class, for example, was strongly depleted in people with the spinal inflammatory condition ankylosing spondylitis (AS). \"As an AS patient, I am thrilled that we are finally gaining a more complete picture of how the microbiome changes in this disease,\" she added. Additionally, the team used IGGsearch microbiome profiles to build predictive models for disease and found that prediction accuracy was \"significantly improved\" compared to existing tools that primarily quantified the abundance of cultivated species. Pollard, who is also a professor at UC San Francisco, added that, until now, microbiome genomic resources have been particularly sparse for individuals living outside North America, Europe, or China. \"By assembling genomes from metagenomes of diverse people, we have helped to close this gap,\" she said. Extending technologies across microbiome areas EGSB senior scientist and team lead Nikos Kyrpides said that several of the computational methods and analyses Nayfach developed for this research are currently being used to enable one of the Joint Genome Institute (JGI) groundbreaking projects: analyzing a massive collection of other JGI-sequenced MAGs from diverse environments.He added that this type of analysis hinges on several critical factors: the availability of the microbiome data; the availability of the sequence data in public archives; and the lack of any data utilization restrictions from the community, as referenced in a recent Science policy paper on which he and Katie Pollard are co-authors. For Kyrpides, the collaboration with Gladstone and CZ Biohub allowed his team to demonstrate the far reach of technologies developed across all microbiome areas. \"This project is another excellent showcase that aggregated data from multiple studies which can enable us to address questions with far reaching implications that cannot be answered using any individual study alone,\" he said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The genome sequences of many species of the human gut microbiome remain unknown, largely owing to challenges in cultivating microorganisms under laboratory conditions. Here we address this problem by reconstructing 60,664 draft prokaryotic genomes from 3,810 faecal metagenomes, from geographically and phenotypically diverse humans. These genomes provide reference points for 2,058 newly identified species-level operational taxonomic units (OTUs), which represents a 50% increase over the previously known phylogenetic diversity of sequenced gut bacteria. On average, the newly identified OTUs comprise 33% of richness and 28% of species abundance per individual, and are enriched in humans from rural populations. A meta-analysis of clinical gut-microbiome studies pinpointed numerous disease associations for the newly identified OTUs, which have the potential to improve predictive models. Finally, our analysis revealed that uncultured gut species have undergone genome reduction that has resulted in the loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future. Main The gut microbiome has myriad important roles in human health and disease 1 . Microbial reference genomes are essential resources for understanding the functional role of specific organisms in the microbiome, and for quantifying their abundance from metagenomes 2 . However, an estimated 40–50% of human gut species lack a reference genome 3 , 4 . Although considerable efforts have been made to culture and sequence members of the gut microbiome 5 , 6 , 7 , many microorganisms have not been grown under laboratory conditions to date and lack a sequenced genome—despite being prevalent in humans 8 . Recent advances in experimental technologies have begun to close this gap: some studies 6 , 7 have used microbial culturomics to isolate and sequence hundreds of previously uncultured organisms in the human gut, and others have performed single-cell genome sequencing 9 . In contrast to experimental approaches, metagenome binning is a computational approach that can be used to obtain genomes directly from samples without isolation or culturing. Sequencing reads are first assembled into contigs, which are then binned into metagenome-assembled genomes (MAGs) on the basis of nucleotide frequency, abundance and/or co-variation of abundance across a group of samples 10 . This process is performed either for individual metagenomes 11 or multiple co-assembled metagenomes 12 . MAGs are subsequently evaluated for various indicators of genome quality, including estimated completeness and contamination, the presence of marker genes and overall contiguity 13 , 14 , 15 . MAGs were first assembled from a low-complexity acid-mine drainage community 16 but—with advances in sequencing technology and computational methods—MAGs have now been recovered from a myriad of environments including the global ocean 17 , cow rumen 12 , aquifer systems 18 and others 11 . These uncultured genomes have expanded the tree of life by revealing novel lineages in diverse environments, as well as unusual biology 11 , 19 . Despite the growing number of publicly available human gut metagenomes, there has not been any large-scale assembly of MAGs from the gut microbiome. Nielsen et al. 20 were the first to recover MAGs from gut metagenomes, and similar concepts have been developed and applied to other individual studies 21 . We hypothesized that human gut MAGs systematically recovered from public metagenomes could substantially increase the diversity of species with a sequenced genome, and shed light on the biology of uncultivated organisms in the gut microbiome. Reconstructing genomes from global gut metagenomes To recover genomes for novel human gut lineages, we performed metagenomic assembly and binning on 3,810 globally distributed samples from phenotypically and demographically diverse human subjects, using a pipeline developed for this study (Fig. 1a, b , Supplementary Tables 1 – 5 ). MAG quality was improved further by using a pipeline that we developed to identify and remove incorrectly binned contigs (Fig. 1c , Extended Data Fig. 1 , Supplementary Tables 6 , 7 , Methods ). We performed single-sample assembly and binning (rather than co-assembly) to preserve strain variation between human hosts, and because co-assembly was not computationally feasible for our large dataset. On the basis of a subset of samples, our pipeline produced 1.8× more non-redundant high-quality MAGs compared to co-assembly, and 3.3× more than a previous study 20 that used abundance co-variation across samples (Extended Data Fig. 2 ). Fig. 1: Recovery of genomes from globally distributed gut metagenomes. a , Geographical distribution of metagenomes. Sample sizes are indicated in parentheses, and pin colour indicates the majority age group and lifestyle (infants, ≤3 years old; adults, ≥18 years old). Several locations are represented by multiple studies; several studies were conducted in multiple locations. b , Computational pipeline for assembling MAGs. c , Pipeline for identifying and removing incorrectly binned contigs. d , Quality metrics across low- ( n = 101,651), medium- (med., n = 36,319) and high-quality ( n = 24,345) MAGs. e , Barriers to MAG recovery. Single nucleotide polymorphisms (SNPs) were called for MAGs with sufficient read depth ( n = 17,671), and compared with N50. Red line is from a Spearman correlation ( ρ = −0.61). f , At least 10–20× depth is required to assemble a MAG, but assembly rates vary between taxa. AB, Actinobacteria; AR, Archaea; BD, Bacteroidetes; FR, Firmicutes; VM, Verrucomicrobia; PR, Proteobacteria; SP, Spirochaetes. Sequencing read depth was estimated using IGGsearch (see Methods ), and curves were fit using logistic regression. For box plots, the middle line denotes the median; the box denotes the interquartile range (IQR); and the whiskers denote 1.5× IQR. Full size image Our pipeline yielded 60,664 MAGs that met or exceeded the medium-quality ‘Minimum information about a metagenome-assembled genome’ (MIMAG) standard 14 which we refer to as the global human gut MAG (HGM) dataset (Fig. 1b , Supplementary Table 8 ). The MAGs form 43,737 clusters at an average-nucleotide-identity threshold of 99%, which indicates that most of the MAGs are unique. The vast majority of MAGs displayed >98% DNA identity within the same species and <98% identity between species at individual marker genes, which suggests that they are not chimeric (Extended Data Fig. 3g–l ).<|im_end|> <|im_start|>assistant A tree's growth is dependent on nutrients from the soil and water, as well as the microbes in, on, and around the roots. Similarly, a human's health is shaped both by environmental factors and the body's interactions with the microbiome, particularly in the gut. Genome sequences are critical for characterizing individual microbes and understanding their functional roles. However, previous studies have estimated that only 50 percent of species in the gut microbiome have a sequenced genome, in part because many species have not yet been cultivated for study. Published this week in Nature, researchers from the Department of Energy's (DOE) Lawrence Berkeley National Laboratory (Berkeley Lab), the Gladstone Institutes, and the Chan-Zuckerberg Biohub presented nearly 61,000 microbial genomes that were computationally reconstructed from 3,810 publicly available human gut metagenomes, which are datasets of all the genetic material present in a microbiome sample. The metagenome-assembled genomes (MAGs) included 2,058 previously unknown species, thereby bringing the number of known human gut species to 4,558 and increasing the phylogenetic diversity of sequenced gut bacteria by 50 percent. A model community for large-scale culturing efforts This work helps answer the question of why certain microbes have not been cultivated in the lab. Scientists have previously used metagenomics and single-cell genomics to discern the specific metabolic capabilities of uncultured microbes present in environmental samples. "However, many environmental communities are poorly studied, so it's not clear whether or not uncultivated organisms are really uncultivable," said Stephen Nayfach, a scientist in Berkeley Lab's Environmental Genomics and Systems Biology (EGSB) division and the study's first author. "The human gut, in contrast, is intensely studied with many large-scale culturing efforts, which suggests that the many of the 'wild,' uncultivated species in the human gut are difficult to culture using current approaches." By comparing the reconstructed genomes of uncultivated species versus those that have been cultivated, the team found that uncultivated species' genomes are roughly 20 percent smaller, on average, and are missing numerous pathways for biosynthesis of fatty acids, amino acids, and vitamins. "Genes that are commonly missing from uncultivated gut bacteria may point towards important growth factors that have been overlooked in previous culture-based studies," Nayfach said. Improving genomic resources for global populations With the help of a new tool called IGGsearch, the team compared the microbiomes of people with 10 different diseases to those of healthy individuals and found that nearly 40 percent of microbe-disease associations involve a species that did not previously have a genome. "These disease links used to be invisible or hard to detect," said Katie Pollard, a senior investigator at the Gladstone Institutes and Biohub, and contributing author on the study. One new species in the Negativicutes class, for example, was strongly depleted in people with the spinal inflammatory condition ankylosing spondylitis (AS). "As an AS patient, I am thrilled that we are finally gaining a more complete picture of how the microbiome changes in this disease," she added. Additionally, the team used IGGsearch microbiome profiles to build predictive models for disease and found that prediction accuracy was "significantly improved" compared to existing tools that primarily quantified the abundance of cultivated species. Pollard, who is also a professor at UC San Francisco, added that, until now, microbiome genomic resources have been particularly sparse for individuals living outside North America, Europe, or China. "By assembling genomes from metagenomes of diverse people, we have helped to close this gap," she said. Extending technologies across microbiome areas EGSB senior scientist and team lead Nikos Kyrpides said that several of the computational methods and analyses Nayfach developed for this research are currently being used to enable one of the Joint Genome Institute (JGI) groundbreaking projects: analyzing a massive collection of other JGI-sequenced MAGs from diverse environments.He added that this type of analysis hinges on several critical factors: the availability of the microbiome data; the availability of the sequence data in public archives; and the lack of any data utilization restrictions from the community, as referenced in a recent Science policy paper on which he and Katie Pollard are co-authors. For Kyrpides, the collaboration with Gladstone and CZ Biohub allowed his team to demonstrate the far reach of technologies developed across all microbiome areas. "This project is another excellent showcase that aggregated data from multiple studies which can enable us to address questions with far reaching implications that cannot be answered using any individual study alone," he said. <|im_end|>

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2,427

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract People with acute COVID-19 due to SARS-CoV-2 infection experience a range of symptoms, but major factors contributing to severe clinical outcomes remain to be understood. Emerging evidence suggests associations between the gut microbiome and the severity and progression of COVID-19. To better understand the host-microbiota interactions in acute COVID-19, we characterized the intestinal microbiome of patients with active SARS-CoV-2 infection in comparison to recovered patients and uninfected healthy controls. We performed 16S rRNA sequencing of stool samples collected between May 2020 and January 2021 from 20 COVID-19-positive patients, 20 COVID-19-recovered subjects and 20 healthy controls. COVID-19-positive patients had altered microbiome community characteristics compared to the recovered and control subjects, as assessed by both α- and β-diversity differences. In COVID-19-positive patients, we observed depletion of Bacteroidaceae, Ruminococcaceae, and Lachnospiraceae, as well as decreased relative abundances of the genera Faecalibacterium, Adlercreutzia , and the Eubacterium brachy group. The enrichment of Prevotellaceae with COVID-19 infection continued after viral clearance; antibiotic use induced further gut microbiota perturbations in COVID-19-positive patients. In conclusion, we present evidence that acute COVID-19 induces gut microbiota dysbiosis with depletion of particular populations of commensal bacteria, a phenomenon heightened by antibiotic exposure, but the general effects do not persist post-recovery. Working on a manuscript? Avoid the common mistakes Introduction Since its introduction into human populations in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been marked by extreme variability in clinical outcomes, ranging from asymptomatic infection to death [ 1 , 2 , 3 ]. Even among those with symptomatic infection, called the coronavirus disease 2019 (COVID-19), clinical severity has been quite variable [ 4 , 5 ]. Worldwide, most of the infected patients have recovered from the disease, as defined by SARS-CoV-2 viral clearance. However, many have suffered from persistent and sometimes different symptoms after acute COVID-19 [ 6 , 7 , 8 ]. In the past 30 months, several factors associated with differences in clinical manifestations and in recovery have been identified including sex, obesity, and presence of comorbidities such as cardiovascular disease and diabetes, but the most important risk factor is advanced age [ 5 , 9 , 10 , 11 ]. Nevertheless, the major factors leading to severe outcomes only account for a portion of the risk [ 9 , 12 ]. Several studies have reported the prevalence of gastrointestinal (GI) symptoms at the presentation of COVID-19 and the consistent detection of viral shedding in the stools of patients, suggesting a substantial involvement of the GI tract in acute COVID-19 infection [ 13 , 14 ]. Therefore, one host factor that could modulate clinical differences is the state of the host microbiota. Humans carry very large and diverse populations of microbes, termed the microbiome, living in the GI tract, skin, and other organs [ 15 , 16 ]. The largest population is in the colon, and it interacts with human metabolism, immunity, and the central nervous system [ 17 , 18 , 19 , 20 , 21 ]. Despite conserved similarities in its population structure [ 22 ], there is extensive inter-personal variation in the types and abundances of the bacterial taxa present [ 23 , 24 ]. Due to this variation, and the general importance of the gut microbiome in host defenses against infections, there has been interest in the characteristics of the host microbiome as a determinant of the interaction of SARS-CoV-2 with humans [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. We now consider the taxonomic characteristics of the intestinal microbiome, as assessed from fecal samples, in patients with active SARS-CoV-2 infections and those at least 2 weeks after viral clearance in relation to uninfected persons. We find that acute COVID-19 induces gut microbiota dysbiosis with depletion of particular populations of commensal bacteria, but the effect does not persist post-recovery. Results Subject characteristics of the study cohort We collected stool samples from 20 subjects each: patients with active COVID-19 infection (Positive), patients recovered from COVID-19 (Recovered), and healthy controls who had not been infected with SARS-CoV-2 (Controls). Demographic and clinical characteristics of these subjects are summarized in Table 1 . The COVID-19-positive patients were significantly older than the Controls ( p = 0.01) and Recovered subjects ( p = 0.049). All subjects were receiving a regular diet except two COVID-19-positive subjects receiving a low sodium diet. Hypertension was the most common comorbidity among COVID-19-positive patients (50%), followed by obesity (35%) and diabetes mellitus (35%). Comorbidities involving gastrointestinal disorders were observed in 5% of the Controls and 5% of COVID-19-positive patients. During the acute SARS-CoV-2 infection, six (30%) patients experienced gastrointestinal symptoms. Subjects across all study groups reported the use of antibiotics in the prior 6 months, including 10% of the Control, 60% of the Positive, and 20% of the Recovered subjects. Among Positive patients, 50% received at least one form of COVID-19 treatment, excluding dietary supplements (Table 1 ). Table 1 Demographic and clinical characteristics of the 60 study subjects Full size table COVID-19 altered gut microbiome community characteristics To determine the effects of COVID-19 on the gut microbiota, we examined the abundances of 16S rRNA genes in stool samples. The sequencing generated a mean of 26,775 demultiplexed and denoised operational taxonomic units (OTUs) per sample (Supplementary Fig. 1 ). The rarefaction curves reached asymptotes, indicating that an even sampling depth of 10,000 reads/sample was sufficient for diversity analyses (Supplementary Fig. 2a ). Significant differences in species richness were observed between COVID-19-positive patients and the Controls, as well as between the Controls and Recovered subjects at all sampling depth above 1000 (Supplementary Fig. 2a ). No significant difference was detected between COVID-19-positive patients and the Recovered group (Supplementary Fig. 2a ). Analysis of α-diversity by observed features and Pielou’s evenness using the rarefied data did not show any significant differences between study groups (Fig. 1 a). Antibiotic use was associated with markedly reduced species richness in COVID-19-positive patients while the Controls and Recovered patients had no", "role": "user" }, { "content": "In an intensive look at the effects of the virus causing COVID-19 on patients' microbiome—the collection of microorganisms that live in and on the human body—Rutgers scientists found that acute infection disrupts a healthy balance between good and bad microbes in the gut, especially with antibiotic treatment. The work may lead to the development of probiotic supplements to redress any gut imbalances in future patients, the scientists said. Reporting in the journal Molecular Biomedicine, researchers described the first results of an ongoing study examining the microbiome of patients and volunteers at Robert Wood Johnson University Hospital in New Brunswick. The study, which began in May 2020, the early days of the pandemic, was designed to zero in on the microbiome because many COVID-19 sufferers complained of gastrointestinal issues—both during the acute phases of their illness and while recuperating. \"We wanted to gain a deeper understanding by looking at specimens that would give us an indication about the state of the gut microbiome in people,\" said Martin Blaser, the Henry Rutgers Chair of the Human Microbiome at Rutgers University, director of the Center for Advanced Biotechnology and Medicine (CABM) at Rutgers and an author on the study. \"What we found was that, while there were differences between people who had COVID-19 and those who were not ill, the biggest difference from others was seen in those who had been administered antibiotics.\" Early in the pandemic, before the introduction of vaccines and other antiviral remedies, it was a common practice to treat COVID-19 patients with a round of antibiotics to attempt to target possible secondary infections, said Blaser, who also is a professor of medicine and pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School. Humans carry large and diverse populations of microbes, Blaser said. These microorganisms live in the gastrointestinal tract, on the skin and in other organs, with the largest population in the colon. Scientists such as Blaser have shown over recent decades that the microbiome plays a pivotal role in human health, interacting with metabolism, the immune system and the central nervous system. The microbiome has many different functions. \"One is to protect the human body against invading pathogens, whether they're bacteria or viruses or fungi,\" Blaser said. \"That goes deep into evolution, maybe a billion years of evolution.\" Medical problems often arise when the balance between beneficial and pathogenic microbes in a person's microbiome is thrown off, a condition known as dysbiosis. The scientists studied microbiomes by measuring populations of microorganisms in stool samples taken from 60 subjects. The study group consisted of 20 COVID-19 patients, 20 healthy donors and 20 COVID-19-recovered subjects. They found major differences in the population numbers of 55 different species of bacteria when comparing the microbiomes of infected patients with the healthy and recovered patients. The Rutgers scientists plan to continue to test and track the microbiomes of patients in the study to ascertain the long-term effect on individual microbiomes from COVID-19. \"Further investigation of patients will enhance understanding of the role of the gut microbiome in COVID-19 disease progression and recovery,\" Blaser said. \"These findings may help identify microbial targets and probiotic supplements for improving COVID-19 treatment.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract People with acute COVID-19 due to SARS-CoV-2 infection experience a range of symptoms, but major factors contributing to severe clinical outcomes remain to be understood. Emerging evidence suggests associations between the gut microbiome and the severity and progression of COVID-19. To better understand the host-microbiota interactions in acute COVID-19, we characterized the intestinal microbiome of patients with active SARS-CoV-2 infection in comparison to recovered patients and uninfected healthy controls. We performed 16S rRNA sequencing of stool samples collected between May 2020 and January 2021 from 20 COVID-19-positive patients, 20 COVID-19-recovered subjects and 20 healthy controls. COVID-19-positive patients had altered microbiome community characteristics compared to the recovered and control subjects, as assessed by both α- and β-diversity differences. In COVID-19-positive patients, we observed depletion of Bacteroidaceae, Ruminococcaceae, and Lachnospiraceae, as well as decreased relative abundances of the genera Faecalibacterium, Adlercreutzia , and the Eubacterium brachy group. The enrichment of Prevotellaceae with COVID-19 infection continued after viral clearance; antibiotic use induced further gut microbiota perturbations in COVID-19-positive patients. In conclusion, we present evidence that acute COVID-19 induces gut microbiota dysbiosis with depletion of particular populations of commensal bacteria, a phenomenon heightened by antibiotic exposure, but the general effects do not persist post-recovery. Working on a manuscript? Avoid the common mistakes Introduction Since its introduction into human populations in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been marked by extreme variability in clinical outcomes, ranging from asymptomatic infection to death [ 1 , 2 , 3 ]. Even among those with symptomatic infection, called the coronavirus disease 2019 (COVID-19), clinical severity has been quite variable [ 4 , 5 ]. Worldwide, most of the infected patients have recovered from the disease, as defined by SARS-CoV-2 viral clearance. However, many have suffered from persistent and sometimes different symptoms after acute COVID-19 [ 6 , 7 , 8 ]. In the past 30 months, several factors associated with differences in clinical manifestations and in recovery have been identified including sex, obesity, and presence of comorbidities such as cardiovascular disease and diabetes, but the most important risk factor is advanced age [ 5 , 9 , 10 , 11 ]. Nevertheless, the major factors leading to severe outcomes only account for a portion of the risk [ 9 , 12 ]. Several studies have reported the prevalence of gastrointestinal (GI) symptoms at the presentation of COVID-19 and the consistent detection of viral shedding in the stools of patients, suggesting a substantial involvement of the GI tract in acute COVID-19 infection [ 13 , 14 ]. Therefore, one host factor that could modulate clinical differences is the state of the host microbiota. Humans carry very large and diverse populations of microbes, termed the microbiome, living in the GI tract, skin, and other organs [ 15 , 16 ]. The largest population is in the colon, and it interacts with human metabolism, immunity, and the central nervous system [ 17 , 18 , 19 , 20 , 21 ]. Despite conserved similarities in its population structure [ 22 ], there is extensive inter-personal variation in the types and abundances of the bacterial taxa present [ 23 , 24 ]. Due to this variation, and the general importance of the gut microbiome in host defenses against infections, there has been interest in the characteristics of the host microbiome as a determinant of the interaction of SARS-CoV-2 with humans [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. We now consider the taxonomic characteristics of the intestinal microbiome, as assessed from fecal samples, in patients with active SARS-CoV-2 infections and those at least 2 weeks after viral clearance in relation to uninfected persons. We find that acute COVID-19 induces gut microbiota dysbiosis with depletion of particular populations of commensal bacteria, but the effect does not persist post-recovery. Results Subject characteristics of the study cohort We collected stool samples from 20 subjects each: patients with active COVID-19 infection (Positive), patients recovered from COVID-19 (Recovered), and healthy controls who had not been infected with SARS-CoV-2 (Controls). Demographic and clinical characteristics of these subjects are summarized in Table 1 . The COVID-19-positive patients were significantly older than the Controls ( p = 0.01) and Recovered subjects ( p = 0.049). All subjects were receiving a regular diet except two COVID-19-positive subjects receiving a low sodium diet. Hypertension was the most common comorbidity among COVID-19-positive patients (50%), followed by obesity (35%) and diabetes mellitus (35%). Comorbidities involving gastrointestinal disorders were observed in 5% of the Controls and 5% of COVID-19-positive patients. During the acute SARS-CoV-2 infection, six (30%) patients experienced gastrointestinal symptoms. Subjects across all study groups reported the use of antibiotics in the prior 6 months, including 10% of the Control, 60% of the Positive, and 20% of the Recovered subjects. Among Positive patients, 50% received at least one form of COVID-19 treatment, excluding dietary supplements (Table 1 ). Table 1 Demographic and clinical characteristics of the 60 study subjects Full size table COVID-19 altered gut microbiome community characteristics To determine the effects of COVID-19 on the gut microbiota, we examined the abundances of 16S rRNA genes in stool samples. The sequencing generated a mean of 26,775 demultiplexed and denoised operational taxonomic units (OTUs) per sample (Supplementary Fig. 1 ). The rarefaction curves reached asymptotes, indicating that an even sampling depth of 10,000 reads/sample was sufficient for diversity analyses (Supplementary Fig. 2a ). Significant differences in species richness were observed between COVID-19-positive patients and the Controls, as well as between the Controls and Recovered subjects at all sampling depth above 1000 (Supplementary Fig. 2a ). No significant difference was detected between COVID-19-positive patients and the Recovered group (Supplementary Fig. 2a ). Analysis of α-diversity by observed features and Pielou’s evenness using the rarefied data did not show any significant differences between study groups (Fig. 1 a). Antibiotic use was associated with markedly reduced species richness in COVID-19-positive patients while the Controls and Recovered patients had no<|im_end|> <|im_start|>assistant In an intensive look at the effects of the virus causing COVID-19 on patients' microbiome—the collection of microorganisms that live in and on the human body—Rutgers scientists found that acute infection disrupts a healthy balance between good and bad microbes in the gut, especially with antibiotic treatment. The work may lead to the development of probiotic supplements to redress any gut imbalances in future patients, the scientists said. Reporting in the journal Molecular Biomedicine, researchers described the first results of an ongoing study examining the microbiome of patients and volunteers at Robert Wood Johnson University Hospital in New Brunswick. The study, which began in May 2020, the early days of the pandemic, was designed to zero in on the microbiome because many COVID-19 sufferers complained of gastrointestinal issues—both during the acute phases of their illness and while recuperating. "We wanted to gain a deeper understanding by looking at specimens that would give us an indication about the state of the gut microbiome in people," said Martin Blaser, the Henry Rutgers Chair of the Human Microbiome at Rutgers University, director of the Center for Advanced Biotechnology and Medicine (CABM) at Rutgers and an author on the study. "What we found was that, while there were differences between people who had COVID-19 and those who were not ill, the biggest difference from others was seen in those who had been administered antibiotics." Early in the pandemic, before the introduction of vaccines and other antiviral remedies, it was a common practice to treat COVID-19 patients with a round of antibiotics to attempt to target possible secondary infections, said Blaser, who also is a professor of medicine and pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School. Humans carry large and diverse populations of microbes, Blaser said. These microorganisms live in the gastrointestinal tract, on the skin and in other organs, with the largest population in the colon. Scientists such as Blaser have shown over recent decades that the microbiome plays a pivotal role in human health, interacting with metabolism, the immune system and the central nervous system. The microbiome has many different functions. "One is to protect the human body against invading pathogens, whether they're bacteria or viruses or fungi," Blaser said. "That goes deep into evolution, maybe a billion years of evolution." Medical problems often arise when the balance between beneficial and pathogenic microbes in a person's microbiome is thrown off, a condition known as dysbiosis. The scientists studied microbiomes by measuring populations of microorganisms in stool samples taken from 60 subjects. The study group consisted of 20 COVID-19 patients, 20 healthy donors and 20 COVID-19-recovered subjects. They found major differences in the population numbers of 55 different species of bacteria when comparing the microbiomes of infected patients with the healthy and recovered patients. The Rutgers scientists plan to continue to test and track the microbiomes of patients in the study to ascertain the long-term effect on individual microbiomes from COVID-19. "Further investigation of patients will enhance understanding of the role of the gut microbiome in COVID-19 disease progression and recovery," Blaser said. "These findings may help identify microbial targets and probiotic supplements for improving COVID-19 treatment." <|im_end|>

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39515, 531, 2711, 574, 279, 1455, 4279, 470, 30986, 19025, 4315, 20562, 12, 777, 69788, 6978, 320, 1135, 34971, 8272, 555, 33048, 320, 1758, 11587, 323, 20335, 54448, 36891, 320, 1758, 53172, 1219, 269, 21301, 1385, 16239, 80311, 24673, 1051, 13468, 304, 220, 20, 4, 315, 279, 33170, 323, 220, 20, 4, 315, 20562, 12, 777, 69788, 6978, 13, 12220, 279, 30883, 328, 17485, 87271, 53, 12, 17, 19405, 11, 4848, 320, 966, 11587, 6978, 10534, 80311, 13803, 13, 65818, 4028, 682, 4007, 5315, 5068, 279, 1005, 315, 46850, 304, 279, 4972, 220, 21, 4038, 11, 2737, 220, 605, 4, 315, 279, 7935, 11, 220, 1399, 4, 315, 279, 45003, 11, 323, 220, 508, 4, 315, 279, 77212, 291, 15223, 13, 22395, 45003, 6978, 11, 220, 1135, 4, 4036, 520, 3325, 832, 1376, 315, 20562, 12, 777, 6514, 11, 44878, 34625, 33690, 320, 2620, 220, 16, 7609, 6771, 220, 16, 4829, 12968, 323, 14830, 17910, 315, 279, 220, 1399, 4007, 15223, 8797, 1404, 2007, 20562, 12, 777, 29852, 18340, 53499, 638, 4029, 17910, 2057, 8417, 279, 6372, 315, 20562, 12, 777, 389, 279, 18340, 53499, 6217, 11, 584, 25078, 279, 23325, 3095, 315, 220, 845, 50, 436, 31820, 21389, 304, 64172, 10688, 13, 578, 62119, 8066, 264, 3152, 315, 220, 1627, 11, 22908, 2486, 10046, 2635, 291, 323, 3453, 78, 4147, 25605, 3827, 48228, 8316, 320, 1831, 3642, 8, 824, 6205, 320, 10254, 67082, 23966, 13, 220, 16, 7609, 578, 9024, 91409, 37033, 8813, 97354, 6429, 11, 19392, 430, 459, 1524, 25936, 8149, 315, 220, 605, 11, 931, 16181, 70951, 574, 14343, 369, 20057, 29060, 320, 10254, 67082, 23966, 13, 220, 17, 64, 7609, 90462, 12062, 304, 9606, 90030, 1051, 13468, 1990, 20562, 12, 777, 69788, 6978, 323, 279, 33170, 11, 439, 1664, 439, 1990, 279, 33170, 323, 77212, 291, 15223, 520, 682, 25936, 8149, 3485, 220, 1041, 15, 320, 10254, 67082, 23966, 13, 220, 17, 64, 7609, 2360, 5199, 6811, 574, 16914, 1990, 20562, 12, 777, 69788, 6978, 323, 279, 77212, 291, 1912, 320, 10254, 67082, 23966, 13, 220, 17, 64, 7609, 18825, 315, 19581, 33885, 388, 488, 555, 13468, 4519, 323, 393, 13327, 283, 753, 1524, 2136, 1701, 279, 9024, 69, 1142, 828, 1550, 539, 1501, 904, 5199, 12062, 1990, 4007, 5315, 320, 30035, 13, 220, 16, 264, 570, 95951, 62114, 1005, 574, 5938, 449, 88101, 11293, 9606, 90030, 304, 20562, 12, 777, 69788, 6978, 1418, 279, 33170, 323, 77212, 291, 6978, 1047, 912, 128257, 198, 128256, 78191, 198, 644, 459, 37295, 1427, 520, 279, 6372, 315, 279, 17188, 14718, 20562, 12, 777, 389, 6978, 6, 53499, 638, 22416, 4526, 315, 8162, 76991, 430, 3974, 304, 323, 389, 279, 3823, 2547, 2345, 49, 332, 10863, 14248, 1766, 430, 30883, 19405, 24927, 82, 264, 9498, 8335, 1990, 1695, 323, 3958, 80727, 304, 279, 18340, 11, 5423, 449, 60595, 6514, 13, 578, 990, 1253, 3063, 311, 279, 4500, 315, 3650, 62114, 33690, 311, 2579, 676, 904, 18340, 737, 76527, 304, 3938, 6978, 11, 279, 14248, 1071, 13, 47793, 304, 279, 8486, 60825, 12371, 25111, 55103, 11, 12074, 7633, 279, 1176, 3135, 315, 459, 14529, 4007, 38936, 279, 53499, 638, 315, 6978, 323, 23872, 520, 8563, 12404, 11605, 3907, 15429, 304, 1561, 61250, 13, 578, 4007, 11, 902, 6137, 304, 3297, 220, 2366, 15, 11, 279, 4216, 2919, 315, 279, 28522, 11, 574, 6319, 311, 7315, 304, 389, 279, 53499, 638, 1606, 1690, 20562, 12, 777, 96460, 35070, 315, 80311, 4819, 2345, 21704, 2391, 279, 30883, 35530, 315, 872, 17563, 323, 1418, 52621, 1113, 13, 330, 1687, 4934, 311, 8895, 264, 19662, 8830, 555, 3411, 520, 57749, 430, 1053, 3041, 603, 459, 28137, 922, 279, 1614, 315, 279, 18340, 53499, 638, 304, 1274, 1359, 1071, 11826, 2563, 12351, 11, 279, 18063, 72091, 16478, 315, 279, 11344, 18654, 8385, 638, 520, 72091, 3907, 11, 7690, 315, 279, 5955, 369, 21844, 12371, 52536, 323, 19152, 320, 34, 1905, 44, 8, 520, 72091, 323, 459, 3229, 389, 279, 4007, 13, 330, 3923, 584, 1766, 574, 430, 11, 1418, 1070, 1051, 12062, 1990, 1274, 889, 1047, 20562, 12, 777, 323, 1884, 889, 1051, 539, 5986, 11, 279, 8706, 6811, 505, 3885, 574, 3970, 304, 1884, 889, 1047, 1027, 38018, 46850, 1210, 23591, 304, 279, 28522, 11, 1603, 279, 17219, 315, 40300, 323, 1023, 3276, 344, 37478, 51236, 11, 433, 574, 264, 4279, 6725, 311, 4322, 20562, 12, 777, 6978, 449, 264, 4883, 315, 46850, 311, 4879, 311, 2218, 3284, 14580, 30020, 11, 1071, 2563, 12351, 11, 889, 1101, 374, 264, 14561, 315, 16088, 323, 77041, 323, 27692, 16088, 520, 72091, 8563, 12404, 11605, 13235, 6150, 13, 66094, 6920, 3544, 323, 17226, 22673, 315, 80727, 11, 2563, 12351, 1071, 13, 4314, 8162, 76991, 3974, 304, 279, 80311, 42929, 11, 389, 279, 6930, 323, 304, 1023, 36853, 11, 449, 279, 7928, 7187, 304, 279, 15235, 13, 57116, 1778, 439, 2563, 12351, 617, 6982, 927, 3293, 11026, 430, 279, 53499, 638, 11335, 264, 60850, 3560, 304, 3823, 2890, 11, 45830, 449, 39097, 11, 279, 22852, 1887, 323, 279, 8792, 23418, 1887, 13, 578, 53499, 638, 706, 1690, 2204, 5865, 13, 330, 4054, 374, 311, 6144, 279, 3823, 2547, 2403, 83631, 78284, 11, 3508, 814, 2351, 24032, 477, 42068, 477, 81540, 1359, 2563, 12351, 1071, 13, 330, 4897, 5900, 5655, 1139, 15740, 11, 7344, 264, 7239, 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330, 9673, 14955, 1253, 1520, 10765, 75418, 11811, 323, 3650, 62114, 33690, 369, 18899, 20562, 12, 777, 6514, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Black phosphorus (bP) is the second known elemental allotrope with a layered crystal structure that can be mechanically exfoliated to atomic layer thickness. Unlike metallic graphite and semi-metallic graphene, bP is a semiconductor in both bulk and few-layer form. Here we fabricate bP-naked quantum wells in a back-gated field effect transistor geometry with bP thicknesses ranging from 6±1 nm to 47±1 nm. Using a polymer encapsulant, we suppress bP oxidation and observe field effect mobilities up to 900 cm 2 V −1 s −1 and on/off current ratios exceeding 10 5 . Shubnikov-de Haas oscillations observed in magnetic fields up to 35 T reveal a 2D hole gas with Schrödinger fermion character in a surface accumulation layer. Our work demonstrates that 2D electronic structure and 2D atomic structure are independent. 2D carrier confinement can be achieved without approaching atomic layer thickness, advantageous for materials that become increasingly reactive in the few-layer limit such as bP. Introduction Layered two-dimensional (2D) materials have undergone a renaissance since the development of mechanical exfoliation techniques 1 . Black phosphorus (bP) is a layered material ( Fig. 1a ) with van der Waals interlayer bonding 2 , and is the only elemental allotrope other than graphene that is presently known to be a 2D material. Recent work has shown that bP can be exfoliated down to the atomic limit 3 , 4 , 5 , 6 , 7 , 8 . In bulk form, bP is a narrow gap semiconductor with a 0.3 eV direct bandgap 9 , which grows to an ∼ 2 eV bandgap in the atomic monolayer limit 2 , ideal for application to transistors 10 . Ambipolar conduction, mobilities approaching ∼ 1,000 cm 2 V −1 s −1 and anisotropic conductivity have been demonstrated 3 , 4 , 5 , leading to a revitalized interest in bP 11 . Figure 1: Structure of black phosphorus FETs. ( a ) The bP crystal structure is composed of puckered honeycomb layers with an interlayer distance of 5.24 Å. ( b ) Three-dimensional schematic view of a bP FET with oxidized silicon back-gate and an encapsulating layer of MMA and PMMA. ( c ) Optical image of an encapsulated bP FET in Hall bar geometry. Scale bar, 10 μm. ( d ) AFM image of the same device with encapsulating layer removed. The bP thickness is 43±2 nm (82±4 atomic layers). Scale bar, 10 μm. Full size image Interestingly, it was long ago observed 2 that despite the weak van der Waals bonding between the 2D atomic layers of bP, the effective mass for electron (hole) motion between planes is remarkably light at 0.13 m 0 (0.28 m 0 ) 12 , where m 0 is the free-electron mass. Exfoliated bP layers are thus effectively naked quantum wells with a low charge trap density at the bP surface due to the absence of broken covalent bonds and the simultaneous delocalization of charge carriers across atomic layers due to the light effective mass. The high electronic quality of the naked bP surface, requiring no passivation, is rare among semiconductors. In our work, we fabricate field effect transistors (FETs) with exfoliated bP layers ranging in thickness from 6±1 nm to 47±1 nm (11±2 to 90±2 atomic layers). Despite being the most stable allotrope of phosphorus, bP suffers from photo-oxidation in a reaction that proceeds faster as atomic film thickness is approached 6 . The deleterious effects of photo-oxidation are mitigated by using bP layers thicker than a few atomic layers, by encapsulating the bP in a polymer superstrate, and by minimizing exposure to oxygen, water and visible light. We measure the electronic transport properties of bP FETs over the temperature range of 0.3 to 300 K, including the measurement of Shubnikov-de Haas (SdH) oscillations at magnetic fields up to 35 T. The observed SdH oscillations indicate the presence of a 2D hole gas in an accumulation layer as in conventional semiconductor heterostructures, demonstrating that 2D carrier confinement can be achieved in bP of ∼ 90 atomic layer thickness, which are much less susceptible to photo-oxidation than few-layer bP. Independent studies of bP on exfoliated hexagonal boron nitride (hBN) 13 , and bP encapsulated within exfoliated hBN layers 14 , 15 report very similar observations of 2D magnetotransport. Results Device structure and characterization Ultra-thin bP samples were prepared by mechanical exfoliation from bulk bP crystals using a polydimethylsiloxane (PDMS) stamp technique 6 . The sample substrates were degenerately doped Si wafers, with 300 nm of dry thermal oxide to allow rapid optical identification of bP flakes and back-gating over a wide temperature range. To protect bP FETs against degradation, 300 nm of copolymer (methyl methacrylate) and 200 nm of polymer (polymethyl methacrylate) were deposited. A schematic of the bP FET structure is shown in Fig. 1b . The polymer layer forms a water-impermeable superstrate-suppressing oxidation. An optical reflection image under white light illumination of a typical encapsulated bP FET is shown in Fig. 1c . Upon completion of electron transport measurements, described in detail below, Raman spectroscopy was performed (see Methods). The encapsulating polymer was then removed with acetone and the bP layer thickness was measured by atomic force microscopy (AFM) within a glove box. An AFM image of an unencapsulated bP FET is shown in Fig. 1d . The bP layer thickness of this representative device in Hall bar geometry was determined to be 43±2 nm (82±4 atomic layers). Importantly, the bP surface is free of the surface roughening that arises from oxidation 6 , 7 , 8 , 16 , despite exposure to ambient conditions. Encapsulation with a PMMA/MMA superstrate, similar to encapsulation with parylene 6 or AlO x (ref. 16 ), was thus found to be an effective means to suppress photo-oxidation of multi-layer bP. Most recently, hBN has also been used to preserve bP quality 14 , 15 . Zero-field electron transport Charge transport was investigated in over 40 bP FETs, of which three representative samples are shown in Fig. 2 .", "role": "user" }, { "content": "As scientists continue to hunt for a material that will make it possible to pack more transistors on a chip, new research from McGill University and Université de Montréal adds to evidence that black phosphorus could emerge as a strong candidate. In a study published today in Nature Communications, the researchers report that when electrons move in a phosphorus transistor, they do so only in two dimensions. The finding suggests that black phosphorus could help engineers surmount one of the big challenges for future electronics: designing energy-efficient transistors. \"Transistors work more efficiently when they are thin, with electrons moving in only two dimensions,\" says Thomas Szkopek, an associate professor in McGill's Department of Electrical and Computer Engineering and senior author of the new study. \"Nothing gets thinner than a single layer of atoms.\" In 2004, physicists at the University of Manchester in the U.K. first isolated and explored the remarkable properties of graphene—a one-atom-thick layer of carbon. Since then scientists have rushed to to investigate a range of other two-dimensional materials. One of those is black phosphorus, a form of phosphorus that is similar to graphite and can be separated easily into single atomic layers, known as phosphorene. Phosphorene has sparked growing interest because it overcomes many of the challenges of using graphene in electronics. Unlike graphene, which acts like a metal, black phosphorus is a natural semiconductor: it can be readily switched on and off. \"To lower the operating voltage of transistors, and thereby reduce the heat they generate, we have to get closer and closer to designing the transistor at the atomic level,\" Szkopek says. \"The toolbox of the future for transistor designers will require a variety of atomic-layered materials: an ideal semiconductor, an ideal metal, and an ideal dielectric. All three components must be optimized for a well designed transistor. Black phosphorus fills the semiconducting-material role.\" The work resulted from a multidisciplinary collaboration among Szkopek's nanoelectronics research group, the nanoscience lab of McGill Physics Prof. Guillaume Gervais, and the nanostructures research group of Prof. Richard Martel in Université de Montréal's Department of Chemistry. To examine how the electrons move in a phosphorus transistor, the researchers observed them under the influence of a magnetic field in experiments performed at the National High Magnetic Field Laboratory in Tallahassee, FL, the largest and highest-powered magnet laboratory in the world. This research \"provides important insights into the fundamental physics that dictate the behavior of black phosphorus,\" says Tim Murphy, DC Field Facility Director at the Florida facility. \"What's surprising in these results is that the electrons are able to be pulled into a sheet of charge which is two-dimensional, even though they occupy a volume that is several atomic layers in thickness,\" Szkopek says. That finding is significant because it could potentially facilitate manufacturing the material—though at this point \"no one knows how to manufacture this material on a large scale.\" \"There is a great emerging interest around the world in black phosphorus,\" Szkopek says. \"We are still a long way from seeing atomic layer transistors in a commercial product, but we have now moved one step closer.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Black phosphorus (bP) is the second known elemental allotrope with a layered crystal structure that can be mechanically exfoliated to atomic layer thickness. Unlike metallic graphite and semi-metallic graphene, bP is a semiconductor in both bulk and few-layer form. Here we fabricate bP-naked quantum wells in a back-gated field effect transistor geometry with bP thicknesses ranging from 6±1 nm to 47±1 nm. Using a polymer encapsulant, we suppress bP oxidation and observe field effect mobilities up to 900 cm 2 V −1 s −1 and on/off current ratios exceeding 10 5 . Shubnikov-de Haas oscillations observed in magnetic fields up to 35 T reveal a 2D hole gas with Schrödinger fermion character in a surface accumulation layer. Our work demonstrates that 2D electronic structure and 2D atomic structure are independent. 2D carrier confinement can be achieved without approaching atomic layer thickness, advantageous for materials that become increasingly reactive in the few-layer limit such as bP. Introduction Layered two-dimensional (2D) materials have undergone a renaissance since the development of mechanical exfoliation techniques 1 . Black phosphorus (bP) is a layered material ( Fig. 1a ) with van der Waals interlayer bonding 2 , and is the only elemental allotrope other than graphene that is presently known to be a 2D material. Recent work has shown that bP can be exfoliated down to the atomic limit 3 , 4 , 5 , 6 , 7 , 8 . In bulk form, bP is a narrow gap semiconductor with a 0.3 eV direct bandgap 9 , which grows to an ∼ 2 eV bandgap in the atomic monolayer limit 2 , ideal for application to transistors 10 . Ambipolar conduction, mobilities approaching ∼ 1,000 cm 2 V −1 s −1 and anisotropic conductivity have been demonstrated 3 , 4 , 5 , leading to a revitalized interest in bP 11 . Figure 1: Structure of black phosphorus FETs. ( a ) The bP crystal structure is composed of puckered honeycomb layers with an interlayer distance of 5.24 Å. ( b ) Three-dimensional schematic view of a bP FET with oxidized silicon back-gate and an encapsulating layer of MMA and PMMA. ( c ) Optical image of an encapsulated bP FET in Hall bar geometry. Scale bar, 10 μm. ( d ) AFM image of the same device with encapsulating layer removed. The bP thickness is 43±2 nm (82±4 atomic layers). Scale bar, 10 μm. Full size image Interestingly, it was long ago observed 2 that despite the weak van der Waals bonding between the 2D atomic layers of bP, the effective mass for electron (hole) motion between planes is remarkably light at 0.13 m 0 (0.28 m 0 ) 12 , where m 0 is the free-electron mass. Exfoliated bP layers are thus effectively naked quantum wells with a low charge trap density at the bP surface due to the absence of broken covalent bonds and the simultaneous delocalization of charge carriers across atomic layers due to the light effective mass. The high electronic quality of the naked bP surface, requiring no passivation, is rare among semiconductors. In our work, we fabricate field effect transistors (FETs) with exfoliated bP layers ranging in thickness from 6±1 nm to 47±1 nm (11±2 to 90±2 atomic layers). Despite being the most stable allotrope of phosphorus, bP suffers from photo-oxidation in a reaction that proceeds faster as atomic film thickness is approached 6 . The deleterious effects of photo-oxidation are mitigated by using bP layers thicker than a few atomic layers, by encapsulating the bP in a polymer superstrate, and by minimizing exposure to oxygen, water and visible light. We measure the electronic transport properties of bP FETs over the temperature range of 0.3 to 300 K, including the measurement of Shubnikov-de Haas (SdH) oscillations at magnetic fields up to 35 T. The observed SdH oscillations indicate the presence of a 2D hole gas in an accumulation layer as in conventional semiconductor heterostructures, demonstrating that 2D carrier confinement can be achieved in bP of ∼ 90 atomic layer thickness, which are much less susceptible to photo-oxidation than few-layer bP. Independent studies of bP on exfoliated hexagonal boron nitride (hBN) 13 , and bP encapsulated within exfoliated hBN layers 14 , 15 report very similar observations of 2D magnetotransport. Results Device structure and characterization Ultra-thin bP samples were prepared by mechanical exfoliation from bulk bP crystals using a polydimethylsiloxane (PDMS) stamp technique 6 . The sample substrates were degenerately doped Si wafers, with 300 nm of dry thermal oxide to allow rapid optical identification of bP flakes and back-gating over a wide temperature range. To protect bP FETs against degradation, 300 nm of copolymer (methyl methacrylate) and 200 nm of polymer (polymethyl methacrylate) were deposited. A schematic of the bP FET structure is shown in Fig. 1b . The polymer layer forms a water-impermeable superstrate-suppressing oxidation. An optical reflection image under white light illumination of a typical encapsulated bP FET is shown in Fig. 1c . Upon completion of electron transport measurements, described in detail below, Raman spectroscopy was performed (see Methods). The encapsulating polymer was then removed with acetone and the bP layer thickness was measured by atomic force microscopy (AFM) within a glove box. An AFM image of an unencapsulated bP FET is shown in Fig. 1d . The bP layer thickness of this representative device in Hall bar geometry was determined to be 43±2 nm (82±4 atomic layers). Importantly, the bP surface is free of the surface roughening that arises from oxidation 6 , 7 , 8 , 16 , despite exposure to ambient conditions. Encapsulation with a PMMA/MMA superstrate, similar to encapsulation with parylene 6 or AlO x (ref. 16 ), was thus found to be an effective means to suppress photo-oxidation of multi-layer bP. Most recently, hBN has also been used to preserve bP quality 14 , 15 . Zero-field electron transport Charge transport was investigated in over 40 bP FETs, of which three representative samples are shown in Fig. 2 .<|im_end|> <|im_start|>assistant As scientists continue to hunt for a material that will make it possible to pack more transistors on a chip, new research from McGill University and Université de Montréal adds to evidence that black phosphorus could emerge as a strong candidate. In a study published today in Nature Communications, the researchers report that when electrons move in a phosphorus transistor, they do so only in two dimensions. The finding suggests that black phosphorus could help engineers surmount one of the big challenges for future electronics: designing energy-efficient transistors. "Transistors work more efficiently when they are thin, with electrons moving in only two dimensions," says Thomas Szkopek, an associate professor in McGill's Department of Electrical and Computer Engineering and senior author of the new study. "Nothing gets thinner than a single layer of atoms." In 2004, physicists at the University of Manchester in the U.K. first isolated and explored the remarkable properties of graphene—a one-atom-thick layer of carbon. Since then scientists have rushed to to investigate a range of other two-dimensional materials. One of those is black phosphorus, a form of phosphorus that is similar to graphite and can be separated easily into single atomic layers, known as phosphorene. Phosphorene has sparked growing interest because it overcomes many of the challenges of using graphene in electronics. Unlike graphene, which acts like a metal, black phosphorus is a natural semiconductor: it can be readily switched on and off. "To lower the operating voltage of transistors, and thereby reduce the heat they generate, we have to get closer and closer to designing the transistor at the atomic level," Szkopek says. "The toolbox of the future for transistor designers will require a variety of atomic-layered materials: an ideal semiconductor, an ideal metal, and an ideal dielectric. All three components must be optimized for a well designed transistor. Black phosphorus fills the semiconducting-material role." The work resulted from a multidisciplinary collaboration among Szkopek's nanoelectronics research group, the nanoscience lab of McGill Physics Prof. Guillaume Gervais, and the nanostructures research group of Prof. Richard Martel in Université de Montréal's Department of Chemistry. To examine how the electrons move in a phosphorus transistor, the researchers observed them under the influence of a magnetic field in experiments performed at the National High Magnetic Field Laboratory in Tallahassee, FL, the largest and highest-powered magnet laboratory in the world. This research "provides important insights into the fundamental physics that dictate the behavior of black phosphorus," says Tim Murphy, DC Field Facility Director at the Florida facility. "What's surprising in these results is that the electrons are able to be pulled into a sheet of charge which is two-dimensional, even though they occupy a volume that is several atomic layers in thickness," Szkopek says. That finding is significant because it could potentially facilitate manufacturing the material—though at this point "no one knows how to manufacture this material on a large scale." "There is a great emerging interest around the world in black phosphorus," Szkopek says. "We are still a long way from seeing atomic layer transistors in a commercial product, but we have now moved one step closer." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, γδ T cells and NKT cells, whereas dendritic cells, B2 cells, CD4 + T and CD8 + T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment. Introduction Immune protection is a remarkably balanced defence mechanism to protect the host from environmental threats and pathogens without triggering aberrant responses to self-antigens that underlie autoimmunity. The balance of a large diversity of leukocyte subpopulations is driven by genetic and environmental influences that maintain homeostasis of innate cell types (pre-programmed to respond to pathogens and cancers), naive adaptive B and T lymphocytes (comprising antigen receptors that theoretically could target any un-encountered pathogen or neo-antigen) and functionally polarized memory B and T lymphocytes (that can rapidly respond to previously encountered antigen). Many cancers, autoimmune diseases and immunodeficiencies result from aberrant homeostatic control over this panoply of cell types. To date, the genetic mechanisms and environmental factors that regulate homeostasis of cell numbers and phenotypes in the peripheral immune system are poorly understood. Genes responsible for variation in the response to pathogens and inflammation regulation are common targets of natural selection 1 . In particular, studies have identified signatures of pathogen-mediated selection in genome-wide association study (GWAS) and numerous single-nucleotide polymorphisms associated with autoimmune diseases such as celiac disease, ulcerative colitis, type 1 diabetes, Crohn’s disease and multiples sclerosis 2 have been identified. Despite this progress, few of these genetic associations have led to mechanistic insight. Studies more than a decade ago showed that overall numbers of CD8 + and CD4 + T cells are under genetic influence 3 . Advances in technology enable detailed analysis of the human immune system on a genetic and phenotype level. Adopting these techniques, several studies 4 , 5 , 6 , 7 , 8 report heritability estimates on selected immune subtypes. Some of the studies emphasize the heritable nature of immune traits, whereas others focus on environmental influences. The differences in interpretation between such studies are mostly due to different assessment methods and/or the size of the analysed data set. With our increasing knowledge of complex disease genetics, as well as quantifiable environmental factors such as lifestyle factors and the microbiome, considerable interest exists regarding the extent to which environmental versus genetic factors influence human immune cell homeostasis. We previously reported the discovery of 11 genetic loci affecting 19 well-defined immune traits by focussing on the analysis of the 151 most heritable immune traits per a prespecified statistical analysis plan. Here we extend that analysis to define the genetic and, uniquely afforded by the twin-based design of our study, the shared environmental influence on the variation in 23,394 robust immune phenotypes in 497 adult female twins (TwinsUK) profiled with a high-resolution deep immunophenotyping flow cytometry approach. We show that there is broad heritability of most human immune traits and, using the power of this well-balanced twin cohort, separately quantify shared versus unique environmental influences. Our study assists precision medicine by defining which human immune traits are under genetic or environmental control and, in particular, which are subject to common shared household exposures such as microbiota and diet. Results Genetic and environmental dependence of immune traits The study cohort comprised 75 monozygotic (MZ), 170 dizygotic (DZ) twin pairs and 7 singletons. The whole data set only included females of Caucasian origin. All twin pairs were raised together. We observed no statistical differences within MZ and DZ pairs for both education level ( P =0.09) and personal welfare ( P =0.2). The MZ pairs were on average 2 years older than the DZ (MZ: 62.4±8.9 years; DZ: 60.9±7.7 years). The use of a twin cohort brought two major advantages to our study that are difficult to obtain in other designs. First, it allowed us to accurately identify heritable traits that were most likely to be informative using GWAS in our original analysis 8 . Second, it allows us now to identify not only heritability, but also common and shared environmental influences, on the variability of the full set of immune traits investigated. Here we report on the influence of both genetics and environment on 23,394 immune traits. As described in Methods, we filtered our complete set of 89,051 traits to focus on those that were robust ( n =23,394); structured equation modelling (SEqM) analysis was performed on these traits. The full results of all this analysis are reported in Supplementary Data 1 . Robust trait values are given in Supplementary Data 1 and demographic information in Supplementary Data 1 . Overall, a large fraction of traits show evidence of genetic control. As illustrated in Fig. 1a , the mean correlation of traits was substantially higher for MZ twins (mean r =0.61) than for DZ twins (mean r =0.35). The mean correlation in longitudinal analysis of these traits is r =0.90, showing a low degree of experimental error. Using Falconer’s formula to estimate heritability ( Fig. 1b ), the mean genetic influence was ∼ 45%, with almost one in eight immune traits above 80%. However, although Falconer’s formula is computationally simple to perform and provides a good overview, it is an imperfect estimate for individual traits, prone to a number of potential biases and assumptions. Thus, we applied SEqM to the trait values. Figure 1: Estimating heritability of immune traits. ( a ) Trait values from MZ twins, DZ twins or longitudinal specimens were correlated; the Pearson'’s correlation coefficients", "role": "user" }, { "content": "Nearly three quarters of immune traits are influenced by genes, new research from King's College London reveals. The study published today in Nature Communications, adds to a growing body of evidence that the genetic influence on our immune system is significantly higher than previously thought. Researchers from King's, supported by the NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust and King's College London, analysed 23,000 immune traits in 497 adult female twins from the TwinsUK cohort. They found that adaptive immune traits - the more complex responses that develop after exposure to a specific pathogen, such as chickenpox - are mostly influenced by genetics. They also highlight the importance of environmental influences such as our diet, on shaping the innate immunity (the simple core immune response found in all animals) in adult life. The findings could help to improve understanding of the immune system and the interaction of environmental factors. It could also form the basis of further research into treatments for various diseases, including rheumatoid arthritis and psoriasis. Dr Massimo Mangino, lead researcher from King's College London said: \"Our genetic analysis resulted in some unusual findings, where adaptive immune responses, which are far more complex in nature, appear to be more influenced by variations in the genome than we had previously thought. In contrast, variation in innate responses (the simple non specific immune response) more often arose from environmental differences. This discovery could have a significant impact in treating a number of autoimmune diseases.\" Professor Tim Spector, Director of the TwinsUK Registry at King's College London said: \"Our results surprisingly showed how most immune responses are genetic, very personalised and finely tuned. What this means is that we are likely to respond in a very individualised way to an infection such as a virus - or an allergen such as a house dust mite causing asthma. This may have big implications for future personalised therapy.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, γδ T cells and NKT cells, whereas dendritic cells, B2 cells, CD4 + T and CD8 + T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment. Introduction Immune protection is a remarkably balanced defence mechanism to protect the host from environmental threats and pathogens without triggering aberrant responses to self-antigens that underlie autoimmunity. The balance of a large diversity of leukocyte subpopulations is driven by genetic and environmental influences that maintain homeostasis of innate cell types (pre-programmed to respond to pathogens and cancers), naive adaptive B and T lymphocytes (comprising antigen receptors that theoretically could target any un-encountered pathogen or neo-antigen) and functionally polarized memory B and T lymphocytes (that can rapidly respond to previously encountered antigen). Many cancers, autoimmune diseases and immunodeficiencies result from aberrant homeostatic control over this panoply of cell types. To date, the genetic mechanisms and environmental factors that regulate homeostasis of cell numbers and phenotypes in the peripheral immune system are poorly understood. Genes responsible for variation in the response to pathogens and inflammation regulation are common targets of natural selection 1 . In particular, studies have identified signatures of pathogen-mediated selection in genome-wide association study (GWAS) and numerous single-nucleotide polymorphisms associated with autoimmune diseases such as celiac disease, ulcerative colitis, type 1 diabetes, Crohn’s disease and multiples sclerosis 2 have been identified. Despite this progress, few of these genetic associations have led to mechanistic insight. Studies more than a decade ago showed that overall numbers of CD8 + and CD4 + T cells are under genetic influence 3 . Advances in technology enable detailed analysis of the human immune system on a genetic and phenotype level. Adopting these techniques, several studies 4 , 5 , 6 , 7 , 8 report heritability estimates on selected immune subtypes. Some of the studies emphasize the heritable nature of immune traits, whereas others focus on environmental influences. The differences in interpretation between such studies are mostly due to different assessment methods and/or the size of the analysed data set. With our increasing knowledge of complex disease genetics, as well as quantifiable environmental factors such as lifestyle factors and the microbiome, considerable interest exists regarding the extent to which environmental versus genetic factors influence human immune cell homeostasis. We previously reported the discovery of 11 genetic loci affecting 19 well-defined immune traits by focussing on the analysis of the 151 most heritable immune traits per a prespecified statistical analysis plan. Here we extend that analysis to define the genetic and, uniquely afforded by the twin-based design of our study, the shared environmental influence on the variation in 23,394 robust immune phenotypes in 497 adult female twins (TwinsUK) profiled with a high-resolution deep immunophenotyping flow cytometry approach. We show that there is broad heritability of most human immune traits and, using the power of this well-balanced twin cohort, separately quantify shared versus unique environmental influences. Our study assists precision medicine by defining which human immune traits are under genetic or environmental control and, in particular, which are subject to common shared household exposures such as microbiota and diet. Results Genetic and environmental dependence of immune traits The study cohort comprised 75 monozygotic (MZ), 170 dizygotic (DZ) twin pairs and 7 singletons. The whole data set only included females of Caucasian origin. All twin pairs were raised together. We observed no statistical differences within MZ and DZ pairs for both education level ( P =0.09) and personal welfare ( P =0.2). The MZ pairs were on average 2 years older than the DZ (MZ: 62.4±8.9 years; DZ: 60.9±7.7 years). The use of a twin cohort brought two major advantages to our study that are difficult to obtain in other designs. First, it allowed us to accurately identify heritable traits that were most likely to be informative using GWAS in our original analysis 8 . Second, it allows us now to identify not only heritability, but also common and shared environmental influences, on the variability of the full set of immune traits investigated. Here we report on the influence of both genetics and environment on 23,394 immune traits. As described in Methods, we filtered our complete set of 89,051 traits to focus on those that were robust ( n =23,394); structured equation modelling (SEqM) analysis was performed on these traits. The full results of all this analysis are reported in Supplementary Data 1 . Robust trait values are given in Supplementary Data 1 and demographic information in Supplementary Data 1 . Overall, a large fraction of traits show evidence of genetic control. As illustrated in Fig. 1a , the mean correlation of traits was substantially higher for MZ twins (mean r =0.61) than for DZ twins (mean r =0.35). The mean correlation in longitudinal analysis of these traits is r =0.90, showing a low degree of experimental error. Using Falconer’s formula to estimate heritability ( Fig. 1b ), the mean genetic influence was ∼ 45%, with almost one in eight immune traits above 80%. However, although Falconer’s formula is computationally simple to perform and provides a good overview, it is an imperfect estimate for individual traits, prone to a number of potential biases and assumptions. Thus, we applied SEqM to the trait values. Figure 1: Estimating heritability of immune traits. ( a ) Trait values from MZ twins, DZ twins or longitudinal specimens were correlated; the Pearson'’s correlation coefficients<|im_end|> <|im_start|>assistant Nearly three quarters of immune traits are influenced by genes, new research from King's College London reveals. The study published today in Nature Communications, adds to a growing body of evidence that the genetic influence on our immune system is significantly higher than previously thought. Researchers from King's, supported by the NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust and King's College London, analysed 23,000 immune traits in 497 adult female twins from the TwinsUK cohort. They found that adaptive immune traits - the more complex responses that develop after exposure to a specific pathogen, such as chickenpox - are mostly influenced by genetics. They also highlight the importance of environmental influences such as our diet, on shaping the innate immunity (the simple core immune response found in all animals) in adult life. The findings could help to improve understanding of the immune system and the interaction of environmental factors. It could also form the basis of further research into treatments for various diseases, including rheumatoid arthritis and psoriasis. Dr Massimo Mangino, lead researcher from King's College London said: "Our genetic analysis resulted in some unusual findings, where adaptive immune responses, which are far more complex in nature, appear to be more influenced by variations in the genome than we had previously thought. In contrast, variation in innate responses (the simple non specific immune response) more often arose from environmental differences. This discovery could have a significant impact in treating a number of autoimmune diseases." Professor Tim Spector, Director of the TwinsUK Registry at King's College London said: "Our results surprisingly showed how most immune responses are genetic, very personalised and finely tuned. What this means is that we are likely to respond in a very individualised way to an infection such as a virus - or an allergen such as a house dust mite causing asthma. This may have big implications for future personalised therapy." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Friction in ordered atomistic layers plays a central role in various nanoscale systems ranging from nanomachines to biological systems. It governs transport properties, wear and dissipation. Defects and incommensurate lattice constants markedly change these properties. Recently, experimental systems have become accessible to probe the dynamics of nanofriction. Here, we present a model system consisting of laser-cooled ions in which nanofriction and transport processes in self-organized systems with back action can be studied with atomic resolution. We show that in a system with local defects resulting in incommensurate layers, there is a transition from sticking to sliding with Aubry-type signatures. We demonstrate spectroscopic measurements of the soft vibrational mode driving this transition and a measurement of the order parameter. We show numerically that both exhibit critical scaling near the transition point. Our studies demonstrate a simple, well-controlled system in which friction in self-organized structures can be studied from classical- to quantum-regimes. Introduction Dry friction is the resistance to the relative movement of two solid layers. It is responsible for many phenomena such as earthquakes, wear or crack propagation and is of enormous practical and technological impact 1 . According to Amontons and Coulomb, friction between solids is proportional to the normal force but independent of the contact areas. This intriguing result was explained by realizing that macroscopic objects touch at asperities that are deformed 2 . A different signature occurs when atomically flat surfaces slide against each other, as for example encountered in micro- or nanoelectromechanical systems or biological molecular motors 1 , 3 , 4 . At this nanoscale level the friction is no longer described by the Amontons-Coulomb law. For this, mathematical models were developed which are simple enough to be analysed analytically and yet should capture the salient features of the friction phenomena. As the sliding atomic layers are in contact with a thermal environment, dry friction phenomena are a problem of non-equilibrium statistical mechanics as well as nonlinear dynamics 5 . One of the most successful models describing friction phenomena is the Frenkel–Kontorova (FK) model 6 . It consists of a chain of coupled particles sliding over a static periodic potential, which mimics a rigid undeformable substrate. The analysis of this model has revealed highly nontrivial, nonlinear dynamics such as the creation of kinks and anti-kinks, which facilitate the sliding. For an infinite system with incommensurate lattice periodicities, this model displays the celebrated Aubry transition 7 , where the sliding motion becomes frictionless, due to the competition of different interaction energies in the atomic many-body system. In solid-state systems, this superlubric regime has been demonstrated in nanocontacts of graphene and gold surfaces 8 , 9 , 10 , 11 . In finite systems a smooth-sliding regime with finite dissipation exists instead of the superlubric phase. An Aubry-type transition with a symmetry breaking signature occurs, when the system changes from the smooth-sliding to stick-slip regime 12 , 13 . With the advent of atomic and friction force microscopes and microbalances it became possible to study individual sliding junctions at the atomistic level 14 , 15 , 16 , 17 . These techniques have identified many friction phenomena at the nanoscale, but many key aspects of friction dynamics are not yet well understood due to the lack of probes that characterize the contact surfaces directly and in situ 1 . Laser-cooled and trapped ions have been proposed to emulate nanocontacts and to provide insights into the dynamics of friction processes 18 , 19 , 20 . In this scenario, the FK model is emulated by a chain of ions trapped in the harmonic potential of an ion trap, which is overlapped with an optical standing wave mimicking the corrugation potential. Signatures of an Aubry-type transition, that is, fragmentation and symmetry breaking of the periodic configuration of the ion chain, have been predicted, when the optical lattice depth increases above a critical value 19 . Another signature of the Aubry transition is the existence of a soft mode, that is, a vibrational mode whose frequency approaches zero at the critical point and drives the transition from pinned to sliding motion 12 . Such behaviour is also predicted for finite chains of ions in an external optical corrugation potential 21 . Recently, Bylinskii et al . 22 succeeded in cooling up to five ions into an optical lattice and demonstrated the onset of reduced friction and dissipation in a coupled atomic many-body system. In this experiment, the symmetry breaking Aubry-type transition has been observed for the first time with microscopic resolution 23 , together with velocity effects in the stick-slip motion 24 . Another synthetic system, in which the microscopic processes of friction have become accessible, are colloidal monolayers driven across external optical potentials 25 . All these systems aim to emulate the classical FK model, where a layer of interacting particles slides over a fixed rigid corrugation potential. Here we report on the microscopic and spectroscopic control of a system without an externally imposed corrugation potential but consisting of two deformable back acting atomic layers, whose relative motion exhibits the phenomena of nanoscale friction. This system has similarities to a refined microscopic model of friction, which replaces the rigid substrate by a deformable substrate monolayer pinned to a solid body 26 . In particular, we investigate static friction under the influence of a structural defect and demonstrate physical properties of the system, which are common to finite incommensurate systems. We use a structural defect (kink) in an ion Coulomb crystal 27 to create a local disturbance in the ion spacing in the upper and lower chain, and demonstrate an Aubry-type transition when the interatomic spacing of the layers is varied. We show, using numerical calculations, that the soft mode frequency exhibits a power law scaling behaviour in the vicinity of the critical point, where the system becomes superlubric. The experimental spectroscopic measurements show a small reduction in the frequency of the soft mode. The non-vanishing frequency of the sliding mode is due to the finite temperature exciting nonlinear dynamics.", "role": "user" }, { "content": "In physics, it is useful to know as precisely as possible how friction phenomena arise—and not only on the macroscopic scale, as in mechanical engineering, but also on the microscopic scale, in areas such as biology and nanotechnology. It is quite difficult to study friction at the atom scale where non-linear effects prevail. Scientists from the QUEST Institute at the Physikalisch-Technische Bundesanstalt (PTB) have now presented a model system that allows the investigation of atomic-scale friction effects and friction dynamics that are similar to those taking place in proteins, DNA strands and other deformable nanocontacts. This model system consists of laser-cooled ions that arrange themselves in Coulomb crystals. The researchers have carried out experiments and numerical simulations and obtained new fundamental findings on friction processes in these atomic systems. They have now presented their results in the scientific journal Nature Communications. Most macroscopic objects have a rough texture from an atomic view point. Even if they feel smooth to the touch, they exhibit asperities. Strictly speaking, two objects never lie directly on top of each other, but only touch each other at these asperities. The atomic lattice structure therefore plays no role in this interaction. This is quite different for objects on the atomic scale, like nanomachines or biomolecules. \"Here, atomically smooth surfaces touch each other. The surface therefore also plays a role and must be taken into account in model calculations,\" explains PTB physicist Tanja E. Mehlstäubler. \"These models also explain fascinating phenomena such as superlubricity, where static friction becomes nearly nonexistent. It occurs when two crystalline surfaces are incommensurate to each other. This means that the ratio of the lattice spacings of the sliding surfaces is irrational. This leads to there being no place where the two surfaces are an exact match for each other.\" There are thus enough reasons to precisely measure friction at the nanoscale and to investigate its dynamics. A powerful instrument already exists for measuring friction, the friction force microscope. \"Direct experimental access to the dynamics of a friction system is nearly impossible. Model systems in which the atoms are easily controlled—both temporally and spatially— are therefore indispensable. This allows us to investigate them,\" explains Mehlstäubler. Such a system has now been presented by the scientists from PTB, together with their partners from Sydney. Ytterbium ions kept in an ion trap are cooled by means of lasers to such an extent (down to a few millikelvins) that they form a crystal consisting of two chains. The ions arrange themselves in such a way that the nearest neighbor is always as far away as possible. This structure is called a zigzag. Two such ion chains are a very accurate representation of the two partners of a friction process—and they are easy to observe very precisely. When ytterbium ions are irradiated with light whose frequency is close to their resonant frequency, they begin to fluoresce. \"We are thus able to observe the individual atomic particles in their motion through our imaging optics,\" adds Jan Kiethe, a physicist at PTB and the main author of the study. A transition between two different phases, which was caused by the presence of a structural lattice defect, has been observed and analyzed here. In one of the regimes, static friction is the main actor in the transport dynamics; in the other regime, it is sliding friction. The dynamics of the ion chains are comparable to those of molecule chains like DNA. In their study, the scientists have created a physical model system to investigate the complex dynamics of friction in 1-D, 2-D and 3-D systems with atomic precision. Moreover, this model system has paved the way for the investigation of transport phenomena in the quantum regime. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Friction in ordered atomistic layers plays a central role in various nanoscale systems ranging from nanomachines to biological systems. It governs transport properties, wear and dissipation. Defects and incommensurate lattice constants markedly change these properties. Recently, experimental systems have become accessible to probe the dynamics of nanofriction. Here, we present a model system consisting of laser-cooled ions in which nanofriction and transport processes in self-organized systems with back action can be studied with atomic resolution. We show that in a system with local defects resulting in incommensurate layers, there is a transition from sticking to sliding with Aubry-type signatures. We demonstrate spectroscopic measurements of the soft vibrational mode driving this transition and a measurement of the order parameter. We show numerically that both exhibit critical scaling near the transition point. Our studies demonstrate a simple, well-controlled system in which friction in self-organized structures can be studied from classical- to quantum-regimes. Introduction Dry friction is the resistance to the relative movement of two solid layers. It is responsible for many phenomena such as earthquakes, wear or crack propagation and is of enormous practical and technological impact 1 . According to Amontons and Coulomb, friction between solids is proportional to the normal force but independent of the contact areas. This intriguing result was explained by realizing that macroscopic objects touch at asperities that are deformed 2 . A different signature occurs when atomically flat surfaces slide against each other, as for example encountered in micro- or nanoelectromechanical systems or biological molecular motors 1 , 3 , 4 . At this nanoscale level the friction is no longer described by the Amontons-Coulomb law. For this, mathematical models were developed which are simple enough to be analysed analytically and yet should capture the salient features of the friction phenomena. As the sliding atomic layers are in contact with a thermal environment, dry friction phenomena are a problem of non-equilibrium statistical mechanics as well as nonlinear dynamics 5 . One of the most successful models describing friction phenomena is the Frenkel–Kontorova (FK) model 6 . It consists of a chain of coupled particles sliding over a static periodic potential, which mimics a rigid undeformable substrate. The analysis of this model has revealed highly nontrivial, nonlinear dynamics such as the creation of kinks and anti-kinks, which facilitate the sliding. For an infinite system with incommensurate lattice periodicities, this model displays the celebrated Aubry transition 7 , where the sliding motion becomes frictionless, due to the competition of different interaction energies in the atomic many-body system. In solid-state systems, this superlubric regime has been demonstrated in nanocontacts of graphene and gold surfaces 8 , 9 , 10 , 11 . In finite systems a smooth-sliding regime with finite dissipation exists instead of the superlubric phase. An Aubry-type transition with a symmetry breaking signature occurs, when the system changes from the smooth-sliding to stick-slip regime 12 , 13 . With the advent of atomic and friction force microscopes and microbalances it became possible to study individual sliding junctions at the atomistic level 14 , 15 , 16 , 17 . These techniques have identified many friction phenomena at the nanoscale, but many key aspects of friction dynamics are not yet well understood due to the lack of probes that characterize the contact surfaces directly and in situ 1 . Laser-cooled and trapped ions have been proposed to emulate nanocontacts and to provide insights into the dynamics of friction processes 18 , 19 , 20 . In this scenario, the FK model is emulated by a chain of ions trapped in the harmonic potential of an ion trap, which is overlapped with an optical standing wave mimicking the corrugation potential. Signatures of an Aubry-type transition, that is, fragmentation and symmetry breaking of the periodic configuration of the ion chain, have been predicted, when the optical lattice depth increases above a critical value 19 . Another signature of the Aubry transition is the existence of a soft mode, that is, a vibrational mode whose frequency approaches zero at the critical point and drives the transition from pinned to sliding motion 12 . Such behaviour is also predicted for finite chains of ions in an external optical corrugation potential 21 . Recently, Bylinskii et al . 22 succeeded in cooling up to five ions into an optical lattice and demonstrated the onset of reduced friction and dissipation in a coupled atomic many-body system. In this experiment, the symmetry breaking Aubry-type transition has been observed for the first time with microscopic resolution 23 , together with velocity effects in the stick-slip motion 24 . Another synthetic system, in which the microscopic processes of friction have become accessible, are colloidal monolayers driven across external optical potentials 25 . All these systems aim to emulate the classical FK model, where a layer of interacting particles slides over a fixed rigid corrugation potential. Here we report on the microscopic and spectroscopic control of a system without an externally imposed corrugation potential but consisting of two deformable back acting atomic layers, whose relative motion exhibits the phenomena of nanoscale friction. This system has similarities to a refined microscopic model of friction, which replaces the rigid substrate by a deformable substrate monolayer pinned to a solid body 26 . In particular, we investigate static friction under the influence of a structural defect and demonstrate physical properties of the system, which are common to finite incommensurate systems. We use a structural defect (kink) in an ion Coulomb crystal 27 to create a local disturbance in the ion spacing in the upper and lower chain, and demonstrate an Aubry-type transition when the interatomic spacing of the layers is varied. We show, using numerical calculations, that the soft mode frequency exhibits a power law scaling behaviour in the vicinity of the critical point, where the system becomes superlubric. The experimental spectroscopic measurements show a small reduction in the frequency of the soft mode. The non-vanishing frequency of the sliding mode is due to the finite temperature exciting nonlinear dynamics.<|im_end|> <|im_start|>assistant In physics, it is useful to know as precisely as possible how friction phenomena arise—and not only on the macroscopic scale, as in mechanical engineering, but also on the microscopic scale, in areas such as biology and nanotechnology. It is quite difficult to study friction at the atom scale where non-linear effects prevail. Scientists from the QUEST Institute at the Physikalisch-Technische Bundesanstalt (PTB) have now presented a model system that allows the investigation of atomic-scale friction effects and friction dynamics that are similar to those taking place in proteins, DNA strands and other deformable nanocontacts. This model system consists of laser-cooled ions that arrange themselves in Coulomb crystals. The researchers have carried out experiments and numerical simulations and obtained new fundamental findings on friction processes in these atomic systems. They have now presented their results in the scientific journal Nature Communications. Most macroscopic objects have a rough texture from an atomic view point. Even if they feel smooth to the touch, they exhibit asperities. Strictly speaking, two objects never lie directly on top of each other, but only touch each other at these asperities. The atomic lattice structure therefore plays no role in this interaction. This is quite different for objects on the atomic scale, like nanomachines or biomolecules. "Here, atomically smooth surfaces touch each other. The surface therefore also plays a role and must be taken into account in model calculations," explains PTB physicist Tanja E. Mehlstäubler. "These models also explain fascinating phenomena such as superlubricity, where static friction becomes nearly nonexistent. It occurs when two crystalline surfaces are incommensurate to each other. This means that the ratio of the lattice spacings of the sliding surfaces is irrational. This leads to there being no place where the two surfaces are an exact match for each other." There are thus enough reasons to precisely measure friction at the nanoscale and to investigate its dynamics. A powerful instrument already exists for measuring friction, the friction force microscope. "Direct experimental access to the dynamics of a friction system is nearly impossible. Model systems in which the atoms are easily controlled—both temporally and spatially— are therefore indispensable. This allows us to investigate them," explains Mehlstäubler. Such a system has now been presented by the scientists from PTB, together with their partners from Sydney. Ytterbium ions kept in an ion trap are cooled by means of lasers to such an extent (down to a few millikelvins) that they form a crystal consisting of two chains. The ions arrange themselves in such a way that the nearest neighbor is always as far away as possible. This structure is called a zigzag. Two such ion chains are a very accurate representation of the two partners of a friction process—and they are easy to observe very precisely. When ytterbium ions are irradiated with light whose frequency is close to their resonant frequency, they begin to fluoresce. "We are thus able to observe the individual atomic particles in their motion through our imaging optics," adds Jan Kiethe, a physicist at PTB and the main author of the study. A transition between two different phases, which was caused by the presence of a structural lattice defect, has been observed and analyzed here. In one of the regimes, static friction is the main actor in the transport dynamics; in the other regime, it is sliding friction. The dynamics of the ion chains are comparable to those of molecule chains like DNA. In their study, the scientists have created a physical model system to investigate the complex dynamics of friction in 1-D, 2-D and 3-D systems with atomic precision. Moreover, this model system has paved the way for the investigation of transport phenomena in the quantum regime. <|im_end|>

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2,062

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Towards exploring advanced applications of terahertz (THz) electromagnetic waves, great efforts are being applied to develop a compact and sensitive THz receiver. Here, we propose a simple coherent detection system using a single resonant tunnelling diode (RTD) oscillator through self-oscillating mixing with an RTD oscillator injection-locked by a carrier wave. Coherent detection is successfully demonstrated with an enhancement in the sensitivity of >20 dB compared to that of direct detection. As a proof of concept, we performed THz wireless communications using an RTD coherent receiver and transmitter. We achieved 30-Gbit/s real-time error-free transmission, which is the highest among all electronic systems without error correction to date. Our results show that the proposed system can reduce the size and power consumption of various THz systems including sensing, imaging and ranging, which would enable progress to be made in a wide range of fields in such as material science, medicine, chemistry, biology, physics, astronomy, security, robotics and motor vehicle. Introduction Terahertz (THz) electromagnetic waves, with frequencies ranging from around 0.1 THz to 10 THz, have gained attention as the frontiers of electronics and photonics and now the subject of an interdisciplinary area of research. Unique potential applications of THz waves, such as high-resolution sensing and broadband communications, have been developed 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Electronic devices are prime candidates to make compact and low-power-consumption systems towards expanding such THz technologies to various fields. Recently, THz diodes such as impact ionisation avalanche transit-time diodes 9 , tunnelling transit-time diodes 10 , Gunn diodes 11 , resonant tunnelling diodes (RTDs) 12 , 13 , 14 , Schottky barrier diodes 15 , 16 , 17 and heterostructure barrier varactor diodes 18 , and THz transistors such as heterojunction bipolar transistors 19 , 20 , high electron mobility transistors 21 , 22 , 23 , and silicon (Si) complementary metal–oxide–semiconductor devices 24 , 25 , 26 , 27 , 28 have been reported. Various studies have been conducted to enhance the output power of the transmitter (Tx) and the sensitivity of the receiver (Rx) in the THz band. However, operation in the THz band is still challenging owing to the limitation of the device speed even though integrated-circuit technologies have been scaled down. Coherent detection assisted by a local oscillator (LO) is an effective way to enhance the sensitivity of the Rx including an amplitude modulation (AM) system. For coherent detection, the frequency and phase of the LO should be aligned with those of the detected radio-frequency (RF) carrier signal or down-converted intermediate-frequency (IF) pilot signal 29 . One of the major methods for coherent detection at THz band is digital signal processing for the IF signal 30 . Another is synchronisation between the Tx and the Rx using a low-frequency reference signal with frequency multipliers for THz operations 31 . These systems are complicated and have a large power consumption. For developing a simple synchronisation system between the Tx and the Rx, we can apply an injection-locking phenomenon to a self-oscillating mixer (SOM) as the Rx 32 , which is a self-oscillating electronic device with a non-linear current–voltage ( I – V ) characteristic that also acts as a mixer to demodulate a data signal. When the received carrier frequency from the Tx is set within the locking range of the LO frequency, the SOM will be injection-locked to the carrier signal, and coherent detection can be achieved in a single device. To develop an injection-locked SOM for the THz band, a THz fundamental oscillator is required. Here, we propose to employ an RTD as the SOM 33 , 34 for the THz coherent detector, which provides the fundamental oscillation in the THz band. The RTD has a negative differential conductance (NDC) region attributable to the quantum tunnelling effect in the I – V characteristic 35 , 36 . Oscillation occurs when the NDC compensates for the loss of the resonant circuit. An oscillator using an RTD was first realised in 1984 with an 18-GHz oscillation frequency at 200 K 37 ; thereafter, the oscillation frequency was increased through an improved layer structure and a reduced parasitic capacitance. In 1991, 712-GHz oscillation was realised at room temperature 38 , and presently, a fundamental oscillation frequency of 1.98 THz, which is the highest oscillation frequency of any electronic single oscillator to date, has been achieved at room temperature 39 . In addition, RTDs are capable of acting as high-sensitivity direct detectors because they have a strong non-linearity in their I – V characteristics 40 . Thus, RTDs can work as both the Tx and Rx in a single device by adjusting the applied bias voltage. In recent years, various applications using THz RTDs have been reported, including wireless communications 41 , 42 , 43 , 44 , sensing 45 , and imaging 46 . Real-time error-free (bit-error rate (BER) < 10 −11 ) transmission at 9 Gbit/s in the 300-GHz band with a system using RTDs has previously been reported 43 . In that system, a direct detection was employed in the Rx. One of the factors limiting the data rate of wireless communications using an RTD is the Rx sensitivity. Therefore, if we enhance the sensitivity by coherent detection using an RTD as an injection-locked SOM, the data rate will be significantly increased. In this paper, we first describe the operating principles of the proposed THz coherent detection system. We then show that the detected power can be improved by introducing this system through an investigation using circuit simulations. Next, we discuss the fabrication of an RTD oscillator that oscillates in the 300-GHz band and demonstrate its operation by experiment. The results show coherent detection characteristics and sensitivity enhancement compared to conventional direct detection. Finally, we apply this system to THz wireless communications and demonstrate high-speed error-free data transmission. Operating principles In this section, we describe the operating principles of the coherent detection system. The configuration of the system is almost the", "role": "user" }, { "content": "An Osaka University research team has introduced a new terahertz detector that allows extremely rapid wireless data communication and highly sensitive radar by using a frequency range that has previously been very difficult to work with. Their approach combined sensitive electronics and a novel method for handling high frequencies to achieve the long-sought goal of using terahertz radiation for sending and receiving wireless data. The record 30 gigabit per second real-time error-free transmission they obtained may lead the way for next-generation (6G) cellular network technology. Wireless data is in great demand. Not only do mobile phones need high speeds to stream videos on the go, but some people living in rural areas rely entirely on wireless for their home broadband connections. Terahertz radiation—electromagnetic waves with frequencies around 1012 cycles per second—has long been tempting scientists and cell phone companies alike. The high frequency of terahertz radiation would allow more data to be transmitted per second, compared with the current standard of about 800 MHz. However, a practical terahertz receiver has remained elusive, for two main reasons. First, the electromagnetic oscillations are just too fast for conventional electronics to handle, and both the terahertz oscillator and detector have poor efficiency. Second, the thermal noise of the room-temperature detector obscures the received signals above. Now, researchers at Osaka University have invented a novel receiver that not only overcomes these obstacles, it also set the record for the fastest error-free real-time transmission speed to date. They used a special electronic component called a resonant tunneling diode. In contrast with normal electronics—for which the current always increases at larger voltages—in a resonant tunneling diode, there is a specific \"resonant\" voltage that yields the peak current. Thus, there exists a region in which the current actually falls with increasing voltage. This nonlinear behavior allows the scientists to synchronize the rapid received terahertz signals with an internal electronic oscillator in the device, and then separate the data from the carrier wave. In the end, the sensitivity was enhanced by a factor of 10,000. \"Among all electronic-based systems, ours achieved the highest error-free wireless transmission data rate,\" says first author Yousuke Nishida. Cell phone towers are not the only places you might find terahertz radiation in the future. \"This technology can be put to work in a wide range of applications, in addition to next-generation 6G wireless communication. These include spectroscopic sensing, non-destructive inspection, and high-resolution radar,\" adds corresponding author Masayuki Fujita. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Towards exploring advanced applications of terahertz (THz) electromagnetic waves, great efforts are being applied to develop a compact and sensitive THz receiver. Here, we propose a simple coherent detection system using a single resonant tunnelling diode (RTD) oscillator through self-oscillating mixing with an RTD oscillator injection-locked by a carrier wave. Coherent detection is successfully demonstrated with an enhancement in the sensitivity of >20 dB compared to that of direct detection. As a proof of concept, we performed THz wireless communications using an RTD coherent receiver and transmitter. We achieved 30-Gbit/s real-time error-free transmission, which is the highest among all electronic systems without error correction to date. Our results show that the proposed system can reduce the size and power consumption of various THz systems including sensing, imaging and ranging, which would enable progress to be made in a wide range of fields in such as material science, medicine, chemistry, biology, physics, astronomy, security, robotics and motor vehicle. Introduction Terahertz (THz) electromagnetic waves, with frequencies ranging from around 0.1 THz to 10 THz, have gained attention as the frontiers of electronics and photonics and now the subject of an interdisciplinary area of research. Unique potential applications of THz waves, such as high-resolution sensing and broadband communications, have been developed 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Electronic devices are prime candidates to make compact and low-power-consumption systems towards expanding such THz technologies to various fields. Recently, THz diodes such as impact ionisation avalanche transit-time diodes 9 , tunnelling transit-time diodes 10 , Gunn diodes 11 , resonant tunnelling diodes (RTDs) 12 , 13 , 14 , Schottky barrier diodes 15 , 16 , 17 and heterostructure barrier varactor diodes 18 , and THz transistors such as heterojunction bipolar transistors 19 , 20 , high electron mobility transistors 21 , 22 , 23 , and silicon (Si) complementary metal–oxide–semiconductor devices 24 , 25 , 26 , 27 , 28 have been reported. Various studies have been conducted to enhance the output power of the transmitter (Tx) and the sensitivity of the receiver (Rx) in the THz band. However, operation in the THz band is still challenging owing to the limitation of the device speed even though integrated-circuit technologies have been scaled down. Coherent detection assisted by a local oscillator (LO) is an effective way to enhance the sensitivity of the Rx including an amplitude modulation (AM) system. For coherent detection, the frequency and phase of the LO should be aligned with those of the detected radio-frequency (RF) carrier signal or down-converted intermediate-frequency (IF) pilot signal 29 . One of the major methods for coherent detection at THz band is digital signal processing for the IF signal 30 . Another is synchronisation between the Tx and the Rx using a low-frequency reference signal with frequency multipliers for THz operations 31 . These systems are complicated and have a large power consumption. For developing a simple synchronisation system between the Tx and the Rx, we can apply an injection-locking phenomenon to a self-oscillating mixer (SOM) as the Rx 32 , which is a self-oscillating electronic device with a non-linear current–voltage ( I – V ) characteristic that also acts as a mixer to demodulate a data signal. When the received carrier frequency from the Tx is set within the locking range of the LO frequency, the SOM will be injection-locked to the carrier signal, and coherent detection can be achieved in a single device. To develop an injection-locked SOM for the THz band, a THz fundamental oscillator is required. Here, we propose to employ an RTD as the SOM 33 , 34 for the THz coherent detector, which provides the fundamental oscillation in the THz band. The RTD has a negative differential conductance (NDC) region attributable to the quantum tunnelling effect in the I – V characteristic 35 , 36 . Oscillation occurs when the NDC compensates for the loss of the resonant circuit. An oscillator using an RTD was first realised in 1984 with an 18-GHz oscillation frequency at 200 K 37 ; thereafter, the oscillation frequency was increased through an improved layer structure and a reduced parasitic capacitance. In 1991, 712-GHz oscillation was realised at room temperature 38 , and presently, a fundamental oscillation frequency of 1.98 THz, which is the highest oscillation frequency of any electronic single oscillator to date, has been achieved at room temperature 39 . In addition, RTDs are capable of acting as high-sensitivity direct detectors because they have a strong non-linearity in their I – V characteristics 40 . Thus, RTDs can work as both the Tx and Rx in a single device by adjusting the applied bias voltage. In recent years, various applications using THz RTDs have been reported, including wireless communications 41 , 42 , 43 , 44 , sensing 45 , and imaging 46 . Real-time error-free (bit-error rate (BER) < 10 −11 ) transmission at 9 Gbit/s in the 300-GHz band with a system using RTDs has previously been reported 43 . In that system, a direct detection was employed in the Rx. One of the factors limiting the data rate of wireless communications using an RTD is the Rx sensitivity. Therefore, if we enhance the sensitivity by coherent detection using an RTD as an injection-locked SOM, the data rate will be significantly increased. In this paper, we first describe the operating principles of the proposed THz coherent detection system. We then show that the detected power can be improved by introducing this system through an investigation using circuit simulations. Next, we discuss the fabrication of an RTD oscillator that oscillates in the 300-GHz band and demonstrate its operation by experiment. The results show coherent detection characteristics and sensitivity enhancement compared to conventional direct detection. Finally, we apply this system to THz wireless communications and demonstrate high-speed error-free data transmission. Operating principles In this section, we describe the operating principles of the coherent detection system. The configuration of the system is almost the<|im_end|> <|im_start|>assistant An Osaka University research team has introduced a new terahertz detector that allows extremely rapid wireless data communication and highly sensitive radar by using a frequency range that has previously been very difficult to work with. Their approach combined sensitive electronics and a novel method for handling high frequencies to achieve the long-sought goal of using terahertz radiation for sending and receiving wireless data. The record 30 gigabit per second real-time error-free transmission they obtained may lead the way for next-generation (6G) cellular network technology. Wireless data is in great demand. Not only do mobile phones need high speeds to stream videos on the go, but some people living in rural areas rely entirely on wireless for their home broadband connections. Terahertz radiation—electromagnetic waves with frequencies around 1012 cycles per second—has long been tempting scientists and cell phone companies alike. The high frequency of terahertz radiation would allow more data to be transmitted per second, compared with the current standard of about 800 MHz. However, a practical terahertz receiver has remained elusive, for two main reasons. First, the electromagnetic oscillations are just too fast for conventional electronics to handle, and both the terahertz oscillator and detector have poor efficiency. Second, the thermal noise of the room-temperature detector obscures the received signals above. Now, researchers at Osaka University have invented a novel receiver that not only overcomes these obstacles, it also set the record for the fastest error-free real-time transmission speed to date. They used a special electronic component called a resonant tunneling diode. In contrast with normal electronics—for which the current always increases at larger voltages—in a resonant tunneling diode, there is a specific "resonant" voltage that yields the peak current. Thus, there exists a region in which the current actually falls with increasing voltage. This nonlinear behavior allows the scientists to synchronize the rapid received terahertz signals with an internal electronic oscillator in the device, and then separate the data from the carrier wave. In the end, the sensitivity was enhanced by a factor of 10,000. "Among all electronic-based systems, ours achieved the highest error-free wireless transmission data rate," says first author Yousuke Nishida. Cell phone towers are not the only places you might find terahertz radiation in the future. "This technology can be put to work in a wide range of applications, in addition to next-generation 6G wireless communication. These include spectroscopic sensing, non-destructive inspection, and high-resolution radar," adds corresponding author Masayuki Fujita. <|im_end|>

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264, 8389, 41264, 6929, 685, 320, 45, 5744, 8, 5654, 71526, 311, 279, 31228, 11716, 77, 6427, 2515, 304, 279, 358, 1389, 650, 29683, 220, 1758, 1174, 220, 1927, 662, 56736, 67184, 13980, 994, 279, 452, 5744, 14573, 988, 369, 279, 4814, 315, 279, 29280, 519, 16622, 13, 1556, 84741, 1701, 459, 10860, 35, 574, 1176, 41193, 304, 220, 3753, 19, 449, 459, 220, 972, 12279, 11732, 43524, 367, 11900, 520, 220, 1049, 735, 220, 1806, 2652, 46095, 11, 279, 43524, 367, 11900, 574, 7319, 1555, 459, 13241, 6324, 6070, 323, 264, 11293, 33403, 49086, 99758, 685, 13, 763, 220, 2550, 16, 11, 220, 22708, 12279, 11732, 43524, 367, 574, 41193, 520, 3130, 9499, 220, 1987, 1174, 323, 50801, 11, 264, 16188, 43524, 367, 11900, 315, 220, 16, 13, 3264, 4534, 89, 11, 902, 374, 279, 8592, 43524, 367, 11900, 315, 904, 14683, 3254, 84741, 311, 2457, 11, 706, 1027, 17427, 520, 3130, 9499, 220, 2137, 662, 763, 5369, 11, 10860, 68050, 527, 13171, 315, 15718, 439, 1579, 1355, 48937, 2167, 69087, 1606, 814, 617, 264, 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1,896

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Acentrosomal meiosis in oocytes represents a gametogenic challenge, requiring spindle bipolarization without predefined bipolar cues. While much is known about the structures that promote acentrosomal microtubule nucleation, less is known about the structures that mediate spindle bipolarization in mammalian oocytes. Here, we show that in mouse oocytes, kinetochores are required for spindle bipolarization in meiosis I. This process is promoted by oocyte-specific, microtubule-independent enrichment of the antiparallel microtubule crosslinker Prc1 at kinetochores via the Ndc80 complex. In contrast, in meiosis II, cytoplasm that contains upregulated factors including Prc1 supports kinetochore-independent pathways for spindle bipolarization. The kinetochore-dependent mode of spindle bipolarization is required for meiosis I to prevent chromosome segregation errors. Human oocytes, where spindle bipolarization is reportedly error prone, exhibit no detectable kinetochore enrichment of Prc1. This study reveals an oocyte-specific function of kinetochores in acentrosomal spindle bipolarization in mice, and provides insights into the error-prone nature of human oocytes. Introduction Bipolar spindle formation is a prerequisite for chromosome segregation. In animal somatic cells, the two centrosomes act as major microtubule nucleation sites and provide spatial cues for the establishment of spindle bipolarity. However, in oocytes of many species, including humans, the meiotic bipolar spindle forms with no centrosomes 1 , 2 , 3 , 4 , 5 , 6 , 7 . The acentrosomal nature of the spindle has been implicated in error-prone chromosome segregation in oocytes 2 , 8 , 9 , 10 . Live imaging analysis of human oocytes has shown that the failure to establish spindle bipolarity precedes a majority of chromosome segregation errors in meiosis I (MI) 11 , 12 . Chromosome segregation errors in oocytes, which are more predominant in MI than in meiosis II (MII), cause aneuploidy in the resulting eggs, which is the leading cause of pregnancy loss and several congenital disease, such as Down syndrome 13 , 14 . Microtubule nucleation promoted by RanGTP is a key pathway in the formation of the bipolar spindle in acentrosomal cells. This pathway is activated around chromosomes, and is required for efficient acentrosomal spindle assembly in fly, frog, mouse, and human oocytes 11 , 15 , 16 , 17 , 18 . In mouse oocytes, many acentriolar microtubule organizing centers (MTOCs), which are activated around chromosomes through well-studied pathways including the RanGTP pathway, act as major sites for microtubule nucleation 16 , 17 , 19 , 20 , 21 , 22 , 23 . While much is known about the structures that function as scaffolds to promote microtubule nucleation, less is known about the structures that promote spindle bipolarization. The balanced activities of microtubule regulators, such as the plus-end-directed motor Kif11 (also known as kinesin-5 and Eg5), the minus-end-directed motor HSET (kinesin-14), the bundle stabilizer HURP, and the minus-end clustering factor NuMA, that act on microtubules are critical for spindle bipolarization 17 , 19 , 21 , 24 , 25 , 26 , 27 . However, scaffolds that primarily enrich spindle bipolarization factors independently of microtubules have not been identified. The kinetochore is a macromolecular structure that links chromosomes to microtubules through multiple protein complexes 28 , 29 , 30 . The primary microtubule receptor at the kinetochore is the Ndc80 complex, which is composed of Ndc80 (also known as Hec1), Nuf2, Spc24, and Spc25 31 , 32 . Ndc80 and Nuf2 mediate microtubule attachment through their microtubule-binding domains and are linked to the kinetochore scaffold through Spc24 and Spc25 33 , 34 , 35 . Several lines of evidence suggest that kinetochores contribute to spindle bipolarity. In centrosomal mitotic cells, the loss of kinetochore–microtubule attachments can cause defects in spindle bipolarity, which are pronounced when centrosomal functions are perturbed 36 , 37 , 38 , 39 . In mouse oocytes, mutations and knockdowns that cause defects in kinetochore–microtubule attachment, including knockdown of the Ndc80 complex, can perturb spindle bipolarity 40 , 41 , 42 , 43 . Based on these previous findings, it is generally thought that forces mediated by kinetochore–microtubule attachment contribute to spindle bipolarity. Whether kinetochores play a role independent of microtubule attachment in spindle bipolarization is unknown. It is well established that kinetochores are dispensable for acentrosomal spindle formation in frog and mouse MII oocytes, because DNA-coated beads can form a bipolar spindle in these cells 44 , 45 , 46 . It is unknown, however, whether kinetochores are required for spindle formation in MI, which may be fundamentally different from that in MII. Consistent with this possibility, MI and MII spindles exhibit markedly different sensitivities to RanGTP inhibition in mouse oocytes 16 . Moreover, spindle formation in MI proceeds slowly (4–6 h in mice and ~16 h in humans), whereas spindle formation in MII is rapid (<1 h in mice and ~3 h in humans) 11 , 16 , 17 . Several microtubule regulators such as HSET, Kif11, Tpx2, Miss, and the phosphorylation of Tacc3 are upregulated in MII 26 , 27 , 47 , 48 , which may contribute to rapid spindle bipolarization. Consistent with this idea, HSET overexpression accelerates spindle bipolarization in MI 26 , 27 . The full repertoire of factors that contribute to the difference in the kinetics of spindle formation between MI and MII is unknown. Here, we identify the kinetochore as a structure that promotes error-free spindle bipolarization during MI in mouse oocytes. Mouse oocytes lacking the kinetochore Ndc80 fail to form a bipolar spindle in MI, but not in MII. We find that the Ndc80 complex recruits the antiparallel microtubule crosslinker Prc1 49 , 50 to kinetochores, independently of its microtubule attachment, in an oocyte-specific manner. The Prc1-rich kinetochore microenvironment is required for slow-mode spindle bipolarization in MI. In contrast, MII spindles rapidly form a bipolar-shaped spindle largely independently of Ndc80, with support from the cytoplasmic environment that contain upregulated factors including Prc1. The kinetochore-dependent mode of spindle bipolarization is required for error-free chromosome segregation in MI. In contrast to mouse oocytes, human oocytes, which have been reported to undergo error-prone spindle bipolarization 11 , 12 , exhibit little enrichment of", "role": "user" }, { "content": "The error-free division of mouse oocytes—the precursors of eggs—needs kinetochores that are rich in a specific microtubule crosslinker, RIKEN researchers have discovered. This finding could explain why the division of human oocytes often gives rise to errors, and thus inform efforts to help prevent pregnancy loss and congenital disorders. Human oocytes are more susceptible to errors during the segregation of genetic material compared to the oocytes of other mammals. These errors can result in miscarriages and congenital disorders such as Down syndrome. When a cell starts dividing, it forms spindles—the microtubule-based machinery for dividing the genetic material in a cell. However, oocytes are unique among cells in that their spindles lack centrosomes—the main apparatus for organizing microtubules in a cell. Thus, oocytes must have a different way for assembling spindles, but much remains unknown about this mechanism. Now, Tomoya Kitajima of the RIKEN Center for Biosystems Dynamics Research and his co-workers have found that mice need kinetochores (the main point of attachment for spindle microtubules) rich in the microtubule crosslinker Prc1 to achieve error-free formation of spindles during oocyte cell division. By drawing on their experience of high-resolution live imaging of chromosome dynamics in mouse oocytes, Kitajima and his colleagues carefully quantified spindle bipolarity in three dimensions in live oocytes. They found that while microtubules polymerize in oocytes that lack functional kinetochores, they do not go on to form spindles. The researchers also discovered that kinetochores recruit Prc1 (Fig. 1), which links microtubules and is thus essential for the efficient assembly of spindles. Significantly, the team found that kinetochores in humans are not rich in Prc1. This difference between mouse and human oocytes could go a long way to explaining why oocyte division in humans is more error prone than that in mice. \"This finding gives key insights into why female meiosis is error prone in humans,\" says Kitajima. \"Failure of spindle assembly is a hallmark of oocytes that have errors in chromosome segregation, which in turn gives rise to eggs having an abnormal number of chromosomes—a major cause of pregnancy loss and congenital disease and thus a critical problem for reproductive health.\" Kitajima did not anticipate this result. \"This finding came as a surprise as we never suspected that a kinetochore protein specific to female meiosis existed,\" says Kitajima. The researchers are now investigating the molecular mechanisms for how Prc1-rich kinetochores sort microtubules for spindle assembly. They will also look for molecules that enhance Prc1 recruitment to kinetochores in mice. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Acentrosomal meiosis in oocytes represents a gametogenic challenge, requiring spindle bipolarization without predefined bipolar cues. While much is known about the structures that promote acentrosomal microtubule nucleation, less is known about the structures that mediate spindle bipolarization in mammalian oocytes. Here, we show that in mouse oocytes, kinetochores are required for spindle bipolarization in meiosis I. This process is promoted by oocyte-specific, microtubule-independent enrichment of the antiparallel microtubule crosslinker Prc1 at kinetochores via the Ndc80 complex. In contrast, in meiosis II, cytoplasm that contains upregulated factors including Prc1 supports kinetochore-independent pathways for spindle bipolarization. The kinetochore-dependent mode of spindle bipolarization is required for meiosis I to prevent chromosome segregation errors. Human oocytes, where spindle bipolarization is reportedly error prone, exhibit no detectable kinetochore enrichment of Prc1. This study reveals an oocyte-specific function of kinetochores in acentrosomal spindle bipolarization in mice, and provides insights into the error-prone nature of human oocytes. Introduction Bipolar spindle formation is a prerequisite for chromosome segregation. In animal somatic cells, the two centrosomes act as major microtubule nucleation sites and provide spatial cues for the establishment of spindle bipolarity. However, in oocytes of many species, including humans, the meiotic bipolar spindle forms with no centrosomes 1 , 2 , 3 , 4 , 5 , 6 , 7 . The acentrosomal nature of the spindle has been implicated in error-prone chromosome segregation in oocytes 2 , 8 , 9 , 10 . Live imaging analysis of human oocytes has shown that the failure to establish spindle bipolarity precedes a majority of chromosome segregation errors in meiosis I (MI) 11 , 12 . Chromosome segregation errors in oocytes, which are more predominant in MI than in meiosis II (MII), cause aneuploidy in the resulting eggs, which is the leading cause of pregnancy loss and several congenital disease, such as Down syndrome 13 , 14 . Microtubule nucleation promoted by RanGTP is a key pathway in the formation of the bipolar spindle in acentrosomal cells. This pathway is activated around chromosomes, and is required for efficient acentrosomal spindle assembly in fly, frog, mouse, and human oocytes 11 , 15 , 16 , 17 , 18 . In mouse oocytes, many acentriolar microtubule organizing centers (MTOCs), which are activated around chromosomes through well-studied pathways including the RanGTP pathway, act as major sites for microtubule nucleation 16 , 17 , 19 , 20 , 21 , 22 , 23 . While much is known about the structures that function as scaffolds to promote microtubule nucleation, less is known about the structures that promote spindle bipolarization. The balanced activities of microtubule regulators, such as the plus-end-directed motor Kif11 (also known as kinesin-5 and Eg5), the minus-end-directed motor HSET (kinesin-14), the bundle stabilizer HURP, and the minus-end clustering factor NuMA, that act on microtubules are critical for spindle bipolarization 17 , 19 , 21 , 24 , 25 , 26 , 27 . However, scaffolds that primarily enrich spindle bipolarization factors independently of microtubules have not been identified. The kinetochore is a macromolecular structure that links chromosomes to microtubules through multiple protein complexes 28 , 29 , 30 . The primary microtubule receptor at the kinetochore is the Ndc80 complex, which is composed of Ndc80 (also known as Hec1), Nuf2, Spc24, and Spc25 31 , 32 . Ndc80 and Nuf2 mediate microtubule attachment through their microtubule-binding domains and are linked to the kinetochore scaffold through Spc24 and Spc25 33 , 34 , 35 . Several lines of evidence suggest that kinetochores contribute to spindle bipolarity. In centrosomal mitotic cells, the loss of kinetochore–microtubule attachments can cause defects in spindle bipolarity, which are pronounced when centrosomal functions are perturbed 36 , 37 , 38 , 39 . In mouse oocytes, mutations and knockdowns that cause defects in kinetochore–microtubule attachment, including knockdown of the Ndc80 complex, can perturb spindle bipolarity 40 , 41 , 42 , 43 . Based on these previous findings, it is generally thought that forces mediated by kinetochore–microtubule attachment contribute to spindle bipolarity. Whether kinetochores play a role independent of microtubule attachment in spindle bipolarization is unknown. It is well established that kinetochores are dispensable for acentrosomal spindle formation in frog and mouse MII oocytes, because DNA-coated beads can form a bipolar spindle in these cells 44 , 45 , 46 . It is unknown, however, whether kinetochores are required for spindle formation in MI, which may be fundamentally different from that in MII. Consistent with this possibility, MI and MII spindles exhibit markedly different sensitivities to RanGTP inhibition in mouse oocytes 16 . Moreover, spindle formation in MI proceeds slowly (4–6 h in mice and ~16 h in humans), whereas spindle formation in MII is rapid (<1 h in mice and ~3 h in humans) 11 , 16 , 17 . Several microtubule regulators such as HSET, Kif11, Tpx2, Miss, and the phosphorylation of Tacc3 are upregulated in MII 26 , 27 , 47 , 48 , which may contribute to rapid spindle bipolarization. Consistent with this idea, HSET overexpression accelerates spindle bipolarization in MI 26 , 27 . The full repertoire of factors that contribute to the difference in the kinetics of spindle formation between MI and MII is unknown. Here, we identify the kinetochore as a structure that promotes error-free spindle bipolarization during MI in mouse oocytes. Mouse oocytes lacking the kinetochore Ndc80 fail to form a bipolar spindle in MI, but not in MII. We find that the Ndc80 complex recruits the antiparallel microtubule crosslinker Prc1 49 , 50 to kinetochores, independently of its microtubule attachment, in an oocyte-specific manner. The Prc1-rich kinetochore microenvironment is required for slow-mode spindle bipolarization in MI. In contrast, MII spindles rapidly form a bipolar-shaped spindle largely independently of Ndc80, with support from the cytoplasmic environment that contain upregulated factors including Prc1. The kinetochore-dependent mode of spindle bipolarization is required for error-free chromosome segregation in MI. In contrast to mouse oocytes, human oocytes, which have been reported to undergo error-prone spindle bipolarization 11 , 12 , exhibit little enrichment of<|im_end|> <|im_start|>assistant The error-free division of mouse oocytes—the precursors of eggs—needs kinetochores that are rich in a specific microtubule crosslinker, RIKEN researchers have discovered. This finding could explain why the division of human oocytes often gives rise to errors, and thus inform efforts to help prevent pregnancy loss and congenital disorders. Human oocytes are more susceptible to errors during the segregation of genetic material compared to the oocytes of other mammals. These errors can result in miscarriages and congenital disorders such as Down syndrome. When a cell starts dividing, it forms spindles—the microtubule-based machinery for dividing the genetic material in a cell. However, oocytes are unique among cells in that their spindles lack centrosomes—the main apparatus for organizing microtubules in a cell. Thus, oocytes must have a different way for assembling spindles, but much remains unknown about this mechanism. Now, Tomoya Kitajima of the RIKEN Center for Biosystems Dynamics Research and his co-workers have found that mice need kinetochores (the main point of attachment for spindle microtubules) rich in the microtubule crosslinker Prc1 to achieve error-free formation of spindles during oocyte cell division. By drawing on their experience of high-resolution live imaging of chromosome dynamics in mouse oocytes, Kitajima and his colleagues carefully quantified spindle bipolarity in three dimensions in live oocytes. They found that while microtubules polymerize in oocytes that lack functional kinetochores, they do not go on to form spindles. The researchers also discovered that kinetochores recruit Prc1 (Fig. 1), which links microtubules and is thus essential for the efficient assembly of spindles. Significantly, the team found that kinetochores in humans are not rich in Prc1. This difference between mouse and human oocytes could go a long way to explaining why oocyte division in humans is more error prone than that in mice. "This finding gives key insights into why female meiosis is error prone in humans," says Kitajima. "Failure of spindle assembly is a hallmark of oocytes that have errors in chromosome segregation, which in turn gives rise to eggs having an abnormal number of chromosomes—a major cause of pregnancy loss and congenital disease and thus a critical problem for reproductive health." Kitajima did not anticipate this result. "This finding came as a surprise as we never suspected that a kinetochore protein specific to female meiosis existed," says Kitajima. The researchers are now investigating the molecular mechanisms for how Prc1-rich kinetochores sort microtubules for spindle assembly. They will also look for molecules that enhance Prc1 recruitment to kinetochores in mice. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultrahigh field 7-T magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug naive (34.6% of the sample) or minimally medicated first episode patients with schizophreniform disorder, schizophrenia, and schizoaffective disorder. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response ( F = 4.86, P = 0.017), while higher glutamate was associated with more severe functional impairment ( F = 5.33, P = 0.008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favorable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis. Introduction Early treatment response has been identified as one of the most robust predictors of longer-term clinical outcomes in schizophrenia [ 1 ]. In particular, lack of early response appears to be strongly indicative of subsequent nonresponse [ 2 ], failure to achieve remission [ 3 ], and higher rates of treatment discontinuation [ 4 ]. Approximately one third of patients with schizophrenia are considered to be treatment resistant [ 5 ], with the majority of these (23–34%) failing to respond appreciably to dopamine-blocking antipsychotic medications from their first episode of psychosis (FEP) [ 6 , 7 ]. Nevertheless, the neurochemical mechanism of early response is poorly understood, precluding efforts to prevent or reduce the rates of treatment failure and persistent disability. The FEP is characterized by a relative state of glutamatergic excess [ 8 , 9 ]. Elevated anterior cingulate cortex (ACC) glutamate has been found to be inversely correlated with striatal dopamine synthesis in patients with FEP [ 10 ]. Given that the elevated striatal dopamine synthesis relates to better treatment response [ 11 ] in psychosis, the observed glutamatergic excess has been considered to be an index of reduced treatment responsiveness in psychosis [ 12 ]. Elevated ACC glutamate has been directly associated with lack of remission in certain samples of chronic [ 13 , 14 , 15 ] or first-episode schizophrenia [ 16 , 17 ] [UK sample], but this has not been a consistent observation. For example, in a sample of patients with established schizophrenia, Iwata et al. [ 18 ] reported no difference in dorsal ACC glutamate levels between treatment responsive and resistant groups. Similarly, the samples in 2 out of 3 sites in another study showed no glutamate excess in patients with FEP who did not achieve remission by 1 month [ 17 ]. Nevertheless, relative glutamatergic excess appears to be specific to early stages of illness [ 8 ], and relates to more severe symptoms at presentation [ 17 ], as well as gray matter decline [ 19 ], cognitive [ 20 ], and functional [ 16 , 17 ] impairments. The lack of dopamine elevation seen in some patients may explain their lack of response to dopamine blocking medications. Glutathione (GSH), the brain’s most prominent intracellular antioxidant, has been suspected to play a key protective role in free-radical-mediated damage to neurons [ 21 ], giving rise to the redox dysregulation hypothesis of schizophrenia [ 22 ]. Magnetic resonance spectroscopy (MRS) studies have found a small but significant GSH deficit in the ACC in patients with schizophrenia [ 23 ], indicating the presence of subgroups of patients with different redox profiles [ 24 ]. The most prominent reduction in GSH seems to occur particularly in patients with persistent residual symptoms, indicating that low levels of GSH may be associated with poor response to antipsychotics [ 25 ]. Furthermore, N-acetyl-cysteine (NAC), a precursor of GSH, appears to increase the rate of symptomatic response when used as an adjunct to antipsychotics [ 26 ]. Glutamate is a precursor of GSH while GSH acts as a neuronal reservoir for glutamate synthesis [ 27 ]. As a result, when neuroglial metabolic integrity is intact, glutamate and GSH levels remain tightly linked in the brain. Glutamatergic excess can result in neurotoxic oxidative stress [ 28 ], while a concomitant elevation of GSH may provide a neuroprotective “gate-keeping” effect [ 29 ], thus a strong covariance may be a marker of a healthy state. Nevertheless, repeated or prolonged exposure to excess glutamate can deplete GSH levels [ 30 ]. Furthermore, the GSH-glutamate homeostasis may also be disrupted in patients with schizophrenia due to deficiencies in GSH synthesis [ 31 ], leading to reduced GSH-glutamate covariance in patients with FEP. In this study, we use ultrahigh field 7T MRS for the first time to test the relative contribution of ACC GSH deficiency and glutamatergic excess in predicting early treatment response in FEP. Given the gatekeeper role of GSH in tackling oxidative stress [ 31 ], we expected GSH to be a more critical determinant of early treatment response in FEP. We hypothesized that FEP patients with higher GSH levels would demonstrate faster symptom reduction upon starting antipsychotic treatment (hypothesis 1). As not all patients with FEP will be able to increase GSH in accordance with glutamate levels, we expected a reduction in the strength of correlation between the GSH and glutamate levels in patients compared with healthy controls (hypothesis 2). Furthermore, in light of the excitotoxic theory of acute schizophrenia [ 32 ], we expected both reduced GSH and increased glutamate levels to predict impaired Social and Occupational Functioning at the onset of illness (hypothesis 3). Methods Participants The sample consisted of 37 new referrals to the PEPP (Prevention and", "role": "user" }, { "content": "Once patients with psychosis start treatment, some get better in weeks while it can take months for others. Seeking to understand and influence this disparity, Schulich School of Medicine & Dentistry professor Dr. Lena Palaniyappan and his team are exploring specific chemicals in the brain with the aim of speeding up the time it takes a patient to respond to medication. Past research has shown that patients who experience their first episode of psychosis and respond early to treatment have better overall outcomes. This includes improved symptoms and daily functioning as well as spending less time in hospital. The research team from Schulich and Lawson Health Research Institute looked specifically at antioxidant levels in the brain and found that these chemicals which rid the body of normal metabolic biproducts, called free radicals, may improve outcomes of early intervention in psychosis. They looked specifically at an area of the brain called cingulate cortex which is well connected to a network of regions that play a major role in generating symptoms of psychosis. The findings showed that patients with higher levels of an antioxidant called glutathione responded more quickly to medication for psychosis and had improved outcomes. They estimated that a 10 percent increase in antioxidants could lead to a reduction in length of hospital stay by at least seven days. \"This study demonstrates that if we can find a way to boost the amount of antioxidants in the brain, we might be able to help patients transition out of hospital more quickly, reduce their suffering more quickly and help them return earlier to their work and studies,\" said Palaniyappan, the Tanna Schulich Endowed Chair in Neuroscience and Mental Health at Western. Antioxidant levels in the brain vary naturally from person to person and those variations can be attributed to lifestyle choices like exercise and diet. There are also ways to pharmaceutically boost these levels. A supplement called N-Acetyl Cysteine (NAC) as well as broccoli extracts can increase the brain's antioxidants if given over a long period of time. Palaniyappan and his team in collaboration with Dr. Jean Theberge at Lawson Imaging used high-field MRI imaging to examine antioxidant levels in the brains of 37 new patients to the Prevention and Early Intervention for Psychoses Program (PEPP) at London Health Sciences Centre. Antioxidant levels were studied prior to beginning treatment for psychosis and followed up for six months post-treatment. The study, \"Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate,\" was published in Nature Molecular Psychiatry. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultrahigh field 7-T magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug naive (34.6% of the sample) or minimally medicated first episode patients with schizophreniform disorder, schizophrenia, and schizoaffective disorder. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response ( F = 4.86, P = 0.017), while higher glutamate was associated with more severe functional impairment ( F = 5.33, P = 0.008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favorable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis. Introduction Early treatment response has been identified as one of the most robust predictors of longer-term clinical outcomes in schizophrenia [ 1 ]. In particular, lack of early response appears to be strongly indicative of subsequent nonresponse [ 2 ], failure to achieve remission [ 3 ], and higher rates of treatment discontinuation [ 4 ]. Approximately one third of patients with schizophrenia are considered to be treatment resistant [ 5 ], with the majority of these (23–34%) failing to respond appreciably to dopamine-blocking antipsychotic medications from their first episode of psychosis (FEP) [ 6 , 7 ]. Nevertheless, the neurochemical mechanism of early response is poorly understood, precluding efforts to prevent or reduce the rates of treatment failure and persistent disability. The FEP is characterized by a relative state of glutamatergic excess [ 8 , 9 ]. Elevated anterior cingulate cortex (ACC) glutamate has been found to be inversely correlated with striatal dopamine synthesis in patients with FEP [ 10 ]. Given that the elevated striatal dopamine synthesis relates to better treatment response [ 11 ] in psychosis, the observed glutamatergic excess has been considered to be an index of reduced treatment responsiveness in psychosis [ 12 ]. Elevated ACC glutamate has been directly associated with lack of remission in certain samples of chronic [ 13 , 14 , 15 ] or first-episode schizophrenia [ 16 , 17 ] [UK sample], but this has not been a consistent observation. For example, in a sample of patients with established schizophrenia, Iwata et al. [ 18 ] reported no difference in dorsal ACC glutamate levels between treatment responsive and resistant groups. Similarly, the samples in 2 out of 3 sites in another study showed no glutamate excess in patients with FEP who did not achieve remission by 1 month [ 17 ]. Nevertheless, relative glutamatergic excess appears to be specific to early stages of illness [ 8 ], and relates to more severe symptoms at presentation [ 17 ], as well as gray matter decline [ 19 ], cognitive [ 20 ], and functional [ 16 , 17 ] impairments. The lack of dopamine elevation seen in some patients may explain their lack of response to dopamine blocking medications. Glutathione (GSH), the brain’s most prominent intracellular antioxidant, has been suspected to play a key protective role in free-radical-mediated damage to neurons [ 21 ], giving rise to the redox dysregulation hypothesis of schizophrenia [ 22 ]. Magnetic resonance spectroscopy (MRS) studies have found a small but significant GSH deficit in the ACC in patients with schizophrenia [ 23 ], indicating the presence of subgroups of patients with different redox profiles [ 24 ]. The most prominent reduction in GSH seems to occur particularly in patients with persistent residual symptoms, indicating that low levels of GSH may be associated with poor response to antipsychotics [ 25 ]. Furthermore, N-acetyl-cysteine (NAC), a precursor of GSH, appears to increase the rate of symptomatic response when used as an adjunct to antipsychotics [ 26 ]. Glutamate is a precursor of GSH while GSH acts as a neuronal reservoir for glutamate synthesis [ 27 ]. As a result, when neuroglial metabolic integrity is intact, glutamate and GSH levels remain tightly linked in the brain. Glutamatergic excess can result in neurotoxic oxidative stress [ 28 ], while a concomitant elevation of GSH may provide a neuroprotective “gate-keeping” effect [ 29 ], thus a strong covariance may be a marker of a healthy state. Nevertheless, repeated or prolonged exposure to excess glutamate can deplete GSH levels [ 30 ]. Furthermore, the GSH-glutamate homeostasis may also be disrupted in patients with schizophrenia due to deficiencies in GSH synthesis [ 31 ], leading to reduced GSH-glutamate covariance in patients with FEP. In this study, we use ultrahigh field 7T MRS for the first time to test the relative contribution of ACC GSH deficiency and glutamatergic excess in predicting early treatment response in FEP. Given the gatekeeper role of GSH in tackling oxidative stress [ 31 ], we expected GSH to be a more critical determinant of early treatment response in FEP. We hypothesized that FEP patients with higher GSH levels would demonstrate faster symptom reduction upon starting antipsychotic treatment (hypothesis 1). As not all patients with FEP will be able to increase GSH in accordance with glutamate levels, we expected a reduction in the strength of correlation between the GSH and glutamate levels in patients compared with healthy controls (hypothesis 2). Furthermore, in light of the excitotoxic theory of acute schizophrenia [ 32 ], we expected both reduced GSH and increased glutamate levels to predict impaired Social and Occupational Functioning at the onset of illness (hypothesis 3). Methods Participants The sample consisted of 37 new referrals to the PEPP (Prevention and<|im_end|> <|im_start|>assistant Once patients with psychosis start treatment, some get better in weeks while it can take months for others. Seeking to understand and influence this disparity, Schulich School of Medicine & Dentistry professor Dr. Lena Palaniyappan and his team are exploring specific chemicals in the brain with the aim of speeding up the time it takes a patient to respond to medication. Past research has shown that patients who experience their first episode of psychosis and respond early to treatment have better overall outcomes. This includes improved symptoms and daily functioning as well as spending less time in hospital. The research team from Schulich and Lawson Health Research Institute looked specifically at antioxidant levels in the brain and found that these chemicals which rid the body of normal metabolic biproducts, called free radicals, may improve outcomes of early intervention in psychosis. They looked specifically at an area of the brain called cingulate cortex which is well connected to a network of regions that play a major role in generating symptoms of psychosis. The findings showed that patients with higher levels of an antioxidant called glutathione responded more quickly to medication for psychosis and had improved outcomes. They estimated that a 10 percent increase in antioxidants could lead to a reduction in length of hospital stay by at least seven days. "This study demonstrates that if we can find a way to boost the amount of antioxidants in the brain, we might be able to help patients transition out of hospital more quickly, reduce their suffering more quickly and help them return earlier to their work and studies," said Palaniyappan, the Tanna Schulich Endowed Chair in Neuroscience and Mental Health at Western. Antioxidant levels in the brain vary naturally from person to person and those variations can be attributed to lifestyle choices like exercise and diet. There are also ways to pharmaceutically boost these levels. A supplement called N-Acetyl Cysteine (NAC) as well as broccoli extracts can increase the brain's antioxidants if given over a long period of time. Palaniyappan and his team in collaboration with Dr. Jean Theberge at Lawson Imaging used high-field MRI imaging to examine antioxidant levels in the brains of 37 new patients to the Prevention and Early Intervention for Psychoses Program (PEPP) at London Health Sciences Centre. Antioxidant levels were studied prior to beginning treatment for psychosis and followed up for six months post-treatment. The study, "Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate," was published in Nature Molecular Psychiatry. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell–cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth. Surprisingly, genetic experiments targeting endothelial tip cells in vivo reveal that they retain their function without Dll4 and are also not replaced by adjacent, Dll4-positive cells. Instead, activation of Notch directs tip-derived endothelial cells into developing arteries and thereby establishes that Dll4–Notch signalling couples sprouting angiogenesis and artery formation. Main Angiogenesis is essential during development and regeneration but is also involved in pathological processes such as cancer. Endothelial cell (EC) sprouting and proliferation, which mediate the extension of vascular networks, are induced by tissue-derived vascular endothelial growth factor A (VEGF-A) and its endothelial receptor VEGFR2, also known as Flk1 or KDR 1 , 2 . Notch signalling interactions between adjacent ECs are thought to coordinate the cooperative behaviour of cells during sprouting angiogenesis. VEGFR2 activity upregulates expression of the Notch ligand Delta-like 4 (Dll4) in filopodia-extending tip cells at the distal end of sprouts 3 , 4 , 5 . In turn, Dll4-mediated activation of Notch suppresses tip cell behaviour in trailing stalk ECs, which form the base of sprouts 3 , 4 , 6 , 7 , 8 . Accordingly, inhibition of Dll4–Notch interactions results in excessive sprouting and EC hyperproliferation 3 , 4 , 6 , 8 , 9 , 10 . Dll4–Notch signalling is opposed by the ligand Jagged1, which is pro-angiogenic and predominantly expressed by stalk and capillary ECs 11 , 12 , 13 . The behaviour of sprouting ECs is thought to be highly dynamic, enabling rapid replacement of tip cells and switching between tip/stalk phenotypes 7 , 14 . Mathematical models have proposed feedback loops involving VEGF-induced Dll4 expression in tip cells and Notch-mediated suppression of VEGFR2 expression in stalk ECs 7 , 15 , 16 , 17 , 18 . Nevertheless, the processes occurring downstream of Notch and the regulation of endothelial sprouting have remained insufficiently understood. Here, we have used genetic and pharmacological approaches in mice to unravel the cooperation between different signalling pathways. Moreover, genetic tools allowing the selective manipulation of tip cells establish that Dll4–Notch signalling induces an endothelial fate switch and specifies future arterial ECs among the tip cell progeny at the angiogenic growth front. RESULTS Notch-dependent expression of angiogenic regulators Consistent with previous reports 4 , 5 , 8 , EC-specific inactivation of the Dll4 gene in mice ( Dll4 iΔEC/ΔEC ) at postnatal day 6 (P6) led to a dramatic increase in retinal vessel density with an accompanying loss of arteriovenous patterning ( Fig. 1a, b ). This phenotype was not enhanced by the simultaneous inactivation of Dll1 , the gene encoding Delta-like 1, a Notch ligand with limited expression in ECs 19 , 20 ( Supplementary Fig. 1a, b ). Arguing that a sufficient threshold of Notch activation is more critical than the actual Dll4-mediated communication between ECs, Cre-dependent expression of active Notch1 intracellular domain ( NICD iOEC ) was sufficient to restore Notch target gene expression in freshly isolated Dll4 iΔEC/ΔEC retinal ECs and rescued defects seen in the Dll4 iΔEC/ΔEC retinal vasculature ( Fig. 1a, b and Supplementary Fig. 1c–g ). The area covered by Dll4 iΔEC/ΔEC NICD iOEC/+ or Dll4 iΔEC/ΔEC NICD iOEC/OEC vessels was reduced close to control levels and vascular outgrowth was restored. The number of branch points, uncountable in Dll4 iΔEC/ΔEC mutants, was normalized in Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas, and arteries and veins were clearly detectable ( Fig. 1a, b and Supplementary Fig. 1c ). Figure 1: Notch-dependent changes in endothelial CXCR4 and VEGF-A. ( a ) Representative overview (top panels) and high-magnification confocal images (bottom panels) of isolectin B4 (IB4)-stained P6 control, Dll4 iΔEC/ΔEC , Dll4 iΔEC/ΔEC NICD iOEC/+ and Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas. Note hyperbranching and artery (A) and vein (V) formation defects in the Dll4 iΔEC/ΔEC vasculature, which were rescued in Dll4 iΔEC/ΔEC NICD iOEC/OEC double mutants. Circles indicate vessel outgrowth in the control. ( b ) Quantification of retinal vessel progression ( n = 10 control, 10 Dll4 iΔEC/ΔEC , 9 Dll4 iΔEC/ΔEC NICD iOEC/+ and 7 Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas), EC area per field ( n = 10 control, 9 Dll4 iΔEC/ΔEC , 10 Dll4 iΔEC/ΔEC NICD iOEC/+ and 12 Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas) and branching points ( n = 10 control, 10 Dll4 iΔEC/ΔEC NICD iOEC/+ and 12 Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas). Data represent mean ± s.e.m. P values, one-way ANOVA with Tukey’s multiple comparison post hoc test. ( c ) Confocal images of IB4-stained (green), VEGF-A-stained (blue/white) and CXCR4-stained (red) P6 Dll4 iΔEC/ΔEC , Dll4 iΔEC/ΔEC NICD iOEC/+ , Dll4 iΔEC/ΔEC NICD iOEC/OEC and control retinal vessels. Dll4 iΔEC/ΔEC mutants exhibit elevated VEGF-A in vascular plexus (arrows) and avascular tissue (arrowheads). Increased CXCR4 expression in IB4-positive Dll4 iΔEC/ΔEC sprouts (arrowheads) and plexus vessels (arrows) was reduced after expression of active Notch in Dll4 iΔEC/ΔEC mutant ECs. The dotted lines mark the leading edge of the vascular plexus. ( d ) Quantitative RT–PCR (RT–qPCR) analysis of Dll4 ( n = 5 control and 8 Dll4 iΔEC/ΔEC mice), Cxcr4 ( n = 5 control and 8 Dll4 iΔEC/ΔEC mice), Vegfa ( n = 8 control and 11 Dll4 iΔEC/ΔEC mice) and Esm1 ( n = 7 control and 12 Dll4 iΔEC/ΔEC mice) transcripts in sorted Dll4 iΔEC/ΔEC and littermate control retinal ECs. Data represent mean ± s.e.m. P values, two-tailed unpaired t -test. ( e ) RT–qPCR analysis of Esm1 and Vegfa splice variants in control and Dll4 iΔEC/ΔEC whole retina samples ( n = 8 control and 7 Dll4 iΔEC/ΔEC mice).", "role": "user" }, { "content": "Arteriogenesis is a critical event - not only during development but also in adult life. Cardiovascular life-threatening events, triggered by disease, could be overcome by alternatives to existing therapies, for example by inducing the formation of new arteries. However, the mechanisms of artery formation are not well understood. A team of scientists led by Ralf Adams from the Max Planck Institute for Molecular Biomedicine in Münster has developed an elegant genetic approach in mice to uncover molecular mechanisms that coordinate arterial growth. Together with Tilman Borggrefe and colleagues from the Institute of Biochemistry of the Justus-Liebig University of Gießen, they found that a receptor called Notch is crucial in this process: high Notch activity directs sprouting cells of the foremost growth front into developing arteries. This is the first study in mice to show a direct coupling of angiogenic sprouting to artery formation. This knowledge from postnatal development may help in identifying new therapeutic approaches that stimulate growth of new arteries after organ injury. The blood vessel system forms an intricate network of arteries, veins and capillaries that transports oxygen, nutrients, cells and waste products throughout the body. Accordingly, the vasculature plays very important roles in virtually all of our body functions. Cardiovascular disorders such as myocardial infarction or stroke, which are caused by dysfunctional arteries, have become the leading cause of death worldwide. Understanding how arteries form and grow in physiological situations could be of tremendous importance for identifying new therapeutic approaches that stimulate growth of new arteries in pathological conditions. Especially artery formation is important, because only this vessel type would be able to supply compromised tissues with enough blood. However, little is known on how the vascular network is established - least of all how arteriogenesis could be stimulated in therapeutical approaches. Max Planck scientists of the laboratory of Ralf Adams have studied angiogenesis - the formation of new blood vessels from a pre-existing capillary network - in the retina vascular system of postnatal mice. \"The so-called tip cells are those cells in the growing vascular network that, by sensing their environment, are guiding following endothelial cells\", says Mara Pitulescu, first author of the study and senior scientist in the department of Ralf Adams. Tip cells are followed by stalk cells, which have a more proliferative phenotype. Directly behind the tip and stalk cells, the blood vessels are arranged in an initially immature plexus, from which arteries, veins and interconnecting capillaries are formed. Endothelial cells in this network constantly interact with their neighbouring cells and their environment by signalling molecules. These interactions depend on receptors found on the endothelial cell surface and on ligands that bind to the receptors. Crucial for angiogenesis is the Notch receptor - among others - and its Dll4 ligand. Notch activation leads tip cells to arteries: overactivity of active notch brings all the marked progeny (green, nuclei) into the arteries of the vascular network of the retina (red; picture below, 96 hours after the start of the experiment). No marked cells are present in the expansion zone of the peripheral plexus (picture above). Credit: MPI f. Molecular Biomedicine/ M.E. Pitulescu Pitulescu combined genetic experiments with pharmacological approaches. \"This approach allowed us to discriminate between signals required for cell-cell interactions and the mere signalling pathways within the cells\", explains Pitulescu. \"We observed that the level of Notch activation per se is more important than the actual endothelial cell-to-cell communication driven by Notch-signalling, which is a new finding\", says Pitulescu. It was long thought that during vessel network expansion, tip cells and stalk cells would follow cues from the environment that is demanding for new blood vessels, while the vascular network behind these cells is growing. Simultaneously with the vascular plexus growth, arteries expand too. In zebrafish, an earlier study by Arndt Siekmann from the MPI for Molecular Biomedicine revealed that the arteries predominantly form via backward migration of cells that sprouted originally from veins. To study the exact mechanisms of artery formation in mice, Ralf Adams' team used elegant mouse genetics to genetically label only the tip cells and to follow their derived daughter cells over time. \"Surprisingly, we found that the progeny of leading tip cells migrates against the general growing direction of the plexus and incorporates into arteries within a few days time\", says Pitulescu. The scientists were able to inactivate the Notch-ligand Dll4 specifically in tip cells and observed how the vascular network extended. Interestingly, Dll4 is not required to keep tip cells in their position at the edge of the growing vessel bed. \"Rather, we found that CXCR4, a chemokine receptor critical for cell migration, is necessary for tip cell maintenance\", says Pitulescu. The experiments, though, clarified the role of Dll4: \"If Dll4 is missing and therefore the Notch receptor is not activated, the backward tip cell migration into growing arteries is impaired\", says Pitulescu. \"This is the first study in mice to show this direct coupling of sprouting to artery formation equally regulated by Notch\", says Ralf Adams, who also is a Professor at the Medical Faculty of the Westphalian Wilhelms-University Münster and faculty member of the Cluster of Excellence \"Cells in Motion\". \"These findings are of great significance for understanding the process of arterial growth\", says Tilman Borggrefe, who with his team performed the biochemical analyses in the current study. \"This could constitute a new therapeutical approach to control angiogenesis via Notch in order to promote artery formation, when needed\", says Borggrefe. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell–cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth. Surprisingly, genetic experiments targeting endothelial tip cells in vivo reveal that they retain their function without Dll4 and are also not replaced by adjacent, Dll4-positive cells. Instead, activation of Notch directs tip-derived endothelial cells into developing arteries and thereby establishes that Dll4–Notch signalling couples sprouting angiogenesis and artery formation. Main Angiogenesis is essential during development and regeneration but is also involved in pathological processes such as cancer. Endothelial cell (EC) sprouting and proliferation, which mediate the extension of vascular networks, are induced by tissue-derived vascular endothelial growth factor A (VEGF-A) and its endothelial receptor VEGFR2, also known as Flk1 or KDR 1 , 2 . Notch signalling interactions between adjacent ECs are thought to coordinate the cooperative behaviour of cells during sprouting angiogenesis. VEGFR2 activity upregulates expression of the Notch ligand Delta-like 4 (Dll4) in filopodia-extending tip cells at the distal end of sprouts 3 , 4 , 5 . In turn, Dll4-mediated activation of Notch suppresses tip cell behaviour in trailing stalk ECs, which form the base of sprouts 3 , 4 , 6 , 7 , 8 . Accordingly, inhibition of Dll4–Notch interactions results in excessive sprouting and EC hyperproliferation 3 , 4 , 6 , 8 , 9 , 10 . Dll4–Notch signalling is opposed by the ligand Jagged1, which is pro-angiogenic and predominantly expressed by stalk and capillary ECs 11 , 12 , 13 . The behaviour of sprouting ECs is thought to be highly dynamic, enabling rapid replacement of tip cells and switching between tip/stalk phenotypes 7 , 14 . Mathematical models have proposed feedback loops involving VEGF-induced Dll4 expression in tip cells and Notch-mediated suppression of VEGFR2 expression in stalk ECs 7 , 15 , 16 , 17 , 18 . Nevertheless, the processes occurring downstream of Notch and the regulation of endothelial sprouting have remained insufficiently understood. Here, we have used genetic and pharmacological approaches in mice to unravel the cooperation between different signalling pathways. Moreover, genetic tools allowing the selective manipulation of tip cells establish that Dll4–Notch signalling induces an endothelial fate switch and specifies future arterial ECs among the tip cell progeny at the angiogenic growth front. RESULTS Notch-dependent expression of angiogenic regulators Consistent with previous reports 4 , 5 , 8 , EC-specific inactivation of the Dll4 gene in mice ( Dll4 iΔEC/ΔEC ) at postnatal day 6 (P6) led to a dramatic increase in retinal vessel density with an accompanying loss of arteriovenous patterning ( Fig. 1a, b ). This phenotype was not enhanced by the simultaneous inactivation of Dll1 , the gene encoding Delta-like 1, a Notch ligand with limited expression in ECs 19 , 20 ( Supplementary Fig. 1a, b ). Arguing that a sufficient threshold of Notch activation is more critical than the actual Dll4-mediated communication between ECs, Cre-dependent expression of active Notch1 intracellular domain ( NICD iOEC ) was sufficient to restore Notch target gene expression in freshly isolated Dll4 iΔEC/ΔEC retinal ECs and rescued defects seen in the Dll4 iΔEC/ΔEC retinal vasculature ( Fig. 1a, b and Supplementary Fig. 1c–g ). The area covered by Dll4 iΔEC/ΔEC NICD iOEC/+ or Dll4 iΔEC/ΔEC NICD iOEC/OEC vessels was reduced close to control levels and vascular outgrowth was restored. The number of branch points, uncountable in Dll4 iΔEC/ΔEC mutants, was normalized in Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas, and arteries and veins were clearly detectable ( Fig. 1a, b and Supplementary Fig. 1c ). Figure 1: Notch-dependent changes in endothelial CXCR4 and VEGF-A. ( a ) Representative overview (top panels) and high-magnification confocal images (bottom panels) of isolectin B4 (IB4)-stained P6 control, Dll4 iΔEC/ΔEC , Dll4 iΔEC/ΔEC NICD iOEC/+ and Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas. Note hyperbranching and artery (A) and vein (V) formation defects in the Dll4 iΔEC/ΔEC vasculature, which were rescued in Dll4 iΔEC/ΔEC NICD iOEC/OEC double mutants. Circles indicate vessel outgrowth in the control. ( b ) Quantification of retinal vessel progression ( n = 10 control, 10 Dll4 iΔEC/ΔEC , 9 Dll4 iΔEC/ΔEC NICD iOEC/+ and 7 Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas), EC area per field ( n = 10 control, 9 Dll4 iΔEC/ΔEC , 10 Dll4 iΔEC/ΔEC NICD iOEC/+ and 12 Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas) and branching points ( n = 10 control, 10 Dll4 iΔEC/ΔEC NICD iOEC/+ and 12 Dll4 iΔEC/ΔEC NICD iOEC/OEC retinas). Data represent mean ± s.e.m. P values, one-way ANOVA with Tukey’s multiple comparison post hoc test. ( c ) Confocal images of IB4-stained (green), VEGF-A-stained (blue/white) and CXCR4-stained (red) P6 Dll4 iΔEC/ΔEC , Dll4 iΔEC/ΔEC NICD iOEC/+ , Dll4 iΔEC/ΔEC NICD iOEC/OEC and control retinal vessels. Dll4 iΔEC/ΔEC mutants exhibit elevated VEGF-A in vascular plexus (arrows) and avascular tissue (arrowheads). Increased CXCR4 expression in IB4-positive Dll4 iΔEC/ΔEC sprouts (arrowheads) and plexus vessels (arrows) was reduced after expression of active Notch in Dll4 iΔEC/ΔEC mutant ECs. The dotted lines mark the leading edge of the vascular plexus. ( d ) Quantitative RT–PCR (RT–qPCR) analysis of Dll4 ( n = 5 control and 8 Dll4 iΔEC/ΔEC mice), Cxcr4 ( n = 5 control and 8 Dll4 iΔEC/ΔEC mice), Vegfa ( n = 8 control and 11 Dll4 iΔEC/ΔEC mice) and Esm1 ( n = 7 control and 12 Dll4 iΔEC/ΔEC mice) transcripts in sorted Dll4 iΔEC/ΔEC and littermate control retinal ECs. Data represent mean ± s.e.m. P values, two-tailed unpaired t -test. ( e ) RT–qPCR analysis of Esm1 and Vegfa splice variants in control and Dll4 iΔEC/ΔEC whole retina samples ( n = 8 control and 7 Dll4 iΔEC/ΔEC mice).<|im_end|> <|im_start|>assistant Arteriogenesis is a critical event - not only during development but also in adult life. Cardiovascular life-threatening events, triggered by disease, could be overcome by alternatives to existing therapies, for example by inducing the formation of new arteries. However, the mechanisms of artery formation are not well understood. A team of scientists led by Ralf Adams from the Max Planck Institute for Molecular Biomedicine in Münster has developed an elegant genetic approach in mice to uncover molecular mechanisms that coordinate arterial growth. Together with Tilman Borggrefe and colleagues from the Institute of Biochemistry of the Justus-Liebig University of Gießen, they found that a receptor called Notch is crucial in this process: high Notch activity directs sprouting cells of the foremost growth front into developing arteries. This is the first study in mice to show a direct coupling of angiogenic sprouting to artery formation. This knowledge from postnatal development may help in identifying new therapeutic approaches that stimulate growth of new arteries after organ injury. The blood vessel system forms an intricate network of arteries, veins and capillaries that transports oxygen, nutrients, cells and waste products throughout the body. Accordingly, the vasculature plays very important roles in virtually all of our body functions. Cardiovascular disorders such as myocardial infarction or stroke, which are caused by dysfunctional arteries, have become the leading cause of death worldwide. Understanding how arteries form and grow in physiological situations could be of tremendous importance for identifying new therapeutic approaches that stimulate growth of new arteries in pathological conditions. Especially artery formation is important, because only this vessel type would be able to supply compromised tissues with enough blood. However, little is known on how the vascular network is established - least of all how arteriogenesis could be stimulated in therapeutical approaches. Max Planck scientists of the laboratory of Ralf Adams have studied angiogenesis - the formation of new blood vessels from a pre-existing capillary network - in the retina vascular system of postnatal mice. "The so-called tip cells are those cells in the growing vascular network that, by sensing their environment, are guiding following endothelial cells", says Mara Pitulescu, first author of the study and senior scientist in the department of Ralf Adams. Tip cells are followed by stalk cells, which have a more proliferative phenotype. Directly behind the tip and stalk cells, the blood vessels are arranged in an initially immature plexus, from which arteries, veins and interconnecting capillaries are formed. Endothelial cells in this network constantly interact with their neighbouring cells and their environment by signalling molecules. These interactions depend on receptors found on the endothelial cell surface and on ligands that bind to the receptors. Crucial for angiogenesis is the Notch receptor - among others - and its Dll4 ligand. Notch activation leads tip cells to arteries: overactivity of active notch brings all the marked progeny (green, nuclei) into the arteries of the vascular network of the retina (red; picture below, 96 hours after the start of the experiment). No marked cells are present in the expansion zone of the peripheral plexus (picture above). Credit: MPI f. Molecular Biomedicine/ M.E. Pitulescu Pitulescu combined genetic experiments with pharmacological approaches. "This approach allowed us to discriminate between signals required for cell-cell interactions and the mere signalling pathways within the cells", explains Pitulescu. "We observed that the level of Notch activation per se is more important than the actual endothelial cell-to-cell communication driven by Notch-signalling, which is a new finding", says Pitulescu. It was long thought that during vessel network expansion, tip cells and stalk cells would follow cues from the environment that is demanding for new blood vessels, while the vascular network behind these cells is growing. Simultaneously with the vascular plexus growth, arteries expand too. In zebrafish, an earlier study by Arndt Siekmann from the MPI for Molecular Biomedicine revealed that the arteries predominantly form via backward migration of cells that sprouted originally from veins. To study the exact mechanisms of artery formation in mice, Ralf Adams' team used elegant mouse genetics to genetically label only the tip cells and to follow their derived daughter cells over time. "Surprisingly, we found that the progeny of leading tip cells migrates against the general growing direction of the plexus and incorporates into arteries within a few days time", says Pitulescu. The scientists were able to inactivate the Notch-ligand Dll4 specifically in tip cells and observed how the vascular network extended. Interestingly, Dll4 is not required to keep tip cells in their position at the edge of the growing vessel bed. "Rather, we found that CXCR4, a chemokine receptor critical for cell migration, is necessary for tip cell maintenance", says Pitulescu. The experiments, though, clarified the role of Dll4: "If Dll4 is missing and therefore the Notch receptor is not activated, the backward tip cell migration into growing arteries is impaired", says Pitulescu. "This is the first study in mice to show this direct coupling of sprouting to artery formation equally regulated by Notch", says Ralf Adams, who also is a Professor at the Medical Faculty of the Westphalian Wilhelms-University Münster and faculty member of the Cluster of Excellence "Cells in Motion". "These findings are of great significance for understanding the process of arterial growth", says Tilman Borggrefe, who with his team performed the biochemical analyses in the current study. "This could constitute a new therapeutical approach to control angiogenesis via Notch in order to promote artery formation, when needed", says Borggrefe. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The timing of the initial India–Asia collision and the mechanisms that led to the eventual formation of the high (>5 km) Tibetan Plateau remain enigmatic. In this Review, we describe the spatio-temporal distribution and geodynamic mechanisms of surface uplift in the Tibetan Plateau, based on geologic and palaeo-altimetric constraints. Localized mountain building was initiated during a Cretaceous microcontinent collision event in central Tibet and ocean–continent convergence in southern Tibet. Geological data indicate that India began colliding with Asian-affinity rocks 65–60 million years ago (Ma). High-elevation (>4 km) east–west mountain belts were established in southern and central Tibet by ~55 Ma and ~45 Ma, respectively. These mountain belts were separated by ≤2 km elevation basins centred on the microcontinent suture in central Tibet, until the basins were uplifted further between ~38 and 29 Ma. Basin uplift to ≥4 km elevation was delayed along the India–Asia suture zone until ~20 Ma, along with that in northern Tibet. Delamination and break-off of the subducted Indian and Asian lithosphere were the dominant mechanisms of surface uplift, with spatial variations controlled by inherited lithospheric heterogeneities. Future research should explore why surface uplift along suture zones — the loci of the initial collision — was substantially delayed compared with the time of initial collision. Key points The Tibetan Plateau did not get uplifted as a large entity or grow systematically outward from the India–Asia suture (IAS), because lithospheric heterogeneities in Asia imparted by pre-Cenozoic tectonic events created relatively weak and strong zones that deformed differently during collision. Cretaceous tectonic events built embryonic mountains belts and weakened the lithosphere in southern and central Tibet. Continental Asian detritus appeared in Indian continental margin sedimentary rocks by 65–60 million years ago (Ma). The most conservative interpretation based on available geologic constraints is that these sediments mark the initiation of India–Asia collision. The quest to further quantify the history of surface elevation change across Tibet spurred the field of quantitative palaeo-altimetry, such as measurement of oxygen and hydrogen isotopes in palaeo-water proxies, carbonate clumped isotope thermometry and fossil leaf physiognomy. Quantitative palaeo-altimetry suggests that high (≥4 km) elevations were obtained in southern Tibet by ~55 Ma and in central Tibet by ~45 Ma, whereas an intervening valley remained at <2 km elevation until between ~38 and 29 Ma. The IAS zone and Himalaya Mountains were rapidly uplifted from <3 km to near-modern elevations at ~20 Ma. Subcrustal processes such as subduction, delamination and break-off of Indian and Asian continental lithosphere were important tectonic events during the formation of the Tibetan Plateau. Introduction The Tibetan Plateau is Earth’s broadest and highest elevation collisional system, with a mean elevation of ~5 km north of the Indian subcontinent (Fig. 1 ). Plateau formation profoundly influenced Asian climate dynamics 1 , development of modern-day water resources and large Asian rivers 2 , biodiversity 3 and the carbon cycle 4 , 5 , 6 through changes in the geographical distribution of land, sea and surface topography and rock erosion and weathering. However, the mechanisms that deform the continental lithosphere and change surface elevation temporally and spatially during continental collision remain unclear. These unknowns are reflected by the ongoing debates regarding Tibetan Plateau growth during the Cenozoic India–Asia collision. Fig. 1: Digital elevation map and cross-section of the Himalaya and Tibetan Plateau. a | Major mountain crests, terranes and sutures along with locations of palaeo-elevation reconstructions. From south to north, major terranes and mountain belts include the Himalaya terrane and Himalaya Mountains, Lhasa terrane and Gangdese Mountains in southern Tibet, Qiangtang terrane and Watershed Mountains in central Tibet, and Hoh-Xil (equivalent to Songpan-Ganzi) terrane and Kunlun Mountains in northern Tibet. Cenozoic potassic–adakitic–alkaline volcanic rocks are most widely distributed in the vast internally drained plateau interior and systematically decrease in age southward and northward from central Tibet. Distributions of Cenozoic volcanic rocks taken from refs. 111 , 116 , 117 . Present-day moisture sources for the Tibetan Plateau (bold arrows) are dominated by the South Asian monsoon, East Asian monsoon and westerlies. Better knowledge of past sources and isotopic compositions of moisture throughout the Cenozoic is critical to advancing palaeo-altimetric studies. b | Topographic profile and tectonic cross-section along the transect a–aʹ (north-east–south-west), displaying the geometry of main Tibetan Plateau terranes and fault zones. Mesozoic assembly of juvenile terranes in Tibet, and their bounding suture zones, strongly influenced the temporal–spatial distribution of deformation, basin development and surface elevation change during the India–Asia collision. EHS, eastern Himalayan syntaxis; EKTB, eastern Kunlun thrust belt; FHTB, Fenghuoshan–Hoh-Xil thrust belt; GCT, Great Counter Thrust; GRTB, Gangdese retroarc thrust belt; IAS, India–Asia suture; JS, Jinsha suture; KS, Kunlun suture; LQS, Lhasa–Qiangtang suture; LQV, Lhasa–Qiangtang suture valley; Ma, million years ago; MFT, Main Frontal Thrust; MBT, Main Boundary Thrust; MCT, Main Central Thrust; QNTB, Qilian–Nanshan thrust belt; STD, south Tibetan detachment; TTB, Tanggula thrust belt; WHS, western Himalayan syntaxis. Panel b adapted with permission from ref. 13 , American Journal of Science . Full size image The Tibetan Plateau is geologically heterogeneous, being composed of several adjoining terranes (Fig. 1 ) that collided with each other during the last ~300 million years (Myr), owing to subduction of intervening ocean basins along southward younging suture zones 7 , 8 , 9 . These multiple subduction and collision events resulted in the formation of heterogenous lithosphere and variable histories of crustal deformation and surface elevation change across Tibet. The timing of the initial continental collision between India and Asia, which is the youngest and most drastic collision event during Tibet’s assembly, is strongly debated, with estimates ranging from >65 million years ago (Ma) 9 , 10 to ~25 Ma 11 , 12 . The controversy over the collision time stems, in part, from the modest amount of documented upper-crustal deformation in Tibet between ~65 and 25 Ma and the proposition that a Cenozoic ocean basin could have subducted between India and Asia without leaving a definitive record in the surface geology 12 , 13 . Tighter constraints on the timing of the initial India–Asia", "role": "user" }, { "content": "A research team led by Prof. Ding Lin from the Institute of Tibetan Plateau Research of the Chinese Academy of Sciences has systematically explained the differential uplift process and its related deep dynamic mechanism of the Tibetan Plateau since the Cretaceous. The review article was published in Nature Reviews: Earth & Environment on July 28. The uplift of the Tibetan Plateau is one of the most important Cenozoic geological events in the world. However, the mechanisms of continental lithospheric deformation and spatial and temporal changes in surface elevation on the Tibetan Plateau during the India-Asia continental collision are still unclear. In recent years, with the accelerated generation of quantitative paleoelevation data, scholars have gradually recognized that the plateau is characterized by differential uplift, and the uplift time in some areas is either earlier or later than previously assumed, and none of the existing dynamical models can fully reflect the uplift process of the plateau. Cretaceous tectonism and initial mountain growth \"A complete evolutionary model of the Tibetan Plateau must take into account the heterogeneity of paleogeomorphology and lithospheric heterogeneity from Asia during tectonic events prior to the Indo-Asian collision, which is essential for understanding the differential uplift of the plateau,\" said Prof. Ding. Through detailed analysis of Cretaceous evidence on the Tibetan Plateau, the research team proposed that the collision of the Lhasa-Qiangtang terrane and subsequent northward subduction of the Lhasa lithosphere led to the initial growth of the Watershed Mountains; the continued subduction of the Neo-tethys Oceanic slab uplifted the Gangdese Mountains above sea level at ~95 million years ago and formed as Andean-type Gangdese Mountains, but the magnitude of surface uplift remains to be quantified. Time and mode of initial India-Asia collision The timing and mode of the collision of the Indo-Asian plates are the key to constrain the magnitude of surface uplift and deep dynamics of the plateau. Current hypotheses for the closure history of the Neo-tethys Ocean and initial collision of Indo-Asia include the Great Indian Basin model, the intra-oceanic subduction model, and the single-stage subduction-collision model. These hypotheses make very different predictions about the size of the Great India (the part of India that has subducted and disappeared beneath the Tibetan Plateau) and the timing of the initial India-Eurasia collision. However, all of these models are based on one key evidence first discovered by Prof. Ding's team, the foreland basin formed by the India-Eurasia collision, which began to receive provenance from the Gangdese arc region 65 to 59 million years ago, indicating that the India-Eurasia collision had already begun by this time. Therefore, the review points out that the single-stage subduction-collision model is the simplest and the one supported by geological evidence to explain the India-Asia collision. Cenozoic differential uplift history of the Tibetan Plateau and its dynamic mechanism Combining the available quantitative paleolatitude results and deep dynamical evidence, the research team further recovered the surface uplift history and lithospheric evolution of the Tibetan Plateau from about 60 million years ago to the present day, suggesting that the different orogenic belts of the Tibetan Plateau have different uplift histories. About 45–40 million years ago, after the breakoff of the Neo-Tethys Ocean plate, the more buoyant Indian lithosphere wedged northward horizontally, activating the suture zone in the north and south of the Qiangtang body to undergo intra-subduction, causing the Watershed Mountains to rise to a high altitude of 5000 m. At this time, the Central Tibetan Valley between the Gangdese Mountains and the Watershed Mountains, the Himalaya Mountain in the south and northern Tibet remained at low elevation. The paleo-topography of the Tibet presented as \"Two high mountains sandwiched a low land valley.\" About 40–30 million years ago, the Lhasa lithosphere was dismantled below the Central Tibetan Valley, and a variety of coupled deep geodynamic processes, such as the shortening of the upper crust, magma inflation and upwelling, make the Central Tibetan Valley uplifted to 4500 m. About 25–15 million years ago, due to the continuous subduction of the Indian continent, the Indian continental lithosphere subducted beneath the Himalaya and the Asian continental lithosphere subducted beneath the Kunlun Mountains in northern Tibet were successively subducted, and the Himalayas and Kunlun Mountains were successively uplifted to their modern heights, and the plateau in the modern sense was formed. However, the uplift history of the northern region is still uncertain and needs to be verified by more quantitative paleo-altitude data. Present day India underthrusting Geophysical evidences reveal that the present-day Indian and Eurasian lithosphere underwent various geodynamic behaviors ranging from horizontal wedging to steep subduction, plate tearing, breaking and delamination. This indicates that similar processes occurred continuously throughout the Cenozoic India-Asia continental collision, culminating in the spatial and temporal variability of tectonic deformation, magmatism, and surface uplift of the Tibetan Plateau. The researchers point out that to address the timing and mechanism of the uplift of the Tibetan Plateau, future research is needed. And the research directions include: resolving the inconsistency between the amount of Indo-Asian convergence and crustal shortening, high-resolution paleoelevation data, Earth system simulation and combined geophysical imaging and geodynamic simulations. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The timing of the initial India–Asia collision and the mechanisms that led to the eventual formation of the high (>5 km) Tibetan Plateau remain enigmatic. In this Review, we describe the spatio-temporal distribution and geodynamic mechanisms of surface uplift in the Tibetan Plateau, based on geologic and palaeo-altimetric constraints. Localized mountain building was initiated during a Cretaceous microcontinent collision event in central Tibet and ocean–continent convergence in southern Tibet. Geological data indicate that India began colliding with Asian-affinity rocks 65–60 million years ago (Ma). High-elevation (>4 km) east–west mountain belts were established in southern and central Tibet by ~55 Ma and ~45 Ma, respectively. These mountain belts were separated by ≤2 km elevation basins centred on the microcontinent suture in central Tibet, until the basins were uplifted further between ~38 and 29 Ma. Basin uplift to ≥4 km elevation was delayed along the India–Asia suture zone until ~20 Ma, along with that in northern Tibet. Delamination and break-off of the subducted Indian and Asian lithosphere were the dominant mechanisms of surface uplift, with spatial variations controlled by inherited lithospheric heterogeneities. Future research should explore why surface uplift along suture zones — the loci of the initial collision — was substantially delayed compared with the time of initial collision. Key points The Tibetan Plateau did not get uplifted as a large entity or grow systematically outward from the India–Asia suture (IAS), because lithospheric heterogeneities in Asia imparted by pre-Cenozoic tectonic events created relatively weak and strong zones that deformed differently during collision. Cretaceous tectonic events built embryonic mountains belts and weakened the lithosphere in southern and central Tibet. Continental Asian detritus appeared in Indian continental margin sedimentary rocks by 65–60 million years ago (Ma). The most conservative interpretation based on available geologic constraints is that these sediments mark the initiation of India–Asia collision. The quest to further quantify the history of surface elevation change across Tibet spurred the field of quantitative palaeo-altimetry, such as measurement of oxygen and hydrogen isotopes in palaeo-water proxies, carbonate clumped isotope thermometry and fossil leaf physiognomy. Quantitative palaeo-altimetry suggests that high (≥4 km) elevations were obtained in southern Tibet by ~55 Ma and in central Tibet by ~45 Ma, whereas an intervening valley remained at <2 km elevation until between ~38 and 29 Ma. The IAS zone and Himalaya Mountains were rapidly uplifted from <3 km to near-modern elevations at ~20 Ma. Subcrustal processes such as subduction, delamination and break-off of Indian and Asian continental lithosphere were important tectonic events during the formation of the Tibetan Plateau. Introduction The Tibetan Plateau is Earth’s broadest and highest elevation collisional system, with a mean elevation of ~5 km north of the Indian subcontinent (Fig. 1 ). Plateau formation profoundly influenced Asian climate dynamics 1 , development of modern-day water resources and large Asian rivers 2 , biodiversity 3 and the carbon cycle 4 , 5 , 6 through changes in the geographical distribution of land, sea and surface topography and rock erosion and weathering. However, the mechanisms that deform the continental lithosphere and change surface elevation temporally and spatially during continental collision remain unclear. These unknowns are reflected by the ongoing debates regarding Tibetan Plateau growth during the Cenozoic India–Asia collision. Fig. 1: Digital elevation map and cross-section of the Himalaya and Tibetan Plateau. a | Major mountain crests, terranes and sutures along with locations of palaeo-elevation reconstructions. From south to north, major terranes and mountain belts include the Himalaya terrane and Himalaya Mountains, Lhasa terrane and Gangdese Mountains in southern Tibet, Qiangtang terrane and Watershed Mountains in central Tibet, and Hoh-Xil (equivalent to Songpan-Ganzi) terrane and Kunlun Mountains in northern Tibet. Cenozoic potassic–adakitic–alkaline volcanic rocks are most widely distributed in the vast internally drained plateau interior and systematically decrease in age southward and northward from central Tibet. Distributions of Cenozoic volcanic rocks taken from refs. 111 , 116 , 117 . Present-day moisture sources for the Tibetan Plateau (bold arrows) are dominated by the South Asian monsoon, East Asian monsoon and westerlies. Better knowledge of past sources and isotopic compositions of moisture throughout the Cenozoic is critical to advancing palaeo-altimetric studies. b | Topographic profile and tectonic cross-section along the transect a–aʹ (north-east–south-west), displaying the geometry of main Tibetan Plateau terranes and fault zones. Mesozoic assembly of juvenile terranes in Tibet, and their bounding suture zones, strongly influenced the temporal–spatial distribution of deformation, basin development and surface elevation change during the India–Asia collision. EHS, eastern Himalayan syntaxis; EKTB, eastern Kunlun thrust belt; FHTB, Fenghuoshan–Hoh-Xil thrust belt; GCT, Great Counter Thrust; GRTB, Gangdese retroarc thrust belt; IAS, India–Asia suture; JS, Jinsha suture; KS, Kunlun suture; LQS, Lhasa–Qiangtang suture; LQV, Lhasa–Qiangtang suture valley; Ma, million years ago; MFT, Main Frontal Thrust; MBT, Main Boundary Thrust; MCT, Main Central Thrust; QNTB, Qilian–Nanshan thrust belt; STD, south Tibetan detachment; TTB, Tanggula thrust belt; WHS, western Himalayan syntaxis. Panel b adapted with permission from ref. 13 , American Journal of Science . Full size image The Tibetan Plateau is geologically heterogeneous, being composed of several adjoining terranes (Fig. 1 ) that collided with each other during the last ~300 million years (Myr), owing to subduction of intervening ocean basins along southward younging suture zones 7 , 8 , 9 . These multiple subduction and collision events resulted in the formation of heterogenous lithosphere and variable histories of crustal deformation and surface elevation change across Tibet. The timing of the initial continental collision between India and Asia, which is the youngest and most drastic collision event during Tibet’s assembly, is strongly debated, with estimates ranging from >65 million years ago (Ma) 9 , 10 to ~25 Ma 11 , 12 . The controversy over the collision time stems, in part, from the modest amount of documented upper-crustal deformation in Tibet between ~65 and 25 Ma and the proposition that a Cenozoic ocean basin could have subducted between India and Asia without leaving a definitive record in the surface geology 12 , 13 . Tighter constraints on the timing of the initial India–Asia<|im_end|> <|im_start|>assistant A research team led by Prof. Ding Lin from the Institute of Tibetan Plateau Research of the Chinese Academy of Sciences has systematically explained the differential uplift process and its related deep dynamic mechanism of the Tibetan Plateau since the Cretaceous. The review article was published in Nature Reviews: Earth & Environment on July 28. The uplift of the Tibetan Plateau is one of the most important Cenozoic geological events in the world. However, the mechanisms of continental lithospheric deformation and spatial and temporal changes in surface elevation on the Tibetan Plateau during the India-Asia continental collision are still unclear. In recent years, with the accelerated generation of quantitative paleoelevation data, scholars have gradually recognized that the plateau is characterized by differential uplift, and the uplift time in some areas is either earlier or later than previously assumed, and none of the existing dynamical models can fully reflect the uplift process of the plateau. Cretaceous tectonism and initial mountain growth "A complete evolutionary model of the Tibetan Plateau must take into account the heterogeneity of paleogeomorphology and lithospheric heterogeneity from Asia during tectonic events prior to the Indo-Asian collision, which is essential for understanding the differential uplift of the plateau," said Prof. Ding. Through detailed analysis of Cretaceous evidence on the Tibetan Plateau, the research team proposed that the collision of the Lhasa-Qiangtang terrane and subsequent northward subduction of the Lhasa lithosphere led to the initial growth of the Watershed Mountains; the continued subduction of the Neo-tethys Oceanic slab uplifted the Gangdese Mountains above sea level at ~95 million years ago and formed as Andean-type Gangdese Mountains, but the magnitude of surface uplift remains to be quantified. Time and mode of initial India-Asia collision The timing and mode of the collision of the Indo-Asian plates are the key to constrain the magnitude of surface uplift and deep dynamics of the plateau. Current hypotheses for the closure history of the Neo-tethys Ocean and initial collision of Indo-Asia include the Great Indian Basin model, the intra-oceanic subduction model, and the single-stage subduction-collision model. These hypotheses make very different predictions about the size of the Great India (the part of India that has subducted and disappeared beneath the Tibetan Plateau) and the timing of the initial India-Eurasia collision. However, all of these models are based on one key evidence first discovered by Prof. Ding's team, the foreland basin formed by the India-Eurasia collision, which began to receive provenance from the Gangdese arc region 65 to 59 million years ago, indicating that the India-Eurasia collision had already begun by this time. Therefore, the review points out that the single-stage subduction-collision model is the simplest and the one supported by geological evidence to explain the India-Asia collision. Cenozoic differential uplift history of the Tibetan Plateau and its dynamic mechanism Combining the available quantitative paleolatitude results and deep dynamical evidence, the research team further recovered the surface uplift history and lithospheric evolution of the Tibetan Plateau from about 60 million years ago to the present day, suggesting that the different orogenic belts of the Tibetan Plateau have different uplift histories. About 45–40 million years ago, after the breakoff of the Neo-Tethys Ocean plate, the more buoyant Indian lithosphere wedged northward horizontally, activating the suture zone in the north and south of the Qiangtang body to undergo intra-subduction, causing the Watershed Mountains to rise to a high altitude of 5000 m. At this time, the Central Tibetan Valley between the Gangdese Mountains and the Watershed Mountains, the Himalaya Mountain in the south and northern Tibet remained at low elevation. The paleo-topography of the Tibet presented as "Two high mountains sandwiched a low land valley." About 40–30 million years ago, the Lhasa lithosphere was dismantled below the Central Tibetan Valley, and a variety of coupled deep geodynamic processes, such as the shortening of the upper crust, magma inflation and upwelling, make the Central Tibetan Valley uplifted to 4500 m. About 25–15 million years ago, due to the continuous subduction of the Indian continent, the Indian continental lithosphere subducted beneath the Himalaya and the Asian continental lithosphere subducted beneath the Kunlun Mountains in northern Tibet were successively subducted, and the Himalayas and Kunlun Mountains were successively uplifted to their modern heights, and the plateau in the modern sense was formed. However, the uplift history of the northern region is still uncertain and needs to be verified by more quantitative paleo-altitude data. Present day India underthrusting Geophysical evidences reveal that the present-day Indian and Eurasian lithosphere underwent various geodynamic behaviors ranging from horizontal wedging to steep subduction, plate tearing, breaking and delamination. This indicates that similar processes occurred continuously throughout the Cenozoic India-Asia continental collision, culminating in the spatial and temporal variability of tectonic deformation, magmatism, and surface uplift of the Tibetan Plateau. The researchers point out that to address the timing and mechanism of the uplift of the Tibetan Plateau, future research is needed. And the research directions include: resolving the inconsistency between the amount of Indo-Asian convergence and crustal shortening, high-resolution paleoelevation data, Earth system simulation and combined geophysical imaging and geodynamic simulations. <|im_end|>

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505, 279, 10181, 315, 73074, 31403, 2933, 8483, 315, 279, 8620, 16192, 315, 23199, 706, 60826, 11497, 279, 41264, 97547, 1920, 323, 1202, 5552, 5655, 8915, 17383, 315, 279, 73074, 31403, 2933, 2533, 279, 356, 2171, 77140, 13, 578, 3477, 4652, 574, 4756, 304, 22037, 19832, 25, 9420, 612, 11847, 389, 5887, 220, 1591, 13, 578, 97547, 315, 279, 73074, 31403, 2933, 374, 832, 315, 279, 1455, 3062, 356, 268, 96614, 292, 86278, 4455, 304, 279, 1917, 13, 4452, 11, 279, 24717, 315, 58636, 46282, 24527, 11893, 91621, 323, 29079, 323, 37015, 4442, 304, 7479, 27255, 389, 279, 73074, 31403, 2933, 2391, 279, 6890, 12, 39563, 58636, 19277, 527, 2103, 25420, 13, 763, 3293, 1667, 11, 449, 279, 49858, 9659, 315, 47616, 28639, 4748, 44857, 828, 11, 31839, 617, 27115, 15324, 430, 279, 65388, 374, 32971, 555, 41264, 97547, 11, 323, 279, 97547, 892, 304, 1063, 5789, 374, 3060, 6931, 477, 3010, 1109, 8767, 19655, 11, 323, 7000, 315, 279, 6484, 18003, 950, 4211, 649, 7373, 8881, 279, 97547, 1920, 315, 279, 65388, 13, 356, 2171, 77140, 259, 440, 263, 2191, 323, 2926, 16700, 6650, 330, 32, 4686, 41993, 1646, 315, 279, 73074, 31403, 2933, 2011, 1935, 1139, 2759, 279, 30548, 76730, 315, 28639, 41632, 316, 16751, 2508, 323, 46282, 24527, 11893, 30548, 76730, 505, 13936, 2391, 259, 440, 14338, 4455, 4972, 311, 279, 76985, 12, 68540, 19277, 11, 902, 374, 7718, 369, 8830, 279, 41264, 97547, 315, 279, 65388, 1359, 1071, 8626, 13, 80473, 13, 17331, 11944, 6492, 315, 356, 2171, 77140, 6029, 389, 279, 73074, 31403, 2933, 11, 279, 3495, 2128, 11223, 430, 279, 19277, 315, 279, 445, 4752, 64, 29342, 28323, 83, 526, 7317, 2194, 323, 17876, 10411, 1637, 1207, 23985, 315, 279, 445, 4752, 64, 46282, 66222, 6197, 311, 279, 2926, 6650, 315, 279, 47978, 42109, 41114, 26, 279, 8738, 1207, 23985, 315, 279, 41744, 2442, 774, 1065, 22302, 292, 55791, 97547, 291, 279, 35517, 67, 2423, 41114, 3485, 9581, 2237, 520, 4056, 2721, 3610, 1667, 4227, 323, 14454, 439, 1628, 5420, 10827, 35517, 67, 2423, 41114, 11, 719, 279, 26703, 315, 7479, 97547, 8625, 311, 387, 10484, 1908, 13, 4212, 323, 3941, 315, 2926, 6890, 12, 39563, 19277, 578, 18912, 323, 3941, 315, 279, 19277, 315, 279, 76985, 12, 68540, 25485, 527, 279, 1401, 311, 80799, 279, 26703, 315, 7479, 97547, 323, 5655, 30295, 315, 279, 65388, 13, 9303, 74513, 369, 279, 22722, 3925, 315, 279, 41744, 2442, 774, 1065, 22302, 323, 2926, 19277, 315, 76985, 12, 39563, 2997, 279, 8681, 7904, 61358, 1646, 11, 279, 50938, 16405, 11455, 292, 1207, 23985, 1646, 11, 323, 279, 3254, 51256, 1207, 23985, 1824, 30137, 1646, 13, 4314, 74513, 1304, 1633, 2204, 20492, 922, 279, 1404, 315, 279, 8681, 6890, 320, 1820, 961, 315, 6890, 430, 706, 1207, 55015, 323, 29496, 24923, 279, 73074, 31403, 2933, 8, 323, 279, 18912, 315, 279, 2926, 6890, 13737, 19879, 689, 19277, 13, 4452, 11, 682, 315, 1521, 4211, 527, 3196, 389, 832, 1401, 6029, 1176, 11352, 555, 8626, 13, 80473, 596, 2128, 11, 279, 2291, 1974, 58309, 14454, 555, 279, 6890, 13737, 19879, 689, 19277, 11, 902, 6137, 311, 5371, 17033, 685, 505, 279, 35517, 67, 2423, 15952, 5654, 220, 2397, 311, 220, 2946, 3610, 1667, 4227, 11, 19392, 430, 279, 6890, 13737, 19879, 689, 19277, 1047, 2736, 22088, 555, 420, 892, 13, 15636, 11, 279, 3477, 3585, 704, 430, 279, 3254, 51256, 1207, 23985, 1824, 30137, 1646, 374, 279, 45648, 323, 279, 832, 7396, 555, 86278, 6029, 311, 10552, 279, 6890, 12, 39563, 19277, 13, 356, 268, 96614, 292, 41264, 97547, 3925, 315, 279, 73074, 31403, 2933, 323, 1202, 8915, 17383, 23262, 5859, 279, 2561, 47616, 28639, 337, 17584, 3135, 323, 5655, 18003, 950, 6029, 11, 279, 3495, 2128, 4726, 26403, 279, 7479, 97547, 3925, 323, 46282, 24527, 11893, 15740, 315, 279, 73074, 31403, 2933, 505, 922, 220, 1399, 3610, 1667, 4227, 311, 279, 3118, 1938, 11, 23377, 430, 279, 2204, 477, 29569, 53779, 315, 279, 73074, 31403, 2933, 617, 2204, 97547, 53210, 13, 10180, 220, 1774, 4235, 1272, 3610, 1667, 4227, 11, 1306, 279, 1464, 1885, 315, 279, 41744, 9469, 774, 1065, 22302, 12235, 11, 279, 810, 75720, 519, 7904, 46282, 66222, 11077, 3640, 10411, 1637, 59988, 11, 72192, 279, 274, 3049, 10353, 304, 279, 10411, 323, 10007, 315, 279, 1229, 28323, 83, 526, 2547, 311, 37771, 50938, 18451, 23985, 11, 14718, 279, 47978, 42109, 41114, 311, 10205, 311, 264, 1579, 36958, 315, 220, 2636, 15, 296, 13, 2468, 420, 892, 11, 279, 10913, 73074, 13345, 1990, 279, 35517, 67, 2423, 41114, 323, 279, 47978, 42109, 41114, 11, 279, 76438, 12874, 19149, 304, 279, 10007, 323, 18671, 45261, 14958, 520, 3428, 27255, 13, 578, 28639, 78, 8338, 5814, 315, 279, 45261, 10666, 439, 330, 11874, 1579, 24405, 28974, 291, 264, 3428, 4363, 34681, 1210, 10180, 220, 1272, 4235, 966, 3610, 1667, 4227, 11, 279, 445, 4752, 64, 46282, 66222, 574, 49212, 839, 3770, 279, 10913, 73074, 13345, 11, 323, 264, 8205, 315, 34356, 5655, 3980, 61002, 11618, 11, 1778, 439, 279, 2875, 6147, 315, 279, 8582, 40712, 11, 64605, 25544, 323, 709, 86, 6427, 11, 1304, 279, 10913, 73074, 13345, 97547, 291, 311, 220, 10617, 15, 296, 13, 10180, 220, 914, 4235, 868, 3610, 1667, 4227, 11, 4245, 311, 279, 19815, 1207, 23985, 315, 279, 7904, 32843, 11, 279, 7904, 58636, 46282, 66222, 1207, 55015, 24923, 279, 76438, 12874, 323, 279, 14875, 58636, 46282, 66222, 1207, 55015, 24923, 279, 43883, 125657, 41114, 304, 18671, 45261, 1051, 2450, 3210, 1207, 55015, 11, 323, 279, 76438, 98440, 323, 43883, 125657, 41114, 1051, 2450, 3210, 97547, 291, 311, 872, 6617, 36394, 11, 323, 279, 65388, 304, 279, 6617, 5647, 574, 14454, 13, 4452, 11, 279, 97547, 3925, 315, 279, 18671, 5654, 374, 2103, 36218, 323, 3966, 311, 387, 24884, 555, 810, 47616, 28639, 78, 34450, 3993, 828, 13, 27740, 1938, 6890, 1234, 339, 36888, 287, 4323, 91004, 5339, 2436, 16805, 430, 279, 3118, 11477, 7904, 323, 88177, 1122, 46282, 66222, 55093, 5370, 3980, 61002, 28198, 24950, 505, 16600, 11077, 3252, 311, 32366, 1207, 23985, 11, 12235, 56836, 11, 15061, 323, 1624, 27935, 13, 1115, 15151, 430, 4528, 11618, 10222, 31978, 6957, 279, 356, 268, 96614, 292, 6890, 12, 39563, 58636, 19277, 11, 11957, 65383, 304, 279, 29079, 323, 37015, 54709, 315, 259, 440, 14338, 91621, 11, 4983, 8637, 2191, 11, 323, 7479, 97547, 315, 279, 73074, 31403, 2933, 13, 578, 12074, 1486, 704, 430, 311, 2686, 279, 18912, 323, 17383, 315, 279, 97547, 315, 279, 73074, 31403, 2933, 11, 3938, 3495, 374, 4460, 13, 1628, 279, 3495, 18445, 2997, 25, 53583, 279, 97249, 1990, 279, 3392, 315, 76985, 12, 68540, 56541, 323, 40712, 278, 2875, 6147, 11, 1579, 64036, 28639, 4748, 44857, 828, 11, 9420, 1887, 19576, 323, 11093, 3980, 91004, 32758, 323, 3980, 61002, 47590, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM + population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2 int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers. Main The liver serves as a central metabolic coordinator with a wide array of essential functions, including the regulation of glucose and lipid metabolism, protein synthesis, and bile synthesis. Furthermore, the liver is a visceral organ that is capable of remarkable natural regeneration after tissue loss 1 . However, the prevalence of liver diseases and mortality associated with them have risen markedly within recent decades 2 . The liver cellular landscape has barely been explored at single-cell resolution, which limits our molecular understanding of liver function and disease biology. The recent emergence of sensitive single-cell RNA sequencing (scRNA-seq) methods 3 allows us to investigate cell types in healthy and diseased tissue. To characterize the human liver at single-cell resolution, we developed a robust pipeline for scRNA-seq of cryopreserved and freshly isolated samples of patient-derived human liver and assembled an atlas consisting of 10,372 cells from nine donors. We performed in-depth analysis of all liver cell types with a focus on epithelial liver cell progenitors. scRNA-seq of the human liver We used mCEL-Seq2 4 for scRNA-seq of non-diseased liver tissue from nine patients who underwent liver resections for colorectal cancer metastasis or cholangiocarcinoma without history of chronic liver disease (Fig. 1a , see Methods ). We sorted and sequenced viable cells both in an unbiased fashion and by enriching specific cell populations on the basis of cell surface marker expression (Extended Data Fig. 1 , see Methods ). Because fresh liver tissue material is scarce and difficult to preserve, and biobanks with cryopreserved liver samples represent rich resources, we generated scRNA-seq data from cryopreserved cells as well as single-cell suspensions from freshly prepared liver samples (see Methods ). We then used RaceID3 for the identification of cell types 4 , 5 (see Methods ). Fig. 1: scRNA-seq reveals cell types in the adult human liver. a , Outline of the protocol used for scRNA-seq of human liver cells. Samples from liver resections were digested to prepare single-cell suspensions. Cells were sorted into 384-well plates and processed according to the mCEL-Seq2 protocol. b , t -SNE map of single-cell transcriptomes from normal liver tissue from nine donors highlighting the main liver cell compartments. ‘Other’ denotes various small populations comprising 22 red blood cells and 46 cells that cannot be unambiguously annotated. ‘Other endothelial cells’ cannot be unambiguously classified as LSECs or MaVECs. c , t -SNE map of single-cell transcriptomes highlighting RaceID3 clusters, which reveals subtype heterogeneity in all major cell populations of the human liver. Numbers denote clusters. d , Heat map showing the expression of established marker genes for each cell compartment. Colour bars indicate patient, major cell type, and RaceID3 cluster. Scale bar, log 2 -transformed normalized expression. b , c , n = 10,372 cells. Full size image Cells from different patients, isolated from freshly prepared or cryopreserved single-cell suspensions, co-clustered (Extended Data Fig. 1 ). Furthermore, fresh and cryopreserved cells from the same patient did not have markedly different gene signatures (Extended Data Fig. 1e–h ). However, there were compositional differences both between fresh and cryopreserved samples derived from the same patient and among different fresh (or cryopreserved) samples. We attribute these differences to variability in cell viability and cell type composition across samples. As scRNA-seq of randomly sampled populations yielded almost exclusively hepatocytes and immune cells (Extended Data Fig. 1i ), we applied additional sorting strategies to enrich for endothelial cells (Extended Data Fig. 1a–c ) and EPCAM + cells (see below). Our atlas comprises all the main liver cell types defined by the expression of marker genes, including hepatocytes, EPCAM + bile duct cells (cholangiocytes), CLEC4G + liver sinusoidal endothelial cells (LSECs), CD34 + PECAM high macrovascular endothelial cells (MaVECs), hepatic stellate cells and myofibroblasts, Kupffer cells, and immune cells (Fig. 1b–d , Supplementary Table 1 ). To facilitate interactive exploration of our human liver cell atlas, we created a web interface: . Zonation of human liver cell types Hepatocytes are spatially heterogeneous and zonated along the portal–central axis of the liver lobule 6 , 7 , 8 . According to metabolic sub-specialization, the liver lobule has been divided into the periportal zone surrounding the portal triad (portal vein, hepatic artery and bile duct), the central zone nearest to the central vein, and the remaining mid zone 6 , 7 , 8 . Whereas previous observations have suggested that non-parenchymal cells such as LSECs and Kupffer cells have specialized subtypes 6 , it has been hard to demonstrate heterogeneity of these cell types, and most studies have been carried out in rodents. We were able to directly compare the signatures of MaVECs and LSECs, and identified several previously unknown subpopulations (Extended Data Fig. 2 , Supplementary Note 1 ). scRNA-seq has been highly informative on hepatocyte zonation in mouse 9 , and the first single-cell analysis of human hepatocyte and endothelial cell zonation at limited resolution was done recently 10 . To infer continuous transcriptome-wide zonation, we reasoned that the major axis of variability for a cell type could reflect gene expression changes", "role": "user" }, { "content": "The liver is one of the largest and most versatile organs of the human body. It turns sugars, proteins, and fats from our food into substances useful for the body and releases them to the cells. In addition to its role in human metabolism, the liver is an immunological organ, which is indispensable for detoxifying the blood. Most strikingly, the liver is the only internal organ that can regenerate back to its full size with only 25% of its original mass. Liver diseases are one of the biggest health problems in the world and a leading cause of death. In Germany, at least five million patients are suffering from fatty liver disease, liver cancer, or hepatitis. Despite the immense importance of the liver for human health, the diversity of individual liver cell types and the associated molecular and cellular processes in both healthy and diseased tissue have not yet been fully investigated. Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and colleagues from the University of Strasbourg are now presenting a comprehensive cell atlas of the human liver published in the science journal Nature. Using what is known as single-cell RNA sequencing, the researchers led by Max Planck Group Leader Dominic Grün and in cooperation with the Baumert Lab succeeded in creating a detailed map of the cell populations in the healthy human liver. Based on the analysis of 10,000 cells from nine human donors, the cell atlas maps all important liver cell types, including hepatocytes, the major metabolic cells of the liver, endothelial cells lining the blood vessels, liver resident macrophages and other immune cell types, as well as bile duct cells and liver epithelial progenitors. With this data, it is possible to capture the diversity of cell types and cell states at an unprecedented resolution and to understand how they change during development or upon disease progression. The cell's fingerprint The researchers also discovered an astonishing diversity among individual cells of the alleged same cell type. They found new subtypes of hepatocytes, endothelial cells, and macrophages, which, although hardly different in their morphological appearance, have discrete gene expression profiles. These discoveries were made possible by the significant progress of experimental and computational single-cell analysis methods, which enable cells to be examined at high resolution. In single-cell RNA sequencing, the organ tissue to be investigated is dissociated into individual cells; these cells are then isolated and sequenced separately. The sequencing is used to determine how many messenger RNA molecules (mRNA) of each gene are present in the cell. \"The messenger RNA transmits the blueprints stored in the DNA to the protein factories. By measuring which RNA molecules are present in a cell at a certain point in time, we can identify which genes are active. This gives us a kind of fingerprint that provides us with a comprehensive insight into the very nature of each cell. This enables us to understand which functions the cell performs, how it is regulated and also what happens when diseases develop,\" explains Dominic Grün. The data obtained in this way are not only extremely extensive, but also very complex since the RNA molecules of thousands of genes in thousands of cells have to be quantified and interpreted simultaneously. In recent years, Dominic Grün has developed tailor-made algorithms helping him and his team to characterize the different cell types and understand their developmental pathways. Identifying progenitors of liver cells Using such fingerprints of cells, the Freiburg researchers also identified previously unknown properties of a subpopulation of bile duct cells. Bile ducts run through the entire liver to transport bile to the gallbladder. \"Our data show that cells within this rare subpopulation are precursor cells or progenitors. They are not only able to form organoids, which is a marked characteristic of stem cells, but also have the potential to develop into different cell types,\" explains Nadim Aizarani, the first author of the study. These progenitor cells either differentiate into hepatocytes or bile duct cells when cultivated in a culture medium. The Max Planck researchers are convinced that this precursor cell population plays an important role in liver regeneration and could also be involved in the development of liver diseases or tumors. Important reference data for cancer patients The cell atlas and the method of single-cell RNA-sequencing, therefore, have great potential for cancer therapy. Current approaches to analyze diseased tissue, such as tumor tissue, only provided an average value of the concentration of active genes for the entire tissue sample and thus only an average view of the tumor's molecular profile. \"The contribution of rare cell types or even individual cells is lost in this average value. Although it is perhaps precisely these few cells that determine whether a tissue is healthy or degenerates into cancer,\" explains Dominic Grün. But single-cell sequencing, on the other hand, captures the molecular signature of each healthy or diseased cell in the sample to be examined. The comparison with reference data from healthy tissue enables scientists to target the disease-causing molecular properties of tumor cells and may help to develop improved treatment options in the future. The Freiburg and Strasbourg researchers demonstrate in their newest study that the cell atlas of the human liver will be an essential reference database for liver cancer research. They compared the data of healthy tissue from the cell atlas with cells from hepatocellular carcinoma, the most common form of primary liver cancer. The comparison enabled conclusions to be drawn, e.g. the identification of new tumor cell markers and perturbed gene activity patterns of different cell types within the tumor. \"I think that research into cancer using single-cell sequencing will help to improve the diagnosis and eventually the treatment of tumors even further. In the future, we will not only be able to uncover possible interactions between different cell types in tumors. It will also be possible to observe these interactions as the disease progresses,\" says Dominic Grün. The researchers are convinced that their cell atlas of the human liver and the developed methods have laid an important foundation within biomedicine, which will advance the research and understanding of liver diseases on the molecular level to possibly create new therapeutic strategies against liver diseases in the future. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM + population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2 int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers. Main The liver serves as a central metabolic coordinator with a wide array of essential functions, including the regulation of glucose and lipid metabolism, protein synthesis, and bile synthesis. Furthermore, the liver is a visceral organ that is capable of remarkable natural regeneration after tissue loss 1 . However, the prevalence of liver diseases and mortality associated with them have risen markedly within recent decades 2 . The liver cellular landscape has barely been explored at single-cell resolution, which limits our molecular understanding of liver function and disease biology. The recent emergence of sensitive single-cell RNA sequencing (scRNA-seq) methods 3 allows us to investigate cell types in healthy and diseased tissue. To characterize the human liver at single-cell resolution, we developed a robust pipeline for scRNA-seq of cryopreserved and freshly isolated samples of patient-derived human liver and assembled an atlas consisting of 10,372 cells from nine donors. We performed in-depth analysis of all liver cell types with a focus on epithelial liver cell progenitors. scRNA-seq of the human liver We used mCEL-Seq2 4 for scRNA-seq of non-diseased liver tissue from nine patients who underwent liver resections for colorectal cancer metastasis or cholangiocarcinoma without history of chronic liver disease (Fig. 1a , see Methods ). We sorted and sequenced viable cells both in an unbiased fashion and by enriching specific cell populations on the basis of cell surface marker expression (Extended Data Fig. 1 , see Methods ). Because fresh liver tissue material is scarce and difficult to preserve, and biobanks with cryopreserved liver samples represent rich resources, we generated scRNA-seq data from cryopreserved cells as well as single-cell suspensions from freshly prepared liver samples (see Methods ). We then used RaceID3 for the identification of cell types 4 , 5 (see Methods ). Fig. 1: scRNA-seq reveals cell types in the adult human liver. a , Outline of the protocol used for scRNA-seq of human liver cells. Samples from liver resections were digested to prepare single-cell suspensions. Cells were sorted into 384-well plates and processed according to the mCEL-Seq2 protocol. b , t -SNE map of single-cell transcriptomes from normal liver tissue from nine donors highlighting the main liver cell compartments. ‘Other’ denotes various small populations comprising 22 red blood cells and 46 cells that cannot be unambiguously annotated. ‘Other endothelial cells’ cannot be unambiguously classified as LSECs or MaVECs. c , t -SNE map of single-cell transcriptomes highlighting RaceID3 clusters, which reveals subtype heterogeneity in all major cell populations of the human liver. Numbers denote clusters. d , Heat map showing the expression of established marker genes for each cell compartment. Colour bars indicate patient, major cell type, and RaceID3 cluster. Scale bar, log 2 -transformed normalized expression. b , c , n = 10,372 cells. Full size image Cells from different patients, isolated from freshly prepared or cryopreserved single-cell suspensions, co-clustered (Extended Data Fig. 1 ). Furthermore, fresh and cryopreserved cells from the same patient did not have markedly different gene signatures (Extended Data Fig. 1e–h ). However, there were compositional differences both between fresh and cryopreserved samples derived from the same patient and among different fresh (or cryopreserved) samples. We attribute these differences to variability in cell viability and cell type composition across samples. As scRNA-seq of randomly sampled populations yielded almost exclusively hepatocytes and immune cells (Extended Data Fig. 1i ), we applied additional sorting strategies to enrich for endothelial cells (Extended Data Fig. 1a–c ) and EPCAM + cells (see below). Our atlas comprises all the main liver cell types defined by the expression of marker genes, including hepatocytes, EPCAM + bile duct cells (cholangiocytes), CLEC4G + liver sinusoidal endothelial cells (LSECs), CD34 + PECAM high macrovascular endothelial cells (MaVECs), hepatic stellate cells and myofibroblasts, Kupffer cells, and immune cells (Fig. 1b–d , Supplementary Table 1 ). To facilitate interactive exploration of our human liver cell atlas, we created a web interface: . Zonation of human liver cell types Hepatocytes are spatially heterogeneous and zonated along the portal–central axis of the liver lobule 6 , 7 , 8 . According to metabolic sub-specialization, the liver lobule has been divided into the periportal zone surrounding the portal triad (portal vein, hepatic artery and bile duct), the central zone nearest to the central vein, and the remaining mid zone 6 , 7 , 8 . Whereas previous observations have suggested that non-parenchymal cells such as LSECs and Kupffer cells have specialized subtypes 6 , it has been hard to demonstrate heterogeneity of these cell types, and most studies have been carried out in rodents. We were able to directly compare the signatures of MaVECs and LSECs, and identified several previously unknown subpopulations (Extended Data Fig. 2 , Supplementary Note 1 ). scRNA-seq has been highly informative on hepatocyte zonation in mouse 9 , and the first single-cell analysis of human hepatocyte and endothelial cell zonation at limited resolution was done recently 10 . To infer continuous transcriptome-wide zonation, we reasoned that the major axis of variability for a cell type could reflect gene expression changes<|im_end|> <|im_start|>assistant The liver is one of the largest and most versatile organs of the human body. It turns sugars, proteins, and fats from our food into substances useful for the body and releases them to the cells. In addition to its role in human metabolism, the liver is an immunological organ, which is indispensable for detoxifying the blood. Most strikingly, the liver is the only internal organ that can regenerate back to its full size with only 25% of its original mass. Liver diseases are one of the biggest health problems in the world and a leading cause of death. In Germany, at least five million patients are suffering from fatty liver disease, liver cancer, or hepatitis. Despite the immense importance of the liver for human health, the diversity of individual liver cell types and the associated molecular and cellular processes in both healthy and diseased tissue have not yet been fully investigated. Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and colleagues from the University of Strasbourg are now presenting a comprehensive cell atlas of the human liver published in the science journal Nature. Using what is known as single-cell RNA sequencing, the researchers led by Max Planck Group Leader Dominic Grün and in cooperation with the Baumert Lab succeeded in creating a detailed map of the cell populations in the healthy human liver. Based on the analysis of 10,000 cells from nine human donors, the cell atlas maps all important liver cell types, including hepatocytes, the major metabolic cells of the liver, endothelial cells lining the blood vessels, liver resident macrophages and other immune cell types, as well as bile duct cells and liver epithelial progenitors. With this data, it is possible to capture the diversity of cell types and cell states at an unprecedented resolution and to understand how they change during development or upon disease progression. The cell's fingerprint The researchers also discovered an astonishing diversity among individual cells of the alleged same cell type. They found new subtypes of hepatocytes, endothelial cells, and macrophages, which, although hardly different in their morphological appearance, have discrete gene expression profiles. These discoveries were made possible by the significant progress of experimental and computational single-cell analysis methods, which enable cells to be examined at high resolution. In single-cell RNA sequencing, the organ tissue to be investigated is dissociated into individual cells; these cells are then isolated and sequenced separately. The sequencing is used to determine how many messenger RNA molecules (mRNA) of each gene are present in the cell. "The messenger RNA transmits the blueprints stored in the DNA to the protein factories. By measuring which RNA molecules are present in a cell at a certain point in time, we can identify which genes are active. This gives us a kind of fingerprint that provides us with a comprehensive insight into the very nature of each cell. This enables us to understand which functions the cell performs, how it is regulated and also what happens when diseases develop," explains Dominic Grün. The data obtained in this way are not only extremely extensive, but also very complex since the RNA molecules of thousands of genes in thousands of cells have to be quantified and interpreted simultaneously. In recent years, Dominic Grün has developed tailor-made algorithms helping him and his team to characterize the different cell types and understand their developmental pathways. Identifying progenitors of liver cells Using such fingerprints of cells, the Freiburg researchers also identified previously unknown properties of a subpopulation of bile duct cells. Bile ducts run through the entire liver to transport bile to the gallbladder. "Our data show that cells within this rare subpopulation are precursor cells or progenitors. They are not only able to form organoids, which is a marked characteristic of stem cells, but also have the potential to develop into different cell types," explains Nadim Aizarani, the first author of the study. These progenitor cells either differentiate into hepatocytes or bile duct cells when cultivated in a culture medium. The Max Planck researchers are convinced that this precursor cell population plays an important role in liver regeneration and could also be involved in the development of liver diseases or tumors. Important reference data for cancer patients The cell atlas and the method of single-cell RNA-sequencing, therefore, have great potential for cancer therapy. Current approaches to analyze diseased tissue, such as tumor tissue, only provided an average value of the concentration of active genes for the entire tissue sample and thus only an average view of the tumor's molecular profile. "The contribution of rare cell types or even individual cells is lost in this average value. Although it is perhaps precisely these few cells that determine whether a tissue is healthy or degenerates into cancer," explains Dominic Grün. But single-cell sequencing, on the other hand, captures the molecular signature of each healthy or diseased cell in the sample to be examined. The comparison with reference data from healthy tissue enables scientists to target the disease-causing molecular properties of tumor cells and may help to develop improved treatment options in the future. The Freiburg and Strasbourg researchers demonstrate in their newest study that the cell atlas of the human liver will be an essential reference database for liver cancer research. They compared the data of healthy tissue from the cell atlas with cells from hepatocellular carcinoma, the most common form of primary liver cancer. The comparison enabled conclusions to be drawn, e.g. the identification of new tumor cell markers and perturbed gene activity patterns of different cell types within the tumor. "I think that research into cancer using single-cell sequencing will help to improve the diagnosis and eventually the treatment of tumors even further. In the future, we will not only be able to uncover possible interactions between different cell types in tumors. It will also be possible to observe these interactions as the disease progresses," says Dominic Grün. The researchers are convinced that their cell atlas of the human liver and the developed methods have laid an important foundation within biomedicine, which will advance the research and understanding of liver diseases on the molecular level to possibly create new therapeutic strategies against liver diseases in the future. <|im_end|>

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2,635

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The significant losses in Arctic sea ice over the past few decades appear to have been accompanied by changes in global-scale and regional-scale atmospheric circulation. Such circulation changes have in turn been used to support arguments that low Arctic sea-ice extent (SIE) has helped to promote extreme weather events within the mid-latitudes. The contemporaneous variability in U.S. tornado incidence over the past decade provides motivation to explore whether the essence of these arguments also applies to tornadoes. Here, robust statistical correlations are found between tornado activity and SIE during boreal summer, specifically in July. The statistical relationship is supported by the presence of anomalous regional circulation and storm track that are unfavorable (favorable) for tornado-bearing thunderstorm formation when SIE is low (high). Introduction The significant losses in Arctic sea ice over the past few decades 1 have been accompanied by lower-tropospheric temperature changes 2 that appear to have contributed to changes in global-scale and regional-scale atmospheric circulation. Such circulation changes—particularly the geographical shifts, enhanced undulations, blocking patterns, and speed reductions in the jet stream 3 , 4 , 5 , 6 , 7 —have been used to support arguments that low Arctic sea ice helps to promote extreme weather events within the mid-latitudes. 8 , 9 , 10 We duly acknowledge the many criticisms of these arguments, which as recently summarized 11 include the possibility that the variance (and trends) in weather extremes and their atmospheric forcings are masked by or convolved with high-frequency variability, subseasonal-to-seasonal (S2S) variability, multi-decadal oscillations, and realizations of anthropogenically enhanced greenhouse gas (GHG) concentrations. 10 , 12 Nonetheless, evidence of cryosphere-associated atmospheric circulation changes during boreal summer 4 , 5 , 6 is particularly compelling here, because we and others are motivated by the possibility of exploiting long-memory processes for S2S predictions of tornado (and hail) activity 13 , 14 , 15 , 16 during the boreal warm season. For reference, the spatio-temporal distribution (i.e., climatology) of U.S. tornadoes is determined by geophysical features like the Rocky Mountains, Central Mexican Plateau, and the Gulf of Mexico, as well as by the seasonal variations in solar forcing and associated mean weather patterns. 17 Our specific interest is in how the mean tornado occurrence would be modulated by anomalous anticyclonic circulation over central North America, which is one of the apparent cryosphere-associated atmospheric modifications during June–July–August (JJA). 4 Consider that such anomalous circulation would cause a northward shift in the synoptic-scale forcing and 3D temperature, humidity, and wind distributions that favor intense-thunderstorm formation. 17 Tornadogenesis within these storms requires precise spatial alignments of favorably distributed temperature, humidity, and wind, and thus any findings of decreases in zonal wind and wind shear 5 would alone suggest a reduced likelihood for tornado formation. This brief physical argument aside, our exploration is also motivated by the U.S. tornado incidence over the past decade, which except for a few years has been abnormally low, as has the Arctic sea ice. The purpose of this paper is to present initial evidence in support of the basic hypothesis is that low Arctic sea ice extent (SIE) contributes to a reduction in U.S. tornado activity as quantified by EF1+ tornado days (TOR). Results Figure 1a shows that the linear correlations between detrended TOR and detrended pan-Arctic SIE are maximized during boreal summer, with a Pearson (Spearman rank) correlation coefficient R p = +0.54 ( R s = +0.55) and p = 0.004 in July. For reference, a linear regression using the raw time series yields R p = +0.70,R s = +0.71, p = 0.000 in July (Fig. 1b ); if we allow the time series to extend over a longer period (1980–2015), regression analyses using the raw and detrended data, respectively, yield R p = +0.77, R s = +0.75, p = 0.000, and R p = +0.48, R s = +0.48, p = 0.003 in July (Supplement Fig. S1 ). Although not the focus of this study, we additionally find that the F/EF1+ tornado reports over this longer time series correlate strongly with SIE in July ( R p = + 0.57, R s = +0.55, p = 0.000 using raw data, and R p = +0.45, R s = +0.40, p = 0.006 using detrended data; Supplement Fig. S2 ). All of the July correlations would be statistically significant at the 5% level even with application of a Bonferroni correction for multiple comparisons (12 months). 18 This, incidentally, is not the case with correlations between TOR and Arctic Oscillation index, which are relatively low in July ( R p = −0.14, p = 0.492) and in all other months. Fig. 1 Scatterplots of a detrended monthly mean sea-ice extent (SIE) versus detrended monthly E/EF1+ tornado days (TOR), b raw monthly mean SIE versus raw monthly TOR, and c time series of monthly TOR, all over the period 1990–2015. Solid lines show linear fit. Pearson correlation coefficient ( R p ), Spearman rank correlation coefficient ( R s ), and p -value for each month are indicated near the top of each plot. Shading shows 95% confidence intervals from 10,000 bootstrapped resamples Full size image These are contemporaneous correlations, but it would seem reasonable to also expect a lagged effect of Arctic sea ice on tornado activity. Thus, we computed the linear regressions between detrended pan-Arctic SIE and the detrended TOR lagged by one and two months. Most of the lagged correlations are relatively low and statistically insignificant (Table 1 ), with notable exception of the regressions with July SIE. For example, Table 1 indicates that the 2-month lag of TOR from July SIE (i.e., July SIE and September TOR) results in R p = +0.51 (and p = 0.007). The 1-month lag of TOR from July SIE (i.e., July SIE and August TOR) results in R p = +0.30 (and p = 0.132), which is higher than that between August SIE and August TOR, but still not statistically significant. The conclusion from this analysis is that July SIE is a", "role": "user" }, { "content": "The effects of global climate change taking place in the Arctic may influence weather much closer to home for millions of Americans, researchers report. The United States has experienced many changes in severe-weather behavior over the past decade, including fewer tornado touchdowns in than in the past. A new study suggests that atmospheric circulation changes that coincide with a loss of Arctic sea ice may be partly to blame. Atmospheric scientists from the University of Illinois at Urbana-Champaign and Purdue University report their findings in the journal Climate and Atmospheric Science. \"A relationship between Arctic sea ice and tornadoes in the U.S. may seem unlikely,\" said (Robert) Jeff Trapp , a professor of atmospheric sciences at the U. of I. and a co-author. \"But it is hard to ignore the mounting evidence in support of the connection.\" The researchers performed statistical analyses of nearly three decades of historical weather and climate data and found significant correlations between tornado activity and the extent of Arctic sea ice—especially during the month July. The team believes that the reduction in tornado activity boils down to how the diminishing Arctic sea ice controls the path of the jet stream. As Arctic sea ice retreats, the jet stream migrates from its traditional summer path over states like Montana and South Dakota to areas farther north, and the atmospheric conditions that are favorable for tornado formation follow suit. \"Tornadoes and their parent thunderstorms are fueled by wind shear and moisture,\" Trapp said. \"When the jet stream migrates north, it takes the wind shear along for the ride, but not always the moisture. So, even though thunderstorms may still develop, they tend not to generate tornadoes because one of the essential ingredients for tornado formation is now missing.\" The team believes that the correlation between Arctic ice retreat and jet stream migration may lead to advances in seasonal severe weather prediction. \"One of the reasons that we focused on sea ice is because, like the ocean and land, it is relatively slow to evolve,\" Trapp said. \"Because sea ice and the atmosphere are coupled, the response of the atmosphere is also relatively slow. We can use this property to help make long-term predictions for tornadoes and hail, similar to the way predictions are made for hurricane seasons.\" But before doing so, Trapp said they still need to understand the drivers of the sea ice changes and what role the tropics may be playing. It remains unclear as to why this correlation is particularly dominant during the month of July, the researchers said, and they admit that they are only at the tip of the iceberg in terms of understanding the overall effects of climate change, and climate variability, on severe weather. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The significant losses in Arctic sea ice over the past few decades appear to have been accompanied by changes in global-scale and regional-scale atmospheric circulation. Such circulation changes have in turn been used to support arguments that low Arctic sea-ice extent (SIE) has helped to promote extreme weather events within the mid-latitudes. The contemporaneous variability in U.S. tornado incidence over the past decade provides motivation to explore whether the essence of these arguments also applies to tornadoes. Here, robust statistical correlations are found between tornado activity and SIE during boreal summer, specifically in July. The statistical relationship is supported by the presence of anomalous regional circulation and storm track that are unfavorable (favorable) for tornado-bearing thunderstorm formation when SIE is low (high). Introduction The significant losses in Arctic sea ice over the past few decades 1 have been accompanied by lower-tropospheric temperature changes 2 that appear to have contributed to changes in global-scale and regional-scale atmospheric circulation. Such circulation changes—particularly the geographical shifts, enhanced undulations, blocking patterns, and speed reductions in the jet stream 3 , 4 , 5 , 6 , 7 —have been used to support arguments that low Arctic sea ice helps to promote extreme weather events within the mid-latitudes. 8 , 9 , 10 We duly acknowledge the many criticisms of these arguments, which as recently summarized 11 include the possibility that the variance (and trends) in weather extremes and their atmospheric forcings are masked by or convolved with high-frequency variability, subseasonal-to-seasonal (S2S) variability, multi-decadal oscillations, and realizations of anthropogenically enhanced greenhouse gas (GHG) concentrations. 10 , 12 Nonetheless, evidence of cryosphere-associated atmospheric circulation changes during boreal summer 4 , 5 , 6 is particularly compelling here, because we and others are motivated by the possibility of exploiting long-memory processes for S2S predictions of tornado (and hail) activity 13 , 14 , 15 , 16 during the boreal warm season. For reference, the spatio-temporal distribution (i.e., climatology) of U.S. tornadoes is determined by geophysical features like the Rocky Mountains, Central Mexican Plateau, and the Gulf of Mexico, as well as by the seasonal variations in solar forcing and associated mean weather patterns. 17 Our specific interest is in how the mean tornado occurrence would be modulated by anomalous anticyclonic circulation over central North America, which is one of the apparent cryosphere-associated atmospheric modifications during June–July–August (JJA). 4 Consider that such anomalous circulation would cause a northward shift in the synoptic-scale forcing and 3D temperature, humidity, and wind distributions that favor intense-thunderstorm formation. 17 Tornadogenesis within these storms requires precise spatial alignments of favorably distributed temperature, humidity, and wind, and thus any findings of decreases in zonal wind and wind shear 5 would alone suggest a reduced likelihood for tornado formation. This brief physical argument aside, our exploration is also motivated by the U.S. tornado incidence over the past decade, which except for a few years has been abnormally low, as has the Arctic sea ice. The purpose of this paper is to present initial evidence in support of the basic hypothesis is that low Arctic sea ice extent (SIE) contributes to a reduction in U.S. tornado activity as quantified by EF1+ tornado days (TOR). Results Figure 1a shows that the linear correlations between detrended TOR and detrended pan-Arctic SIE are maximized during boreal summer, with a Pearson (Spearman rank) correlation coefficient R p = +0.54 ( R s = +0.55) and p = 0.004 in July. For reference, a linear regression using the raw time series yields R p = +0.70,R s = +0.71, p = 0.000 in July (Fig. 1b ); if we allow the time series to extend over a longer period (1980–2015), regression analyses using the raw and detrended data, respectively, yield R p = +0.77, R s = +0.75, p = 0.000, and R p = +0.48, R s = +0.48, p = 0.003 in July (Supplement Fig. S1 ). Although not the focus of this study, we additionally find that the F/EF1+ tornado reports over this longer time series correlate strongly with SIE in July ( R p = + 0.57, R s = +0.55, p = 0.000 using raw data, and R p = +0.45, R s = +0.40, p = 0.006 using detrended data; Supplement Fig. S2 ). All of the July correlations would be statistically significant at the 5% level even with application of a Bonferroni correction for multiple comparisons (12 months). 18 This, incidentally, is not the case with correlations between TOR and Arctic Oscillation index, which are relatively low in July ( R p = −0.14, p = 0.492) and in all other months. Fig. 1 Scatterplots of a detrended monthly mean sea-ice extent (SIE) versus detrended monthly E/EF1+ tornado days (TOR), b raw monthly mean SIE versus raw monthly TOR, and c time series of monthly TOR, all over the period 1990–2015. Solid lines show linear fit. Pearson correlation coefficient ( R p ), Spearman rank correlation coefficient ( R s ), and p -value for each month are indicated near the top of each plot. Shading shows 95% confidence intervals from 10,000 bootstrapped resamples Full size image These are contemporaneous correlations, but it would seem reasonable to also expect a lagged effect of Arctic sea ice on tornado activity. Thus, we computed the linear regressions between detrended pan-Arctic SIE and the detrended TOR lagged by one and two months. Most of the lagged correlations are relatively low and statistically insignificant (Table 1 ), with notable exception of the regressions with July SIE. For example, Table 1 indicates that the 2-month lag of TOR from July SIE (i.e., July SIE and September TOR) results in R p = +0.51 (and p = 0.007). The 1-month lag of TOR from July SIE (i.e., July SIE and August TOR) results in R p = +0.30 (and p = 0.132), which is higher than that between August SIE and August TOR, but still not statistically significant. The conclusion from this analysis is that July SIE is a<|im_end|> <|im_start|>assistant The effects of global climate change taking place in the Arctic may influence weather much closer to home for millions of Americans, researchers report. The United States has experienced many changes in severe-weather behavior over the past decade, including fewer tornado touchdowns in than in the past. A new study suggests that atmospheric circulation changes that coincide with a loss of Arctic sea ice may be partly to blame. Atmospheric scientists from the University of Illinois at Urbana-Champaign and Purdue University report their findings in the journal Climate and Atmospheric Science. "A relationship between Arctic sea ice and tornadoes in the U.S. may seem unlikely," said (Robert) Jeff Trapp , a professor of atmospheric sciences at the U. of I. and a co-author. "But it is hard to ignore the mounting evidence in support of the connection." The researchers performed statistical analyses of nearly three decades of historical weather and climate data and found significant correlations between tornado activity and the extent of Arctic sea ice—especially during the month July. The team believes that the reduction in tornado activity boils down to how the diminishing Arctic sea ice controls the path of the jet stream. As Arctic sea ice retreats, the jet stream migrates from its traditional summer path over states like Montana and South Dakota to areas farther north, and the atmospheric conditions that are favorable for tornado formation follow suit. "Tornadoes and their parent thunderstorms are fueled by wind shear and moisture," Trapp said. "When the jet stream migrates north, it takes the wind shear along for the ride, but not always the moisture. So, even though thunderstorms may still develop, they tend not to generate tornadoes because one of the essential ingredients for tornado formation is now missing." The team believes that the correlation between Arctic ice retreat and jet stream migration may lead to advances in seasonal severe weather prediction. "One of the reasons that we focused on sea ice is because, like the ocean and land, it is relatively slow to evolve," Trapp said. "Because sea ice and the atmosphere are coupled, the response of the atmosphere is also relatively slow. We can use this property to help make long-term predictions for tornadoes and hail, similar to the way predictions are made for hurricane seasons." But before doing so, Trapp said they still need to understand the drivers of the sea ice changes and what role the tropics may be playing. It remains unclear as to why this correlation is particularly dominant during the month of July, the researchers said, and they admit that they are only at the tip of the iceberg in terms of understanding the overall effects of climate change, and climate variability, on severe weather. <|im_end|>

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1,989

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Seismological models from Apollo missions provided the first records of the Moon inner structure with a decrease in seismic wave velocities at the core–mantle boundary 1 , 2 , 3 . The resolution of these records prevents a strict detection of a putative lunar solid inner core and the impact of the lunar mantle overturn in the lowest part of the Moon is still discussed 4 , 5 , 6 , 7 . Here we combine geophysical and geodesic constraints from Monte Carlo exploration and thermodynamical simulations for different Moon internal structures to show that only models with a low viscosity zone enriched in ilmenite and an inner core present densities deduced from thermodynamic constraints compatible with densities deduced from tidal deformations. We thus obtain strong indications in favour of the lunar mantle overturn scenario and, in this context, demonstrate the existence of the lunar inner core with a radius of 258 ± 40 km and density 7,822 ± 1,615 kg m −3 . Our results question the evolution of the Moon magnetic field thanks to its demonstration of the existence of the inner core and support a global mantle overturn scenario that brings substantial insights on the timeline of the lunar bombardment in the first billion years of the Solar System 8 . Main The lunar mantle overturn has been proposed to explain the abundances of TiO 2 , FeO and heat-producing elements (U, Th and K) in the source region of lunar basalts and the sequestration of highly siderophile elements (HSEs) and iron–sulfur in the lunar mantle 8 , 9 , 10 , 11 . Rocks containing iron–titanium oxide are called ilmenite-bearing cumulates (IBCs) and form during the slow cooling of lunar magma ocean. These IBCs are concentrated through the process of magmatic segregation 12 . The IBCs would contain ilmenite, a dense iron–titanium oxide (FeTiO 3 ) forming a solid solution with geikielite (MgTiO 3 ) 13 . The partial melt of the IBCs is denser and less buoyant than the surrounding mantle. Hence, the IBCs may sink through the mantle by gravitational instability and stabilize at the core–mantle boundary (CMB) of the Moon 6 . This event is invoked to drive the deep lunar mantle overturn, hereafter called DLMO (see Methods ). These IBCs tracers of the DLMO can be identified by their lower viscosity and lower solidus temperature in comparison with other lunar mantle material 6 . Furthermore, the existence of a solid inner core is not clearly demonstrated, as the seismic profiles obtained with the Apollo missions can be explained equally well with or without an inner core 2 , 3 ; see also ref. 14 . Here we combine lunar tidal deformations of degree 2 Love numbers, frequency-dependent quality factors, mass and the moment of inertia to estimate the thicknesses, densities and viscosities of a layered Moon with or without an inner core. To compute the tidal deformations, we use the semi-analytical code ALMA 15 adapted to the tidal forcing 16 and using 1D profiles of density, rigidity and viscosity as input parameters. Geophysical and geodesic constraints On the basis of random-walk Monte Carlo samplings for these quantities and over intervals corresponding to state-of-the-art estimations, we select models that are consistent at 2 σ with the published geophysical constraints (see Methods for more details). These observational constraints are the total mass of the Moon, its moment of inertia and its tidal deformation (characterized by parameters k 2 , h 2 and the monthly and yearly quality factors) at 2 σ uncertainties of the published estimations. In the case of several estimations (as for h 2 with the lunar laser ranging and altimetry determinations), we consider as uncertainty the largest interval encompassing the different published values. The selected profiles given in Table 1 represent 0.12% of a total of 120,000 simulations. The crustal thickness is fixed according to the GRAIL average crustal model with a density of 2,649 kg m −3 , representative to an average crustal bulk porosity of 9.5% (ref. 17 ). For the mantle, its density determination is part of the random-walk Monte Carlo sampling but only to keep the balance of the global mass. Furthermore, we verified that the deduced mantle densities are consistent with the S-wave velocity models of refs. 2 , 3 , as given in Extended Data Table 3 . Finally, we define the inner core with a fixed rigidity and as purely elastic with infinite viscosity, in contrast with the outer core, which is a Newtonian fluid with no rigidity and a non-zero viscosity (see Extended Data Table 3 ). In Table 1 , the radii of the different layers are well constrained as their 2 σ uncertainties and are usually smaller than 9.5%, except for the radius of the inner core, for which the dispersion reaches 15.5%. In the hypothesis of a Moon without an inner core, our estimate for the density of the viscous core is 7,757 ± 1,749 kg m −3 . This density is on average, slightly lower than that expected for a purely metal-rich core. It rather indicates an alloy of iron with lighter elements, similar to a liquid Fe-S at 0.1% of sulfide content despite the wide range of uncertainty 18 . The large viscosity (10 18.45 ± 1.85 Pa s) we derived for the models without an inner core allows rejecting the hypothesis of an entirely inviscid fluid core (for example, refs. 2 , 19 ). Table 1 Lunar 1D profile characteristics deduced from this study Full size table For the hypothesis of a Moon having both a viscous core and a solid inner core, the density and the viscosity of the outer core as given in Table 1 are even smaller (5,025 ± 604 kg m −3 and 10 16.92 ± 0.08 Pa s, respectively). Despite the wide dispersion in densities, this is compatible with a differentiation scenario in which the heavier elements sunk to the solid inner core and only lighter elements remain in the outer", "role": "user" }, { "content": "A small team of astronomers at Université Côte d'Azur, Observatoire de la Côte d'Azur, working with a colleague from MCCE, Observatoire de Paris, Sorbonne Université, has found more evidence that the moon has an inner core similar to Earth's. In their study, reported in the journal Nature, the group analyzed data from a wide variety of sources and used it to create models depicting the inner parts of the moon In 2011, planetary scientists at NASA used seismic data recorded by Apollo astronauts to predict what might lie at the center of the moon. They suggested it was likely that there was a solid inner core with a radius of approximately 240 kilometers. In this new effort, the researchers used a variety of sources to make similar estimates and found evidence that matches closely with the NASA results. To learn more about the moon's core, the research team collected data from several space missions and from several lunar-based ranging experiments. They used that data to create a likely profile for the interior of the moon, including characteristics such as deformations created due to gravitational interactions with the Earth, the moon's distance from Earth and also the moon's density. They then input all of their data into a modeling application. Next, they ran multiple modeling scenarios to see which corresponded most closely with real-world data. The model that fit most closely to observations revealed evidence of active overturn, where denser material is pulled closer to the core over time, forcing lighter material upward. This finding helps explain how many of the elements found in volcanic regions of the moon got there. The other main finding was that the density of the inner core matched closely with that of Earth's, suggesting it is likely made of iron. The models also showed that the inner core has a radius of approximately 258 kilometers and a density of approximately 7,822 kilograms per cubic meter. It also showed the outer core to be a fluid layer covering the inner core with a radius of 362 kilometers. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Seismological models from Apollo missions provided the first records of the Moon inner structure with a decrease in seismic wave velocities at the core–mantle boundary 1 , 2 , 3 . The resolution of these records prevents a strict detection of a putative lunar solid inner core and the impact of the lunar mantle overturn in the lowest part of the Moon is still discussed 4 , 5 , 6 , 7 . Here we combine geophysical and geodesic constraints from Monte Carlo exploration and thermodynamical simulations for different Moon internal structures to show that only models with a low viscosity zone enriched in ilmenite and an inner core present densities deduced from thermodynamic constraints compatible with densities deduced from tidal deformations. We thus obtain strong indications in favour of the lunar mantle overturn scenario and, in this context, demonstrate the existence of the lunar inner core with a radius of 258 ± 40 km and density 7,822 ± 1,615 kg m −3 . Our results question the evolution of the Moon magnetic field thanks to its demonstration of the existence of the inner core and support a global mantle overturn scenario that brings substantial insights on the timeline of the lunar bombardment in the first billion years of the Solar System 8 . Main The lunar mantle overturn has been proposed to explain the abundances of TiO 2 , FeO and heat-producing elements (U, Th and K) in the source region of lunar basalts and the sequestration of highly siderophile elements (HSEs) and iron–sulfur in the lunar mantle 8 , 9 , 10 , 11 . Rocks containing iron–titanium oxide are called ilmenite-bearing cumulates (IBCs) and form during the slow cooling of lunar magma ocean. These IBCs are concentrated through the process of magmatic segregation 12 . The IBCs would contain ilmenite, a dense iron–titanium oxide (FeTiO 3 ) forming a solid solution with geikielite (MgTiO 3 ) 13 . The partial melt of the IBCs is denser and less buoyant than the surrounding mantle. Hence, the IBCs may sink through the mantle by gravitational instability and stabilize at the core–mantle boundary (CMB) of the Moon 6 . This event is invoked to drive the deep lunar mantle overturn, hereafter called DLMO (see Methods ). These IBCs tracers of the DLMO can be identified by their lower viscosity and lower solidus temperature in comparison with other lunar mantle material 6 . Furthermore, the existence of a solid inner core is not clearly demonstrated, as the seismic profiles obtained with the Apollo missions can be explained equally well with or without an inner core 2 , 3 ; see also ref. 14 . Here we combine lunar tidal deformations of degree 2 Love numbers, frequency-dependent quality factors, mass and the moment of inertia to estimate the thicknesses, densities and viscosities of a layered Moon with or without an inner core. To compute the tidal deformations, we use the semi-analytical code ALMA 15 adapted to the tidal forcing 16 and using 1D profiles of density, rigidity and viscosity as input parameters. Geophysical and geodesic constraints On the basis of random-walk Monte Carlo samplings for these quantities and over intervals corresponding to state-of-the-art estimations, we select models that are consistent at 2 σ with the published geophysical constraints (see Methods for more details). These observational constraints are the total mass of the Moon, its moment of inertia and its tidal deformation (characterized by parameters k 2 , h 2 and the monthly and yearly quality factors) at 2 σ uncertainties of the published estimations. In the case of several estimations (as for h 2 with the lunar laser ranging and altimetry determinations), we consider as uncertainty the largest interval encompassing the different published values. The selected profiles given in Table 1 represent 0.12% of a total of 120,000 simulations. The crustal thickness is fixed according to the GRAIL average crustal model with a density of 2,649 kg m −3 , representative to an average crustal bulk porosity of 9.5% (ref. 17 ). For the mantle, its density determination is part of the random-walk Monte Carlo sampling but only to keep the balance of the global mass. Furthermore, we verified that the deduced mantle densities are consistent with the S-wave velocity models of refs. 2 , 3 , as given in Extended Data Table 3 . Finally, we define the inner core with a fixed rigidity and as purely elastic with infinite viscosity, in contrast with the outer core, which is a Newtonian fluid with no rigidity and a non-zero viscosity (see Extended Data Table 3 ). In Table 1 , the radii of the different layers are well constrained as their 2 σ uncertainties and are usually smaller than 9.5%, except for the radius of the inner core, for which the dispersion reaches 15.5%. In the hypothesis of a Moon without an inner core, our estimate for the density of the viscous core is 7,757 ± 1,749 kg m −3 . This density is on average, slightly lower than that expected for a purely metal-rich core. It rather indicates an alloy of iron with lighter elements, similar to a liquid Fe-S at 0.1% of sulfide content despite the wide range of uncertainty 18 . The large viscosity (10 18.45 ± 1.85 Pa s) we derived for the models without an inner core allows rejecting the hypothesis of an entirely inviscid fluid core (for example, refs. 2 , 19 ). Table 1 Lunar 1D profile characteristics deduced from this study Full size table For the hypothesis of a Moon having both a viscous core and a solid inner core, the density and the viscosity of the outer core as given in Table 1 are even smaller (5,025 ± 604 kg m −3 and 10 16.92 ± 0.08 Pa s, respectively). Despite the wide dispersion in densities, this is compatible with a differentiation scenario in which the heavier elements sunk to the solid inner core and only lighter elements remain in the outer<|im_end|> <|im_start|>assistant A small team of astronomers at Université Côte d'Azur, Observatoire de la Côte d'Azur, working with a colleague from MCCE, Observatoire de Paris, Sorbonne Université, has found more evidence that the moon has an inner core similar to Earth's. In their study, reported in the journal Nature, the group analyzed data from a wide variety of sources and used it to create models depicting the inner parts of the moon In 2011, planetary scientists at NASA used seismic data recorded by Apollo astronauts to predict what might lie at the center of the moon. They suggested it was likely that there was a solid inner core with a radius of approximately 240 kilometers. In this new effort, the researchers used a variety of sources to make similar estimates and found evidence that matches closely with the NASA results. To learn more about the moon's core, the research team collected data from several space missions and from several lunar-based ranging experiments. They used that data to create a likely profile for the interior of the moon, including characteristics such as deformations created due to gravitational interactions with the Earth, the moon's distance from Earth and also the moon's density. They then input all of their data into a modeling application. Next, they ran multiple modeling scenarios to see which corresponded most closely with real-world data. The model that fit most closely to observations revealed evidence of active overturn, where denser material is pulled closer to the core over time, forcing lighter material upward. This finding helps explain how many of the elements found in volcanic regions of the moon got there. The other main finding was that the density of the inner core matched closely with that of Earth's, suggesting it is likely made of iron. The models also showed that the inner core has a radius of approximately 258 kilometers and a density of approximately 7,822 kilograms per cubic meter. It also showed the outer core to be a fluid layer covering the inner core with a radius of 362 kilometers. <|im_end|>

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91004, 323, 3980, 2601, 292, 17413, 1952, 279, 8197, 315, 4288, 2695, 1727, 46867, 58870, 10167, 81402, 369, 1521, 33776, 323, 927, 28090, 12435, 311, 1614, 8838, 10826, 38921, 15279, 811, 11, 584, 3373, 4211, 430, 527, 13263, 520, 220, 17, 48823, 449, 279, 4756, 3980, 91004, 17413, 320, 4151, 19331, 369, 810, 3649, 570, 4314, 90380, 17413, 527, 279, 2860, 3148, 315, 279, 17781, 11, 1202, 4545, 315, 78552, 323, 1202, 86559, 91621, 320, 19740, 1534, 555, 5137, 597, 220, 17, 1174, 305, 220, 17, 323, 279, 15438, 323, 45370, 4367, 9547, 8, 520, 220, 17, 48823, 69867, 315, 279, 4756, 15279, 811, 13, 763, 279, 1162, 315, 3892, 15279, 811, 320, 300, 369, 305, 220, 17, 449, 279, 57811, 21120, 24950, 323, 4902, 318, 15501, 6449, 811, 705, 584, 2980, 439, 27924, 279, 7928, 10074, 38632, 287, 279, 2204, 4756, 2819, 13, 578, 4183, 21542, 2728, 304, 6771, 220, 16, 4097, 220, 15, 13, 717, 4, 315, 264, 2860, 315, 220, 4364, 11, 931, 47590, 13, 578, 40712, 278, 26839, 374, 8521, 4184, 311, 279, 65120, 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30239, 828, 505, 264, 7029, 8205, 315, 8336, 323, 1511, 433, 311, 1893, 4211, 60794, 279, 9358, 5596, 315, 279, 18266, 763, 220, 679, 16, 11, 62938, 14248, 520, 22146, 1511, 72579, 828, 12715, 555, 36250, 69522, 311, 7168, 1148, 2643, 10457, 520, 279, 4219, 315, 279, 18266, 13, 2435, 12090, 433, 574, 4461, 430, 1070, 574, 264, 6573, 9358, 6332, 449, 264, 10801, 315, 13489, 220, 8273, 41668, 13, 763, 420, 502, 5149, 11, 279, 12074, 1511, 264, 8205, 315, 8336, 311, 1304, 4528, 17989, 323, 1766, 6029, 430, 9248, 15499, 449, 279, 22146, 3135, 13, 2057, 4048, 810, 922, 279, 18266, 596, 6332, 11, 279, 3495, 2128, 14890, 828, 505, 3892, 3634, 25664, 323, 505, 3892, 57811, 6108, 24950, 21896, 13, 2435, 1511, 430, 828, 311, 1893, 264, 4461, 5643, 369, 279, 15135, 315, 279, 18266, 11, 2737, 17910, 1778, 439, 79212, 811, 3549, 4245, 311, 71019, 22639, 449, 279, 9420, 11, 279, 18266, 596, 6138, 505, 9420, 323, 1101, 279, 18266, 596, 17915, 13, 2435, 1243, 1988, 682, 315, 872, 828, 1139, 264, 34579, 3851, 13, 9479, 11, 814, 10837, 5361, 34579, 26350, 311, 1518, 902, 8024, 291, 1455, 15499, 449, 1972, 31184, 828, 13, 578, 1646, 430, 5052, 1455, 15499, 311, 24654, 10675, 6029, 315, 4642, 67687, 11, 1405, 39950, 261, 3769, 374, 13541, 12401, 311, 279, 6332, 927, 892, 11, 25957, 30673, 3769, 40872, 13, 1115, 9455, 8779, 10552, 1268, 1690, 315, 279, 5540, 1766, 304, 67164, 13918, 315, 279, 18266, 2751, 1070, 13, 578, 1023, 1925, 9455, 574, 430, 279, 17915, 315, 279, 9358, 6332, 18545, 15499, 449, 430, 315, 9420, 596, 11, 23377, 433, 374, 4461, 1903, 315, 11245, 13, 578, 4211, 1101, 8710, 430, 279, 9358, 6332, 706, 264, 10801, 315, 13489, 220, 15966, 41668, 323, 264, 17915, 315, 13489, 220, 22, 11, 23105, 85402, 824, 41999, 23819, 13, 1102, 1101, 8710, 279, 16335, 6332, 311, 387, 264, 15962, 6324, 18702, 279, 9358, 6332, 449, 264, 10801, 315, 220, 18509, 41668, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective We investigated whether the evaluation of bone mineral density (BMD) provides independent and incremental prognostic value for predicting atherosclerotic cardiovascular disease (ASCVD) in women. Methods A total of 12 681 women aged 50–80 years (mean, 63.0±7.8 years) who underwent dual-energy X-ray absorptiometry were retrospectively analysed. We assessed the hazard ratio (HR) for ASCVD events (ASCVD death, non-fatal myocardial infarction and ischaemic stroke) according to the BMD or a clinical diagnosis of osteopenia or osteoporosis, with adjustment for clinical risk factors, including age, body mass index, hypertension, type 2 diabetes, hyperlipidaemia, current smoking and previous fracture. We also evaluated whether the addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors improved the prediction for ASCVD events. Results In total, 468 women (3.7%) experienced ASCVD events during follow-up (median, 9.2 years). Lower BMD at the lumbar spine, femur neck and total hip was independently associated with higher risk for ASCVD events (adjusted HR per 1-standard deviation decrease in BMD: 1.16, p<0.001; 1.29, p<0.001; 1.38, p<0.001; respectively). A clinical diagnosis of osteoporosis was also independently associated with higher risk for ASCVD events (adjusted HR: 1.79, p<0.001). The addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors demonstrated significant incremental value in discriminating ASCVD events (addition of total hip BMD, p for difference <0.001). Conclusion The evaluation of BMD provides independent and incremental prognostic value for ASCVD in women and thus may improve risk stratification in women. coronary artery disease Data availability statement Data are available on reasonable request by contacting the corresponding authors ([email protected]; [email protected]). googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 10 news outlets Blogged by 1 Tweeted by 14 28 readers on Mendeley Supplementary materials Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions coronary artery disease Introduction Atherosclerosis and osteoporosis are major age-related diseases, predominantly contributing to significant morbidity and mortality in women. 1 Atherosclerosis comprises a multifactorial process resulting in atherosclerotic cardiovascular disease (ASCVD), which is the leading cause of death globally. 2 Osteoporosis, characterised by low bone mineral density (BMD) and bone structure deterioration, reflects a condition of impaired bone strength and, thus, higher risk of fracture, leading to a loss of independence and higher financial burden. 3 Previous epidemiologic studies indicate the coincidental occurrence of atherosclerosis and osteoporosis, 4 suggesting a potential association between these diseases. 1 4 However, most of the available data were derived from cross-sectional studies, and the prognostic value of BMD in predicting ASCVD has not been well evaluated. Furthermore, there is conflicting evidence regarding an independent association between osteoporosis and atherosclerosis, which both occur during the ageing process and share common risk factors. 1 4–7 As the population-adjusted risk of ASCVD mortality is higher in women (21%) than in men (15%), traditional risk factors may differentially affect men and women. 8 Additionally, as the performance of the conventional prediction algorithm is limited in women, 9 10 new strategies that go beyond the measurement of conventional risk factors are needed to better identify women at higher risk of ASCVD. Given that millions of women are screened for osteoporosis using dual-energy X-ray absorptiometry (DXA), potential associations between low bone mass and ASCVD in women would provide an opportunity to improve the risk stratification of women without any additional costs. Therefore, we investigated whether the evaluation of BMD provides independent and incremental prognostic value for ASCVD events in a large cohort of women who underwent DXA. Methods Study population The medical records of consecutive women aged 50–80 years who underwent DXA as a screening for osteoporosis at Seoul National University Bundang Hospital between 2005 and 2014 were retrospectively reviewed. For women who underwent repeated DXAs during the study period, only the first DXA was included. Among this initial cohort (n=14 333), we excluded patients with a history of myocardial infarction (MI) or coronary revascularisation (n=285), malignant tumour (n=870), chronic kidney disease (n=89) and previous osteoporosis treatment (n=11). Additionally, patients without complete BMD measurements at the lumbar spine, femur neck and total hip (n=121) and those without follow-up data (n=276) were excluded. Finally, a total of 12 681 women were included for analysis ( online supplemental figure 1 ). Supplemental material [heartjnl-2020-318764supp001.pdf] Patient and public involvement Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of the study. Ascertainment of risk factors Baseline characteristics were acquired by a dedicated review of the electronic health records of our institution, which was fully digitalised from its foundation. 11 The diagnostic definitions for the clinical risk factors were as previously validated: hypertension (HTN) was defined as the presence of a diagnosis of HTN, blood pressure higher than 140/90 mm Hg, or anti-hypertensive medication use within 6 months of the index DXA study date; type 2 diabetes mellitus (T2DM) was defined as the presence of a diagnosis of T2DM, fasting plasma glucose level of 126 mg/dL or higher, haemoglobin A1c level of 6.5% or higher, or anti-diabetic medication use within 6 months of the index date; and hyperlipidaemia (HL) was defined as the presence of a diagnosis of HL, total cholesterol level of 240 mg/dL or higher, low-density lipoprotein cholesterol level of 160 mg/dL or higher, or treatment with statins within 6 months of the index date. 12–16 Body mass index (BMI) was calculated by the weight (kg) divided by the square of the height (m 2 ), required during the DXA scan. The predicted 10-year ASCVD risk was estimated using the Korean Risk Prediction Model, which is a recalibration of the Pooled Cohort Equation specifically for the Korean population. 17 Measurement of BMD BMD was measured at the lumbar spine, femoral neck and", "role": "user" }, { "content": "Thin and brittle bones are strongly linked to women's heart disease risk, with thinning of the lower (lumbar) spine, top of the thigh bone (femoral neck), and hip especially predictive of a heightened heart attack and stroke risk, suggests research in the journal Heart. Osteoporosis, often dubbed brittle bone disease, is common, particularly among women after the menopause. It is characterised by thinning and weakened bones and a heightened fracture risk. Previously published research indicates that people with osteoporosis often have atherosclerosis (artery hardening and narrowing), suggesting that both conditions may be linked. The risk of a cardiovascular death is higher in women (21%) than it is in men (15%), and the predictive risk framework for heart disease is skewed towards men, so factors that better identify women at higher risk of a heart attack or stroke are needed, say the researchers. Millions of women are screened for osteoporosis using a DXA scan, so this assessment might provide an ideal opportunity to identify any potential associations between thinning bones and atherosclerosis, and those women most at risk of heart disease, without incurring any additional costs or further exposure to radiation, they add. To test this out, the researchers reviewed the medical records of 50-80 year old women who had had a DXA scan to check for osteoporosis at Seoul National University Bundang Hospital between 2005 and 2014. After excluding those who already had heart disease and other serious illness at the time of the scan, the final analysis included 12,681 women whose health was tracked for an average of 9 years, using national registry data. In all, 468 women (around 4%) had a heart attack or stroke during the monitoring period. Some 237 (2%) died. Thinning/weakened bones, expressed as a low bone mineral density score at the lumbar spine, femoral neck, and hip, were independently associated with a heightened (16% to 38%) risk of heart attack or stroke after taking account of potentially influential factors, such as age, high blood pressure, high cholesterol, smoking, and a previous bone break. And a formal diagnosis of osteoporosis was also independently associated with a 79% higher risk of cardiovascular disease. Adding bone mineral density score or a clinical diagnosis of osteoporosis or osteopenia (precursor to osteoporosis) to clinical risk factors more effectively predicted risk than clinical risk factors alone. It's not clear exactly how osteoporosis and atherosclerosis might be linked, but long term inflammation and cumulative oxidative stress have key roles in both age-related bone loss and atherosclerosis, while sex hormones, particularly oestrogen, help regulate bone turnover and the vascular system, explain the researchers. This is an observational study, and as such can't establish cause, only correlation. And the researchers acknowledge several limitations to their findings: the study included women from one medical centre in South Korea so the results might not be more widely applicable. And they weren't able to gather potentially important information on physical activity levels or steroid use, both of which affect bone mineral density and cardiovascular disease risk. Nevertheless, they conclude: \"Considering that [DXA scanning] is widely used to screen for osteopenia and osteoporosis in asymptomatic women, the significant association between [bone mineral density] and higher risk of [cardiovascular disease] provides an opportunity for large-scale risk assessment in women without additional cost and radiation exposure.\" In a linked editorial, Drs Dexter Canoy and Kazem Rahimi of the Nuffield Department of Women's and Reproductive Health, University of Oxford, agree, adding that further research in different settings is warranted. But they suggest: \"Perhaps it is high time to establish how bone health affects vasculature and understand the underlying pathophysiology that links osteoporotic and atherosclerotic conditions. In doing so, we might just discover new ways to improve the treatment of, and care for, the hearts and minds of women, as well as of men.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective We investigated whether the evaluation of bone mineral density (BMD) provides independent and incremental prognostic value for predicting atherosclerotic cardiovascular disease (ASCVD) in women. Methods A total of 12 681 women aged 50–80 years (mean, 63.0±7.8 years) who underwent dual-energy X-ray absorptiometry were retrospectively analysed. We assessed the hazard ratio (HR) for ASCVD events (ASCVD death, non-fatal myocardial infarction and ischaemic stroke) according to the BMD or a clinical diagnosis of osteopenia or osteoporosis, with adjustment for clinical risk factors, including age, body mass index, hypertension, type 2 diabetes, hyperlipidaemia, current smoking and previous fracture. We also evaluated whether the addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors improved the prediction for ASCVD events. Results In total, 468 women (3.7%) experienced ASCVD events during follow-up (median, 9.2 years). Lower BMD at the lumbar spine, femur neck and total hip was independently associated with higher risk for ASCVD events (adjusted HR per 1-standard deviation decrease in BMD: 1.16, p<0.001; 1.29, p<0.001; 1.38, p<0.001; respectively). A clinical diagnosis of osteoporosis was also independently associated with higher risk for ASCVD events (adjusted HR: 1.79, p<0.001). The addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors demonstrated significant incremental value in discriminating ASCVD events (addition of total hip BMD, p for difference <0.001). Conclusion The evaluation of BMD provides independent and incremental prognostic value for ASCVD in women and thus may improve risk stratification in women. coronary artery disease Data availability statement Data are available on reasonable request by contacting the corresponding authors ([email protected]; [email protected]). googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 10 news outlets Blogged by 1 Tweeted by 14 28 readers on Mendeley Supplementary materials Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions coronary artery disease Introduction Atherosclerosis and osteoporosis are major age-related diseases, predominantly contributing to significant morbidity and mortality in women. 1 Atherosclerosis comprises a multifactorial process resulting in atherosclerotic cardiovascular disease (ASCVD), which is the leading cause of death globally. 2 Osteoporosis, characterised by low bone mineral density (BMD) and bone structure deterioration, reflects a condition of impaired bone strength and, thus, higher risk of fracture, leading to a loss of independence and higher financial burden. 3 Previous epidemiologic studies indicate the coincidental occurrence of atherosclerosis and osteoporosis, 4 suggesting a potential association between these diseases. 1 4 However, most of the available data were derived from cross-sectional studies, and the prognostic value of BMD in predicting ASCVD has not been well evaluated. Furthermore, there is conflicting evidence regarding an independent association between osteoporosis and atherosclerosis, which both occur during the ageing process and share common risk factors. 1 4–7 As the population-adjusted risk of ASCVD mortality is higher in women (21%) than in men (15%), traditional risk factors may differentially affect men and women. 8 Additionally, as the performance of the conventional prediction algorithm is limited in women, 9 10 new strategies that go beyond the measurement of conventional risk factors are needed to better identify women at higher risk of ASCVD. Given that millions of women are screened for osteoporosis using dual-energy X-ray absorptiometry (DXA), potential associations between low bone mass and ASCVD in women would provide an opportunity to improve the risk stratification of women without any additional costs. Therefore, we investigated whether the evaluation of BMD provides independent and incremental prognostic value for ASCVD events in a large cohort of women who underwent DXA. Methods Study population The medical records of consecutive women aged 50–80 years who underwent DXA as a screening for osteoporosis at Seoul National University Bundang Hospital between 2005 and 2014 were retrospectively reviewed. For women who underwent repeated DXAs during the study period, only the first DXA was included. Among this initial cohort (n=14 333), we excluded patients with a history of myocardial infarction (MI) or coronary revascularisation (n=285), malignant tumour (n=870), chronic kidney disease (n=89) and previous osteoporosis treatment (n=11). Additionally, patients without complete BMD measurements at the lumbar spine, femur neck and total hip (n=121) and those without follow-up data (n=276) were excluded. Finally, a total of 12 681 women were included for analysis ( online supplemental figure 1 ). Supplemental material [heartjnl-2020-318764supp001.pdf] Patient and public involvement Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of the study. Ascertainment of risk factors Baseline characteristics were acquired by a dedicated review of the electronic health records of our institution, which was fully digitalised from its foundation. 11 The diagnostic definitions for the clinical risk factors were as previously validated: hypertension (HTN) was defined as the presence of a diagnosis of HTN, blood pressure higher than 140/90 mm Hg, or anti-hypertensive medication use within 6 months of the index DXA study date; type 2 diabetes mellitus (T2DM) was defined as the presence of a diagnosis of T2DM, fasting plasma glucose level of 126 mg/dL or higher, haemoglobin A1c level of 6.5% or higher, or anti-diabetic medication use within 6 months of the index date; and hyperlipidaemia (HL) was defined as the presence of a diagnosis of HL, total cholesterol level of 240 mg/dL or higher, low-density lipoprotein cholesterol level of 160 mg/dL or higher, or treatment with statins within 6 months of the index date. 12–16 Body mass index (BMI) was calculated by the weight (kg) divided by the square of the height (m 2 ), required during the DXA scan. The predicted 10-year ASCVD risk was estimated using the Korean Risk Prediction Model, which is a recalibration of the Pooled Cohort Equation specifically for the Korean population. 17 Measurement of BMD BMD was measured at the lumbar spine, femoral neck and<|im_end|> <|im_start|>assistant Thin and brittle bones are strongly linked to women's heart disease risk, with thinning of the lower (lumbar) spine, top of the thigh bone (femoral neck), and hip especially predictive of a heightened heart attack and stroke risk, suggests research in the journal Heart. Osteoporosis, often dubbed brittle bone disease, is common, particularly among women after the menopause. It is characterised by thinning and weakened bones and a heightened fracture risk. Previously published research indicates that people with osteoporosis often have atherosclerosis (artery hardening and narrowing), suggesting that both conditions may be linked. The risk of a cardiovascular death is higher in women (21%) than it is in men (15%), and the predictive risk framework for heart disease is skewed towards men, so factors that better identify women at higher risk of a heart attack or stroke are needed, say the researchers. Millions of women are screened for osteoporosis using a DXA scan, so this assessment might provide an ideal opportunity to identify any potential associations between thinning bones and atherosclerosis, and those women most at risk of heart disease, without incurring any additional costs or further exposure to radiation, they add. To test this out, the researchers reviewed the medical records of 50-80 year old women who had had a DXA scan to check for osteoporosis at Seoul National University Bundang Hospital between 2005 and 2014. After excluding those who already had heart disease and other serious illness at the time of the scan, the final analysis included 12,681 women whose health was tracked for an average of 9 years, using national registry data. In all, 468 women (around 4%) had a heart attack or stroke during the monitoring period. Some 237 (2%) died. Thinning/weakened bones, expressed as a low bone mineral density score at the lumbar spine, femoral neck, and hip, were independently associated with a heightened (16% to 38%) risk of heart attack or stroke after taking account of potentially influential factors, such as age, high blood pressure, high cholesterol, smoking, and a previous bone break. And a formal diagnosis of osteoporosis was also independently associated with a 79% higher risk of cardiovascular disease. Adding bone mineral density score or a clinical diagnosis of osteoporosis or osteopenia (precursor to osteoporosis) to clinical risk factors more effectively predicted risk than clinical risk factors alone. It's not clear exactly how osteoporosis and atherosclerosis might be linked, but long term inflammation and cumulative oxidative stress have key roles in both age-related bone loss and atherosclerosis, while sex hormones, particularly oestrogen, help regulate bone turnover and the vascular system, explain the researchers. This is an observational study, and as such can't establish cause, only correlation. And the researchers acknowledge several limitations to their findings: the study included women from one medical centre in South Korea so the results might not be more widely applicable. And they weren't able to gather potentially important information on physical activity levels or steroid use, both of which affect bone mineral density and cardiovascular disease risk. Nevertheless, they conclude: "Considering that [DXA scanning] is widely used to screen for osteopenia and osteoporosis in asymptomatic women, the significant association between [bone mineral density] and higher risk of [cardiovascular disease] provides an opportunity for large-scale risk assessment in women without additional cost and radiation exposure." In a linked editorial, Drs Dexter Canoy and Kazem Rahimi of the Nuffield Department of Women's and Reproductive Health, University of Oxford, agree, adding that further research in different settings is warranted. But they suggest: "Perhaps it is high time to establish how bone health affects vasculature and understand the underlying pathophysiology that links osteoporotic and atherosclerotic conditions. In doing so, we might just discover new ways to improve the treatment of, and care for, the hearts and minds of women, as well as of men." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Seminal fluid factors modulate the female immune response at conception to facilitate embryo implantation and reproductive success. Whether sperm affect this response has not been clear. We evaluated global gene expression by microarray in the mouse uterus after mating with intact or vasectomized males. Intact males induced greater changes in gene transcription, prominently affecting pro-inflammatory cytokine and immune regulatory genes, with TLR4 signaling identified as a top-ranked upstream driver. Recruitment of neutrophils and expansion of peripheral regulatory T cells were elevated by seminal fluid of intact males. In vitro, epididymal sperm induced IL6, CXCL2, and CSF3 in uterine epithelial cells of wild-type, but not Tlr4 null females. Collectively these experiments show that sperm assist in promoting female immune tolerance by eliciting uterine cytokine expression through TLR4-dependent signaling. The findings indicate a biological role for sperm beyond oocyte fertilization, in modulating immune mechanisms involved in female control of reproductive investment. Introduction Events at mating exert substantial influence on the likelihood of conception, embryo implantation and pregnancy success 1 , 2 . Male seminal fluid stimulates the female immune response to provoke a controlled inflammatory response that facilitates embryo implantation 2 , and promotes generation of immune tolerance for pregnancy 3 , 4 . Insufficient immune tolerance is linked with common reproductive disorders in women, including infertility, miscarriage, and pregnancy disorders 3 , and unresolved uterine inflammation after mating is associated with poor breeding performance in livestock animals 5 . Pregnancies conceived without seminal fluid contact have compromised outcomes in several mammalian species 2 , 6 . The female immune changes induced by seminal fluid at conception can in turn affect fetal development, and offspring survival and phenotype 7 , 8 , 9 , 10 . Interactions between seminal fluid and the female tract are described in several mammalian and invertebrate species 2 , 6 , 11 , 12 . In mammals, the female response to seminal fluid signals is best characterized in mice and humans 2 , 6 . We showed previously in mice, that factors in seminal fluid stimulate uterine epithelial cells to trigger an altered gene expression program, with more than 300 genes differentially expressed in the endometrium at 8 h after mating 13 . Cytokine signaling, inflammation and immune response pathways were prominent amongst the genes induced 13 . Ensuing production of pro-inflammatory cytokines and chemokines draws neutrophils, macrophages and dendritic cells from peripheral blood into the underlying endometrial stromal tissue 14 , 15 . Neutrophils are exuded across the uterine epithelium and into the uterine lumen, where they release neutrophil extracellular traps to eliminate microorganisms and selectively sequester a large proportion of sperm, permitting a smaller subset to retain fertilizing capacity 14 , 15 . This controlled inflammatory response extends from the cervix and uterus into the higher reproductive tract, to induce oviductal cytokines that support embryo development, and promote progesterone synthesis in the ovary 2 . In the lymph nodes draining the uterus, seminal fluid antigens prime the female adaptive immune response 4 , 16 , eliciting activation and expansion of suppressive regulatory T cells (Treg cells) 17 , 18 . Treg cells have essential functions at embryo implantation – acting to prevent immune destruction of the foreign embryo, to suppress and resolve inflammation, and to facilitate uterine vascular changes that support optimal placental and fetal development 4 , 19 . To date, the immune regulatory activity of seminal fluid has been attributed to factors in its plasma fraction, notably transforming growth factor beta (TGFB) 20 , 21 and E-series prostaglandins 20 , 22 , 23 . However, TGFB does not account for the full effect of seminal fluid in female tissues 20 , 24 and other signaling components likely exist 25 , 26 . TLR4 signaling is implicated as a key upstream driver of the uterine response, suggesting a signaling role for endogenous ligands of TLR4 in seminal fluid 13 . The extent to which sperm might contribute to evoking the female response to seminal fluid has not been determined. Close physical association between sperm and immune cells and/or epithelial cells lining the female tract occurs in mice 27 and many other species 28 . Sperm attachment to the uterine and oviductal epithelial is a mechanism for sperm sequestration and storage prior to ovulation 28 , but whether sperm elicit effects on female immune activation has not been formally considered. We have previously reported that the Treg cell-specific transcription factor Foxp3 , as well as a critical Treg cell-attracting chemokine Ccl19 , are more strongly expressed at the time of embryo implantation in the uterus of mice earlier exposed to seminal fluid of intact males, as opposed to vasectomized males 18 , implying that stronger immune tolerance may be generated when sperm are present. Here, we have investigated the specific contribution of sperm in the female response to seminal fluid. Initially, we compared global gene expression in the uterine endometrium of females mated to intact males versus vasectomized males, using Affymetrix microarray. We show that whole seminal fluid containing sperm elicits a pattern of immune response genes and pathways that is distinct to the expression profile elicited by seminal plasma alone, and is associated with elevated neutrophil recruitment into the uterus, and stronger expansion of Treg cells within draining lymph nodes. We then confirm using an in vitro model and Tlr4 null mutant mice, that sperm specifically induce neutrophil-regulating cytokines IL6, CXCL2, and CSF3 through TLR4 signaling. These data reveal a novel physiological role for sperm at the time of conception and expand understanding of the mechanisms by which seminal fluid interacts with female tissues to generate maternal immune tolerance and reproductive success. Results Vasectomy alters the female response to seminal fluid after mating Previously we showed that seminal fluid induces substantial gene expression changes in the endometrial surface layer of the uterus after mating 13 . We have demonstrated using in vivo and in vitro approaches that soluble signaling factors in seminal plasma regulate several endometrial genes 7 , 14 , 20 ,", "role": "user" }, { "content": "Sperm are generally viewed as having just one action in reproduction—to fertilize the female's egg—but studies at the University of Adelaide are overturning that view. Published in Nature Research journal Communications Biology, new research shows that sperm also deliver signals directly to the female reproductive tissues to increase the chances of conception. Robinson Research Institute's Professor Sarah Robertson, who led the project, said: \"This research is the first to show that the female immune response is persuaded by signals in sperm to allow the male partner to fertilize her eggs and conceive a pregnancy. \"This overturns our current understanding of what sperm are capable of—they are not just carriers of genetic material, but also agents for convincing the female to invest reproductive resources with that male.\" It has been known that proteins in seminal fluid modulate the female immune response at conception to encourage her body to accept the foreign embryo. Whether sperm affect this response has not been clear until now. The team evaluated effects on global gene expression in the mouse uterus after mating with males with intact sperm, or vasectomized males. Intact males induced greater changes in female genes, particularly affecting immune response pathways. The females that had contact with sperm produced stronger immune tolerance than those females mated with vasectomised males. By examining effects of sperm interactions with female cells in cell culture experiments, the researchers confirmed the sperm were directly responsible. These new findings suggest that sperm health isn't only important for conceiving, but also has ongoing effects on the chances of a healthy baby. Factors like age, diet, weight, alcohol and smoking, and exposures to environmental chemicals can affect sperm quality in men and so might have greater consequences for pregnancy health than previously considered. \"Recognition that sperm influence reproductive events beyond simply fertilizing oocytes shows that sperm quality can have consequences for pregnancy health, beyond just conception,'' Professor Robertson said. \"Conditions like recurrent miscarriage, preeclampsia, preterm birth and stillbirth are affected by the female's immune response in ways that the partner's sperm contribute to.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Seminal fluid factors modulate the female immune response at conception to facilitate embryo implantation and reproductive success. Whether sperm affect this response has not been clear. We evaluated global gene expression by microarray in the mouse uterus after mating with intact or vasectomized males. Intact males induced greater changes in gene transcription, prominently affecting pro-inflammatory cytokine and immune regulatory genes, with TLR4 signaling identified as a top-ranked upstream driver. Recruitment of neutrophils and expansion of peripheral regulatory T cells were elevated by seminal fluid of intact males. In vitro, epididymal sperm induced IL6, CXCL2, and CSF3 in uterine epithelial cells of wild-type, but not Tlr4 null females. Collectively these experiments show that sperm assist in promoting female immune tolerance by eliciting uterine cytokine expression through TLR4-dependent signaling. The findings indicate a biological role for sperm beyond oocyte fertilization, in modulating immune mechanisms involved in female control of reproductive investment. Introduction Events at mating exert substantial influence on the likelihood of conception, embryo implantation and pregnancy success 1 , 2 . Male seminal fluid stimulates the female immune response to provoke a controlled inflammatory response that facilitates embryo implantation 2 , and promotes generation of immune tolerance for pregnancy 3 , 4 . Insufficient immune tolerance is linked with common reproductive disorders in women, including infertility, miscarriage, and pregnancy disorders 3 , and unresolved uterine inflammation after mating is associated with poor breeding performance in livestock animals 5 . Pregnancies conceived without seminal fluid contact have compromised outcomes in several mammalian species 2 , 6 . The female immune changes induced by seminal fluid at conception can in turn affect fetal development, and offspring survival and phenotype 7 , 8 , 9 , 10 . Interactions between seminal fluid and the female tract are described in several mammalian and invertebrate species 2 , 6 , 11 , 12 . In mammals, the female response to seminal fluid signals is best characterized in mice and humans 2 , 6 . We showed previously in mice, that factors in seminal fluid stimulate uterine epithelial cells to trigger an altered gene expression program, with more than 300 genes differentially expressed in the endometrium at 8 h after mating 13 . Cytokine signaling, inflammation and immune response pathways were prominent amongst the genes induced 13 . Ensuing production of pro-inflammatory cytokines and chemokines draws neutrophils, macrophages and dendritic cells from peripheral blood into the underlying endometrial stromal tissue 14 , 15 . Neutrophils are exuded across the uterine epithelium and into the uterine lumen, where they release neutrophil extracellular traps to eliminate microorganisms and selectively sequester a large proportion of sperm, permitting a smaller subset to retain fertilizing capacity 14 , 15 . This controlled inflammatory response extends from the cervix and uterus into the higher reproductive tract, to induce oviductal cytokines that support embryo development, and promote progesterone synthesis in the ovary 2 . In the lymph nodes draining the uterus, seminal fluid antigens prime the female adaptive immune response 4 , 16 , eliciting activation and expansion of suppressive regulatory T cells (Treg cells) 17 , 18 . Treg cells have essential functions at embryo implantation – acting to prevent immune destruction of the foreign embryo, to suppress and resolve inflammation, and to facilitate uterine vascular changes that support optimal placental and fetal development 4 , 19 . To date, the immune regulatory activity of seminal fluid has been attributed to factors in its plasma fraction, notably transforming growth factor beta (TGFB) 20 , 21 and E-series prostaglandins 20 , 22 , 23 . However, TGFB does not account for the full effect of seminal fluid in female tissues 20 , 24 and other signaling components likely exist 25 , 26 . TLR4 signaling is implicated as a key upstream driver of the uterine response, suggesting a signaling role for endogenous ligands of TLR4 in seminal fluid 13 . The extent to which sperm might contribute to evoking the female response to seminal fluid has not been determined. Close physical association between sperm and immune cells and/or epithelial cells lining the female tract occurs in mice 27 and many other species 28 . Sperm attachment to the uterine and oviductal epithelial is a mechanism for sperm sequestration and storage prior to ovulation 28 , but whether sperm elicit effects on female immune activation has not been formally considered. We have previously reported that the Treg cell-specific transcription factor Foxp3 , as well as a critical Treg cell-attracting chemokine Ccl19 , are more strongly expressed at the time of embryo implantation in the uterus of mice earlier exposed to seminal fluid of intact males, as opposed to vasectomized males 18 , implying that stronger immune tolerance may be generated when sperm are present. Here, we have investigated the specific contribution of sperm in the female response to seminal fluid. Initially, we compared global gene expression in the uterine endometrium of females mated to intact males versus vasectomized males, using Affymetrix microarray. We show that whole seminal fluid containing sperm elicits a pattern of immune response genes and pathways that is distinct to the expression profile elicited by seminal plasma alone, and is associated with elevated neutrophil recruitment into the uterus, and stronger expansion of Treg cells within draining lymph nodes. We then confirm using an in vitro model and Tlr4 null mutant mice, that sperm specifically induce neutrophil-regulating cytokines IL6, CXCL2, and CSF3 through TLR4 signaling. These data reveal a novel physiological role for sperm at the time of conception and expand understanding of the mechanisms by which seminal fluid interacts with female tissues to generate maternal immune tolerance and reproductive success. Results Vasectomy alters the female response to seminal fluid after mating Previously we showed that seminal fluid induces substantial gene expression changes in the endometrial surface layer of the uterus after mating 13 . We have demonstrated using in vivo and in vitro approaches that soluble signaling factors in seminal plasma regulate several endometrial genes 7 , 14 , 20 ,<|im_end|> <|im_start|>assistant Sperm are generally viewed as having just one action in reproduction—to fertilize the female's egg—but studies at the University of Adelaide are overturning that view. Published in Nature Research journal Communications Biology, new research shows that sperm also deliver signals directly to the female reproductive tissues to increase the chances of conception. Robinson Research Institute's Professor Sarah Robertson, who led the project, said: "This research is the first to show that the female immune response is persuaded by signals in sperm to allow the male partner to fertilize her eggs and conceive a pregnancy. "This overturns our current understanding of what sperm are capable of—they are not just carriers of genetic material, but also agents for convincing the female to invest reproductive resources with that male." It has been known that proteins in seminal fluid modulate the female immune response at conception to encourage her body to accept the foreign embryo. Whether sperm affect this response has not been clear until now. The team evaluated effects on global gene expression in the mouse uterus after mating with males with intact sperm, or vasectomized males. Intact males induced greater changes in female genes, particularly affecting immune response pathways. The females that had contact with sperm produced stronger immune tolerance than those females mated with vasectomised males. By examining effects of sperm interactions with female cells in cell culture experiments, the researchers confirmed the sperm were directly responsible. These new findings suggest that sperm health isn't only important for conceiving, but also has ongoing effects on the chances of a healthy baby. Factors like age, diet, weight, alcohol and smoking, and exposures to environmental chemicals can affect sperm quality in men and so might have greater consequences for pregnancy health than previously considered. "Recognition that sperm influence reproductive events beyond simply fertilizing oocytes shows that sperm quality can have consequences for pregnancy health, beyond just conception,'' Professor Robertson said. "Conditions like recurrent miscarriage, preeclampsia, preterm birth and stillbirth are affected by the female's immune response in ways that the partner's sperm contribute to." <|im_end|>

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1,747

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Discovered more than 200 years ago in 1821, thermoelectricity is nowadays of global interest as it enables direct interconversion of thermal and electrical energy via the Seebeck/Peltier effect. In their seminal work, Mahan and Sofo mathematically derived the conditions for ’the best thermoelectric’—a delta-distribution-shaped electronic transport function, where charge carriers contribute to transport only in an infinitely narrow energy interval. So far, however, only approximations to this concept were expected to exist in nature. Here, we propose the Anderson transition in a narrow impurity band as a physical realisation of this seemingly unrealisable scenario. An innovative approach of continuous disorder tuning allows us to drive the Anderson transition within a single sample: variable amounts of antisite defects are introduced in a controlled fashion by thermal quenching from high temperatures. Consequently, we obtain a significant enhancement and dramatic change of the thermoelectric properties from p -type to n -type in stoichiometric Fe 2 VAl, which we assign to a narrow region of delocalised electrons in the energy spectrum near the Fermi energy. Based on our electronic transport and magnetisation experiments, supported by Monte-Carlo and density functional theory calculations, we present a novel strategy to enhance the performance of thermoelectric materials. Introduction Thermoelectric (TE) devices are capable of converting waste heat into useful electrical energy or act as Peltier coolers. Facing an increasing worldwide demand for efficient energy utilisation, the immense diversity of potential technological applications has sparked great interest 1 , 2 . Still, TE devices are currently restrained in their applicability due to their limited efficiency. The dimensionless figure of merit Z T = S 2 σ T /( κ e + κ ph ), which is closely related to the conversion efficiency, comprises three material-dependent parameters. These are the thermopower S , the electrical conductivity σ and the thermal conductivity κ , consisting of a contribution from electrons κ e and phonons κ ph . While considerable progress towards achieving high Z T has been achieved so far by reducing κ ph 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , increasing the electronic part of Z T is a much more formidable, yet necessary task and new exotic concepts for enhancement are required. In 1996, Mahan and Sofo mathematically identified ‘the best thermoelectric’ as an ideal system, characterised by a delta-distribution-shaped transport function Σ( E ), where charge carriers are confined in an infinitely narrow energy interval 11 . Here, we propose that this intriguing mathematical concept becomes actually realised in real materials at the Anderson transition in an impurity band, as has been recently discussed theoretically 12 . As sketched in Fig. 1 , such a transition occurs when the number of randomly distributed impurities increases above a critical value x c , known as quantum percolation threshold 13 . Below x c , all impurity states are Anderson-localised due to disorder 14 . A singularity of the transport function occurs at x c when an infinitesimally small region in the density of states (DOS) becomes delocalised. This was explained by Mott in 1967 through the concept of ‘mobility edges’, which are two critical energies \${E}_{{{{{{{{{\\rm{c}}}}}}}}}_{1,2}}\$ that appear at the centre of an impurity band, separating localised states in the band tails from delocalised, extended states in the centre 15 . Far above x c , \${E}_{{{{{{{{{\\rm{c}}}}}}}}}_{1}}\$ and \${E}_{{{{{{{{{\\rm{c}}}}}}}}}_{2}}\$ shift towards the band edges, eventually delocalising all impurity states. Fig. 1: Sketch of Anderson transition in an impurity band. When the number of randomly distributed impurities in a peridocally ordered crystal increases, the impurity electrons remain localised below a threshold value due to Anderson localisation. At the Anderson transition, the critical density of impurities allows for delocalisation of an infinitely narrow energy region of extended states inside the localised impurity states. The delocalised impurity band is marked by two mobility edges \${E}_{{{{{{{{{\\rm{c}}}}}}}}}_{1,2}}\$ , which are critical energies that separate the localised from delocalised states. Full size image The merit of Anderson localisation to enhance thermoelectricity has been recently shown for the case of one mobility edge, where the electronic states near the valence or conduction band edge of a narrow-gap semiconductor are localised in the presence of a random potential, which may suppress bipolar conduction at higher temperatures 16 , 17 . Agne et al. argued that simultaneously tuning carrier concentration and disorder for one band with a single mobility edge can increase Z T by ≈20% 17 . Our study, on the other hand, is focused on the insulator–metal transition in an impurity band (e.g. occurring in lightly doped semiconductors), which has long been considered a fundamental problem in condensed matter physics. In this case, the appearance of two mobility edges directly accomplishes Mahan and Sofo’s idea of confined electronic transport (see Fig. 1) . We experimentally realised such a scenario in an undoped, stoichiometric bulk Fe 2 VAl specimen by controlling the degree of lattice disorder directly via thermal quenching. This Heusler compound was recently found to be an excellent candidate for studying new TE optimisation strategies 18 , 19 , 20 , 21 . Our measurements of the electronic transport and magnetisation in this work, supported by Monte Carlo and density functional theory (DFT) simulations, show clear evidence for a significant enhancement of the TE performance, which we attribute to the Anderson insulator–metal transition. In the following, we describe the structural, electronic and magnetic properties of disorder-tuned Fe 2 VAl as obtained by our experiments and simulations. Finally, we show the transport properties of the material across the Anderson transition. Results Structural and electronic properties Ternary Fe 2 VAl forms a fully ordered L2 1 structure at low temperatures that undergoes two second-order structural phase transitions (see Fig. 2 a) into the partly disordered B2 structure at T B2 ≈ 1100 ∘ C and fully disordered A2 structure at T A2 ≈ 1250 ∘ C 22 . Our Monte Carlo simulations based on effective cluster interactions show how the degree of atomic disorder in bulk Fe", "role": "user" }, { "content": "A lot of heat gets lost during the conversion of energy. Estimates even put it at more than 70%. However, in thermoelectric materials, such as those being studied at the Institute of Solid State Physics at TU Wien, heat can be converted directly into electrical energy. This effect (the Seebeck effect) can be used in numerous applications in industry but also in everyday life. Recently, Ernst Bauer's research team made an exciting discovery in a thermoelectric material consisting of iron, vanadium and aluminum (Fe2VAl). The researchers recently published their results in Nature Communications. The ideal thermoelectric To achieve the greatest possible energy conversion effect, researchers are looking for materials that fulfill a number of characteristics: They should have a large Seebeck effect, high electrical conductivity and low thermal conductivity. However, this is extremely difficult because these properties are interrelated and interdependent. Therefore, the researchers asked themselves what a material would have to look like physically in order to fulfill all these conditions in the best possible way. Thus, physicists at TU Wien have succeeded in finding a new concept to resolve this contradiction and optimize all thermoelectric properties in one material at the same time. \"At the so-called Anderson transition, a quantum phase transition from localized to mobile electron states, the conditions for the ideal thermoelectric are met. This means that all conduction electrons have approximately the same energy,\" reports Fabian Garmroudi, first author of the study. The Anderson transition occurs in semiconductors when impurity atoms are added, strongly binding their electrons. \"Analogous to ice floes in the sea, these are initially isolated from each other and cannot be stepped on. However, if the number of ice floes is large enough, you have a continuous connection through which you can cross the sea,\" Fabian Garmroudi draws a comparison. This happens in a similar way in solids: if the number of impurity atoms exceeds a critical value, the electrons can suddenly move freely from one atom to another and electricity can flow. Atoms swap places when it gets hot The Anderson transition was demonstrated in close collaboration with researchers from Sweden and Japan as well as the University of Vienna, and was linked for the first time to a significant change in thermoelectric properties. The team made the exciting discovery when they heated the material to very high temperatures, close to the melting point. \"At high temperatures, the atoms vibrate so strongly that they occasionally swap their lattice positions. For example, iron atoms are then located where vanadium atoms were before. We succeeded in freezing this 'atomic confusion', which occurs at high temperatures, by so-called 'quenching', that is, rapid cooling in a water bath,\" reports Ernst Bauer. These irregular defects serve exactly the same purpose as the impurity atoms mentioned earlier, without the need to change the chemical composition of the material. Energy conversion thanks to disorder In many research areas of solid-state physics, one is interested in materials that are as pure as possible and have an ideal crystal structure. The reason: the regularity of the atoms simplifies a theoretical description of the physical properties. In the case of Fe2VAl, however, it is precisely the imperfections that account for most of the thermoelectric performance. It has also already been shown in neighboring disciplines that irregularities can be advantageous: \"Basic research on quantum materials is a good example of this. There, science has already been able to show that disorder is often the necessary spice in the 'quantum soup',\" says Andrej Pustogow, one of the co-authors. \"Now this concept has also arrived in applied solid-state research.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Discovered more than 200 years ago in 1821, thermoelectricity is nowadays of global interest as it enables direct interconversion of thermal and electrical energy via the Seebeck/Peltier effect. In their seminal work, Mahan and Sofo mathematically derived the conditions for ’the best thermoelectric’—a delta-distribution-shaped electronic transport function, where charge carriers contribute to transport only in an infinitely narrow energy interval. So far, however, only approximations to this concept were expected to exist in nature. Here, we propose the Anderson transition in a narrow impurity band as a physical realisation of this seemingly unrealisable scenario. An innovative approach of continuous disorder tuning allows us to drive the Anderson transition within a single sample: variable amounts of antisite defects are introduced in a controlled fashion by thermal quenching from high temperatures. Consequently, we obtain a significant enhancement and dramatic change of the thermoelectric properties from p -type to n -type in stoichiometric Fe 2 VAl, which we assign to a narrow region of delocalised electrons in the energy spectrum near the Fermi energy. Based on our electronic transport and magnetisation experiments, supported by Monte-Carlo and density functional theory calculations, we present a novel strategy to enhance the performance of thermoelectric materials. Introduction Thermoelectric (TE) devices are capable of converting waste heat into useful electrical energy or act as Peltier coolers. Facing an increasing worldwide demand for efficient energy utilisation, the immense diversity of potential technological applications has sparked great interest 1 , 2 . Still, TE devices are currently restrained in their applicability due to their limited efficiency. The dimensionless figure of merit Z T = S 2 σ T /( κ e + κ ph ), which is closely related to the conversion efficiency, comprises three material-dependent parameters. These are the thermopower S , the electrical conductivity σ and the thermal conductivity κ , consisting of a contribution from electrons κ e and phonons κ ph . While considerable progress towards achieving high Z T has been achieved so far by reducing κ ph 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , increasing the electronic part of Z T is a much more formidable, yet necessary task and new exotic concepts for enhancement are required. In 1996, Mahan and Sofo mathematically identified ‘the best thermoelectric’ as an ideal system, characterised by a delta-distribution-shaped transport function Σ( E ), where charge carriers are confined in an infinitely narrow energy interval 11 . Here, we propose that this intriguing mathematical concept becomes actually realised in real materials at the Anderson transition in an impurity band, as has been recently discussed theoretically 12 . As sketched in Fig. 1 , such a transition occurs when the number of randomly distributed impurities increases above a critical value x c , known as quantum percolation threshold 13 . Below x c , all impurity states are Anderson-localised due to disorder 14 . A singularity of the transport function occurs at x c when an infinitesimally small region in the density of states (DOS) becomes delocalised. This was explained by Mott in 1967 through the concept of ‘mobility edges’, which are two critical energies ${E}_{{{{{{{{{\rm{c}}}}}}}}}_{1,2}}$ that appear at the centre of an impurity band, separating localised states in the band tails from delocalised, extended states in the centre 15 . Far above x c , ${E}_{{{{{{{{{\rm{c}}}}}}}}}_{1}}$ and ${E}_{{{{{{{{{\rm{c}}}}}}}}}_{2}}$ shift towards the band edges, eventually delocalising all impurity states. Fig. 1: Sketch of Anderson transition in an impurity band. When the number of randomly distributed impurities in a peridocally ordered crystal increases, the impurity electrons remain localised below a threshold value due to Anderson localisation. At the Anderson transition, the critical density of impurities allows for delocalisation of an infinitely narrow energy region of extended states inside the localised impurity states. The delocalised impurity band is marked by two mobility edges ${E}_{{{{{{{{{\rm{c}}}}}}}}}_{1,2}}$ , which are critical energies that separate the localised from delocalised states. Full size image The merit of Anderson localisation to enhance thermoelectricity has been recently shown for the case of one mobility edge, where the electronic states near the valence or conduction band edge of a narrow-gap semiconductor are localised in the presence of a random potential, which may suppress bipolar conduction at higher temperatures 16 , 17 . Agne et al. argued that simultaneously tuning carrier concentration and disorder for one band with a single mobility edge can increase Z T by ≈20% 17 . Our study, on the other hand, is focused on the insulator–metal transition in an impurity band (e.g. occurring in lightly doped semiconductors), which has long been considered a fundamental problem in condensed matter physics. In this case, the appearance of two mobility edges directly accomplishes Mahan and Sofo’s idea of confined electronic transport (see Fig. 1) . We experimentally realised such a scenario in an undoped, stoichiometric bulk Fe 2 VAl specimen by controlling the degree of lattice disorder directly via thermal quenching. This Heusler compound was recently found to be an excellent candidate for studying new TE optimisation strategies 18 , 19 , 20 , 21 . Our measurements of the electronic transport and magnetisation in this work, supported by Monte Carlo and density functional theory (DFT) simulations, show clear evidence for a significant enhancement of the TE performance, which we attribute to the Anderson insulator–metal transition. In the following, we describe the structural, electronic and magnetic properties of disorder-tuned Fe 2 VAl as obtained by our experiments and simulations. Finally, we show the transport properties of the material across the Anderson transition. Results Structural and electronic properties Ternary Fe 2 VAl forms a fully ordered L2 1 structure at low temperatures that undergoes two second-order structural phase transitions (see Fig. 2 a) into the partly disordered B2 structure at T B2 ≈ 1100 ∘ C and fully disordered A2 structure at T A2 ≈ 1250 ∘ C 22 . Our Monte Carlo simulations based on effective cluster interactions show how the degree of atomic disorder in bulk Fe<|im_end|> <|im_start|>assistant A lot of heat gets lost during the conversion of energy. Estimates even put it at more than 70%. However, in thermoelectric materials, such as those being studied at the Institute of Solid State Physics at TU Wien, heat can be converted directly into electrical energy. This effect (the Seebeck effect) can be used in numerous applications in industry but also in everyday life. Recently, Ernst Bauer's research team made an exciting discovery in a thermoelectric material consisting of iron, vanadium and aluminum (Fe2VAl). The researchers recently published their results in Nature Communications. The ideal thermoelectric To achieve the greatest possible energy conversion effect, researchers are looking for materials that fulfill a number of characteristics: They should have a large Seebeck effect, high electrical conductivity and low thermal conductivity. However, this is extremely difficult because these properties are interrelated and interdependent. Therefore, the researchers asked themselves what a material would have to look like physically in order to fulfill all these conditions in the best possible way. Thus, physicists at TU Wien have succeeded in finding a new concept to resolve this contradiction and optimize all thermoelectric properties in one material at the same time. "At the so-called Anderson transition, a quantum phase transition from localized to mobile electron states, the conditions for the ideal thermoelectric are met. This means that all conduction electrons have approximately the same energy," reports Fabian Garmroudi, first author of the study. The Anderson transition occurs in semiconductors when impurity atoms are added, strongly binding their electrons. "Analogous to ice floes in the sea, these are initially isolated from each other and cannot be stepped on. However, if the number of ice floes is large enough, you have a continuous connection through which you can cross the sea," Fabian Garmroudi draws a comparison. This happens in a similar way in solids: if the number of impurity atoms exceeds a critical value, the electrons can suddenly move freely from one atom to another and electricity can flow. Atoms swap places when it gets hot The Anderson transition was demonstrated in close collaboration with researchers from Sweden and Japan as well as the University of Vienna, and was linked for the first time to a significant change in thermoelectric properties. The team made the exciting discovery when they heated the material to very high temperatures, close to the melting point. "At high temperatures, the atoms vibrate so strongly that they occasionally swap their lattice positions. For example, iron atoms are then located where vanadium atoms were before. We succeeded in freezing this 'atomic confusion', which occurs at high temperatures, by so-called 'quenching', that is, rapid cooling in a water bath," reports Ernst Bauer. These irregular defects serve exactly the same purpose as the impurity atoms mentioned earlier, without the need to change the chemical composition of the material. Energy conversion thanks to disorder In many research areas of solid-state physics, one is interested in materials that are as pure as possible and have an ideal crystal structure. The reason: the regularity of the atoms simplifies a theoretical description of the physical properties. In the case of Fe2VAl, however, it is precisely the imperfections that account for most of the thermoelectric performance. It has also already been shown in neighboring disciplines that irregularities can be advantageous: "Basic research on quantum materials is a good example of this. There, science has already been able to show that disorder is often the necessary spice in the 'quantum soup'," says Andrej Pustogow, one of the co-authors. "Now this concept has also arrived in applied solid-state research." <|im_end|>

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2,153

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Healthcare industry players make payments to medical providers for non-research expenses. While these payments may pose conflicts of interest, their relationship with overall healthcare costs remains largely unknown. In this study, we linked Open Payments data on providers’ industry payments with Medicare data on healthcare costs. We investigated 374,766 providers’ industry payments and healthcare costs. We demonstrate that providers receiving higher amounts of industry payments tend to bill higher drug and medical costs. Specifically, we find that a 10% increase in industry payments is associated with 1.3% higher medical and 1.8% higher drug costs. For a typical provider, for example, a 10% or $25 increase in annual industry payments would be associated with approximately $1,100 higher medical costs and $100 higher drug costs. Furthermore, the association between payments and healthcare costs varies markedly across states and correlates with political leaning, being stronger in more conservative states. Introduction Human behavior and decision-making are subjective and can be influenced by political, economic, and even social factors, such as norms 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . A global conversation is underway regarding the potential influence of financial players on decision-making related to public policy and social systems. Although much of this conversation has focused on the influence of money in politics, these concerns also extend to other aspects of society. In the United States, healthcare providers, in particular, are allowed to sustain financial relationships with corporations that sell medical devices and pharmaceuticals. At the same time, the United States is also dealing with the highest healthcare costs in the world 9 . Concern has been put forth about the extent and manner of the industry’s influence on the behavior of individual healthcare providers and the implications for healthcare costs 10 . As of today, the full extent of such influence is not well understood. In 2016, healthcare consumers in the United States paid more for less, spending about twice as much per capita ($10,348) than people in other developed countries, while falling short of those countries in terms of performance measures, such as health outcomes and access 11 , 12 . In aggregate, healthcare costs amounted to $3.3 trillion or 17.9% of the US Gross Domestic Product (GDP) in 2016 and are expected to grow to almost 20% of GDP by 2026 13 . In response to this growing problem, academics, policymakers, and the general public are striving to understand the drivers of and ultimately reduce healthcare costs 14 . Two expenditure categories are the primary drivers of healthcare costs in the United States: pharmaceuticals and healthcare service utilization 9 . The US Department of Health and Human Services reported that drug-related costs are among the largest cost drivers in Medicare 13 , accounting for ~17% of total individual healthcare spending ($457B) or $1443 per capita in 2016 9 , 15 . It has also been noted that pharmaceuticals are a major source of the differences in healthcare costs between the United States and other similar countries 9 . As for utilization of services, it is established that medical providers in the US bill for more medical services and charge a higher cost per service versus those in comparable countries 16 . While previous work has examined these two cost drivers in isolation, the role of pharmaceutical companies in healthcare costs is complex and involves potential conflicts of interest 17 . For example, in the United States, healthcare industry players are allowed to pay for medical providers’ general and research expenditures, and providers are allowed to directly own and invest in the healthcare industry 18 , 19 . This relationship and its association with healthcare costs are the focus of this article. To help address concerns about this potential conflict of interest between medical providers and the healthcare industry, the 2010 Affordable Care Act (ACA) established the Open Payments (OP) system. OP aims to provide a more transparent and accountable healthcare system by publishing data on the financial ties between industry and medical providers 20 . As a result of the ACA, medical device corporations (the official name for healthcare industry organizations that include pharmaceutical companies) are required to report payments to all medical providers participating in Medicare 21 . Extant work examining OP data have demonstrated the large scale of the financial ties between pharmaceuticals and medical providers. For example, in 2016, 2005 medical device corporations spent $9.15B collectively on 904,922 physicians across the United States 22 . It is also estimated that US pharmaceuticals spend more on advertising and marketing than on R&D 19 , 23 . Substantial research has focused on the impact of industry payments and more generally medical marketing on providers’ attitudes and behavior in the US 24 . For example, higher payments to medical providers by the healthcare industry have been linked to the prescription of brand-name drugs, even when equally effective generic substitutes are available 25 , 26 , 27 , 28 , 29 , 30 . In a more pernicious context, previous work demonstrated a relationship between payments to medical providers from opioid manufacturers and an increase of opioid prescriptions, which may have contributed to the ongoing opioid epidemic 18 , 31 . These findings have also been documented in the press by Propublica, a nonprofit investigative news organization, in their Dollars for Docs report 32 . Although most of these studies have focused on the healthcare industry’s influence over drug prescriptions 10 , medical spending on services (e.g., procedures, utilization) represents a much larger fraction of overall healthcare costs than drug spending. For example, in the 2016 Medicare data, we report on below, allowed medical costs amounted to over $82B, or over five times the total drug costs of $15B. There is a paucity of research on the association between industry payments and overall healthcare costs. This may be in part owing to the challenge in linking OP to healthcare data on individual providers, because the National Provider Identifier (NPI) is missing from", "role": "user" }, { "content": "An interdisciplinary team of Indiana University scientists studying Medicare data have found an association between health care industry payments to medical providers for non-research expenses and what these providers charge for medical services—shedding new light on potential hidden costs to the public. Their findings, published Sept. 20 in Nature Communications, demonstrate that medical providers receiving higher amounts of industry payments tend to bill higher drug andmedical costs. Specifically, they found that a 10 percent increase in industry payments to medical providers is associated with 1.3 percent higher medical costs and 1.8 percent higher drug costs. For example, a $25 increase in annual industry payments to a typical medical provider would be associated with approximately $1,100 higher medical costs and $100 higher drug costs. \"Let's be clear here, we should not find such an association,\" said Jorge Mejia, co-author on the paper and an assistant professor of operations and decision technologies at the IU Kelley School of Business. \"Our findings raise the possibility that medical providers may be unduly influenced by payments from the healthcare industry.\" It's important to note that an association shows that two variables appear to change at the same time, whereas causality implies that one variable causes another variable to change. This study does not prove causality, which the researchers said would be difficult to do with secondary data. Jorge Mejia's co-authors were Amanda Mejia, assistant professor in the Department of Statistics, and Franco Pestilli, associate professor in the Department of Psychological and Brain Sciences, both at the IU College of Arts and Sciences. Amanda Mejia said the team controlled for several key variables to rule out the possibility of other drivers of the association between industry payments and medical costs. \"We found that the association was still there after taking into account the size of the practice, its location and drug prescribing levels,\" she said. Pestilli said the large Medicare data sets that the researchers used were made openly available as part of the 2010 Affordable Care Act. \"Our research capitalized on such openly shared data,\" Pestilli said. \"We demonstrate the value of open data in providing society with critical insights on hidden costs that can be addressed at the policy level.\" But Jorge Mejia said transparency alone is not enough to fix these hidden costs. That's why studies like this one are important; they help interpret the data so the public can better understand what it means. \"As a society, we have had the potential for quantifying and qualifying the influence of the industry on our medical costs,\" he said. \"However, we have not done so. For example, we are just discovering the extent to which certain health care companies may be involved in the current opioid crisis in the U.S. We need tools to guide patients and consumers with all the data that is available.\" To help achieve this goal, Jorge Mejia said he hopes Medicare will make it easier for researchers and the public to quantify the effect of the payments received by medical providers by adding the national physician identifier (NPI) to their Open Payments data set. Additionally, he hopes the research team's findings will start a conversation about how to communicate this information to consumers. \"We have energy efficiency scorecards for appliances, cars and many consumer products,\" Jorge Mejia said. \"How can the public understand whether their physician is close to the health care industry? Instead of making this about whether it's good or bad, I'd like to kickstart a conversation about how information can be delivered in a simple way. Let's put patients in the driver's seat.\" The researchers have several follow-up projects in progress, including one that aims to investigate how industry payments may drive future medical costs, which would bring them one step closer to establishing a causal relationship between payments and costs. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Healthcare industry players make payments to medical providers for non-research expenses. While these payments may pose conflicts of interest, their relationship with overall healthcare costs remains largely unknown. In this study, we linked Open Payments data on providers’ industry payments with Medicare data on healthcare costs. We investigated 374,766 providers’ industry payments and healthcare costs. We demonstrate that providers receiving higher amounts of industry payments tend to bill higher drug and medical costs. Specifically, we find that a 10% increase in industry payments is associated with 1.3% higher medical and 1.8% higher drug costs. For a typical provider, for example, a 10% or $25 increase in annual industry payments would be associated with approximately $1,100 higher medical costs and $100 higher drug costs. Furthermore, the association between payments and healthcare costs varies markedly across states and correlates with political leaning, being stronger in more conservative states. Introduction Human behavior and decision-making are subjective and can be influenced by political, economic, and even social factors, such as norms 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . A global conversation is underway regarding the potential influence of financial players on decision-making related to public policy and social systems. Although much of this conversation has focused on the influence of money in politics, these concerns also extend to other aspects of society. In the United States, healthcare providers, in particular, are allowed to sustain financial relationships with corporations that sell medical devices and pharmaceuticals. At the same time, the United States is also dealing with the highest healthcare costs in the world 9 . Concern has been put forth about the extent and manner of the industry’s influence on the behavior of individual healthcare providers and the implications for healthcare costs 10 . As of today, the full extent of such influence is not well understood. In 2016, healthcare consumers in the United States paid more for less, spending about twice as much per capita ($10,348) than people in other developed countries, while falling short of those countries in terms of performance measures, such as health outcomes and access 11 , 12 . In aggregate, healthcare costs amounted to $3.3 trillion or 17.9% of the US Gross Domestic Product (GDP) in 2016 and are expected to grow to almost 20% of GDP by 2026 13 . In response to this growing problem, academics, policymakers, and the general public are striving to understand the drivers of and ultimately reduce healthcare costs 14 . Two expenditure categories are the primary drivers of healthcare costs in the United States: pharmaceuticals and healthcare service utilization 9 . The US Department of Health and Human Services reported that drug-related costs are among the largest cost drivers in Medicare 13 , accounting for ~17% of total individual healthcare spending ($457B) or $1443 per capita in 2016 9 , 15 . It has also been noted that pharmaceuticals are a major source of the differences in healthcare costs between the United States and other similar countries 9 . As for utilization of services, it is established that medical providers in the US bill for more medical services and charge a higher cost per service versus those in comparable countries 16 . While previous work has examined these two cost drivers in isolation, the role of pharmaceutical companies in healthcare costs is complex and involves potential conflicts of interest 17 . For example, in the United States, healthcare industry players are allowed to pay for medical providers’ general and research expenditures, and providers are allowed to directly own and invest in the healthcare industry 18 , 19 . This relationship and its association with healthcare costs are the focus of this article. To help address concerns about this potential conflict of interest between medical providers and the healthcare industry, the 2010 Affordable Care Act (ACA) established the Open Payments (OP) system. OP aims to provide a more transparent and accountable healthcare system by publishing data on the financial ties between industry and medical providers 20 . As a result of the ACA, medical device corporations (the official name for healthcare industry organizations that include pharmaceutical companies) are required to report payments to all medical providers participating in Medicare 21 . Extant work examining OP data have demonstrated the large scale of the financial ties between pharmaceuticals and medical providers. For example, in 2016, 2005 medical device corporations spent $9.15B collectively on 904,922 physicians across the United States 22 . It is also estimated that US pharmaceuticals spend more on advertising and marketing than on R&D 19 , 23 . Substantial research has focused on the impact of industry payments and more generally medical marketing on providers’ attitudes and behavior in the US 24 . For example, higher payments to medical providers by the healthcare industry have been linked to the prescription of brand-name drugs, even when equally effective generic substitutes are available 25 , 26 , 27 , 28 , 29 , 30 . In a more pernicious context, previous work demonstrated a relationship between payments to medical providers from opioid manufacturers and an increase of opioid prescriptions, which may have contributed to the ongoing opioid epidemic 18 , 31 . These findings have also been documented in the press by Propublica, a nonprofit investigative news organization, in their Dollars for Docs report 32 . Although most of these studies have focused on the healthcare industry’s influence over drug prescriptions 10 , medical spending on services (e.g., procedures, utilization) represents a much larger fraction of overall healthcare costs than drug spending. For example, in the 2016 Medicare data, we report on below, allowed medical costs amounted to over $82B, or over five times the total drug costs of $15B. There is a paucity of research on the association between industry payments and overall healthcare costs. This may be in part owing to the challenge in linking OP to healthcare data on individual providers, because the National Provider Identifier (NPI) is missing from<|im_end|> <|im_start|>assistant An interdisciplinary team of Indiana University scientists studying Medicare data have found an association between health care industry payments to medical providers for non-research expenses and what these providers charge for medical services—shedding new light on potential hidden costs to the public. Their findings, published Sept. 20 in Nature Communications, demonstrate that medical providers receiving higher amounts of industry payments tend to bill higher drug andmedical costs. Specifically, they found that a 10 percent increase in industry payments to medical providers is associated with 1.3 percent higher medical costs and 1.8 percent higher drug costs. For example, a $25 increase in annual industry payments to a typical medical provider would be associated with approximately $1,100 higher medical costs and $100 higher drug costs. "Let's be clear here, we should not find such an association," said Jorge Mejia, co-author on the paper and an assistant professor of operations and decision technologies at the IU Kelley School of Business. "Our findings raise the possibility that medical providers may be unduly influenced by payments from the healthcare industry." It's important to note that an association shows that two variables appear to change at the same time, whereas causality implies that one variable causes another variable to change. This study does not prove causality, which the researchers said would be difficult to do with secondary data. Jorge Mejia's co-authors were Amanda Mejia, assistant professor in the Department of Statistics, and Franco Pestilli, associate professor in the Department of Psychological and Brain Sciences, both at the IU College of Arts and Sciences. Amanda Mejia said the team controlled for several key variables to rule out the possibility of other drivers of the association between industry payments and medical costs. "We found that the association was still there after taking into account the size of the practice, its location and drug prescribing levels," she said. Pestilli said the large Medicare data sets that the researchers used were made openly available as part of the 2010 Affordable Care Act. "Our research capitalized on such openly shared data," Pestilli said. "We demonstrate the value of open data in providing society with critical insights on hidden costs that can be addressed at the policy level." But Jorge Mejia said transparency alone is not enough to fix these hidden costs. That's why studies like this one are important; they help interpret the data so the public can better understand what it means. "As a society, we have had the potential for quantifying and qualifying the influence of the industry on our medical costs," he said. "However, we have not done so. For example, we are just discovering the extent to which certain health care companies may be involved in the current opioid crisis in the U.S. We need tools to guide patients and consumers with all the data that is available." To help achieve this goal, Jorge Mejia said he hopes Medicare will make it easier for researchers and the public to quantify the effect of the payments received by medical providers by adding the national physician identifier (NPI) to their Open Payments data set. Additionally, he hopes the research team's findings will start a conversation about how to communicate this information to consumers. "We have energy efficiency scorecards for appliances, cars and many consumer products," Jorge Mejia said. "How can the public understand whether their physician is close to the health care industry? Instead of making this about whether it's good or bad, I'd like to kickstart a conversation about how information can be delivered in a simple way. Let's put patients in the driver's seat." The researchers have several follow-up projects in progress, including one that aims to investigate how industry payments may drive future medical costs, which would bring them one step closer to establishing a causal relationship between payments and costs. <|im_end|>

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2,007

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Recent technological advances have enabled DNA methylation to be assayed at single-cell resolution. However, current protocols are limited by incomplete CpG coverage and hence methods to predict missing methylation states are critical to enable genome-wide analyses. We report DeepCpG, a computational approach based on deep neural networks to predict methylation states in single cells. We evaluate DeepCpG on single-cell methylation data from five cell types generated using alternative sequencing protocols. DeepCpG yields substantially more accurate predictions than previous methods. Additionally, we show that the model parameters can be interpreted, thereby providing insights into how sequence composition affects methylation variability. Background DNA methylation is one of the most extensively studied epigenetic marks and is known to be implicated in a wide range of biological processes, including chromosome instability, X-chromosome inactivation, cell differentiation, cancer progression and gene regulation [ 1 – 4 ]. Well-established protocols exist for quantifying average DNA methylation levels in populations of cells. Recent technological advances have enabled profiling DNA methylation at single-cell resolution, either using genome-wide bisulfite sequencing (scBS-seq [ 5 ]) or reduced representation protocols (scRRBS-seq [ 6 – 8 ]). These protocols have already provided unprecedented insights into the regulation and the dynamics of DNA methylation in single cells [ 6 , 9 ], and have uncovered new linkages between epigenetic and transcriptional heterogeneity [ 8 , 10 , 11 ]. Because of the small amounts of genomic DNA starting material per cell, single-cell methylation analyses are intrinsically limited by moderate CpG coverage (Fig. 1a ; 20–40% for scBS-seq [ 5 ]; 1–10% for scRRBS-seq [ 6 – 8 ]). Consequently, a first critical step is to predict missing methylation states to enable genome-wide analyses. While methods exist for predicting average DNA methylation profiles in cell populations [ 12 – 16 ], these approaches do not account for cell-to-cell variability. Additionally, existing methods require a priori defined features and genome annotations, which are typically limited to a narrow set of cell types and conditions. Fig. 1 DeepCpG model training and applications. a Sparse single-cell CpG profiles as obtained from scBS-seq [ 5 ] or scRRBS-seq [ 6 – 8 ]. Methylated CpG sites are denoted by ones , un-methylated CpG sites by zeros , and question marks denote CpG sites with unknown methylation state (missing data). b Modular architecture of DeepCpG. The DNA module consists of two convolutional and pooling layers to identify predictive motifs from the local sequence context and one fully connected layer to model motif interactions. The CpG module scans the CpG neighbourhood of multiple cells (rows in b ) using a bidirectional gated recurrent network ( GRU ) [ 36 ], yielding compressed features in a vector of constant size. The Joint module learns interactions between higher-level features derived from the DNA and CpG modules to predict methylation states in all cells. c , d The trained DeepCpG model can be used for different downstream analyses, including genome-wide imputation of missing CpG sites ( c ) and the discovery of DNA sequence motifs that are associated with DNA methylation levels or cell-to-cell variability ( d ) Full size image Here, we report DeepCpG, a computational method based on deep neural networks [ 17 – 19 ] for predicting single-cell methylation states and for modelling the sources of DNA methylation variability. DeepCpG leverages associations between DNA sequence patterns and methylation states as well as between neighbouring CpG sites, both within individual cells and across cells. Unlike previous methods [ 12 , 13 , 15 , 20 – 23 ], our approach does not separate the extraction of informative features and model training. Instead, DeepCpG is based on a modular architecture and learns predictive DNA sequence and methylation patterns in a data-driven manner. We evaluated DeepCpG on mouse embryonic stem cells profiled using whole-genome single-cell methylation profiling (scBS-seq [ 5 ]), as well as on human and mouse cells profiled using a reduced representation protocol (scRRBS-seq [ 8 ]). Across all cell types, DeepCpG yielded substantially more accurate predictions of methylation states than previous approaches. Additionally, DeepCpG uncovered both previously known and de novo sequence motifs that are associated with methylation changes and methylation variability between cells. Results and discussion DeepCpG is trained to predict binary CpG methylation states from local DNA sequence windows and observed neighbouring methylation states (Fig. 1a ). A major feature of the model is its modular architecture, consisting of a CpG module to account for correlations between CpG sites within and across cells, a DNA module to detect informative sequence patterns, and a Joint module that integrates the evidence from the CpG and DNA module to predict methylation states at target CpG sites (Fig. 1b ). Briefly, the DNA and CpG modules were designed to specifically model each of these data modalities. The DNA module is based on a convolutional architecture, which has been successfully applied in different domains [ 24 – 27 ], including genomics [ 28 – 33 ]. The module takes DNA sequences in windows centred on target CpG sites as input, which are scanned for sequence motifs using convolutional filters, analogous to conventional position weight matrices [ 34 , 35 ] (“ Methods ”). The CpG module is based on a bidirectional gated recurrent network [ 36 ], a sequential model that compresses patterns of neighbouring CpG states from a variable number of cells into a fixed-size feature vector (“ Methods ”). Finally, the Joint module learns interactions between output features of the DNA and CpG modules and predicts the methylation state at target sites in all cells using a multi-task architecture. The trained DeepCpG model can be used for different downstream analyses, including i) to impute low-coverage methylation profiles for sets of cells (Fig. 1c ) and ii) to discover DNA sequence motifs that are associated with methylation states and cell-to-cell variability (Fig. 1d ). Accurate prediction of single-cell methylation states First, we assessed the ability of DeepCpG to predict single-cell methylation states and compared the model to existing imputation strategies for DNA", "role": "user" }, { "content": "A new 'deep learning' method, DeepCpG, has been designed by researchers at the Wellcome Trust Sanger Institute, the European Bioinformatics Institute and the Babraham Institute to help scientists better understand the epigenome – the biochemical activity around the genome. Reported today in Genome Biology, DeepCpG leverages 'deep neural networks', a multi-layered machine learning model inspired by the brain, and provides a valuable tool for research into health and disease. As a result of projects like 1000 Genomes, scientists now have a 'book' of the human genome divided up into chapters and annotated in parts. However, to fully understand how life works, scientists need to decipher both the genome – the set of instructions repeated in every cell – and the epigenome, the part that varies wildly between cells. To better understand how DNA sequences relate to biological changes, the genomics community is turning to artificial neural networks – a class of machine learning methods first introduced in the 1980s and inspired by the wiring of the brain. More recently, these models have been rebranded as 'deep neural networks', which form the field of deep learning. Scientists have leveraged the capacity of deep learning to fill in the gaps in single-cell genomics, an emerging technology that offers a close-up view on epigenetics. A new technique, DeepCpG, has been designed to help scientists learn about the connections between DNA sequences and DNA methylation – a biochemical modification of the genome sequence that can act like an off-switch for individual genes. Methylation plays a key part in important biological processes, including cell development, ageing and cancer progression. The new method uses genomic and epigenomic data to make predictions about DNA methylation in single cells. This is important because current technologies provide incomplete information about this. With DeepCpG, researchers can obtain a more complete picture of DNA methylation. The model can also be used to obtain new biological insights, for example on the connection between the DNA sequence and methylation. \"DeepCpG actually learns meaningful features in a data-driven manner. It has major advantages over previous methods, including the ability to more accurately predict DNA methylation and to study intercellular differences. By studying the wiring of the learnt network, we can understand how the biology of DNA methylation works. This has allowed us to recover known DNA sequence motifs that are important for methylation changes, as well as to discover new motifs, which are the starting point for future studies,\" says Christof Angermueller, PhD candidate at EMBL-EBI. \"We have demonstrated that DeepCpG enables us to accurately predict and analyse DNA methylation in single cells. However, DeepCpG is just one example of how we can apply deep learning to genomics and single-cell technologies. It is exciting to see the versatile applications deep learning has already found in genomics. I am looking forward to seeing more deep learning techniques come online. I believe it will make a big difference to how we study biology and has the potential to yield new answers about how life works,\" says Dr Oliver Stegle, Group Leader at EMBL-EBI. \"Single cell epigenomics methods provide exciting insights into cell heterogeneity in development, ageing and disease; however if you are just dealing with two genomes in a single cell, bits of information are often lost during the experiment. This new method recognises patterns of the epigenome in single cells and then reconstructs lost information, returning a data-rich single cell epigenome,\" says Professor Wolf Reik from The Babraham Institute and Associate Faculty member at the Wellcome Trust Sanger Institute. \"Deep learning is now the state-of-the art in many fields. We are exploring its utility for making sense of large scale biological data. Pioneering studies, such as the one by Angermueller and colleagues, prove that there is lot to be gained by using deep learning methods in computational biology,\" says Dr Leopold Parts, Group Leader at the Sanger Institute. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Recent technological advances have enabled DNA methylation to be assayed at single-cell resolution. However, current protocols are limited by incomplete CpG coverage and hence methods to predict missing methylation states are critical to enable genome-wide analyses. We report DeepCpG, a computational approach based on deep neural networks to predict methylation states in single cells. We evaluate DeepCpG on single-cell methylation data from five cell types generated using alternative sequencing protocols. DeepCpG yields substantially more accurate predictions than previous methods. Additionally, we show that the model parameters can be interpreted, thereby providing insights into how sequence composition affects methylation variability. Background DNA methylation is one of the most extensively studied epigenetic marks and is known to be implicated in a wide range of biological processes, including chromosome instability, X-chromosome inactivation, cell differentiation, cancer progression and gene regulation [ 1 – 4 ]. Well-established protocols exist for quantifying average DNA methylation levels in populations of cells. Recent technological advances have enabled profiling DNA methylation at single-cell resolution, either using genome-wide bisulfite sequencing (scBS-seq [ 5 ]) or reduced representation protocols (scRRBS-seq [ 6 – 8 ]). These protocols have already provided unprecedented insights into the regulation and the dynamics of DNA methylation in single cells [ 6 , 9 ], and have uncovered new linkages between epigenetic and transcriptional heterogeneity [ 8 , 10 , 11 ]. Because of the small amounts of genomic DNA starting material per cell, single-cell methylation analyses are intrinsically limited by moderate CpG coverage (Fig. 1a ; 20–40% for scBS-seq [ 5 ]; 1–10% for scRRBS-seq [ 6 – 8 ]). Consequently, a first critical step is to predict missing methylation states to enable genome-wide analyses. While methods exist for predicting average DNA methylation profiles in cell populations [ 12 – 16 ], these approaches do not account for cell-to-cell variability. Additionally, existing methods require a priori defined features and genome annotations, which are typically limited to a narrow set of cell types and conditions. Fig. 1 DeepCpG model training and applications. a Sparse single-cell CpG profiles as obtained from scBS-seq [ 5 ] or scRRBS-seq [ 6 – 8 ]. Methylated CpG sites are denoted by ones , un-methylated CpG sites by zeros , and question marks denote CpG sites with unknown methylation state (missing data). b Modular architecture of DeepCpG. The DNA module consists of two convolutional and pooling layers to identify predictive motifs from the local sequence context and one fully connected layer to model motif interactions. The CpG module scans the CpG neighbourhood of multiple cells (rows in b ) using a bidirectional gated recurrent network ( GRU ) [ 36 ], yielding compressed features in a vector of constant size. The Joint module learns interactions between higher-level features derived from the DNA and CpG modules to predict methylation states in all cells. c , d The trained DeepCpG model can be used for different downstream analyses, including genome-wide imputation of missing CpG sites ( c ) and the discovery of DNA sequence motifs that are associated with DNA methylation levels or cell-to-cell variability ( d ) Full size image Here, we report DeepCpG, a computational method based on deep neural networks [ 17 – 19 ] for predicting single-cell methylation states and for modelling the sources of DNA methylation variability. DeepCpG leverages associations between DNA sequence patterns and methylation states as well as between neighbouring CpG sites, both within individual cells and across cells. Unlike previous methods [ 12 , 13 , 15 , 20 – 23 ], our approach does not separate the extraction of informative features and model training. Instead, DeepCpG is based on a modular architecture and learns predictive DNA sequence and methylation patterns in a data-driven manner. We evaluated DeepCpG on mouse embryonic stem cells profiled using whole-genome single-cell methylation profiling (scBS-seq [ 5 ]), as well as on human and mouse cells profiled using a reduced representation protocol (scRRBS-seq [ 8 ]). Across all cell types, DeepCpG yielded substantially more accurate predictions of methylation states than previous approaches. Additionally, DeepCpG uncovered both previously known and de novo sequence motifs that are associated with methylation changes and methylation variability between cells. Results and discussion DeepCpG is trained to predict binary CpG methylation states from local DNA sequence windows and observed neighbouring methylation states (Fig. 1a ). A major feature of the model is its modular architecture, consisting of a CpG module to account for correlations between CpG sites within and across cells, a DNA module to detect informative sequence patterns, and a Joint module that integrates the evidence from the CpG and DNA module to predict methylation states at target CpG sites (Fig. 1b ). Briefly, the DNA and CpG modules were designed to specifically model each of these data modalities. The DNA module is based on a convolutional architecture, which has been successfully applied in different domains [ 24 – 27 ], including genomics [ 28 – 33 ]. The module takes DNA sequences in windows centred on target CpG sites as input, which are scanned for sequence motifs using convolutional filters, analogous to conventional position weight matrices [ 34 , 35 ] (“ Methods ”). The CpG module is based on a bidirectional gated recurrent network [ 36 ], a sequential model that compresses patterns of neighbouring CpG states from a variable number of cells into a fixed-size feature vector (“ Methods ”). Finally, the Joint module learns interactions between output features of the DNA and CpG modules and predicts the methylation state at target sites in all cells using a multi-task architecture. The trained DeepCpG model can be used for different downstream analyses, including i) to impute low-coverage methylation profiles for sets of cells (Fig. 1c ) and ii) to discover DNA sequence motifs that are associated with methylation states and cell-to-cell variability (Fig. 1d ). Accurate prediction of single-cell methylation states First, we assessed the ability of DeepCpG to predict single-cell methylation states and compared the model to existing imputation strategies for DNA<|im_end|> <|im_start|>assistant A new 'deep learning' method, DeepCpG, has been designed by researchers at the Wellcome Trust Sanger Institute, the European Bioinformatics Institute and the Babraham Institute to help scientists better understand the epigenome – the biochemical activity around the genome. Reported today in Genome Biology, DeepCpG leverages 'deep neural networks', a multi-layered machine learning model inspired by the brain, and provides a valuable tool for research into health and disease. As a result of projects like 1000 Genomes, scientists now have a 'book' of the human genome divided up into chapters and annotated in parts. However, to fully understand how life works, scientists need to decipher both the genome – the set of instructions repeated in every cell – and the epigenome, the part that varies wildly between cells. To better understand how DNA sequences relate to biological changes, the genomics community is turning to artificial neural networks – a class of machine learning methods first introduced in the 1980s and inspired by the wiring of the brain. More recently, these models have been rebranded as 'deep neural networks', which form the field of deep learning. Scientists have leveraged the capacity of deep learning to fill in the gaps in single-cell genomics, an emerging technology that offers a close-up view on epigenetics. A new technique, DeepCpG, has been designed to help scientists learn about the connections between DNA sequences and DNA methylation – a biochemical modification of the genome sequence that can act like an off-switch for individual genes. Methylation plays a key part in important biological processes, including cell development, ageing and cancer progression. The new method uses genomic and epigenomic data to make predictions about DNA methylation in single cells. This is important because current technologies provide incomplete information about this. With DeepCpG, researchers can obtain a more complete picture of DNA methylation. The model can also be used to obtain new biological insights, for example on the connection between the DNA sequence and methylation. "DeepCpG actually learns meaningful features in a data-driven manner. It has major advantages over previous methods, including the ability to more accurately predict DNA methylation and to study intercellular differences. By studying the wiring of the learnt network, we can understand how the biology of DNA methylation works. This has allowed us to recover known DNA sequence motifs that are important for methylation changes, as well as to discover new motifs, which are the starting point for future studies," says Christof Angermueller, PhD candidate at EMBL-EBI. "We have demonstrated that DeepCpG enables us to accurately predict and analyse DNA methylation in single cells. However, DeepCpG is just one example of how we can apply deep learning to genomics and single-cell technologies. It is exciting to see the versatile applications deep learning has already found in genomics. I am looking forward to seeing more deep learning techniques come online. I believe it will make a big difference to how we study biology and has the potential to yield new answers about how life works," says Dr Oliver Stegle, Group Leader at EMBL-EBI. "Single cell epigenomics methods provide exciting insights into cell heterogeneity in development, ageing and disease; however if you are just dealing with two genomes in a single cell, bits of information are often lost during the experiment. This new method recognises patterns of the epigenome in single cells and then reconstructs lost information, returning a data-rich single cell epigenome," says Professor Wolf Reik from The Babraham Institute and Associate Faculty member at the Wellcome Trust Sanger Institute. "Deep learning is now the state-of-the art in many fields. We are exploring its utility for making sense of large scale biological data. Pioneering studies, such as the one by Angermueller and colleagues, prove that there is lot to be gained by using deep learning methods in computational biology," says Dr Leopold Parts, Group Leader at the Sanger Institute. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As global deaths from COVID-19 continue to rise, the world’s governments, institutions, and agencies are still working toward an understanding of who is most at risk of death. In this study, data on all recorded COVID-19 deaths in Sweden up to May 7, 2020 are linked to high-quality and accurate individual-level background data from administrative registers of the total population. By means of individual-level survival analysis we demonstrate that being male, having less individual income, lower education, not being married all independently predict a higher risk of death from COVID-19 and from all other causes of death. Being an immigrant from a low- or middle-income country predicts higher risk of death from COVID-19 but not for all other causes of death. The main message of this work is that the interaction of the virus causing COVID-19 and its social environment exerts an unequal burden on the most disadvantaged members of society. Introduction As global deaths from COVID-19 continue to rise 1 , the world’s governments, institutions, and agencies are still working toward an understanding of who is most at risk of death. This is due to a lack of high-quality microlevel data linking death records to other data sources (e.g., censuses, surveys, and registers) that contain information on sociodemographic background characteristics associated with variation in the risk of death. Until now, our understanding has been limited to rudimentary inferences drawn from comparisons of counts or proportions for different sections of society, more formal analyses of highly aggregated data, and a small number of microlevel analyses focused on comorbidities that give scant attention to sociodemographic factors beyond age and sex. These initial findings suggest that men 2 , 3 , 4 , 5 , 6 , the elderly 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , racial and ethnic minorities 4 , 6 , 7 , 12 , and people occupying lower socioeconomic positions 4 , 6 , are more prone to developing severe COVID-19, or dying from it. In light of the widely adopted message that COVID-19 “does not discriminate”, one given credence by the Director-General of the World Health Organization 13 , these patterns have been met with alarm. Indeed, they have spurred calls for the release of more detailed case and fatality data that would permit a more rigorous investigation of the apparent sociodemographic inequalities in COVID-19 death 8 . In response to this call, the present study examines sociodemographic risk factors of COVID-19 mortality in Sweden. Owing to the special provision of new data from the Swedish authorities, we have access to data on all recorded COVID-19 deaths in Sweden up to May 7, 2020 linked to high-quality and accurate individual-level background data from administrative registers. Using these data, we aim to advance the understanding of the sociodemographic risk factors associated with the risk of COVID-19 death for the entire population of Sweden. As many nations now have begun to ease distance restrictions and plan a roadmap through the pandemic, the provision of reliable information on which members of society are most at risk of death will be essential to informing national strategy. Compared to most other nations, Sweden has taken a less-restrictive approach to containing COVID-19 by encouraging working from home and promoting social distancing rather than mandating quarantine, while relying on a high level of compliance of its population to these measures from the very beginning. Kindergarten and schools have remained open for children below age 16 throughout the pandemic, while upper secondary schools and universities were closed on March 17 (ref. 14 ). While Sweden has experienced relatively high levels of COVID-19 mortality per capita 1 , its experience may provide invaluable insight for other countries to prepare for upcoming developments. As such, the results from the present study are not only important for the Swedish context, but also informative for other contexts to identify vulnerable populations and the circumstances in which they are at higher risk. Here, we examine how the risk of death varies across fundamental sociodemographic characteristics, including age, sex, civil status, individual disposable income, region of residence, and country of birth. Our results reveal an additional burden on the most vulnerable individuals of society that should be of interest to decision makers in all countries. Results During the 1,189,484 person-years of observation, 17,181 deaths occurred in our study population between March 13, 2020 and May 7, 2020. Table 1 shows the distribution of population at risk, and deaths from COVID-19 and all other causes of deaths for all variables used in our analyses, as well as categorized in broad age groups. A more detailed stratification of deaths and time at risk by age group and sex is presented in Supplementary Tables 1 and 2 . Table 1 shows an increasing risk of dying from COVID-19 by increasing age, as well as excess mortality for men, widowed, primary educated, those with low income, those from high-income countries (HIC), and those living in Stockholm county. For all other causes of death similar patterns were mostly found, except for the county of residence; those living outside Stockholm experience higher crude mortality rates than those in Stockholm. Table 1 Observations, deaths, and exposure time to the risk of death from COVID-19, and all other causes of death in Sweden (March 13, 2020–May 7, 2020). Full size table Figure 1 compares the mortality risks from COVID-19, separately for men and women, controlled for age from a multivariate Cox survival analysis. All point estimates and confidence intervals from these models can be found in the corresponding Supplementary Table 3 . Figure 1 shows, for men and women alike, that never married, divorced, and widowed individuals experience ~1.5–2 times higher mortality from COVID-19 than those who are married. We consider socioeconomic position as measured by both education and individual net income for both sexes. With respect to education, and net of income, we find a gradient for both men and women with individuals with", "role": "user" }, { "content": "Being a man, having a lower income, having a lower level of education, not being married, and being born abroad in low- or middle-income countries—these are factors that, independent of one another, are related to an elevated risk of dying from COVID-19 in Sweden. These are the findings of a new study in the journal Nature Communications from Stockholm University. \"We can show that there are independent effects of various separate risk factors that have been brought up in debates and news about COVID-19. All of these factors are accordingly individually associated with a strongly elevated risk of dying from COVID-19,\" said Sven Drefahl, Associate Professor of Demography at Stockholm University Demography Unit in the Department of Sociology, and main-author of the study. When it comes to the elevated risk for people from low- and middle-income countries in, for example, the Middle East and North Africa of dying from COVID-19, it does not agree with the general patterns of mortality for that group. Sven Drefahl explains that those born abroad generally have a lower mortality than people born in Sweden. This also applies when the research took income and level of education into account. The elevated risk of dying from COVID-19 for this group remains after the researchers controlled for circumstances, such as income and level of education. The study also shows that the risk of dying from COVID-19 was much higher in the Stockholm area than outside, both for those born in Sweden and those born abroad, which can be explained by the spread of disease being greater in that area. The study shows that being a man, having a lower income and lower level of education also result in a strongly elevated risk of dying from COVID-19. As to these aspects, this also agrees with the patterns for mortality from other diseases. \"Men generally have a higher mortality at comparable ages, which is considered to be due to a combination of biology and lifestyle. The fact that people with little education or a low income have a higher mortality may largely be due to lifestyle factors including finances –how much one can afford to prioritize one's health. Similarly, we can explain the elevated mortality from COVID-19 for these groups,\" said Gunnar Andersson. A number of earlier studies have also shown that single and unmarried people have a higher mortality from various diseases. This is usually to some part explained by selection, meaning that people who have worse health from the beginning are less attractive on the partner market and therefore get married to a lesser degree. \"The explanation is also considered to be in singles having a less protected environment than those who live in a couple relationship. Accordingly, marriage can lead to a healthier life with a lower risk of disease than for the unmarried. This can also explain the elevated risk of dying from COVID-19 for unmarried individuals shown by our study,\" said Sven Drefahl. Facts: How the study was done The study is based on data from the Swedish National Board of Health and Welfare on all registered deaths from COVID-19 in Sweden for adults aged 20 and older, until 7 May 2020. This was combined with register data from Statistics Sweden on city of residence, marital status, country of birth, income, level of education and age. The research is being funded by Forte, the Swedish Research Council for Health, Working Life and Welfare. Facts: Mortality from COVID-19 Men had more than twice as high a risk of dying from COVID-19 than women.Unmarried men and women (including those never married, widows/widowers and the divorced) had a 1.5-2 times as high a risk of dying from COVID-19 as those who were married.Living in the Stockholm area was linked to a 4.5 times as high risk of dying from COVID-19 (for both men and women) compared with the rest of the country.Those born abroad from low- and middle-income countries in the Middle East and North Africa had twice as high a mortality from COVID-19 for women and 3 times as high for men compared with people born in Sweden.Those born abroad from low- and middle-income countries outside the Middle East and North Africa had a more than 1.5 times as high mortality from COVID-19.Men with a compulsory-school and upper-secondary education ran an approximately 25 per-cent higher risk of dying from COVID-19 compared with men with post-upper-secondary education.Women with a compulsory-school and upper-secondary education ran a 40-50 per-cent higher risk of dying from COVID-19 compared with women with post-upper-secondary education. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract As global deaths from COVID-19 continue to rise, the world’s governments, institutions, and agencies are still working toward an understanding of who is most at risk of death. In this study, data on all recorded COVID-19 deaths in Sweden up to May 7, 2020 are linked to high-quality and accurate individual-level background data from administrative registers of the total population. By means of individual-level survival analysis we demonstrate that being male, having less individual income, lower education, not being married all independently predict a higher risk of death from COVID-19 and from all other causes of death. Being an immigrant from a low- or middle-income country predicts higher risk of death from COVID-19 but not for all other causes of death. The main message of this work is that the interaction of the virus causing COVID-19 and its social environment exerts an unequal burden on the most disadvantaged members of society. Introduction As global deaths from COVID-19 continue to rise 1 , the world’s governments, institutions, and agencies are still working toward an understanding of who is most at risk of death. This is due to a lack of high-quality microlevel data linking death records to other data sources (e.g., censuses, surveys, and registers) that contain information on sociodemographic background characteristics associated with variation in the risk of death. Until now, our understanding has been limited to rudimentary inferences drawn from comparisons of counts or proportions for different sections of society, more formal analyses of highly aggregated data, and a small number of microlevel analyses focused on comorbidities that give scant attention to sociodemographic factors beyond age and sex. These initial findings suggest that men 2 , 3 , 4 , 5 , 6 , the elderly 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , racial and ethnic minorities 4 , 6 , 7 , 12 , and people occupying lower socioeconomic positions 4 , 6 , are more prone to developing severe COVID-19, or dying from it. In light of the widely adopted message that COVID-19 “does not discriminate”, one given credence by the Director-General of the World Health Organization 13 , these patterns have been met with alarm. Indeed, they have spurred calls for the release of more detailed case and fatality data that would permit a more rigorous investigation of the apparent sociodemographic inequalities in COVID-19 death 8 . In response to this call, the present study examines sociodemographic risk factors of COVID-19 mortality in Sweden. Owing to the special provision of new data from the Swedish authorities, we have access to data on all recorded COVID-19 deaths in Sweden up to May 7, 2020 linked to high-quality and accurate individual-level background data from administrative registers. Using these data, we aim to advance the understanding of the sociodemographic risk factors associated with the risk of COVID-19 death for the entire population of Sweden. As many nations now have begun to ease distance restrictions and plan a roadmap through the pandemic, the provision of reliable information on which members of society are most at risk of death will be essential to informing national strategy. Compared to most other nations, Sweden has taken a less-restrictive approach to containing COVID-19 by encouraging working from home and promoting social distancing rather than mandating quarantine, while relying on a high level of compliance of its population to these measures from the very beginning. Kindergarten and schools have remained open for children below age 16 throughout the pandemic, while upper secondary schools and universities were closed on March 17 (ref. 14 ). While Sweden has experienced relatively high levels of COVID-19 mortality per capita 1 , its experience may provide invaluable insight for other countries to prepare for upcoming developments. As such, the results from the present study are not only important for the Swedish context, but also informative for other contexts to identify vulnerable populations and the circumstances in which they are at higher risk. Here, we examine how the risk of death varies across fundamental sociodemographic characteristics, including age, sex, civil status, individual disposable income, region of residence, and country of birth. Our results reveal an additional burden on the most vulnerable individuals of society that should be of interest to decision makers in all countries. Results During the 1,189,484 person-years of observation, 17,181 deaths occurred in our study population between March 13, 2020 and May 7, 2020. Table 1 shows the distribution of population at risk, and deaths from COVID-19 and all other causes of deaths for all variables used in our analyses, as well as categorized in broad age groups. A more detailed stratification of deaths and time at risk by age group and sex is presented in Supplementary Tables 1 and 2 . Table 1 shows an increasing risk of dying from COVID-19 by increasing age, as well as excess mortality for men, widowed, primary educated, those with low income, those from high-income countries (HIC), and those living in Stockholm county. For all other causes of death similar patterns were mostly found, except for the county of residence; those living outside Stockholm experience higher crude mortality rates than those in Stockholm. Table 1 Observations, deaths, and exposure time to the risk of death from COVID-19, and all other causes of death in Sweden (March 13, 2020–May 7, 2020). Full size table Figure 1 compares the mortality risks from COVID-19, separately for men and women, controlled for age from a multivariate Cox survival analysis. All point estimates and confidence intervals from these models can be found in the corresponding Supplementary Table 3 . Figure 1 shows, for men and women alike, that never married, divorced, and widowed individuals experience ~1.5–2 times higher mortality from COVID-19 than those who are married. We consider socioeconomic position as measured by both education and individual net income for both sexes. With respect to education, and net of income, we find a gradient for both men and women with individuals with<|im_end|> <|im_start|>assistant Being a man, having a lower income, having a lower level of education, not being married, and being born abroad in low- or middle-income countries—these are factors that, independent of one another, are related to an elevated risk of dying from COVID-19 in Sweden. These are the findings of a new study in the journal Nature Communications from Stockholm University. "We can show that there are independent effects of various separate risk factors that have been brought up in debates and news about COVID-19. All of these factors are accordingly individually associated with a strongly elevated risk of dying from COVID-19," said Sven Drefahl, Associate Professor of Demography at Stockholm University Demography Unit in the Department of Sociology, and main-author of the study. When it comes to the elevated risk for people from low- and middle-income countries in, for example, the Middle East and North Africa of dying from COVID-19, it does not agree with the general patterns of mortality for that group. Sven Drefahl explains that those born abroad generally have a lower mortality than people born in Sweden. This also applies when the research took income and level of education into account. The elevated risk of dying from COVID-19 for this group remains after the researchers controlled for circumstances, such as income and level of education. The study also shows that the risk of dying from COVID-19 was much higher in the Stockholm area than outside, both for those born in Sweden and those born abroad, which can be explained by the spread of disease being greater in that area. The study shows that being a man, having a lower income and lower level of education also result in a strongly elevated risk of dying from COVID-19. As to these aspects, this also agrees with the patterns for mortality from other diseases. "Men generally have a higher mortality at comparable ages, which is considered to be due to a combination of biology and lifestyle. The fact that people with little education or a low income have a higher mortality may largely be due to lifestyle factors including finances –how much one can afford to prioritize one's health. Similarly, we can explain the elevated mortality from COVID-19 for these groups," said Gunnar Andersson. A number of earlier studies have also shown that single and unmarried people have a higher mortality from various diseases. This is usually to some part explained by selection, meaning that people who have worse health from the beginning are less attractive on the partner market and therefore get married to a lesser degree. "The explanation is also considered to be in singles having a less protected environment than those who live in a couple relationship. Accordingly, marriage can lead to a healthier life with a lower risk of disease than for the unmarried. This can also explain the elevated risk of dying from COVID-19 for unmarried individuals shown by our study," said Sven Drefahl. Facts: How the study was done The study is based on data from the Swedish National Board of Health and Welfare on all registered deaths from COVID-19 in Sweden for adults aged 20 and older, until 7 May 2020. This was combined with register data from Statistics Sweden on city of residence, marital status, country of birth, income, level of education and age. The research is being funded by Forte, the Swedish Research Council for Health, Working Life and Welfare. Facts: Mortality from COVID-19 Men had more than twice as high a risk of dying from COVID-19 than women.Unmarried men and women (including those never married, widows/widowers and the divorced) had a 1.5-2 times as high a risk of dying from COVID-19 as those who were married.Living in the Stockholm area was linked to a 4.5 times as high risk of dying from COVID-19 (for both men and women) compared with the rest of the country.Those born abroad from low- and middle-income countries in the Middle East and North Africa had twice as high a mortality from COVID-19 for women and 3 times as high for men compared with people born in Sweden.Those born abroad from low- and middle-income countries outside the Middle East and North Africa had a more than 1.5 times as high mortality from COVID-19.Men with a compulsory-school and upper-secondary education ran an approximately 25 per-cent higher risk of dying from COVID-19 compared with men with post-upper-secondary education.Women with a compulsory-school and upper-secondary education ran a 40-50 per-cent higher risk of dying from COVID-19 compared with women with post-upper-secondary education. <|im_end|>

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4829, 5814, 520, 53182, 3907, 4829, 5814, 8113, 304, 279, 6011, 315, 97157, 11, 323, 1925, 43802, 315, 279, 4007, 13, 3277, 433, 4131, 311, 279, 32389, 5326, 369, 1274, 505, 3428, 12, 323, 6278, 32197, 5961, 304, 11, 369, 3187, 11, 279, 12877, 6460, 323, 4892, 10384, 315, 23069, 505, 20562, 12, 777, 11, 433, 1587, 539, 7655, 449, 279, 4689, 12912, 315, 29528, 369, 430, 1912, 13, 328, 1055, 423, 1116, 17137, 15100, 430, 1884, 9405, 22917, 8965, 617, 264, 4827, 29528, 1109, 1274, 9405, 304, 24067, 13, 1115, 1101, 17208, 994, 279, 3495, 3952, 8070, 323, 2237, 315, 6873, 1139, 2759, 13, 578, 32389, 5326, 315, 23069, 505, 20562, 12, 777, 369, 420, 1912, 8625, 1306, 279, 12074, 14400, 369, 13463, 11, 1778, 439, 8070, 323, 2237, 315, 6873, 13, 578, 4007, 1101, 5039, 430, 279, 5326, 315, 23069, 505, 20562, 12, 777, 574, 1790, 5190, 304, 279, 53182, 3158, 1109, 4994, 11, 2225, 369, 1884, 9405, 304, 24067, 323, 1884, 9405, 22917, 11, 902, 649, 387, 11497, 555, 279, 9041, 315, 8624, 1694, 7191, 304, 430, 3158, 13, 578, 4007, 5039, 430, 1694, 264, 893, 11, 3515, 264, 4827, 8070, 323, 4827, 2237, 315, 6873, 1101, 1121, 304, 264, 16917, 32389, 5326, 315, 23069, 505, 20562, 12, 777, 13, 1666, 311, 1521, 13878, 11, 420, 1101, 34008, 449, 279, 12912, 369, 29528, 505, 1023, 19338, 13, 330, 29819, 8965, 617, 264, 5190, 29528, 520, 30139, 17051, 11, 902, 374, 6646, 311, 387, 4245, 311, 264, 10824, 315, 34458, 323, 19433, 13, 578, 2144, 430, 1274, 449, 2697, 6873, 477, 264, 3428, 8070, 617, 264, 5190, 29528, 1253, 14090, 387, 4245, 311, 19433, 9547, 2737, 40382, 1389, 5269, 1790, 832, 649, 10150, 311, 63652, 832, 596, 2890, 13, 35339, 11, 584, 649, 10552, 279, 32389, 29528, 505, 20562, 12, 777, 369, 1521, 5315, 1359, 1071, 66249, 277, 48693, 942, 13, 362, 1396, 315, 6931, 7978, 617, 1101, 6982, 430, 3254, 323, 95587, 1274, 617, 264, 5190, 29528, 505, 5370, 19338, 13, 1115, 374, 6118, 311, 1063, 961, 11497, 555, 6727, 11, 7438, 430, 1274, 889, 617, 11201, 2890, 505, 279, 7314, 527, 2753, 19411, 389, 279, 8427, 3157, 323, 9093, 636, 12502, 311, 264, 32415, 8547, 13, 330, 791, 16540, 374, 1101, 6646, 311, 387, 304, 17845, 3515, 264, 2753, 2682, 4676, 1109, 1884, 889, 3974, 304, 264, 5743, 5133, 13, 63909, 11, 11103, 649, 3063, 311, 264, 39345, 2324, 449, 264, 4827, 5326, 315, 8624, 1109, 369, 279, 95587, 13, 1115, 649, 1101, 10552, 279, 32389, 5326, 315, 23069, 505, 20562, 12, 777, 369, 95587, 7931, 6982, 555, 1057, 4007, 1359, 1071, 328, 1055, 423, 1116, 17137, 13, 46083, 25, 2650, 279, 4007, 574, 2884, 578, 4007, 374, 3196, 389, 828, 505, 279, 31209, 5165, 8925, 315, 6401, 323, 66187, 389, 682, 9879, 16779, 505, 20562, 12, 777, 304, 24067, 369, 12884, 20330, 220, 508, 323, 9191, 11, 3156, 220, 22, 3297, 220, 2366, 15, 13, 1115, 574, 11093, 449, 4254, 828, 505, 25647, 24067, 389, 3363, 315, 22423, 11, 60439, 2704, 11, 3224, 315, 7342, 11, 8070, 11, 2237, 315, 6873, 323, 4325, 13, 578, 3495, 374, 1694, 24853, 555, 11246, 68, 11, 279, 31209, 8483, 9251, 369, 6401, 11, 22938, 9601, 323, 66187, 13, 46083, 25, 22806, 2786, 505, 20562, 12, 777, 11258, 1047, 810, 1109, 11157, 439, 1579, 264, 5326, 315, 23069, 505, 20562, 12, 777, 1109, 3278, 10840, 70582, 3026, 323, 3278, 320, 16564, 1884, 2646, 12502, 11, 9923, 4336, 6458, 307, 16345, 323, 279, 50592, 8, 1047, 264, 220, 16, 13, 20, 12, 17, 3115, 439, 1579, 264, 5326, 315, 23069, 505, 20562, 12, 777, 439, 1884, 889, 1051, 12502, 1236, 2299, 304, 279, 53182, 3158, 574, 10815, 311, 264, 220, 19, 13, 20, 3115, 439, 1579, 5326, 315, 23069, 505, 20562, 12, 777, 320, 2000, 2225, 3026, 323, 3278, 8, 7863, 449, 279, 2800, 315, 279, 3224, 5221, 974, 9405, 22917, 505, 3428, 12, 323, 6278, 32197, 5961, 304, 279, 12877, 6460, 323, 4892, 10384, 1047, 11157, 439, 1579, 264, 29528, 505, 20562, 12, 777, 369, 3278, 323, 220, 18, 3115, 439, 1579, 369, 3026, 7863, 449, 1274, 9405, 304, 24067, 5221, 974, 9405, 22917, 505, 3428, 12, 323, 6278, 32197, 5961, 4994, 279, 12877, 6460, 323, 4892, 10384, 1047, 264, 810, 1109, 220, 16, 13, 20, 3115, 439, 1579, 29528, 505, 20562, 12, 777, 1345, 268, 449, 264, 65868, 35789, 323, 8582, 30483, 6873, 10837, 459, 13489, 220, 914, 824, 21911, 5190, 5326, 315, 23069, 505, 20562, 12, 777, 7863, 449, 3026, 449, 1772, 54362, 30483, 6873, 1196, 6431, 449, 264, 65868, 35789, 323, 8582, 30483, 6873, 10837, 264, 220, 1272, 12, 1135, 824, 21911, 5190, 5326, 315, 23069, 505, 20562, 12, 777, 7863, 449, 3278, 449, 1772, 54362, 30483, 6873, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Ecosystem service assessments rarely consider flows between distant regions. Hence, telecoupling effects such as conservation burdens in distant ecosystems are ignored. We identified service-providing species for two cultural ecosystem services (existence and bequest, and birdwatching) and two receiving, i.e. benefitting, regions (Germany, the Netherlands). We delineated and analysed sending, i.e. service-providing, regions on a global scale. The proportion of service-providing species with distant habitats was higher for birdwatching (Germany: 58.6%, Netherlands: 59.4%), than for existence and bequest (Germany: 49.3%, Netherlands: 57.1%). Hotspots of sending regions were predominantly situated in tropical and subtropical grasslands, savannas and shrublands and were significantly more threatened and poorer than the global mean. Hotspot protection levels for flows to Germany were higher than the global mean, and lower for the Dutch hotspots. Our findings increase understanding on how distant regions underpin ecosystem services and necessitate interregional assessment as well as conservation efforts. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Spatial assessments of ecosystem services (ES) rarely consider benefits from distant areas through flows of ES to the studied region, and in turn, how these flows affect distant regions (Pascual et al. 2017 ). Interregional ES flows are defined as movements of goods, energy and information derived from ecosystems between a region providing the service, i.e. the sending region, and a region using the service, i.e. the receiving region (Schröter et al. 2018 ). ES often flow over large distances and hence ‘telecouple’ distant sending and receiving regions (Schröter et al. 2018 ; Koellner et al. 2019 ). Telecoupling refers to processes that interlink distant regions through material or immaterial flows of energy, matter or information (Liu et al. 2015 ). Climate change, land-use change or overexploitation in a sending region might undermine continued ES provision in a receiving region. For example, the destruction of breeding habitat for migratory birds in a sending region might affect population numbers and ES provision like pest control or opportunities for leisure hunting in distant receiving regions (López-Hoffman et al. 2017 ). As some ES rely on conservation mechanisms, for instance through protection of key service-providing species (Luck et al. 2009 ), interregional ES flows also pose equity questions. Some countries bear costs of conservation while other regions benefit. Studying interregional ES flows could hence identify inequitable distributions of these costs and benefits (Schröter et al. 2018 ). This is of particular relevance when regions in the Global South are bearing costs while the Global North benefits (Martín-López et al. 2018 ). The regional assessment report for Europe and Central Asia of IPBES (Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services) identified interregional ES flows as a key knowledge gap (Martín-López et al. 2018 ). Thus, to date ES assessments provide a limited picture of the dependence of ES on ecosystems abroad (Pascual et al. 2017 ). Yet, Schröter et al. ( 2016 ) found that national ecosystem assessments in Europe cover interregional ES flows to a minor extent. Exceptions include studies of provisioning ES that are traded goods, such as timber (Kastner et al. 2011 ), crops (Yu et al. 2013 ) and fishery products (Watson et al. 2015 ). Also, some studies have addressed passive biophysical flows of regulating services such as carbon sequestration (Serna-Chavez et al. 2014 ) or migrating species that provide pollination (López-Hoffman et al. 2010 ) and pest control (López-Hoffman et al. 2014 ). The largest knowledge gaps remain for interregional flows of cultural ES (Martín-López et al. 2018 ; Koellner et al. 2019 ), which comprise non-material contributions of ecosystems to human well-being. Finding suitable indicators and developing methods for cultural ES is already challenging within case-study boundaries (Milcu et al. 2013 ), and even more so when quantifying interregional flows. Schröter et al. ( 2018 ) distinguish two types of flows that are relevant for cultural ES. First, cultural ES flows comprise the movement of migratory species between sending and receiving regions, which provide opportunities to experience wildlife, such as through birdwatching. Second, cultural ES flows comprise the transmission of information as the basis for cognitive, non-material use, such as aesthetic appreciation, spiritual activities and inspiration for art. Challenges remain in quantifying interregional flows for cultural ES. For instance, it is difficult to identify and characterise landscapes or ecosystems, i.e. environmental spaces (Fish et al. 2016 ), that provide cultural ES in interaction with cultural practices. Examples are value attribution to certain species, or active use through observation and enjoyment. Data on how cultural practices relate to specific places are scarce; methods need to be developed to delineate the regions that are linked through flows (Koellner et al. 2019 ). Distant sending regions can have an existence or bequest value for receiving regions, i.e. their persistence is important to present or future generations (Hansjürgens et al. 2017 ). In addition, these spaces can provide valuable breeding or wintering areas for migratory birds that provide opportunities for birdwatching elsewhere (López-Hoffman et al. 2017 ). Another challenge remains in linking ES assessments more strongly to biodiversity (Schröter et al. 2016 ). Different aspects of biodiversity are of different importance for quantifying cultural ES directly (Harrison et al. 2014 ). For instance, species richness can be directly valued as a cultural ES, as done by birdwatchers (Karp et al. 2015 ; Cumming and Maciejewski 2017 ). Furthermore, the persistence of iconic, charismatic species or landscapes is appreciated by people who hold existence and bequest values (Schirpke et al. 2018 ). Iconic species are often highlighted by conservation organisations as culturally valued species to justify and attract funding (Bowen-Jones and Entwistle 2002 ). While the cultural role of such species and landscapes for supporting identities is conceptually acknowledged (Díaz et al. 2018 ), large-scale quantification approaches are still lacking. To address these challenges, our study aims to identify and characterise sending regions for interregional flows of two understudied cultural ES. We selected existence and bequest values that people have for bird and mammal", "role": "user" }, { "content": "Soya and beef from South America, timber from Russia, fish from China—in an era of globalisation, central Europe has become a market for animal and plant products from all over the world. But in addition to these tangible goods, faraway ecosystems also supply intangible or cultural services that do not appear in any trade balance sheet. For example, they provide habitats for species whose existence is of interest to many Europeans. But what kind of regions provide such cultural ecosystem services for highly developed and densely populated countries in Europe? Together with colleagues in the Netherlands, researchers at the Helmholtz Centre for Environmental Research (UFZ) in Leipzig investigated this question. Their findings reveal that Germany and the Netherlands benefit predominantly from services in particularly threatened ecosystems in very poor regions of the world. Responsibility for protecting these ecosystems must therefore be more fairly distributed, argue the researchers in the journal Ambio. Large, charismatic birds like the black stork and the common crane are extremely popular in Germany, and not just among ornithologists. Every year, hordes of people head outdoors with binoculars to watch the cranes' migration. In some parts of the country, this event has even become a significant tourist attraction. But in many cases, for people in central Europe to enjoy natural phenomena like these, the conditions elsewhere need to be right. A number of popular bird species migrate, crossing the Mediterranean by different routes to spend the winter in Africa. \"If the climate or land uses change in the African winter quarters, this can have obvious effects here in Germany,\" says environmental scientist Dr. Matthias Schröter. The effects may be both ecological and psychological. The smaller the number of birds that return in the spring, the less effectively they can fulfill their role in local ecosystems—and the fewer opportunities there are for wildlife lovers in central Europe to experience pleasure, relaxation or inspiration from encounters with these animals. Experts refer to such close interconnections between humans and ecosystems in faraway regions as 'telecoupling.' So far, research into how these relationships function and what consequences they have for the supplier at one end of the world at the consumer at the other has mostly focused on agricultural and forestry products. \"There are also a couple of studies on industrialised countries that use forests in other regions as carbon sinks to improve their carbon footprint,\" says Schröter. Some researchers have also studied migrating species that function as pest controllers or pollinators in far-apart regions. But when it comes to intangible ecosystem services, the situation is more difficult. The effect that nature has on human wellbeing is hard to quantify and analyse numerically. Accordingly, little is currently known about this form of telecoupling. For example, which other regions of the world do people in Germany depend on to be able to enjoy wildlife? And how can we go about demonstrating the link? \"There have only been a very few studies so far, and they focus on individual species,\" says Schröter. \"For example, they looked at the links created by the giant panda between its native habitats in China and zoos all over the world.\" But he and his colleagues wanted to take a broader look at the phenomenon by including as many animal species as possible. Firstly they analysed data from two online platforms on which German and Dutch bird lovers can post their sightings. They narrowed the data down to the 300 most frequently mentioned species and examined the ranges of these species. People in Germany and the Netherlands also have a weakness for more exotic species that they may never encounter themselves. Many people in central Europe couldn't imagine a world without lions, elephants, pandas or great apes, even if they experience no direct benefit from these animals. \"Charismatic species like these have value to many people simply through the fact that they exist,\" says Schröter. So to identify these valued species, he and his colleagues combed through 40 annual reports from major conservation organisations such as Naturschutzbund Deutschland (NABU) and the Dutch branch of WWF. \"We worked on the assumption that the species mentioned here are particularly popular and have high societal relevance,\" the UFZ scientist explains. In this way, the team identified 108 birds and 22 mammals that enjoy celebrity status in Germany. The top five places were taken by the common crane, the white-tailed eagle, the osprey, the northern lapwing and the black stork, with the tiger, the first mammal, following in sixth place. In the Netherlands, meanwhile, the African elephant topped the list. \"Almost half of the popular animals among German conservation organisations spend at least part of their lives in distant countries,\" says Schröter. For the species important to German birdwatchers, the figure is nearly 60%. Next the researchers overlaid the ranges of all these treasured animals, allowing them to identify the regions that are home to particularly large numbers of the species and whose ecosystems therefore provide the widest range of services for the two countries in question. For Germany, the hotspots are mainly in the African savannah and scrubland south of the Sahara. In the Netherlands, an important role is also played by forests and grasslands closer to home in eastern Europe and central Asia. \"When you take a closer look at these regions, you notice two trends,\" Schröter explains. Firstly, these are habitats that are heavily influenced by humans, only a small portion of which are protected. For example, less than five percent of the hotspots of value to Germany are located in national parks or other reserves with similarly strict regulations. Moreover, these are also especially poor regions. In the regions important to Germany, the average annual income is just 1,424 US dollars per capita. \"For one thing, we can use findings like these to support more effective and better coordinated conservation efforts,\" says Schröter. \"But it also raises questions of justice.\" Are poorer countries adequately compensated for ecosystem services that benefit richer ones? In the researcher's opinion, this is not the case. The cost burden of setting up protected areas should not be borne only by the countries that provide the ecosystem services and a few international conservation organisations: \"Countries whose citizens benefit from these services far away should also make a financial contribution.\" To create more justice, he adds, such contributions could, for example, be integrated into the targets of the international Convention on Biological Diversity. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Ecosystem service assessments rarely consider flows between distant regions. Hence, telecoupling effects such as conservation burdens in distant ecosystems are ignored. We identified service-providing species for two cultural ecosystem services (existence and bequest, and birdwatching) and two receiving, i.e. benefitting, regions (Germany, the Netherlands). We delineated and analysed sending, i.e. service-providing, regions on a global scale. The proportion of service-providing species with distant habitats was higher for birdwatching (Germany: 58.6%, Netherlands: 59.4%), than for existence and bequest (Germany: 49.3%, Netherlands: 57.1%). Hotspots of sending regions were predominantly situated in tropical and subtropical grasslands, savannas and shrublands and were significantly more threatened and poorer than the global mean. Hotspot protection levels for flows to Germany were higher than the global mean, and lower for the Dutch hotspots. Our findings increase understanding on how distant regions underpin ecosystem services and necessitate interregional assessment as well as conservation efforts. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Spatial assessments of ecosystem services (ES) rarely consider benefits from distant areas through flows of ES to the studied region, and in turn, how these flows affect distant regions (Pascual et al. 2017 ). Interregional ES flows are defined as movements of goods, energy and information derived from ecosystems between a region providing the service, i.e. the sending region, and a region using the service, i.e. the receiving region (Schröter et al. 2018 ). ES often flow over large distances and hence ‘telecouple’ distant sending and receiving regions (Schröter et al. 2018 ; Koellner et al. 2019 ). Telecoupling refers to processes that interlink distant regions through material or immaterial flows of energy, matter or information (Liu et al. 2015 ). Climate change, land-use change or overexploitation in a sending region might undermine continued ES provision in a receiving region. For example, the destruction of breeding habitat for migratory birds in a sending region might affect population numbers and ES provision like pest control or opportunities for leisure hunting in distant receiving regions (López-Hoffman et al. 2017 ). As some ES rely on conservation mechanisms, for instance through protection of key service-providing species (Luck et al. 2009 ), interregional ES flows also pose equity questions. Some countries bear costs of conservation while other regions benefit. Studying interregional ES flows could hence identify inequitable distributions of these costs and benefits (Schröter et al. 2018 ). This is of particular relevance when regions in the Global South are bearing costs while the Global North benefits (Martín-López et al. 2018 ). The regional assessment report for Europe and Central Asia of IPBES (Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services) identified interregional ES flows as a key knowledge gap (Martín-López et al. 2018 ). Thus, to date ES assessments provide a limited picture of the dependence of ES on ecosystems abroad (Pascual et al. 2017 ). Yet, Schröter et al. ( 2016 ) found that national ecosystem assessments in Europe cover interregional ES flows to a minor extent. Exceptions include studies of provisioning ES that are traded goods, such as timber (Kastner et al. 2011 ), crops (Yu et al. 2013 ) and fishery products (Watson et al. 2015 ). Also, some studies have addressed passive biophysical flows of regulating services such as carbon sequestration (Serna-Chavez et al. 2014 ) or migrating species that provide pollination (López-Hoffman et al. 2010 ) and pest control (López-Hoffman et al. 2014 ). The largest knowledge gaps remain for interregional flows of cultural ES (Martín-López et al. 2018 ; Koellner et al. 2019 ), which comprise non-material contributions of ecosystems to human well-being. Finding suitable indicators and developing methods for cultural ES is already challenging within case-study boundaries (Milcu et al. 2013 ), and even more so when quantifying interregional flows. Schröter et al. ( 2018 ) distinguish two types of flows that are relevant for cultural ES. First, cultural ES flows comprise the movement of migratory species between sending and receiving regions, which provide opportunities to experience wildlife, such as through birdwatching. Second, cultural ES flows comprise the transmission of information as the basis for cognitive, non-material use, such as aesthetic appreciation, spiritual activities and inspiration for art. Challenges remain in quantifying interregional flows for cultural ES. For instance, it is difficult to identify and characterise landscapes or ecosystems, i.e. environmental spaces (Fish et al. 2016 ), that provide cultural ES in interaction with cultural practices. Examples are value attribution to certain species, or active use through observation and enjoyment. Data on how cultural practices relate to specific places are scarce; methods need to be developed to delineate the regions that are linked through flows (Koellner et al. 2019 ). Distant sending regions can have an existence or bequest value for receiving regions, i.e. their persistence is important to present or future generations (Hansjürgens et al. 2017 ). In addition, these spaces can provide valuable breeding or wintering areas for migratory birds that provide opportunities for birdwatching elsewhere (López-Hoffman et al. 2017 ). Another challenge remains in linking ES assessments more strongly to biodiversity (Schröter et al. 2016 ). Different aspects of biodiversity are of different importance for quantifying cultural ES directly (Harrison et al. 2014 ). For instance, species richness can be directly valued as a cultural ES, as done by birdwatchers (Karp et al. 2015 ; Cumming and Maciejewski 2017 ). Furthermore, the persistence of iconic, charismatic species or landscapes is appreciated by people who hold existence and bequest values (Schirpke et al. 2018 ). Iconic species are often highlighted by conservation organisations as culturally valued species to justify and attract funding (Bowen-Jones and Entwistle 2002 ). While the cultural role of such species and landscapes for supporting identities is conceptually acknowledged (Díaz et al. 2018 ), large-scale quantification approaches are still lacking. To address these challenges, our study aims to identify and characterise sending regions for interregional flows of two understudied cultural ES. We selected existence and bequest values that people have for bird and mammal<|im_end|> <|im_start|>assistant Soya and beef from South America, timber from Russia, fish from China—in an era of globalisation, central Europe has become a market for animal and plant products from all over the world. But in addition to these tangible goods, faraway ecosystems also supply intangible or cultural services that do not appear in any trade balance sheet. For example, they provide habitats for species whose existence is of interest to many Europeans. But what kind of regions provide such cultural ecosystem services for highly developed and densely populated countries in Europe? Together with colleagues in the Netherlands, researchers at the Helmholtz Centre for Environmental Research (UFZ) in Leipzig investigated this question. Their findings reveal that Germany and the Netherlands benefit predominantly from services in particularly threatened ecosystems in very poor regions of the world. Responsibility for protecting these ecosystems must therefore be more fairly distributed, argue the researchers in the journal Ambio. Large, charismatic birds like the black stork and the common crane are extremely popular in Germany, and not just among ornithologists. Every year, hordes of people head outdoors with binoculars to watch the cranes' migration. In some parts of the country, this event has even become a significant tourist attraction. But in many cases, for people in central Europe to enjoy natural phenomena like these, the conditions elsewhere need to be right. A number of popular bird species migrate, crossing the Mediterranean by different routes to spend the winter in Africa. "If the climate or land uses change in the African winter quarters, this can have obvious effects here in Germany," says environmental scientist Dr. Matthias Schröter. The effects may be both ecological and psychological. The smaller the number of birds that return in the spring, the less effectively they can fulfill their role in local ecosystems—and the fewer opportunities there are for wildlife lovers in central Europe to experience pleasure, relaxation or inspiration from encounters with these animals. Experts refer to such close interconnections between humans and ecosystems in faraway regions as 'telecoupling.' So far, research into how these relationships function and what consequences they have for the supplier at one end of the world at the consumer at the other has mostly focused on agricultural and forestry products. "There are also a couple of studies on industrialised countries that use forests in other regions as carbon sinks to improve their carbon footprint," says Schröter. Some researchers have also studied migrating species that function as pest controllers or pollinators in far-apart regions. But when it comes to intangible ecosystem services, the situation is more difficult. The effect that nature has on human wellbeing is hard to quantify and analyse numerically. Accordingly, little is currently known about this form of telecoupling. For example, which other regions of the world do people in Germany depend on to be able to enjoy wildlife? And how can we go about demonstrating the link? "There have only been a very few studies so far, and they focus on individual species," says Schröter. "For example, they looked at the links created by the giant panda between its native habitats in China and zoos all over the world." But he and his colleagues wanted to take a broader look at the phenomenon by including as many animal species as possible. Firstly they analysed data from two online platforms on which German and Dutch bird lovers can post their sightings. They narrowed the data down to the 300 most frequently mentioned species and examined the ranges of these species. People in Germany and the Netherlands also have a weakness for more exotic species that they may never encounter themselves. Many people in central Europe couldn't imagine a world without lions, elephants, pandas or great apes, even if they experience no direct benefit from these animals. "Charismatic species like these have value to many people simply through the fact that they exist," says Schröter. So to identify these valued species, he and his colleagues combed through 40 annual reports from major conservation organisations such as Naturschutzbund Deutschland (NABU) and the Dutch branch of WWF. "We worked on the assumption that the species mentioned here are particularly popular and have high societal relevance," the UFZ scientist explains. In this way, the team identified 108 birds and 22 mammals that enjoy celebrity status in Germany. The top five places were taken by the common crane, the white-tailed eagle, the osprey, the northern lapwing and the black stork, with the tiger, the first mammal, following in sixth place. In the Netherlands, meanwhile, the African elephant topped the list. "Almost half of the popular animals among German conservation organisations spend at least part of their lives in distant countries," says Schröter. For the species important to German birdwatchers, the figure is nearly 60%. Next the researchers overlaid the ranges of all these treasured animals, allowing them to identify the regions that are home to particularly large numbers of the species and whose ecosystems therefore provide the widest range of services for the two countries in question. For Germany, the hotspots are mainly in the African savannah and scrubland south of the Sahara. In the Netherlands, an important role is also played by forests and grasslands closer to home in eastern Europe and central Asia. "When you take a closer look at these regions, you notice two trends," Schröter explains. Firstly, these are habitats that are heavily influenced by humans, only a small portion of which are protected. For example, less than five percent of the hotspots of value to Germany are located in national parks or other reserves with similarly strict regulations. Moreover, these are also especially poor regions. In the regions important to Germany, the average annual income is just 1,424 US dollars per capita. "For one thing, we can use findings like these to support more effective and better coordinated conservation efforts," says Schröter. "But it also raises questions of justice." Are poorer countries adequately compensated for ecosystem services that benefit richer ones? In the researcher's opinion, this is not the case. The cost burden of setting up protected areas should not be borne only by the countries that provide the ecosystem services and a few international conservation organisations: "Countries whose citizens benefit from these services far away should also make a financial contribution." To create more justice, he adds, such contributions could, for example, be integrated into the targets of the international Convention on Biological Diversity. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Integrated circuits utilize networked logic gates to compute Boolean logic operations that are the foundation of modern computation and electronics. With the emergence of flexible electronic materials and devices, an opportunity exists to formulate digital logic from compliant, conductive materials. Here, we introduce a general method of leveraging cellular, mechanical metamaterials composed of conductive polymers to realize all digital logic gates and gate assemblies. We establish a method for applying conductive polymer networks to metamaterial constituents and correlate mechanical buckling modes with network connectivity. With this foundation, each of the conventional logic gates is realized in an equivalent mechanical metamaterial, leading to soft, conductive matter that thinks about applied mechanical stress. These findings may advance the growing fields of soft robotics and smart mechanical matter, and may be leveraged across length scales and physics. Introduction Structurally and materially compliant integrated circuits with reconfigurable electrical functions are an essential foundation for human-machine interfaces, soft robotics, and other future electronics that will serve medicine, science, engineering, and industry. These compliant conductors alleviate concerns of failure traditionally encountered when conventional metallic conductors are subjected to mechanical stress 1 , 2 , 3 , 4 , 5 . Liquid metal is often leveraged in compliant integrated circuits for the high conductivity and reversible self-healing behavior realized by liquid metal-based circuit interconnects 6 , 7 , 8 . Two-phase materials that combine conductive microparticles with a polymer substrate also support electrical function when subjected to large strains, while moreover being amenable to diverse fabrication practices 9 , 10 , 11 , 12 . To design the substrate for reconfiguration of a compliant integrated circuit, programmable mechanical deformation is often a candidate for reversible shape change 3 , 4 . For instance, kirigami 13 and origami 14 have inspired substrates that fold to tailor electrical behavior 15 . Elastic instabilities are also considered to transition electrical states in response to mechanical 16 and thermal 17 stresses. Reconfiguration of electrical networks is indeed the basis of digital logic, which is integral for information processing in modern computers as well as in the human brain 18 . The search for logic-based information processing in artificial materials has led to concepts of discrete transmittance outputs resulting from elastic wave logic operations in mechanical metamaterials 19 and from infrared wave logic operations in photonic metamaterials 20 . Logic functions in soft matter have also been emulated by high contrast colorimetric outputs from thermochromic elastomers subjected to input pressure states 21 . Recent progress on embodiments of mechanologic provide another modality of information processing in soft matter. By the concept of mechanologic, a digital bit is abstracted as a reversible, mechanical, or material configuration 22 , 23 . Recently, discrete shape reconfigurations are cultivated by elastic beam buckling 24 , 25 . In formulations of buckling-based mechanologic, the two statically stable configurations represent the physical abstraction of discrete digital bits. Together, the digitized bits associated with mechanical buckling modes facilitate logic operations according to the design and assembly of the switch-able constituents 26 . This stratagem has been shown for mechanically 27 , chemically 28 , and humidity 29 triggered elastic instabilities. Controller signaling for pressurized soft robots has also been demonstrated through mechanologic-based signal processing, suggesting one means for soft matter autonomy 30 . Yet, current embodiments of logic processing of mechanical stress inputs lack digital electrical outputs, which limits means to communicate with actuation and sensory mechanisms that may require electrical feedback to function 26 , 27 . Similar to anatomical realizations of intelligence and information processing to monitor and transmit sensory and motor impulses 31 , a means to cultivate decision - making capability in mechanically-robust compliant materials would provide a significant step towards autonomous soft matter able to assess and react to mechanical-electrical stimuli in a dynamic environment. This report introduces a class of soft, conductive mechanical metamaterials with programmable elastic instabilities that function as electronic logic gates able to perform digital computations on mechanical stress input combinations. Here, we exploit reversible compact-to-deployed state transitions in conductive mechanical metamaterials through a strategic patterning of compliant substrate and soft, conductive material networks. We demonstrate physically reconfigurable metamaterials that respond to mechanical stress in discrete modes leading to changes in the compliant conductor network to realize all digital logic functions and logic assemblies. Results A conductive mechanical metamaterial digital switch The metamaterials employ a constant cross-section consisting of a fundamental square tiling tessellation with square voids at the intersections. Shim et al. 32 report that this geometry exhibits a negative Poisson’s ratio and a fully compacted state wherein the porosity of the compacted material is 0% in the ideal case of kinematic reconfiguration. In Fig. 1 , we integrate this substrate architecture with conductive ink patterns that leverage the deformation of the metamaterial to reconfigure electrical circuits in discrete modes. Through this report, we build upon such fundamental building block to formulate all digital logic gates and to establish gate assembly and interconnection methods. Fig. 1: Compaction principle of electrical network switching in soft, conductive mechanical metamaterials. a Introduction of a metamaterial composed of C 2 unit cell with conductive Ag-TPU trace. b C 2 metamaterial in series with a power source and LED array to illustrate switching functionality. Uncompressed: Open circuit, LED off. Compacted: Closed circuit, LED on. Full size image The elastomeric material substrates considered here are fabricated by casting liquid urethane rubber (Smooth-On VytaFlex 60) in 3D-printed molds (FlashForge Creator Pro) containing the negative of the sample architecture. The substrates also include surface channels in which the conductive networks are applied, Fig. 1(a) . The conductive ink utilized in the channels is a composite containing silver (Ag) microflakes (Inframat Advanced Materials, 47MR-10F) and thermoplastic polyurethane (TPU) elastomer (BASF Elastollan Soft 35 A) to create conductive percolating networks. Copper wire leads that pass through the specimen via internal channels allow for electrical connections from an external voltage source or readout to the Ag-TPU trace terminals. Complete sample fabrication and characterization details are given in the Supplementary", "role": "user" }, { "content": "Engineered, autonomous machines combined with artificial intelligence have long been a staple of science fiction, and often in the role of villain like the Cylons in the \"Battlestar Galactica\" reboot, creatures composed of biological and engineered materials. But what if these autonomous soft machines were ... helpful? This is the vision of a team of Penn State and U.S. Air Force researchers, outlined in a recent paper in Nature Communications. These researchers produced a soft, mechanical metamaterial that can \"think\" about how forces are applied to it and respond via programmed reactions. This platform holds great potential for a variety of applications from medical treatments to improving the environment. \"We created soft, mechanical metamaterials with flexible, conductive polymer networks that can compute all digital logic computations,\" said Ryan Harne, James F. Will Career Development Associate Professor, Penn State. \"Our paper reports a way to create decision-making functionality in engineered materials in a way that could support future soft, autonomous engineered systems that are invested with the basic elements of lifeforms yet are programmed to perform helpful services for people. These could include helping maintain sustainable and robust infrastructure, monitoring of airborne and waterborne contaminants and pathogens, assisting with patient wound healing, and more.\" Human thought processes are based on logic, Harne notes, which is similar to Boolean logic from mathematics. This approach uses binary inputs to process binary control outputs—using only \"on\" and \"off\" sequences to represent all thought and cognition. The soft materials that the research team created \"think\" using the reconfiguration of the conductive polymer networks. Mechanical force, applied to the materials, connects, and reconnects the network. Using a low voltage input into the materials, the research team created a way for the soft material to decide how to react according to the output voltage signal from the reconfigured conductive polymer network. The type of logic that Harne and the team uses goes beyond pure mechanical logic, which is a way of using combinations of bistable switches—switches with two stable states—to represent the \"0s\" and \"1s\" of a binary number sequence. They found that when they used pure mechanical logic, the researchers ended up getting stuck because certain logical operations cannot be constructed. \"You hit a point where you can't actually process all of the eight logic gates,\" Harne said. \"You can process four of them, but you can't process the last four. We discovered the way to incorporate electrical signals along with mechanical signals, allowing us to process all of the logic gates used in modern digital computing.\" The key to realizing all the logic gates was in the combination of the electrical polymer network with the soft, deformable material. The researchers created the logic operations by simultaneously reconfiguring the soft material and the electrically conductive network. This also ensures that the binary output is in the form of electricity, which is needed to drive an actuation mechanism that makes the material respond to the applied mechanical force. The combination of electrical and mechanical signals allows the machine to move to get out of the way or to push back in a certain direction. Harne and the team want to go beyond a single material and design something more complex. \"I have a vision for how scientists and engineers can create engineered living systems that help society,\" Harne said. \"All you need to do is bring together all of the functions of life forms. And when you do that, you have at your disposal the building blocks of engineered life.\" While this all seems like science fiction, Harne believes it has tremendous potential. \"It is somewhat sci-fi, I do have to admit that, and I will say, I've had colleagues think I'm a little crazy,\" Harne said. \"But if we as engineers and scientists understand all of the things that make up life, why aren't we trying to make engineered living things that can help people?\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Integrated circuits utilize networked logic gates to compute Boolean logic operations that are the foundation of modern computation and electronics. With the emergence of flexible electronic materials and devices, an opportunity exists to formulate digital logic from compliant, conductive materials. Here, we introduce a general method of leveraging cellular, mechanical metamaterials composed of conductive polymers to realize all digital logic gates and gate assemblies. We establish a method for applying conductive polymer networks to metamaterial constituents and correlate mechanical buckling modes with network connectivity. With this foundation, each of the conventional logic gates is realized in an equivalent mechanical metamaterial, leading to soft, conductive matter that thinks about applied mechanical stress. These findings may advance the growing fields of soft robotics and smart mechanical matter, and may be leveraged across length scales and physics. Introduction Structurally and materially compliant integrated circuits with reconfigurable electrical functions are an essential foundation for human-machine interfaces, soft robotics, and other future electronics that will serve medicine, science, engineering, and industry. These compliant conductors alleviate concerns of failure traditionally encountered when conventional metallic conductors are subjected to mechanical stress 1 , 2 , 3 , 4 , 5 . Liquid metal is often leveraged in compliant integrated circuits for the high conductivity and reversible self-healing behavior realized by liquid metal-based circuit interconnects 6 , 7 , 8 . Two-phase materials that combine conductive microparticles with a polymer substrate also support electrical function when subjected to large strains, while moreover being amenable to diverse fabrication practices 9 , 10 , 11 , 12 . To design the substrate for reconfiguration of a compliant integrated circuit, programmable mechanical deformation is often a candidate for reversible shape change 3 , 4 . For instance, kirigami 13 and origami 14 have inspired substrates that fold to tailor electrical behavior 15 . Elastic instabilities are also considered to transition electrical states in response to mechanical 16 and thermal 17 stresses. Reconfiguration of electrical networks is indeed the basis of digital logic, which is integral for information processing in modern computers as well as in the human brain 18 . The search for logic-based information processing in artificial materials has led to concepts of discrete transmittance outputs resulting from elastic wave logic operations in mechanical metamaterials 19 and from infrared wave logic operations in photonic metamaterials 20 . Logic functions in soft matter have also been emulated by high contrast colorimetric outputs from thermochromic elastomers subjected to input pressure states 21 . Recent progress on embodiments of mechanologic provide another modality of information processing in soft matter. By the concept of mechanologic, a digital bit is abstracted as a reversible, mechanical, or material configuration 22 , 23 . Recently, discrete shape reconfigurations are cultivated by elastic beam buckling 24 , 25 . In formulations of buckling-based mechanologic, the two statically stable configurations represent the physical abstraction of discrete digital bits. Together, the digitized bits associated with mechanical buckling modes facilitate logic operations according to the design and assembly of the switch-able constituents 26 . This stratagem has been shown for mechanically 27 , chemically 28 , and humidity 29 triggered elastic instabilities. Controller signaling for pressurized soft robots has also been demonstrated through mechanologic-based signal processing, suggesting one means for soft matter autonomy 30 . Yet, current embodiments of logic processing of mechanical stress inputs lack digital electrical outputs, which limits means to communicate with actuation and sensory mechanisms that may require electrical feedback to function 26 , 27 . Similar to anatomical realizations of intelligence and information processing to monitor and transmit sensory and motor impulses 31 , a means to cultivate decision - making capability in mechanically-robust compliant materials would provide a significant step towards autonomous soft matter able to assess and react to mechanical-electrical stimuli in a dynamic environment. This report introduces a class of soft, conductive mechanical metamaterials with programmable elastic instabilities that function as electronic logic gates able to perform digital computations on mechanical stress input combinations. Here, we exploit reversible compact-to-deployed state transitions in conductive mechanical metamaterials through a strategic patterning of compliant substrate and soft, conductive material networks. We demonstrate physically reconfigurable metamaterials that respond to mechanical stress in discrete modes leading to changes in the compliant conductor network to realize all digital logic functions and logic assemblies. Results A conductive mechanical metamaterial digital switch The metamaterials employ a constant cross-section consisting of a fundamental square tiling tessellation with square voids at the intersections. Shim et al. 32 report that this geometry exhibits a negative Poisson’s ratio and a fully compacted state wherein the porosity of the compacted material is 0% in the ideal case of kinematic reconfiguration. In Fig. 1 , we integrate this substrate architecture with conductive ink patterns that leverage the deformation of the metamaterial to reconfigure electrical circuits in discrete modes. Through this report, we build upon such fundamental building block to formulate all digital logic gates and to establish gate assembly and interconnection methods. Fig. 1: Compaction principle of electrical network switching in soft, conductive mechanical metamaterials. a Introduction of a metamaterial composed of C 2 unit cell with conductive Ag-TPU trace. b C 2 metamaterial in series with a power source and LED array to illustrate switching functionality. Uncompressed: Open circuit, LED off. Compacted: Closed circuit, LED on. Full size image The elastomeric material substrates considered here are fabricated by casting liquid urethane rubber (Smooth-On VytaFlex 60) in 3D-printed molds (FlashForge Creator Pro) containing the negative of the sample architecture. The substrates also include surface channels in which the conductive networks are applied, Fig. 1(a) . The conductive ink utilized in the channels is a composite containing silver (Ag) microflakes (Inframat Advanced Materials, 47MR-10F) and thermoplastic polyurethane (TPU) elastomer (BASF Elastollan Soft 35 A) to create conductive percolating networks. Copper wire leads that pass through the specimen via internal channels allow for electrical connections from an external voltage source or readout to the Ag-TPU trace terminals. Complete sample fabrication and characterization details are given in the Supplementary<|im_end|> <|im_start|>assistant Engineered, autonomous machines combined with artificial intelligence have long been a staple of science fiction, and often in the role of villain like the Cylons in the "Battlestar Galactica" reboot, creatures composed of biological and engineered materials. But what if these autonomous soft machines were ... helpful? This is the vision of a team of Penn State and U.S. Air Force researchers, outlined in a recent paper in Nature Communications. These researchers produced a soft, mechanical metamaterial that can "think" about how forces are applied to it and respond via programmed reactions. This platform holds great potential for a variety of applications from medical treatments to improving the environment. "We created soft, mechanical metamaterials with flexible, conductive polymer networks that can compute all digital logic computations," said Ryan Harne, James F. Will Career Development Associate Professor, Penn State. "Our paper reports a way to create decision-making functionality in engineered materials in a way that could support future soft, autonomous engineered systems that are invested with the basic elements of lifeforms yet are programmed to perform helpful services for people. These could include helping maintain sustainable and robust infrastructure, monitoring of airborne and waterborne contaminants and pathogens, assisting with patient wound healing, and more." Human thought processes are based on logic, Harne notes, which is similar to Boolean logic from mathematics. This approach uses binary inputs to process binary control outputs—using only "on" and "off" sequences to represent all thought and cognition. The soft materials that the research team created "think" using the reconfiguration of the conductive polymer networks. Mechanical force, applied to the materials, connects, and reconnects the network. Using a low voltage input into the materials, the research team created a way for the soft material to decide how to react according to the output voltage signal from the reconfigured conductive polymer network. The type of logic that Harne and the team uses goes beyond pure mechanical logic, which is a way of using combinations of bistable switches—switches with two stable states—to represent the "0s" and "1s" of a binary number sequence. They found that when they used pure mechanical logic, the researchers ended up getting stuck because certain logical operations cannot be constructed. "You hit a point where you can't actually process all of the eight logic gates," Harne said. "You can process four of them, but you can't process the last four. We discovered the way to incorporate electrical signals along with mechanical signals, allowing us to process all of the logic gates used in modern digital computing." The key to realizing all the logic gates was in the combination of the electrical polymer network with the soft, deformable material. The researchers created the logic operations by simultaneously reconfiguring the soft material and the electrically conductive network. This also ensures that the binary output is in the form of electricity, which is needed to drive an actuation mechanism that makes the material respond to the applied mechanical force. The combination of electrical and mechanical signals allows the machine to move to get out of the way or to push back in a certain direction. Harne and the team want to go beyond a single material and design something more complex. "I have a vision for how scientists and engineers can create engineered living systems that help society," Harne said. "All you need to do is bring together all of the functions of life forms. And when you do that, you have at your disposal the building blocks of engineered life." While this all seems like science fiction, Harne believes it has tremendous potential. "It is somewhat sci-fi, I do have to admit that, and I will say, I've had colleagues think I'm a little crazy," Harne said. "But if we as engineers and scientists understand all of the things that make up life, why aren't we trying to make engineered living things that can help people?" <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objectives The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients’ data. Methods Sleep disturbance stress (SDS) for 2 weeks was placed on 6–8-week-old female MRL/ lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. Results SDS-subjected MRL/ lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/ lpr . A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b . We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/ lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/ lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. Conclusions The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE. cytokines lupus erythematosus, systemic psychology Magnetic Resonance Imaging inflammation Data availability statement Data are available in a public, open access repository. Data are available upon reasonable request. In detail, RNA-seq datasets that support the observations of this study have been deposited in the Gene Expression Omnibus with the series accession number GSE176429. MRI data have been stored locally following national and Japanese laws on the protection of individuals with regard to the processing of personal data. Other data are available in the main text or the supplementary materials and are available upon reasonable request to the corresponding author. googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 11 news outlets Tweeted by 9 20 readers on Mendeley Supplementary materials Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions cytokines lupus erythematosus, systemic psychology Magnetic Resonance Imaging inflammation WHAT IS ALREADY KNOWN ON THIS TOPIC Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE) is attributed to a variety of factors, including vascular occlusions, blood–brain barrier impairment, cytokines, autoantibodies and direct neuronal cell damage. Stress affects the activation status of central neurons and glial cells, probably leading to neuroinflammation. Stress, particularly chronic stress, is involved in the development of autoimmune diseases, including lupus, and has adverse effects on the disease activity with neuropsychiatric symptoms. WHAT THIS STUDY ADDS Stress-subjected MRL/ lpr mice showed disinhibited behaviour, microglial activation with IL-12/23p40 upregulation and neuronal activation in the medial prefrontal cortex (mPFC). Anti-IL-12/23p40 neutralising antibody or tyrosine kinase 2 inhibitor ameliorated these stress-elicited neuropsychiatric phenotypes in MRL/ lpr . A higher level of IL-12/23p40 in the cerebrospinal fluid and more atrophic changes in the mPFC were observed in patients with dNPSLE than those with non-dNPSLE. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY An association of the stress-elicited IL-12/23 axis in the mPFC with the pathogenesis of disinhibited agitative behaviour in patients with dNPSLE was suggested. Blockade of IL-12/23 signalling in the mPFC may be a novel therapeutic target for dNPSLE. Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease with a predilection for young women of childbearing age, leading to a profound impact on their lives. Patients with SLE manifest multiple organ disorders such as skin rash, arthritis, nephritis, haematologic abnormality and inflammation in the central nervous system (CNS). 1 Among them, CNS diseases occur in up to 50% of patients and demonstrate a wide range of symptoms, including headache, stroke, anxiety, depression, cognitive dysfunction, seizures, psychosis and acute confusional state (ACS). The CNS disorder, neuropsychiatric SLE (NPSLE), is one of the most severe manifestations and is further classified into diffuse neuropsychological syndrome (dNPSLE) and focal neurological syndrome (fNPSLE). Although a variety of factors, including vascular occlusions, blood–brain barrier impairment, cytokines, autoantibodies and direct neuronal cell damage, have been suggested for the development of dNPSLE, 2 3 its pathogenesis remains poorly understood. In addition, neuropsychiatric symptoms often occur independently of the systemic disease activity among patients with SLE, making it difficult to predict the development of dNPSLE. 4 Rheumatologists have been using glucocorticoids and pancytotoxic immunosuppressants for treatment, but there is no available therapeutic strategy that targets the disease-specific pathogenesis. 1 5 Stress as emotional and physiological challenges can affect the neural activation status in the CNS. In the short term, it promotes allostasis for adaptation to the surrounding environment, but in the long term, it exhausts the body physically and mentally. It has been known that stress affects the functions of several physiological systems via the neuroendocrine pathway. 6 Stress also targets and remodels the CNS itself structurally and functionally, contributing to alterations in behavioural and physiological responses. 7 In animal models, stress induced by sleep deprivation atrophies hippocampal and cortical neurons, resulting in impaired retention and memory. 7–9 Also, sleep deprivation increases cytokines and oxidative stress markers in neurons. 7 We previously reported sleep disturbance stress (SDS) induced brain microinflammation in the presence of CNS-specific autoreactive CD4-positive T cells, exacerbating clinical symptoms of experimental autoimmune encephalomyelitis (EAE). 10 Thus, stress together with immune cells would be involved in the exacerbation of autoimmune diseases. Indeed, SDS is reported to impair metabolism and upregulate proinflammatory cytokine in humans.", "role": "user" }, { "content": "Systemic lupus erythematosus (SLE) is an autoimmune disease that affects all the organ systems of the body. This chronic disease includes periods of illness, called flare ups, and periods of remission, when symptoms are few. There is so far no cure for this disease; treatments involve preventing flare ups and reducing their severity and duration. One of the most severe forms of SLE is neuropsychiatric systemic lupus erythromatosus (NPSLE), which affects the central nervous system—the brain and spinal cord. A team of researchers, led by Professor Masaaki Murakami at the Institute for Genetic Medicine, Hokkaido University, have identified a stress-induced molecular mechanism that affects NPSLE, revealing a potential target for the treatment of the disease. Their findings were published in the journal Annals of the Rheumatic Diseases. The research team focused on a specific type of NPSLE called Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE). There are believed to be many causes for dNPSLE, but its pathogenesis remains poorly understood. The researchers were most interested in the effects of stress, as chronic stress is known to be involved in the development of many autoimmune diseases. In order to identify stress-induced molecular mechanisms that might affect dNPSLE, they conducted experiments on mice models that exhibit SLE-like symptoms. After subjecting a set of these mice to sleep deprivation stress, they were able to identify that the medial prefrontal cortex (mPFC) of the brain was abnormally activated. Brains of patients with dNPSLE show atrophy of the medial prefrontal cortex (mPFC, in red) compared to the reference brain of healthy individuals. Credit: Nobuya Abe et al, Annals of the Rheumatic Diseases (2022) In the mPFC, the expression of at least 509 genes was significantly affected by sleep deprivation. The team specifically noted the upregulation of a microglial proinflammatory gene that is required for two interleukins, IL12 and IL23. Further, they showed that upregulation of these two interleukins caused activation of the microglial cells of the mPFC. Blocking IL12 and IL23 pathways in these sleep-deprived mice models inhibited the stress-induced neuropsychiatric symptoms. Most importantly, they showed that levels of IL12 and IL23 in the cerebrospinal fluid of human patients with dNPSLE were higher than that of healthy individuals, to such an extent that it can be used as a diagnostic marker. They also showed that the mPFC in dNPSLE patients is atrophied. Together, these indicate that the findings from the mice models may be applicable to humans. \"In revealing the effect of the stress-induced effects on the expression of IL12 and IL23 in dNPSLE, we have identified them as not only a diagnostic marker but also a novel therapeutic target for this disease,\" said Masaaki Murakami. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objectives The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients’ data. Methods Sleep disturbance stress (SDS) for 2 weeks was placed on 6–8-week-old female MRL/ lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. Results SDS-subjected MRL/ lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/ lpr . A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b . We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/ lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/ lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. Conclusions The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE. cytokines lupus erythematosus, systemic psychology Magnetic Resonance Imaging inflammation Data availability statement Data are available in a public, open access repository. Data are available upon reasonable request. In detail, RNA-seq datasets that support the observations of this study have been deposited in the Gene Expression Omnibus with the series accession number GSE176429. MRI data have been stored locally following national and Japanese laws on the protection of individuals with regard to the processing of personal data. Other data are available in the main text or the supplementary materials and are available upon reasonable request to the corresponding author. googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 11 news outlets Tweeted by 9 20 readers on Mendeley Supplementary materials Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions cytokines lupus erythematosus, systemic psychology Magnetic Resonance Imaging inflammation WHAT IS ALREADY KNOWN ON THIS TOPIC Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE) is attributed to a variety of factors, including vascular occlusions, blood–brain barrier impairment, cytokines, autoantibodies and direct neuronal cell damage. Stress affects the activation status of central neurons and glial cells, probably leading to neuroinflammation. Stress, particularly chronic stress, is involved in the development of autoimmune diseases, including lupus, and has adverse effects on the disease activity with neuropsychiatric symptoms. WHAT THIS STUDY ADDS Stress-subjected MRL/ lpr mice showed disinhibited behaviour, microglial activation with IL-12/23p40 upregulation and neuronal activation in the medial prefrontal cortex (mPFC). Anti-IL-12/23p40 neutralising antibody or tyrosine kinase 2 inhibitor ameliorated these stress-elicited neuropsychiatric phenotypes in MRL/ lpr . A higher level of IL-12/23p40 in the cerebrospinal fluid and more atrophic changes in the mPFC were observed in patients with dNPSLE than those with non-dNPSLE. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY An association of the stress-elicited IL-12/23 axis in the mPFC with the pathogenesis of disinhibited agitative behaviour in patients with dNPSLE was suggested. Blockade of IL-12/23 signalling in the mPFC may be a novel therapeutic target for dNPSLE. Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease with a predilection for young women of childbearing age, leading to a profound impact on their lives. Patients with SLE manifest multiple organ disorders such as skin rash, arthritis, nephritis, haematologic abnormality and inflammation in the central nervous system (CNS). 1 Among them, CNS diseases occur in up to 50% of patients and demonstrate a wide range of symptoms, including headache, stroke, anxiety, depression, cognitive dysfunction, seizures, psychosis and acute confusional state (ACS). The CNS disorder, neuropsychiatric SLE (NPSLE), is one of the most severe manifestations and is further classified into diffuse neuropsychological syndrome (dNPSLE) and focal neurological syndrome (fNPSLE). Although a variety of factors, including vascular occlusions, blood–brain barrier impairment, cytokines, autoantibodies and direct neuronal cell damage, have been suggested for the development of dNPSLE, 2 3 its pathogenesis remains poorly understood. In addition, neuropsychiatric symptoms often occur independently of the systemic disease activity among patients with SLE, making it difficult to predict the development of dNPSLE. 4 Rheumatologists have been using glucocorticoids and pancytotoxic immunosuppressants for treatment, but there is no available therapeutic strategy that targets the disease-specific pathogenesis. 1 5 Stress as emotional and physiological challenges can affect the neural activation status in the CNS. In the short term, it promotes allostasis for adaptation to the surrounding environment, but in the long term, it exhausts the body physically and mentally. It has been known that stress affects the functions of several physiological systems via the neuroendocrine pathway. 6 Stress also targets and remodels the CNS itself structurally and functionally, contributing to alterations in behavioural and physiological responses. 7 In animal models, stress induced by sleep deprivation atrophies hippocampal and cortical neurons, resulting in impaired retention and memory. 7–9 Also, sleep deprivation increases cytokines and oxidative stress markers in neurons. 7 We previously reported sleep disturbance stress (SDS) induced brain microinflammation in the presence of CNS-specific autoreactive CD4-positive T cells, exacerbating clinical symptoms of experimental autoimmune encephalomyelitis (EAE). 10 Thus, stress together with immune cells would be involved in the exacerbation of autoimmune diseases. Indeed, SDS is reported to impair metabolism and upregulate proinflammatory cytokine in humans.<|im_end|> <|im_start|>assistant Systemic lupus erythematosus (SLE) is an autoimmune disease that affects all the organ systems of the body. This chronic disease includes periods of illness, called flare ups, and periods of remission, when symptoms are few. There is so far no cure for this disease; treatments involve preventing flare ups and reducing their severity and duration. One of the most severe forms of SLE is neuropsychiatric systemic lupus erythromatosus (NPSLE), which affects the central nervous system—the brain and spinal cord. A team of researchers, led by Professor Masaaki Murakami at the Institute for Genetic Medicine, Hokkaido University, have identified a stress-induced molecular mechanism that affects NPSLE, revealing a potential target for the treatment of the disease. Their findings were published in the journal Annals of the Rheumatic Diseases. The research team focused on a specific type of NPSLE called Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE). There are believed to be many causes for dNPSLE, but its pathogenesis remains poorly understood. The researchers were most interested in the effects of stress, as chronic stress is known to be involved in the development of many autoimmune diseases. In order to identify stress-induced molecular mechanisms that might affect dNPSLE, they conducted experiments on mice models that exhibit SLE-like symptoms. After subjecting a set of these mice to sleep deprivation stress, they were able to identify that the medial prefrontal cortex (mPFC) of the brain was abnormally activated. Brains of patients with dNPSLE show atrophy of the medial prefrontal cortex (mPFC, in red) compared to the reference brain of healthy individuals. Credit: Nobuya Abe et al, Annals of the Rheumatic Diseases (2022) In the mPFC, the expression of at least 509 genes was significantly affected by sleep deprivation. The team specifically noted the upregulation of a microglial proinflammatory gene that is required for two interleukins, IL12 and IL23. Further, they showed that upregulation of these two interleukins caused activation of the microglial cells of the mPFC. Blocking IL12 and IL23 pathways in these sleep-deprived mice models inhibited the stress-induced neuropsychiatric symptoms. Most importantly, they showed that levels of IL12 and IL23 in the cerebrospinal fluid of human patients with dNPSLE were higher than that of healthy individuals, to such an extent that it can be used as a diagnostic marker. They also showed that the mPFC in dNPSLE patients is atrophied. Together, these indicate that the findings from the mice models may be applicable to humans. "In revealing the effect of the stress-induced effects on the expression of IL12 and IL23 in dNPSLE, we have identified them as not only a diagnostic marker but also a novel therapeutic target for this disease," said Masaaki Murakami. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background A lack of defined correlates of immunity for malaria, combined with the inability to induce long-lived sterile immune responses in a human host, demonstrate a need for improved understanding of potentially protective immune mechanisms for enhanced vaccine efficacy. Protective sterile immunity (>90%) against the Plasmodium falciparum circumsporozoite protein (CSP) has been achieved using a transgenically modified Plasmodium berghei sporozoite (Tg- Pb / Pf CSP) and a self-assembling protein nanoparticle (SAPN) vaccine presenting CSP epitopes ( Pf CSP-SAPN). Here, several possible mechanisms involved in the independently protective humoral and cellular responses induced following SAPN immunization are described. Methods Inbred mice were vaccinated with Pf CSP-SAPN in PBS. Serum antibodies were harvested and effects on P . falciparum sporozoites mobility and integrity were examined using phase contrast microscopy. The functionality of SAPN-induced antibodies on inhibition of sporozoite invasion and growth within primary human hepatocytes was also examined. The internal processing of SAPN by bone marrow-derived dendritic cells (BMDDC), using organelle-specific, fluorescent-tagged antibody or gold-encapsulated SAPN, was observed using confocal or electron microscopy, respectively. Results The results of this work demonstrate that Pf CSP-SAPN induces epitope-specific antibody titers, predominantly of the Th2 isotype IgG1, and that serum antibodies from PfCSP-SAPN-immunized mice appear to target P . falciparum sporozoites via the classical pathway of complement. This results in sporozoite death as indicated by cessation of motility and the circumsporozoite precipitation reaction. Moreover, Pf CSP-SAPN-induced antibodies are able to inhibit wild-type P . falciparum sporozoite invasion and growth within cultured primary human hepatocytes. In addition, the observation that Pf CSP-SAPN are processed (and presented) to the immune system by dendritic cells in a slow and continuous fashion via transporter associated with antigen processing (TAP) recruitment to the early endosome (EE), and have partially delayed processing through the endoplasmic reticulum, has the potential to induce the long-lived, effector memory CD8 + T-cells as described previously. Conclusion This paper describes the examination of humoral and cellular immune mechanisms induced by Pf CSP-SAPN vaccination which result in sterile host protection against a transgenic P . berghei malaria sporozoite expressing the P . falciparum CSP, and which significantly inhibits native P . falciparum sporozoites from invading and developing within cultured human hepatocytes. These results may indicate the type and mode of action of protective antibodies needed to control P . falciparum sporozoites from infecting humans as well as a potential mechanism of induction of protective long-lived effector memory CD8 + T-cells. Background The most basic and desirable outcome of a successful vaccine is that it will induce sterile and long-lived immunity in the host. Historically, with most vaccines, this result has been best achieved through the use of chemically fixed, heat-killed or live-attenuated organisms. In the case of malaria this approach has been relatively unsuccessful but more interest has recently been dedicated to these methods[ 1 – 3 ]. Recombinant subunit protein vaccines targeting various parasite proteins of choice, used in combination with immune-boosting adjuvants, have been examined and have yielded promising but limited results. The vaccine RTS,S, currently in Phase 3 human trials, is a subunit circumsporozoite protein (CSP) linked to the Hepatitis B surface protein (HBSP) which self-assembles with native HBSP to form a virus-like particle. RTS,S vaccination has resulted in somewhat reduced clinical infection[ 4 , 5 ]. Longevity studies examining the observed reduced parasite loads, as well as more detailed investigations into possible correlates of this protection, will hopefully be forthcoming in the next few years to further evaluate this vaccine delivery platform. Malaria vaccinology suffers from a lack of understanding of viable mechanisms by which the host’s immune system is able to efficiently respond to such a highly polymorphic parasite. Even naturally acquired immunity is slow to develop and is easily lost[ 6 ]. There is little evidence to support correlations of vaccine-induced human Plasmodium immunity or sterile protection from vaccines for malaria. If we could understand, induce and/or manipulate effective mechanisms that would lead to complete protection and long-lived immunity against Plasmodium infection, we may be better armed to improve on or design novel vaccine platforms that could enhance host immunity to this end. The studies presented here are an investigation into the mechanisms behind the efficacy of a novel type of immunogen, a self-assembling protein nanoparticle (SAPN)[ 7 – 9 ]. These SAPN have been successfully used to deliver Plasmodium falciparum CSP-derived T- and B-cell epitopes to generate a protective immune response against malaria, which is believed to act, in part, by enhanced repetitive display of highly immunogenic peptides[ 10 , 11 ]. The innate immune system can be a critical player in effective immunity to malaria infection[ 12 ]. Innate mechanisms of protection are the first and most non-specific immunity the host has in its arsenal against a primary infection. These initial mechanisms link and relate tailored responses that are required to properly and effectively protect against secondary infections. Other than the use of some poorly understood classes of adjuvants, little is known about the specific initial responses required, in conjunction with vaccine administration, to provide complete protection against human malaria infection. The innate system, targeted in synergy with adaptive immune responses, can often outweigh the immunological importance of either in isolation[ 12 ]. Various vaccines have demonstrated potential roles for non-specific mediators such as secreted factors and cells in managing malaria infection[ 13 – 16 ], but more may be required from both branches of the immune system in terms of understanding and promoting “cross-talk” between branches to achieve an efficacious vaccine product against human malaria. To improve this understanding, and enhance an awareness of potential avenues for boosting vaccine efficacy, this paper examines several interactions between innate and adaptive immunity following SAPN immunization. The results show that SAPN-induced antibodies exhibit an ability to inhibit motility and induce complement (C’) lysis of malaria parasites prior to liver infection. Moreover, tracking fluorescently labeled or gold-tagged SAPN demonstrate a delayed processing and (presentation) of Pf CSP-SAPN by dendritic cells that may help explain the induction of the previously reported highly", "role": "user" }, { "content": "A self-assembling nanoparticle designed by a UConn professor is the key component of a potent new malaria vaccine that is showing promise in early tests. For years, scientists trying to develop a malaria vaccine have been stymied by the malaria parasite's ability to transform itself and \"hide\" in the liver and red blood cells of an infected person to avoid detection by the immune system. But a novel protein nanoparticle developed by Peter Burkhard, a professor in the Department of Molecular & Cell Biology, in collaboration with David Lanar, an infectious disease specialist with the Walter Reed Army Institute of Research, has shown to be effective at getting the immune system to attack the most lethal species of malaria parasite, Plasmodium falciparum, after it enters the body and before it has a chance to hide and aggressively spread. The key to the vaccine's success lies in the nanoparticle's perfect icosahedral symmetry (think of the pattern on a soccer ball) and ability to carry on its surface up to 60 copies of the parasite's protein. The proteins are arranged in a dense, carefully constructed cluster that the immune system perceives as a threat, prompting it to release large amounts of antibodies that can attack and kill the parasite. In tests with mice, the vaccine was 90-100 percent effective in eradicating the Plasmodium falciparum parasite and maintaining long-term immunity over 15 months. That success rate is considerably higher than the reported success rate for RTS,S, the world's most advanced malaria vaccine candidate currently undergoing phase 3 clinical trials, which is the last stage of testing before licensing. \"Both vaccines are similar, it's just that the density of the RTS,S protein displays is much lower than ours,\" says Burkhard. \"The homogeneity of our vaccine is much higher, which produces a stronger immune system response. That is why we are confident that ours will be an improvement. \"Every single protein chain that forms our particle displays one of the pathogen's protein molecules that are recognized by the immune system,\" adds Burkhard, an expert in structural biology affiliated with UConn's Institute of Materials Science. \"With RTS,S, only about 14 percent of the vaccine's protein is from the malaria parasite. We are able to achieve our high density because of the design of the nanoparticle, which we control.\" The research was published in Malaria Journal in 2013. The search for a malaria vaccine is one of the most important research projects in global public health. The disease is commonly transported through the bites of nighttime mosquitoes. Those infected suffer from severe fevers, chills, and a flu-like illness. In severe cases, malaria causes seizures, severe anemia, respiratory distress, and kidney failure. Each year, more than 200 million cases of malaria are reported worldwide. The World Health Organization estimated that 627,000 people died from malaria in 2012, many of them children living in sub-Saharan Africa. It took the researchers more than 10 years to finalize the precise assembly of the nanoparticle as the critical carrier of the vaccine and find the right parts of the malaria protein to trigger an effective immune response. The research was further complicated by the fact that the malaria parasite that impacts mice used in lab tests is structurally different from the one infecting humans. The scientists used a creative approach to get around the problem. \"Testing the vaccine's efficacy was difficult because the parasite that causes malaria in humans only grows in humans,\" Lanar says. \"But we developed a little trick. We took a mouse malaria parasite and put in its DNA a piece of DNA from the human malaria parasite that we wanted our vaccine to attack. That allowed us to conduct inexpensive mouse studies to test the vaccine before going to expensive human trials.\" The pair's research has been supported by a $2 million grant from the National Institutes of Health and $2 million from the U.S. Military Infectious Disease Research Program. A request for an additional $7 million in funding from the U.S. Army to conduct the next phase of vaccine development, including manufacturing and human trials, is pending. \"We are on schedule to manufacture the vaccine for human use early next year,\" says Lanar. \"It will take about six months to finish quality control and toxicology studies on the final product and get permission from the FDA to do human trials.\" Lanar says the team hopes to begin early testing in humans in 2016 and, if the results are promising, field trials in malaria endemic areas will follow in 2017. The required field trial testing could last five years or more before the vaccine is available for licensure and public use, Lanar says. Martin Edlund, CEO of Malaria No More, a New York-based nonprofit focused on fighting deaths from malaria, says, \"This research presents a promising new approach to developing a malaria vaccine. Innovative work such as what's being done at the University of Connecticut puts us closer than we've ever been to ending one of the world's oldest, costliest, and deadliest diseases.\" A Switzerland-based company, Alpha-O-Peptides, founded by Burkhard, holds the patent on the self-assembling nanoparticle used in the malaria vaccine. Burkhard is also exploring other potential uses for the nanoparticle, including a vaccine that will fight animal flu and one that will help people with nicotine addiction. Professor Mazhar Khan from UConn's Department of Pathobiology is collaborating with Burkhard on the animal flu vaccine. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background A lack of defined correlates of immunity for malaria, combined with the inability to induce long-lived sterile immune responses in a human host, demonstrate a need for improved understanding of potentially protective immune mechanisms for enhanced vaccine efficacy. Protective sterile immunity (>90%) against the Plasmodium falciparum circumsporozoite protein (CSP) has been achieved using a transgenically modified Plasmodium berghei sporozoite (Tg- Pb / Pf CSP) and a self-assembling protein nanoparticle (SAPN) vaccine presenting CSP epitopes ( Pf CSP-SAPN). Here, several possible mechanisms involved in the independently protective humoral and cellular responses induced following SAPN immunization are described. Methods Inbred mice were vaccinated with Pf CSP-SAPN in PBS. Serum antibodies were harvested and effects on P . falciparum sporozoites mobility and integrity were examined using phase contrast microscopy. The functionality of SAPN-induced antibodies on inhibition of sporozoite invasion and growth within primary human hepatocytes was also examined. The internal processing of SAPN by bone marrow-derived dendritic cells (BMDDC), using organelle-specific, fluorescent-tagged antibody or gold-encapsulated SAPN, was observed using confocal or electron microscopy, respectively. Results The results of this work demonstrate that Pf CSP-SAPN induces epitope-specific antibody titers, predominantly of the Th2 isotype IgG1, and that serum antibodies from PfCSP-SAPN-immunized mice appear to target P . falciparum sporozoites via the classical pathway of complement. This results in sporozoite death as indicated by cessation of motility and the circumsporozoite precipitation reaction. Moreover, Pf CSP-SAPN-induced antibodies are able to inhibit wild-type P . falciparum sporozoite invasion and growth within cultured primary human hepatocytes. In addition, the observation that Pf CSP-SAPN are processed (and presented) to the immune system by dendritic cells in a slow and continuous fashion via transporter associated with antigen processing (TAP) recruitment to the early endosome (EE), and have partially delayed processing through the endoplasmic reticulum, has the potential to induce the long-lived, effector memory CD8 + T-cells as described previously. Conclusion This paper describes the examination of humoral and cellular immune mechanisms induced by Pf CSP-SAPN vaccination which result in sterile host protection against a transgenic P . berghei malaria sporozoite expressing the P . falciparum CSP, and which significantly inhibits native P . falciparum sporozoites from invading and developing within cultured human hepatocytes. These results may indicate the type and mode of action of protective antibodies needed to control P . falciparum sporozoites from infecting humans as well as a potential mechanism of induction of protective long-lived effector memory CD8 + T-cells. Background The most basic and desirable outcome of a successful vaccine is that it will induce sterile and long-lived immunity in the host. Historically, with most vaccines, this result has been best achieved through the use of chemically fixed, heat-killed or live-attenuated organisms. In the case of malaria this approach has been relatively unsuccessful but more interest has recently been dedicated to these methods[ 1 – 3 ]. Recombinant subunit protein vaccines targeting various parasite proteins of choice, used in combination with immune-boosting adjuvants, have been examined and have yielded promising but limited results. The vaccine RTS,S, currently in Phase 3 human trials, is a subunit circumsporozoite protein (CSP) linked to the Hepatitis B surface protein (HBSP) which self-assembles with native HBSP to form a virus-like particle. RTS,S vaccination has resulted in somewhat reduced clinical infection[ 4 , 5 ]. Longevity studies examining the observed reduced parasite loads, as well as more detailed investigations into possible correlates of this protection, will hopefully be forthcoming in the next few years to further evaluate this vaccine delivery platform. Malaria vaccinology suffers from a lack of understanding of viable mechanisms by which the host’s immune system is able to efficiently respond to such a highly polymorphic parasite. Even naturally acquired immunity is slow to develop and is easily lost[ 6 ]. There is little evidence to support correlations of vaccine-induced human Plasmodium immunity or sterile protection from vaccines for malaria. If we could understand, induce and/or manipulate effective mechanisms that would lead to complete protection and long-lived immunity against Plasmodium infection, we may be better armed to improve on or design novel vaccine platforms that could enhance host immunity to this end. The studies presented here are an investigation into the mechanisms behind the efficacy of a novel type of immunogen, a self-assembling protein nanoparticle (SAPN)[ 7 – 9 ]. These SAPN have been successfully used to deliver Plasmodium falciparum CSP-derived T- and B-cell epitopes to generate a protective immune response against malaria, which is believed to act, in part, by enhanced repetitive display of highly immunogenic peptides[ 10 , 11 ]. The innate immune system can be a critical player in effective immunity to malaria infection[ 12 ]. Innate mechanisms of protection are the first and most non-specific immunity the host has in its arsenal against a primary infection. These initial mechanisms link and relate tailored responses that are required to properly and effectively protect against secondary infections. Other than the use of some poorly understood classes of adjuvants, little is known about the specific initial responses required, in conjunction with vaccine administration, to provide complete protection against human malaria infection. The innate system, targeted in synergy with adaptive immune responses, can often outweigh the immunological importance of either in isolation[ 12 ]. Various vaccines have demonstrated potential roles for non-specific mediators such as secreted factors and cells in managing malaria infection[ 13 – 16 ], but more may be required from both branches of the immune system in terms of understanding and promoting “cross-talk” between branches to achieve an efficacious vaccine product against human malaria. To improve this understanding, and enhance an awareness of potential avenues for boosting vaccine efficacy, this paper examines several interactions between innate and adaptive immunity following SAPN immunization. The results show that SAPN-induced antibodies exhibit an ability to inhibit motility and induce complement (C’) lysis of malaria parasites prior to liver infection. Moreover, tracking fluorescently labeled or gold-tagged SAPN demonstrate a delayed processing and (presentation) of Pf CSP-SAPN by dendritic cells that may help explain the induction of the previously reported highly<|im_end|> <|im_start|>assistant A self-assembling nanoparticle designed by a UConn professor is the key component of a potent new malaria vaccine that is showing promise in early tests. For years, scientists trying to develop a malaria vaccine have been stymied by the malaria parasite's ability to transform itself and "hide" in the liver and red blood cells of an infected person to avoid detection by the immune system. But a novel protein nanoparticle developed by Peter Burkhard, a professor in the Department of Molecular & Cell Biology, in collaboration with David Lanar, an infectious disease specialist with the Walter Reed Army Institute of Research, has shown to be effective at getting the immune system to attack the most lethal species of malaria parasite, Plasmodium falciparum, after it enters the body and before it has a chance to hide and aggressively spread. The key to the vaccine's success lies in the nanoparticle's perfect icosahedral symmetry (think of the pattern on a soccer ball) and ability to carry on its surface up to 60 copies of the parasite's protein. The proteins are arranged in a dense, carefully constructed cluster that the immune system perceives as a threat, prompting it to release large amounts of antibodies that can attack and kill the parasite. In tests with mice, the vaccine was 90-100 percent effective in eradicating the Plasmodium falciparum parasite and maintaining long-term immunity over 15 months. That success rate is considerably higher than the reported success rate for RTS,S, the world's most advanced malaria vaccine candidate currently undergoing phase 3 clinical trials, which is the last stage of testing before licensing. "Both vaccines are similar, it's just that the density of the RTS,S protein displays is much lower than ours," says Burkhard. "The homogeneity of our vaccine is much higher, which produces a stronger immune system response. That is why we are confident that ours will be an improvement. "Every single protein chain that forms our particle displays one of the pathogen's protein molecules that are recognized by the immune system," adds Burkhard, an expert in structural biology affiliated with UConn's Institute of Materials Science. "With RTS,S, only about 14 percent of the vaccine's protein is from the malaria parasite. We are able to achieve our high density because of the design of the nanoparticle, which we control." The research was published in Malaria Journal in 2013. The search for a malaria vaccine is one of the most important research projects in global public health. The disease is commonly transported through the bites of nighttime mosquitoes. Those infected suffer from severe fevers, chills, and a flu-like illness. In severe cases, malaria causes seizures, severe anemia, respiratory distress, and kidney failure. Each year, more than 200 million cases of malaria are reported worldwide. The World Health Organization estimated that 627,000 people died from malaria in 2012, many of them children living in sub-Saharan Africa. It took the researchers more than 10 years to finalize the precise assembly of the nanoparticle as the critical carrier of the vaccine and find the right parts of the malaria protein to trigger an effective immune response. The research was further complicated by the fact that the malaria parasite that impacts mice used in lab tests is structurally different from the one infecting humans. The scientists used a creative approach to get around the problem. "Testing the vaccine's efficacy was difficult because the parasite that causes malaria in humans only grows in humans," Lanar says. "But we developed a little trick. We took a mouse malaria parasite and put in its DNA a piece of DNA from the human malaria parasite that we wanted our vaccine to attack. That allowed us to conduct inexpensive mouse studies to test the vaccine before going to expensive human trials." The pair's research has been supported by a $2 million grant from the National Institutes of Health and $2 million from the U.S. Military Infectious Disease Research Program. A request for an additional $7 million in funding from the U.S. Army to conduct the next phase of vaccine development, including manufacturing and human trials, is pending. "We are on schedule to manufacture the vaccine for human use early next year," says Lanar. "It will take about six months to finish quality control and toxicology studies on the final product and get permission from the FDA to do human trials." Lanar says the team hopes to begin early testing in humans in 2016 and, if the results are promising, field trials in malaria endemic areas will follow in 2017. The required field trial testing could last five years or more before the vaccine is available for licensure and public use, Lanar says. Martin Edlund, CEO of Malaria No More, a New York-based nonprofit focused on fighting deaths from malaria, says, "This research presents a promising new approach to developing a malaria vaccine. Innovative work such as what's being done at the University of Connecticut puts us closer than we've ever been to ending one of the world's oldest, costliest, and deadliest diseases." A Switzerland-based company, Alpha-O-Peptides, founded by Burkhard, holds the patent on the self-assembling nanoparticle used in the malaria vaccine. Burkhard is also exploring other potential uses for the nanoparticle, including a vaccine that will fight animal flu and one that will help people with nicotine addiction. Professor Mazhar Khan from UConn's Department of Pathobiology is collaborating with Burkhard on the animal flu vaccine. <|im_end|>

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2,499

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4 + T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (T H 1) cells, whereas variants associated with Alzheimer’s disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages. Main Functional interpretation of complex-disease-associated variants is challenging because the majority of loci mapped through genome-wide association studies (GWAS) reside in non-coding regions of the genome. Multiple studies have mapped GWAS variants to regulatory elements, such as open chromatin regions and regions tagged by histone modifications 1 , 2 , 3 , 4 , 5 , indicating the role of these elements in the regulation of gene expression. The functional effects of non-coding GWAS variants are difficult to deconvolute and may be specific to a particular cell type as well as a cell state, for example, the different stages of cell activation 6 . Integrating GWAS variants with cell-type-specific chromatin marks can provide insights into disease-causal cell types 1 , 4 , 7 . This approach has previously identified CD4 + T cells 4 , 8 and monocytes 6 , 9 as relevant cell types in the pathobiology of various complex immune diseases. CD4 + T cells are key regulators of the immune response and are crucial in the protection against pathogens. One of the hallmarks of CD4 + T cells is their plasticity; in particular, the ability to differentiate into a range of cell states in response to environmental signals. CD4 + T cells undergo initial activation when they recognize antigens displayed by antigen-presenting cells in the context of co-stimulatory signals. Subsequently, activated T cells undergo proliferation and can be driven to differentiate into distinct T helper phenotypes, depending on the specific cytokines secreted by antigen-presenting cells. The major T helper types include T H 1, T H 2, T H 17 and induced regulatory T cells, each of which has different functions in the immune response. Effector T helper phenotypes are defined by the specific cytokines that they secrete, which in turn instruct other immune cells to acquire different phenotypes. For example, the T H 1 cytokine interferon-γ (IFNγ) polarizes macrophages to a proinflammatory (M1) phenotype with increased pathogen-killing ability, whereas the T H 2 cytokine interleukin-4 (IL-4) induces a tissue-remodeling macrophage phenotype (M2) 10 . As such, the proper differentiation of T cells and macrophages after activation by cytokine signals is a crucial step in eliciting an appropriate immune response. Although it is established that immune-disease-associated variants localize to chromatin regions that are specific to CD4 + T cells and monocytes, it is not yet known whether immune-disease-associated variants are further enriched in chromatin regions that are specific to a particular cytokine-induced cell state. To identify whether immune-disease-associated variants regulate cellular responses to cytokine polarization, we profiled chromatin accessibility using assay for transposase-accessible chromatin using sequencing (ATAC-seq), and active enhancers and promoters marked by histone H3 K27 acetylation (H3K27ac; see Methods ) in naive and memory CD4 + T cells as well as macrophages across 55 cell activation states, including early and late responses to activation and cytokine polarization (Supplementary Table 1 ). We developed a statistical method for assessing SNP enrichment in chromatin marks to analyze the effects of immune-disease-associated variants in specific cell states. Results Overview of the experimental design The enrichment of GWAS variants in CD4 + T cells places this cell type at the center of the dysregulated immune responses in disease pathobiology. Key steps in the regulation of the quality of an immune response include the initial activation and differentiation of CD4 + T cells and the subsequent interaction of polarized T cells with downstream effector cells such as macrophages, the activity of which is regulated by T-cell-derived factors. In this study, we focused on dissecting the role of immune-disease-associated risk variants in regulating this circuitry. For this purpose, we stimulated monocyte-derived macrophages with T-cell-produced cytokines associated with inflammation and autoimmunity, including IFNγ, TNF, IL-4, IL-23 and IL-26 (Supplementary Table 1 ). As macrophages are part of the fast-responding innate immune system, we measured cytokine-induced activation at 6 h (early response) and 24 h (late response) and profiled the chromatin regulatory landscape. To mimic T cell activation in vitro, we stimulated T cells by delivering T cell receptor and CD28 signals using beads coated with anti-CD3 and anti-CD28 antibodies. In addition, we exposed cells to cytokine cocktails that promote the differentiation towards T H 1, T H 2, T H 17 or induced regulatory T cell fates, or to individual cytokines relevant to autoimmunity (IL-10, IL-21, IL-27, TNF and IFNβ) 11 , 12 , 13 , 14 , 15 (Supplementary Table 1 , see Methods ). These stimuli were applied to memory and naive CD4 + T cells, which constitute the two major subsets of CD4 + T cells. We treated naive and memory cells separately because the two subsets differ in their response to stimulation 16 . Given that the response to stimulation develops over time 17 , we profiled T cells during both early and late activation. We defined early response as 16 h, in order to capture the regulation of gene expression before the first cell division. For the late response, we chose 5 d, which is when T cells acquire a defined effector phenotype. At each time", "role": "user" }, { "content": "Scientists are one step closer to discovering the causes of immune diseases such as asthma, multiple sclerosis and arthritis. Research from the Wellcome Sanger Institute, GSK and Biogen, under the Open Targets initiative, has shown that thousands of differences in DNA between individuals, associated with immune diseases, are linked with the switching-on of a specific subtype of immune cells. Published today (23rd September) in Nature Genetics, this study will help narrow down the search for the molecular pathways involved in immune diseases and could lead to finding drug targets for developing new treatments. The immune system keeps us healthy by fighting infections. However, if something goes wrong, the cells in our immune system can mistakenly cause inflammation, leading to immune diseases like asthma, multiple sclerosis and inflammatory bowel disease (IBD). These diseases affect millions of people worldwide, with more than 5 million asthma patients in the UK alone, yet it is not known what triggers the immune system to respond in this way, or even the exact cell types involved. Previous research found that there are thousands of genetic changes—known as genetic variants—that are more common in patients with immune diseases than in healthy people. Understanding these genetic changes could provide clues to the causes and biological pathways involved in immune disease, and in time, lead to identifying new drug targets. Many of these genetic variants are in poorly understood areas of the genome and are thought to be involved in regulating functions of immune cells. Add to this, cytokines—the signalling proteins released to allow communication between the immune cells during inflammation—and the picture becomes even more complex, making it extremely difficult to pinpoint what is causing the disease. Researchers at the Sanger Institute and their collaborators aim to understand which immune cell states are most important for immune diseases, in an effort to hone in on potential new drug targets for diseases like asthma and IBD. In this new study, the team looked at which parts of the genome were active in three types of immune cells from healthy volunteers, and cross-checked these positions against all the genetic variants implicated in different immune diseases. They also added different cytokines, creating a total of 55 different cell states, to mimic immune disease inflammation and understand the effects of the signalling chemicals in these cells. The study revealed that one particular cell type and cell state—early activation of memory T cells—had the most active DNA across the same regions as the genetic variants implicated in immune diseases. This pointed towards the initial activation of these T cells being important in disease development. Surprisingly, the research showed that the cytokines generally only had subtle effects on the DNA activity, and played a lesser role in most of the diseases studied. Dr. Blagoje Soskic, a lead author on the paper from the Wellcome Sanger Institute and Open Targets, said: \"Our study is the first in depth analysis of immune cells and cytokine signals in the context of genetic differences linked to immune diseases. We found links between the disease variants and early activation of memory T cells, suggesting that problems with regulating this early T cell activation could lead to immune diseases.\" Dr. Rab Prinjha, Chair of the Open Targets Governance Board and Head of Adaptive Immunity and Immuno-Epigenetics Research Unit, GSK said: \"At GSK, we deploy both genetics and genomics to identify which parts of the immune system are central to a range of human diseases and to yield better validated targets that could become transformational medicines. To investigate the science of the immune system, functional genomics helps us better understand the role that individual genes may or may not play in triggering pathogenic immune mechanisms. This paper is yet another result from our 5-year collaboration with Open Targets to advance the field and shows our focus on advanced technologies to drive our science.\" To enable this complex analysis, the researchers developed a new computational method, called CHEERS, which enabled them to identify cell states relevant for immune diseases. Openly available, this resource could also be used to find links between genetic variation and mechanisms for other complex diseases. Dr. Gosia Trynka, the senior author from the Wellcome Sanger Institute and Open Targets, said: \"There are thousands of different cell types and states in the body, and finding the cause of autoimmune diseases is like finding a needle in a haystack. We have identified early activation of memory T cells as being particularly relevant to immune diseases, and will now be able to dive deeper into studying how this is regulated, to discover genes and pathways that could be used as drug targets.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4 + T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (T H 1) cells, whereas variants associated with Alzheimer’s disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages. Main Functional interpretation of complex-disease-associated variants is challenging because the majority of loci mapped through genome-wide association studies (GWAS) reside in non-coding regions of the genome. Multiple studies have mapped GWAS variants to regulatory elements, such as open chromatin regions and regions tagged by histone modifications 1 , 2 , 3 , 4 , 5 , indicating the role of these elements in the regulation of gene expression. The functional effects of non-coding GWAS variants are difficult to deconvolute and may be specific to a particular cell type as well as a cell state, for example, the different stages of cell activation 6 . Integrating GWAS variants with cell-type-specific chromatin marks can provide insights into disease-causal cell types 1 , 4 , 7 . This approach has previously identified CD4 + T cells 4 , 8 and monocytes 6 , 9 as relevant cell types in the pathobiology of various complex immune diseases. CD4 + T cells are key regulators of the immune response and are crucial in the protection against pathogens. One of the hallmarks of CD4 + T cells is their plasticity; in particular, the ability to differentiate into a range of cell states in response to environmental signals. CD4 + T cells undergo initial activation when they recognize antigens displayed by antigen-presenting cells in the context of co-stimulatory signals. Subsequently, activated T cells undergo proliferation and can be driven to differentiate into distinct T helper phenotypes, depending on the specific cytokines secreted by antigen-presenting cells. The major T helper types include T H 1, T H 2, T H 17 and induced regulatory T cells, each of which has different functions in the immune response. Effector T helper phenotypes are defined by the specific cytokines that they secrete, which in turn instruct other immune cells to acquire different phenotypes. For example, the T H 1 cytokine interferon-γ (IFNγ) polarizes macrophages to a proinflammatory (M1) phenotype with increased pathogen-killing ability, whereas the T H 2 cytokine interleukin-4 (IL-4) induces a tissue-remodeling macrophage phenotype (M2) 10 . As such, the proper differentiation of T cells and macrophages after activation by cytokine signals is a crucial step in eliciting an appropriate immune response. Although it is established that immune-disease-associated variants localize to chromatin regions that are specific to CD4 + T cells and monocytes, it is not yet known whether immune-disease-associated variants are further enriched in chromatin regions that are specific to a particular cytokine-induced cell state. To identify whether immune-disease-associated variants regulate cellular responses to cytokine polarization, we profiled chromatin accessibility using assay for transposase-accessible chromatin using sequencing (ATAC-seq), and active enhancers and promoters marked by histone H3 K27 acetylation (H3K27ac; see Methods ) in naive and memory CD4 + T cells as well as macrophages across 55 cell activation states, including early and late responses to activation and cytokine polarization (Supplementary Table 1 ). We developed a statistical method for assessing SNP enrichment in chromatin marks to analyze the effects of immune-disease-associated variants in specific cell states. Results Overview of the experimental design The enrichment of GWAS variants in CD4 + T cells places this cell type at the center of the dysregulated immune responses in disease pathobiology. Key steps in the regulation of the quality of an immune response include the initial activation and differentiation of CD4 + T cells and the subsequent interaction of polarized T cells with downstream effector cells such as macrophages, the activity of which is regulated by T-cell-derived factors. In this study, we focused on dissecting the role of immune-disease-associated risk variants in regulating this circuitry. For this purpose, we stimulated monocyte-derived macrophages with T-cell-produced cytokines associated with inflammation and autoimmunity, including IFNγ, TNF, IL-4, IL-23 and IL-26 (Supplementary Table 1 ). As macrophages are part of the fast-responding innate immune system, we measured cytokine-induced activation at 6 h (early response) and 24 h (late response) and profiled the chromatin regulatory landscape. To mimic T cell activation in vitro, we stimulated T cells by delivering T cell receptor and CD28 signals using beads coated with anti-CD3 and anti-CD28 antibodies. In addition, we exposed cells to cytokine cocktails that promote the differentiation towards T H 1, T H 2, T H 17 or induced regulatory T cell fates, or to individual cytokines relevant to autoimmunity (IL-10, IL-21, IL-27, TNF and IFNβ) 11 , 12 , 13 , 14 , 15 (Supplementary Table 1 , see Methods ). These stimuli were applied to memory and naive CD4 + T cells, which constitute the two major subsets of CD4 + T cells. We treated naive and memory cells separately because the two subsets differ in their response to stimulation 16 . Given that the response to stimulation develops over time 17 , we profiled T cells during both early and late activation. We defined early response as 16 h, in order to capture the regulation of gene expression before the first cell division. For the late response, we chose 5 d, which is when T cells acquire a defined effector phenotype. At each time<|im_end|> <|im_start|>assistant Scientists are one step closer to discovering the causes of immune diseases such as asthma, multiple sclerosis and arthritis. Research from the Wellcome Sanger Institute, GSK and Biogen, under the Open Targets initiative, has shown that thousands of differences in DNA between individuals, associated with immune diseases, are linked with the switching-on of a specific subtype of immune cells. Published today (23rd September) in Nature Genetics, this study will help narrow down the search for the molecular pathways involved in immune diseases and could lead to finding drug targets for developing new treatments. The immune system keeps us healthy by fighting infections. However, if something goes wrong, the cells in our immune system can mistakenly cause inflammation, leading to immune diseases like asthma, multiple sclerosis and inflammatory bowel disease (IBD). These diseases affect millions of people worldwide, with more than 5 million asthma patients in the UK alone, yet it is not known what triggers the immune system to respond in this way, or even the exact cell types involved. Previous research found that there are thousands of genetic changes—known as genetic variants—that are more common in patients with immune diseases than in healthy people. Understanding these genetic changes could provide clues to the causes and biological pathways involved in immune disease, and in time, lead to identifying new drug targets. Many of these genetic variants are in poorly understood areas of the genome and are thought to be involved in regulating functions of immune cells. Add to this, cytokines—the signalling proteins released to allow communication between the immune cells during inflammation—and the picture becomes even more complex, making it extremely difficult to pinpoint what is causing the disease. Researchers at the Sanger Institute and their collaborators aim to understand which immune cell states are most important for immune diseases, in an effort to hone in on potential new drug targets for diseases like asthma and IBD. In this new study, the team looked at which parts of the genome were active in three types of immune cells from healthy volunteers, and cross-checked these positions against all the genetic variants implicated in different immune diseases. They also added different cytokines, creating a total of 55 different cell states, to mimic immune disease inflammation and understand the effects of the signalling chemicals in these cells. The study revealed that one particular cell type and cell state—early activation of memory T cells—had the most active DNA across the same regions as the genetic variants implicated in immune diseases. This pointed towards the initial activation of these T cells being important in disease development. Surprisingly, the research showed that the cytokines generally only had subtle effects on the DNA activity, and played a lesser role in most of the diseases studied. Dr. Blagoje Soskic, a lead author on the paper from the Wellcome Sanger Institute and Open Targets, said: "Our study is the first in depth analysis of immune cells and cytokine signals in the context of genetic differences linked to immune diseases. We found links between the disease variants and early activation of memory T cells, suggesting that problems with regulating this early T cell activation could lead to immune diseases." Dr. Rab Prinjha, Chair of the Open Targets Governance Board and Head of Adaptive Immunity and Immuno-Epigenetics Research Unit, GSK said: "At GSK, we deploy both genetics and genomics to identify which parts of the immune system are central to a range of human diseases and to yield better validated targets that could become transformational medicines. To investigate the science of the immune system, functional genomics helps us better understand the role that individual genes may or may not play in triggering pathogenic immune mechanisms. This paper is yet another result from our 5-year collaboration with Open Targets to advance the field and shows our focus on advanced technologies to drive our science." To enable this complex analysis, the researchers developed a new computational method, called CHEERS, which enabled them to identify cell states relevant for immune diseases. Openly available, this resource could also be used to find links between genetic variation and mechanisms for other complex diseases. Dr. Gosia Trynka, the senior author from the Wellcome Sanger Institute and Open Targets, said: "There are thousands of different cell types and states in the body, and finding the cause of autoimmune diseases is like finding a needle in a haystack. We have identified early activation of memory T cells as being particularly relevant to immune diseases, and will now be able to dive deeper into studying how this is regulated, to discover genes and pathways that could be used as drug targets." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, − 0.22 points (95% confidence interval, 0.54–0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population. ClinicalTrials.gov NCT01701362. Working on a manuscript? Avoid the common mistakes Introduction Diverse types of nerve injury are recognized as triggers of chronic post-traumatic neuropathic pain (PTNP), including post-surgical syndromes [ 1 , 2 , 3 ]. Tissue injury may chronically alter peripheral nociceptive processing, shifting pain from acute to chronic [ 4 , 5 ]. The need for symptomatic treatment of PTNP is increasing but remains inadequately addressed [ 6 , 7 , 8 ]. Pregabalin, an alpha 2 -delta (α 2 δ) ligand (gabapentinoid), is approved in the United States for the treatment of three neuropathic pain (NeP) conditions: diabetic peripheral neuropathy (DPN), post-herpetic neuralgia (PHN), and post-spinal cord injury (SCI) [ 9 ]. An 8-week randomized clinical trial demonstrated the efficacy of pregabalin for the management of chronic post-traumatic/post-surgical pain [ 10 ]. A study of longer duration was designed to meet the US regulatory standard for a chronic pain indication: 12 weeks of maintenance or fixed dosing [ 11 ]. Methodologic features were incorporated to increase assay sensitivity for the detection of an analgesic signal in this heterogeneous patient population [ 12 ]. The primary objective was to compare the efficacy of pregabalin (flexibly dosed, 150–600 mg/day) versus placebo in the treatment of PTNP. Secondary objectives compared the efficacy of pregabalin vs placebo with respect to overall status, pain-related activity limitation, and sleep, in addition to safety and tolerability assessments. Methods Study patients Eligible patients were aged ≥ 18 years and had PTNP for ≥ 6 months after a surgical or non-surgical traumatic event (e.g., history of a motor vehicle accident, fall, sports injury, knee or hip replacement, hernia repair, thoracotomy, mastectomy, focal/localized burns, or crush injury), a mean score of ≥ 4 in pain recall for the past week at screening, and a mean score of ≥ 4 and ≤ 9 on a 0–10 numeric rating scale (NRS) of average pain (0, “no pain” to 10, “worst possible pain”) based on ≥ 4 daily diary scores from the last week of a single-blind baseline screening period (5–14 days before randomization). Peripheral nerve(s) implicated in the pain was identified to confirm nerve trauma, and pain was categorized as neuropathic based on prespecified criteria (i.e., neurologic exam, study-specific PTNP assessment including use of the PainDETECT questionnaire to identify neuropathic components of back pain [ 13 ]) and diagnostic tests (e.g., electromyography, nerve conduction tests, skin or nerve biopsy) if available. While PainDETECT was a screening assessment and used as part of the initial diagnostic assessment, since it is not specifically validated for this indication, this instrument itself did not determine eligibility in the study. Each neuropathic symptom or sign, mapped separately, was submitted to a team of independent neurologists (contracted by Analgesic Solutions, Natick, MA, USA) who determined the plausibility of matching a PTNP syndrome with respect to the history, anatomic distribution of reported pain, and associated signs identified on neurologic examination in the corresponding body region. Exclusion criteria included NeP due to PHN, DPN, complex regional pain syndrome, and other conditions; other sources of pain that might confound assessment of PTNP; disallowed concomitant medications; nonpharmacologic treatments for PTNP; severe or acute medical or psychiatric conditions; or clinically significant laboratory abnormalities. Patients scoring ≥ 15 on the Patient Health Questionnaire (PHQ-8) at screening or who were at risk based on Columbia-Suicide Severity Rating (C-SSRS) responses were recommended for evaluation by a mental health professional prior to randomization [ 14 , 15 , 16 ]. Prohibited medications included opioids, local anesthetics, topical and intraspinal steroids, antiepileptics, and antipsychotics. Allowed medications included stable regimens of nonsteroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics, antidepressants [including serotonin-specific reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin–norepinephrine reuptake inhibitors (SNRIs)], tramadol and triptans, and/or sleep medications; acetaminophen ≤ 3 g/day was allowed as rescue medication. Study design and procedures Eligible patients were randomized at 101 centers in 11 countries (Bulgaria, Canada, Denmark, Germany, Hungary, Poland, Romania, Sweden, South Africa, South Korea, and the United States). Following a single-blind screening period, the 15-week double-blind treatment period comprised 3 weeks of dose titration/optimization and 12 weeks of maintenance treatment (Supplementary Fig. S1). After randomization, clinic visits occurred every 3 weeks. Patients were randomized (1:1) to pregabalin or matching placebo. The pregabalin dose was individually optimized via telephone contact to 150, 300, 450, or 600 mg/day over the titration period, with 4 days at each dose before titration to the next level. Dose adjustments were not allowed during the maintenance period, except for a single dose reduction if the investigator judged it necessary for tolerability. Outcome measures The primary", "role": "user" }, { "content": "A new study out today in the Journal of Neurology finds that pregabalin is not effective in controlling the chronic pain that sometimes develops following traumatic nerve injury. The results of the international study, which was driven by an effort to identify effective non-opioid pain medications, did show potential in relieving in pain that sometimes lingers after surgery. \"The unrelenting burning or stabbing symptoms due to nerve trauma are a leading reason why people seek treatment for chronic pain after a fall, car accident, or surgery,\" said John Markman, M.D., director of the Translational Pain Research Program in the University of Rochester Department of Neurosurgery and lead author of the study. \"While these finding show that pregabalin is not effective in controlling the long-term pain for traumatic injury, it may provide relief for patients experience post-surgical pain.\" Pregabalin, which is marketed by Pfizer under the name Lyrica, is approved to treat chronic pain associated with shingles, spinal cord injury, fibromyalgia, and diabetic peripheral neuropathy. However, it is also commonly prescribed as an \"off label\" treatment for chronic nerve injury syndromes that occur after motor vehicle accidents, falls, sports injuries, knee or hip replacement and surgeries such as hernia repair or mastectomy. A previous eight-week study had shown that pregabalin reduced pain intensity better than placebo in these chronic, post-traumatic pain syndromes. These results led many doctors to prescribe this medication for long-term pain that does not resolve as expected. Chronic postsurgical pain syndromes occur in approximately one or two out of every 10 surgical patients and the levels rated as intolerable after roughly one or two in every 100 operations. With 55 million surgeries performed in the U.S. every year, severe chronic pain impacts more than a million new people annually. Roughly one third of these patients are believed to have neuropathic pain or ongoing pain related to nerve injury. These rates vary widely by type of surgery. The risks factors and underlying mechanisms of this type of chronic pain are not well understood, but because the types of symptoms patients describe like \"burning\", \"unpleasant tingling,\" or \"numbness\" resemble other nerve pain syndromes like shingles pain. As a result, physicians trying to find useful non-opioid pain relievers have often turned to prescribing gabapentin or pregabalin. The current study was conducted in 101 centers in in North America, Europe, Africa, and Asia and followed 539 individuals for three months. Study participants were randomized into two groups who either prescribed pregabalin or a placebo. The study found that pregabalin was not effective in controlling pain for individuals with traumatic nerve injury. A retrospective analysis of a subgroup of study of participants, whose nerve pain was attributed to surgery, showed that the drug did provide better pain relief than placebo at 3 months. \"The possibility that there was pain relief for those patients who had a hernia repair, or breast surgery for cancer, or a joint replacement lays the groundwork for future studies in these post-surgical syndromes where there is so much need for non-opioid treatments,\" said Markman. One major challenge is that different biological changes in the nerves and other tissues that cause pain to persist after healing from trauma vary from one patient to the next. Currently, there is no diagnostic method that allows doctors to readily identify the patients whose pain will respond to a particular type of pain treatment. Despite employing new strategies to reduce placebo effects, the patients receiving placebo also had a steady lowering of their pain over the course of the study. The pattern of these placebo effects in longer studies has proved to be a major challenge to the development of new pain medications. \"Given the rising rates of surgery and shrinking reliance on opioids, it is critical that we understand how to study new drugs that work differently in patients like the ones included in this study,\" Markman added. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, − 0.22 points (95% confidence interval, 0.54–0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population. ClinicalTrials.gov NCT01701362. Working on a manuscript? Avoid the common mistakes Introduction Diverse types of nerve injury are recognized as triggers of chronic post-traumatic neuropathic pain (PTNP), including post-surgical syndromes [ 1 , 2 , 3 ]. Tissue injury may chronically alter peripheral nociceptive processing, shifting pain from acute to chronic [ 4 , 5 ]. The need for symptomatic treatment of PTNP is increasing but remains inadequately addressed [ 6 , 7 , 8 ]. Pregabalin, an alpha 2 -delta (α 2 δ) ligand (gabapentinoid), is approved in the United States for the treatment of three neuropathic pain (NeP) conditions: diabetic peripheral neuropathy (DPN), post-herpetic neuralgia (PHN), and post-spinal cord injury (SCI) [ 9 ]. An 8-week randomized clinical trial demonstrated the efficacy of pregabalin for the management of chronic post-traumatic/post-surgical pain [ 10 ]. A study of longer duration was designed to meet the US regulatory standard for a chronic pain indication: 12 weeks of maintenance or fixed dosing [ 11 ]. Methodologic features were incorporated to increase assay sensitivity for the detection of an analgesic signal in this heterogeneous patient population [ 12 ]. The primary objective was to compare the efficacy of pregabalin (flexibly dosed, 150–600 mg/day) versus placebo in the treatment of PTNP. Secondary objectives compared the efficacy of pregabalin vs placebo with respect to overall status, pain-related activity limitation, and sleep, in addition to safety and tolerability assessments. Methods Study patients Eligible patients were aged ≥ 18 years and had PTNP for ≥ 6 months after a surgical or non-surgical traumatic event (e.g., history of a motor vehicle accident, fall, sports injury, knee or hip replacement, hernia repair, thoracotomy, mastectomy, focal/localized burns, or crush injury), a mean score of ≥ 4 in pain recall for the past week at screening, and a mean score of ≥ 4 and ≤ 9 on a 0–10 numeric rating scale (NRS) of average pain (0, “no pain” to 10, “worst possible pain”) based on ≥ 4 daily diary scores from the last week of a single-blind baseline screening period (5–14 days before randomization). Peripheral nerve(s) implicated in the pain was identified to confirm nerve trauma, and pain was categorized as neuropathic based on prespecified criteria (i.e., neurologic exam, study-specific PTNP assessment including use of the PainDETECT questionnaire to identify neuropathic components of back pain [ 13 ]) and diagnostic tests (e.g., electromyography, nerve conduction tests, skin or nerve biopsy) if available. While PainDETECT was a screening assessment and used as part of the initial diagnostic assessment, since it is not specifically validated for this indication, this instrument itself did not determine eligibility in the study. Each neuropathic symptom or sign, mapped separately, was submitted to a team of independent neurologists (contracted by Analgesic Solutions, Natick, MA, USA) who determined the plausibility of matching a PTNP syndrome with respect to the history, anatomic distribution of reported pain, and associated signs identified on neurologic examination in the corresponding body region. Exclusion criteria included NeP due to PHN, DPN, complex regional pain syndrome, and other conditions; other sources of pain that might confound assessment of PTNP; disallowed concomitant medications; nonpharmacologic treatments for PTNP; severe or acute medical or psychiatric conditions; or clinically significant laboratory abnormalities. Patients scoring ≥ 15 on the Patient Health Questionnaire (PHQ-8) at screening or who were at risk based on Columbia-Suicide Severity Rating (C-SSRS) responses were recommended for evaluation by a mental health professional prior to randomization [ 14 , 15 , 16 ]. Prohibited medications included opioids, local anesthetics, topical and intraspinal steroids, antiepileptics, and antipsychotics. Allowed medications included stable regimens of nonsteroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics, antidepressants [including serotonin-specific reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin–norepinephrine reuptake inhibitors (SNRIs)], tramadol and triptans, and/or sleep medications; acetaminophen ≤ 3 g/day was allowed as rescue medication. Study design and procedures Eligible patients were randomized at 101 centers in 11 countries (Bulgaria, Canada, Denmark, Germany, Hungary, Poland, Romania, Sweden, South Africa, South Korea, and the United States). Following a single-blind screening period, the 15-week double-blind treatment period comprised 3 weeks of dose titration/optimization and 12 weeks of maintenance treatment (Supplementary Fig. S1). After randomization, clinic visits occurred every 3 weeks. Patients were randomized (1:1) to pregabalin or matching placebo. The pregabalin dose was individually optimized via telephone contact to 150, 300, 450, or 600 mg/day over the titration period, with 4 days at each dose before titration to the next level. Dose adjustments were not allowed during the maintenance period, except for a single dose reduction if the investigator judged it necessary for tolerability. Outcome measures The primary<|im_end|> <|im_start|>assistant A new study out today in the Journal of Neurology finds that pregabalin is not effective in controlling the chronic pain that sometimes develops following traumatic nerve injury. The results of the international study, which was driven by an effort to identify effective non-opioid pain medications, did show potential in relieving in pain that sometimes lingers after surgery. "The unrelenting burning or stabbing symptoms due to nerve trauma are a leading reason why people seek treatment for chronic pain after a fall, car accident, or surgery," said John Markman, M.D., director of the Translational Pain Research Program in the University of Rochester Department of Neurosurgery and lead author of the study. "While these finding show that pregabalin is not effective in controlling the long-term pain for traumatic injury, it may provide relief for patients experience post-surgical pain." Pregabalin, which is marketed by Pfizer under the name Lyrica, is approved to treat chronic pain associated with shingles, spinal cord injury, fibromyalgia, and diabetic peripheral neuropathy. However, it is also commonly prescribed as an "off label" treatment for chronic nerve injury syndromes that occur after motor vehicle accidents, falls, sports injuries, knee or hip replacement and surgeries such as hernia repair or mastectomy. A previous eight-week study had shown that pregabalin reduced pain intensity better than placebo in these chronic, post-traumatic pain syndromes. These results led many doctors to prescribe this medication for long-term pain that does not resolve as expected. Chronic postsurgical pain syndromes occur in approximately one or two out of every 10 surgical patients and the levels rated as intolerable after roughly one or two in every 100 operations. With 55 million surgeries performed in the U.S. every year, severe chronic pain impacts more than a million new people annually. Roughly one third of these patients are believed to have neuropathic pain or ongoing pain related to nerve injury. These rates vary widely by type of surgery. The risks factors and underlying mechanisms of this type of chronic pain are not well understood, but because the types of symptoms patients describe like "burning", "unpleasant tingling," or "numbness" resemble other nerve pain syndromes like shingles pain. As a result, physicians trying to find useful non-opioid pain relievers have often turned to prescribing gabapentin or pregabalin. The current study was conducted in 101 centers in in North America, Europe, Africa, and Asia and followed 539 individuals for three months. Study participants were randomized into two groups who either prescribed pregabalin or a placebo. The study found that pregabalin was not effective in controlling pain for individuals with traumatic nerve injury. A retrospective analysis of a subgroup of study of participants, whose nerve pain was attributed to surgery, showed that the drug did provide better pain relief than placebo at 3 months. "The possibility that there was pain relief for those patients who had a hernia repair, or breast surgery for cancer, or a joint replacement lays the groundwork for future studies in these post-surgical syndromes where there is so much need for non-opioid treatments," said Markman. One major challenge is that different biological changes in the nerves and other tissues that cause pain to persist after healing from trauma vary from one patient to the next. Currently, there is no diagnostic method that allows doctors to readily identify the patients whose pain will respond to a particular type of pain treatment. Despite employing new strategies to reduce placebo effects, the patients receiving placebo also had a steady lowering of their pain over the course of the study. The pattern of these placebo effects in longer studies has proved to be a major challenge to the development of new pain medications. "Given the rising rates of surgery and shrinking reliance on opioids, it is critical that we understand how to study new drugs that work differently in patients like the ones included in this study," Markman added. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Respiratory chain complexes can super-assemble into quaternary structures called supercomplexes that optimize cellular metabolism 1 . The interaction between complexes III (CIII) and IV (CIV) is modulated by supercomplex assembly factor 1 (SCAF1, also known as COX7A2L) 2 . The discovery of SCAF1 represented strong genetic evidence that supercomplexes exist in vivo 2 , 3 . SCAF1 is present as a long isoform (113 amino acids) or a short isoform (111 amino acids) in different mouse strains 2 , 4 . Only the long isoform can induce the super-assembly of CIII and CIV 2 , 3 , 4 , 5 , 6 , but it is not clear whether SCAF1 is required for the formation of the respirasome (a supercomplex of CI, CIII 2 and CIV) 1 , 2 , 4 , 5 , 6 . Here we show, by combining deep proteomics and immunodetection analysis, that SCAF1 is always required for the interaction between CIII and CIV and that the respirasome is absent from most tissues of animals containing the short isoform of SCAF1, with the exception of heart and skeletal muscle. We used directed mutagenesis to characterize SCAF1 regions that interact with CIII and CIV and discovered that this interaction requires the correct orientation of a histidine residue at position 73 that is altered in the short isoform of SCAF1, explaining its inability to interact with CIV. Furthermore, we find that the CIV subunit COX7A2 is replaced by SCAF1 in supercomplexes containing CIII and CIV and by COX7A1 in CIV dimers, and that dimers seem to be more stable when they include COX6A2 rather than the COX6A1 isoform. Main We analysed the organization of the respiratory chain by blue native gel electrophoresis (BNGE) in different tissues ( Fig. 1a, b ). In CD1 mice, CIII and CIV are distributed among several well-characterized structures (IV, IV 2 , III 2 , supercomplex III 2 +IV, supercomplex I+III 2 and supercomplex I+III 2 +IV). Other structures of uncertain composition showing co-migration of I and III; I, III and IV, or only IV are also observed. SCAF1 is present in all superassemblies containing CIII and CIV ( Fig. 1a ). By contrast, C57BL/6J mice showed a depletion of SCAF1 with loss of supercomplex III 2 +IV and a concomitant reduction in supercomplex I+III 2 +IV, which only remains in relevant amounts in skeletal muscle and heart ( Fig. 1b ). Further analysis confirmed that supercomplex III 2 +IV was virtually absent in C57BL/6J mice while heart, but not liver, retained a significant amount of supercomplex I+III 2 +IV ( Fig. 1c–e ). In adult heart mitochondria from both strains, additional bands containing CIV but not CIII or SCAF1 were detected ( Fig. 1f–h ). These supernumerary CIV bands were also observed in neonatal C57BL/6J but not in CD1 mitochondria ( Fig. 1f–h ). The respirasome and supercomplex III 2 +IV were present in adult and post-natal day 3 (P3) CD1 hearts while both were absent in P3 C57BL/6J hearts ( Fig. 1f–h ). Finally, two-dimensional BNGE/SDS–PAGE immunoblotting showed that supercomplex III 2 +IV was still undetectable in C57BL/6 heart ( Fig. 1i–l ) and that the proportion of respirasome was significantly lower than in CD1 heart. Figure 1: Super-assembly between CIII and CIV requires functional SCAF1. a – h , Immunodetection of the indicated proteins after BNGE of digitonin-solubilized mitochondria from CD1 and C57BL/6J mice (BL/6). Mitochondria were extracted from the indicated tissues (Lv, liver; Kd, kidney; Br, brain; MS, skeletal muscle; Hr, heart; Ln, lung) ( a – d ), from liver ( e ) or from adult (A) and 3 days post-natal (P3) heart ( f – h ). i – l , Immunodetection after BNGE followed by a second dimension SDS–PAGE. OE, overexposed. Red arrows indicate supercomplex III 2 +IV and supercomplex I+III 2 +IV. Gels representative of 2 ( a , b ), 4 ( c , d ), 2 ( e ) or 1 ( i – l ) biological replicates; in f – h representative of 2 biological and 3 technical replicates. PowerPoint slide Full size image Next, BNGE lanes were sliced into 26 fractions and analysed by mass spectrometry using a data-independent scanning method (DiS) 7 . We obtained near-complete protein coverage of complex components ( Fig. 2a–c ). Again, in C57BL/6J mice (SCAF1 111 ) supercomplex III 2 +IV was virtually absent in C57BL/6J livers and heart while the respirasome was detected in heart mitochondria from both strains ( Fig. 2a–c ). CIV contains several tissue-specific subunit isoforms; COX7A1 and COX6A2 are heart/skeletal-muscle-specific isoforms whereas COX7A2 and COX6A1 are liver-type isoforms that are present in rodent hearts in significant proportions. SCAF1 is also named COX7A2-like owing to its high similarity to this CIV subunit. We reanalysed the DiS fragmentation data to generate specific quantitative profiles of these isoforms and of representative protein components of the complexes ( Fig. 2d–g and Extended Data Figs 1 , 2 , 3 , 4 ). Notably, COX7A2 was found almost exclusively in the monomeric CIV form in CD1 heart and liver ( Fig. 2d, f , green), while SCAF1 was found in the supercomplex III 2 +IV and in the respirasome in both tissues ( Fig. 2d, f , red). These results strongly suggest that COX7A2 is replaced by SCAF1 when CIV is assembled into supercomplexes containing CIII. Figure 2: Super-assembly of the different CIII and CIV structures depends on the subunit composition of CIV. DiS mass spectrometry analysis of BNGE gel slices of digitonin-solubilized mitochondria from heart and liver from CD1 and C57BL/6J mice. a – c , Quantitative profiles of CI ( a ), CIII ( b ) and CIV ( c ), expressed in total peptide-spectrum matches (PSMs); the diagrams indicate the subunits detected of each complex. X boxes indicate proteins not yet described in mice; proteins encoded in nucleus or mitochondria are marked in black or red, respectively; complex IV tissue-specific isoforms are marked in blue; white boxes, not detected; R, respirasome.", "role": "user" }, { "content": "Scientists at the Centro Nacional de Enfermedades Cardiovasculares Carlos III (CNIC) have defined the molecular organization underlying energy production in living cells. The discovery, published in the journal Nature, sheds light on the regulation of metabolism and is a milestone in the understanding of the organization of the mitochondrial electron transport chain (mETC), which releases energy from nutrient-derived molecules. The study also suggests ways in which different mETC organizations could affect metabolism and be linked to the tendency to develop distinct diseases. For many years scientists believed that the structures within mitochondria that permit cell respiration were mixed randomly and had no precise organization. This view held back understanding of mitochondrial respiration and the importance of its regulation in the control of metabolic and cellular stress and its possible role in disease. The new study was carried out by groups led by professors José Antonio Enríquez and Jesús Vázquez, with first authors Dr. Sara Cogiati and Dr. Enrique Calvo. The study centers on the role of the terminal mETC complex, called complex IV. Complex IV is composed of 14 proteins. Cells can produce different versions of some of these proteins, but the function of these different versions was unknown. Complex IV can occur as an isolated complex, paired in dimers, or in assemblies with other respiratory chain complexes. The Nature study shows that the exchange of different versions of one component protein (called SCAF1 or Cox7a1 and Cox7a2) regulates the association of complex IV in different structures. According to professor Enriquez, \"these alternative versions determine the final form of mitochondrial structures\". Different mitochdondrial structures have different functions, explains Dr. Cogliati: \"It's useful to think of children's building blocks of different sizes, with each block fitting in its correct location in a structure, related to its specific function. Depending on how we assemble the blocks, we could build a house, a bridge or a fire station; all are possible structures, but with different characteristics and functions.\" In a similar way, mitochondria organize the mETC in specific ways. According to Dr. Calvo, \"by using different versions of component proteins, structures are built with slightly differing functions.\" Prof. Vázquez explains that \"Thanks to our work, we now know that exchange of one version of SCAF1 for another is a mechanism for regulating the structure and activity of the mETC, and thus cell metabolism.\" The researchers conclude that these results, in addition to uncovering the mechanisms that organize the mETC, are a milestone in understanding how different mETC structures affect metabolism and the relation of these structures to the risk of developing specific diseases. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Respiratory chain complexes can super-assemble into quaternary structures called supercomplexes that optimize cellular metabolism 1 . The interaction between complexes III (CIII) and IV (CIV) is modulated by supercomplex assembly factor 1 (SCAF1, also known as COX7A2L) 2 . The discovery of SCAF1 represented strong genetic evidence that supercomplexes exist in vivo 2 , 3 . SCAF1 is present as a long isoform (113 amino acids) or a short isoform (111 amino acids) in different mouse strains 2 , 4 . Only the long isoform can induce the super-assembly of CIII and CIV 2 , 3 , 4 , 5 , 6 , but it is not clear whether SCAF1 is required for the formation of the respirasome (a supercomplex of CI, CIII 2 and CIV) 1 , 2 , 4 , 5 , 6 . Here we show, by combining deep proteomics and immunodetection analysis, that SCAF1 is always required for the interaction between CIII and CIV and that the respirasome is absent from most tissues of animals containing the short isoform of SCAF1, with the exception of heart and skeletal muscle. We used directed mutagenesis to characterize SCAF1 regions that interact with CIII and CIV and discovered that this interaction requires the correct orientation of a histidine residue at position 73 that is altered in the short isoform of SCAF1, explaining its inability to interact with CIV. Furthermore, we find that the CIV subunit COX7A2 is replaced by SCAF1 in supercomplexes containing CIII and CIV and by COX7A1 in CIV dimers, and that dimers seem to be more stable when they include COX6A2 rather than the COX6A1 isoform. Main We analysed the organization of the respiratory chain by blue native gel electrophoresis (BNGE) in different tissues ( Fig. 1a, b ). In CD1 mice, CIII and CIV are distributed among several well-characterized structures (IV, IV 2 , III 2 , supercomplex III 2 +IV, supercomplex I+III 2 and supercomplex I+III 2 +IV). Other structures of uncertain composition showing co-migration of I and III; I, III and IV, or only IV are also observed. SCAF1 is present in all superassemblies containing CIII and CIV ( Fig. 1a ). By contrast, C57BL/6J mice showed a depletion of SCAF1 with loss of supercomplex III 2 +IV and a concomitant reduction in supercomplex I+III 2 +IV, which only remains in relevant amounts in skeletal muscle and heart ( Fig. 1b ). Further analysis confirmed that supercomplex III 2 +IV was virtually absent in C57BL/6J mice while heart, but not liver, retained a significant amount of supercomplex I+III 2 +IV ( Fig. 1c–e ). In adult heart mitochondria from both strains, additional bands containing CIV but not CIII or SCAF1 were detected ( Fig. 1f–h ). These supernumerary CIV bands were also observed in neonatal C57BL/6J but not in CD1 mitochondria ( Fig. 1f–h ). The respirasome and supercomplex III 2 +IV were present in adult and post-natal day 3 (P3) CD1 hearts while both were absent in P3 C57BL/6J hearts ( Fig. 1f–h ). Finally, two-dimensional BNGE/SDS–PAGE immunoblotting showed that supercomplex III 2 +IV was still undetectable in C57BL/6 heart ( Fig. 1i–l ) and that the proportion of respirasome was significantly lower than in CD1 heart. Figure 1: Super-assembly between CIII and CIV requires functional SCAF1. a – h , Immunodetection of the indicated proteins after BNGE of digitonin-solubilized mitochondria from CD1 and C57BL/6J mice (BL/6). Mitochondria were extracted from the indicated tissues (Lv, liver; Kd, kidney; Br, brain; MS, skeletal muscle; Hr, heart; Ln, lung) ( a – d ), from liver ( e ) or from adult (A) and 3 days post-natal (P3) heart ( f – h ). i – l , Immunodetection after BNGE followed by a second dimension SDS–PAGE. OE, overexposed. Red arrows indicate supercomplex III 2 +IV and supercomplex I+III 2 +IV. Gels representative of 2 ( a , b ), 4 ( c , d ), 2 ( e ) or 1 ( i – l ) biological replicates; in f – h representative of 2 biological and 3 technical replicates. PowerPoint slide Full size image Next, BNGE lanes were sliced into 26 fractions and analysed by mass spectrometry using a data-independent scanning method (DiS) 7 . We obtained near-complete protein coverage of complex components ( Fig. 2a–c ). Again, in C57BL/6J mice (SCAF1 111 ) supercomplex III 2 +IV was virtually absent in C57BL/6J livers and heart while the respirasome was detected in heart mitochondria from both strains ( Fig. 2a–c ). CIV contains several tissue-specific subunit isoforms; COX7A1 and COX6A2 are heart/skeletal-muscle-specific isoforms whereas COX7A2 and COX6A1 are liver-type isoforms that are present in rodent hearts in significant proportions. SCAF1 is also named COX7A2-like owing to its high similarity to this CIV subunit. We reanalysed the DiS fragmentation data to generate specific quantitative profiles of these isoforms and of representative protein components of the complexes ( Fig. 2d–g and Extended Data Figs 1 , 2 , 3 , 4 ). Notably, COX7A2 was found almost exclusively in the monomeric CIV form in CD1 heart and liver ( Fig. 2d, f , green), while SCAF1 was found in the supercomplex III 2 +IV and in the respirasome in both tissues ( Fig. 2d, f , red). These results strongly suggest that COX7A2 is replaced by SCAF1 when CIV is assembled into supercomplexes containing CIII. Figure 2: Super-assembly of the different CIII and CIV structures depends on the subunit composition of CIV. DiS mass spectrometry analysis of BNGE gel slices of digitonin-solubilized mitochondria from heart and liver from CD1 and C57BL/6J mice. a – c , Quantitative profiles of CI ( a ), CIII ( b ) and CIV ( c ), expressed in total peptide-spectrum matches (PSMs); the diagrams indicate the subunits detected of each complex. X boxes indicate proteins not yet described in mice; proteins encoded in nucleus or mitochondria are marked in black or red, respectively; complex IV tissue-specific isoforms are marked in blue; white boxes, not detected; R, respirasome.<|im_end|> <|im_start|>assistant Scientists at the Centro Nacional de Enfermedades Cardiovasculares Carlos III (CNIC) have defined the molecular organization underlying energy production in living cells. The discovery, published in the journal Nature, sheds light on the regulation of metabolism and is a milestone in the understanding of the organization of the mitochondrial electron transport chain (mETC), which releases energy from nutrient-derived molecules. The study also suggests ways in which different mETC organizations could affect metabolism and be linked to the tendency to develop distinct diseases. For many years scientists believed that the structures within mitochondria that permit cell respiration were mixed randomly and had no precise organization. This view held back understanding of mitochondrial respiration and the importance of its regulation in the control of metabolic and cellular stress and its possible role in disease. The new study was carried out by groups led by professors José Antonio Enríquez and Jesús Vázquez, with first authors Dr. Sara Cogiati and Dr. Enrique Calvo. The study centers on the role of the terminal mETC complex, called complex IV. Complex IV is composed of 14 proteins. Cells can produce different versions of some of these proteins, but the function of these different versions was unknown. Complex IV can occur as an isolated complex, paired in dimers, or in assemblies with other respiratory chain complexes. The Nature study shows that the exchange of different versions of one component protein (called SCAF1 or Cox7a1 and Cox7a2) regulates the association of complex IV in different structures. According to professor Enriquez, "these alternative versions determine the final form of mitochondrial structures". Different mitochdondrial structures have different functions, explains Dr. Cogliati: "It's useful to think of children's building blocks of different sizes, with each block fitting in its correct location in a structure, related to its specific function. Depending on how we assemble the blocks, we could build a house, a bridge or a fire station; all are possible structures, but with different characteristics and functions." In a similar way, mitochondria organize the mETC in specific ways. According to Dr. Calvo, "by using different versions of component proteins, structures are built with slightly differing functions." Prof. Vázquez explains that "Thanks to our work, we now know that exchange of one version of SCAF1 for another is a mechanism for regulating the structure and activity of the mETC, and thus cell metabolism." The researchers conclude that these results, in addition to uncovering the mechanisms that organize the mETC, are a milestone in understanding how different mETC structures affect metabolism and the relation of these structures to the risk of developing specific diseases. <|im_end|>

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19338, 13, 220, 128257, 198 ]

2,169

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT. Introduction Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy, is the most common hereditary neuromuscular condition affecting 1 in 2500 individuals 1 . The disease is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment, sensory loss, and skeletal deformities. CMT patients typically develop slowly progressive disability early in life, while there is no causal treatment available. CMT is one of the most heterogeneous Mendelian disorders, with causal mutations in over 80 genes known so far. Notably, CMT gene products are implicated in diverse cellular pathways and their function related to the disease is not always apparent. A prominent example are aminoacyl-tRNA synthetases (aaRSs). With six members involved, they represent the largest family of proteins implicated in the etiology of peripheral neuropathies 2 , 3 . aaRSs are ubiquitously expressed enzymes catalyzing the charging of tRNAs with their cognate amino acids and are therefore indispensable for viability. The specific sub-population of neurons affected in CMT sharply contrasts with the broad requirement of aaRSs for protein biosynthesis, indicating that the impact of aaRSs in peripheral nerves may not be limited to protein translation. In addition to their well characterized localization in the cytoplasm, aaRSs are detected in the nucleus of eukaryotic cells. While the early hypothesis was that nuclear aaRSs function in proofreading newly-synthesized tRNAs 4 , 5 , 6 , later findings suggest that they are involved in regulating a wide range of biological processes including vascular development, inflammation, and stress responses mainly due to their peculiar abilities to interact with the transcriptional machinery 7 , 8 , 9 . For example, we identified the nuclear localization signal in human tyrosyl-tRNA synthetase (TyrRS or YARS) and demonstrated its presence in the nucleus under oxidative stress to transcriptionally upregulate the expression of DNA damage response genes 8 , 10 . Overexpression of TyrRS strongly protects against UV-induced DNA damage in zebrafish, whereas restricting TyrRS nuclear entry abolishes this effect. The beneficial effect of nuclear TyrRS is mediated by activating the transcription factor E2F1. Notably, TyrRS is one of the aaRSs causally linked to CMT disease. Five pathogenic dominant mutations have been reported so far, all of them located in the catalytic domain of the enzyme 11 , 12 , 13 . Three have been extensively characterized both in vitro and in vivo and the results show that a defect in aminoacylation activity is not a shared property (i.e., TyrRS-G41R is enzymatically inactive, while TyrRS-E196K is fully active, and TyrRS-Δ153-156VKQV has partial activity), suggesting that a simple loss of canonical function is not a prerequisite for the disease to occur 14 . Pathogenicity of these three mutations has been recapitulated in transgenic Drosophila models displaying progressive loss of motor abilities, electrophysiological neuronal dysfunction, and terminal axonal degeneration 15 . Flies expressing the enzymatically intact TyrRS-E196K mutant show comparable or, in some aspects, more pronounced features of neurodegeneration than flies expressing the aminoacylation compromised mutants, therefore indicating that a gain of toxic function or interference with a non-enzymatic function of the wild type (WT) protein is likely underlying the disease 15 . In this study, we set out to investigate how this neurotoxic function is generated from a molecular perspective. Because neuronal identity and maintenance are largely controlled by transcriptionally regulated programs 16 , we further investigated whether the nuclear localization and function of TyrRS plays any role in the disease mechanism of CMT. We show that CMT-causing mutations in TyrRS induce unique conformational changes, provoking aberrant interactions. These interactions in the nucleus lead to transcription factor E2F1 hyperactivation. Furthermore, a broad transcriptional regulation network associated with wild-type TyrRS expression in Drosophila is disturbed when a CMT-mutant is expressed. Excluding mutant TyrRS from the nucleus using pharmacological and genetic approaches suppresses the CMT hallmark phenotypes of CMT in the Drosophila model. These data highlight that TyrRS may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT. Results Conformational changes and altered functionalities of TyrRS In a previous work, we demonstrated that the three established CMT-causing TyrRS mutants (TyrRS-E196K, TyrRS-G41R, and TyrRS-Δ153-156VKQV) induce a conformational opening and expose a consensus area in the catalytic domain of the enzyme 17 (Fig. 1a, b ). In order to link this unique structural change to specific interactional and functional consequences related to CMT, we included two control mutants in this study. An alternative conformational change can be induced by a rationally designed mutation in the anticodon binding domain (Y341A) to expose a different area of the catalytic domain that is responsible for a “cytokine”-like activity of TyrRS 18 . Separately, an established benign polymorphism in the anticodon binding domain (K265N) was included, because it shows no toxicity of the protein in human or when overexpressed in Drosophila and we found that it does not trigger any conformational change 19 (Fig. 1a, b ). Fig. 1 TyrRS mutations induce structural changes leading to aberrant transcription regulation. a Domain structure of human TyrRS and the location of the different mutations. Red indicates CMT-causing mutations, blue indicates the cytokine-activating Y341A mutation, and orange indicates the benign substitution K265N. b Schematic illustration", "role": "user" }, { "content": "An unexpected finding from the Scripps Research laboratory of Xiang-Lei Yang, Ph.D., has illuminated a potential strategy for treating the inherited neurological disease Charcot-Marie-Tooth (CMT), for which there is no approved medicine today. CMT is a progressive disease that typically develops early in life, affecting roughly 1 in 2,500 people. Over time, the disease inflicts damage on patients' peripheral nervous system—which extends from the spinal cord into the hands and feet—often resulting in difficulties with balance, walking and fine motor skills such as writing or buttoning a shirt. In a study that appears in Nature Communications, Yang and her team show that a drug may be able to prevent the disease-causing mechanisms from occurring within cells, quelling many key symptoms, including motor deficits. The approach centers on enzymes known as aminoacyl-tRNA synthetases (aaRSs), which are pervasive throughout the body. They are the largest protein family linked to CMT disease, and also the long-running research specialty of Yang's lab. These enzymes are essential to life because they kick off the first step of making new proteins, which are the building blocks of everything from blood and hormones to skin and bones. But in patients with CMT, some of the aaRS enzymes don't function as they should. As a result, peripheral neurons aren't made properly and become toxic to the peripheral nervous system. In her search for a potential treatment approach, Yang wanted to find out why the mutated enzymes only seem to affect peripheral neurons. She discovered that while aaRS enzymes typically function in a part of the cell known as the cytoplasm, one mutated form of the enzyme known as TyrRS—which is known to be linked to the disease—exists inside a cell's nucleus. \"The nucleus is the site for gene expression or transcription to take place, which made this finding of special interest to us,\" Yang says. \"Transcription regulates the identity of cells and cell-specific maintenance programs, and if something goes awry during this process, disease can result.\" Fueled by the excitement of her nucleus discovery, Yang collaborated with Albena Jordanova, Ph.D., at the University of Antwerp. Jordanova is the scientist who first linked the mutant TyrRS enzyme to CMT disease and established a fruit fly model that exhibits CMT, enabling disease-focused research efforts. Working together, the teams conducted experiments on fruit flies that showed \"unequivocally\" that the location of TyrRS in the nucleus was contributing to disease in a significant way. Then, by using a small-molecule drug called embelin to keep the enzyme from entering the nucleus, the team \"achieved a complete rescue\" of a fruit fly with CMT disease. Yang noted that the discovery is most immediately relevant for patients who have a form of the disease known to be caused by mutant TyrRS. However, the findings may translate to subtypes caused by other mutant aaRS enzymes. \"This work paves the way for developing a viable therapy for CMT patients affected by TyrRS mutations,\" Yang says. \"We're excited to advance this research by further validating the therapeutic approach and finding the best-possible pharmaceutical product to inhibit this enzyme from entering the nucleus. We also will investigate whether the nuclear relevance can be generalized to other CMT subtypes.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT. Introduction Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy, is the most common hereditary neuromuscular condition affecting 1 in 2500 individuals 1 . The disease is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment, sensory loss, and skeletal deformities. CMT patients typically develop slowly progressive disability early in life, while there is no causal treatment available. CMT is one of the most heterogeneous Mendelian disorders, with causal mutations in over 80 genes known so far. Notably, CMT gene products are implicated in diverse cellular pathways and their function related to the disease is not always apparent. A prominent example are aminoacyl-tRNA synthetases (aaRSs). With six members involved, they represent the largest family of proteins implicated in the etiology of peripheral neuropathies 2 , 3 . aaRSs are ubiquitously expressed enzymes catalyzing the charging of tRNAs with their cognate amino acids and are therefore indispensable for viability. The specific sub-population of neurons affected in CMT sharply contrasts with the broad requirement of aaRSs for protein biosynthesis, indicating that the impact of aaRSs in peripheral nerves may not be limited to protein translation. In addition to their well characterized localization in the cytoplasm, aaRSs are detected in the nucleus of eukaryotic cells. While the early hypothesis was that nuclear aaRSs function in proofreading newly-synthesized tRNAs 4 , 5 , 6 , later findings suggest that they are involved in regulating a wide range of biological processes including vascular development, inflammation, and stress responses mainly due to their peculiar abilities to interact with the transcriptional machinery 7 , 8 , 9 . For example, we identified the nuclear localization signal in human tyrosyl-tRNA synthetase (TyrRS or YARS) and demonstrated its presence in the nucleus under oxidative stress to transcriptionally upregulate the expression of DNA damage response genes 8 , 10 . Overexpression of TyrRS strongly protects against UV-induced DNA damage in zebrafish, whereas restricting TyrRS nuclear entry abolishes this effect. The beneficial effect of nuclear TyrRS is mediated by activating the transcription factor E2F1. Notably, TyrRS is one of the aaRSs causally linked to CMT disease. Five pathogenic dominant mutations have been reported so far, all of them located in the catalytic domain of the enzyme 11 , 12 , 13 . Three have been extensively characterized both in vitro and in vivo and the results show that a defect in aminoacylation activity is not a shared property (i.e., TyrRS-G41R is enzymatically inactive, while TyrRS-E196K is fully active, and TyrRS-Δ153-156VKQV has partial activity), suggesting that a simple loss of canonical function is not a prerequisite for the disease to occur 14 . Pathogenicity of these three mutations has been recapitulated in transgenic Drosophila models displaying progressive loss of motor abilities, electrophysiological neuronal dysfunction, and terminal axonal degeneration 15 . Flies expressing the enzymatically intact TyrRS-E196K mutant show comparable or, in some aspects, more pronounced features of neurodegeneration than flies expressing the aminoacylation compromised mutants, therefore indicating that a gain of toxic function or interference with a non-enzymatic function of the wild type (WT) protein is likely underlying the disease 15 . In this study, we set out to investigate how this neurotoxic function is generated from a molecular perspective. Because neuronal identity and maintenance are largely controlled by transcriptionally regulated programs 16 , we further investigated whether the nuclear localization and function of TyrRS plays any role in the disease mechanism of CMT. We show that CMT-causing mutations in TyrRS induce unique conformational changes, provoking aberrant interactions. These interactions in the nucleus lead to transcription factor E2F1 hyperactivation. Furthermore, a broad transcriptional regulation network associated with wild-type TyrRS expression in Drosophila is disturbed when a CMT-mutant is expressed. Excluding mutant TyrRS from the nucleus using pharmacological and genetic approaches suppresses the CMT hallmark phenotypes of CMT in the Drosophila model. These data highlight that TyrRS may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT. Results Conformational changes and altered functionalities of TyrRS In a previous work, we demonstrated that the three established CMT-causing TyrRS mutants (TyrRS-E196K, TyrRS-G41R, and TyrRS-Δ153-156VKQV) induce a conformational opening and expose a consensus area in the catalytic domain of the enzyme 17 (Fig. 1a, b ). In order to link this unique structural change to specific interactional and functional consequences related to CMT, we included two control mutants in this study. An alternative conformational change can be induced by a rationally designed mutation in the anticodon binding domain (Y341A) to expose a different area of the catalytic domain that is responsible for a “cytokine”-like activity of TyrRS 18 . Separately, an established benign polymorphism in the anticodon binding domain (K265N) was included, because it shows no toxicity of the protein in human or when overexpressed in Drosophila and we found that it does not trigger any conformational change 19 (Fig. 1a, b ). Fig. 1 TyrRS mutations induce structural changes leading to aberrant transcription regulation. a Domain structure of human TyrRS and the location of the different mutations. Red indicates CMT-causing mutations, blue indicates the cytokine-activating Y341A mutation, and orange indicates the benign substitution K265N. b Schematic illustration<|im_end|> <|im_start|>assistant An unexpected finding from the Scripps Research laboratory of Xiang-Lei Yang, Ph.D., has illuminated a potential strategy for treating the inherited neurological disease Charcot-Marie-Tooth (CMT), for which there is no approved medicine today. CMT is a progressive disease that typically develops early in life, affecting roughly 1 in 2,500 people. Over time, the disease inflicts damage on patients' peripheral nervous system—which extends from the spinal cord into the hands and feet—often resulting in difficulties with balance, walking and fine motor skills such as writing or buttoning a shirt. In a study that appears in Nature Communications, Yang and her team show that a drug may be able to prevent the disease-causing mechanisms from occurring within cells, quelling many key symptoms, including motor deficits. The approach centers on enzymes known as aminoacyl-tRNA synthetases (aaRSs), which are pervasive throughout the body. They are the largest protein family linked to CMT disease, and also the long-running research specialty of Yang's lab. These enzymes are essential to life because they kick off the first step of making new proteins, which are the building blocks of everything from blood and hormones to skin and bones. But in patients with CMT, some of the aaRS enzymes don't function as they should. As a result, peripheral neurons aren't made properly and become toxic to the peripheral nervous system. In her search for a potential treatment approach, Yang wanted to find out why the mutated enzymes only seem to affect peripheral neurons. She discovered that while aaRS enzymes typically function in a part of the cell known as the cytoplasm, one mutated form of the enzyme known as TyrRS—which is known to be linked to the disease—exists inside a cell's nucleus. "The nucleus is the site for gene expression or transcription to take place, which made this finding of special interest to us," Yang says. "Transcription regulates the identity of cells and cell-specific maintenance programs, and if something goes awry during this process, disease can result." Fueled by the excitement of her nucleus discovery, Yang collaborated with Albena Jordanova, Ph.D., at the University of Antwerp. Jordanova is the scientist who first linked the mutant TyrRS enzyme to CMT disease and established a fruit fly model that exhibits CMT, enabling disease-focused research efforts. Working together, the teams conducted experiments on fruit flies that showed "unequivocally" that the location of TyrRS in the nucleus was contributing to disease in a significant way. Then, by using a small-molecule drug called embelin to keep the enzyme from entering the nucleus, the team "achieved a complete rescue" of a fruit fly with CMT disease. Yang noted that the discovery is most immediately relevant for patients who have a form of the disease known to be caused by mutant TyrRS. However, the findings may translate to subtypes caused by other mutant aaRS enzymes. "This work paves the way for developing a viable therapy for CMT patients affected by TyrRS mutations," Yang says. "We're excited to advance this research by further validating the therapeutic approach and finding the best-possible pharmaceutical product to inhibit this enzyme from entering the nucleus. We also will investigate whether the nuclear relevance can be generalized to other CMT subtypes." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the past decade, observations of giant exoplanets (Jupiter-size) have provided key insights into their atmospheres 1 , 2 , but the properties of lower-mass exoplanets (sub-Neptune) remain largely unconstrained because of the challenges of observing small planets. Numerous efforts to observe the spectra of super-Earths—exoplanets with masses of one to ten times that of Earth—have so far revealed only featureless spectra 3 . Here we report a longitudinal thermal brightness map of the nearby transiting super-Earth 55 Cancri e (refs 4 , 5 ) revealing highly asymmetric dayside thermal emission and a strong day–night temperature contrast. Dedicated space-based monitoring of the planet in the infrared revealed a modulation of the thermal flux as 55 Cancri e revolves around its star in a tidally locked configuration. These observations reveal a hot spot that is located 41 ± 12 degrees east of the substellar point (the point at which incident light from the star is perpendicular to the surface of the planet). From the orbital phase curve, we also constrain the nightside brightness temperature of the planet to 1,380 ± 400 kelvin and the temperature of the warmest hemisphere (centred on the hot spot) to be about 1,300 kelvin hotter (2,700 ± 270 kelvin) at a wavelength of 4.5 micrometres, which indicates inefficient heat redistribution from the dayside to the nightside. Our observations are consistent with either an optically thick atmosphere with heat recirculation confined to the planetary dayside, or a planet devoid of atmosphere with low-viscosity magma flows at the surface 6 . Main We observed the super-Earth 55 Cancri e for 75 h in total from 15 June to 15 July 2013 in the 4.5-μm channel of the Spitzer Space Telescope Infrared Array Camera (IRAC). The observations were split into eight continuous visits, each spanning 9 h and corresponding to half of the 18-h orbital period of 55 Cancri e. We acquired a total of 4,981,760 frames in subarray mode with an individual 0.02-s integration time. We extract the photometric time series from the raw frames using a previously described 4 aperture photometry pipeline. Each of the eight resulting light curves exhibit periodic flux variations due to the strong intra-pixel sensitivity of the IRAC detector combined to Spitzer’s pointing wobble. The data reduction of this data set has been published elsewhere 7 , but a summary is provided in Methods. We analyse the light curves using a Markov chain Monte Carlo (MCMC) algorithm 8 . We simultaneously fit the eight half phase curves and a model of the detector systematics. Our MCMC algorithm includes an implementation of a pixel-level correction 9 and propagates the contribution from correlated noise in the data to the system best-fit parameters. In our implementation of the method, we build a sub-pixel mesh of n 2 grid points, evenly distributed along the x and y axes. Similar to a previous study 10 , we find that the full-width at half-maximum (FWHM) of the point response function (PRF) along the x and y axes of the detector evolves with time and allows further improvement to the systematics correction. We thus combine the pixel-mapping algorithm with a linear function of the FWHM of the PRF along each axis. We find that this model provides the best correction to the data. The free planetary parameters in the MCMC fit are the phase-curve amplitude and offset (the angle between the peak of the modulation and the substellar point), the occultation depth, the impact parameter, the orbital period, the transit centre and the transit depth. The functional form of the phase curve used in this fit is detailed in Methods. We combine the data points into 30-s bins for computing efficiency, which has previously been shown to have no effect on the derived parameters 7 , 11 . We find an average photometric precision of 363 p.p.m. per 30 s, and evaluate the level of correlated noise in the data for each data set using a time-averaging technique 12 . Results from the MCMC fits are shown in Table 1 . We perform two additional analyses of this data set (see Methods) using a different model for the pixel-level correction, which results in phase-curve parameters in agreement with our main analysis. Table 1 55 Cancri e planetary parameters Full size table The combined light curve ( Fig. 1 ) exhibits a flux increase that starts slightly before the transit and reaches a maximum at 2.1 ± 0.6 h before opposition. We find a phase-curve peak amplitude of 197 ± 34 p.p.m., a minimum of 48 ± 34 p.p.m. and an occultation depth of 154 ± 23 p.p.m. (mid-eclipse). Figure 1: 55 Cancri e Spitzer/IRAC 4.5-μm phase curve. Photometry for all eight data sets combined and folded onto the 0.74-day orbital period of 55 Cancri e. The black filled circles represent the relative flux ( F p / F ⋆ ) variation in phase and are data binned per 15 min. The best-fit model using a three-longitudinal-band model is shown in red; the best-fit model using a one-longitudinal-band model is shown in blue. The error bars are the standard deviation of the mean within each orbital-phase bin. PowerPoint slide Source data Full size image We find that stellar variability could not cause the observed phase variation. The host is known to be an old, quiet star with a rotation period of 42 days that shows, on rare occasions, variability at the 6-millimagnitude level, corresponding to <1% coverage in star spots 13 . The periodic modulation that we observe is equal to the planetary orbital period and has a shape that remains consistent over the 4 weeks of the Spitzer observations. At infrared wavelengths, the effect of starspots on the photometry is markedly reduced 14 , but it is still possible that 1% spot coverage could produce a signal of the order of 200 p.p.m. However, the periodicity of the signal produced by such a starspot would be similar to the stellar rotation. We also investigate the amplitude of the ellipsoidal", "role": "user" }, { "content": "An international team of astronomers, led by the University of Cambridge, has obtained the most detailed 'fingerprint' of a rocky planet outside our solar system to date, and found a planet of two halves: one that is almost completely molten, and the other which is almost completely solid. According to the researchers, conditions on the hot side of the planet are so extreme that it may have caused the atmosphere to evaporate, with the result that conditions on the two sides of the planet vary widely: temperatures on the hot side can reach 2500 degrees Celsius, while temperatures on the cool side are around 1100 degrees. The results are reported in the journal Nature. Using data from NASA's Spitzer Space Telescope, the researchers examined a planet known as 55 Cancri e, which orbits a sun-like star located 40 light years away in the Cancer constellation, and have mapped how conditions on the planet change throughout a complete orbit, the first time this has been accomplished for such a small planet. 55 Cancri e is a 'super Earth': a rocky exoplanet about twice the size and eight times the mass of Earth, and orbits its parent star so closely that a year lasts just 18 hours. The planet is also tidally locked, meaning that it always shows the same face to its parent star, similar to the Moon, so there is a permanent 'day' side and a 'night' side. Since it is among the nearest super Earths whose composition can be studied, 55 Cancri e is among the best candidates for detailed observations of surface and atmospheric conditions on rocky exoplanets. An illustration of 55 Cancri e. Credit: NASA/JPL-Caltech Uncovering the characteristics of super Earths is difficult, since they are so small compared to the parent star and their contrast relative to the star is extremely small compared to larger, hotter gas giant planets, the so-called 'hot Jupiters'. \"We haven't yet found any other planet that is this small and orbits so close to its parent star, and is relatively close to us, so 55 Cancri e offers lots of possibilities,\" said Dr Brice-Olivier Demory of the University's Cavendish Laboratory, the paper's lead author. \"We still don't know exactly what this planet is made of - it's still a riddle. These results are like adding another brick to the wall, but the exact nature of this planet is still not completely understood.\" 55 Cancri e has been extensively studied since it was discovered in 2011. Based on readings taken at different points in time, it was thought to be a water world, or even made of diamond, but researchers now believe that it is almost completely covered by lava. \"We have entered a new era of atmospheric remote sensing of rocky exoplanets,\" said study co-author Dr Nikku Madhusudhan, from the Institute of Astronomy at Cambridge. \"It is incredible that we are now able to measure the large scale temperature distribution on the surface of a rocky exoplanet.\" Based on these new infrared measurements, the 'day' side of the planet appears to be almost completely molten, while the 'night' side is almost completely solid. The heat from the day side is not efficiently circulated to the night side, however. On Earth, the atmosphere aids in the recirculation of heat, keeping the temperature across the whole planet within a relatively narrow range. But on 55 Cancri e, the hot side stays hot, and the cold side stays cold. According to Demory, one possibility for this variation could be either a complete lack of atmosphere, or one which has been partially destroyed due to the strong irradiation from the nearby host star. \"On the day side, the temperature is around 2500 degrees Celsius, while on the night side it's about 1100 degrees - that's a huge difference,\" he said. \"We think that there could still be an atmosphere on the night side, but temperatures on the day side are so extreme that the atmosphere may have evaporated completely, meaning that heat is not being efficiently transferred, or transferred at all from the day side to the night side.\" Another possibility for the huge discrepancy between the day side and the night side may be that the molten lava on the day side moves heat along the surface, but since lava is mostly solid on the night side, heat is not moved around as efficiently. What is unclear however, is where exactly the 'extra' heat on 55 Cancri e comes from in the first place, since the observations reveal an unknown source of heat that makes the planet hotter than expected solely from the irradiation from the star - but the researchers may have to wait until the next generation of space telescopes are launched to find out. For Demory, these new readings also show just how difficult it will be to detect a planet that is similar to Earth. The smaller a planet is, the more difficult it is to detect. And once a rocky planet has been found, there is the question of whether it lies in the so-called habitable zone, where life can be supported. \"The problem is, people don't agree on what the habitable zone is,\" said Demory. \"For example, some studies consider Mars and Venus to be in the habitable zone, but life as we know it is not possible on either of those planets. Understanding the surface and climate properties of these other worlds will eventually allow us to put the Earth's climate and habitability into context.\" One possibility might be to look at stars which are much cooler and smaller than our sun, such as the M-dwarfs, which would mean that planets could be much closer to their star and still be in the habitable zone. The sizes of such planets relative to their star would be larger, which make them more detectable from Earth. But for the time being, Demory and his colleagues plan to keep studying 55 Cancri e, in order to see what other secrets it might hold, including the possibility that it might be surrounded by a torus of gas and dust, which could account for some of the variations in the data. And in 2018, the successor to Hubble and Spitzer, the James Webb Space Telescope, will launch, allowing astronomers to look at planets outside our solar system with entirely new levels of precision. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Over the past decade, observations of giant exoplanets (Jupiter-size) have provided key insights into their atmospheres 1 , 2 , but the properties of lower-mass exoplanets (sub-Neptune) remain largely unconstrained because of the challenges of observing small planets. Numerous efforts to observe the spectra of super-Earths—exoplanets with masses of one to ten times that of Earth—have so far revealed only featureless spectra 3 . Here we report a longitudinal thermal brightness map of the nearby transiting super-Earth 55 Cancri e (refs 4 , 5 ) revealing highly asymmetric dayside thermal emission and a strong day–night temperature contrast. Dedicated space-based monitoring of the planet in the infrared revealed a modulation of the thermal flux as 55 Cancri e revolves around its star in a tidally locked configuration. These observations reveal a hot spot that is located 41 ± 12 degrees east of the substellar point (the point at which incident light from the star is perpendicular to the surface of the planet). From the orbital phase curve, we also constrain the nightside brightness temperature of the planet to 1,380 ± 400 kelvin and the temperature of the warmest hemisphere (centred on the hot spot) to be about 1,300 kelvin hotter (2,700 ± 270 kelvin) at a wavelength of 4.5 micrometres, which indicates inefficient heat redistribution from the dayside to the nightside. Our observations are consistent with either an optically thick atmosphere with heat recirculation confined to the planetary dayside, or a planet devoid of atmosphere with low-viscosity magma flows at the surface 6 . Main We observed the super-Earth 55 Cancri e for 75 h in total from 15 June to 15 July 2013 in the 4.5-μm channel of the Spitzer Space Telescope Infrared Array Camera (IRAC). The observations were split into eight continuous visits, each spanning 9 h and corresponding to half of the 18-h orbital period of 55 Cancri e. We acquired a total of 4,981,760 frames in subarray mode with an individual 0.02-s integration time. We extract the photometric time series from the raw frames using a previously described 4 aperture photometry pipeline. Each of the eight resulting light curves exhibit periodic flux variations due to the strong intra-pixel sensitivity of the IRAC detector combined to Spitzer’s pointing wobble. The data reduction of this data set has been published elsewhere 7 , but a summary is provided in Methods. We analyse the light curves using a Markov chain Monte Carlo (MCMC) algorithm 8 . We simultaneously fit the eight half phase curves and a model of the detector systematics. Our MCMC algorithm includes an implementation of a pixel-level correction 9 and propagates the contribution from correlated noise in the data to the system best-fit parameters. In our implementation of the method, we build a sub-pixel mesh of n 2 grid points, evenly distributed along the x and y axes. Similar to a previous study 10 , we find that the full-width at half-maximum (FWHM) of the point response function (PRF) along the x and y axes of the detector evolves with time and allows further improvement to the systematics correction. We thus combine the pixel-mapping algorithm with a linear function of the FWHM of the PRF along each axis. We find that this model provides the best correction to the data. The free planetary parameters in the MCMC fit are the phase-curve amplitude and offset (the angle between the peak of the modulation and the substellar point), the occultation depth, the impact parameter, the orbital period, the transit centre and the transit depth. The functional form of the phase curve used in this fit is detailed in Methods. We combine the data points into 30-s bins for computing efficiency, which has previously been shown to have no effect on the derived parameters 7 , 11 . We find an average photometric precision of 363 p.p.m. per 30 s, and evaluate the level of correlated noise in the data for each data set using a time-averaging technique 12 . Results from the MCMC fits are shown in Table 1 . We perform two additional analyses of this data set (see Methods) using a different model for the pixel-level correction, which results in phase-curve parameters in agreement with our main analysis. Table 1 55 Cancri e planetary parameters Full size table The combined light curve ( Fig. 1 ) exhibits a flux increase that starts slightly before the transit and reaches a maximum at 2.1 ± 0.6 h before opposition. We find a phase-curve peak amplitude of 197 ± 34 p.p.m., a minimum of 48 ± 34 p.p.m. and an occultation depth of 154 ± 23 p.p.m. (mid-eclipse). Figure 1: 55 Cancri e Spitzer/IRAC 4.5-μm phase curve. Photometry for all eight data sets combined and folded onto the 0.74-day orbital period of 55 Cancri e. The black filled circles represent the relative flux ( F p / F ⋆ ) variation in phase and are data binned per 15 min. The best-fit model using a three-longitudinal-band model is shown in red; the best-fit model using a one-longitudinal-band model is shown in blue. The error bars are the standard deviation of the mean within each orbital-phase bin. PowerPoint slide Source data Full size image We find that stellar variability could not cause the observed phase variation. The host is known to be an old, quiet star with a rotation period of 42 days that shows, on rare occasions, variability at the 6-millimagnitude level, corresponding to <1% coverage in star spots 13 . The periodic modulation that we observe is equal to the planetary orbital period and has a shape that remains consistent over the 4 weeks of the Spitzer observations. At infrared wavelengths, the effect of starspots on the photometry is markedly reduced 14 , but it is still possible that 1% spot coverage could produce a signal of the order of 200 p.p.m. However, the periodicity of the signal produced by such a starspot would be similar to the stellar rotation. We also investigate the amplitude of the ellipsoidal<|im_end|> <|im_start|>assistant An international team of astronomers, led by the University of Cambridge, has obtained the most detailed 'fingerprint' of a rocky planet outside our solar system to date, and found a planet of two halves: one that is almost completely molten, and the other which is almost completely solid. According to the researchers, conditions on the hot side of the planet are so extreme that it may have caused the atmosphere to evaporate, with the result that conditions on the two sides of the planet vary widely: temperatures on the hot side can reach 2500 degrees Celsius, while temperatures on the cool side are around 1100 degrees. The results are reported in the journal Nature. Using data from NASA's Spitzer Space Telescope, the researchers examined a planet known as 55 Cancri e, which orbits a sun-like star located 40 light years away in the Cancer constellation, and have mapped how conditions on the planet change throughout a complete orbit, the first time this has been accomplished for such a small planet. 55 Cancri e is a 'super Earth': a rocky exoplanet about twice the size and eight times the mass of Earth, and orbits its parent star so closely that a year lasts just 18 hours. The planet is also tidally locked, meaning that it always shows the same face to its parent star, similar to the Moon, so there is a permanent 'day' side and a 'night' side. Since it is among the nearest super Earths whose composition can be studied, 55 Cancri e is among the best candidates for detailed observations of surface and atmospheric conditions on rocky exoplanets. An illustration of 55 Cancri e. Credit: NASA/JPL-Caltech Uncovering the characteristics of super Earths is difficult, since they are so small compared to the parent star and their contrast relative to the star is extremely small compared to larger, hotter gas giant planets, the so-called 'hot Jupiters'. "We haven't yet found any other planet that is this small and orbits so close to its parent star, and is relatively close to us, so 55 Cancri e offers lots of possibilities," said Dr Brice-Olivier Demory of the University's Cavendish Laboratory, the paper's lead author. "We still don't know exactly what this planet is made of - it's still a riddle. These results are like adding another brick to the wall, but the exact nature of this planet is still not completely understood." 55 Cancri e has been extensively studied since it was discovered in 2011. Based on readings taken at different points in time, it was thought to be a water world, or even made of diamond, but researchers now believe that it is almost completely covered by lava. "We have entered a new era of atmospheric remote sensing of rocky exoplanets," said study co-author Dr Nikku Madhusudhan, from the Institute of Astronomy at Cambridge. "It is incredible that we are now able to measure the large scale temperature distribution on the surface of a rocky exoplanet." Based on these new infrared measurements, the 'day' side of the planet appears to be almost completely molten, while the 'night' side is almost completely solid. The heat from the day side is not efficiently circulated to the night side, however. On Earth, the atmosphere aids in the recirculation of heat, keeping the temperature across the whole planet within a relatively narrow range. But on 55 Cancri e, the hot side stays hot, and the cold side stays cold. According to Demory, one possibility for this variation could be either a complete lack of atmosphere, or one which has been partially destroyed due to the strong irradiation from the nearby host star. "On the day side, the temperature is around 2500 degrees Celsius, while on the night side it's about 1100 degrees - that's a huge difference," he said. "We think that there could still be an atmosphere on the night side, but temperatures on the day side are so extreme that the atmosphere may have evaporated completely, meaning that heat is not being efficiently transferred, or transferred at all from the day side to the night side." Another possibility for the huge discrepancy between the day side and the night side may be that the molten lava on the day side moves heat along the surface, but since lava is mostly solid on the night side, heat is not moved around as efficiently. What is unclear however, is where exactly the 'extra' heat on 55 Cancri e comes from in the first place, since the observations reveal an unknown source of heat that makes the planet hotter than expected solely from the irradiation from the star - but the researchers may have to wait until the next generation of space telescopes are launched to find out. For Demory, these new readings also show just how difficult it will be to detect a planet that is similar to Earth. The smaller a planet is, the more difficult it is to detect. And once a rocky planet has been found, there is the question of whether it lies in the so-called habitable zone, where life can be supported. "The problem is, people don't agree on what the habitable zone is," said Demory. "For example, some studies consider Mars and Venus to be in the habitable zone, but life as we know it is not possible on either of those planets. Understanding the surface and climate properties of these other worlds will eventually allow us to put the Earth's climate and habitability into context." One possibility might be to look at stars which are much cooler and smaller than our sun, such as the M-dwarfs, which would mean that planets could be much closer to their star and still be in the habitable zone. The sizes of such planets relative to their star would be larger, which make them more detectable from Earth. But for the time being, Demory and his colleagues plan to keep studying 55 Cancri e, in order to see what other secrets it might hold, including the possibility that it might be surrounded by a torus of gas and dust, which could account for some of the variations in the data. And in 2018, the successor to Hubble and Spitzer, the James Webb Space Telescope, will launch, allowing astronomers to look at planets outside our solar system with entirely new levels of precision. <|im_end|>

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2,668

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here, we identify 6703 and 1536 protein–protein interactions for 109 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. The BioID analysis identifies more high-confidence interactions, highlighting the transient and dynamic nature of many of the TF interactions. By performing clustering and correlation analyses, we identify subgroups of TFs associated with specific biological functions, such as RNA splicing or chromatin remodeling. We also observe 202 TF-TF interactions, of which 118 are interactions with nuclear factor 1 (NFI) family members, indicating uncharacterized cross-talk between NFI signaling and other TF signaling pathways. Moreover, TF interactions with basal transcription machinery are mainly observed through TFIID and SAGA complexes. This study provides a rich resource of human TF interactions and also act as a starting point for future studies aimed at understanding TF-mediated transcription. Introduction ‘The central dogma’ states that genetic sequence information from DNA is transcribed to RNA and subsequently translated into proteins. These processes are tightly regulated and employ a plethora of proteins. Transcription, the first step, is regulated by transcription factors (TFs), which represent one of the largest families of human genes. In humans, 6–9% (~1400–1900) of proteins are predicted to regulate gene expression through DNA binding (refs. 1 , 2 , 3 , ), and the most recent manual curation identified 1639 likely human TFs 4 . Complex and multilayer regulation of transcription involves not only direct binding of TFs to a target gene’s regulatory element(s) but also a complicated interplay between TFs and TF binding proteins. These include several cofactors, the Mediator complex, basal transcription machinery, TF activity modulating enzymes (such as phosphatases and kinases), dimerization partners, subunits and inhibitory proteins 5 , 6 , 7 , 8 . Moreover, as chromosomal DNA is packed into chromatin to prevent uncontrolled transcription, TFs also interact with several chromatin remodeling proteins. The formed complexes are necessary to regulate the accessibility of DNA to allow chromatin opening and thereby gene transcription. TFs play crucial roles in regulating numerous cellular mechanisms and are key regulators of tissue growth and embryonic development – processes that may cause cancer and other disorders when aberrantly controlled. Therefore, understanding the TF network at the systems level would build an important foundation for future studies as well as for therapeutic approaches 7 . While the binding of TFs to DNA is relatively well studied, for the most part, we still lack a global understanding of TF protein–protein interactions (PPIs) and their roles in the regulation of transcription. Therefore, we sought to fill this knowledge gap by using recently developed state-of-the-art PPI identification methods, which allow unprecedented sensitivity and depth of analysis. In this study, we systemically characterized the PPIs of a selected set of 109 human TFs using affinity purification mass spectrometry (AP-MS) and proximity-dependent biotinylation (BioID) mass spectrometry. We identified 6703 PPIs in the BioID analysis and 1536 PPIs in the AP-MS analysis. Most of the detected interactions were contextually nuclear and linked to transcription and transcriptional regulation. These interactions paint a picture of how transcription factors are activated or repressed and add experimental evidence for the potential relevance of transient interactions in the advent of transcription-related nuclear condensates and phase separation. This large interactome network of TFs allowed us to recognize several interactome subgroups of TFs, such as TFs linked to mRNA splicing and TFs linked to chromatin remodeling. In addition, we observed that most of the studied TFs interacted with nuclear factor 1 (NFI) TFs, which are essential for several developmental and oncogenic processes. Overall, this work represents a rich resource to direct future studies aimed at understanding TF-mediated transcription and how TF-formed interactions regulate important cellular phenomena in both health and disease. Results Identification of TF protein–protein interactions To systematically investigate the protein–protein interactions of human TFs, we selected a representative set of 109 TF genes from different TF families (Supplementary Data 1a ). Selection was based on the availability of full-length TF constructs. Selected TFs were analyzed in two biological replicates and, as the correlation between the technical and biological replicates were excellent (Supplementary Fig. 1a ), either in one or two technical replicates. TFs are often classified according to their DNA-binding domains (DBDs), and the DBD distribution of studied TFs compared to all human TFs is shown in Fig. 1a . The majority of the studied TFs had C2H2 zing finger (ZF) or homeodomain DBDs, which are the most common DBDs among the human TFs 4 . Fig. 1: TF protein interactome identified using the BioID and AP-MS methods. a The distribution of the DNA-binding domains of the studied TFs. The corresponding proportion of each DNA-binding domain from 1639 TFs in the study of Lambert et al. is shown as a percentage value below the graph. b Schematic illustration of the analysis methods used to comprehensively map the physical and functional interactions formed by the TFs. The TFs were tagged N-terminally with MAC, StrepIII-HA or BirA -tags (Supplementary Data 1a ) and cotransfected with Flp-In recombinase to generate stable isogenic and inducible cell lines. Cells were induced by tetracycline addition for the corresponding TF expression and for the BioID analysis supplemented with biotin for 24 h. This was followed by cell harvesting, lysis, and affinity purification with Strep-beads. Purified proteins were further digested into peptides and analyzed by LC–MS/MS. Proteins were later identified, quantified, and analyzed to distill the high-confidence interactors using different statistical and bioinformatic methods. c A total of 6503 high-confidence protein–protein interactions were detected only with the BioID method, 1336 with the AP-MS method, and 200 with both the BioID and AP-MS methods. d Localization of interacting prey-proteins from BioID data according to the annotated localizations of Cell Atlas 12 . Yellow nodes (large circle) indicate nuclear localization, and red (small circle) indicates nonnuclear localization. Of the mapped proteins, >80% had nuclear localization. e Protein–protein interactions were identified using the AP-MS (1536) and BioID (6703) methods. Interactions were compared", "role": "user" }, { "content": "A research team from University of Helsinki introduces a new large-scale study on human transcription factors combining two state-of-the art interactomics methods that allow rapid identification of protein-protein interactions and extensive functional information of this important gene family. Transcription factors (TFs) are the most essential protein group for the cellular development, differentiation and maintaining homeostasis. They drive complex patterns of gene expression in cells in all stages of development. Defects in TF signaling often lead to developmental disorders and diseases. However, while TF DNA binding has been widely studied, we are still lacking a systems-level understanding on how TF activity and signaling is controlled via their interactions with multiple proteins, such as cofactors, dimerization partners, chromatin modulating proteins, enzymes, inhibitory proteins and general transcription factors. A research team at the University of Helsinki decided to initiate a large study to shed light on TF protein-protein interactions and TF regulation. The new study is published in Nature Communications. \"We introduced a comprehensive interactome analysis of more than 100 TFs, revealing over 7,000 TF protein-protein interactions, most of which are in nuclear and play important roles in transcriptional regulation,\" says Research Director Markku Varjosalo from the Institute of Biotechnology, HiLIFE. Findings pave the way for further studies on the TF regulation The large number of TF interactions discovered in this study enabled researchers to conduct a systems-level analysis that revealed groups of TFs with specific biological functions, such as chromatin remodeling and RNA splicing. \"Interestingly, almost half of the studied TFs interacted with the nuclear factor family of TFs. Nuclear factors are known to control a plethora of genes and organogenesis during development and their aberrant activity is linked to several human cancer types. Our data suggest that transcription control by NFIs may be regulated by nuclear factor interactions with other TFs,\" says Dr. Helka Göös, the lead author of the study. The study provides the first comprehensive and complimentary overview on the physical and functional interactions of the human transcription factors. The new findings pave the way for further studies on the TF regulation. \"Our lab has been for that last 10 years heavily involved in identifying and studying the disease mechanisms of individual transcription factor mutations in cancer and in immunodeficiencies. TFs have proven to be difficult drug targets, however several of their key regulators are much more promising. Our generated large information atlas on the TFs could act as a rich resource for also drug discovery studies to identify pharmaceutical treatment for TF-related diseases,\" says Dr. Varjosalo. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here, we identify 6703 and 1536 protein–protein interactions for 109 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. The BioID analysis identifies more high-confidence interactions, highlighting the transient and dynamic nature of many of the TF interactions. By performing clustering and correlation analyses, we identify subgroups of TFs associated with specific biological functions, such as RNA splicing or chromatin remodeling. We also observe 202 TF-TF interactions, of which 118 are interactions with nuclear factor 1 (NFI) family members, indicating uncharacterized cross-talk between NFI signaling and other TF signaling pathways. Moreover, TF interactions with basal transcription machinery are mainly observed through TFIID and SAGA complexes. This study provides a rich resource of human TF interactions and also act as a starting point for future studies aimed at understanding TF-mediated transcription. Introduction ‘The central dogma’ states that genetic sequence information from DNA is transcribed to RNA and subsequently translated into proteins. These processes are tightly regulated and employ a plethora of proteins. Transcription, the first step, is regulated by transcription factors (TFs), which represent one of the largest families of human genes. In humans, 6–9% (~1400–1900) of proteins are predicted to regulate gene expression through DNA binding (refs. 1 , 2 , 3 , ), and the most recent manual curation identified 1639 likely human TFs 4 . Complex and multilayer regulation of transcription involves not only direct binding of TFs to a target gene’s regulatory element(s) but also a complicated interplay between TFs and TF binding proteins. These include several cofactors, the Mediator complex, basal transcription machinery, TF activity modulating enzymes (such as phosphatases and kinases), dimerization partners, subunits and inhibitory proteins 5 , 6 , 7 , 8 . Moreover, as chromosomal DNA is packed into chromatin to prevent uncontrolled transcription, TFs also interact with several chromatin remodeling proteins. The formed complexes are necessary to regulate the accessibility of DNA to allow chromatin opening and thereby gene transcription. TFs play crucial roles in regulating numerous cellular mechanisms and are key regulators of tissue growth and embryonic development – processes that may cause cancer and other disorders when aberrantly controlled. Therefore, understanding the TF network at the systems level would build an important foundation for future studies as well as for therapeutic approaches 7 . While the binding of TFs to DNA is relatively well studied, for the most part, we still lack a global understanding of TF protein–protein interactions (PPIs) and their roles in the regulation of transcription. Therefore, we sought to fill this knowledge gap by using recently developed state-of-the-art PPI identification methods, which allow unprecedented sensitivity and depth of analysis. In this study, we systemically characterized the PPIs of a selected set of 109 human TFs using affinity purification mass spectrometry (AP-MS) and proximity-dependent biotinylation (BioID) mass spectrometry. We identified 6703 PPIs in the BioID analysis and 1536 PPIs in the AP-MS analysis. Most of the detected interactions were contextually nuclear and linked to transcription and transcriptional regulation. These interactions paint a picture of how transcription factors are activated or repressed and add experimental evidence for the potential relevance of transient interactions in the advent of transcription-related nuclear condensates and phase separation. This large interactome network of TFs allowed us to recognize several interactome subgroups of TFs, such as TFs linked to mRNA splicing and TFs linked to chromatin remodeling. In addition, we observed that most of the studied TFs interacted with nuclear factor 1 (NFI) TFs, which are essential for several developmental and oncogenic processes. Overall, this work represents a rich resource to direct future studies aimed at understanding TF-mediated transcription and how TF-formed interactions regulate important cellular phenomena in both health and disease. Results Identification of TF protein–protein interactions To systematically investigate the protein–protein interactions of human TFs, we selected a representative set of 109 TF genes from different TF families (Supplementary Data 1a ). Selection was based on the availability of full-length TF constructs. Selected TFs were analyzed in two biological replicates and, as the correlation between the technical and biological replicates were excellent (Supplementary Fig. 1a ), either in one or two technical replicates. TFs are often classified according to their DNA-binding domains (DBDs), and the DBD distribution of studied TFs compared to all human TFs is shown in Fig. 1a . The majority of the studied TFs had C2H2 zing finger (ZF) or homeodomain DBDs, which are the most common DBDs among the human TFs 4 . Fig. 1: TF protein interactome identified using the BioID and AP-MS methods. a The distribution of the DNA-binding domains of the studied TFs. The corresponding proportion of each DNA-binding domain from 1639 TFs in the study of Lambert et al. is shown as a percentage value below the graph. b Schematic illustration of the analysis methods used to comprehensively map the physical and functional interactions formed by the TFs. The TFs were tagged N-terminally with MAC, StrepIII-HA or BirA -tags (Supplementary Data 1a ) and cotransfected with Flp-In recombinase to generate stable isogenic and inducible cell lines. Cells were induced by tetracycline addition for the corresponding TF expression and for the BioID analysis supplemented with biotin for 24 h. This was followed by cell harvesting, lysis, and affinity purification with Strep-beads. Purified proteins were further digested into peptides and analyzed by LC–MS/MS. Proteins were later identified, quantified, and analyzed to distill the high-confidence interactors using different statistical and bioinformatic methods. c A total of 6503 high-confidence protein–protein interactions were detected only with the BioID method, 1336 with the AP-MS method, and 200 with both the BioID and AP-MS methods. d Localization of interacting prey-proteins from BioID data according to the annotated localizations of Cell Atlas 12 . Yellow nodes (large circle) indicate nuclear localization, and red (small circle) indicates nonnuclear localization. Of the mapped proteins, >80% had nuclear localization. e Protein–protein interactions were identified using the AP-MS (1536) and BioID (6703) methods. Interactions were compared<|im_end|> <|im_start|>assistant A research team from University of Helsinki introduces a new large-scale study on human transcription factors combining two state-of-the art interactomics methods that allow rapid identification of protein-protein interactions and extensive functional information of this important gene family. Transcription factors (TFs) are the most essential protein group for the cellular development, differentiation and maintaining homeostasis. They drive complex patterns of gene expression in cells in all stages of development. Defects in TF signaling often lead to developmental disorders and diseases. However, while TF DNA binding has been widely studied, we are still lacking a systems-level understanding on how TF activity and signaling is controlled via their interactions with multiple proteins, such as cofactors, dimerization partners, chromatin modulating proteins, enzymes, inhibitory proteins and general transcription factors. A research team at the University of Helsinki decided to initiate a large study to shed light on TF protein-protein interactions and TF regulation. The new study is published in Nature Communications. "We introduced a comprehensive interactome analysis of more than 100 TFs, revealing over 7,000 TF protein-protein interactions, most of which are in nuclear and play important roles in transcriptional regulation," says Research Director Markku Varjosalo from the Institute of Biotechnology, HiLIFE. Findings pave the way for further studies on the TF regulation The large number of TF interactions discovered in this study enabled researchers to conduct a systems-level analysis that revealed groups of TFs with specific biological functions, such as chromatin remodeling and RNA splicing. "Interestingly, almost half of the studied TFs interacted with the nuclear factor family of TFs. Nuclear factors are known to control a plethora of genes and organogenesis during development and their aberrant activity is linked to several human cancer types. Our data suggest that transcription control by NFIs may be regulated by nuclear factor interactions with other TFs," says Dr. Helka Göös, the lead author of the study. The study provides the first comprehensive and complimentary overview on the physical and functional interactions of the human transcription factors. The new findings pave the way for further studies on the TF regulation. "Our lab has been for that last 10 years heavily involved in identifying and studying the disease mechanisms of individual transcription factor mutations in cancer and in immunodeficiencies. TFs have proven to be difficult drug targets, however several of their key regulators are much more promising. Our generated large information atlas on the TFs could act as a rich resource for also drug discovery studies to identify pharmaceutical treatment for TF-related diseases," says Dr. Varjosalo. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the aftermath of Michael Brown’s death in Ferguson, Missouri, confidence in police has weakened. Body-worn cameras (BWCs) are perceived to increase law enforcement transparency and accountability, and, by proxy, restore law enforcement legitimacy. Though the empirical status of BWCs has grown in recent years, missing from these accounts are the actual words and narratives of officers. Through a qualitative approach, the data and analysis within this paper overcome this issue and indicate that BWCs have had an impact on police–citizen interactions in one Southern American State. More specifically, citizen and officer accountability from BWCs was found to have positive and negative consequence. Officers articulated this supposition in a number of ways and the paper contextualizes these perspectives within the extant literature. The policy implications and areas of future research from these findings are discussed as they inform a non-positivist approach to research. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction There is a movement to implement body-worn cameras (BWCs) in law enforcement agencies across the USA (Moriarty 2017 ). The impact of this trend on crime, policing strategies, and practices has been the subject of a growing body of research (see, e.g., Gaub et al. 2017 ; Yokum et al. 2017 ). The demand for BWCs was shaped by news and social media coverage of unarmed, young, black males dying at the hands of law enforcement (Doleac 2017 ; Hedberg et al. 2017 ; Smykla et al. 2016 ). Nowhere was this more evident than the death of Michael Brown in Ferguson (Missouri). The officer involved in this shooting did not have a BWC and his account of the incident conflicted with bystanders who reported that Mr. Brown had his hands up, was facing away from the officer, and was cooperating with his commands when shots were fired. Footnote 1 In the aftermath of the shooting, the Ferguson community mobilized to publicly display their outrage when the officer implicated in the incident was not indicted or charged with a crime. Protests in Ferguson were followed by similar tragic events throughout the Nation, including the police-involved deaths of John Crawford II in Beavercreek (Ohio), Tamir Rice in Cleveland (Ohio), Laquan McDonald in Chicago (Illinois), Walter Scott in North Charleston (South Carolina), Freddie Gray in Baltimore (Maryland), and Philandro Castile in St. Anthony’s (Minnesota). With each controversial police use-of-force incident, public sentiments and the national discourse on officer decision-making shifted. In fact, unfavorable attitudes toward police have grown and prompted many citizens to question the institutional order of law enforcement within the context of procedural justice (McLaughlin 2015 ). Accordingly and as Tyler ( 2006 ) proposed, law enforcement legitimacy has suffered and provoked events like Ferguson to be viewed through a different lens. Much like the Rodney King beating by Los Angeles (California) Police Department officers, these occurrences were no longer seen as an anomaly but part of a broader pattern of events that awakened the Nation’s consciousness. The post-Ferguson era, as it has been discussed in the empirical literature, constitutes the continued crisis of confidence in law enforcement and a search for innovative policing approaches that foster greater community trust (Hedberg et al. 2017 ; La Vigne et al. 2017 ). The efficacy of BWCs, particularly in the post-Ferguson era, has been queried as a potential solution to growing community discord and as an opportunity to prevent similar use-of-force instances (Maskaly et al. 2017 ). The purpose of this paper is to contribute to the empirical status of BWCs. Though previously explored in other scholarship (Gaub et al. 2017 ; Jennings et al. 2014 ; Pelrey and Keener 2016 ; Smykla et al. 2016 ), this examination differs by giving direct voice to officers on this issue. As part of a larger empirical endeavor on law enforcement-articulated strategies and views on policing gang violence, this subset of analyses presents officer insights on BWCs in a Southern American State. Personal experiences with and perspectives of BWCs are illuminated through officer interviews and an ethnographic approach to research that was conducted against the backdrop of the post-Ferguson era. Accordingly, BWCs were uniquely at the forefront of officer thoughts and behaviors, which is highlighted in the forthcoming material. Prior to presenting the data, however, this study is firstly situated within our existing knowledge of BWCs. Background Following Mr. Brown’s death, President Barack Obama constituted a Taskforce on twenty-first Century Policing (PTF 2015 ) that sought to identify police practices that prompt crime reduction, while simultaneously building public trust. Among the recommendations from the PTF ( 2015 ) was a commitment to purchase 50,000 BWCs for police officers across the Nation. This signaled a major vote of confidence from the Federal Government for the potential of BWC technology (Crow et al. 2017 ). Since then, approximately 4000–6000 BWCs have been adopted by the nearly 18,000 law enforcement agencies in the USA (Hedberg et al. 2017 ). This estimate is expected to rise considerably in the years to come as more and more law enforcement agencies are opting to add BWCs to their policing strategies. Initial Law Enforcement Opposition to BWCs Despite the growing interest in BWCs, putting them into practice has been accompanied by law enforcement hesitation. In fact, even where BWCs are available, they may not be used as intended. Hedberg et al. ( 2017 ), for example, in their non-equivalent matched treatment design of 56 BWC deployments, reported that BWC activation was “relatively limited” and officers were most likely to initiate filming for violent, property, and traffic offenses (see also Katz et al. 2014 ). Focus groups with specialized units in Tempe (Arizona) and Spokane (Washington), according to Gaub et al. ( 2017 ), found that some aspects of the law enforcement profession inhibit BWC use, such as covert operations. Accordingly, continuous filming policies, where BWCs are available, tend to be inconsistent with law enforcement “occupational culture,” according to Hedberg et al. ( 2017 , p. 644). On", "role": "user" }, { "content": "The fatal shooting of Michael Brown by a police officer in Ferguson, Missouri, generated political and media backlash that continues to erode law enforcement legitimacy today. As a result, the Taskforce on Twenty-first Century Policing was mandated to reduce crime and build trust between law enforcement and the communities they serve. A key recommendation from the taskforce was to equip police departments with body-worn cameras and commit to purchasing 50,000 cameras for police officers nationwide. To date, between 4,000 and 6,000 body-worn cameras have been adopted by the nearly 18,000 law enforcement agencies in the U.S., and these numbers are expected to rise considerably in the coming years. Body-worn cameras are believed to increase law enforcement transparency and accountability, and by proxy restore law enforcement legitimacy. But are they really a game-changer in contemporary policing? There are many claims about the perceived benefits and drawbacks of body-worn cameras, which stem from the media and public opinion. There also is extensive discussion about the potential existence of a so-called \"Ferguson Effect,\" which is long on anecdotes but short on data. Furthermore, research is sparse on the experiences and attitudes of law enforcement officers in response to the growing demand for this technology. To address this knowledge gap, a study by researchers at Florida Atlantic University and the University of the West of Scotland, is the first to use ethnographic or qualitative research to provide deeper insight into law enforcement officers' personal experiences with and perspectives on body-worn cameras. The study, published in the Journal of Police and Criminal Psychology, illustrates police officers' perspectives on one of the most overt strategic changes to modern American policing. Results of the study reveal that overwhelmingly, body-worn cameras have prompted a new consciousness in law enforcement, and according to one police officer, \"have compelled changes in officer behaviors.\" While the researchers found an increased conceptual awareness of procedural justice, they also found a reduction in police morale and an emphasis on proactive policing strategies. They note that Ferguson often is drawn upon as a reference point among police officers. \"It is clear that police officers are grappling to understand and come to terms with their diminished role, and declining levels of public respect and cooperation,\" said Seth Wyatt Fallik, Ph.D., lead author and an assistant professor in FAU's School of Criminology and Criminal Justice within the College for Design and Social Inquiry. \"Solutions for healing the rift between police and citizens should not solely be the responsibility of police.\" The study is based on a long and deep immersion in the field in two counties in a Southern U.S. state as a means of generating insider knowledge. Both counties fully deployed body-worn cameras in early 2016. Field observations included ride-alongs, covert surveillance work, pre-deployment briefings, and rest breaks with officers and sheriff's deputies of various ranks and responsibilities. In addition to adopting the \"participant as observer\" role, field experiences were probed with in-depth semi-structured interviews. Questions focused on the impact of officer confidence, morale, and policing strategies in the post-Ferguson era. \"Being accepted by the study participants prompted our formal and informal dialogs and allowed the police officers to share their body-worn camera insights without repercussion,\" said Ross Deuchar, Ph.D., co-author and an affiliate professor in FAU's School of Criminology and Criminal Justice, and a professor and assistant dean at the University of the West of Scotland, who conducted the four-month field work as a visiting Fulbright Scholar at FAU. \"Officers were under no obligation to participate in the study and could—without penalty—withdraw their consent to be included in these analyses at any time.\" Deuchar observed citizen behavior through car windows, engaged in informal dialog with local people on the streets, visited people's homes to respond to local reported crime issues, and even wore a police ballistic vest. During this time, he also routinely observed officer behavior and listened to officer dialog with other officers and with citizens. In general, the study shows that police officers' perceptions of body-worn cameras were positive. Officers believe that the cameras protect them like an \"extra set of eyes\" and provide a better idea of what really happens during their public encounters, offering a more complete narrative of what actually transpired when the facts of an incident are contested. Among their concerns are that the body-worn cameras restrain their work and will not overcome public attitudes toward police and public bias against police officers. Most of the officers felt that focusing on a few rogue cops and playing negative images across multiple news cycles do little to improve public perception of the police. Other results of the study show that body-worn cameras also prompted changes in citizens' behaviors and resulted in reduced numbers of complaints levied against the police because they knew that the officers were wearing cameras. Regarding the use of force, the researchers note that Taser use also declined with the adoption of body-worn cameras. Collectively, police officers believe that body-worn cameras have the ability to foster a culture of accountability for law enforcement as well as citizens. \"One of the interesting aspects from our study is that during the interviews many of the officers went out of their way to report that most law enforcement officers are good or are doing the right thing,\" said Vaughn J. Crichlow, Ph.D., co-author and an assistant professor in FAU's School of Criminology and Criminal Justice. \"One detective even told us that he believed that 'no good cop should fear a camera.'\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the aftermath of Michael Brown’s death in Ferguson, Missouri, confidence in police has weakened. Body-worn cameras (BWCs) are perceived to increase law enforcement transparency and accountability, and, by proxy, restore law enforcement legitimacy. Though the empirical status of BWCs has grown in recent years, missing from these accounts are the actual words and narratives of officers. Through a qualitative approach, the data and analysis within this paper overcome this issue and indicate that BWCs have had an impact on police–citizen interactions in one Southern American State. More specifically, citizen and officer accountability from BWCs was found to have positive and negative consequence. Officers articulated this supposition in a number of ways and the paper contextualizes these perspectives within the extant literature. The policy implications and areas of future research from these findings are discussed as they inform a non-positivist approach to research. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction There is a movement to implement body-worn cameras (BWCs) in law enforcement agencies across the USA (Moriarty 2017 ). The impact of this trend on crime, policing strategies, and practices has been the subject of a growing body of research (see, e.g., Gaub et al. 2017 ; Yokum et al. 2017 ). The demand for BWCs was shaped by news and social media coverage of unarmed, young, black males dying at the hands of law enforcement (Doleac 2017 ; Hedberg et al. 2017 ; Smykla et al. 2016 ). Nowhere was this more evident than the death of Michael Brown in Ferguson (Missouri). The officer involved in this shooting did not have a BWC and his account of the incident conflicted with bystanders who reported that Mr. Brown had his hands up, was facing away from the officer, and was cooperating with his commands when shots were fired. Footnote 1 In the aftermath of the shooting, the Ferguson community mobilized to publicly display their outrage when the officer implicated in the incident was not indicted or charged with a crime. Protests in Ferguson were followed by similar tragic events throughout the Nation, including the police-involved deaths of John Crawford II in Beavercreek (Ohio), Tamir Rice in Cleveland (Ohio), Laquan McDonald in Chicago (Illinois), Walter Scott in North Charleston (South Carolina), Freddie Gray in Baltimore (Maryland), and Philandro Castile in St. Anthony’s (Minnesota). With each controversial police use-of-force incident, public sentiments and the national discourse on officer decision-making shifted. In fact, unfavorable attitudes toward police have grown and prompted many citizens to question the institutional order of law enforcement within the context of procedural justice (McLaughlin 2015 ). Accordingly and as Tyler ( 2006 ) proposed, law enforcement legitimacy has suffered and provoked events like Ferguson to be viewed through a different lens. Much like the Rodney King beating by Los Angeles (California) Police Department officers, these occurrences were no longer seen as an anomaly but part of a broader pattern of events that awakened the Nation’s consciousness. The post-Ferguson era, as it has been discussed in the empirical literature, constitutes the continued crisis of confidence in law enforcement and a search for innovative policing approaches that foster greater community trust (Hedberg et al. 2017 ; La Vigne et al. 2017 ). The efficacy of BWCs, particularly in the post-Ferguson era, has been queried as a potential solution to growing community discord and as an opportunity to prevent similar use-of-force instances (Maskaly et al. 2017 ). The purpose of this paper is to contribute to the empirical status of BWCs. Though previously explored in other scholarship (Gaub et al. 2017 ; Jennings et al. 2014 ; Pelrey and Keener 2016 ; Smykla et al. 2016 ), this examination differs by giving direct voice to officers on this issue. As part of a larger empirical endeavor on law enforcement-articulated strategies and views on policing gang violence, this subset of analyses presents officer insights on BWCs in a Southern American State. Personal experiences with and perspectives of BWCs are illuminated through officer interviews and an ethnographic approach to research that was conducted against the backdrop of the post-Ferguson era. Accordingly, BWCs were uniquely at the forefront of officer thoughts and behaviors, which is highlighted in the forthcoming material. Prior to presenting the data, however, this study is firstly situated within our existing knowledge of BWCs. Background Following Mr. Brown’s death, President Barack Obama constituted a Taskforce on twenty-first Century Policing (PTF 2015 ) that sought to identify police practices that prompt crime reduction, while simultaneously building public trust. Among the recommendations from the PTF ( 2015 ) was a commitment to purchase 50,000 BWCs for police officers across the Nation. This signaled a major vote of confidence from the Federal Government for the potential of BWC technology (Crow et al. 2017 ). Since then, approximately 4000–6000 BWCs have been adopted by the nearly 18,000 law enforcement agencies in the USA (Hedberg et al. 2017 ). This estimate is expected to rise considerably in the years to come as more and more law enforcement agencies are opting to add BWCs to their policing strategies. Initial Law Enforcement Opposition to BWCs Despite the growing interest in BWCs, putting them into practice has been accompanied by law enforcement hesitation. In fact, even where BWCs are available, they may not be used as intended. Hedberg et al. ( 2017 ), for example, in their non-equivalent matched treatment design of 56 BWC deployments, reported that BWC activation was “relatively limited” and officers were most likely to initiate filming for violent, property, and traffic offenses (see also Katz et al. 2014 ). Focus groups with specialized units in Tempe (Arizona) and Spokane (Washington), according to Gaub et al. ( 2017 ), found that some aspects of the law enforcement profession inhibit BWC use, such as covert operations. Accordingly, continuous filming policies, where BWCs are available, tend to be inconsistent with law enforcement “occupational culture,” according to Hedberg et al. ( 2017 , p. 644). On<|im_end|> <|im_start|>assistant The fatal shooting of Michael Brown by a police officer in Ferguson, Missouri, generated political and media backlash that continues to erode law enforcement legitimacy today. As a result, the Taskforce on Twenty-first Century Policing was mandated to reduce crime and build trust between law enforcement and the communities they serve. A key recommendation from the taskforce was to equip police departments with body-worn cameras and commit to purchasing 50,000 cameras for police officers nationwide. To date, between 4,000 and 6,000 body-worn cameras have been adopted by the nearly 18,000 law enforcement agencies in the U.S., and these numbers are expected to rise considerably in the coming years. Body-worn cameras are believed to increase law enforcement transparency and accountability, and by proxy restore law enforcement legitimacy. But are they really a game-changer in contemporary policing? There are many claims about the perceived benefits and drawbacks of body-worn cameras, which stem from the media and public opinion. There also is extensive discussion about the potential existence of a so-called "Ferguson Effect," which is long on anecdotes but short on data. Furthermore, research is sparse on the experiences and attitudes of law enforcement officers in response to the growing demand for this technology. To address this knowledge gap, a study by researchers at Florida Atlantic University and the University of the West of Scotland, is the first to use ethnographic or qualitative research to provide deeper insight into law enforcement officers' personal experiences with and perspectives on body-worn cameras. The study, published in the Journal of Police and Criminal Psychology, illustrates police officers' perspectives on one of the most overt strategic changes to modern American policing. Results of the study reveal that overwhelmingly, body-worn cameras have prompted a new consciousness in law enforcement, and according to one police officer, "have compelled changes in officer behaviors." While the researchers found an increased conceptual awareness of procedural justice, they also found a reduction in police morale and an emphasis on proactive policing strategies. They note that Ferguson often is drawn upon as a reference point among police officers. "It is clear that police officers are grappling to understand and come to terms with their diminished role, and declining levels of public respect and cooperation," said Seth Wyatt Fallik, Ph.D., lead author and an assistant professor in FAU's School of Criminology and Criminal Justice within the College for Design and Social Inquiry. "Solutions for healing the rift between police and citizens should not solely be the responsibility of police." The study is based on a long and deep immersion in the field in two counties in a Southern U.S. state as a means of generating insider knowledge. Both counties fully deployed body-worn cameras in early 2016. Field observations included ride-alongs, covert surveillance work, pre-deployment briefings, and rest breaks with officers and sheriff's deputies of various ranks and responsibilities. In addition to adopting the "participant as observer" role, field experiences were probed with in-depth semi-structured interviews. Questions focused on the impact of officer confidence, morale, and policing strategies in the post-Ferguson era. "Being accepted by the study participants prompted our formal and informal dialogs and allowed the police officers to share their body-worn camera insights without repercussion," said Ross Deuchar, Ph.D., co-author and an affiliate professor in FAU's School of Criminology and Criminal Justice, and a professor and assistant dean at the University of the West of Scotland, who conducted the four-month field work as a visiting Fulbright Scholar at FAU. "Officers were under no obligation to participate in the study and could—without penalty—withdraw their consent to be included in these analyses at any time." Deuchar observed citizen behavior through car windows, engaged in informal dialog with local people on the streets, visited people's homes to respond to local reported crime issues, and even wore a police ballistic vest. During this time, he also routinely observed officer behavior and listened to officer dialog with other officers and with citizens. In general, the study shows that police officers' perceptions of body-worn cameras were positive. Officers believe that the cameras protect them like an "extra set of eyes" and provide a better idea of what really happens during their public encounters, offering a more complete narrative of what actually transpired when the facts of an incident are contested. Among their concerns are that the body-worn cameras restrain their work and will not overcome public attitudes toward police and public bias against police officers. Most of the officers felt that focusing on a few rogue cops and playing negative images across multiple news cycles do little to improve public perception of the police. Other results of the study show that body-worn cameras also prompted changes in citizens' behaviors and resulted in reduced numbers of complaints levied against the police because they knew that the officers were wearing cameras. Regarding the use of force, the researchers note that Taser use also declined with the adoption of body-worn cameras. Collectively, police officers believe that body-worn cameras have the ability to foster a culture of accountability for law enforcement as well as citizens. "One of the interesting aspects from our study is that during the interviews many of the officers went out of their way to report that most law enforcement officers are good or are doing the right thing," said Vaughn J. Crichlow, Ph.D., co-author and an assistant professor in FAU's School of Criminology and Criminal Justice. "One detective even told us that he believed that 'no good cop should fear a camera.'" <|im_end|>

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2,472

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In all organisms, major biological processes are controlled by complex protein–protein interactions networks (interactomes), yet their structural complexity presents major analytical challenges. Here, we integrate a compendium of over 4300 phenotypes with Arabidopsis interactome (AI-1 MAIN ). We show that nodes with high connectivity and betweenness are enriched and depleted in conditional and essential phenotypes, respectively. Such nodes are located in the innermost layers of AI-1 MAIN and are preferential targets of pathogen effectors. We extend these network-centric analyses to Cell Surface Interactome (CSI LRR ) and predict its 35 most influential nodes. To determine their biological relevance, we show that these proteins physically interact with pathogen effectors and modulate plant immunity. Overall, our findings contrast with centrality-lethality rule, discover fast information spreading nodes, and highlight the structural properties of pathogen targets in two different interactomes. Finally, this theoretical framework could possibly be applicable to other inter-species interactomes to reveal pathogen contact points. Introduction Networks consist of systems’ components, referred to as nodes and interactions between them, termed ‘edges’ 1 , 2 . Network representation of a typical biological system constitutes the direct and indirect interactions among diverse molecular components. These molecular players, proteins in particular, participate in a wide range of biological processes, cellular pathways, and signaling cascades 1 , 3 , 4 . To achieve these cellular functions, proteins operate in conjunction with other partners, typically through direct physical protein–protein interactions (PPIs) 3 , 5 . The overall proteome-scale of these cellular interactions constitutes an “interactome”. Thus, elucidating the physical characteristics and functional interaction properties of an interactome could potentially reveal novel relationships between host proteins, new community structures as well as unique nodes with signaling cascades 6 , 7 . Such structural and functional topological features provide a range of information on individual nodes and edges, distinct modules, and the entire network as a whole 5 , 8 , 9 . Considering that diverse networks share similar organizational landscapes 10 , 11 , 12 , and the rate of information flowing through a network is dependent on the connectivity of its components 4 , several parameters of centrality measurements may act as indicators of important nodes in an interactome. For instance, network architectural properties can determine the connectivity and the critical distribution of a particular node within a network. These include degree, the number of connections of a node; betweenness, the fraction of the shortest paths that pass through a node; and eigenvector, a measure of the influence of a node in a network (Fig. 1 a). Scale-free topology of a network follows a power law degree (a heavy-tailed) distribution exhibiting a few nodes with increased connectivity 1 , 4 , 8 , 13 . Recently, k -shell decomposition was shown to identify influential spreaders of information in social platforms and scientific publishing society 14 . Thus, deciphering the network architecture and understanding these topological properties could lead to the discovery of novel components in a complex system, which then provide biological insights as well as testable hypotheses. Fig. 1 Hubs and bottlenecks are enriched in conditional phenotypes. a Schematic representation of high degree (hub; red), high betweenness (bottleneck; blue), and high eigenvector (green) nodes in a hypothetical network. b Cataloging loss-of-function mutant phenotypes in Arabidopsis based on five phenotypic groups: essential (ESN), morphological (MRP), cellular-biochemical (CLB), conditional (CND), and no phenotypes (NPH). c , d Node distribution corresponding to degree ( c ) and betweenness ( d ) for five phenotypic groups. CND phenotype enrichment for hub and betweenness are shown. e Relationship between node betweenness and degree distribution to identify high degree/high betweenness (HDHB), high degree/low betweenness (HDLB), low degree/high betweenness (LDHB) as well as low degree/low betweenness (LDLB) nodes (correlation coefficient of r 2 = 0.87). f Hypergeometric test to determine the overrepresentation of a particular phenotypic group in nodes belonging to HDHB ( P = 0.03), HDLB ( P > 0.05), LDHB ( P > 0.05), and LDLB ( P > 0.05) categories Full size image Several proteome-scale interactomes have been generated in both prokaryotes and eukaryotes including human 6 , 15 , and the reference plant Arabidopsis thaliana (hereafter Arabidopsis) 7 , 16 , 17 , 18 . These not only mapped the network and module organization of protein interactions onto the overall cellular organization and function but also allowed understanding of genotype-to-phenotype relationships as well as evolution of biological networks and ancestral gene function 19 . As such, several studies in yeast interactomes suggest that high degree (hubs) and high betweenness (bottlenecks) are likely to be encoded by essential genes, a phenomenon termed as centrality-lethality rule 5 , 20 , 21 , 22 . In addition, PPI networks can also be exploited to decipher the complex interplay between hosts and their pathogens during the process of infection 3 , 4 , 23 . Analyses of inter-species interactomes demonstrated that proteins corresponding to hubs and bottlenecks are targets of pathogen attack 1 , 24 , 25 . Thus, a conceptual challenge posed by the centrality-lethality rule in analyzing inter-species interactome dataset stems from diverse lifestyles of pathogens on their hosts. Of particular interests are the pathogens that must keep their hosts alive (e.g. obligate biotrophs) throughout their life cycle. Therefore, association of hubs and/or bottlenecks (potential pathogens’ targets) with essentiality/lethality would principally undermine the pathogens’ infectious process. Thus, the phenotypic characteristics of nodes defined as hubs and/or other network centrality measures are a requisite layer of information to biologically understand inter-species interactome datasets. Previously, we generated an Arabidopsis binary PPI map using ~8000 open reading frames representing ~30% of its protein-coding genes. Known as Arabidopsis Interactome version 1 “main screen” (AI-1 MAIN ), this network encompasses 5664 binary interactions between 2661 proteins 7 . We showed that AI-1 MAIN displays properties of a scale-free network that exhibits only 15 nodes with more than 50 interactions, i.e., ≥50 edges. These high-degree nodes are referred as hubs 50 . In addition, we also constructed two inter-species Plant–Pathogen Interaction Networks (PPIN-1 and PPIN-2) 26", "role": "user" }, { "content": "How are proteins in the cells of a flowering plant similar to social networks on Twitter or Facebook? And how might both of those be related to the way pathogens make plants or people sick? Shahid Mukhtar, Ph.D., and colleagues at the University of Alabama at Birmingham address these questions in a collaborative study with researchers at the Gregor Mendel Institute, Vienna, Austria. Using systems biology, they successfully identified previously unknown protein targets of plant pathogens in the flowering plant Arabidopsis thaliana, employing some of the same methods used to analyze social networks or biological networks. Their theoretical framework, they say, could help analyze other interactions between species to reveal pathogen contact points. In a social network, one can map the connections between followers or friends on Twitter and Facebook. A few people will have a huge number of connections, some will have many, and a vast majority will have much fewer. A map of these connections is akin to an airline route map, and the architecture of the networks shows topological features like hubs and bottlenecks. Analysis of social networks has allowed experts to identify people who are the \"best information spreaders.\" Similarly, for biology, deciphering the network architecture in an ecosystem or among macromolecules within cells of a lifeform can help discover novel components in those complex systems and provide biological insights and testable hypotheses. One biological network is protein-protein interactions inside cells. Such networks have been studied in organisms as diverse as plants, humans and roundworms. A network map of those protein-protein interactions, which signify proteins' operating in conjunction with other partners, is called a protein interactome. In a study published in Nature Communications, Mukhtar, an assistant professor in the Department of Biology, UAB College of Arts and Sciences, together with colleagues at UAB and the Gregor Mendel Institute, analyzed two different interactomes. The first one is the global protein interactome for proteins inside leaf cells of the model plant A. thaliana, called the Arabidopsis interactome. They also analyzed another, more specific protein interactome for receptors on the cell surface that allow plants to see, hear, smell and respond to environmental cues and dangers—especially to virulent pathogens. This second network is called cell surface interactome. For the proteins inside cells, they first matched more than 4,300 Arabidopsis protein-coding genes to five classes of observable traits, known as phenotypes. The five phenotype groups were essential genes that are needed for plant survival; morphological genes that control a plant's shape or appearance; genes for cellular or biochemical processes; conditional genes, where a mutation shows its effect only when the plant is subjected to stresses like water shortage or temperature extremes; and genes with no known phenotype. When they associated the phenotypes with a protein interactome network they had previously mapped, they found the large hub and bottleneck nodes were enriched for conditional phenotype genes and depleted for essential genes. This contrasts with the controversial centrality-lethality rule seen in yeast protein interactomes, where the large hub and bottleneck nodes are enriched for essential genes. Pathogens of Arabidopsis are able to inject pathogen proteins into the plant cells, and those injected \"effector\" proteins manipulate the plant's network to the pathogen's advantage. Mukhtar and colleagues had previously constructed two interspecies plant-pathogen interaction networks between pathogen effector proteins and Arabidopsis proteins inside the cell. The team found that large hubs in the Arabidopsis interactome comprised only 6.5 percent of the targets of the pathogen effector proteins, which made it a limited way to identify targets using network biology. But when the researchers applied a method called weighted k-shell decomposition to identify the best \"information spreaders,\" akin to recent analysis of social networks, the Arabidopsis protein nodes in the internal layers of the k-shell decomposition gave a 33 percent discovery rate for pathogen effector targets. Thus, k-shell decomposition analysis surpasses other centrality measure for effector target discovery. To test this, they then looked at an unrelated network, the cell surface interactome. These cell-surface proteins allow plants to sense the environment around them. The k-shell analysis predicted that 35 of these cell-surface proteins were the most influential spreaders of information. When the internal portions of the cell-surface proteins were tested for interactions with effector proteins from the bacterial pathogen Pseudomonas syringae, the researchers were able to identify seven previously unknown effector targets, a discovery rate of 40 percent. The researchers made mutants of the seven effector targets and found that all of the newly identified targets showed changes in pathogen growth on Arabidopsis plant leaves when mutated. \"Our network-centric approach,\" the researchers wrote, \"has exciting potential applicability on diverse intra- and inter-species interactomes, including human protein-protein interaction networks, in efforts to unravel host-pathogen contact points, while fostering the design of targeted therapeutic strategies.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In all organisms, major biological processes are controlled by complex protein–protein interactions networks (interactomes), yet their structural complexity presents major analytical challenges. Here, we integrate a compendium of over 4300 phenotypes with Arabidopsis interactome (AI-1 MAIN ). We show that nodes with high connectivity and betweenness are enriched and depleted in conditional and essential phenotypes, respectively. Such nodes are located in the innermost layers of AI-1 MAIN and are preferential targets of pathogen effectors. We extend these network-centric analyses to Cell Surface Interactome (CSI LRR ) and predict its 35 most influential nodes. To determine their biological relevance, we show that these proteins physically interact with pathogen effectors and modulate plant immunity. Overall, our findings contrast with centrality-lethality rule, discover fast information spreading nodes, and highlight the structural properties of pathogen targets in two different interactomes. Finally, this theoretical framework could possibly be applicable to other inter-species interactomes to reveal pathogen contact points. Introduction Networks consist of systems’ components, referred to as nodes and interactions between them, termed ‘edges’ 1 , 2 . Network representation of a typical biological system constitutes the direct and indirect interactions among diverse molecular components. These molecular players, proteins in particular, participate in a wide range of biological processes, cellular pathways, and signaling cascades 1 , 3 , 4 . To achieve these cellular functions, proteins operate in conjunction with other partners, typically through direct physical protein–protein interactions (PPIs) 3 , 5 . The overall proteome-scale of these cellular interactions constitutes an “interactome”. Thus, elucidating the physical characteristics and functional interaction properties of an interactome could potentially reveal novel relationships between host proteins, new community structures as well as unique nodes with signaling cascades 6 , 7 . Such structural and functional topological features provide a range of information on individual nodes and edges, distinct modules, and the entire network as a whole 5 , 8 , 9 . Considering that diverse networks share similar organizational landscapes 10 , 11 , 12 , and the rate of information flowing through a network is dependent on the connectivity of its components 4 , several parameters of centrality measurements may act as indicators of important nodes in an interactome. For instance, network architectural properties can determine the connectivity and the critical distribution of a particular node within a network. These include degree, the number of connections of a node; betweenness, the fraction of the shortest paths that pass through a node; and eigenvector, a measure of the influence of a node in a network (Fig. 1 a). Scale-free topology of a network follows a power law degree (a heavy-tailed) distribution exhibiting a few nodes with increased connectivity 1 , 4 , 8 , 13 . Recently, k -shell decomposition was shown to identify influential spreaders of information in social platforms and scientific publishing society 14 . Thus, deciphering the network architecture and understanding these topological properties could lead to the discovery of novel components in a complex system, which then provide biological insights as well as testable hypotheses. Fig. 1 Hubs and bottlenecks are enriched in conditional phenotypes. a Schematic representation of high degree (hub; red), high betweenness (bottleneck; blue), and high eigenvector (green) nodes in a hypothetical network. b Cataloging loss-of-function mutant phenotypes in Arabidopsis based on five phenotypic groups: essential (ESN), morphological (MRP), cellular-biochemical (CLB), conditional (CND), and no phenotypes (NPH). c , d Node distribution corresponding to degree ( c ) and betweenness ( d ) for five phenotypic groups. CND phenotype enrichment for hub and betweenness are shown. e Relationship between node betweenness and degree distribution to identify high degree/high betweenness (HDHB), high degree/low betweenness (HDLB), low degree/high betweenness (LDHB) as well as low degree/low betweenness (LDLB) nodes (correlation coefficient of r 2 = 0.87). f Hypergeometric test to determine the overrepresentation of a particular phenotypic group in nodes belonging to HDHB ( P = 0.03), HDLB ( P > 0.05), LDHB ( P > 0.05), and LDLB ( P > 0.05) categories Full size image Several proteome-scale interactomes have been generated in both prokaryotes and eukaryotes including human 6 , 15 , and the reference plant Arabidopsis thaliana (hereafter Arabidopsis) 7 , 16 , 17 , 18 . These not only mapped the network and module organization of protein interactions onto the overall cellular organization and function but also allowed understanding of genotype-to-phenotype relationships as well as evolution of biological networks and ancestral gene function 19 . As such, several studies in yeast interactomes suggest that high degree (hubs) and high betweenness (bottlenecks) are likely to be encoded by essential genes, a phenomenon termed as centrality-lethality rule 5 , 20 , 21 , 22 . In addition, PPI networks can also be exploited to decipher the complex interplay between hosts and their pathogens during the process of infection 3 , 4 , 23 . Analyses of inter-species interactomes demonstrated that proteins corresponding to hubs and bottlenecks are targets of pathogen attack 1 , 24 , 25 . Thus, a conceptual challenge posed by the centrality-lethality rule in analyzing inter-species interactome dataset stems from diverse lifestyles of pathogens on their hosts. Of particular interests are the pathogens that must keep their hosts alive (e.g. obligate biotrophs) throughout their life cycle. Therefore, association of hubs and/or bottlenecks (potential pathogens’ targets) with essentiality/lethality would principally undermine the pathogens’ infectious process. Thus, the phenotypic characteristics of nodes defined as hubs and/or other network centrality measures are a requisite layer of information to biologically understand inter-species interactome datasets. Previously, we generated an Arabidopsis binary PPI map using ~8000 open reading frames representing ~30% of its protein-coding genes. Known as Arabidopsis Interactome version 1 “main screen” (AI-1 MAIN ), this network encompasses 5664 binary interactions between 2661 proteins 7 . We showed that AI-1 MAIN displays properties of a scale-free network that exhibits only 15 nodes with more than 50 interactions, i.e., ≥50 edges. These high-degree nodes are referred as hubs 50 . In addition, we also constructed two inter-species Plant–Pathogen Interaction Networks (PPIN-1 and PPIN-2) 26<|im_end|> <|im_start|>assistant How are proteins in the cells of a flowering plant similar to social networks on Twitter or Facebook? And how might both of those be related to the way pathogens make plants or people sick? Shahid Mukhtar, Ph.D., and colleagues at the University of Alabama at Birmingham address these questions in a collaborative study with researchers at the Gregor Mendel Institute, Vienna, Austria. Using systems biology, they successfully identified previously unknown protein targets of plant pathogens in the flowering plant Arabidopsis thaliana, employing some of the same methods used to analyze social networks or biological networks. Their theoretical framework, they say, could help analyze other interactions between species to reveal pathogen contact points. In a social network, one can map the connections between followers or friends on Twitter and Facebook. A few people will have a huge number of connections, some will have many, and a vast majority will have much fewer. A map of these connections is akin to an airline route map, and the architecture of the networks shows topological features like hubs and bottlenecks. Analysis of social networks has allowed experts to identify people who are the "best information spreaders." Similarly, for biology, deciphering the network architecture in an ecosystem or among macromolecules within cells of a lifeform can help discover novel components in those complex systems and provide biological insights and testable hypotheses. One biological network is protein-protein interactions inside cells. Such networks have been studied in organisms as diverse as plants, humans and roundworms. A network map of those protein-protein interactions, which signify proteins' operating in conjunction with other partners, is called a protein interactome. In a study published in Nature Communications, Mukhtar, an assistant professor in the Department of Biology, UAB College of Arts and Sciences, together with colleagues at UAB and the Gregor Mendel Institute, analyzed two different interactomes. The first one is the global protein interactome for proteins inside leaf cells of the model plant A. thaliana, called the Arabidopsis interactome. They also analyzed another, more specific protein interactome for receptors on the cell surface that allow plants to see, hear, smell and respond to environmental cues and dangers—especially to virulent pathogens. This second network is called cell surface interactome. For the proteins inside cells, they first matched more than 4,300 Arabidopsis protein-coding genes to five classes of observable traits, known as phenotypes. The five phenotype groups were essential genes that are needed for plant survival; morphological genes that control a plant's shape or appearance; genes for cellular or biochemical processes; conditional genes, where a mutation shows its effect only when the plant is subjected to stresses like water shortage or temperature extremes; and genes with no known phenotype. When they associated the phenotypes with a protein interactome network they had previously mapped, they found the large hub and bottleneck nodes were enriched for conditional phenotype genes and depleted for essential genes. This contrasts with the controversial centrality-lethality rule seen in yeast protein interactomes, where the large hub and bottleneck nodes are enriched for essential genes. Pathogens of Arabidopsis are able to inject pathogen proteins into the plant cells, and those injected "effector" proteins manipulate the plant's network to the pathogen's advantage. Mukhtar and colleagues had previously constructed two interspecies plant-pathogen interaction networks between pathogen effector proteins and Arabidopsis proteins inside the cell. The team found that large hubs in the Arabidopsis interactome comprised only 6.5 percent of the targets of the pathogen effector proteins, which made it a limited way to identify targets using network biology. But when the researchers applied a method called weighted k-shell decomposition to identify the best "information spreaders," akin to recent analysis of social networks, the Arabidopsis protein nodes in the internal layers of the k-shell decomposition gave a 33 percent discovery rate for pathogen effector targets. Thus, k-shell decomposition analysis surpasses other centrality measure for effector target discovery. To test this, they then looked at an unrelated network, the cell surface interactome. These cell-surface proteins allow plants to sense the environment around them. The k-shell analysis predicted that 35 of these cell-surface proteins were the most influential spreaders of information. When the internal portions of the cell-surface proteins were tested for interactions with effector proteins from the bacterial pathogen Pseudomonas syringae, the researchers were able to identify seven previously unknown effector targets, a discovery rate of 40 percent. The researchers made mutants of the seven effector targets and found that all of the newly identified targets showed changes in pathogen growth on Arabidopsis plant leaves when mutated. "Our network-centric approach," the researchers wrote, "has exciting potential applicability on diverse intra- and inter-species interactomes, including human protein-protein interaction networks, in efforts to unravel host-pathogen contact points, while fostering the design of targeted therapeutic strategies." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Properties of solid-state materials depend on their crystal structures. In solid solution high entropy alloy (HEA), its mechanical properties such as strength and ductility depend on its phase. Therefore, the crystal structure prediction should be preceded to find new functional materials. Recently, the machine learning-based approach has been successfully applied to the prediction of structural phases. However, since about 80% of the data set is used as a training set in machine learning, it is well known that it requires vast cost for preparing a dataset of multi-element alloy as training. In this work, we develop an efficient approach to predicting the multi-element alloys' structural phases without preparing a large scale of the training dataset. We demonstrate that our method trained from binary alloy dataset can be applied to the multi-element alloys' crystal structure prediction by designing a transformation module from raw features to expandable form. Surprisingly, without involving the multi-element alloys in the training process, we obtain an accuracy, 80.56% for the phase of the multi-element alloy and 84.20% accuracy for the phase of HEA. It is comparable with the previous machine learning results. Besides, our approach saves at least three orders of magnitude computational cost for HEA by employing expandable features. We suggest that this accelerated approach can be applied to predicting various structural properties of multi-elements alloys that do not exist in the current structural database. Introduction Properties of solid-state materials are strongly related to their crystal structures. Even in the same elemental composition, the physical properties such as magnetization and adsorption energy are significantly affected by the crystal structures 1 , 2 , 3 , 4 . HEA, which consists of more than five elements, has drawn intensive attention for its outstanding mechanical properties 5 , 6 when forming the solid solution phase. The mechanical properties of solid solution HEA depend on its phase. The fcc HEA has high ductility 7 , and the bcc HEA has high strength 8 . That`s why valence electron concentration (VEC) is used to classify the bcc and the fcc solid solution phase of HEA 9 , 10 . To confirm the crystal structures efficiently, the structural searching in combination with the evolutionary algorithm with density functional theory (DFT) have been applied 11 , 12 . Recent approaches for crystal structure prediction become accelerated by adopting machine learning algorithms trained with the available experimental and theoretical database. Learning-based methods even predict the crystal structures of unknown materials using a sufficient number of training data 13 , 14 . As a result, one can bypass direct experiments or calculations to find the structural phases, so the cost for exploring the unknown materials and their characteristics becomes significantly reduced. In practice, the existing database, such as the inorganic crystal structure database (ICSD) 15 and Automatic-Flow (AFLOW) 16 have been used for training data. For instance, to investigate the most probable Mn-Ge and Li-Mn-Ge system structure, deep neural network (DNN) with ICSD has been used to predict the crystal structures 13 . When the number of the existing training data is insufficient, the calculation based on DFT can be applied to generate the training data 17 . However, the above approaches cannot be applied to the unexplored multi-elements alloys such as HEA 18 because of the insufficient data in the experiment. In addition, the possible compositional number of HEA is more than 10 6 , so preparing training data set of HEA using DFT calculation like other crystal system 19 , 20 is infeasible. Although some machine learning-based approach shows accurate performance 21 , 22 , the most approaches for predicting phases of unexplored HEA are restricted to nearly equiatomic cases 23 , 24 . It is because the calculation of the non-equiatomic HEA dataset requires huge computation due to its vast compositional space 25 . Therefore, the prediction of the HEA’s crystal structures without the calculation in the vast space is a demanding issue 26 . In this sense, we develop a learning-based approach to predict the vast compositional space of multi-element alloys (binary alloy, ternary alloy, and HEA), while only the binary alloy dataset is involved as the training set. For structural phase prediction using a learning-based approach, designing proper features is crucial, because it determines the cost and accuracy of the prediction. Conventionally, the compositional properties such as Z ( i ) (atomic number), \$n_{d}\$ ( i ) ( d -orbital occupancy), and \$\\sigma_{d}\$ ( i ) ( d -orbital spin) for i th atom are used as proper features for predicting structural phases of binary alloys 27 . Especially in previous works, it is revealed that \$n_{d}\$ and \$\\sigma_{d}\$ denotes occupancy of d electrons 30 . The d electron occupancy effectively involves in cohesive interaction and determines the stability of the crystal structural phase. Therefore, from several decades ago, this occupancy is widely used to classify the structural phase of transition metal. H. L. Skriver classify bcc , fcc, and hcp phase of 3 d , 4 d and 5 d non-magnetic transition metal using \$n_{d}\$ 28 , and it is expanded to magnetic transition metal using \$n_{d}\$ and \$\\sigma_{d}\$ features 29 , 30 . However, this approach is not directly applicable to multi-element alloys because the number of features is increasing as the types of elements increase. Although { \$n_{d}\$ ( N ) , \$\\sigma_{d}\$ ( N ) }, as a list of paired features for N -elements alloy, are well known as features for the crystal structure prediction of transition metal 30 , expensive DFT calculation is still necessary to obtain those values for multi-element alloys. In this work, we propose expandable { \$n_{d}^{ex}\$ , \$\\sigma_{d}^{ex}\$ } features, which are transformed from { \$n_{d}\$ (N) , \$\\sigma_{d}\$ (N) } features as illustrated in Fig. 1 . For the transformation from { \$n_{d}\$ (N) , \$\\sigma_{d}\$ (N) } to { \$n_{d}^{ex}\$ , \$\\sigma_{d}^{ex}\$ }, we utilized ensemble trees 31 considering each atoms’ surrounding condition in the alloy. In practice, \$n_{d}\$ and \$\\sigma_{d}\$ of the transition metal can", "role": "user" }, { "content": "Alchemy, which attempted to turn cheap metals such as lead and copper into gold, has not yet succeeded. However, with the development of alloys in which two or three auxiliary elements are mixed with the best elements of the times, modern alchemy can produce high-tech metal materials with high strength, such as high entropy alloys. Now, together with artificial intelligence, the era of predicting the crystal structure of high-tech materials has arrived without requiring repetitive experiments. A joint research team of Professor Ji Hoon Shim and Dr. Taewon Jin (first author, currently at KAIST) of POSTECH's Department of Chemistry, and Professor Jaesik Park of POSTECH Graduate School of Artificial Intelligence have together developed a system that predicts the crystal structures of multi-element alloys with expandable features without needing massive training data. These research findings were recently published in Scientific Reports. Properties of solid-state materials depend on their crystal structures. In solid solution high entropy alloy (HEA)—a material that has the same crystal structure but continuously changes its chemical composition within a certain range—mechanical properties such as strength and ductility vary depending on the structural phase. Therefore, predicting the crystal structure of a material plays a crucial role in finding new functional materials. Methods to predict the crystal structure through machine learning have been studied recently, but there is an enormous cost attached to prepare the data necessary for training. To this, the research team designed an artificial intelligence model that predicts the crystal structure of HEAs through expandable features and binary alloy data instead of the conventional models that use more than 80% of the HEA data in the training process. This is the first study to predict the crystal structure of multi-element alloys, including HEAs, with an artificial intelligence model trained only with the compositions and structural phase data of binary alloys. Through experiments, the researchers confirmed that the structural phase of the multi-element alloy was predicted with an accuracy of 80.56%, even though the multi-element alloy data were not involved in the training process. In the case of HEAs, it was predicted with an accuracy of 84.20%. According to the method developed by the research team, it is anticipated that the calculation cost can be saved by about 1,000 times compared to previous methods. \"An immense dataset is required to apply an artificial intelligence methodology to the development of new materials,\" explained Professor Ji Hoon Shim who led the research. \"This study is significant in that it enables to effectively predict the crystal structure of advanced materials without securing a huge data set.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Properties of solid-state materials depend on their crystal structures. In solid solution high entropy alloy (HEA), its mechanical properties such as strength and ductility depend on its phase. Therefore, the crystal structure prediction should be preceded to find new functional materials. Recently, the machine learning-based approach has been successfully applied to the prediction of structural phases. However, since about 80% of the data set is used as a training set in machine learning, it is well known that it requires vast cost for preparing a dataset of multi-element alloy as training. In this work, we develop an efficient approach to predicting the multi-element alloys' structural phases without preparing a large scale of the training dataset. We demonstrate that our method trained from binary alloy dataset can be applied to the multi-element alloys' crystal structure prediction by designing a transformation module from raw features to expandable form. Surprisingly, without involving the multi-element alloys in the training process, we obtain an accuracy, 80.56% for the phase of the multi-element alloy and 84.20% accuracy for the phase of HEA. It is comparable with the previous machine learning results. Besides, our approach saves at least three orders of magnitude computational cost for HEA by employing expandable features. We suggest that this accelerated approach can be applied to predicting various structural properties of multi-elements alloys that do not exist in the current structural database. Introduction Properties of solid-state materials are strongly related to their crystal structures. Even in the same elemental composition, the physical properties such as magnetization and adsorption energy are significantly affected by the crystal structures 1 , 2 , 3 , 4 . HEA, which consists of more than five elements, has drawn intensive attention for its outstanding mechanical properties 5 , 6 when forming the solid solution phase. The mechanical properties of solid solution HEA depend on its phase. The fcc HEA has high ductility 7 , and the bcc HEA has high strength 8 . That`s why valence electron concentration (VEC) is used to classify the bcc and the fcc solid solution phase of HEA 9 , 10 . To confirm the crystal structures efficiently, the structural searching in combination with the evolutionary algorithm with density functional theory (DFT) have been applied 11 , 12 . Recent approaches for crystal structure prediction become accelerated by adopting machine learning algorithms trained with the available experimental and theoretical database. Learning-based methods even predict the crystal structures of unknown materials using a sufficient number of training data 13 , 14 . As a result, one can bypass direct experiments or calculations to find the structural phases, so the cost for exploring the unknown materials and their characteristics becomes significantly reduced. In practice, the existing database, such as the inorganic crystal structure database (ICSD) 15 and Automatic-Flow (AFLOW) 16 have been used for training data. For instance, to investigate the most probable Mn-Ge and Li-Mn-Ge system structure, deep neural network (DNN) with ICSD has been used to predict the crystal structures 13 . When the number of the existing training data is insufficient, the calculation based on DFT can be applied to generate the training data 17 . However, the above approaches cannot be applied to the unexplored multi-elements alloys such as HEA 18 because of the insufficient data in the experiment. In addition, the possible compositional number of HEA is more than 10 6 , so preparing training data set of HEA using DFT calculation like other crystal system 19 , 20 is infeasible. Although some machine learning-based approach shows accurate performance 21 , 22 , the most approaches for predicting phases of unexplored HEA are restricted to nearly equiatomic cases 23 , 24 . It is because the calculation of the non-equiatomic HEA dataset requires huge computation due to its vast compositional space 25 . Therefore, the prediction of the HEA’s crystal structures without the calculation in the vast space is a demanding issue 26 . In this sense, we develop a learning-based approach to predict the vast compositional space of multi-element alloys (binary alloy, ternary alloy, and HEA), while only the binary alloy dataset is involved as the training set. For structural phase prediction using a learning-based approach, designing proper features is crucial, because it determines the cost and accuracy of the prediction. Conventionally, the compositional properties such as Z ( i ) (atomic number), $n_{d}$ ( i ) ( d -orbital occupancy), and $\sigma_{d}$ ( i ) ( d -orbital spin) for i th atom are used as proper features for predicting structural phases of binary alloys 27 . Especially in previous works, it is revealed that $n_{d}$ and $\sigma_{d}$ denotes occupancy of d electrons 30 . The d electron occupancy effectively involves in cohesive interaction and determines the stability of the crystal structural phase. Therefore, from several decades ago, this occupancy is widely used to classify the structural phase of transition metal. H. L. Skriver classify bcc , fcc, and hcp phase of 3 d , 4 d and 5 d non-magnetic transition metal using $n_{d}$ 28 , and it is expanded to magnetic transition metal using $n_{d}$ and $\sigma_{d}$ features 29 , 30 . However, this approach is not directly applicable to multi-element alloys because the number of features is increasing as the types of elements increase. Although { $n_{d}$ ( N ) , $\sigma_{d}$ ( N ) }, as a list of paired features for N -elements alloy, are well known as features for the crystal structure prediction of transition metal 30 , expensive DFT calculation is still necessary to obtain those values for multi-element alloys. In this work, we propose expandable { $n_{d}^{ex}$ , $\sigma_{d}^{ex}$ } features, which are transformed from { $n_{d}$ (N) , $\sigma_{d}$ (N) } features as illustrated in Fig. 1 . For the transformation from { $n_{d}$ (N) , $\sigma_{d}$ (N) } to { $n_{d}^{ex}$ , $\sigma_{d}^{ex}$ }, we utilized ensemble trees 31 considering each atoms’ surrounding condition in the alloy. In practice, $n_{d}$ and $\sigma_{d}$ of the transition metal can<|im_end|> <|im_start|>assistant Alchemy, which attempted to turn cheap metals such as lead and copper into gold, has not yet succeeded. However, with the development of alloys in which two or three auxiliary elements are mixed with the best elements of the times, modern alchemy can produce high-tech metal materials with high strength, such as high entropy alloys. Now, together with artificial intelligence, the era of predicting the crystal structure of high-tech materials has arrived without requiring repetitive experiments. A joint research team of Professor Ji Hoon Shim and Dr. Taewon Jin (first author, currently at KAIST) of POSTECH's Department of Chemistry, and Professor Jaesik Park of POSTECH Graduate School of Artificial Intelligence have together developed a system that predicts the crystal structures of multi-element alloys with expandable features without needing massive training data. These research findings were recently published in Scientific Reports. Properties of solid-state materials depend on their crystal structures. In solid solution high entropy alloy (HEA)—a material that has the same crystal structure but continuously changes its chemical composition within a certain range—mechanical properties such as strength and ductility vary depending on the structural phase. Therefore, predicting the crystal structure of a material plays a crucial role in finding new functional materials. Methods to predict the crystal structure through machine learning have been studied recently, but there is an enormous cost attached to prepare the data necessary for training. To this, the research team designed an artificial intelligence model that predicts the crystal structure of HEAs through expandable features and binary alloy data instead of the conventional models that use more than 80% of the HEA data in the training process. This is the first study to predict the crystal structure of multi-element alloys, including HEAs, with an artificial intelligence model trained only with the compositions and structural phase data of binary alloys. Through experiments, the researchers confirmed that the structural phase of the multi-element alloy was predicted with an accuracy of 80.56%, even though the multi-element alloy data were not involved in the training process. In the case of HEAs, it was predicted with an accuracy of 84.20%. According to the method developed by the research team, it is anticipated that the calculation cost can be saved by about 1,000 times compared to previous methods. "An immense dataset is required to apply an artificial intelligence methodology to the development of new materials," explained Professor Ji Hoon Shim who led the research. "This study is significant in that it enables to effectively predict the crystal structure of advanced materials without securing a huge data set." <|im_end|>

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1,904

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the past two decades several nano-structuring methods have helped improve the figure of merit ( ZT ) in the state-of-the art bulk thermoelectric materials. While these methods could enhance the thermoelectric performance of p -type Bi 2 Te 3 , it was frustrating to researchers that they proved ineffective for n -type Bi 2 Te 3 due to the inevitable deterioration of its thermoelectric properties in the basal plane. Here, we describe a novel chemical-exfoliation spark-plasma-sintering (CE-SPS) nano-structuring process, which transforms the microstructure of n -type Bi 2 Te 3 in an extraordinary manner without compromising its basal plane properties. The CE-SPS processing leads to preferential scattering of electrons at charged grain boundaries and thereby increases the electrical conductivity despite the presence of numerous grain boundaries and mitigates the bipolar effect via band occupancy optimization leading to an upshift (by ~ 100 K) and stabilization of the ZT peak over a broad temperature range of ~ 150 K. Introduction Despite its simplistic nature and unique technical merits, thermoelectricity has previously found only a few niche applications mainly due to its low conversion efficiency 1 , 2 . For broader applications, it is crucial to develop high performance thermoelectric (TE) materials whose figure of merit ( ZT ) is in the neighbourhood of 2, where and α is the thermopower ( i.e. , Seebeck coefficient), ρ the electrical resistivity, κ T the total thermal conductivity, T the absolute temperature and PF the power factor. The inherent inter-dependence among α, ρ and κ poses a major roadblock in realizing TE materials with higher ZT values 2 , 3 . In this context, tailoring the micro- and nano-structures at multiple length scales using advanced materials preparation methods has to a certain extent been able to decouple the inter-dependence among the TE properties; α, ρ and κ 4 , 5 . However, with many TE elements (or materials) in a TE device, there are several secondary “limiting factors” besides ZT that must be overcome to achieve high TE device efficiency, viz. : ( i ) suitability of n- and p-type materials : a similar composition, performance, thermal and mechanical stability for the n - and p -legs of a TE device is required; ( ii ) a wide operating temperature range for ZT : in practice, a less temperature-dependent and a reasonably high ZT over a broad temperature range is desirable in contrast to a high ZT over a narrow temperature range; ( iii ) a low electrode contact resistance : for a given PF , a lower ρ is preferred over a higher α since the former results in a lower electrode contact resistance and thus lesser parasitic losses; and ( iv ) a weak temperature dependence of the compatibility factor (Σ) : a weakly temperature-dependent compatibility factor (ratio of the electrical current density to heat flux) is highly desirable 6 , 7 , 8 . Failure to properly address these limiting factors makes the effort of enhancing ZT futile. It is then quite pertinent to explore nano-structuring processes that improve ZT without adversely effecting factors ( i )–( iv ). Since its discovery in 1950s 9 , Bi 2 Te 3 alloys have been probably the most widely studied and device utilized TE materials to date. More recently, Bi 2 Te 3 has gained renewed interest as an intriguing example of a three-dimensional topological insulator 10 , 11 . In regards to its TE properties, state-of-the-art Bi 2 Te 3 materials (typically, p -type Bi 0.5 Sb 1.5 Te 3 and n -type Bi 2 Te 2.7 Se 0.3 ) are the only TE materials that can be used for both power generation and refrigeration with a room temperature value of ZT ~ 1 12 . A greater opportunity for an improved performance in these TE materials can be expected if the above limiting factors ( i ) to ( iv ) are mitigated. Thus far, researchers have successfully enhanced ZT in p -type Bi 2 Te 3 by subjecting the bulk materials to nano-structuring processes, such as ball milling 13 , melt spinning 14 , 15 , thermal forging 16 , 17 and hydrothermal synthesis 18 , 19 , etc . and melt-spun p -type Bi 2 Te 3 ranks high in the list of current state-of-the-art TE materials with a room temperature ZT ~ 1.5 20 . In contrast, similar approaches have been ineffective so far in enhancing ZT in n -type Bi 2 Te 3 due to its strong texture and highly anisotropic transport properties 21 , 22 , 23 , 24 . Compared to bulk p -type Bi 2 Te 3 , bulk n -type Bi 2 Te 3 is easily cleavable 25 and traditional nano-structuring processes ( e.g. , ball milling 26 ) severely deteriorates its in-plane (basal plane) transport that is crucial for realizing potential high ZT values . Furthermore, the mismatch of grain boundaries adversely affects the electrical conduction and hence an effective nano-structuring process is needed for n-type Bi 2 Te 3 that preserves the in-plane micro-morphology to a maximum extent. The chemical exfoliation method has been successful in generating quasi-two-dimensional materials, which exhibit the same basal plane properties as that of the parent bulk materials 27 , 28 . Upon densification of chemically exfoliated n -type Bi 2 Te 3 , one can then control structuring at micro- and nano- length scales, while preserving the basal-plane properties. Ideally, grain boundaries should exhibit multi-tier scattering, i.e. , they should scatter: i ) phonons more effectively than charge carriers, ii ) low energy charge carriers more effectively than high energy charge carriers ( i.e. , energy filtering) and iii ) holes (minority carriers) more effectively than electrons (majority carriers) in the case of n -type materials to suppress the bipolar effect 29 , 30 . In this article, we prepared bulk materials comprised of nanostructured n -type Bi 2 Te 3 (Bi 2 Te 2.7 Se 0.3 ) and optimized its ZT over", "role": "user" }, { "content": "A team of Clemson University physicists consisting of nanomaterial scientists Apparao Rao and Ramakrishna Podila and thermoelectricians Terry Tritt, Jian He and Pooja Puneet worked synergistically through the newly established Clemson Nanomaterials Center to develop a novel technique of tailoring thermoelectric properties of n-type bismuth telluride for high thermoelectric performance. Their findings were published in journal Scientific Reports. The current US energy economy and environment are increasingly threatened by fast-dwindling domestic reserves of fossil fuel coupled with severe environmental impact of fossil fuel combustion. Highly-efficient thermoelectric devices are expected to provide clean energy technology-needs of the hour for US energy sustainability. This research is a step towards optimizing the device performance since it outlines a methodology to overcome a challenge that has \"frustrated\" thermoelectric researchers to date. Thermoelectric (TE) devices convert waste heat into electricity through a unique material's property called the Seebeck effect. Basically, the Seebeck effect results in a voltage across the two ends of a TE material, akin to the voltage present across the two ends of a AA battery, when the TE material is properly exposed to the waste heat. In such devices, the efficiency of converting heat into electricity is governed by certain strongly coupled materials properties, viz., electrical resistivity, Seebeck coefficient, and thermal conductivity. A functional TE device consists of multiple legs made up of p-type and n-type materials, just as a diode comprises of a p-n junction. Bismuth telluride (Bi2Te3) is a layered material and can be viewed as a deck of playing cards, wherein each card is only a few atoms thick. Bi2Te3 is currently regarded as the state-of-the-art TE material with high efficiency for converting waste heat into electricity, and is therefore attractive for energy harvesting processes. Traditional nanosizing methods failed to improve the performance of n-type Bi2Te3 since they simply downgrade all materials properties simultaneously. Therefore, Clemson researchers and colleagues developed a novel nanosizing method in which we first peel n-type Bi2Te3 into atomically thin-sheets (akin to graphene which is one atom thick sheet of carbon atoms) and reassemble them using a spark plasma sintering process. The researchers found that that the above described two-step process of first separating the deck of cards into individual cards and then re-assembling them into a deck via spark plasma sintering does enable us to suitably tailor the materials properties of n-type Bi2Te3for high TE performance. In this approach, the so-called 'interfacial charged defects' are generated in the sintered n-type Bi2Te3 which not only improves its structural properties but also its thermoelectric efficiency over a wide temperature window, thus making it extremely compatible with p-type Bi2Te3 for manufacturing efficient TE devices. The improved compatibility factor (demonstrated in this paper) is expected to open new possibilities for highly efficient TE devices. The fascinating and noteworthy element of this research is that defects, which often connote impurity and are associated with low performance or efficiency, can indeed be used to tune the properties of materials to our advantage. Today's scientific community lacks a comprehensive understanding of defects, mainly due to the absence of methods that can controllably generate and manipulate defects. The future of this research will be aimed at developing tools to generate and study defects at a fundamental level which will in turn allow the researchers to optimize materials properties of not only TE materials but also of a new class of two-dimensional materials beyond the Nobel-winning graphene for energy generation and storage. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Over the past two decades several nano-structuring methods have helped improve the figure of merit ( ZT ) in the state-of-the art bulk thermoelectric materials. While these methods could enhance the thermoelectric performance of p -type Bi 2 Te 3 , it was frustrating to researchers that they proved ineffective for n -type Bi 2 Te 3 due to the inevitable deterioration of its thermoelectric properties in the basal plane. Here, we describe a novel chemical-exfoliation spark-plasma-sintering (CE-SPS) nano-structuring process, which transforms the microstructure of n -type Bi 2 Te 3 in an extraordinary manner without compromising its basal plane properties. The CE-SPS processing leads to preferential scattering of electrons at charged grain boundaries and thereby increases the electrical conductivity despite the presence of numerous grain boundaries and mitigates the bipolar effect via band occupancy optimization leading to an upshift (by ~ 100 K) and stabilization of the ZT peak over a broad temperature range of ~ 150 K. Introduction Despite its simplistic nature and unique technical merits, thermoelectricity has previously found only a few niche applications mainly due to its low conversion efficiency 1 , 2 . For broader applications, it is crucial to develop high performance thermoelectric (TE) materials whose figure of merit ( ZT ) is in the neighbourhood of 2, where and α is the thermopower ( i.e. , Seebeck coefficient), ρ the electrical resistivity, κ T the total thermal conductivity, T the absolute temperature and PF the power factor. The inherent inter-dependence among α, ρ and κ poses a major roadblock in realizing TE materials with higher ZT values 2 , 3 . In this context, tailoring the micro- and nano-structures at multiple length scales using advanced materials preparation methods has to a certain extent been able to decouple the inter-dependence among the TE properties; α, ρ and κ 4 , 5 . However, with many TE elements (or materials) in a TE device, there are several secondary “limiting factors” besides ZT that must be overcome to achieve high TE device efficiency, viz. : ( i ) suitability of n- and p-type materials : a similar composition, performance, thermal and mechanical stability for the n - and p -legs of a TE device is required; ( ii ) a wide operating temperature range for ZT : in practice, a less temperature-dependent and a reasonably high ZT over a broad temperature range is desirable in contrast to a high ZT over a narrow temperature range; ( iii ) a low electrode contact resistance : for a given PF , a lower ρ is preferred over a higher α since the former results in a lower electrode contact resistance and thus lesser parasitic losses; and ( iv ) a weak temperature dependence of the compatibility factor (Σ) : a weakly temperature-dependent compatibility factor (ratio of the electrical current density to heat flux) is highly desirable 6 , 7 , 8 . Failure to properly address these limiting factors makes the effort of enhancing ZT futile. It is then quite pertinent to explore nano-structuring processes that improve ZT without adversely effecting factors ( i )–( iv ). Since its discovery in 1950s 9 , Bi 2 Te 3 alloys have been probably the most widely studied and device utilized TE materials to date. More recently, Bi 2 Te 3 has gained renewed interest as an intriguing example of a three-dimensional topological insulator 10 , 11 . In regards to its TE properties, state-of-the-art Bi 2 Te 3 materials (typically, p -type Bi 0.5 Sb 1.5 Te 3 and n -type Bi 2 Te 2.7 Se 0.3 ) are the only TE materials that can be used for both power generation and refrigeration with a room temperature value of ZT ~ 1 12 . A greater opportunity for an improved performance in these TE materials can be expected if the above limiting factors ( i ) to ( iv ) are mitigated. Thus far, researchers have successfully enhanced ZT in p -type Bi 2 Te 3 by subjecting the bulk materials to nano-structuring processes, such as ball milling 13 , melt spinning 14 , 15 , thermal forging 16 , 17 and hydrothermal synthesis 18 , 19 , etc . and melt-spun p -type Bi 2 Te 3 ranks high in the list of current state-of-the-art TE materials with a room temperature ZT ~ 1.5 20 . In contrast, similar approaches have been ineffective so far in enhancing ZT in n -type Bi 2 Te 3 due to its strong texture and highly anisotropic transport properties 21 , 22 , 23 , 24 . Compared to bulk p -type Bi 2 Te 3 , bulk n -type Bi 2 Te 3 is easily cleavable 25 and traditional nano-structuring processes ( e.g. , ball milling 26 ) severely deteriorates its in-plane (basal plane) transport that is crucial for realizing potential high ZT values . Furthermore, the mismatch of grain boundaries adversely affects the electrical conduction and hence an effective nano-structuring process is needed for n-type Bi 2 Te 3 that preserves the in-plane micro-morphology to a maximum extent. The chemical exfoliation method has been successful in generating quasi-two-dimensional materials, which exhibit the same basal plane properties as that of the parent bulk materials 27 , 28 . Upon densification of chemically exfoliated n -type Bi 2 Te 3 , one can then control structuring at micro- and nano- length scales, while preserving the basal-plane properties. Ideally, grain boundaries should exhibit multi-tier scattering, i.e. , they should scatter: i ) phonons more effectively than charge carriers, ii ) low energy charge carriers more effectively than high energy charge carriers ( i.e. , energy filtering) and iii ) holes (minority carriers) more effectively than electrons (majority carriers) in the case of n -type materials to suppress the bipolar effect 29 , 30 . In this article, we prepared bulk materials comprised of nanostructured n -type Bi 2 Te 3 (Bi 2 Te 2.7 Se 0.3 ) and optimized its ZT over<|im_end|> <|im_start|>assistant A team of Clemson University physicists consisting of nanomaterial scientists Apparao Rao and Ramakrishna Podila and thermoelectricians Terry Tritt, Jian He and Pooja Puneet worked synergistically through the newly established Clemson Nanomaterials Center to develop a novel technique of tailoring thermoelectric properties of n-type bismuth telluride for high thermoelectric performance. Their findings were published in journal Scientific Reports. The current US energy economy and environment are increasingly threatened by fast-dwindling domestic reserves of fossil fuel coupled with severe environmental impact of fossil fuel combustion. Highly-efficient thermoelectric devices are expected to provide clean energy technology-needs of the hour for US energy sustainability. This research is a step towards optimizing the device performance since it outlines a methodology to overcome a challenge that has "frustrated" thermoelectric researchers to date. Thermoelectric (TE) devices convert waste heat into electricity through a unique material's property called the Seebeck effect. Basically, the Seebeck effect results in a voltage across the two ends of a TE material, akin to the voltage present across the two ends of a AA battery, when the TE material is properly exposed to the waste heat. In such devices, the efficiency of converting heat into electricity is governed by certain strongly coupled materials properties, viz., electrical resistivity, Seebeck coefficient, and thermal conductivity. A functional TE device consists of multiple legs made up of p-type and n-type materials, just as a diode comprises of a p-n junction. Bismuth telluride (Bi2Te3) is a layered material and can be viewed as a deck of playing cards, wherein each card is only a few atoms thick. Bi2Te3 is currently regarded as the state-of-the-art TE material with high efficiency for converting waste heat into electricity, and is therefore attractive for energy harvesting processes. Traditional nanosizing methods failed to improve the performance of n-type Bi2Te3 since they simply downgrade all materials properties simultaneously. Therefore, Clemson researchers and colleagues developed a novel nanosizing method in which we first peel n-type Bi2Te3 into atomically thin-sheets (akin to graphene which is one atom thick sheet of carbon atoms) and reassemble them using a spark plasma sintering process. The researchers found that that the above described two-step process of first separating the deck of cards into individual cards and then re-assembling them into a deck via spark plasma sintering does enable us to suitably tailor the materials properties of n-type Bi2Te3for high TE performance. In this approach, the so-called 'interfacial charged defects' are generated in the sintered n-type Bi2Te3 which not only improves its structural properties but also its thermoelectric efficiency over a wide temperature window, thus making it extremely compatible with p-type Bi2Te3 for manufacturing efficient TE devices. The improved compatibility factor (demonstrated in this paper) is expected to open new possibilities for highly efficient TE devices. The fascinating and noteworthy element of this research is that defects, which often connote impurity and are associated with low performance or efficiency, can indeed be used to tune the properties of materials to our advantage. Today's scientific community lacks a comprehensive understanding of defects, mainly due to the absence of methods that can controllably generate and manipulate defects. The future of this research will be aimed at developing tools to generate and study defects at a fundamental level which will in turn allow the researchers to optimize materials properties of not only TE materials but also of a new class of two-dimensional materials beyond the Nobel-winning graphene for energy generation and storage. <|im_end|>

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2,091

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Artificial light at night (ALAN) is a major form of anthropogenic pollution. ALAN is well known to affect different behaviours during nighttime, when changes in light conditions often have immediate consequences for the trade-offs individuals experience. How ALAN affects daytime behaviours, however, has received far less attention. Here we studied how ALAN affected daytime personality traits and learning ability. We exposed Trinidadian guppies, Poecilia reticulata , for 10 weeks to different ALAN levels: bright light (24 hrs bright light, ~5,000 lx), dim light (12 hrs bright light; 12 hrs dim light, ~0.5 lx) and control (12 hrs bright light; 12 hrs dark). Afterwards, we tested how the treatments affected diurnal emergence from a refuge, space use, activity, sociability and the ability to memorize the location of companion fish. Individuals exposed to the light treatments (both dim and bright light) emerged quicker from a refuge and fish from the bright light treatment spent relatively more time in the open area of the arena. ALAN did not affect any of the other behaviours, although memory could not be tested since fish did not learn the companions’ location. Our results demonstrate that ALAN, next to affecting nocturnal behaviours, can also affect key diurnal behavioural processes, associated with risk-taking. Introduction The use of artificial light at night (ALAN) is a major form of anthropogenic pollution affecting a wide range of environmental processes 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . The two main sources of light pollution are direct artificial light and skyglow. Direct light is usually high in intensity as it originates directly from street lighting, domestic and commercial light sources, or is reflected via surrounding surfaces 1 . Skyglow, on the other hand, is the portion of artificial light that is scattered and reflected back to Earth within the atmosphere 10 , 11 . Skyglow is a growing global phenomenon that is highly dynamic 12 , 13 , 14 . Compared to direct light, it is dim and spatially homogenous on a small scale, but can be bright compared to natural celestial light sources, such as stars or even moonlight 15 and can alter nightscapes located far from urban areas 16 , 17 . In terms of behavioural processes, ALAN can have distinct effects on the behaviour of animals during the nighttime 1 . Many species use light for orientation during nighttime navigation. ALAN can thus alter the movement trajectories of individuals, either because individuals are directly attracted to light (‘flight-to-light’) or because natural light sources used for navigation are masked (e.g., by skyglow). These effects have been observed in insects 18 , 19 , birds 20 , amphibians 21 , 22 , reptiles 23 and fish 24 . Next to direct attraction, ALAN can alter the trade-offs animals face during the night. Especially, foraging benefits and predation risk can be strongly influenced by light conditions 1 , 25 . Approximately 30% of all vertebrates and more than 60% of all invertebrates are nocturnal, and for these organisms, their temporally differentiated niche has been promoted by highly developed senses 2 . Consequently, ALAN has different effects on diurnal and nocturnal species. Diurnal (and crepuscular) animals often become more night active with increasing ALAN (‘exploiting the night light niche’) 26 , 27 , 28 , whereas nocturnal animals often become less night active 29 , 30 , 31 , 32 . Next to affecting behavioural processes during nighttime, ALAN can also alter behavioural processes during daytime. This has received especially attention in the context of activity patterns: ALAN has been shown to advance the onset of daily activity in European blackbirds, Turdus merula 33 , 34 , great tits, Parus major 26 and to increase overall daily activity in zebra finches, Taeniopygia guttata 35 . Moreover, several studies, predominantly in rodents, have shown that ALAN can impair cognitive abilities such as spatial learning and memory. Rats and mice exposed to ALAN performed poorly in the Morris water maze 36 , 37 , 38 . In the diurnal rodent, the Nile grass rat, Arvicanthis niloticus , individuals exposed to three weeks of dim light during night showed impaired learning and memory in the Barnes maze 39 . In zebra finches, constant ALAN also resulted in impaired learning and cognition 35 . In contrast, in peafowls, Pavo cristatus , one-night light exposure did not affect problem-solving success 40 . Although the effects of ALAN on daytime behaviour have received some attention, most notably in the context of (the onset of) activity and cognition, the extent to which ALAN affects other important behavioural traits such as risk-taking or sociability, has received very little attention (but see 35 ). Such personality traits that are known to differ consistently among individuals can be linked to important life history traits of individuals, including survival and reproductive success 41 , 42 , 43 . Thus, to understand how ALAN affects a broader range of personality traits can be important to further increase our understanding of the potential impact of ALAN on animal populations. Here we studied how ALAN affects several such personality traits, including emergence, activity, space use, sociability and memory ability in the Trinidadian guppy, Poecilia reticulata . Animals living in aquatic habitats, including fish, are by no means exempt from light pollution 6 , 24 , 44 . Skyglow, streetlights, floodlights at harbours and (fishing) boats can emit light onto the water surface that reaches higher intensities than the light of the natural full moon light 45 and can be detected even off-shore in marine ecosystems above 46 , 47 and under water 48 . ALAN might not only alter fish communities 49 and physiology 50 , but also fish behaviour 51 . Several studies have shown that fish become disoriented when swimming near lights 24 , 52 . In Atlantic salmon, Salmon salar , ALAN disrupted the timing of migration (and thereby the social synchrony) 53 , 54 . ALAN may also affect schooling behaviour because", "role": "user" }, { "content": "Artificial light at night makes guppies more courageous during the day, according to a behavioural study led by researchers from the Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB) and the Max Planck Institute for Human Development. Exposing fish to artificial light at night made fish more active during the night, and also made them emerge quicker from hiding places during the day, which could increase their exposure to predators. Nocturnal lighting, however, did not affect their swimming speed or social behaviour during the day. Light pollution can have many influences on ecological processes. Previous research has shown that artificial light at night can have several direct consequences on nighttime activity and movement patterns of animals. Many animal species like birds and insects are attracted by artificial light sources at night, which causes disorientation. But how artificial light at night impacts the behaviour of individuals during the day, when the source of light pollution is absent, is largely unknown. In this study, a team led by Ralf Kurvers of the MPI for Human Development in collaboration with the IGB, tested how exposure to artificial light at night affected the behaviour of fish during the day. As study species, they used guppies, tropical freshwater fish and one a model organism commonly used in animal behavioural science. The scientists studied three groups of animals. Each group was exposed to the same bright light conditions during the day, but to different illuminations during the night. The first group experienced complete darkness at night; the second group was kept at a low light level at night, comparable to nocturnal illuminance under a street lamp; the third group experienced bright light at night. After 10 weeks of exposure, the scientists conducted behavioural tests to study the consequences of nightly light exposure on daytime behaviours. The results: Fish left their hiding places faster during the day and swam more often in the riskier, open areas of the aquarium when exposed to strong, but also weak, artificial light at night. The light exposed fish thus increased their willingness to take risks. \"The consequences of this increased risk taking behaviour are difficult to predict, but it is possible that they could be more at risk of predation by birds or other fish\" says IGB researcher David Bierbach, co-author of the study. The light exposed fish did not differ in swimming speed and sociality, as compared to the control fish. \"We suspect that the nocturnal light causes a stress response in the fish, and fish generally increase their risk taking when experiencing stress,\" explains Ralf Kurvers, lead author of the study. Also in humans, a disruption of the night can cause a stress response. For example, firefighters who slept fewer hours during the night had elevated levels of the stress hormone cortisol. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Artificial light at night (ALAN) is a major form of anthropogenic pollution. ALAN is well known to affect different behaviours during nighttime, when changes in light conditions often have immediate consequences for the trade-offs individuals experience. How ALAN affects daytime behaviours, however, has received far less attention. Here we studied how ALAN affected daytime personality traits and learning ability. We exposed Trinidadian guppies, Poecilia reticulata , for 10 weeks to different ALAN levels: bright light (24 hrs bright light, ~5,000 lx), dim light (12 hrs bright light; 12 hrs dim light, ~0.5 lx) and control (12 hrs bright light; 12 hrs dark). Afterwards, we tested how the treatments affected diurnal emergence from a refuge, space use, activity, sociability and the ability to memorize the location of companion fish. Individuals exposed to the light treatments (both dim and bright light) emerged quicker from a refuge and fish from the bright light treatment spent relatively more time in the open area of the arena. ALAN did not affect any of the other behaviours, although memory could not be tested since fish did not learn the companions’ location. Our results demonstrate that ALAN, next to affecting nocturnal behaviours, can also affect key diurnal behavioural processes, associated with risk-taking. Introduction The use of artificial light at night (ALAN) is a major form of anthropogenic pollution affecting a wide range of environmental processes 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . The two main sources of light pollution are direct artificial light and skyglow. Direct light is usually high in intensity as it originates directly from street lighting, domestic and commercial light sources, or is reflected via surrounding surfaces 1 . Skyglow, on the other hand, is the portion of artificial light that is scattered and reflected back to Earth within the atmosphere 10 , 11 . Skyglow is a growing global phenomenon that is highly dynamic 12 , 13 , 14 . Compared to direct light, it is dim and spatially homogenous on a small scale, but can be bright compared to natural celestial light sources, such as stars or even moonlight 15 and can alter nightscapes located far from urban areas 16 , 17 . In terms of behavioural processes, ALAN can have distinct effects on the behaviour of animals during the nighttime 1 . Many species use light for orientation during nighttime navigation. ALAN can thus alter the movement trajectories of individuals, either because individuals are directly attracted to light (‘flight-to-light’) or because natural light sources used for navigation are masked (e.g., by skyglow). These effects have been observed in insects 18 , 19 , birds 20 , amphibians 21 , 22 , reptiles 23 and fish 24 . Next to direct attraction, ALAN can alter the trade-offs animals face during the night. Especially, foraging benefits and predation risk can be strongly influenced by light conditions 1 , 25 . Approximately 30% of all vertebrates and more than 60% of all invertebrates are nocturnal, and for these organisms, their temporally differentiated niche has been promoted by highly developed senses 2 . Consequently, ALAN has different effects on diurnal and nocturnal species. Diurnal (and crepuscular) animals often become more night active with increasing ALAN (‘exploiting the night light niche’) 26 , 27 , 28 , whereas nocturnal animals often become less night active 29 , 30 , 31 , 32 . Next to affecting behavioural processes during nighttime, ALAN can also alter behavioural processes during daytime. This has received especially attention in the context of activity patterns: ALAN has been shown to advance the onset of daily activity in European blackbirds, Turdus merula 33 , 34 , great tits, Parus major 26 and to increase overall daily activity in zebra finches, Taeniopygia guttata 35 . Moreover, several studies, predominantly in rodents, have shown that ALAN can impair cognitive abilities such as spatial learning and memory. Rats and mice exposed to ALAN performed poorly in the Morris water maze 36 , 37 , 38 . In the diurnal rodent, the Nile grass rat, Arvicanthis niloticus , individuals exposed to three weeks of dim light during night showed impaired learning and memory in the Barnes maze 39 . In zebra finches, constant ALAN also resulted in impaired learning and cognition 35 . In contrast, in peafowls, Pavo cristatus , one-night light exposure did not affect problem-solving success 40 . Although the effects of ALAN on daytime behaviour have received some attention, most notably in the context of (the onset of) activity and cognition, the extent to which ALAN affects other important behavioural traits such as risk-taking or sociability, has received very little attention (but see 35 ). Such personality traits that are known to differ consistently among individuals can be linked to important life history traits of individuals, including survival and reproductive success 41 , 42 , 43 . Thus, to understand how ALAN affects a broader range of personality traits can be important to further increase our understanding of the potential impact of ALAN on animal populations. Here we studied how ALAN affects several such personality traits, including emergence, activity, space use, sociability and memory ability in the Trinidadian guppy, Poecilia reticulata . Animals living in aquatic habitats, including fish, are by no means exempt from light pollution 6 , 24 , 44 . Skyglow, streetlights, floodlights at harbours and (fishing) boats can emit light onto the water surface that reaches higher intensities than the light of the natural full moon light 45 and can be detected even off-shore in marine ecosystems above 46 , 47 and under water 48 . ALAN might not only alter fish communities 49 and physiology 50 , but also fish behaviour 51 . Several studies have shown that fish become disoriented when swimming near lights 24 , 52 . In Atlantic salmon, Salmon salar , ALAN disrupted the timing of migration (and thereby the social synchrony) 53 , 54 . ALAN may also affect schooling behaviour because<|im_end|> <|im_start|>assistant Artificial light at night makes guppies more courageous during the day, according to a behavioural study led by researchers from the Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB) and the Max Planck Institute for Human Development. Exposing fish to artificial light at night made fish more active during the night, and also made them emerge quicker from hiding places during the day, which could increase their exposure to predators. Nocturnal lighting, however, did not affect their swimming speed or social behaviour during the day. Light pollution can have many influences on ecological processes. Previous research has shown that artificial light at night can have several direct consequences on nighttime activity and movement patterns of animals. Many animal species like birds and insects are attracted by artificial light sources at night, which causes disorientation. But how artificial light at night impacts the behaviour of individuals during the day, when the source of light pollution is absent, is largely unknown. In this study, a team led by Ralf Kurvers of the MPI for Human Development in collaboration with the IGB, tested how exposure to artificial light at night affected the behaviour of fish during the day. As study species, they used guppies, tropical freshwater fish and one a model organism commonly used in animal behavioural science. The scientists studied three groups of animals. Each group was exposed to the same bright light conditions during the day, but to different illuminations during the night. The first group experienced complete darkness at night; the second group was kept at a low light level at night, comparable to nocturnal illuminance under a street lamp; the third group experienced bright light at night. After 10 weeks of exposure, the scientists conducted behavioural tests to study the consequences of nightly light exposure on daytime behaviours. The results: Fish left their hiding places faster during the day and swam more often in the riskier, open areas of the aquarium when exposed to strong, but also weak, artificial light at night. The light exposed fish thus increased their willingness to take risks. "The consequences of this increased risk taking behaviour are difficult to predict, but it is possible that they could be more at risk of predation by birds or other fish" says IGB researcher David Bierbach, co-author of the study. The light exposed fish did not differ in swimming speed and sociality, as compared to the control fish. "We suspect that the nocturnal light causes a stress response in the fish, and fish generally increase their risk taking when experiencing stress," explains Ralf Kurvers, lead author of the study. Also in humans, a disruption of the night can cause a stress response. For example, firefighters who slept fewer hours during the night had elevated levels of the stress hormone cortisol. <|im_end|>

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315, 10099, 2391, 279, 93744, 220, 16, 662, 9176, 9606, 1005, 3177, 369, 17140, 2391, 93744, 10873, 13, 8927, 1111, 649, 8617, 11857, 279, 7351, 86648, 315, 7931, 11, 3060, 1606, 7931, 527, 6089, 29123, 311, 3177, 320, 14336, 39490, 4791, 18179, 96206, 477, 1606, 5933, 3177, 8336, 1511, 369, 10873, 527, 43248, 320, 68, 1326, 2637, 555, 13180, 6200, 363, 570, 4314, 6372, 617, 1027, 13468, 304, 41911, 220, 972, 1174, 220, 777, 1174, 20229, 220, 508, 1174, 89022, 5493, 220, 1691, 1174, 220, 1313, 1174, 64873, 3742, 220, 1419, 323, 7795, 220, 1187, 662, 9479, 311, 2167, 33464, 11, 8927, 1111, 649, 11857, 279, 6696, 65039, 10099, 3663, 2391, 279, 3814, 13, 36625, 11, 369, 4210, 7720, 323, 4255, 367, 5326, 649, 387, 16917, 28160, 555, 3177, 4787, 220, 16, 1174, 220, 914, 662, 79904, 220, 966, 4, 315, 682, 67861, 99868, 323, 810, 1109, 220, 1399, 4, 315, 682, 304, 65932, 99868, 527, 93101, 63550, 11, 323, 369, 1521, 44304, 11, 872, 19502, 750, 89142, 35149, 706, 1027, 30026, 555, 7701, 8040, 38207, 220, 17, 662, 53123, 11, 8927, 1111, 706, 2204, 6372, 389, 1891, 63550, 323, 93101, 63550, 9606, 13, 7923, 63550, 320, 438, 1922, 18299, 22077, 8, 10099, 3629, 3719, 810, 3814, 4642, 449, 7859, 8927, 1111, 320, 14336, 69331, 5977, 279, 3814, 3177, 35149, 96206, 220, 1627, 1174, 220, 1544, 1174, 220, 1591, 1174, 20444, 93101, 63550, 10099, 3629, 3719, 2753, 3814, 4642, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 1174, 220, 843, 662, 9479, 311, 28987, 88979, 11618, 2391, 93744, 11, 8927, 1111, 649, 1101, 11857, 88979, 11618, 2391, 62182, 13, 1115, 706, 4036, 5423, 6666, 304, 279, 2317, 315, 5820, 12912, 25, 8927, 1111, 706, 1027, 6982, 311, 12178, 279, 42080, 315, 7446, 5820, 304, 7665, 3776, 67461, 11, 8877, 67, 355, 4809, 5724, 220, 1644, 1174, 220, 1958, 1174, 2294, 30682, 11, 4366, 355, 3682, 220, 1627, 323, 311, 5376, 8244, 7446, 5820, 304, 1167, 51313, 1913, 8696, 11, 24172, 34229, 1289, 55901, 18340, 83, 460, 220, 1758, 662, 23674, 11, 3892, 7978, 11, 47904, 304, 94209, 11, 617, 6982, 430, 8927, 1111, 649, 38974, 25702, 18000, 1778, 439, 29079, 6975, 323, 5044, 13, 432, 1900, 323, 24548, 15246, 311, 8927, 1111, 10887, 31555, 304, 279, 30283, 3090, 36196, 220, 1927, 1174, 220, 1806, 1174, 220, 1987, 662, 763, 279, 1891, 63550, 21236, 306, 11, 279, 77290, 16763, 11494, 11, 1676, 85, 7210, 576, 2139, 14546, 355, 1174, 7931, 15246, 311, 2380, 5672, 315, 5213, 3177, 2391, 3814, 8710, 50160, 6975, 323, 5044, 304, 279, 44954, 36196, 220, 2137, 662, 763, 1167, 51313, 1913, 8696, 11, 6926, 8927, 1111, 1101, 19543, 304, 50160, 6975, 323, 75310, 220, 1758, 662, 763, 13168, 11, 304, 1069, 2642, 363, 4835, 11, 393, 28316, 69084, 1015, 1174, 832, 45427, 3177, 14675, 1550, 539, 7958, 3575, 99246, 2450, 220, 1272, 662, 10541, 279, 6372, 315, 8927, 1111, 389, 62182, 17432, 617, 4036, 1063, 6666, 11, 1455, 35146, 304, 279, 2317, 315, 320, 1820, 42080, 315, 8, 5820, 323, 75310, 11, 279, 13112, 311, 902, 8927, 1111, 22223, 1023, 3062, 88979, 25022, 1778, 439, 5326, 80671, 477, 15983, 2968, 11, 706, 4036, 1633, 2697, 6666, 320, 8248, 1518, 220, 1758, 7609, 15483, 17743, 25022, 430, 527, 3967, 311, 1782, 21356, 4315, 7931, 649, 387, 10815, 311, 3062, 2324, 3925, 25022, 315, 7931, 11, 2737, 20237, 323, 42889, 2450, 220, 3174, 1174, 220, 2983, 1174, 220, 3391, 662, 14636, 11, 311, 3619, 1268, 8927, 1111, 22223, 264, 27927, 2134, 315, 17743, 25022, 649, 387, 3062, 311, 4726, 5376, 1057, 8830, 315, 279, 4754, 5536, 315, 8927, 1111, 389, 10065, 22673, 13, 5810, 584, 20041, 1268, 8927, 1111, 22223, 3892, 1778, 17743, 25022, 11, 2737, 49179, 11, 5820, 11, 3634, 1005, 11, 15983, 2968, 323, 5044, 5845, 304, 279, 86230, 1122, 342, 65129, 11, 14128, 762, 25045, 2160, 292, 360, 460, 662, 47966, 5496, 304, 72491, 71699, 11, 2737, 7795, 11, 527, 555, 912, 3445, 39028, 505, 3177, 25793, 220, 21, 1174, 220, 1187, 1174, 220, 2096, 662, 15064, 6200, 363, 11, 8761, 14146, 11, 18197, 14146, 520, 69566, 2530, 323, 320, 69, 11218, 8, 32731, 649, 17105, 3177, 8800, 279, 3090, 7479, 430, 25501, 5190, 25228, 1385, 1109, 279, 3177, 315, 279, 5933, 2539, 18266, 3177, 220, 1774, 323, 649, 387, 16914, 1524, 1022, 7666, 461, 304, 29691, 61951, 3485, 220, 2790, 1174, 220, 2618, 323, 1234, 3090, 220, 2166, 662, 8927, 1111, 2643, 539, 1193, 11857, 7795, 10977, 220, 2491, 323, 78152, 220, 1135, 1174, 719, 1101, 7795, 17432, 220, 3971, 662, 26778, 7978, 617, 6982, 430, 7795, 3719, 834, 33536, 994, 24269, 3221, 13001, 220, 1187, 1174, 220, 4103, 662, 763, 23179, 41420, 11, 62826, 4371, 277, 1174, 8927, 1111, 69627, 279, 18912, 315, 12172, 320, 438, 28592, 279, 3674, 14453, 88, 8, 220, 4331, 1174, 220, 4370, 662, 8927, 1111, 1253, 1101, 7958, 68721, 17432, 1606, 128257, 198, 128256, 78191, 198, 9470, 16895, 3177, 520, 3814, 3727, 342, 95847, 810, 75748, 2391, 279, 1938, 11, 4184, 311, 264, 88979, 4007, 6197, 555, 12074, 505, 279, 2009, 581, 77, 450, 10181, 315, 30260, 13284, 78375, 323, 763, 1974, 94505, 320, 1953, 33, 8, 323, 279, 7639, 9878, 377, 10181, 369, 11344, 11050, 13, 1398, 8478, 7795, 311, 21075, 3177, 520, 3814, 1903, 7795, 810, 4642, 2391, 279, 3814, 11, 323, 1101, 1903, 1124, 34044, 39392, 505, 26092, 7634, 2391, 279, 1938, 11, 902, 1436, 5376, 872, 14675, 311, 56217, 13, 2360, 302, 63550, 18186, 11, 4869, 11, 1550, 539, 7958, 872, 24269, 4732, 477, 3674, 17432, 2391, 279, 1938, 13, 8828, 25793, 649, 617, 1690, 34453, 389, 50953, 11618, 13, 30013, 3495, 706, 6982, 430, 21075, 3177, 520, 3814, 649, 617, 3892, 2167, 16296, 389, 93744, 5820, 323, 7351, 12912, 315, 10099, 13, 9176, 10065, 9606, 1093, 20229, 323, 41911, 527, 29123, 555, 21075, 3177, 8336, 520, 3814, 11, 902, 11384, 834, 25280, 13, 2030, 1268, 21075, 3177, 520, 3814, 25949, 279, 17432, 315, 7931, 2391, 279, 1938, 11, 994, 279, 2592, 315, 3177, 25793, 374, 28310, 11, 374, 14090, 9987, 13, 763, 420, 4007, 11, 264, 2128, 6197, 555, 432, 3181, 32375, 3078, 315, 279, 17542, 369, 11344, 11050, 304, 20632, 449, 279, 358, 5494, 11, 12793, 1268, 14675, 311, 21075, 3177, 520, 3814, 11754, 279, 17432, 315, 7795, 2391, 279, 1938, 13, 1666, 4007, 9606, 11, 814, 1511, 342, 95847, 11, 35148, 80744, 7795, 323, 832, 264, 1646, 47120, 17037, 1511, 304, 10065, 88979, 8198, 13, 578, 14248, 20041, 2380, 5315, 315, 10099, 13, 9062, 1912, 574, 15246, 311, 279, 1890, 10107, 3177, 4787, 2391, 279, 1938, 11, 719, 311, 2204, 44087, 811, 2391, 279, 3814, 13, 578, 1176, 1912, 10534, 4686, 27394, 520, 3814, 26, 279, 2132, 1912, 574, 8774, 520, 264, 3428, 3177, 2237, 520, 3814, 11, 30139, 311, 93101, 63550, 44087, 685, 1234, 264, 8761, 29062, 26, 279, 4948, 1912, 10534, 10107, 3177, 520, 3814, 13, 4740, 220, 605, 5672, 315, 14675, 11, 279, 14248, 13375, 88979, 7177, 311, 4007, 279, 16296, 315, 75860, 3177, 14675, 389, 62182, 71177, 13, 578, 3135, 25, 17019, 2163, 872, 26092, 7634, 10819, 2391, 279, 1938, 323, 2064, 309, 810, 3629, 304, 279, 5326, 1291, 11, 1825, 5789, 315, 279, 62283, 994, 15246, 311, 3831, 11, 719, 1101, 7621, 11, 21075, 3177, 520, 3814, 13, 578, 3177, 15246, 7795, 8617, 7319, 872, 39375, 311, 1935, 15635, 13, 330, 791, 16296, 315, 420, 7319, 5326, 4737, 17432, 527, 5107, 311, 7168, 11, 719, 433, 374, 3284, 430, 814, 1436, 387, 810, 520, 5326, 315, 4255, 367, 555, 20229, 477, 1023, 7795, 1, 2795, 358, 5494, 32185, 6941, 426, 1291, 35638, 11, 1080, 43802, 315, 279, 4007, 13, 578, 3177, 15246, 7795, 1550, 539, 1782, 304, 24269, 4732, 323, 3674, 488, 11, 439, 7863, 311, 279, 2585, 7795, 13, 330, 1687, 15562, 430, 279, 93101, 63550, 3177, 11384, 264, 8631, 2077, 304, 279, 7795, 11, 323, 7795, 8965, 5376, 872, 5326, 4737, 994, 25051, 8631, 1359, 15100, 432, 3181, 32375, 3078, 11, 3063, 3229, 315, 279, 4007, 13, 7429, 304, 12966, 11, 264, 44219, 315, 279, 3814, 649, 5353, 264, 8631, 2077, 13, 1789, 3187, 11, 53206, 889, 46498, 17162, 4207, 2391, 279, 3814, 1047, 32389, 5990, 315, 279, 8631, 36908, 89942, 13, 220, 128257, 198 ]

1,899

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective To describe trends in the rate and daily dose of opioids used among commercial and Medicare Advantage beneficiaries from 2007 to 2016. Design Retrospective cohort study of administrative claims data. Setting National database of medical and pharmacy claims for commercially insured and Medicare Advantage beneficiaries in the United States. Participants 48 million individuals with any period of insurance coverage between 1 January 2007 and 31 December 2016, including commercial beneficiaries, Medicare Advantage beneficiaries aged 65 years and over, and Medicare Advantage beneficiaries under age 65 years (eligible owing to permanent disability). Main endpoints Proportion of beneficiaries with any opioid prescription per quarter, average daily dose in milligram morphine equivalents (MME), and proportion of opioid use episodes that represented long term use. Results Across all years of the study, annual opioid use prevalence was 14% for commercial beneficiaries, 26% for aged Medicare beneficiaries, and 52% for disabled Medicare beneficiaries. In the commercial beneficiary group, quarterly prevalence of opioid use changed little, starting and ending the study period at 6%; the average daily dose of 17 MME remained unchanged since 2011. For aged Medicare beneficiaries, quarterly use prevalence was also relatively stable, ranging from 11% at the beginning of the study period to 14% at the end. Disabled Medicare beneficiaries had the highest rates of opioid use, the highest rate of long term use, and the largest average daily doses. In this group, both quarterly use rates (39%) and average daily dose (56 MME) were higher at the end of 2016 than the low points observed in 2007 for each endpoint (26% prevalence and 53 MME). Conclusions Opioid use rates were high during the study period of 2007-16, with the highest rates in disabled Medicare beneficiaries versus aged Medicare beneficiaries and commercial beneficiaries. Opioid use and average daily dose have not substantially declined from their peaks, despite increased attention to opioid abuse and awareness of their risks. Introduction The United States has the highest rate of opioid use in the world, consuming 88% more prescription opioids per capita than second ranked Germany and seven times more than the United Kingdom. 1 An average of 40 people die in the US every day from a prescription opioid overdose—a fourfold increase since 1999. 2 Opioid use has been declared a public health emergency, with legally prescribed drugs contributing to substantial morbidity and mortality from addiction and overdose. 3 4 5 Studies reporting on population level opioid use have had some key limitations. Sales and supply data track nearly all legally distributed opioids, but these data do not link to patient demographics. 6 7 The National Survey on Drug Use and Health includes patient information, but is limited to patient self report of opioid use and excludes children under age 12 years. 8 The most commonly used source of healthcare claims data—Medicare fee-for-service data—provides excellent patient level data, but is limited to Medicare beneficiaries. 9 10 As a result, current knowledge about opioid use in the US is largely derived from studies of a single state or healthcare system, 11 12 13 14 or market level information that limits detailed examination of prevalence, patient level use, or subgroup analyses. 6 15 Market level data from prescription fills cannot be used to determine the proportion of people who use opioids in a given year unless prescriptions filled by the same person can be identified. Without a unique person level identifier, only the rate of prescriptions per capita can be calculated, rather than the proportion of people using opioids in a given year; the two estimates can diverge if a small number of people fill a large proportion of prescriptions. As a result, relatively little is known about person level opioid use in large national samples outside of Medicare fee-for-service beneficiaries. There are few sources of claims data for Medicare Advantage beneficiaries, who are believed to be healthier than fee-for-service beneficiaries, 16 but have not been studied in depth; there are also few datasets that cover a geographically diverse group of commercially insured beneficiaries. Both of these populations are included in the OptumLabs Data Warehouse. Accordingly, our objective was to describe the prevalence of use, dose, and duration of prescription opioids used in a large population, including both commercially insured and Medicare Advantage beneficiaries (31% of all Medicare beneficiaries 17 ), from 2007 to 2016. Using a national claims database, we aimed to explore the prevalence of opioid use and trends over the study period in subpopulations defined by insurance type (commercial, aged Medicare, and disabled Medicare) and by age. The primary goal of this paper was to estimate the change in opioid use across age and coverage types since 2007, in the face of increasing emphasis on improving prescribing patterns and preventing adverse outcomes. As a secondary goal, we also assessed the extent of concentration of opioid use in long term use episodes and among the beneficiaries with the greatest use of opioids. Methods Participants We drew pharmacy claims from the OptumLabs Data Warehouse (OLDW), a database of claims for healthcare services, insurance enrollment, and demographic information. The OLDW includes both commercially insured and Medicare Advantage beneficiaries, including age eligible beneficiaries (age ≥65 years) and individuals eligible for Medicare before age 65 years owing to permanent disability. Our study included all beneficiaries with medical and pharmacy coverage for any period of time between 1 January 2007 and 31 December 2016. The OLDW includes 20% of the commercially insured population in the US and 24% of the Medicare Advantage population. The distributions of age, sex, and race or ethnicity in the database are similar to the US commercial and Medicare Advantage populations. People from all census divisions are represented in the OLDW, with a higher proportion of OLDW beneficiaries in the West North Central and South Atlantic census divisions than in the entire insured population. We report results adjusted for patient characteristics, including census division, to mitigate the effect of the differences. Appendix 1 shows a comparison of the OLDW population with the US insured", "role": "user" }, { "content": "Use of prescription opioids in the United States has not substantially declined over the last decade, despite increased attention to opioid abuse and awareness of their risks, finds a study published by The BMJ today. The results show that, although opioid use and average dose of opioids levelled off after a peak in 2012-13, all patient groups had a higher average daily dose in 2017 than in 2007, and use was particularly high among patients with a disability. The US has the highest rate of opioid use in the world, consuming seven times more prescription opioids per person than the UK. An average of 40 people die in the US every day from prescription opioid overdose, and opioid use has been declared a public health emergency. Recent studies have focused on the sale and supply of opioids, but information on patient demographics is limited. As a result, relatively little is known about opioid use among people outside of the government-provided Medicare insurance scheme. So a team of US based researchers used data from a national database of medical and pharmacy claims to examine trends in opioid use among 48 million people with health insurance at any time between 2007 to 2016. Participants were covered either by commercial (private) insurance, or by Medicare Advantage (cover offered by private insurers on behalf of Medicare). The majority of non-elderly people in the US are covered by commercial insurance, often through their employer or a family member's employer. Most US citizens aged 65 and older are eligible for Medicare, while others are eligible owing to permanent disability. The research team took certain information into account, such as age, sex and place of residence, race or ethnicity, and type of medical coverage. To allow for comparison of doses across different drugs they used conversion factors from the Centers for Disease Control and Prevention to translate prescriptions of each drug into milligram morphine equivalents (MME). The researchers found that although the rate of opioid use and average dose of opioids levelled off after a peak in 2012-13, all three insurance groups had a higher average MME dose in 2017 than in 2007. Disabled Medicare beneficiaries were much more likely to use opioids than others. They were also more likely to take higher daily doses over a longer period of time. For example, they found that 52% of disabled Medicare beneficiaries used opioids annually, compared with 14% of commercially insured people and 26% of aged Medicare Advantage beneficiaries. Disabled Medicare beneficiaries aged 45 to 54 had the highest rate of opioid use. In the third quarter of 2012, 45% of disabled Medicare beneficiaries aged 45 to 54 used opioids. They also report that within the commercially insured group, by far the most commonly dispensed drug was hydrocodone, but in terms of volume, oxycodone and hydrocodone were similar. During the study period, the average daily observed dose for disabled Medicare beneficiaries using opioids never dropped below 50 MME per day, a level at which odds of overdose are up to four times higher than with doses of less than 20 MME per day. The researchers point out that this is an observational study so cannot establish cause, and they outline some limitations. For example, the study did not capture all groups of people, including uninsured people, and claims data may have missed prescriptions for people with multiple sources of insurance. Nevertheless, they say their results make clear that opioid use rates are high in the US compared with other countries. And they suggest that doctors and patients should consider whether long term opioid use is improving the patient's ability to function, and if not, should consider other treatments either as an addition or replacement to opioid use. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective To describe trends in the rate and daily dose of opioids used among commercial and Medicare Advantage beneficiaries from 2007 to 2016. Design Retrospective cohort study of administrative claims data. Setting National database of medical and pharmacy claims for commercially insured and Medicare Advantage beneficiaries in the United States. Participants 48 million individuals with any period of insurance coverage between 1 January 2007 and 31 December 2016, including commercial beneficiaries, Medicare Advantage beneficiaries aged 65 years and over, and Medicare Advantage beneficiaries under age 65 years (eligible owing to permanent disability). Main endpoints Proportion of beneficiaries with any opioid prescription per quarter, average daily dose in milligram morphine equivalents (MME), and proportion of opioid use episodes that represented long term use. Results Across all years of the study, annual opioid use prevalence was 14% for commercial beneficiaries, 26% for aged Medicare beneficiaries, and 52% for disabled Medicare beneficiaries. In the commercial beneficiary group, quarterly prevalence of opioid use changed little, starting and ending the study period at 6%; the average daily dose of 17 MME remained unchanged since 2011. For aged Medicare beneficiaries, quarterly use prevalence was also relatively stable, ranging from 11% at the beginning of the study period to 14% at the end. Disabled Medicare beneficiaries had the highest rates of opioid use, the highest rate of long term use, and the largest average daily doses. In this group, both quarterly use rates (39%) and average daily dose (56 MME) were higher at the end of 2016 than the low points observed in 2007 for each endpoint (26% prevalence and 53 MME). Conclusions Opioid use rates were high during the study period of 2007-16, with the highest rates in disabled Medicare beneficiaries versus aged Medicare beneficiaries and commercial beneficiaries. Opioid use and average daily dose have not substantially declined from their peaks, despite increased attention to opioid abuse and awareness of their risks. Introduction The United States has the highest rate of opioid use in the world, consuming 88% more prescription opioids per capita than second ranked Germany and seven times more than the United Kingdom. 1 An average of 40 people die in the US every day from a prescription opioid overdose—a fourfold increase since 1999. 2 Opioid use has been declared a public health emergency, with legally prescribed drugs contributing to substantial morbidity and mortality from addiction and overdose. 3 4 5 Studies reporting on population level opioid use have had some key limitations. Sales and supply data track nearly all legally distributed opioids, but these data do not link to patient demographics. 6 7 The National Survey on Drug Use and Health includes patient information, but is limited to patient self report of opioid use and excludes children under age 12 years. 8 The most commonly used source of healthcare claims data—Medicare fee-for-service data—provides excellent patient level data, but is limited to Medicare beneficiaries. 9 10 As a result, current knowledge about opioid use in the US is largely derived from studies of a single state or healthcare system, 11 12 13 14 or market level information that limits detailed examination of prevalence, patient level use, or subgroup analyses. 6 15 Market level data from prescription fills cannot be used to determine the proportion of people who use opioids in a given year unless prescriptions filled by the same person can be identified. Without a unique person level identifier, only the rate of prescriptions per capita can be calculated, rather than the proportion of people using opioids in a given year; the two estimates can diverge if a small number of people fill a large proportion of prescriptions. As a result, relatively little is known about person level opioid use in large national samples outside of Medicare fee-for-service beneficiaries. There are few sources of claims data for Medicare Advantage beneficiaries, who are believed to be healthier than fee-for-service beneficiaries, 16 but have not been studied in depth; there are also few datasets that cover a geographically diverse group of commercially insured beneficiaries. Both of these populations are included in the OptumLabs Data Warehouse. Accordingly, our objective was to describe the prevalence of use, dose, and duration of prescription opioids used in a large population, including both commercially insured and Medicare Advantage beneficiaries (31% of all Medicare beneficiaries 17 ), from 2007 to 2016. Using a national claims database, we aimed to explore the prevalence of opioid use and trends over the study period in subpopulations defined by insurance type (commercial, aged Medicare, and disabled Medicare) and by age. The primary goal of this paper was to estimate the change in opioid use across age and coverage types since 2007, in the face of increasing emphasis on improving prescribing patterns and preventing adverse outcomes. As a secondary goal, we also assessed the extent of concentration of opioid use in long term use episodes and among the beneficiaries with the greatest use of opioids. Methods Participants We drew pharmacy claims from the OptumLabs Data Warehouse (OLDW), a database of claims for healthcare services, insurance enrollment, and demographic information. The OLDW includes both commercially insured and Medicare Advantage beneficiaries, including age eligible beneficiaries (age ≥65 years) and individuals eligible for Medicare before age 65 years owing to permanent disability. Our study included all beneficiaries with medical and pharmacy coverage for any period of time between 1 January 2007 and 31 December 2016. The OLDW includes 20% of the commercially insured population in the US and 24% of the Medicare Advantage population. The distributions of age, sex, and race or ethnicity in the database are similar to the US commercial and Medicare Advantage populations. People from all census divisions are represented in the OLDW, with a higher proportion of OLDW beneficiaries in the West North Central and South Atlantic census divisions than in the entire insured population. We report results adjusted for patient characteristics, including census division, to mitigate the effect of the differences. Appendix 1 shows a comparison of the OLDW population with the US insured<|im_end|> <|im_start|>assistant Use of prescription opioids in the United States has not substantially declined over the last decade, despite increased attention to opioid abuse and awareness of their risks, finds a study published by The BMJ today. The results show that, although opioid use and average dose of opioids levelled off after a peak in 2012-13, all patient groups had a higher average daily dose in 2017 than in 2007, and use was particularly high among patients with a disability. The US has the highest rate of opioid use in the world, consuming seven times more prescription opioids per person than the UK. An average of 40 people die in the US every day from prescription opioid overdose, and opioid use has been declared a public health emergency. Recent studies have focused on the sale and supply of opioids, but information on patient demographics is limited. As a result, relatively little is known about opioid use among people outside of the government-provided Medicare insurance scheme. So a team of US based researchers used data from a national database of medical and pharmacy claims to examine trends in opioid use among 48 million people with health insurance at any time between 2007 to 2016. Participants were covered either by commercial (private) insurance, or by Medicare Advantage (cover offered by private insurers on behalf of Medicare). The majority of non-elderly people in the US are covered by commercial insurance, often through their employer or a family member's employer. Most US citizens aged 65 and older are eligible for Medicare, while others are eligible owing to permanent disability. The research team took certain information into account, such as age, sex and place of residence, race or ethnicity, and type of medical coverage. To allow for comparison of doses across different drugs they used conversion factors from the Centers for Disease Control and Prevention to translate prescriptions of each drug into milligram morphine equivalents (MME). The researchers found that although the rate of opioid use and average dose of opioids levelled off after a peak in 2012-13, all three insurance groups had a higher average MME dose in 2017 than in 2007. Disabled Medicare beneficiaries were much more likely to use opioids than others. They were also more likely to take higher daily doses over a longer period of time. For example, they found that 52% of disabled Medicare beneficiaries used opioids annually, compared with 14% of commercially insured people and 26% of aged Medicare Advantage beneficiaries. Disabled Medicare beneficiaries aged 45 to 54 had the highest rate of opioid use. In the third quarter of 2012, 45% of disabled Medicare beneficiaries aged 45 to 54 used opioids. They also report that within the commercially insured group, by far the most commonly dispensed drug was hydrocodone, but in terms of volume, oxycodone and hydrocodone were similar. During the study period, the average daily observed dose for disabled Medicare beneficiaries using opioids never dropped below 50 MME per day, a level at which odds of overdose are up to four times higher than with doses of less than 20 MME per day. The researchers point out that this is an observational study so cannot establish cause, and they outline some limitations. For example, the study did not capture all groups of people, including uninsured people, and claims data may have missed prescriptions for people with multiple sources of insurance. Nevertheless, they say their results make clear that opioid use rates are high in the US compared with other countries. And they suggest that doctors and patients should consider whether long term opioid use is improving the patient's ability to function, and if not, should consider other treatments either as an addition or replacement to opioid use. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Developing efficient and stable electrocatalysts is crucial for the electrochemical production of pure and clean hydrogen. For practical applications, an economical and facile method of producing catalysts for the hydrogen evolution reaction (HER) is essential. Here, we report ruthenium (Ru) nanoparticles uniformly deposited on multi-walled carbon nanotubes (MWCNTs) as an efficient HER catalyst. The catalyst exhibits the small overpotentials of 13 and 17 mV at a current density of 10 mA cm –2 in 0.5 M aq. H 2 SO 4 and 1.0 M aq. KOH, respectively, surpassing the commercial Pt/C (16 mV and 33 mV). Moreover, the catalyst has excellent stability in both media, showing almost “zeroloss” during cycling. In a real device, the catalyst produces 15.4% more hydrogen per power consumed, and shows a higher Faradaic efficiency (92.28%) than the benchmark Pt/C (85.97%). Density functional theory calculations suggest that Ru–C bonding is the most plausible active site for the HER. Introduction Given the ongoing depletion of fossil fuels and growing global environmental challenges, the search for carbon less (or free) energy is taking on increasing importance in energy engineering. Among carbon-free energy sources, hydrogen (H 2 ), is particularly popular because it contributes no environmental pollutants 1 . The most promising eco-friendly and economical way to produce pure hydrogen is by electrochemical water splitting 2 , 3 , 4 , 5 . To ensure the hydrogen evolution reaction (HER) is efficient and continuous, the catalyst must promote proton reduction with minimal overpotential, to minimize additional energy consumption 6 , 7 . This requirement has made the efficient production of hydrogen using electrochemical catalysts a challenge for scientists over the last several decades 8 , 9 , 10 , 11 , 12 , 13 , 14 . Platinum (Pt) is still considered the benchmark catalyst for the HER, with low overpotentials, small Tafel slopes and high exchange current densities due to its optimum binding force with hydrogen 15 . However, in addition to soaring cost and scarcity, Pt has poor electrochemical stability, which is associated with leaching in corrosive electrolytes and irreversible aggregation of Pt nanoparticles by Ostwald ripening 16 , 17 , limiting its practical applications. In order to replace Pt, efforts have been devoted to developing earth abundant element-based catalysts for HER, e.g., phosphates 18 , carbides 19 , 20 , oxides 21 , and transition metal sulfides 15 , 22 . However, they typically suffer from both limited electrochemical activity and durability. Recent efforts have focused on designing new catalysts with superior activity and durability compared to commercial Pt 23 , 24 , 25 . Among the many metal-based catalysts evaluated for HER catalysis, ruthenium (Ru), one of the platinum group metals, has been widely tested, because of its low-cost (1/3 the price of Pt) 26 , high HER efficiency, and stability 25 , 27 , 28 . In principle, HER efficiency is closely related to the strength of the metal-hydrogen (M–H) bonds on the surface of the catalysts 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 and the overpotential required for hydrogen reduction. The Gibbs free energy (∆G H ) of the Ru–H bond is very close to that of the optimum Pt–H bond at the center of the volcanic plot for HER 25 , 38 , 39 . But even though Ru has potentially high electrochemical HER activity, it is prone to agglomerate, because it has a much larger cohesive energy than Pt 40 . To resolve this issue, a strategy of uniformly dispersing and sequestering Ru nanoparticles in a two-dimensional (2D) carbon structure was developed, and it demonstrated excellent HER performance with low overpotentials, outstanding durability and high turnover frequencies in both acidic and alkaline conditions 25 . Developing methods to produce active but low-cost catalysts remains one of the most crucial obstacles to the realization of a hydrogen economy. Among various approaches, carbon-based materials have attracted interest as low-cost supports for active HER catalysts. Various advanced electrocatalysts have been fabricated by incorporating electrochemically active transition metals into one- or two-dimensional carbon nanostructures, including carbon nanotubes 41 and graphene nanosheets 42 . These conductive supports are important because they enable the mass production of highly efficient and stable catalysts at low-cost. And in addition to the activity of the catalytic metal nanoparticles, the conductive supports can also make a significant contribution to the overall catalytic performance. For efficient catalysis, the catalytic nanoparticles need to be dispersed and stabilized on an appropriate substrate. Here, we demonstrate that an electrocatalyst of Ru nanoparticles anchored on multiwalled carbon nanotube (Ru@MWCNT) is capable of catalysing HER with excellent activity and stability. The Ru@MWCNT catalyst exhibits superior HER activity to Ru@MWCNT and commercial Pt/C catalysts in both acidic and alkaline media. Notably, Ru carboxylate complex is formed through the introduction of carboxylic acid groups (–COOH) on MWCNT to form uniform and small Ru nanoparticles. This suggests the formation of Ru nanoparticles, Ru–C and Ru–O bonds through Extended X-ray absorption fine structure (EXAFS). In the actual water-splitting system construction and analysis, Ru@MWCNT produces 15.4% more hydrogen per power consumption than commercial Pt/C and Faradaic efficiency (92.28%) is higher than Pt/C (85.97%). Density functional theory (DFT) calculations identify the Ru–C structure as the most plausible active site structure with most stable energies for hydrogen binding energies of possible H binding sites. The Ru@MWCNT catalysts comprising Ru–C sites as reported herein have appropriate hydrogen binding energies for HER, and strong Ru–C bonding energies reflects the excellent stability. Fig. 1 Schematic illustration of the process steps for forming Ru@MWCNT catalyst. Full size image Results Preparation and characterization of catalyst A simple schematic diagram of the Ru nanoparticle-impregnated MWCNT (Ru@MWCNT) catalyst is shown in Fig. 1 . Commercial MWCNTs were mildly oxidized with nitric acid to introduce oxygenated functional groups (specifically, carboxylic acids, –COOH) on the surface of MWCNT. With abundant carboxylic acids on the surface of the MWCNT, the Ru ions (Ru 3+ ) can be easily adsorbed on the surface of", "role": "user" }, { "content": "Researchers throughout the world are working actively to accelerate the development of new catalysts that can greatly cut the cost of hydrogen production. A number of breakthrough catalysts have been reported, yet their expected performance are often unknown before implementation, and thus further research is required for practical use. A recent study, affiliated UNIST, has introduced a novel highly-efficient catalyst for hydrogen generation and its expected catalytic performance has been also demonstrated. Professor Jong-Beom Baek and his research team in the School of Energy and Chemical Engineering at UNIST have successfully developed a new water-splitting hydrogen catalyst, which consists of ruthenium (Ru) nanoparticles uniformly distributed and anchored on the surface of multiwalled carbon nanotubes (MWCNTs), or (Ru@MWCNT). The research team also evaluated the catalytic performance of the Ru@MWCNT. The results indicated that the Ru@MWCNT catalyst is superior in many ways to the commercial Pt/C catalysts. The new catalysts are simple to synthesize and can be mass-produced, according to the research team. \"In addition to introducing highly-efficient and stable catalysts that surpass the characteristics of existing materials, this study aims at evaluating the catalytic performance of catalyst electrodes, which is an essential part of commercialization,\" says Professor Baek. Hydrogen is the most abundant element, which accounts for 75% of the universe, and has been regarded as an efficient and environment friendly power source for the future. Currently, the majority of hydrogen is produced from fossil fuels, such as natural gas and this often release carbon dioxide (CO2) emissions in the process. As an alternative, the process of using electricity to split water into hydrogen and oxygen has been suggested, but this requires the usage of expensive catalysts, such as platinum. Figure 2. Schematic illustration of the process steps for forming Ru@MWCNT catalyst. Credit: Professor Jong-Beom Baek, UNIST Hence, Professor Baek's team has been steadily developing catalysts that are not only superior in performance to traditional platinum catalysts, but have lower production costs. The Ru@MWCNT catalyst exhibits superior electrochemical properties over the previously announced metal-organic catalysts. The catalyst demonstrates excellent HER performance with low overpotentials (See Figure 1), outstanding durability and high turnover frequencies in both acidic and alkaline conditions. The Ru@MWCNT catalysts take the structure, in which ruthenium (Ru) nanoparticles are uniformly distributed and anchored on the surface of multiwalled carbon nanotubes (MWCNTs). Thanks to the smaller particle size distribution and particle uniformity, it displays excellent HER performance and for this, a manufacturing process has been also developed. \"The existing method of combining Ru and CNTs, there is a tendency for Ru particles stick together and by steadily increasing the size of the agglomerate during the heat treatment,\" says Do Hyung Kweon (Combined M.S/Ph.D. of Energy and Chemical Engineering, UNIST), the first author of the study. \"We suppress this particle agglomeration via the introduction of 'Ru salt' and '-COOH' and this enabled the uniform distribution of Ru nanoparticles on the surface of the MWCNT.\" Figure 3. HER performance evaluation in actual water splitting. Credit: Professor Jong-Beom Baek, UNIST In order to accurately determine the performance of the new catalyst, Professor Baek has conducted the HER performance evaluation in the actual water-splitting system construction and analysis, in addition to the existing overpotential measurement. Their results show that Ru@MWCNT produces 15.4% more hydrogen per power consumption than commercial Pt/C and Faradaic efficiency (92.28%) is higher than Pt/C (85.97%). \"Previous studies on hydrogen catalysts focus on the evaluation of the catalytic performance itself, and they were inadequate to deal with the actual water-splitting system construction and analysis,\" says Professor Baek. \"This study is significant as it can predict the actual HER applicability.\" The findings of this research have been published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Developing efficient and stable electrocatalysts is crucial for the electrochemical production of pure and clean hydrogen. For practical applications, an economical and facile method of producing catalysts for the hydrogen evolution reaction (HER) is essential. Here, we report ruthenium (Ru) nanoparticles uniformly deposited on multi-walled carbon nanotubes (MWCNTs) as an efficient HER catalyst. The catalyst exhibits the small overpotentials of 13 and 17 mV at a current density of 10 mA cm –2 in 0.5 M aq. H 2 SO 4 and 1.0 M aq. KOH, respectively, surpassing the commercial Pt/C (16 mV and 33 mV). Moreover, the catalyst has excellent stability in both media, showing almost “zeroloss” during cycling. In a real device, the catalyst produces 15.4% more hydrogen per power consumed, and shows a higher Faradaic efficiency (92.28%) than the benchmark Pt/C (85.97%). Density functional theory calculations suggest that Ru–C bonding is the most plausible active site for the HER. Introduction Given the ongoing depletion of fossil fuels and growing global environmental challenges, the search for carbon less (or free) energy is taking on increasing importance in energy engineering. Among carbon-free energy sources, hydrogen (H 2 ), is particularly popular because it contributes no environmental pollutants 1 . The most promising eco-friendly and economical way to produce pure hydrogen is by electrochemical water splitting 2 , 3 , 4 , 5 . To ensure the hydrogen evolution reaction (HER) is efficient and continuous, the catalyst must promote proton reduction with minimal overpotential, to minimize additional energy consumption 6 , 7 . This requirement has made the efficient production of hydrogen using electrochemical catalysts a challenge for scientists over the last several decades 8 , 9 , 10 , 11 , 12 , 13 , 14 . Platinum (Pt) is still considered the benchmark catalyst for the HER, with low overpotentials, small Tafel slopes and high exchange current densities due to its optimum binding force with hydrogen 15 . However, in addition to soaring cost and scarcity, Pt has poor electrochemical stability, which is associated with leaching in corrosive electrolytes and irreversible aggregation of Pt nanoparticles by Ostwald ripening 16 , 17 , limiting its practical applications. In order to replace Pt, efforts have been devoted to developing earth abundant element-based catalysts for HER, e.g., phosphates 18 , carbides 19 , 20 , oxides 21 , and transition metal sulfides 15 , 22 . However, they typically suffer from both limited electrochemical activity and durability. Recent efforts have focused on designing new catalysts with superior activity and durability compared to commercial Pt 23 , 24 , 25 . Among the many metal-based catalysts evaluated for HER catalysis, ruthenium (Ru), one of the platinum group metals, has been widely tested, because of its low-cost (1/3 the price of Pt) 26 , high HER efficiency, and stability 25 , 27 , 28 . In principle, HER efficiency is closely related to the strength of the metal-hydrogen (M–H) bonds on the surface of the catalysts 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 and the overpotential required for hydrogen reduction. The Gibbs free energy (∆G H ) of the Ru–H bond is very close to that of the optimum Pt–H bond at the center of the volcanic plot for HER 25 , 38 , 39 . But even though Ru has potentially high electrochemical HER activity, it is prone to agglomerate, because it has a much larger cohesive energy than Pt 40 . To resolve this issue, a strategy of uniformly dispersing and sequestering Ru nanoparticles in a two-dimensional (2D) carbon structure was developed, and it demonstrated excellent HER performance with low overpotentials, outstanding durability and high turnover frequencies in both acidic and alkaline conditions 25 . Developing methods to produce active but low-cost catalysts remains one of the most crucial obstacles to the realization of a hydrogen economy. Among various approaches, carbon-based materials have attracted interest as low-cost supports for active HER catalysts. Various advanced electrocatalysts have been fabricated by incorporating electrochemically active transition metals into one- or two-dimensional carbon nanostructures, including carbon nanotubes 41 and graphene nanosheets 42 . These conductive supports are important because they enable the mass production of highly efficient and stable catalysts at low-cost. And in addition to the activity of the catalytic metal nanoparticles, the conductive supports can also make a significant contribution to the overall catalytic performance. For efficient catalysis, the catalytic nanoparticles need to be dispersed and stabilized on an appropriate substrate. Here, we demonstrate that an electrocatalyst of Ru nanoparticles anchored on multiwalled carbon nanotube (Ru@MWCNT) is capable of catalysing HER with excellent activity and stability. The Ru@MWCNT catalyst exhibits superior HER activity to Ru@MWCNT and commercial Pt/C catalysts in both acidic and alkaline media. Notably, Ru carboxylate complex is formed through the introduction of carboxylic acid groups (–COOH) on MWCNT to form uniform and small Ru nanoparticles. This suggests the formation of Ru nanoparticles, Ru–C and Ru–O bonds through Extended X-ray absorption fine structure (EXAFS). In the actual water-splitting system construction and analysis, Ru@MWCNT produces 15.4% more hydrogen per power consumption than commercial Pt/C and Faradaic efficiency (92.28%) is higher than Pt/C (85.97%). Density functional theory (DFT) calculations identify the Ru–C structure as the most plausible active site structure with most stable energies for hydrogen binding energies of possible H binding sites. The Ru@MWCNT catalysts comprising Ru–C sites as reported herein have appropriate hydrogen binding energies for HER, and strong Ru–C bonding energies reflects the excellent stability. Fig. 1 Schematic illustration of the process steps for forming Ru@MWCNT catalyst. Full size image Results Preparation and characterization of catalyst A simple schematic diagram of the Ru nanoparticle-impregnated MWCNT (Ru@MWCNT) catalyst is shown in Fig. 1 . Commercial MWCNTs were mildly oxidized with nitric acid to introduce oxygenated functional groups (specifically, carboxylic acids, –COOH) on the surface of MWCNT. With abundant carboxylic acids on the surface of the MWCNT, the Ru ions (Ru 3+ ) can be easily adsorbed on the surface of<|im_end|> <|im_start|>assistant Researchers throughout the world are working actively to accelerate the development of new catalysts that can greatly cut the cost of hydrogen production. A number of breakthrough catalysts have been reported, yet their expected performance are often unknown before implementation, and thus further research is required for practical use. A recent study, affiliated UNIST, has introduced a novel highly-efficient catalyst for hydrogen generation and its expected catalytic performance has been also demonstrated. Professor Jong-Beom Baek and his research team in the School of Energy and Chemical Engineering at UNIST have successfully developed a new water-splitting hydrogen catalyst, which consists of ruthenium (Ru) nanoparticles uniformly distributed and anchored on the surface of multiwalled carbon nanotubes (MWCNTs), or (Ru@MWCNT). The research team also evaluated the catalytic performance of the Ru@MWCNT. The results indicated that the Ru@MWCNT catalyst is superior in many ways to the commercial Pt/C catalysts. The new catalysts are simple to synthesize and can be mass-produced, according to the research team. "In addition to introducing highly-efficient and stable catalysts that surpass the characteristics of existing materials, this study aims at evaluating the catalytic performance of catalyst electrodes, which is an essential part of commercialization," says Professor Baek. Hydrogen is the most abundant element, which accounts for 75% of the universe, and has been regarded as an efficient and environment friendly power source for the future. Currently, the majority of hydrogen is produced from fossil fuels, such as natural gas and this often release carbon dioxide (CO2) emissions in the process. As an alternative, the process of using electricity to split water into hydrogen and oxygen has been suggested, but this requires the usage of expensive catalysts, such as platinum. Figure 2. Schematic illustration of the process steps for forming Ru@MWCNT catalyst. Credit: Professor Jong-Beom Baek, UNIST Hence, Professor Baek's team has been steadily developing catalysts that are not only superior in performance to traditional platinum catalysts, but have lower production costs. The Ru@MWCNT catalyst exhibits superior electrochemical properties over the previously announced metal-organic catalysts. The catalyst demonstrates excellent HER performance with low overpotentials (See Figure 1), outstanding durability and high turnover frequencies in both acidic and alkaline conditions. The Ru@MWCNT catalysts take the structure, in which ruthenium (Ru) nanoparticles are uniformly distributed and anchored on the surface of multiwalled carbon nanotubes (MWCNTs). Thanks to the smaller particle size distribution and particle uniformity, it displays excellent HER performance and for this, a manufacturing process has been also developed. "The existing method of combining Ru and CNTs, there is a tendency for Ru particles stick together and by steadily increasing the size of the agglomerate during the heat treatment," says Do Hyung Kweon (Combined M.S/Ph.D. of Energy and Chemical Engineering, UNIST), the first author of the study. "We suppress this particle agglomeration via the introduction of 'Ru salt' and '-COOH' and this enabled the uniform distribution of Ru nanoparticles on the surface of the MWCNT." Figure 3. HER performance evaluation in actual water splitting. Credit: Professor Jong-Beom Baek, UNIST In order to accurately determine the performance of the new catalyst, Professor Baek has conducted the HER performance evaluation in the actual water-splitting system construction and analysis, in addition to the existing overpotential measurement. Their results show that Ru@MWCNT produces 15.4% more hydrogen per power consumption than commercial Pt/C and Faradaic efficiency (92.28%) is higher than Pt/C (85.97%). "Previous studies on hydrogen catalysts focus on the evaluation of the catalytic performance itself, and they were inadequate to deal with the actual water-splitting system construction and analysis," says Professor Baek. "This study is significant as it can predict the actual HER applicability." The findings of this research have been published in Nature Communications. <|im_end|>

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2,285

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Polygenic scores (PGSs) have limited portability across different groupings of individuals (for example, by genetic ancestries and/or social determinants of health), preventing their equitable use 1 , 2 , 3 . PGS portability has typically been assessed using a single aggregate population-level statistic (for example, R 2 ) 4 , ignoring inter-individual variation within the population. Here, using a large and diverse Los Angeles biobank 5 (ATLAS, n = 36,778) along with the UK Biobank 6 (UKBB, n = 487,409), we show that PGS accuracy decreases individual-to-individual along the continuum of genetic ancestries 7 in all considered populations, even within traditionally labelled ‘homogeneous’ genetic ancestries. The decreasing trend is well captured by a continuous measure of genetic distance (GD) from the PGS training data: Pearson correlation of −0.95 between GD and PGS accuracy averaged across 84 traits. When applying PGS models trained on individuals labelled as white British in the UKBB to individuals with European ancestries in ATLAS, individuals in the furthest GD decile have 14% lower accuracy relative to the closest decile; notably, the closest GD decile of individuals with Hispanic Latino American ancestries show similar PGS performance to the furthest GD decile of individuals with European ancestries. GD is significantly correlated with PGS estimates themselves for 82 of 84 traits, further emphasizing the importance of incorporating the continuum of genetic ancestries in PGS interpretation. Our results highlight the need to move away from discrete genetic ancestry clusters towards the continuum of genetic ancestries when considering PGSs. Main PGSs—estimates of an individual’s genetic predisposition for complex traits and diseases (that is, genetic liability; also referred to as genetic value)—have garnered tremendous attention recently across a wide range of fields, from personalized genomic medicine 4 , 8 , 9 , 10 to disease risk prediction and prevention 11 , 12 , 13 , 14 to socio-genomics 3 , 15 . However, the variation in PGS performance across different genetic ancestries and/or socio-demographic features (for example, sex, age and social determinants of health) 2 poses a critical equity barrier that has prevented widespread adoption of PGSs. Similar portability issues have also been reported for non-genetic clinical models 16 , 17 , 18 . The interpretation and application of PGSs are further complicated by the conflation of genetic ancestries with social constructs such as nationality, race and/or ethnicity. Here we investigate PGS performance across genetically inferred ancestry (GIA), which describes the genetic similarity of an individual to a reference dataset (for example, 1000 Genomes 19 ) as inferred by methods such as principal component analysis (PCA); GIAs do not represent the full genetic diversity of human populations. Genetic prediction and its accuracy (or reliability) have been extensively studied in agricultural settings with a focus on breeding programmes 20 , 21 , 22 , 23 . At the population level, PGS accuracy can be expressed as a function of heritability, training sample size and the number of markers used in the predictor in single 24 , 25 , 26 or multi-population settings with or without effect size heterogeneity 27 . At the individual level, accuracy of genetic prediction from pedigree data 28 , 29 , 30 can be derived as a function of the inverse of the coefficient matrix of mixed-models equations, whereas accuracy of genetic prediction using whole-genome genetic data can be derived similarly, with the pedigree matrix replaced with the genomic relationships matrix 21 , 22 , 23 , 27 , 31 , 32 among training and testing individuals. Simulations guided by dairy breeding programmes showcase that genomic prediction accuracy varies with genetic relatedness of the testing individual to the training data 33 , 34 as well as across generations, owing to the decay of genetic relationships 35 . In humans, PGS performance evaluation has traditionally relied on population-level accuracy metrics (for example, R 2 ) 2 , 4 . PGS accuracy decays as the target populations become more dissimilar from the training data using either relatedness 36 , 37 or continental or subcontinental ancestry groupings 1 , 38 , 39 , 40 ; the decay may be explained by differences in linkage disequilibrium, minor allele frequencies and/or heterogeneity in genetic effects due to gene–gene and gene–environment interactions 41 . However, population-level metrics of accuracy provide only an aggregate (average) metric for all individuals in the population, thus implicitly assuming some level of homogeneity across individuals 2 , 4 , 42 . Homogeneous populations are an idealized concept that only roughly approximate human data; human diversity exists along a genetic ancestry continuum without clearly defined clusters and with various correlations between genetic and socio-environmental factors 7 , 42 , 43 , 44 , 45 , 46 . Grouping individuals into discrete GIA clusters obscures the impact of individual variation on PGS accuracy. This is evident among individuals with recently admixed genomes for which genetic ancestries vary individual-to-individual and locus-to-locus in the genome. For example, a single population-level PGS accuracy estimated across all African Americans overestimates PGS accuracy for African Americans with large proportions of African GIA 40 ; likewise, coronary artery disease PGS performs poorly in Hispanic individuals with high proportions of African GIA 47 . The genetic ancestry continuum affects PGS accuracy even in traditionally labelled ‘homogeneous’ or ‘non-admixed’ populations. For example, PGS accuracy decays across a gradient of subcontinental ancestries within Europe as the target cohorts become more genetically dissimilar from the PGS training data 39 , 45 . Assessing PGS accuracy using population-level metrics is further complicated by technical issues in assigning individuals to discrete clusters of GIA. Different algorithms and/or reference panels may assign the same individual to different clusters 39 , 42 , 48 , leading to different PGS accuracies. Moreover, many individuals are not assigned to any cluster owing to limited reference panels used for genetic ancestry inference 5 , 39 , leaving such individuals outside PGS characterization. This poses equity concerns as it limits PGS applications only to individuals within well-defined GIAs. Here we leverage classical theory 28 , 29 , 30 and", "role": "user" }, { "content": "Polygenic scores—estimates of an individual's predisposition for complex traits and diseases—hold promise for identifying patients at risk of disease and guiding early, personalized treatments, but UCLA experts found the scores fail to account for the wide range of genetic diversity across individuals in all ancestries. \"Polygenic scores can estimate the likelihood of an individual having a certain trait by pulling together and analyzing the small effects of thousands to millions of common genetic variants into a single score, but their performance among individuals from diverse genetic backgrounds is limited,\" said Bogdan Pasaniuc, Ph.D., a UCLA Health expert in statistical and computational methods for understanding genetic risk factors for common diseases. The researchers' analysis, published in Nature, shows that the accuracy of polygenic scores (PGSs) varies between individuals across a continuum of genetic ancestry—and this is true even in populations that are traditionally considered as \"homogeneous,\" (e.g., Europeans) said Pasaniuc, the paper's senior author. Assessing PGS performance has commonly been done at the \"population\" level, such as in \"Europeans,\" clumping individuals of similar ancestries in a genetic-ancestry cluster, the authors said. \"Imposing artificial boundaries onto this continuum and ignoring the diversity, or 'heterogeneity,' within clusters can obscure variation within a group, conceal the similarities that may exist in individuals in different groups, and leave out individuals who do not fit neatly into a particular genetic ancestry,\" said Yi Ding, a graduate student in bioinformatics at UCLA, a member of the Pasaniuc Lab, and the paper's first author. To provide a more precise estimate of PGS accuracy, the researchers developed a method to evaluate PGS accuracy at the individual level. To test it, they applied PGSs for 84 complex traits to data from more than 35,000 individuals in the UCLA ATLAS Precision Health Biobank, one of the most diverse biobanks in the world, in part because the Los Angeles area is home to one of the most ancestrally diverse populations globally. The new tool's \"training\" data came from a subset of individuals in the UK Biobank in the United Kingdom. As a substitute for discrete genetic ancestries, a continuous metric of \"genetic distance\" was used to establish the position of each individual in the ATLAS database on the genetic-ancestry continuum, essentially showing how similar or dissimilar a target (ATLAS) individual's genome was to that from the UK training population. \"We found that the more dissimilar—or genetically 'distant'—a target individual's genome was from the UK Biobank training data, the lower the accuracy of the PGS,\" Ding said. The accuracy of PGSs declined as genetic distance became greater even when the researchers looked specifically at genetic-ancestry groupings that have been considered homogeneous, such as among individuals of European genetic ancestries. Conversely, some individuals not identified with European ancestry could have higher levels of genetic similarity, showing that PGS performance could differ between two individuals from the same ancestry but be comparable for two people from different ancestries—depending on their genetic similarity. \"Our genetic-distance metric outperformed discrete clustering in identifying individuals who could benefit from PGSs,\" said Pasaniuc, a researcher at the David Geffen School of Medicine at UCLA and the UCLA Health Institute for Precision Health. The research team identified several factors—subjects for ongoing and future studies—that could impact PGS accuracy and usefulness, especially in people with \"admixed\" ancestries. These are usually defined as individuals with recent ancestry from two or more continental sources—such as African Americans and Latinos. Pasaniuc, whose research focuses on improving genetic risk factor predictions for people with admixed ancestry, said these individuals have \"mosaic\" genomes, with segments of different continental ancestries at every region. With different portions contributed by different ancestries, it is extremely difficult to accurately classify these individuals using conventional ancestry labels. \"For PGSs to be equitably used,\" he said, \"the assessment of PGS accuracy should account for the full spectrum of genetic diversity.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Polygenic scores (PGSs) have limited portability across different groupings of individuals (for example, by genetic ancestries and/or social determinants of health), preventing their equitable use 1 , 2 , 3 . PGS portability has typically been assessed using a single aggregate population-level statistic (for example, R 2 ) 4 , ignoring inter-individual variation within the population. Here, using a large and diverse Los Angeles biobank 5 (ATLAS, n = 36,778) along with the UK Biobank 6 (UKBB, n = 487,409), we show that PGS accuracy decreases individual-to-individual along the continuum of genetic ancestries 7 in all considered populations, even within traditionally labelled ‘homogeneous’ genetic ancestries. The decreasing trend is well captured by a continuous measure of genetic distance (GD) from the PGS training data: Pearson correlation of −0.95 between GD and PGS accuracy averaged across 84 traits. When applying PGS models trained on individuals labelled as white British in the UKBB to individuals with European ancestries in ATLAS, individuals in the furthest GD decile have 14% lower accuracy relative to the closest decile; notably, the closest GD decile of individuals with Hispanic Latino American ancestries show similar PGS performance to the furthest GD decile of individuals with European ancestries. GD is significantly correlated with PGS estimates themselves for 82 of 84 traits, further emphasizing the importance of incorporating the continuum of genetic ancestries in PGS interpretation. Our results highlight the need to move away from discrete genetic ancestry clusters towards the continuum of genetic ancestries when considering PGSs. Main PGSs—estimates of an individual’s genetic predisposition for complex traits and diseases (that is, genetic liability; also referred to as genetic value)—have garnered tremendous attention recently across a wide range of fields, from personalized genomic medicine 4 , 8 , 9 , 10 to disease risk prediction and prevention 11 , 12 , 13 , 14 to socio-genomics 3 , 15 . However, the variation in PGS performance across different genetic ancestries and/or socio-demographic features (for example, sex, age and social determinants of health) 2 poses a critical equity barrier that has prevented widespread adoption of PGSs. Similar portability issues have also been reported for non-genetic clinical models 16 , 17 , 18 . The interpretation and application of PGSs are further complicated by the conflation of genetic ancestries with social constructs such as nationality, race and/or ethnicity. Here we investigate PGS performance across genetically inferred ancestry (GIA), which describes the genetic similarity of an individual to a reference dataset (for example, 1000 Genomes 19 ) as inferred by methods such as principal component analysis (PCA); GIAs do not represent the full genetic diversity of human populations. Genetic prediction and its accuracy (or reliability) have been extensively studied in agricultural settings with a focus on breeding programmes 20 , 21 , 22 , 23 . At the population level, PGS accuracy can be expressed as a function of heritability, training sample size and the number of markers used in the predictor in single 24 , 25 , 26 or multi-population settings with or without effect size heterogeneity 27 . At the individual level, accuracy of genetic prediction from pedigree data 28 , 29 , 30 can be derived as a function of the inverse of the coefficient matrix of mixed-models equations, whereas accuracy of genetic prediction using whole-genome genetic data can be derived similarly, with the pedigree matrix replaced with the genomic relationships matrix 21 , 22 , 23 , 27 , 31 , 32 among training and testing individuals. Simulations guided by dairy breeding programmes showcase that genomic prediction accuracy varies with genetic relatedness of the testing individual to the training data 33 , 34 as well as across generations, owing to the decay of genetic relationships 35 . In humans, PGS performance evaluation has traditionally relied on population-level accuracy metrics (for example, R 2 ) 2 , 4 . PGS accuracy decays as the target populations become more dissimilar from the training data using either relatedness 36 , 37 or continental or subcontinental ancestry groupings 1 , 38 , 39 , 40 ; the decay may be explained by differences in linkage disequilibrium, minor allele frequencies and/or heterogeneity in genetic effects due to gene–gene and gene–environment interactions 41 . However, population-level metrics of accuracy provide only an aggregate (average) metric for all individuals in the population, thus implicitly assuming some level of homogeneity across individuals 2 , 4 , 42 . Homogeneous populations are an idealized concept that only roughly approximate human data; human diversity exists along a genetic ancestry continuum without clearly defined clusters and with various correlations between genetic and socio-environmental factors 7 , 42 , 43 , 44 , 45 , 46 . Grouping individuals into discrete GIA clusters obscures the impact of individual variation on PGS accuracy. This is evident among individuals with recently admixed genomes for which genetic ancestries vary individual-to-individual and locus-to-locus in the genome. For example, a single population-level PGS accuracy estimated across all African Americans overestimates PGS accuracy for African Americans with large proportions of African GIA 40 ; likewise, coronary artery disease PGS performs poorly in Hispanic individuals with high proportions of African GIA 47 . The genetic ancestry continuum affects PGS accuracy even in traditionally labelled ‘homogeneous’ or ‘non-admixed’ populations. For example, PGS accuracy decays across a gradient of subcontinental ancestries within Europe as the target cohorts become more genetically dissimilar from the PGS training data 39 , 45 . Assessing PGS accuracy using population-level metrics is further complicated by technical issues in assigning individuals to discrete clusters of GIA. Different algorithms and/or reference panels may assign the same individual to different clusters 39 , 42 , 48 , leading to different PGS accuracies. Moreover, many individuals are not assigned to any cluster owing to limited reference panels used for genetic ancestry inference 5 , 39 , leaving such individuals outside PGS characterization. This poses equity concerns as it limits PGS applications only to individuals within well-defined GIAs. Here we leverage classical theory 28 , 29 , 30 and<|im_end|> <|im_start|>assistant Polygenic scores—estimates of an individual's predisposition for complex traits and diseases—hold promise for identifying patients at risk of disease and guiding early, personalized treatments, but UCLA experts found the scores fail to account for the wide range of genetic diversity across individuals in all ancestries. "Polygenic scores can estimate the likelihood of an individual having a certain trait by pulling together and analyzing the small effects of thousands to millions of common genetic variants into a single score, but their performance among individuals from diverse genetic backgrounds is limited," said Bogdan Pasaniuc, Ph.D., a UCLA Health expert in statistical and computational methods for understanding genetic risk factors for common diseases. The researchers' analysis, published in Nature, shows that the accuracy of polygenic scores (PGSs) varies between individuals across a continuum of genetic ancestry—and this is true even in populations that are traditionally considered as "homogeneous," (e.g., Europeans) said Pasaniuc, the paper's senior author. Assessing PGS performance has commonly been done at the "population" level, such as in "Europeans," clumping individuals of similar ancestries in a genetic-ancestry cluster, the authors said. "Imposing artificial boundaries onto this continuum and ignoring the diversity, or 'heterogeneity,' within clusters can obscure variation within a group, conceal the similarities that may exist in individuals in different groups, and leave out individuals who do not fit neatly into a particular genetic ancestry," said Yi Ding, a graduate student in bioinformatics at UCLA, a member of the Pasaniuc Lab, and the paper's first author. To provide a more precise estimate of PGS accuracy, the researchers developed a method to evaluate PGS accuracy at the individual level. To test it, they applied PGSs for 84 complex traits to data from more than 35,000 individuals in the UCLA ATLAS Precision Health Biobank, one of the most diverse biobanks in the world, in part because the Los Angeles area is home to one of the most ancestrally diverse populations globally. The new tool's "training" data came from a subset of individuals in the UK Biobank in the United Kingdom. As a substitute for discrete genetic ancestries, a continuous metric of "genetic distance" was used to establish the position of each individual in the ATLAS database on the genetic-ancestry continuum, essentially showing how similar or dissimilar a target (ATLAS) individual's genome was to that from the UK training population. "We found that the more dissimilar—or genetically 'distant'—a target individual's genome was from the UK Biobank training data, the lower the accuracy of the PGS," Ding said. The accuracy of PGSs declined as genetic distance became greater even when the researchers looked specifically at genetic-ancestry groupings that have been considered homogeneous, such as among individuals of European genetic ancestries. Conversely, some individuals not identified with European ancestry could have higher levels of genetic similarity, showing that PGS performance could differ between two individuals from the same ancestry but be comparable for two people from different ancestries—depending on their genetic similarity. "Our genetic-distance metric outperformed discrete clustering in identifying individuals who could benefit from PGSs," said Pasaniuc, a researcher at the David Geffen School of Medicine at UCLA and the UCLA Health Institute for Precision Health. The research team identified several factors—subjects for ongoing and future studies—that could impact PGS accuracy and usefulness, especially in people with "admixed" ancestries. These are usually defined as individuals with recent ancestry from two or more continental sources—such as African Americans and Latinos. Pasaniuc, whose research focuses on improving genetic risk factor predictions for people with admixed ancestry, said these individuals have "mosaic" genomes, with segments of different continental ancestries at every region. With different portions contributed by different ancestries, it is extremely difficult to accurately classify these individuals using conventional ancestry labels. "For PGSs to be equitably used," he said, "the assessment of PGS accuracy should account for the full spectrum of genetic diversity." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The central challenge in building a quantum computer is error correction. Unlike classical bits, which are susceptible to only one type of error, quantum bits (qubits) are susceptible to two types of error, corresponding to flips of the qubit state about the X and Z directions. Although the Heisenberg uncertainty principle precludes simultaneous monitoring of X - and Z -flips on a single qubit, it is possible to encode quantum information in large arrays of entangled qubits that enable accurate monitoring of all errors in the system, provided that the error rate is low 1 . Another crucial requirement is that errors cannot be correlated. Here we characterize a superconducting multiqubit circuit and find that charge noise in the chip is highly correlated on a length scale over 600 micrometres; moreover, discrete charge jumps are accompanied by a strong transient reduction of qubit energy relaxation time across the millimetre-scale chip. The resulting correlated errors are explained in terms of the charging event and phonon-mediated quasiparticle generation associated with absorption of γ-rays and cosmic-ray muons in the qubit substrate. Robust quantum error correction will require the development of mitigation strategies to protect multiqubit arrays from correlated errors due to particle impacts. Main The two-dimensional surface code is widely seen as a promising approach to realization of a fault-tolerant quantum computer based on superconducting integrated circuits 1 . In this architecture, quantum information is encoded in a two-dimensional fabric of superconducting qubits with nearest-neighbour connectivity. Provided that gate operations and measurements are performed above a certain fault-tolerant threshold, it is possible to uniquely identify and correct errors in the system by monitoring multiqubit parity operators of the form XXXX and ZZZZ , where X and Z are single-qubit Pauli operators. In recent years, a number of groups have achieved beyond-threshold fidelities for single- and two-qubit gate operations 2 , 3 and for qubit measurement 4 , 5 , 6 , and steady improvements in performance are expected. The rigorous proof that it is possible, in principle, to achieve fault tolerance once threshold levels of fidelity are reached underpins much of the optimism for the surface code. However, this proof rests on the assumption that errors across the multiqubit array are uncorrelated in both space and time. Although it is possible to mitigate errors that are weakly correlated across neighbouring qubits (L.F. & L.B.I., manuscript in preparation), quantum error correction will break down in the face of simultaneous errors that are correlated over large length scales. Here we demonstrate spatially correlated charge fluctuations in a superconducting multiqubit chip over length scales of hundreds of micrometres, accompanied by correlated relaxation errors that extend over several millimetres. The data are compatible with absorption in the qubit substrate of cosmic-ray muons and γ-rays from background radioactivity. We perform detailed numerical modelling to determine the spatial profile of the charge burst associated with an absorption event; in addition, we present a simple model that describes the propagation of energy released by the event through scattering of pair-breaking phonons. These results have far-reaching implications for proposed error correction schemes such as the surface code that rely on large-scale arrays of qubits to monitor multiqubit stabilizers. A thorough understanding of the physics of particle impact events will be required to develop appropriate mitigation strategies and to engineer new approaches for fault-tolerant multiqubit arrays. The sample geometry is shown in Fig. 1a–c . The 6.25 × 6.25 mm 2 chip incorporates four weakly charge-sensitive transmon qubits with a ratio of Josephson energy to single-electron charging energy E J / E c = 24; the detailed device parameters are presented in the Supplementary Information . Each qubit comprises a circular superconducting Nb island with radius r i = 70 μm embedded in a circular cavity with radius r o = 90.5 μm in the superconducting Nb groundplane. Two of the qubits are positioned on one side of the chip with a centre-to-centre separation of 340 μm, while two of the qubits are on the opposite side of the chip with 640 μm centre-to-centre separation. The qubit pairs are separated by around 3 mm. Each qubit is coupled to a local readout resonator that is in turn coupled to a common feedline. Fig. 1: Chip layout and charge response. a , Optical micrograph of the multiqubit chip. Four charge-sensitive transmon qubits (Q1–Q4, magenta) are coupled to local readout resonators (cyan) and charge gate lines (orange). The readout resonators are coupled to a common feedline (purple). Image is a stitched composite (see Supplementary Information ). b , Close-up view of a single qubit. c , Circuit diagram of the chip. Colour coding matches the false colouring in a and b . d , Simulation of the charge induced on the qubit island from a unit point charge at various locations in the Si substrate. Full size image For the purposes of interpreting the experiments described here, it is useful to consider the qubits as electrometers with a large effective sensing area for electric fields in the substrate. For our concentric qubit geometry, the sensing area for uniform electric fields is π εr i r o , where ε is the relative permittivity of the medium. In Fig. 1d , we display the numerically computed offset charge on the qubit island induced by a unit point charge at various locations in the substrate; for an applied unit charge, the induced offset charge is simply the fraction of electric field lines that terminate on the qubit island. In a first series of experiments, we perform simultaneous Ramsey tomography on the four qubits to generate time series of fluctuating offset charge. In Fig. 2a , we show representative qubit spectroscopy, and in Fig. 2b we show the experimental pulse sequence for the charge measurements 7 . The Ramsey X /2−idle− X /2 sequence maps precession frequency to occupation of the qubit |1 ⟩ state irrespective of the quasiparticle parity of the qubit island. We perform a series of such experiments for different applied gate charge", "role": "user" }, { "content": "Quantum computers could outperform classical computers at many tasks, but only if the errors that are an inevitable part of computational tasks are isolated rather than widespread events. Now, researchers at the University of Wisconsin-Madison have found evidence that errors are correlated across an entire superconducting quantum computing chip—highlighting a problem that must be acknowledged and addressed in the quest for fault-tolerant quantum computers. The researchers report their findings in a study published June 16 in the journal Nature, Importantly, their work also points to mitigation strategies. \"I think people have been approaching the problem of error correction in an overly optimistic way, blindly making the assumption that errors are not correlated,\" says UW-Madison physics Professor Robert McDermott, senior author of the study. \"Our experiments show absolutely that errors are correlated, but as we identify problems and develop a deep physical understanding, we're going to find ways to work around them.\" The bits in a classical computer can either be a 1 or a 0, but the qubits in a quantum computer can be 1, 0, or an arbitrary mixture—a superposition—of 1 and 0. Classical bits, then, can only make bit flip errors, such as when a 1 flips to 0. Qubits, however, can make two types of error: bit flips or phase flips, where a quantum superposition state changes. To fix errors, computers must monitor them as they happen. But the laws of quantum physics say that only one error type can be monitored at a time in a single qubit, so a clever error correction protocol called the surface code has been proposed. The surface code involves a large array of connected qubits—some do the computational work, while others are monitored to infer errors in the computational qubits. However, the surface code protocol works reliably only if events that cause errors are isolated, affecting at most a few qubits. In earlier experiments, McDermott's group had seen hints that something was causing multiple qubits to flip at the same time. In this new study, they directly asked: are these flips independent, or are they correlated? The research team designed a chip with four qubits made of the superconducting elements niobium and aluminum. The scientists cool the chip to nearly absolute zero, which makes it superconduct and protects it from error-causing interference from the outside environment. To assess whether qubit flips were correlated, the researchers measured fluctuations in offset charge for all four qubits. The fluctuating offset charge is effectively a change in electric field at the qubit. The team observed long periods of relative stability followed by sudden jumps in offset charge. The closer two qubits were together, the more likely they were to jump at the same time. These sudden changes were most likely caused by cosmic rays or background radiation in the lab, which both release charged particles. When one of these particles hits the chip, it frees up charges that affect nearby qubits. This local effect can be easily mitigated with simple design changes. The bigger concern is what could happen next. \"If our model about particle impacts is correct, then we would expect that most of the energy is converted into vibrations in the chip that propagate over long distances,\" says Chris Wilen, a graduate student and lead author of the study. \"As the energy spreads, the disturbance would lead to qubit flips that are correlated across the entire chip.\" In their next set of experiments, that effect is exactly what they saw. They measured charge jumps in one qubit, as in the earlier experiments, then used the timing of these jumps to align measurements of the quantum states of two other qubits. Those two qubits should always be in the computational 1 state. Yet the researchers found that any time they saw a charge jump in the first qubit, the other two—no matter how far away on the chip—quickly flipped from the computational 1 state to the 0 state. \"It's a long-range effect, and it's really damaging,\" Wilen says. \"It's destroying the quantum information stored in qubits.\" Though this work could be viewed as a setback in the development of superconducting quantum computers, the researchers believe that their results will guide new research toward this problem. Groups at UW-Madison are already working on mitigation strategies. \"As we get closer to the ultimate goal of a fault-tolerant quantum computer, we're going to identify one new problem after another,\" McDermott says. \"This is just part of the process of learning more about the system, providing a path to implementation of more resilient designs.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The central challenge in building a quantum computer is error correction. Unlike classical bits, which are susceptible to only one type of error, quantum bits (qubits) are susceptible to two types of error, corresponding to flips of the qubit state about the X and Z directions. Although the Heisenberg uncertainty principle precludes simultaneous monitoring of X - and Z -flips on a single qubit, it is possible to encode quantum information in large arrays of entangled qubits that enable accurate monitoring of all errors in the system, provided that the error rate is low 1 . Another crucial requirement is that errors cannot be correlated. Here we characterize a superconducting multiqubit circuit and find that charge noise in the chip is highly correlated on a length scale over 600 micrometres; moreover, discrete charge jumps are accompanied by a strong transient reduction of qubit energy relaxation time across the millimetre-scale chip. The resulting correlated errors are explained in terms of the charging event and phonon-mediated quasiparticle generation associated with absorption of γ-rays and cosmic-ray muons in the qubit substrate. Robust quantum error correction will require the development of mitigation strategies to protect multiqubit arrays from correlated errors due to particle impacts. Main The two-dimensional surface code is widely seen as a promising approach to realization of a fault-tolerant quantum computer based on superconducting integrated circuits 1 . In this architecture, quantum information is encoded in a two-dimensional fabric of superconducting qubits with nearest-neighbour connectivity. Provided that gate operations and measurements are performed above a certain fault-tolerant threshold, it is possible to uniquely identify and correct errors in the system by monitoring multiqubit parity operators of the form XXXX and ZZZZ , where X and Z are single-qubit Pauli operators. In recent years, a number of groups have achieved beyond-threshold fidelities for single- and two-qubit gate operations 2 , 3 and for qubit measurement 4 , 5 , 6 , and steady improvements in performance are expected. The rigorous proof that it is possible, in principle, to achieve fault tolerance once threshold levels of fidelity are reached underpins much of the optimism for the surface code. However, this proof rests on the assumption that errors across the multiqubit array are uncorrelated in both space and time. Although it is possible to mitigate errors that are weakly correlated across neighbouring qubits (L.F. & L.B.I., manuscript in preparation), quantum error correction will break down in the face of simultaneous errors that are correlated over large length scales. Here we demonstrate spatially correlated charge fluctuations in a superconducting multiqubit chip over length scales of hundreds of micrometres, accompanied by correlated relaxation errors that extend over several millimetres. The data are compatible with absorption in the qubit substrate of cosmic-ray muons and γ-rays from background radioactivity. We perform detailed numerical modelling to determine the spatial profile of the charge burst associated with an absorption event; in addition, we present a simple model that describes the propagation of energy released by the event through scattering of pair-breaking phonons. These results have far-reaching implications for proposed error correction schemes such as the surface code that rely on large-scale arrays of qubits to monitor multiqubit stabilizers. A thorough understanding of the physics of particle impact events will be required to develop appropriate mitigation strategies and to engineer new approaches for fault-tolerant multiqubit arrays. The sample geometry is shown in Fig. 1a–c . The 6.25 × 6.25 mm 2 chip incorporates four weakly charge-sensitive transmon qubits with a ratio of Josephson energy to single-electron charging energy E J / E c = 24; the detailed device parameters are presented in the Supplementary Information . Each qubit comprises a circular superconducting Nb island with radius r i = 70 μm embedded in a circular cavity with radius r o = 90.5 μm in the superconducting Nb groundplane. Two of the qubits are positioned on one side of the chip with a centre-to-centre separation of 340 μm, while two of the qubits are on the opposite side of the chip with 640 μm centre-to-centre separation. The qubit pairs are separated by around 3 mm. Each qubit is coupled to a local readout resonator that is in turn coupled to a common feedline. Fig. 1: Chip layout and charge response. a , Optical micrograph of the multiqubit chip. Four charge-sensitive transmon qubits (Q1–Q4, magenta) are coupled to local readout resonators (cyan) and charge gate lines (orange). The readout resonators are coupled to a common feedline (purple). Image is a stitched composite (see Supplementary Information ). b , Close-up view of a single qubit. c , Circuit diagram of the chip. Colour coding matches the false colouring in a and b . d , Simulation of the charge induced on the qubit island from a unit point charge at various locations in the Si substrate. Full size image For the purposes of interpreting the experiments described here, it is useful to consider the qubits as electrometers with a large effective sensing area for electric fields in the substrate. For our concentric qubit geometry, the sensing area for uniform electric fields is π εr i r o , where ε is the relative permittivity of the medium. In Fig. 1d , we display the numerically computed offset charge on the qubit island induced by a unit point charge at various locations in the substrate; for an applied unit charge, the induced offset charge is simply the fraction of electric field lines that terminate on the qubit island. In a first series of experiments, we perform simultaneous Ramsey tomography on the four qubits to generate time series of fluctuating offset charge. In Fig. 2a , we show representative qubit spectroscopy, and in Fig. 2b we show the experimental pulse sequence for the charge measurements 7 . The Ramsey X /2−idle− X /2 sequence maps precession frequency to occupation of the qubit |1 ⟩ state irrespective of the quasiparticle parity of the qubit island. We perform a series of such experiments for different applied gate charge<|im_end|> <|im_start|>assistant Quantum computers could outperform classical computers at many tasks, but only if the errors that are an inevitable part of computational tasks are isolated rather than widespread events. Now, researchers at the University of Wisconsin-Madison have found evidence that errors are correlated across an entire superconducting quantum computing chip—highlighting a problem that must be acknowledged and addressed in the quest for fault-tolerant quantum computers. The researchers report their findings in a study published June 16 in the journal Nature, Importantly, their work also points to mitigation strategies. "I think people have been approaching the problem of error correction in an overly optimistic way, blindly making the assumption that errors are not correlated," says UW-Madison physics Professor Robert McDermott, senior author of the study. "Our experiments show absolutely that errors are correlated, but as we identify problems and develop a deep physical understanding, we're going to find ways to work around them." The bits in a classical computer can either be a 1 or a 0, but the qubits in a quantum computer can be 1, 0, or an arbitrary mixture—a superposition—of 1 and 0. Classical bits, then, can only make bit flip errors, such as when a 1 flips to 0. Qubits, however, can make two types of error: bit flips or phase flips, where a quantum superposition state changes. To fix errors, computers must monitor them as they happen. But the laws of quantum physics say that only one error type can be monitored at a time in a single qubit, so a clever error correction protocol called the surface code has been proposed. The surface code involves a large array of connected qubits—some do the computational work, while others are monitored to infer errors in the computational qubits. However, the surface code protocol works reliably only if events that cause errors are isolated, affecting at most a few qubits. In earlier experiments, McDermott's group had seen hints that something was causing multiple qubits to flip at the same time. In this new study, they directly asked: are these flips independent, or are they correlated? The research team designed a chip with four qubits made of the superconducting elements niobium and aluminum. The scientists cool the chip to nearly absolute zero, which makes it superconduct and protects it from error-causing interference from the outside environment. To assess whether qubit flips were correlated, the researchers measured fluctuations in offset charge for all four qubits. The fluctuating offset charge is effectively a change in electric field at the qubit. The team observed long periods of relative stability followed by sudden jumps in offset charge. The closer two qubits were together, the more likely they were to jump at the same time. These sudden changes were most likely caused by cosmic rays or background radiation in the lab, which both release charged particles. When one of these particles hits the chip, it frees up charges that affect nearby qubits. This local effect can be easily mitigated with simple design changes. The bigger concern is what could happen next. "If our model about particle impacts is correct, then we would expect that most of the energy is converted into vibrations in the chip that propagate over long distances," says Chris Wilen, a graduate student and lead author of the study. "As the energy spreads, the disturbance would lead to qubit flips that are correlated across the entire chip." In their next set of experiments, that effect is exactly what they saw. They measured charge jumps in one qubit, as in the earlier experiments, then used the timing of these jumps to align measurements of the quantum states of two other qubits. Those two qubits should always be in the computational 1 state. Yet the researchers found that any time they saw a charge jump in the first qubit, the other two—no matter how far away on the chip—quickly flipped from the computational 1 state to the 0 state. "It's a long-range effect, and it's really damaging," Wilen says. "It's destroying the quantum information stored in qubits." Though this work could be viewed as a setback in the development of superconducting quantum computers, the researchers believe that their results will guide new research toward this problem. Groups at UW-Madison are already working on mitigation strategies. "As we get closer to the ultimate goal of a fault-tolerant quantum computer, we're going to identify one new problem after another," McDermott says. "This is just part of the process of learning more about the system, providing a path to implementation of more resilient designs." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mass and electrical charge are fundamental properties of biological macromolecules. Although molecular mass has long been determined with atomic precision, a direct and precise determination of molecular charge remains an outstanding challenge. Here we report high-precision (<1 e ) measurements of the electrical charge of molecules such as nucleic acids, and globular and disordered proteins in solution. The measurement is based on parallel external field-free trapping of single macromolecules, permits the estimation of a dielectric coefficient of the molecular interior and can be performed in real time. Further, we demonstrate the direct detection of single amino acid substitution and chemical modifications in proteins. As the electrical charge of a macromolecule strongly depends on its three-dimensional conformation, this kind of high-precision electrometry offers an approach to probe the structure, fluctuations and interactions of a single molecule in solution. Main The electrostatic properties of macromolecules—specifically, their electrical charge and interior dielectric characteristics—are a vital component of their function as they contribute to the physical basis of mechanisms that range from molecular recognition, signalling and enzymatic catalysis to protein folding and aggregation, and are of fundamental relevance in experiment and theory 1 , 2 , 3 , 4 . ‘Supercharged’ isoforms of evolutionarily conserved proteins are known to confer extreme physiological capacities on certain species, presumably because of their enhanced stability to aggregation at high concentrations 5 , 6 . Moreover, the addition and removal of small amounts of structural charge—in the form of phosphate groups or other post-translational modifications—modulates not only such a basic phenomenon as protein stability, but also subcellular localization or function, and can regulate macroscopic processes such as metabolism at the systemic level 4 . A recent study demonstrated that the addition of as few as two phosphate groups to a protein induced a folding–unfolding transition and altered its binding affinity by orders of magnitude 3 . Not surprisingly, several disease states are correlated with altered phosphorylation of proteins, for example, disordered proteins, such as tau and α-synuclein involved in Alzheimer's and Parkinson's disease, and multimeric proteins, such as the stress-activated p53 implicated both in ageing and cancer 7 , 8 . A high-precision, direct measurement of the effective charge of a macromolecule in solution would not only permit the detection of minute differences of chemical composition in molecules, but would also offer a new physical dimension to systematically probe three-dimensional (3D) molecular structures and monitor structural changes in real time, which has important biochemical and biophysical implications. At the simplest level, a direct sum over a macromolecule's charged groups yields a qualitative estimate of its net electrical charge at a given solution pH: where i denotes each ionizable group, p K i is the negative logarithm of its acid dissociation constant and j = +1 or −1 for basic or acidic groups, respectively. In practice, however, collective interactions in a densely packed system of charges can dramatically modify the molecule's effective charge in solution via two separate phenomena—namely, charge regulation and charge renormalization. The former concerns an alteration in the charged state of an ionizable group in the context of the molecular environment, whereas the latter deals with the highly nonlinear screening of molecular charge by counterions in the surrounding electrolyte phase. Both phenomena generally result in a reduced effective charge of an electrically charged object, and have received extensive theoretical attention, from polyelectrolytes 9 , 10 and proteins 11 , 12 to colloidal particles 10 , 13 , 14 , 15 and charged surfaces in solution. Here we present a methodology to measure a macromolecule's electric charge with the precision of a single charge and below (<1 e ) by exploiting the electrostatic fluidic trap for nanoscale matter in solution 16 , 17 . Trapping charged macromolecules in solution The trap is created in a fluid-filled gap between two electrically charged walls. Nanoscale structuring of one of the surfaces leads to a modulation of the local electrostatic potential, which creates a deep thermodynamic potential well for a like-charged molecule ( Fig. 1a,b ). In our experiment, we introduce the molecular species of interest labelled with two fluorescent dye molecules, at a typical concentration of 50 pM in a solution of total salt concentration c ∼ 1–3 mM (up to 2.5 mM NaCl, 1 mM Tris, pH 8.7–9.1), into an array of electrostatic fluidic traps and image the dynamics using wide-field fluorescence microscopy. In our current work, the physical dimensions of the geometric perturbation that creates the trap (nanostructure depth and diameter generally 200–600 nm) are much larger than the Debye length, κ −1 ∼ 10 nm, the characteristic length scale of electrostatic interactions. As a result, a molecule in a trap inhabits a region of zero electric field and zero electrical potential, and chemical equilibrium ensures that the solution conditions at the bottom of the potential well, where the molecule spends most of its time, are identical to those in the bulk solution. Figure 1: Long-term trapping of single nucleic acid and protein molecules in solution. a , Schematic representation of fluorescently labelled disordered protein Stm-l confined in an electrostatic fluidic trap (top), with a slit height of 2 h = 75 nm, a trapping nanostructure diameter of 600 nm and a depth of 160 nm in a solution of 1 mM Tris (salt concentration, c = 0.25 mM). The bottom panels present spatial scatter plots of single confined molecules superimposed on a scanning electron micrograph (SEM) of the surface topography. Scale bar, 1 µm (left panel). Scatter plots were generated from stroboscopic images acquired using exposure times, t exp = 10 ms, at a sampling rate of 70 mHz over a total measurement period >30 min using wide-field fluorescence microscopy and single-particle tracking. b , The inferred x – y distribution of the minimum axial ( z ) electrostatic free energy in the confining potential well, F z ( r t ) (top), and measured radial sampling probability, P ( r t ), of a single trapped Stm-l molecule (bottom), where . c , Structural", "role": "user" }, { "content": "For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics. Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve interactions between molecules like proteins, where their charge plays an essential role. Yet, the charge of a protein in an aqueous environment – its natural context in a living organism – is hard to determine accurately using traditional approaches. Madhavi Krishnan, who holds an SNSF professorship at the University of Zurich, has developed a method to precisely measure the charge of a single molecule in solution. Her advance was described in a series of articles in Nature Nanotechnology, Physical Review E and the Journal of Chemical Physics. This discovery could pave the way to new diagnostic tools since, at a chemical level, many diseases are linked to a shift in a protein's electrical charge, which prevents the molecule from acting the way it should. A molecule's electrical charge can be quite different in the gas phase and in solution. The reason for this difference lies in complex interactions between the object and the surrounding liquid. Hence, standard gas-phase measurements do not directly yield information on the molecule's behaviour in its biological context. \"Like kids kicking a ball\" Molecules in solution are in constant motion, randomly kicking each other. Krishnan and Ph.D. student Francesca Ruggeri took advantage of this well-known phenomenon, called Brownian motion, in order to measure the effective charge of a molecule directly in solution. First, they trapped the molecule in a \"potential well\". Rather than an actual well, this is a situation where the potential energy of the molecule is at its minimum. In such a situation, bouncing water molecules continuously attempt to expel the molecule from the well. \"It is like kids playing with a ball at the bottom of a pit,\" explains Krishnan. \"The ball is the molecule we are interested in, and the children are the water molecules. The ball would have to receive quite a hard kick in order to fly out of the pit.\" The higher the effective charge of the molecule, the greater the depth of the potential well and, consequently, the lower the likelihood that the molecule is ejected from the well. In practice, this means that the time needed for the molecule to be kicked out of the well is directly related to its effective charge. \"Ultimately it boils down to a statistical principle,\" explains Krishnan. \"If we know how long a molecule remains trapped in the well, we know precisely how deep the well is. And since this depth depends directly on the molecule's effective charge, we can deduce this value very precisely too.\" Two glass plates In order to create a potential well, scientists compressed a solution containing the proteins between two glass plates, one of them being covered with microscopic holes. Molecules trapped in potential wells were labelled with fluorescent agents, which allowed them to be tracked with an optical microscope. While the discovery has important fundamental implications, it could also pave the way towards novel diagnostic tools for many diseases caused by misshaped proteins, such as Alzheimer's and cancers. \"We know that the 3-D conformation of a protein influences its effective charge, and our work might present a novel route to detecting defective proteins.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mass and electrical charge are fundamental properties of biological macromolecules. Although molecular mass has long been determined with atomic precision, a direct and precise determination of molecular charge remains an outstanding challenge. Here we report high-precision (<1 e ) measurements of the electrical charge of molecules such as nucleic acids, and globular and disordered proteins in solution. The measurement is based on parallel external field-free trapping of single macromolecules, permits the estimation of a dielectric coefficient of the molecular interior and can be performed in real time. Further, we demonstrate the direct detection of single amino acid substitution and chemical modifications in proteins. As the electrical charge of a macromolecule strongly depends on its three-dimensional conformation, this kind of high-precision electrometry offers an approach to probe the structure, fluctuations and interactions of a single molecule in solution. Main The electrostatic properties of macromolecules—specifically, their electrical charge and interior dielectric characteristics—are a vital component of their function as they contribute to the physical basis of mechanisms that range from molecular recognition, signalling and enzymatic catalysis to protein folding and aggregation, and are of fundamental relevance in experiment and theory 1 , 2 , 3 , 4 . ‘Supercharged’ isoforms of evolutionarily conserved proteins are known to confer extreme physiological capacities on certain species, presumably because of their enhanced stability to aggregation at high concentrations 5 , 6 . Moreover, the addition and removal of small amounts of structural charge—in the form of phosphate groups or other post-translational modifications—modulates not only such a basic phenomenon as protein stability, but also subcellular localization or function, and can regulate macroscopic processes such as metabolism at the systemic level 4 . A recent study demonstrated that the addition of as few as two phosphate groups to a protein induced a folding–unfolding transition and altered its binding affinity by orders of magnitude 3 . Not surprisingly, several disease states are correlated with altered phosphorylation of proteins, for example, disordered proteins, such as tau and α-synuclein involved in Alzheimer's and Parkinson's disease, and multimeric proteins, such as the stress-activated p53 implicated both in ageing and cancer 7 , 8 . A high-precision, direct measurement of the effective charge of a macromolecule in solution would not only permit the detection of minute differences of chemical composition in molecules, but would also offer a new physical dimension to systematically probe three-dimensional (3D) molecular structures and monitor structural changes in real time, which has important biochemical and biophysical implications. At the simplest level, a direct sum over a macromolecule's charged groups yields a qualitative estimate of its net electrical charge at a given solution pH: where i denotes each ionizable group, p K i is the negative logarithm of its acid dissociation constant and j = +1 or −1 for basic or acidic groups, respectively. In practice, however, collective interactions in a densely packed system of charges can dramatically modify the molecule's effective charge in solution via two separate phenomena—namely, charge regulation and charge renormalization. The former concerns an alteration in the charged state of an ionizable group in the context of the molecular environment, whereas the latter deals with the highly nonlinear screening of molecular charge by counterions in the surrounding electrolyte phase. Both phenomena generally result in a reduced effective charge of an electrically charged object, and have received extensive theoretical attention, from polyelectrolytes 9 , 10 and proteins 11 , 12 to colloidal particles 10 , 13 , 14 , 15 and charged surfaces in solution. Here we present a methodology to measure a macromolecule's electric charge with the precision of a single charge and below (<1 e ) by exploiting the electrostatic fluidic trap for nanoscale matter in solution 16 , 17 . Trapping charged macromolecules in solution The trap is created in a fluid-filled gap between two electrically charged walls. Nanoscale structuring of one of the surfaces leads to a modulation of the local electrostatic potential, which creates a deep thermodynamic potential well for a like-charged molecule ( Fig. 1a,b ). In our experiment, we introduce the molecular species of interest labelled with two fluorescent dye molecules, at a typical concentration of 50 pM in a solution of total salt concentration c ∼ 1–3 mM (up to 2.5 mM NaCl, 1 mM Tris, pH 8.7–9.1), into an array of electrostatic fluidic traps and image the dynamics using wide-field fluorescence microscopy. In our current work, the physical dimensions of the geometric perturbation that creates the trap (nanostructure depth and diameter generally 200–600 nm) are much larger than the Debye length, κ −1 ∼ 10 nm, the characteristic length scale of electrostatic interactions. As a result, a molecule in a trap inhabits a region of zero electric field and zero electrical potential, and chemical equilibrium ensures that the solution conditions at the bottom of the potential well, where the molecule spends most of its time, are identical to those in the bulk solution. Figure 1: Long-term trapping of single nucleic acid and protein molecules in solution. a , Schematic representation of fluorescently labelled disordered protein Stm-l confined in an electrostatic fluidic trap (top), with a slit height of 2 h = 75 nm, a trapping nanostructure diameter of 600 nm and a depth of 160 nm in a solution of 1 mM Tris (salt concentration, c = 0.25 mM). The bottom panels present spatial scatter plots of single confined molecules superimposed on a scanning electron micrograph (SEM) of the surface topography. Scale bar, 1 µm (left panel). Scatter plots were generated from stroboscopic images acquired using exposure times, t exp = 10 ms, at a sampling rate of 70 mHz over a total measurement period >30 min using wide-field fluorescence microscopy and single-particle tracking. b , The inferred x – y distribution of the minimum axial ( z ) electrostatic free energy in the confining potential well, F z ( r t ) (top), and measured radial sampling probability, P ( r t ), of a single trapped Stm-l molecule (bottom), where . c , Structural<|im_end|> <|im_start|>assistant For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics. Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve interactions between molecules like proteins, where their charge plays an essential role. Yet, the charge of a protein in an aqueous environment – its natural context in a living organism – is hard to determine accurately using traditional approaches. Madhavi Krishnan, who holds an SNSF professorship at the University of Zurich, has developed a method to precisely measure the charge of a single molecule in solution. Her advance was described in a series of articles in Nature Nanotechnology, Physical Review E and the Journal of Chemical Physics. This discovery could pave the way to new diagnostic tools since, at a chemical level, many diseases are linked to a shift in a protein's electrical charge, which prevents the molecule from acting the way it should. A molecule's electrical charge can be quite different in the gas phase and in solution. The reason for this difference lies in complex interactions between the object and the surrounding liquid. Hence, standard gas-phase measurements do not directly yield information on the molecule's behaviour in its biological context. "Like kids kicking a ball" Molecules in solution are in constant motion, randomly kicking each other. Krishnan and Ph.D. student Francesca Ruggeri took advantage of this well-known phenomenon, called Brownian motion, in order to measure the effective charge of a molecule directly in solution. First, they trapped the molecule in a "potential well". Rather than an actual well, this is a situation where the potential energy of the molecule is at its minimum. In such a situation, bouncing water molecules continuously attempt to expel the molecule from the well. "It is like kids playing with a ball at the bottom of a pit," explains Krishnan. "The ball is the molecule we are interested in, and the children are the water molecules. The ball would have to receive quite a hard kick in order to fly out of the pit." The higher the effective charge of the molecule, the greater the depth of the potential well and, consequently, the lower the likelihood that the molecule is ejected from the well. In practice, this means that the time needed for the molecule to be kicked out of the well is directly related to its effective charge. "Ultimately it boils down to a statistical principle," explains Krishnan. "If we know how long a molecule remains trapped in the well, we know precisely how deep the well is. And since this depth depends directly on the molecule's effective charge, we can deduce this value very precisely too." Two glass plates In order to create a potential well, scientists compressed a solution containing the proteins between two glass plates, one of them being covered with microscopic holes. Molecules trapped in potential wells were labelled with fluorescent agents, which allowed them to be tracked with an optical microscope. While the discovery has important fundamental implications, it could also pave the way towards novel diagnostic tools for many diseases caused by misshaped proteins, such as Alzheimer's and cancers. "We know that the 3-D conformation of a protein influences its effective charge, and our work might present a novel route to detecting defective proteins." <|im_end|>

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279, 1665, 323, 279, 14932, 14812, 13, 32140, 11, 5410, 6962, 82710, 22323, 656, 539, 6089, 7692, 2038, 389, 279, 43030, 596, 17432, 304, 1202, 24156, 2317, 13, 330, 13246, 6980, 40294, 264, 5041, 1, 386, 82206, 304, 6425, 527, 304, 6926, 11633, 11, 27716, 40294, 1855, 1023, 13, 62064, 19285, 323, 2405, 920, 13, 5575, 43833, 936, 37450, 1414, 72, 3952, 9610, 315, 420, 1664, 22015, 25885, 11, 2663, 10690, 1122, 11633, 11, 304, 2015, 311, 6767, 279, 7524, 6900, 315, 264, 43030, 6089, 304, 6425, 13, 5629, 11, 814, 31691, 279, 43030, 304, 264, 330, 93036, 1664, 3343, 26848, 1109, 459, 5150, 1664, 11, 420, 374, 264, 6671, 1405, 279, 4754, 4907, 315, 279, 43030, 374, 520, 1202, 8187, 13, 763, 1778, 264, 6671, 11, 65128, 3090, 35715, 31978, 4879, 311, 1367, 301, 279, 43030, 505, 279, 1664, 13, 330, 2181, 374, 1093, 6980, 5737, 449, 264, 5041, 520, 279, 5740, 315, 264, 20428, 1359, 15100, 62064, 19285, 13, 330, 791, 5041, 374, 279, 43030, 584, 527, 8173, 304, 11, 323, 279, 2911, 527, 279, 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2,016

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cardiac accessory pathways (APs) in Wolff–Parkinson–White (WPW) syndrome are conventionally diagnosed with decision tree algorithms; however, there are problems with clinical usage. We assessed the efficacy of the artificial intelligence model using electrocardiography (ECG) and chest X-rays to identify the location of APs. We retrospectively used ECG and chest X-rays to analyse 206 patients with WPW syndrome. Each AP location was defined by an electrophysiological study and divided into four classifications. We developed a deep learning model to classify AP locations and compared the accuracy with that of conventional algorithms. Moreover, 1519 chest X-ray samples from other datasets were used for prior learning, and the combined chest X-ray image and ECG data were put into the previous model to evaluate whether the accuracy improved. The convolutional neural network (CNN) model using ECG data was significantly more accurate than the conventional tree algorithm. In the multimodal model, which implemented input from the combined ECG and chest X-ray data, the accuracy was significantly improved. Deep learning with a combination of ECG and chest X-ray data could effectively identify the AP location, which may be a novel deep learning model for a multimodal model. Introduction Wolff–Parkinson–White (WPW) syndrome is caused by a congenital cardiac accessory pathway (AP) that can cause paroxysmal palpitations and occasionally fatal arrhythmias owing to complications involving atrial fibrillation 1 , 2 . In addition, as delta waves, which are characteristics of 12-lead electrocardiogram (ECG) waveforms obtained for patients with WPW syndrome, can be observed even in the absence of arrhythmia 3 , the diagnosis of WPW syndrome is relatively simple, while concealed WPW syndrome diagnosis is not. Conventionally, a decision tree algorithm using a 12-lead ECG has been used to diagnose APs in WPW syndrome 4 , 5 , 6 . However, problems have been reported. First, if the ECG is very ambiguous (e.g., when the polarity of the delta wave or QRS is exactly in the middle or when the electrical potential is too small to be judged), the decision-tree algorithm may not be able to provide a decision. Second, as conventional algorithms have been created by excluding atypical cases involving dual pathways and malformations 6 , those cases would always be classified into one of the categories that do not match them. Third, even if the polarity of the 12-lead ECG is the same, the location of the AP may subtly differ depending on the orientation and size of each heart. Owing to these problems, differences often exist between conventional and definitive results obtained by electrophysiological studies. In recent years, artificial intelligence (AI) has rapidly developed in medicine. Various definitions of AI exist. One has recently attracted attention and is commonly known as deep learning, which is a machine learning model that uses multiple layers of neural networks. Extensive AI models based on deep learning have been developed, particularly for image classification. AI models corresponding to various modality images have been reported and include a model that classifies whether COVID-19 is present in the diagnosis of pneumonia by chest computed tomography 7 and a model that identifies asynergy in echocardiography images 8 . In addition, deep learning can handle not only images but also time-series data, such as language and waveform data 9 . Generally, deep learning requires a large amount of annotated data. It is relatively simple to collect data in authenticating ubiquitous objects, such as cars and human faces 10 , but the amount of medical data that we can collect is limited because of the limited number of patients. Notably, few medical AI models exist for practical use. In addition, because machine learning requires definitive answers together with training data, it cannot be applied to ambiguous cases that cannot be diagnosed, which hinders its practical use in medicine 11 . To solve the abovementioned problems, we created a new model for the diagnosis of AP localization in WPW syndrome by using a medical deep learning model. The primary goal of this study was to make a model that was more accurate than a conventional algorithm. The secondary goal of this study was to resolve the problem that the location of an AP differs depending on the orientation and size of each heart, which can be solved by adding a chest X-ray image into the model so that the model can consider the axis or size of the heart. Methods Patients and data A total of 294 cases, including 240 cases with WPW syndrome and 54 normal cases from seven centres, were collected during the period from March 2009 to January 2021 (Fig. 1 ). A total of 206 cases collected from six centres were used as the training dataset and internal validation dataset, and a total of 88 cases collected from another centre were used as the external validation dataset. We collected preoperative 12-lead ECG data and preoperative chest X-ray data from patients who underwent ablation therapy for WPW syndrome. The chest X-ray data were acquired from posterior to anterior. Patients with atrioventricular reentrant tachycardia whose delta waves could not be observed during normal sinus rhythm were excluded from this study. All methods were carried out in accordance with the relevant directives and regulations, as well as the Declaration of Helsinki, and informed consent was obtained from all the participants of the experiments. This clinical study was approved by the ethical review boards of Kobe University Medical Ethical Committee (No. 190164) on November 1, 2019. Figure 1 Study population and design. The primary endpoint was assessed by comparing the accuracy of each algorithm. The secondary endpoint was assessed by determining how the second model outcomes differed when the chest X-ray images were added into the model, rather than using only the ECG. Full size image Electrophysiology studies An electrophysiological study and catheter ablation were performed in a total of 174 patients. After precise mapping was performed without or with saline irrigation using a 7-Fr or 8-Fr deflectable catheter with a 4- or 3.5-mm tip and an interelectrode spacing of 2.5 or 2 mm,", "role": "user" }, { "content": "Kobe University Hospital's Dr. Nishimori Makoto and Project Assistant Professor Kiuchi Kunihiko et al. (of the Division of Cardiovascular Medicine, Department of Internal Medicine) have developed an AI that uses multiple kinds of test data to predict the location of surplus pathways in the heart called 'accessory pathways', which cause the heart to beat irregularly. In this study, the researchers were able to improve diagnosis accuracy by having the AI learn from two completely different types of test results—electrocardiography (ECG) data and X-ray images. It is hoped that this methodology can be applied to other disorders based upon the successful results of this research. These research results were published online in Scientific Reports on April 13, 2021. Wolff-Parkinson-White (WPW) is an arrhythmic disorder. Patients with WPW syndrome are born with surplus pathways inside their hearts called 'accessory pathways', which can cause tachycardia episodes where the pulse speeds up. Catheter ablation involves using a catheter to selectively cauterize accessory pathways and can completely cure this disorder. However, the success rate of catheter ablation varies depending on the location of the accessory pathways. Conventionally, a 12-lead ECG (i.e. a regular electrocardiography) has been used to predict accessory pathway location prior to treatment. However, this current method that relies solely on ECG is insufficiently accurate, which makes it difficult to give patients a full explanation that includes the success rate of treatment. This research study tried using AI to solve this problem. The researchers used a methodology for teaching AI called deep learning. Deep learning involves entering the data for each patient and the corresponding answers into a program. By repeating this learning process, the program automatically becomes smarter. Using this methodology, the research group was able to present a solution to a previously unresolved problem, thus further promoting the application of AI to modern medicine. Figure 2: A graph to show the number of learning sessions and the AI’s accuracy. Credit: Kobe University Firstly, Dr. Nishimori's team developed AI using only ECG data and compared its performance to previous methods. They conducted repeated learning where they gave the AI each patients' ECG data and the accessory pathway location (i.e. the answer) in each case at the same time, successfully creating an AI with a higher accuracy rate than previous methods. However, the AI was unable to perform correct predictions every time from ECG data alone. The cause of this issue was thought to be that the ECG data is affected by the differences in size and position of each heart, therefore the ECG data did not match even when the location of the accessory pathway was the same. This problem was resolved by having the AI learn data, such as information on each heart's size, from chest X-ray images at the same time (Figure 1). By simultaneously learning both the pre-treatment ECG and X-ray image data, the AI was able to obtain the missing information and its diagnostic accuracy was significantly improved (Figure 2) compared to when only ECG data was used. The advancement of AI technology in recent years has made it possible for AI to make highly accurate diagnoses based on various kinds of test data in the field of medicine. However, there are cases where data from a single test is insufficient for AI to perform an accurate diagnosis. This research study successfully increased the accuracy by having the AI learn not only from ECG results but also from chest X-ray images, which are a completely different type of data. AI-mediated accurate diagnoses will enable doctors to give pre-treatment patients a more accurate explanation of their condition, which will hopefully put patients at ease. In addition, this research could be applied to various other disorders and will hopefully lead to the implementation of AI diagnosis software. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cardiac accessory pathways (APs) in Wolff–Parkinson–White (WPW) syndrome are conventionally diagnosed with decision tree algorithms; however, there are problems with clinical usage. We assessed the efficacy of the artificial intelligence model using electrocardiography (ECG) and chest X-rays to identify the location of APs. We retrospectively used ECG and chest X-rays to analyse 206 patients with WPW syndrome. Each AP location was defined by an electrophysiological study and divided into four classifications. We developed a deep learning model to classify AP locations and compared the accuracy with that of conventional algorithms. Moreover, 1519 chest X-ray samples from other datasets were used for prior learning, and the combined chest X-ray image and ECG data were put into the previous model to evaluate whether the accuracy improved. The convolutional neural network (CNN) model using ECG data was significantly more accurate than the conventional tree algorithm. In the multimodal model, which implemented input from the combined ECG and chest X-ray data, the accuracy was significantly improved. Deep learning with a combination of ECG and chest X-ray data could effectively identify the AP location, which may be a novel deep learning model for a multimodal model. Introduction Wolff–Parkinson–White (WPW) syndrome is caused by a congenital cardiac accessory pathway (AP) that can cause paroxysmal palpitations and occasionally fatal arrhythmias owing to complications involving atrial fibrillation 1 , 2 . In addition, as delta waves, which are characteristics of 12-lead electrocardiogram (ECG) waveforms obtained for patients with WPW syndrome, can be observed even in the absence of arrhythmia 3 , the diagnosis of WPW syndrome is relatively simple, while concealed WPW syndrome diagnosis is not. Conventionally, a decision tree algorithm using a 12-lead ECG has been used to diagnose APs in WPW syndrome 4 , 5 , 6 . However, problems have been reported. First, if the ECG is very ambiguous (e.g., when the polarity of the delta wave or QRS is exactly in the middle or when the electrical potential is too small to be judged), the decision-tree algorithm may not be able to provide a decision. Second, as conventional algorithms have been created by excluding atypical cases involving dual pathways and malformations 6 , those cases would always be classified into one of the categories that do not match them. Third, even if the polarity of the 12-lead ECG is the same, the location of the AP may subtly differ depending on the orientation and size of each heart. Owing to these problems, differences often exist between conventional and definitive results obtained by electrophysiological studies. In recent years, artificial intelligence (AI) has rapidly developed in medicine. Various definitions of AI exist. One has recently attracted attention and is commonly known as deep learning, which is a machine learning model that uses multiple layers of neural networks. Extensive AI models based on deep learning have been developed, particularly for image classification. AI models corresponding to various modality images have been reported and include a model that classifies whether COVID-19 is present in the diagnosis of pneumonia by chest computed tomography 7 and a model that identifies asynergy in echocardiography images 8 . In addition, deep learning can handle not only images but also time-series data, such as language and waveform data 9 . Generally, deep learning requires a large amount of annotated data. It is relatively simple to collect data in authenticating ubiquitous objects, such as cars and human faces 10 , but the amount of medical data that we can collect is limited because of the limited number of patients. Notably, few medical AI models exist for practical use. In addition, because machine learning requires definitive answers together with training data, it cannot be applied to ambiguous cases that cannot be diagnosed, which hinders its practical use in medicine 11 . To solve the abovementioned problems, we created a new model for the diagnosis of AP localization in WPW syndrome by using a medical deep learning model. The primary goal of this study was to make a model that was more accurate than a conventional algorithm. The secondary goal of this study was to resolve the problem that the location of an AP differs depending on the orientation and size of each heart, which can be solved by adding a chest X-ray image into the model so that the model can consider the axis or size of the heart. Methods Patients and data A total of 294 cases, including 240 cases with WPW syndrome and 54 normal cases from seven centres, were collected during the period from March 2009 to January 2021 (Fig. 1 ). A total of 206 cases collected from six centres were used as the training dataset and internal validation dataset, and a total of 88 cases collected from another centre were used as the external validation dataset. We collected preoperative 12-lead ECG data and preoperative chest X-ray data from patients who underwent ablation therapy for WPW syndrome. The chest X-ray data were acquired from posterior to anterior. Patients with atrioventricular reentrant tachycardia whose delta waves could not be observed during normal sinus rhythm were excluded from this study. All methods were carried out in accordance with the relevant directives and regulations, as well as the Declaration of Helsinki, and informed consent was obtained from all the participants of the experiments. This clinical study was approved by the ethical review boards of Kobe University Medical Ethical Committee (No. 190164) on November 1, 2019. Figure 1 Study population and design. The primary endpoint was assessed by comparing the accuracy of each algorithm. The secondary endpoint was assessed by determining how the second model outcomes differed when the chest X-ray images were added into the model, rather than using only the ECG. Full size image Electrophysiology studies An electrophysiological study and catheter ablation were performed in a total of 174 patients. After precise mapping was performed without or with saline irrigation using a 7-Fr or 8-Fr deflectable catheter with a 4- or 3.5-mm tip and an interelectrode spacing of 2.5 or 2 mm,<|im_end|> <|im_start|>assistant Kobe University Hospital's Dr. Nishimori Makoto and Project Assistant Professor Kiuchi Kunihiko et al. (of the Division of Cardiovascular Medicine, Department of Internal Medicine) have developed an AI that uses multiple kinds of test data to predict the location of surplus pathways in the heart called 'accessory pathways', which cause the heart to beat irregularly. In this study, the researchers were able to improve diagnosis accuracy by having the AI learn from two completely different types of test results—electrocardiography (ECG) data and X-ray images. It is hoped that this methodology can be applied to other disorders based upon the successful results of this research. These research results were published online in Scientific Reports on April 13, 2021. Wolff-Parkinson-White (WPW) is an arrhythmic disorder. Patients with WPW syndrome are born with surplus pathways inside their hearts called 'accessory pathways', which can cause tachycardia episodes where the pulse speeds up. Catheter ablation involves using a catheter to selectively cauterize accessory pathways and can completely cure this disorder. However, the success rate of catheter ablation varies depending on the location of the accessory pathways. Conventionally, a 12-lead ECG (i.e. a regular electrocardiography) has been used to predict accessory pathway location prior to treatment. However, this current method that relies solely on ECG is insufficiently accurate, which makes it difficult to give patients a full explanation that includes the success rate of treatment. This research study tried using AI to solve this problem. The researchers used a methodology for teaching AI called deep learning. Deep learning involves entering the data for each patient and the corresponding answers into a program. By repeating this learning process, the program automatically becomes smarter. Using this methodology, the research group was able to present a solution to a previously unresolved problem, thus further promoting the application of AI to modern medicine. Figure 2: A graph to show the number of learning sessions and the AI’s accuracy. Credit: Kobe University Firstly, Dr. Nishimori's team developed AI using only ECG data and compared its performance to previous methods. They conducted repeated learning where they gave the AI each patients' ECG data and the accessory pathway location (i.e. the answer) in each case at the same time, successfully creating an AI with a higher accuracy rate than previous methods. However, the AI was unable to perform correct predictions every time from ECG data alone. The cause of this issue was thought to be that the ECG data is affected by the differences in size and position of each heart, therefore the ECG data did not match even when the location of the accessory pathway was the same. This problem was resolved by having the AI learn data, such as information on each heart's size, from chest X-ray images at the same time (Figure 1). By simultaneously learning both the pre-treatment ECG and X-ray image data, the AI was able to obtain the missing information and its diagnostic accuracy was significantly improved (Figure 2) compared to when only ECG data was used. The advancement of AI technology in recent years has made it possible for AI to make highly accurate diagnoses based on various kinds of test data in the field of medicine. However, there are cases where data from a single test is insufficient for AI to perform an accurate diagnosis. This research study successfully increased the accuracy by having the AI learn not only from ECG results but also from chest X-ray images, which are a completely different type of data. AI-mediated accurate diagnoses will enable doctors to give pre-treatment patients a more accurate explanation of their condition, which will hopefully put patients at ease. In addition, this research could be applied to various other disorders and will hopefully lead to the implementation of AI diagnosis software. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Dynamic signaling on branching axons is critical for rapid and efficient communication between neurons in the brain. Efficient signaling in axon arbors depends on a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron’s morphology (material cost). However, where the balance between structural and dynamical considerations for achieving signaling efficiency is, and the design principle that neurons optimize to preserve this balance, is still elusive. In this work, we introduce a novel analysis that compares morphology and signaling dynamics in axonal networks to address this open problem. We show that in Basket cell neurons the design principle being optimized is the ratio between the refractory period of the membrane, and action potential latencies between the initial segment and the synaptic terminals. Our results suggest that the convoluted paths taken by axons reflect a design compensation by the neuron to slow down signaling latencies in order to optimize this ratio. Deviations in this ratio may result in a breakdown of signaling efficiency in the cell. These results pave the way to new approaches for investigating more complex neurophysiological phenomena that involve considerations of neuronal structure-function relationships. Introduction The mechanisms underlying the successful integration and rapid transmission of information in the brain rely on interactions between structural and dynamical properties that begin at the level of the single neuron. The complexity of these interactions are reflected in the wide variability of axon arbor morphologies and dynamical states neurons can take on. A still unsolved fundamental question is what is the relationship between the morphological design principles of individual branching axons and their role in optimizing action potential signaling in the neuron? Neuronal morphologies are the outcome of complex developmental processes including axon growth, stabilization of synaptic connections and axon pruning 1 , 2 , 3 . These processes are dependent on a multitude of local molecular and cellular mechanisms and conditions 4 , 5 , 6 . Despite the stochastic nature of morphological development, as well as other biological, physical, and molecular constraints, evolutionarily neurons have achieved a degree of common computational efficiency. A growing list of experimental and computational results, including those we present in this paper, suggest that these developmental processes in neurons satisfy a set of specific optimization principles 7 , 8 , 9 , 10 . Until recently, the prevailing dominant hypotheses has been that neurons are morphologically designed to optimize for the least amount of cellular material necessary. The logic was that the less amount of material that was used, the greater the conservation of energy and cellular resources. In particular, a number of studies have argued that wiring minimization principles that maximize the conservation of material underlie the morphological design of neurons and even the broader anatomical organization responsible for functional maps in the neocortex 7 , 10 , 11 , 12 , 13 , such as the intracortical wiring underlying functional maps in mammalian visual cortex 10 , 14 . However, more recent work has shown that neurons are not minimized for wiring length but instead are designed somewhere in between the two extremes of minimizing wiring costs versus maximizing action potential conduction velocities. They use more material than minimal construction costs would allow in order to increase conduction velocities that decrease temporal costs, but at the same time they do not signal as fast at they could if the wiring design was optimized strictly for speed, thereby offsetting the material cost 9 , 15 . Budd et al . have recently examined the functional consequences and temporal cost of wiring minimization principles. Their results suggest that there exists a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron’s morphology (material cost) 9 . This can be interpreted as a need to balance the advantages to the organism of signaling and processing information as fast as possible, while keeping material and cellular costs within reason. However, where this spatio-temporal trade-off lies and the design principles being optimized remain unknown. Identifying them is critical to ultimately understanding why neurons are designed the way they are, and the effect they may have on a neuron’s ability to represent and process information in the brain. This would also allow many other seemingly unrelated neurobiological results that involve considerations of neuronal structure-function relationships to be understood within this new context. As a result, completely disconnected results, models, and interpretations of data would have an underlying ‘constraint’ that nature necessitates they conform to. This would have a significant impact on our understanding of the brain as a system. The work by Budd and colleagues suggested that the spatio-temporal trade-off observed in axon arbors contributes to the maximization of temporal precision, or conversely, the minimization of temporal dispersion in neuronal circuits 9 . Here, we explored the functional role of axon morphologies in the propagation of action potentials. The result of our analysis suggests a new putative underlying optimization principle between temporal and material costs in axon arbors. We investigated the signaling dynamics of action potentials in individual axonal branches using a model that computes a metric associated with the efficiency of signaling in spatial geometric networks. We have recently shown that optimal efficient signaling between connected node pairs in geometric networks is bounded by a ratio that approaches unity, between the signaling latency on the edge and the internal dynamics of the individual nodes 16 . We call this ratio the refraction ratio. It reflects a necessary balance between the internal dynamics of the participating nodes that make up the network, and the dynamics of signaling or information flow on the network. We have previously shown in numerical simulation experiments that a deviation of this principle can result in the complete breakdown of signaling dynamics 17 . In this work, we propose the refraction ratio as a measure of", "role": "user" }, { "content": "A team of bioengineers at UC San Diego has answered a question that has long puzzled neuroscientists, and may hold a key to better understanding the complexities of neurological disorders: Why are axons, the spindly arms extending from neurons that transmit information from neuron to neuron in the brain, designed the way they are? Axons are not designed to minimize the use of cell tissue— they wouldn't be so long and convoluted if that were the case. Conversely, they're not optimized for speed, as recent studies have shown that axons don't fire as fast as they physically could, since this would overwhelm the neuron and lead to a loss of network activity. So what is the role of the geometry of axons in information flow in the brain? The answer—that axons are designed and optimized to balance the speed that information flows into the neuron relative to the time it takes the neuron to process that information—seems intuitive, but has never been quantified until now. This underlying principle of neuroscience, published July 11 in Scientific Reports, could revolutionize our understanding of how signal flow in the brain can be measured and perturbed, and could have an equally large impact on artificial neural networks in the field of machine learning. Refraction Ratio The specific balance that biological neurons are designed to accommodate is called the refraction ratio: it's the ratio between the refractory period of a neuron—when the neuron is unable to process incoming signals since its ion channels are resetting after being flooded with sodium— and the signal latency of information traveling down the axon. When that ratio approaches one, there is perfect balance, and the neuron is operating as efficiently as possible. Graph-based model of the geometric network of an axon and its arborizations. Credit: Francesca Puppo. In the study conducted by first author Francesca Puppo, a postdoctoral researcher in Bioengineering Professor Gabriel Silva's lab at the Jacobs School of Engineering at UC San Diego, the median refraction ratio value of the nearly 12,000 axonal branches examined was 0.92, quite close to the theoretically predicted perfect balance. The study used a dataset from the NeuroMorpho database that looked at a type of neuron called basket cells. This data was from rats, but humans have basket cells too. Puppo used the 3-D morphological data to reconstruct a graph-based model of the neurons' axons and axon branches. Then she calculated the conduction velocity along the axons given the diameter at different points along the axonal arborizations, and estimated the refractory period along the axon from soma to synaptic terminals based on data in the literature. The conduction velocity and length of each axon branch were used to calculate the propagation delay, which she compared to the refraction period to calculate the refraction ratio. Stylized axon arbor of a neuron. Yellow circle: root vertex at the axon initial segment; red circles: bifurcation vertices; black circles: terminal vertices at the axon's synaptic terminals. Credit: Francesca Puppo. Long, short, straight and curvy axons all had a refraction ratio approaching one. This means that when axons grow in a long and curved shape, it's designed that way by the neuron to slow down the action potential of signals in order to optimize the refraction ratio. When neurons aren't signaling at this ratio, there is a breakdown in information flow efficiency between cells. One example of this breakdown in efficiency that Silva and colleagues at the UC San Diego School of Medicine are starting to investigate is in patients with autism spectrum disorder. \"The hypothesis we have is that the refraction ratio deviates from the ideal in neurodevelopmental disorders such as autism,\" Silva said. \"We think that may be the case for individual neurons, as well as networks of neurons.\" Puppo added that understanding this baseline of optimal function in neurons will allow researchers to better understand how information flow is perturbed in a variety of ways, including other neurological disorders such as schizophrenia, for example, as well as better understanding how drugs affect neuron function, since pharmacological drugs impact the cell's activity and the way synaptic transmission occurs in networks of neurons. \"It would be interesting to investigate how drug perturbation affects signaling efficiency through computation of the refraction ratio for pairs of neurons in in-vitro networks of neurons before and after exposure to different chemical compounds,\" Puppo said. \"The detection of a change in the refraction ratio could be helpful in the determination of their neural rescue properties.\" Machine Learning On the non-biological side, understanding the function of the refraction ratio and the shape of axons has implications in the development of more brain-like artificial neural networks. Whereas traditional artificial neural networks have many weighted incoming signals with an output that's a summation of all of these signals, Silva and his lab are developing a new paradigm that adds the element of time to the mix—like the refractory period does in biological systems—so not all incoming signals are calculated in the output. In geometric spatial-temporal artificial networks they are building, the time a signal takes to reach the node is also a factor in the output, similar to the way the refractory period functions in the human brain. This adds complexity to the system, but makes the learning process richer. Silva is developing a fundamentally novel machine learning architecture based on these networks as part of the Center for Engineering Natural Intelligence at the Jacobs School of Engineering. In addition to studying the refraction ratio of people with neurological disorders and applying the concept to artificial neural networks, Puppo said additional further work includes studying varying types of neurons to understand if some have refraction ratios that deviate slightly from 1 to serve a specific purpose in a cell's dynamics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Dynamic signaling on branching axons is critical for rapid and efficient communication between neurons in the brain. Efficient signaling in axon arbors depends on a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron’s morphology (material cost). However, where the balance between structural and dynamical considerations for achieving signaling efficiency is, and the design principle that neurons optimize to preserve this balance, is still elusive. In this work, we introduce a novel analysis that compares morphology and signaling dynamics in axonal networks to address this open problem. We show that in Basket cell neurons the design principle being optimized is the ratio between the refractory period of the membrane, and action potential latencies between the initial segment and the synaptic terminals. Our results suggest that the convoluted paths taken by axons reflect a design compensation by the neuron to slow down signaling latencies in order to optimize this ratio. Deviations in this ratio may result in a breakdown of signaling efficiency in the cell. These results pave the way to new approaches for investigating more complex neurophysiological phenomena that involve considerations of neuronal structure-function relationships. Introduction The mechanisms underlying the successful integration and rapid transmission of information in the brain rely on interactions between structural and dynamical properties that begin at the level of the single neuron. The complexity of these interactions are reflected in the wide variability of axon arbor morphologies and dynamical states neurons can take on. A still unsolved fundamental question is what is the relationship between the morphological design principles of individual branching axons and their role in optimizing action potential signaling in the neuron? Neuronal morphologies are the outcome of complex developmental processes including axon growth, stabilization of synaptic connections and axon pruning 1 , 2 , 3 . These processes are dependent on a multitude of local molecular and cellular mechanisms and conditions 4 , 5 , 6 . Despite the stochastic nature of morphological development, as well as other biological, physical, and molecular constraints, evolutionarily neurons have achieved a degree of common computational efficiency. A growing list of experimental and computational results, including those we present in this paper, suggest that these developmental processes in neurons satisfy a set of specific optimization principles 7 , 8 , 9 , 10 . Until recently, the prevailing dominant hypotheses has been that neurons are morphologically designed to optimize for the least amount of cellular material necessary. The logic was that the less amount of material that was used, the greater the conservation of energy and cellular resources. In particular, a number of studies have argued that wiring minimization principles that maximize the conservation of material underlie the morphological design of neurons and even the broader anatomical organization responsible for functional maps in the neocortex 7 , 10 , 11 , 12 , 13 , such as the intracortical wiring underlying functional maps in mammalian visual cortex 10 , 14 . However, more recent work has shown that neurons are not minimized for wiring length but instead are designed somewhere in between the two extremes of minimizing wiring costs versus maximizing action potential conduction velocities. They use more material than minimal construction costs would allow in order to increase conduction velocities that decrease temporal costs, but at the same time they do not signal as fast at they could if the wiring design was optimized strictly for speed, thereby offsetting the material cost 9 , 15 . Budd et al . have recently examined the functional consequences and temporal cost of wiring minimization principles. Their results suggest that there exists a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron’s morphology (material cost) 9 . This can be interpreted as a need to balance the advantages to the organism of signaling and processing information as fast as possible, while keeping material and cellular costs within reason. However, where this spatio-temporal trade-off lies and the design principles being optimized remain unknown. Identifying them is critical to ultimately understanding why neurons are designed the way they are, and the effect they may have on a neuron’s ability to represent and process information in the brain. This would also allow many other seemingly unrelated neurobiological results that involve considerations of neuronal structure-function relationships to be understood within this new context. As a result, completely disconnected results, models, and interpretations of data would have an underlying ‘constraint’ that nature necessitates they conform to. This would have a significant impact on our understanding of the brain as a system. The work by Budd and colleagues suggested that the spatio-temporal trade-off observed in axon arbors contributes to the maximization of temporal precision, or conversely, the minimization of temporal dispersion in neuronal circuits 9 . Here, we explored the functional role of axon morphologies in the propagation of action potentials. The result of our analysis suggests a new putative underlying optimization principle between temporal and material costs in axon arbors. We investigated the signaling dynamics of action potentials in individual axonal branches using a model that computes a metric associated with the efficiency of signaling in spatial geometric networks. We have recently shown that optimal efficient signaling between connected node pairs in geometric networks is bounded by a ratio that approaches unity, between the signaling latency on the edge and the internal dynamics of the individual nodes 16 . We call this ratio the refraction ratio. It reflects a necessary balance between the internal dynamics of the participating nodes that make up the network, and the dynamics of signaling or information flow on the network. We have previously shown in numerical simulation experiments that a deviation of this principle can result in the complete breakdown of signaling dynamics 17 . In this work, we propose the refraction ratio as a measure of<|im_end|> <|im_start|>assistant A team of bioengineers at UC San Diego has answered a question that has long puzzled neuroscientists, and may hold a key to better understanding the complexities of neurological disorders: Why are axons, the spindly arms extending from neurons that transmit information from neuron to neuron in the brain, designed the way they are? Axons are not designed to minimize the use of cell tissue— they wouldn't be so long and convoluted if that were the case. Conversely, they're not optimized for speed, as recent studies have shown that axons don't fire as fast as they physically could, since this would overwhelm the neuron and lead to a loss of network activity. So what is the role of the geometry of axons in information flow in the brain? The answer—that axons are designed and optimized to balance the speed that information flows into the neuron relative to the time it takes the neuron to process that information—seems intuitive, but has never been quantified until now. This underlying principle of neuroscience, published July 11 in Scientific Reports, could revolutionize our understanding of how signal flow in the brain can be measured and perturbed, and could have an equally large impact on artificial neural networks in the field of machine learning. Refraction Ratio The specific balance that biological neurons are designed to accommodate is called the refraction ratio: it's the ratio between the refractory period of a neuron—when the neuron is unable to process incoming signals since its ion channels are resetting after being flooded with sodium— and the signal latency of information traveling down the axon. When that ratio approaches one, there is perfect balance, and the neuron is operating as efficiently as possible. Graph-based model of the geometric network of an axon and its arborizations. Credit: Francesca Puppo. In the study conducted by first author Francesca Puppo, a postdoctoral researcher in Bioengineering Professor Gabriel Silva's lab at the Jacobs School of Engineering at UC San Diego, the median refraction ratio value of the nearly 12,000 axonal branches examined was 0.92, quite close to the theoretically predicted perfect balance. The study used a dataset from the NeuroMorpho database that looked at a type of neuron called basket cells. This data was from rats, but humans have basket cells too. Puppo used the 3-D morphological data to reconstruct a graph-based model of the neurons' axons and axon branches. Then she calculated the conduction velocity along the axons given the diameter at different points along the axonal arborizations, and estimated the refractory period along the axon from soma to synaptic terminals based on data in the literature. The conduction velocity and length of each axon branch were used to calculate the propagation delay, which she compared to the refraction period to calculate the refraction ratio. Stylized axon arbor of a neuron. Yellow circle: root vertex at the axon initial segment; red circles: bifurcation vertices; black circles: terminal vertices at the axon's synaptic terminals. Credit: Francesca Puppo. Long, short, straight and curvy axons all had a refraction ratio approaching one. This means that when axons grow in a long and curved shape, it's designed that way by the neuron to slow down the action potential of signals in order to optimize the refraction ratio. When neurons aren't signaling at this ratio, there is a breakdown in information flow efficiency between cells. One example of this breakdown in efficiency that Silva and colleagues at the UC San Diego School of Medicine are starting to investigate is in patients with autism spectrum disorder. "The hypothesis we have is that the refraction ratio deviates from the ideal in neurodevelopmental disorders such as autism," Silva said. "We think that may be the case for individual neurons, as well as networks of neurons." Puppo added that understanding this baseline of optimal function in neurons will allow researchers to better understand how information flow is perturbed in a variety of ways, including other neurological disorders such as schizophrenia, for example, as well as better understanding how drugs affect neuron function, since pharmacological drugs impact the cell's activity and the way synaptic transmission occurs in networks of neurons. "It would be interesting to investigate how drug perturbation affects signaling efficiency through computation of the refraction ratio for pairs of neurons in in-vitro networks of neurons before and after exposure to different chemical compounds," Puppo said. "The detection of a change in the refraction ratio could be helpful in the determination of their neural rescue properties." Machine Learning On the non-biological side, understanding the function of the refraction ratio and the shape of axons has implications in the development of more brain-like artificial neural networks. Whereas traditional artificial neural networks have many weighted incoming signals with an output that's a summation of all of these signals, Silva and his lab are developing a new paradigm that adds the element of time to the mix—like the refractory period does in biological systems—so not all incoming signals are calculated in the output. In geometric spatial-temporal artificial networks they are building, the time a signal takes to reach the node is also a factor in the output, similar to the way the refractory period functions in the human brain. This adds complexity to the system, but makes the learning process richer. Silva is developing a fundamentally novel machine learning architecture based on these networks as part of the Center for Engineering Natural Intelligence at the Jacobs School of Engineering. In addition to studying the refraction ratio of people with neurological disorders and applying the concept to artificial neural networks, Puppo said additional further work includes studying varying types of neurons to understand if some have refraction ratios that deviate slightly from 1 to serve a specific purpose in a cell's dynamics. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The fast solar wind’s high speeds and non-thermal features require that considerable heating occurs well above the Sun’s surface. Two leading theories seem incompatible: low-frequency ‘Alfvénic’ turbulence, which transports energy outwards and is observed ubiquitously by spacecraft but seems insufficient to explain the observed dominance of ion over electron heating; and high-frequency ion-cyclotron waves, which explain the non-thermal heating of ions but lack an obvious source. Here we argue that the recently proposed ‘helicity barrier’ effect, which limits electron heating by inhibiting the turbulent cascade of energy to the smallest scales, can unify these two paradigms. Our six-dimensional simulations show how the helicity barrier causes the large-scale energy to grow through time, generating small parallel scales and high-frequency ion-cyclotron-wave heating from low-frequency turbulence, while simultaneously explaining various other long-standing observational puzzles. The predicted causal link between plasma expansion and the ion-to-electron heating ratio suggests that the helicity barrier could contribute to key observed differences between fast and slow wind streams. Main The basic mechanisms that heat the solar corona and accelerate the solar wind remain mysterious despite intensive study over many decades 1 . A successful theory must explain how energy contained in photospheric motions and magnetic fields can be liberated to cause extreme and sudden heating of the coronal plasma, along with its acceleration to velocities well in excess of the escape velocity of the Sun. Adding to the complexity, the coronal plasma is collisionless—the mean-free path of protons can be large compared with the largest observed structures—meaning that it can be far out of local thermal equilibrium. This freedom opens up a wide array of channels for plasma heating: ions might be heated more than electrons (or vice versa), or particles might gain energy preferentially in a particular direction with respect to the local magnetic field 2 . Such differences can have pronounced macroscopic consequences. The dominant heating mechanism(s) must be consistent with an extensive array of measurements taken both remotely, from the low corona itself, and in situ, from spacecraft spread throughout the solar wind. In fast wind streams, these data indicate that the heating must be spatially extended out to several solar radii to drive observed wind speeds 3 . The mechanism must preferentially heat protons over electrons 4 , while heating heavier ions (for example, α-particles) even more effectively 5 ; it must heat protons in the direction perpendicular to the local magnetic field more than in the parallel direction to explain temperature anisotropies 6 ; and its features and/or after-effects should be observable in the measured field fluctuations and particle distribution, particularly at the low altitudes now being explored by the Parker Solar Probe (PSP) 7 . One paradigm that can—at least in principle—satisfy the above requirements is heating through Alfvénic turbulence. Low-frequency Alfvénic motions in the low corona are observed to contain sufficient energy to power the wind 8 , 9 , and there are well-developed theories for how such motions become turbulent following reflection from large-scale density gradients 10 , 11 , 12 . This turbulence transfers energy into successively smaller-scale motions perpendicular to the magnetic field (larger k ⊥ , where k ⊥ is the inverse perpendicular scale), ultimately dissipating to heat the plasma. The difficulty is that most theories predict that in the strongly magnetized limit relevant to the solar corona (the low- β limit, where β is the ratio of thermal to magnetic pressure), such low-frequency, high- k ⊥ structures dissipate to heat predominantly electrons 13 , 14 . Other low-frequency plasma motions, such as compressive waves, generally cause parallel heating of ions 15 . Both possibilities are inconsistent with observations. More promisingly, for turbulence of sufficient amplitudes, ‘stochastic heating’ 16 can heat ions through a random walk on ion-gyroscale electric field fluctuations. Although it could plausibly explain key observations 17 , 18 , questions remain, such as its possible quenching due to flattening of the distribution function 19 , 20 and the influence of cross helicity 21 . Another possibility, that ions are heated by kinetic-Alfvén-wave (KAW) turbulence at sub-gyroradius scales 19 , 22 , remains less well understood and may be inefficient at low β (ref. 20 ). In the opposite limit of short field-parallel wavelengths (large k ∣ ∣ ), high-frequency ion-cyclotron waves (ICWs) provide a simpler mechanism for strong perpendicular ion heating 6 , 23 . At wavenumbers approaching \${k}_{\\parallel } \\approx{d}_{{{\\mathrm{i}}}}^{-1}\$ , where d i is the ion inertial length, their frequency approaches the ion gyrofrequency, where the cyclotron resonance causes highly efficient energy transfer from electromagnetic fields to ion velocities 24 , 25 . ICWs are observed ubiquitously in situ 7 and can suprathermally heat minor ions in a way that is observationally compelling 26 , 27 . However, a sufficiently energetic direct solar source of ICWs is highly unlikely 28 , and the Alfvénic cascade does not efficiently transfer energy to small parallel scales 29 , seemingly ruling out their turbulent origin. Although their occurrence in data can be explained by kinetic instabilities 30 , in most theories this implies that they would cool, rather than heat, the plasma 24 ; except perhaps in the presence of strong non-thermal particle beams 31 . If combined, these two heating paradigms—via Alfvénic turbulence or ICWs—can conceivably satisfy the fast-wind heating requirements described above, maintaining an abundant source of perpendicular ion heating well above the solar surface. Here we assess whether a newly discovered effect, termed the helicity barrier 32 , can fulfil this role by obstructing the dissipation of collisionless Alfvénic turbulence into electron heat. Using six-dimensional, high-resolution, hybrid-kinetic simulations, we explore the effect of the helicity barrier on collisionless turbulent heating, choosing parameters to match the conditions observed in fast wind streams as closely as possible. We assess the relevance of our results to the solar wind by comparing detailed features of the turbulent spectra and ion distribution function to observations from PSP and other spacecraft. The helicity barrier Solar-wind turbulence is imbalanced (possessing cross helicity), meaning that it is energetically dominated", "role": "user" }, { "content": "The further we move away from a heat source, the cooler the air gets. Bizarrely, the same can't be said for the sun, but University of Otago scientists may have just explained a key part of why. Study lead Dr. Jonathan Squire, of the Department of Physics, says the surface of the sun starts at 6,000 C, but over a short distance of only a few hundred kilometers, it suddenly heats up to more than a million degrees, becoming its atmosphere, or corona. \"This is so hot that the gas escapes the sun's gravity as 'solar wind,' and flies into space, smashing into Earth and other planets. \"We know from measurements and theory that the sudden temperature jump is related to magnetic fields which thread out of the sun's surface. But, exactly how these work to heat the gas is not well understood—this is known as the Coronal Heating Problem. \"Astrophysicists have several different ideas about how the magnetic-field energy could be converted into heat to explain the heating, but most have difficulty explaining some aspect of observations,\" he says. Dr. Squire and co-author Dr. Romain Meyrand have been working with scientists at Princeton University and the University of Oxford and found two previous theories can be merged into one to solve a key piece of the \"problem.\" The group's findings have just been published in Nature Astronomy. The popular theories are based on heating caused by turbulence, and heating caused by a type of magnetic wave called ion cyclotron waves. \"Both, however, have some problem—turbulence struggles to explain why Hydrogen, Helium and Oxygen in the gas become as hot as they do, while electrons remain surprisingly cold; while the magnetic waves theory could explain this feature, there doesn't seem to be enough of the waves coming off the sun's surface to heat up the gas,\" Dr. Meyrand says. The group used six-dimensional supercomputer simulations of the coronal gas to show how these two theories are actually part of the same process, linked together by a bizarre effect called the \"helicity barrier.\" This intriguing occurrence was discovered in an earlier Otago study, led by Dr. Meyrand. \"If we imagine plasma heating as occurring a bit like water flowing down a hill, with electrons heated right at the bottom, then the helicity barrier acts like a dam, stopping the flow and diverting its energy into ion cyclotron waves. In this way, the helicity barrier links the two theories and resolves each of their individual problems,\" he explains. For this latest study, the group stirred the magnetic field lines in simulations and found the turbulence created the waves, which then caused the heating. \"As this happens, the structures and eddies that form end up looking extremely similar to cutting-edge measurements from NASA's Parker Solar Probe spacecraft, which has recently become the first man-made object to actually fly into the corona. \"This gives us confidence that we are accurately capturing key physics in the corona, which—coupled with the theoretical findings about the heating mechanisms—is a promising path to understanding the coronal heating problem,\" Dr. Meyrand says. \"Understanding more about the sun's atmosphere and the subsequent solar wind is important because of the profound impacts they have on Earth,\" Dr. Squire explains. \"Effects which result from solar wind's interaction with the Earth's magnetic field is called 'space weather,' which causes everything from Aurora to satellite-destroying radiation and geomagnetic currents which damage the power grid. \"All of this is sourced, fundamentally, by the corona and its heating by magnetic fields, so as well as being interesting for our general understanding of the solar system, the solar-corona's dynamics can have profound impacts on Earth. \"Perhaps, with a better understanding of its basic physics, we will be able to build better models to predict space weather in the future, thus allowing the implementation of protection strategies that could head off—literally—billions of dollars of damage.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The fast solar wind’s high speeds and non-thermal features require that considerable heating occurs well above the Sun’s surface. Two leading theories seem incompatible: low-frequency ‘Alfvénic’ turbulence, which transports energy outwards and is observed ubiquitously by spacecraft but seems insufficient to explain the observed dominance of ion over electron heating; and high-frequency ion-cyclotron waves, which explain the non-thermal heating of ions but lack an obvious source. Here we argue that the recently proposed ‘helicity barrier’ effect, which limits electron heating by inhibiting the turbulent cascade of energy to the smallest scales, can unify these two paradigms. Our six-dimensional simulations show how the helicity barrier causes the large-scale energy to grow through time, generating small parallel scales and high-frequency ion-cyclotron-wave heating from low-frequency turbulence, while simultaneously explaining various other long-standing observational puzzles. The predicted causal link between plasma expansion and the ion-to-electron heating ratio suggests that the helicity barrier could contribute to key observed differences between fast and slow wind streams. Main The basic mechanisms that heat the solar corona and accelerate the solar wind remain mysterious despite intensive study over many decades 1 . A successful theory must explain how energy contained in photospheric motions and magnetic fields can be liberated to cause extreme and sudden heating of the coronal plasma, along with its acceleration to velocities well in excess of the escape velocity of the Sun. Adding to the complexity, the coronal plasma is collisionless—the mean-free path of protons can be large compared with the largest observed structures—meaning that it can be far out of local thermal equilibrium. This freedom opens up a wide array of channels for plasma heating: ions might be heated more than electrons (or vice versa), or particles might gain energy preferentially in a particular direction with respect to the local magnetic field 2 . Such differences can have pronounced macroscopic consequences. The dominant heating mechanism(s) must be consistent with an extensive array of measurements taken both remotely, from the low corona itself, and in situ, from spacecraft spread throughout the solar wind. In fast wind streams, these data indicate that the heating must be spatially extended out to several solar radii to drive observed wind speeds 3 . The mechanism must preferentially heat protons over electrons 4 , while heating heavier ions (for example, α-particles) even more effectively 5 ; it must heat protons in the direction perpendicular to the local magnetic field more than in the parallel direction to explain temperature anisotropies 6 ; and its features and/or after-effects should be observable in the measured field fluctuations and particle distribution, particularly at the low altitudes now being explored by the Parker Solar Probe (PSP) 7 . One paradigm that can—at least in principle—satisfy the above requirements is heating through Alfvénic turbulence. Low-frequency Alfvénic motions in the low corona are observed to contain sufficient energy to power the wind 8 , 9 , and there are well-developed theories for how such motions become turbulent following reflection from large-scale density gradients 10 , 11 , 12 . This turbulence transfers energy into successively smaller-scale motions perpendicular to the magnetic field (larger k ⊥ , where k ⊥ is the inverse perpendicular scale), ultimately dissipating to heat the plasma. The difficulty is that most theories predict that in the strongly magnetized limit relevant to the solar corona (the low- β limit, where β is the ratio of thermal to magnetic pressure), such low-frequency, high- k ⊥ structures dissipate to heat predominantly electrons 13 , 14 . Other low-frequency plasma motions, such as compressive waves, generally cause parallel heating of ions 15 . Both possibilities are inconsistent with observations. More promisingly, for turbulence of sufficient amplitudes, ‘stochastic heating’ 16 can heat ions through a random walk on ion-gyroscale electric field fluctuations. Although it could plausibly explain key observations 17 , 18 , questions remain, such as its possible quenching due to flattening of the distribution function 19 , 20 and the influence of cross helicity 21 . Another possibility, that ions are heated by kinetic-Alfvén-wave (KAW) turbulence at sub-gyroradius scales 19 , 22 , remains less well understood and may be inefficient at low β (ref. 20 ). In the opposite limit of short field-parallel wavelengths (large k ∣ ∣ ), high-frequency ion-cyclotron waves (ICWs) provide a simpler mechanism for strong perpendicular ion heating 6 , 23 . At wavenumbers approaching ${k}_{\parallel } \approx{d}_{{{\mathrm{i}}}}^{-1}$ , where d i is the ion inertial length, their frequency approaches the ion gyrofrequency, where the cyclotron resonance causes highly efficient energy transfer from electromagnetic fields to ion velocities 24 , 25 . ICWs are observed ubiquitously in situ 7 and can suprathermally heat minor ions in a way that is observationally compelling 26 , 27 . However, a sufficiently energetic direct solar source of ICWs is highly unlikely 28 , and the Alfvénic cascade does not efficiently transfer energy to small parallel scales 29 , seemingly ruling out their turbulent origin. Although their occurrence in data can be explained by kinetic instabilities 30 , in most theories this implies that they would cool, rather than heat, the plasma 24 ; except perhaps in the presence of strong non-thermal particle beams 31 . If combined, these two heating paradigms—via Alfvénic turbulence or ICWs—can conceivably satisfy the fast-wind heating requirements described above, maintaining an abundant source of perpendicular ion heating well above the solar surface. Here we assess whether a newly discovered effect, termed the helicity barrier 32 , can fulfil this role by obstructing the dissipation of collisionless Alfvénic turbulence into electron heat. Using six-dimensional, high-resolution, hybrid-kinetic simulations, we explore the effect of the helicity barrier on collisionless turbulent heating, choosing parameters to match the conditions observed in fast wind streams as closely as possible. We assess the relevance of our results to the solar wind by comparing detailed features of the turbulent spectra and ion distribution function to observations from PSP and other spacecraft. The helicity barrier Solar-wind turbulence is imbalanced (possessing cross helicity), meaning that it is energetically dominated<|im_end|> <|im_start|>assistant The further we move away from a heat source, the cooler the air gets. Bizarrely, the same can't be said for the sun, but University of Otago scientists may have just explained a key part of why. Study lead Dr. Jonathan Squire, of the Department of Physics, says the surface of the sun starts at 6,000 C, but over a short distance of only a few hundred kilometers, it suddenly heats up to more than a million degrees, becoming its atmosphere, or corona. "This is so hot that the gas escapes the sun's gravity as 'solar wind,' and flies into space, smashing into Earth and other planets. "We know from measurements and theory that the sudden temperature jump is related to magnetic fields which thread out of the sun's surface. But, exactly how these work to heat the gas is not well understood—this is known as the Coronal Heating Problem. "Astrophysicists have several different ideas about how the magnetic-field energy could be converted into heat to explain the heating, but most have difficulty explaining some aspect of observations," he says. Dr. Squire and co-author Dr. Romain Meyrand have been working with scientists at Princeton University and the University of Oxford and found two previous theories can be merged into one to solve a key piece of the "problem." The group's findings have just been published in Nature Astronomy. The popular theories are based on heating caused by turbulence, and heating caused by a type of magnetic wave called ion cyclotron waves. "Both, however, have some problem—turbulence struggles to explain why Hydrogen, Helium and Oxygen in the gas become as hot as they do, while electrons remain surprisingly cold; while the magnetic waves theory could explain this feature, there doesn't seem to be enough of the waves coming off the sun's surface to heat up the gas," Dr. Meyrand says. The group used six-dimensional supercomputer simulations of the coronal gas to show how these two theories are actually part of the same process, linked together by a bizarre effect called the "helicity barrier." This intriguing occurrence was discovered in an earlier Otago study, led by Dr. Meyrand. "If we imagine plasma heating as occurring a bit like water flowing down a hill, with electrons heated right at the bottom, then the helicity barrier acts like a dam, stopping the flow and diverting its energy into ion cyclotron waves. In this way, the helicity barrier links the two theories and resolves each of their individual problems," he explains. For this latest study, the group stirred the magnetic field lines in simulations and found the turbulence created the waves, which then caused the heating. "As this happens, the structures and eddies that form end up looking extremely similar to cutting-edge measurements from NASA's Parker Solar Probe spacecraft, which has recently become the first man-made object to actually fly into the corona. "This gives us confidence that we are accurately capturing key physics in the corona, which—coupled with the theoretical findings about the heating mechanisms—is a promising path to understanding the coronal heating problem," Dr. Meyrand says. "Understanding more about the sun's atmosphere and the subsequent solar wind is important because of the profound impacts they have on Earth," Dr. Squire explains. "Effects which result from solar wind's interaction with the Earth's magnetic field is called 'space weather,' which causes everything from Aurora to satellite-destroying radiation and geomagnetic currents which damage the power grid. "All of this is sourced, fundamentally, by the corona and its heating by magnetic fields, so as well as being interesting for our general understanding of the solar system, the solar-corona's dynamics can have profound impacts on Earth. "Perhaps, with a better understanding of its basic physics, we will be able to build better models to predict space weather in the future, thus allowing the implementation of protection strategies that could head off—literally—billions of dollars of damage." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Growing evidence indicates that prolonged sedentary behaviour increases the risk of several chronic health conditions and all-cause mortality. Sedentary behaviour is prevalent among adults in the UK. Quantifying the costs associated with sedentary behaviour is an important step in the development of public health policy. Methods National Health Service (NHS) costs associated with prolonged sedentary behaviour (≥6 hours/day) were estimated over a 1-year period in 2016–2017 costs. We calculated a population attributable fraction (PAF) for five health outcomes (type 2 diabetes, cardiovascular disease [CVD], colon cancer, endometrial cancer and lung cancer). Adjustments were made for potential double-counting due to comorbidities. We also calculated the avoidable deaths due to prolonged sedentary behaviour using the PAF for all-cause mortality. Results The total NHS costs attributable to prolonged sedentary behaviour in the UK in 2016–2017 were £0.8 billion, which included expenditure on CVD (£424 million), type 2 diabetes (£281 million), colon cancer (£30 million), lung cancer (£19 million) and endometrial cancer (£7 million). After adjustment for potential double-counting, the estimated total was £0.7 billion. If prolonged sedentary behaviour was eliminated, 69 276 UK deaths might have been avoided in 2016. Conclusions In this conservative estimate of direct healthcare costs, prolonged sedentary behaviour causes a considerable burden to the NHS in the UK. This estimate may be used by decision makers when prioritising healthcare resources and investing in preventative public health programmes. public health sedentary behaviour sitting time cost analysis health expenditure healthcare cost physical activity googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 47 news outlets Blogged by 4 Referenced in 1 policy sources Tweeted by 160 On 4 Facebook pages 207 readers on Mendeley Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions public health sedentary behaviour sitting time cost analysis health expenditure healthcare cost physical activity Introduction Adults in the UK have become increasingly sedentary as modern technology has changed everyday life. 1 Sedentary behaviour is distinct from physical inactivity and refers to sitting or lying while expending low amounts of energy (≤1.5 metabolic equivalents). 2 National guidelines recommend minimising time spent sedentary 3 without specifying how many hours/day of sitting might be harmful. A recent meta-analysis reported that spending 6–8 hours/day sedentary increases future risk of all-cause and cardiovascular mortality. 4 In this study, we defined sedentary behaviour as spending at least six hours of waking time sedentary. Thirty per cent of adults in the UK are sedentary for at least six hours/day during the week, which rises to 37% on the weekend. 5 Consequently, many individuals in the UK are at greater risk of chronic disease. Sedentary behaviour is an established risk factor for several non-communicable diseases. Strong evidence suggests that high levels of sitting time lead to increased risk of cardiovascular disease (CVD), type 2 diabetes and all-cause mortality (risk of mortality from all causes, not only those mentioned here). 6 Additionally, moderate evidence indicates an increased risk of colon, endometrial and lung cancer. 6 These diseases all contribute considerably to morbidity and mortality in the UK. Thus, addressing the problem of sedentary behaviour could potentially reduce the burden of disease. Awareness of the economic burden of sedentary behaviour could inform and motivate policymakers to address this risk factor. Estimates of the cost impacts allow decision makers to prioritise funding and make an economic argument for investment in prevention. Estimates for the financial impact of many lifestyle risk factors in the UK are available, such as obesity, smoking and physical inactivity 7 8 ; however, none exists thus far for sedentary behaviour. As a result, this study aims to estimate the direct healthcare costs of prolonged sedentary behaviour in the UK. Methods Costs were estimated from a healthcare payer perspective (UK National Health Service [NHS]) using a prevalence-based and population attributable fraction (PAF) approach, following the methodology employed by Ding et al . 7 Quantifying the increased risk to health due to sedentary behaviour We selected the most suitable meta-analyses cited in a recent report of the relationship between sedentary behaviour and health 6 in order to extract the relative risks (RRs). Appropriate studies employed a prospective design, non-diseased participants at baseline and adjusted for levels of physical activity in their statistical model. Furthermore, the researchers had investigated the association by comparing the most sedentary individuals with the least sedentary, and we preferred studies which had used sedentary time as an exposure. Two studies were appropriate for the outcome of CVD 9 10 : we chose the more recent meta-analysis by Pandey et al 10 as it had included three additional applicable studies. After examining data from the primary studies, we excluded those that did not meet the exact criteria above and repooled the risk estimate using Review Manager (RevMan V.5.3). Estimating the extent of sedentary behaviour in the UK population The Health Survey for England 2012 5 reported that 30% of adults in England spent at least six hours/day sedentary on weekdays and 37% of adults on weekends. We used these figures to estimate the percentage of UK adults who are sedentary on any given day of the week ( ). The PAF formula we have used requires the prevalence of sedentary behaviour at baseline in those who went on to become cases (ie, experiencing the adverse outcome). This information is not readily available. Therefore, we calculated prevalence ‘adjustment factors’ 11 using data from cohort studies ( table 1 ). We searched for cohort studies 12–17 on PubMed that fitted the same criteria mentioned in the previous section and had specifically measured and reported sedentary behaviour for the total population and for cases only at baseline. We preferred European-based studies and larger studies with longer follow-up times to give more reliable adjustment factors. The", "role": "user" }, { "content": "Spending large amounts of time sitting or lounging around during the day is linked to around 50,000 deaths per year in the UK and the NHS spends in excess of £0.7bn per year treating the health consequences, suggests research from Queen's University Belfast and Ulster University published online in the Journal of Epidemiology & Community Health. A large proportion of the UK population have sedentary jobs and leisure activities, and official physical activity recommendations regarding sedentary behaviour are vague. Previous studies have shown that spending large parts of the day sitting down increases the risk of cardiovascular disease, type 2 diabetes, cancer and death and is a burden on health services. But no estimate of the financial impact that sedentary behaviour has on the NHS has been calculated, so the authors set out to do just that. Figures calculated by other researchers on the impact sedentary behaviour has on the relative risks of five specific health conditions (type 2 diabetes, cardiovascular disease, colon cancer, endometrial cancer and lung cancer) and deaths from all causes were combined with figures on the percentage of adults who are sedentary on any given day of the week to estimate the overall impact sedentary behaviour has at a UK population level (population attributable fraction). Figures on sedentary behaviour were taken from the Health Survey for England 2012, which reported that 30% of adults in England spent at least six hours/day sedentary on weekdays and that this increased to 37% of adults on weekends. Actual overall NHS spending on each of the five conditions, uplifted for inflation, was used to estimate the financial impact sedentary behaviour had on the NHS for each of the conditions in the UK in 2016-17. For all five conditions combined, this amounted to £0.8bn in 2016-17. As a proportion of patients will have more than one of the five conditions, for example around 30% of people with type 2 diabetes will also have cardiovascular disease, the researchers revised their figures to adjust for double-counting caused by comorbidity. This reduced the overall cost of sedentary behaviour to the NHS for these five health conditions to £0.7bn in 2016-17. Next they took the figure calculated for the fraction of deaths from all causes that could be attributed to a sedentary lifestyle and multiplied it with the actual numbers of deaths that occurred in the UK in 2016. The researchers say their results suggest that 11.6% of all deaths were associated with sedentary behaviour and that 69,276 deaths might have been avoided in 2016 if sedentary behaviour was eliminated in the UK. This is an observational study, and as such, can't establish cause, and it also relied on estimates of people's self-reported activity levels, which may not be accurate. The study was also limited by the evidence available for the link between sedentary behaviour and health outcomes. The authors point out that these costs are probably a conservative estimate of the true burden of sedentary behaviour because sedentary behaviour is likely to be associated with several other cancers, musculoskeletal disorders, and mental health disorders, not included in their analysis. Official physical activity recommendations regarding sedentary behaviour are vague, they say. Lead Investigator, Leonie Heron from the Centre of Public Health at Queen's University Belfast, said: \"Many individuals in the UK spend their leisure time in sedentary behaviour, and the workplace represents a significant proportion of unavoidable daily sitting time for many people.\" Measures should be taken to reduce sedentary behaviour with the aim of improving population health and reducing the financial burden to the health service, they conclude. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Growing evidence indicates that prolonged sedentary behaviour increases the risk of several chronic health conditions and all-cause mortality. Sedentary behaviour is prevalent among adults in the UK. Quantifying the costs associated with sedentary behaviour is an important step in the development of public health policy. Methods National Health Service (NHS) costs associated with prolonged sedentary behaviour (≥6 hours/day) were estimated over a 1-year period in 2016–2017 costs. We calculated a population attributable fraction (PAF) for five health outcomes (type 2 diabetes, cardiovascular disease [CVD], colon cancer, endometrial cancer and lung cancer). Adjustments were made for potential double-counting due to comorbidities. We also calculated the avoidable deaths due to prolonged sedentary behaviour using the PAF for all-cause mortality. Results The total NHS costs attributable to prolonged sedentary behaviour in the UK in 2016–2017 were £0.8 billion, which included expenditure on CVD (£424 million), type 2 diabetes (£281 million), colon cancer (£30 million), lung cancer (£19 million) and endometrial cancer (£7 million). After adjustment for potential double-counting, the estimated total was £0.7 billion. If prolonged sedentary behaviour was eliminated, 69 276 UK deaths might have been avoided in 2016. Conclusions In this conservative estimate of direct healthcare costs, prolonged sedentary behaviour causes a considerable burden to the NHS in the UK. This estimate may be used by decision makers when prioritising healthcare resources and investing in preventative public health programmes. public health sedentary behaviour sitting time cost analysis health expenditure healthcare cost physical activity googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 47 news outlets Blogged by 4 Referenced in 1 policy sources Tweeted by 160 On 4 Facebook pages 207 readers on Mendeley Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions public health sedentary behaviour sitting time cost analysis health expenditure healthcare cost physical activity Introduction Adults in the UK have become increasingly sedentary as modern technology has changed everyday life. 1 Sedentary behaviour is distinct from physical inactivity and refers to sitting or lying while expending low amounts of energy (≤1.5 metabolic equivalents). 2 National guidelines recommend minimising time spent sedentary 3 without specifying how many hours/day of sitting might be harmful. A recent meta-analysis reported that spending 6–8 hours/day sedentary increases future risk of all-cause and cardiovascular mortality. 4 In this study, we defined sedentary behaviour as spending at least six hours of waking time sedentary. Thirty per cent of adults in the UK are sedentary for at least six hours/day during the week, which rises to 37% on the weekend. 5 Consequently, many individuals in the UK are at greater risk of chronic disease. Sedentary behaviour is an established risk factor for several non-communicable diseases. Strong evidence suggests that high levels of sitting time lead to increased risk of cardiovascular disease (CVD), type 2 diabetes and all-cause mortality (risk of mortality from all causes, not only those mentioned here). 6 Additionally, moderate evidence indicates an increased risk of colon, endometrial and lung cancer. 6 These diseases all contribute considerably to morbidity and mortality in the UK. Thus, addressing the problem of sedentary behaviour could potentially reduce the burden of disease. Awareness of the economic burden of sedentary behaviour could inform and motivate policymakers to address this risk factor. Estimates of the cost impacts allow decision makers to prioritise funding and make an economic argument for investment in prevention. Estimates for the financial impact of many lifestyle risk factors in the UK are available, such as obesity, smoking and physical inactivity 7 8 ; however, none exists thus far for sedentary behaviour. As a result, this study aims to estimate the direct healthcare costs of prolonged sedentary behaviour in the UK. Methods Costs were estimated from a healthcare payer perspective (UK National Health Service [NHS]) using a prevalence-based and population attributable fraction (PAF) approach, following the methodology employed by Ding et al . 7 Quantifying the increased risk to health due to sedentary behaviour We selected the most suitable meta-analyses cited in a recent report of the relationship between sedentary behaviour and health 6 in order to extract the relative risks (RRs). Appropriate studies employed a prospective design, non-diseased participants at baseline and adjusted for levels of physical activity in their statistical model. Furthermore, the researchers had investigated the association by comparing the most sedentary individuals with the least sedentary, and we preferred studies which had used sedentary time as an exposure. Two studies were appropriate for the outcome of CVD 9 10 : we chose the more recent meta-analysis by Pandey et al 10 as it had included three additional applicable studies. After examining data from the primary studies, we excluded those that did not meet the exact criteria above and repooled the risk estimate using Review Manager (RevMan V.5.3). Estimating the extent of sedentary behaviour in the UK population The Health Survey for England 2012 5 reported that 30% of adults in England spent at least six hours/day sedentary on weekdays and 37% of adults on weekends. We used these figures to estimate the percentage of UK adults who are sedentary on any given day of the week ( ). The PAF formula we have used requires the prevalence of sedentary behaviour at baseline in those who went on to become cases (ie, experiencing the adverse outcome). This information is not readily available. Therefore, we calculated prevalence ‘adjustment factors’ 11 using data from cohort studies ( table 1 ). We searched for cohort studies 12–17 on PubMed that fitted the same criteria mentioned in the previous section and had specifically measured and reported sedentary behaviour for the total population and for cases only at baseline. We preferred European-based studies and larger studies with longer follow-up times to give more reliable adjustment factors. The<|im_end|> <|im_start|>assistant Spending large amounts of time sitting or lounging around during the day is linked to around 50,000 deaths per year in the UK and the NHS spends in excess of £0.7bn per year treating the health consequences, suggests research from Queen's University Belfast and Ulster University published online in the Journal of Epidemiology & Community Health. A large proportion of the UK population have sedentary jobs and leisure activities, and official physical activity recommendations regarding sedentary behaviour are vague. Previous studies have shown that spending large parts of the day sitting down increases the risk of cardiovascular disease, type 2 diabetes, cancer and death and is a burden on health services. But no estimate of the financial impact that sedentary behaviour has on the NHS has been calculated, so the authors set out to do just that. Figures calculated by other researchers on the impact sedentary behaviour has on the relative risks of five specific health conditions (type 2 diabetes, cardiovascular disease, colon cancer, endometrial cancer and lung cancer) and deaths from all causes were combined with figures on the percentage of adults who are sedentary on any given day of the week to estimate the overall impact sedentary behaviour has at a UK population level (population attributable fraction). Figures on sedentary behaviour were taken from the Health Survey for England 2012, which reported that 30% of adults in England spent at least six hours/day sedentary on weekdays and that this increased to 37% of adults on weekends. Actual overall NHS spending on each of the five conditions, uplifted for inflation, was used to estimate the financial impact sedentary behaviour had on the NHS for each of the conditions in the UK in 2016-17. For all five conditions combined, this amounted to £0.8bn in 2016-17. As a proportion of patients will have more than one of the five conditions, for example around 30% of people with type 2 diabetes will also have cardiovascular disease, the researchers revised their figures to adjust for double-counting caused by comorbidity. This reduced the overall cost of sedentary behaviour to the NHS for these five health conditions to £0.7bn in 2016-17. Next they took the figure calculated for the fraction of deaths from all causes that could be attributed to a sedentary lifestyle and multiplied it with the actual numbers of deaths that occurred in the UK in 2016. The researchers say their results suggest that 11.6% of all deaths were associated with sedentary behaviour and that 69,276 deaths might have been avoided in 2016 if sedentary behaviour was eliminated in the UK. This is an observational study, and as such, can't establish cause, and it also relied on estimates of people's self-reported activity levels, which may not be accurate. The study was also limited by the evidence available for the link between sedentary behaviour and health outcomes. The authors point out that these costs are probably a conservative estimate of the true burden of sedentary behaviour because sedentary behaviour is likely to be associated with several other cancers, musculoskeletal disorders, and mental health disorders, not included in their analysis. Official physical activity recommendations regarding sedentary behaviour are vague, they say. Lead Investigator, Leonie Heron from the Centre of Public Health at Queen's University Belfast, said: "Many individuals in the UK spend their leisure time in sedentary behaviour, and the workplace represents a significant proportion of unavoidable daily sitting time for many people." Measures should be taken to reduce sedentary behaviour with the aim of improving population health and reducing the financial burden to the health service, they conclude. <|im_end|>

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2,130

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex–dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico–reticulo–spinal circuit reorganization may also improve recovery in humans. Main After a spinal cord injury (SCI), only half of affected individuals regain supraspinal control of movements below the level of the lesion. However, imaging 1 , electrophysiological 2 , 3 and anatomical 4 evaluations reveal that even the most severe SCIs usually spare regions of white matter. These bridges contain residual fibers from mixed populations of projection neurons that maintain a physical connection with the lumbar spinal cord, where the circuits coordinating leg movements reside. Nevertheless, these residual connections are insufficient to elicit volitional muscle contractions Two main reasons have been invoked to explain this failure. First, the interruption of descending pathways suppresses the sources of modulation and excitation that render lumbar spinal circuits functional 5 , 6 . Second, conduction failure in the vicinity of injured regions 7 contributes to silencing residual fibers that could contribute to recovery 8 . These findings guided the design of therapies that specifically target spared lumbar circuits and projection neurons with residual fibers below injury to improve recovery from SCI 2 , 5 , 9 , 10 , 11 , 12 . These interventions act over two time windows. In the short term, monoamine receptor agonists and epidural electrical stimulation are delivered to the lumbar spinal cord to compensate for the interrupted source of modulation and excitation. Electrochemical neuromodulation therapies instantly enables paralyzed rats to execute complex locomotor behaviors. Similarly, electrical stimulation enables individuals with motor complete paralysis to produce isolated leg movements 2 . In the long term, rehabilitation enabled by these neuromodulation therapies improves volitional motor performance 2 , 10 , 13 , suggesting a reorganization of residual projections that enhances supraspinal control of spinal circuits 11 . However, both in animal models and humans, movements occur only in the presence of neuromodulation therapies. The mechanisms enabling motor control when delivering neuromodulation therapies and improvements with rehabilitation remain enigmatic and vividly debated 14 , 15 . It is therefore critical to address these knowledge gaps to support mechanism-based therapeutic development and apply these findings clinically. Various investigations have uncovered key mechanisms of recovery from SCI. These studies were primarily conducted in moderate cut models of SCI, which combine two important advantages. First, precise cuts into defined regions interrupt specific pathways, which supports unambiguous conclusions on anatomical reorganization. Second, multiple spared neural pathways allow a progressive spontaneous recovery of function. These well-controlled conditions demonstrated that the formation of detour circuits reconnecting cortical, brainstem and intraspinal projection neurons to denervated circuits below injury contributes to spontaneous recovery 11 , 16 , 17 , 18 , 19 , 20 , 21 . Nevertheless, spinal cord damage in humans primarily results from contusions. These injuries induce highly variable pathway interruption and pronounced secondary damage, including cavity formation 22 , inflammatory responses 23 and demyelination 7 , that impair residual pathway functionality. Consequently, the mechanisms supporting recovery from contusion remain undefined. Moreover, the capacity of neuromodulation therapies and rehabilitation to restore motor control after severe contusions is unknown. We tackled these questions in rodent models of severe contusions leading to permanent paralysis. Electrochemical neuromodulation therapies and gravity-assisted rehabilitation enabled rats to regain supraspinal control of locomotion that persisted without neuromodulation, even during unpracticed, natural tasks. Using cell-specific optogenetics, circuit-level inactivation and unbiased whole brain–spinal cord microscopy, we demonstrate that the reorganization of cortico–reticulo–spinal circuits mediated a motor cortex–dependent recovery in these animals. Results Contusion model leading to paralysis We modeled severe contusions in rats (Fig. 1a ) using robotically controlled impacts (255.5 ± 1.3 kdyn) onto T8/T9 segments (Supplementary Fig. 1 ). This lesion spared 9.75 ± 0.57% of intact cross-sectional tissue (Fig. 1b ) and induced highly variable white matter sparing (Supplementary Fig. 2 ). Fig. 1: Neurorehabilitation restores supraspinal control of leg movements in rats. a , Scheme and timeline summarizing the experiments. b , Top and side view of a 3D reconstruction of the lesion cavity. Photograph of a representative coronal section through the contusion epicenter (GFAP, glial fibrillary acidic protein). Scale bars 1 mm for 3D reconstructions, 250 µm for cross-section. c , Untrained and trained rats tested during bipedal locomotion with gravity assist, both without and with electrochemical neuromodulation. Stick diagram decompositions of right leg movements; leg endpoint trajectory with acceleration at toe-off; activity of extensor and flexor muscles of the ankle. The gray, white and orange backgrounds correspond to the stance, swing and drag phases of gait, respectively. d , Circular plots reporting the gross leg motor performance of untrained and trained rats under the different conditions of neuromodulation. e , PC analysis of gait parameters averaged for each rat and condition (small circles). Large circles show the average per group. Bar plot show the average scores on PC1, which quantify the locomotor performance of untrained rats (9 weeks post-injury, n = 8), trained rats (9 weeks post-injury, n = 7) and subacute rats (1 week post-injury, n = 9) compared to intact rats ( n = 5). ** P < 0.01; *** P < 0.001. One-way ANOVA followed by Bonferroni’s post hoc test. Mtp, metatarsophalangeal joint; BWS, body weight support. Full size image One week after injury (the subacute condition), all rats showed flaccid leg paralysis (Supplementary Video 1 ). We reactivated lumbar circuits with agonists to serotonergic and dopaminergic receptors and with epidural electrical stimulation applied to lumbosacral segments. These", "role": "user" }, { "content": "With the help of robot-assisted rehabilitation and electrochemical spinal cord stimulation, rats with clinically relevant spinal cord injuries regained control of their otherwise paralyzed limbs. But how do brain commands for walking, swimming and stair-climbing bypass the injury and still reach the spinal cord to execute these complex tasks? EPFL scientists have observed for the first time that the brain reroutes task-specific motor commands through alternative pathways originating in the brainstem and projecting to the spinal cord. The therapy triggers the growth of new connections from the motor cortex into the brainstem and from the brainstem into the spinal cord, thus reconnecting the brain with the spinal cord below the injury. The results are published in Nature Neuroscience March 19th. \"The brain develops new anatomical connections through regions of the nervous system that are still intact after injury,\" says EPFL scientist Grégoire Courtine. \"The brain essentially rewires circuits from the cerebral cortex, brainstem and spinal cord—an extensive rewiring that we exposed to unprecedented detail using next-generation whole brain-spinal cord microscopy.\" \"The recovery is not spontaneous,\" says EPFL scientist and lead author Léonie Asboth. \"You need to engage the animals in an intense rehabilitation therapy for the rewiring to take place. In our case, this therapy involves electrochemical stimulation of the spinal cord and active physiotherapy in a smart assistive harness.\" In Courtine's lab, rats with a contusion causing complete paraplegia learned to walk again via therapy that combines electrochemical stimulation of the spinal cord and robot-assisted rehabilitation. The rat's spinal cord is first stimulated with pharmaceuticals, then electrically stimulated below the injury to activate muscles in the legs. Combined with therapy in a smart harness that alleviates the body's weight, providing natural walking conditions, and after just a few weeks of training, the rats regained extensive control over their hind limbs at will, even without electrochemical stimulation or the harness. In 2012, Courtine and his team showed that rats with spinal injury could climb stairs and swim with neuroprosthetic rehabilitation. Comparing the brains of injured rats after rehabilitation with those of healthy ones, the scientists were able to identify the reticular formation, a region in the brainstem, as key in recovery. The scientists uncovered this role using optogenetics and chemogenetics in transgenic animals, an ensemble of precise tools that allowed the activation and inactivation of well-defined circuits in the brain and brainstem to probe their function. They also exploited a new, powerful light-sheet microscope developed by the Wyss Center for Bio and Neuroengineering in Geneva to visualize neural tracts. The entire central nervous system was rendered transparent, with the exception of the neural tracts that expressed a fluorescent protein. By passing a sheet of light throughout the non-sectioned brain and spinal cord, the scientists obtained previously unseen 3-D images that showed the organisation of neural tracts in healthy animals and how the therapy reorganised these pathways without any bias. The injured neurons do not regrow spontaneously, but a reorganisation of the neural branching occurs above the injury leading to new connections. It remains to be seen if neuroprosthetic rehabilitation in people leads to an analogous rewiring of the brain, brainstem and spinal cord. Courtine is optimistic: \"We previously showed that plasticity, the remarkable ability of the nervous system to grow new connections after spinal cord injury, is even more robust in humans than in rodents. We are currently testing our therapy in people with spinal cord injury at the Lausanne university hospital (CHUV).\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex–dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico–reticulo–spinal circuit reorganization may also improve recovery in humans. Main After a spinal cord injury (SCI), only half of affected individuals regain supraspinal control of movements below the level of the lesion. However, imaging 1 , electrophysiological 2 , 3 and anatomical 4 evaluations reveal that even the most severe SCIs usually spare regions of white matter. These bridges contain residual fibers from mixed populations of projection neurons that maintain a physical connection with the lumbar spinal cord, where the circuits coordinating leg movements reside. Nevertheless, these residual connections are insufficient to elicit volitional muscle contractions Two main reasons have been invoked to explain this failure. First, the interruption of descending pathways suppresses the sources of modulation and excitation that render lumbar spinal circuits functional 5 , 6 . Second, conduction failure in the vicinity of injured regions 7 contributes to silencing residual fibers that could contribute to recovery 8 . These findings guided the design of therapies that specifically target spared lumbar circuits and projection neurons with residual fibers below injury to improve recovery from SCI 2 , 5 , 9 , 10 , 11 , 12 . These interventions act over two time windows. In the short term, monoamine receptor agonists and epidural electrical stimulation are delivered to the lumbar spinal cord to compensate for the interrupted source of modulation and excitation. Electrochemical neuromodulation therapies instantly enables paralyzed rats to execute complex locomotor behaviors. Similarly, electrical stimulation enables individuals with motor complete paralysis to produce isolated leg movements 2 . In the long term, rehabilitation enabled by these neuromodulation therapies improves volitional motor performance 2 , 10 , 13 , suggesting a reorganization of residual projections that enhances supraspinal control of spinal circuits 11 . However, both in animal models and humans, movements occur only in the presence of neuromodulation therapies. The mechanisms enabling motor control when delivering neuromodulation therapies and improvements with rehabilitation remain enigmatic and vividly debated 14 , 15 . It is therefore critical to address these knowledge gaps to support mechanism-based therapeutic development and apply these findings clinically. Various investigations have uncovered key mechanisms of recovery from SCI. These studies were primarily conducted in moderate cut models of SCI, which combine two important advantages. First, precise cuts into defined regions interrupt specific pathways, which supports unambiguous conclusions on anatomical reorganization. Second, multiple spared neural pathways allow a progressive spontaneous recovery of function. These well-controlled conditions demonstrated that the formation of detour circuits reconnecting cortical, brainstem and intraspinal projection neurons to denervated circuits below injury contributes to spontaneous recovery 11 , 16 , 17 , 18 , 19 , 20 , 21 . Nevertheless, spinal cord damage in humans primarily results from contusions. These injuries induce highly variable pathway interruption and pronounced secondary damage, including cavity formation 22 , inflammatory responses 23 and demyelination 7 , that impair residual pathway functionality. Consequently, the mechanisms supporting recovery from contusion remain undefined. Moreover, the capacity of neuromodulation therapies and rehabilitation to restore motor control after severe contusions is unknown. We tackled these questions in rodent models of severe contusions leading to permanent paralysis. Electrochemical neuromodulation therapies and gravity-assisted rehabilitation enabled rats to regain supraspinal control of locomotion that persisted without neuromodulation, even during unpracticed, natural tasks. Using cell-specific optogenetics, circuit-level inactivation and unbiased whole brain–spinal cord microscopy, we demonstrate that the reorganization of cortico–reticulo–spinal circuits mediated a motor cortex–dependent recovery in these animals. Results Contusion model leading to paralysis We modeled severe contusions in rats (Fig. 1a ) using robotically controlled impacts (255.5 ± 1.3 kdyn) onto T8/T9 segments (Supplementary Fig. 1 ). This lesion spared 9.75 ± 0.57% of intact cross-sectional tissue (Fig. 1b ) and induced highly variable white matter sparing (Supplementary Fig. 2 ). Fig. 1: Neurorehabilitation restores supraspinal control of leg movements in rats. a , Scheme and timeline summarizing the experiments. b , Top and side view of a 3D reconstruction of the lesion cavity. Photograph of a representative coronal section through the contusion epicenter (GFAP, glial fibrillary acidic protein). Scale bars 1 mm for 3D reconstructions, 250 µm for cross-section. c , Untrained and trained rats tested during bipedal locomotion with gravity assist, both without and with electrochemical neuromodulation. Stick diagram decompositions of right leg movements; leg endpoint trajectory with acceleration at toe-off; activity of extensor and flexor muscles of the ankle. The gray, white and orange backgrounds correspond to the stance, swing and drag phases of gait, respectively. d , Circular plots reporting the gross leg motor performance of untrained and trained rats under the different conditions of neuromodulation. e , PC analysis of gait parameters averaged for each rat and condition (small circles). Large circles show the average per group. Bar plot show the average scores on PC1, which quantify the locomotor performance of untrained rats (9 weeks post-injury, n = 8), trained rats (9 weeks post-injury, n = 7) and subacute rats (1 week post-injury, n = 9) compared to intact rats ( n = 5). ** P < 0.01; *** P < 0.001. One-way ANOVA followed by Bonferroni’s post hoc test. Mtp, metatarsophalangeal joint; BWS, body weight support. Full size image One week after injury (the subacute condition), all rats showed flaccid leg paralysis (Supplementary Video 1 ). We reactivated lumbar circuits with agonists to serotonergic and dopaminergic receptors and with epidural electrical stimulation applied to lumbosacral segments. These<|im_end|> <|im_start|>assistant With the help of robot-assisted rehabilitation and electrochemical spinal cord stimulation, rats with clinically relevant spinal cord injuries regained control of their otherwise paralyzed limbs. But how do brain commands for walking, swimming and stair-climbing bypass the injury and still reach the spinal cord to execute these complex tasks? EPFL scientists have observed for the first time that the brain reroutes task-specific motor commands through alternative pathways originating in the brainstem and projecting to the spinal cord. The therapy triggers the growth of new connections from the motor cortex into the brainstem and from the brainstem into the spinal cord, thus reconnecting the brain with the spinal cord below the injury. The results are published in Nature Neuroscience March 19th. "The brain develops new anatomical connections through regions of the nervous system that are still intact after injury," says EPFL scientist Grégoire Courtine. "The brain essentially rewires circuits from the cerebral cortex, brainstem and spinal cord—an extensive rewiring that we exposed to unprecedented detail using next-generation whole brain-spinal cord microscopy." "The recovery is not spontaneous," says EPFL scientist and lead author Léonie Asboth. "You need to engage the animals in an intense rehabilitation therapy for the rewiring to take place. In our case, this therapy involves electrochemical stimulation of the spinal cord and active physiotherapy in a smart assistive harness." In Courtine's lab, rats with a contusion causing complete paraplegia learned to walk again via therapy that combines electrochemical stimulation of the spinal cord and robot-assisted rehabilitation. The rat's spinal cord is first stimulated with pharmaceuticals, then electrically stimulated below the injury to activate muscles in the legs. Combined with therapy in a smart harness that alleviates the body's weight, providing natural walking conditions, and after just a few weeks of training, the rats regained extensive control over their hind limbs at will, even without electrochemical stimulation or the harness. In 2012, Courtine and his team showed that rats with spinal injury could climb stairs and swim with neuroprosthetic rehabilitation. Comparing the brains of injured rats after rehabilitation with those of healthy ones, the scientists were able to identify the reticular formation, a region in the brainstem, as key in recovery. The scientists uncovered this role using optogenetics and chemogenetics in transgenic animals, an ensemble of precise tools that allowed the activation and inactivation of well-defined circuits in the brain and brainstem to probe their function. They also exploited a new, powerful light-sheet microscope developed by the Wyss Center for Bio and Neuroengineering in Geneva to visualize neural tracts. The entire central nervous system was rendered transparent, with the exception of the neural tracts that expressed a fluorescent protein. By passing a sheet of light throughout the non-sectioned brain and spinal cord, the scientists obtained previously unseen 3-D images that showed the organisation of neural tracts in healthy animals and how the therapy reorganised these pathways without any bias. The injured neurons do not regrow spontaneously, but a reorganisation of the neural branching occurs above the injury leading to new connections. It remains to be seen if neuroprosthetic rehabilitation in people leads to an analogous rewiring of the brain, brainstem and spinal cord. Courtine is optimistic: "We previously showed that plasticity, the remarkable ability of the nervous system to grow new connections after spinal cord injury, is even more robust in humans than in rodents. We are currently testing our therapy in people with spinal cord injury at the Lausanne university hospital (CHUV)." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signalling, cell death and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function. Here we show that A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7). We provide genetic evidence that RIPK1 kinase-dependent, RIPK3–MLKL-mediated necroptosis drives inflammasome activation in A20-deficient macrophages and causes inflammatory arthritis in mice. Single-cell imaging revealed that RIPK3-dependent death caused inflammasome-dependent IL-1β release from lipopolysaccharide-stimulated A20-deficient macrophages. Importantly, mutation of the A20 ZnF7 ubiquitin binding domain caused arthritis in mice, arguing that ZnF7-dependent inhibition of necroptosis is critical for A20 anti-inflammatory function in vivo. Main A20 (also known as TNF inducible protein 3, TNFAIP3) is a deubiquitinating enzyme with critical anti-inflammatory functions. Genome wide association studies have identified A20 as a susceptibility gene in several human inflammatory and autoimmune diseases, including psoriasis, systemic lupus erythematosus, Crohn’s disease and rheumatoid arthritis (reviewed in refs. 1 , 2 , 3 , 4 ). Moreover, mutations in the A20 gene have been identified in B cell lymphoma patients 5 , 6 , 7 , 8 . More recently, A20 haploinsufficiency was identified as the cause of early-onset autoinflammatory and autoimmune conditions 9 , 10 , 11 , 12 , 13 . Studies in genetic mouse models support a key role for A20 as an inhibitor of inflammation. Depending on the genetic background, A20-deficient mice die perinatally or in the first weeks of life due to severe lethal multi-organ inflammation 14 , 15 , 16 . In addition, tissue-specific A20 deficiency sensitizes mice to inflammatory and autoimmune pathologies 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 . Although its important anti-inflammatory role in both humans and mice is indisputable, the mechanisms by which A20 suppresses inflammation in vivo remain poorly understood. Inhibition of NF-κB activation is considered the primary anti-inflammatory function of A20 (refs. 1 , 2 , 27 , 28 ). In addition, A20 was also suggested to inhibit necroptosis by deubiquitinating receptor interacting protein kinase 3 (RIPK3) 15 . Although RIPK3 deficiency prolonged the survival of A20 -knockout mice, mixed lineage kinase-like (MLKL) deficiency did not have any protective effects, arguing against a role for necroptosis in the pathology caused by A20 deficiency 15 , 16 . Degradation of lysine 63 (K63)-linked ubiquitin chains by A20 is considered important for the inhibition of inflammation by preventing the ubiquitin-dependent recruitment of the inhibitor of NF-κB kinase (IKK) and transforming growth factor beta-activating kinase 1 (TAK1) signalling complexes to upstream receptors 1 , 2 , 27 , 28 , 29 . In addition, the ZnF4 domain of A20 was proposed to limit tumour necrosis factor receptor 1 (TNFR1) signalling by mediating K48-linked ubiquitination of RIPK1 29 . However, knock-in mice expressing A20 with mutated catalytic ovarian tumour or ZnF4 domains did not develop spontaneous inflammatory pathology, arguing that ubiquitin-chain degradation and ZnF4-dependent functions are not essential for the A20-mediated suppression of inflammation in vivo 28 , 30 , 31 . The capacity to bind to ubiquitin chains through its ZnF domains 4 and 7 has also been implicated in A20 function 32 , 33 , 34 , 35 , 36 . In particular, the ZnF7 of A20 was implicated in regulating TNFR1 signalling by binding specifically to linear ubiquitin chains 28 , 37 and inhibiting TNFR1-mediated apoptosis and necroptosis 35 , 37 . However, the in vivo function of the A20 ZnF7 remains unknown. We showed previously that mice with myeloid-cell-specific A20 deficiency (A20 MYC-KO ) spontaneously develop inflammatory joint pathology resembling rheumatoid arthritis 23 . Arthritis development in A20 MYC-KO mice requires NLR family pyrin domain containing 3 (NLRP3), caspase-1 and interleukin 1 receptor (IL-1R1) signalling, suggesting that the regulation of inflammasome activation is a key anti-inflammatory function of A20 23 , 38 . However, the mechanisms by which A20 limits inflammasome activation remain poorly understood. Excessive inflammasome priming through impaired A20-dependent negative regulation of NF-κB-mediated expression of NLRP3 and pro-IL-1β was suggested to contribute to inflammasome hyperactivation and arthritis development based on in vitro studies using macrophages from A20 MYC-KO mice 38 . In addition, A20 was reported to negatively regulate the ubiquitination of pro-IL-1β as well as components of the NLRP3–Caspase-1 inflammasome in a RIPK3-dependent, but cell death-independent manner, suggesting that A20 directly regulates inflammasome activity by deubiquitination 39 . Therefore, the pathways that are controlled by A20 and are critical for the inhibition of inflammation in vivo as well as the functional domains of A20 that regulate these activities remain elusive. Here we provide genetic and biochemical evidence that A20 prevents inflammasome activation and arthritis pathology indirectly by inhibiting macrophage necroptosis. Moreover, we show that knock-in mice expressing A20 with mutated ZnF7 develop spontaneous arthritis, revealing an indispensable function of ZnF7-mediated binding to linear ubiquitin chains in the A20-mediated suppression of inflammation in vivo. Together, these results identify the inhibition of necroptosis as a critical anti-inflammatory function of A20 in vivo and suggest that necroptosis inhibitors could be effective for the treatment of arthritis and other inflammatory pathologies associated with impaired A20 activity. Results Inflammasome activation in myeloid cells causes arthritis in A20 MYC-KO mice A20 MYC-KO mice spontaneously develop inflammatory joint pathology resembling rheumatoid arthritis, which is characterised by immune cell infiltration, bone erosion and cartilage destruction, and show splenomegaly and elevated numbers of blood monocytes and neutrophils 23 (Fig. 1a–c and Supplementary Fig. 1a ). We showed previously that crossing A20 MYC-KO mice with Nlpr3 −/− , Casp1/11 − / − or Il-1r1 −/− mice strongly ameliorated arthritis development, suggesting that NLRP3 inflammasome-mediated IL-1β production drives the pathology 23 , 38 . To assess whether cell-intrinsic inflammasome activation in A20-deficient myeloid", "role": "user" }, { "content": "A collaborative study has identified a new molecular mechanism causing rheumatoid arthritis. The researchers found that death of macrophages, an immune cell type, can trigger the disease. Moreover, they discovered how the protein A20 prevents macrophage death and protects against arthritis. These findings open up new possibilities for the treatment of this debilitating disease. Understanding arthritis Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that affects the joints, causing a painful swelling that eventually results in bone erosion and joint deformity. It affects 1 to 2 percent of the population, is very painful and severely affects the patients' quality of life. There is no cure for RA, but the disease progression in most patients can be slowed down with anti-inflammatory drugs. The underlying molecular mechanisms that cause the disease have remained largely unclear. Understanding these mechanisms is very important and may help in developing new therapies to treat patients suffering from RA. Cell death and inflammation The collaboration involved Prof. Manolis Pasparakis and Dr. Apostolos Polykratis (University of Cologne), Dr. Marietta Armaka (BSRC \"Alexander Fleming,\" Athens), Dr. Yoshitaka Shirasaki and Dr. Yoshifumi Yamaguchi (University of Tokyo), and Prof. Geert van Loo and Arne Martens (VIB-UGent). The study builds further upon earlier research at the VIB-UGent Center for Inflammation Research that demonstrated that the protein A20 suppressed arthritis by preventing inflammation. Now, the researchers show that the inflammatory response is caused by the fact that a fraction of specialized immune cells, macrophages, die by a specific inflammation-promoting type of cell death called necroptosis. The researchers were able to prevent the development of RA by blocking necroptosis. Prof. Geert van Loo (VIB-UGent) says, \"We could also identify why these macrophages are dying, and could demonstrate the importance of a specific part in the protein A20 for the prevention of cell death and RA development.\" Dr. Marietta Armaka says, \"We revealed how the particular type of macrophage demise shapes the activation of synovial fibroblasts, a key cell type that orchestrates the destruction of cartilage and bone tissue in RA.\" New therapies This study confirms the crucial importance of A20 in the control of inflammation, but now also shows that preventing cell death is a critical anti-inflammatory function of A20 to protect against arthritis. Prof. Manolis Pasparakis says, \"From a therapeutic perspective, this is a very important finding, since it suggests that drugs inhibiting cell death could be effective in the treatment of RA, at least in a subset of patients where macrophage death could provide the underlying trigger.\" Several pharmaceutical companies are developing new drugs to inhibit cell death, which will hopefully help to treat patients suffering from inflammatory diseases, including rheumatoid arthritis. The study is published in Nature Cell Biology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signalling, cell death and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function. Here we show that A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7). We provide genetic evidence that RIPK1 kinase-dependent, RIPK3–MLKL-mediated necroptosis drives inflammasome activation in A20-deficient macrophages and causes inflammatory arthritis in mice. Single-cell imaging revealed that RIPK3-dependent death caused inflammasome-dependent IL-1β release from lipopolysaccharide-stimulated A20-deficient macrophages. Importantly, mutation of the A20 ZnF7 ubiquitin binding domain caused arthritis in mice, arguing that ZnF7-dependent inhibition of necroptosis is critical for A20 anti-inflammatory function in vivo. Main A20 (also known as TNF inducible protein 3, TNFAIP3) is a deubiquitinating enzyme with critical anti-inflammatory functions. Genome wide association studies have identified A20 as a susceptibility gene in several human inflammatory and autoimmune diseases, including psoriasis, systemic lupus erythematosus, Crohn’s disease and rheumatoid arthritis (reviewed in refs. 1 , 2 , 3 , 4 ). Moreover, mutations in the A20 gene have been identified in B cell lymphoma patients 5 , 6 , 7 , 8 . More recently, A20 haploinsufficiency was identified as the cause of early-onset autoinflammatory and autoimmune conditions 9 , 10 , 11 , 12 , 13 . Studies in genetic mouse models support a key role for A20 as an inhibitor of inflammation. Depending on the genetic background, A20-deficient mice die perinatally or in the first weeks of life due to severe lethal multi-organ inflammation 14 , 15 , 16 . In addition, tissue-specific A20 deficiency sensitizes mice to inflammatory and autoimmune pathologies 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 . Although its important anti-inflammatory role in both humans and mice is indisputable, the mechanisms by which A20 suppresses inflammation in vivo remain poorly understood. Inhibition of NF-κB activation is considered the primary anti-inflammatory function of A20 (refs. 1 , 2 , 27 , 28 ). In addition, A20 was also suggested to inhibit necroptosis by deubiquitinating receptor interacting protein kinase 3 (RIPK3) 15 . Although RIPK3 deficiency prolonged the survival of A20 -knockout mice, mixed lineage kinase-like (MLKL) deficiency did not have any protective effects, arguing against a role for necroptosis in the pathology caused by A20 deficiency 15 , 16 . Degradation of lysine 63 (K63)-linked ubiquitin chains by A20 is considered important for the inhibition of inflammation by preventing the ubiquitin-dependent recruitment of the inhibitor of NF-κB kinase (IKK) and transforming growth factor beta-activating kinase 1 (TAK1) signalling complexes to upstream receptors 1 , 2 , 27 , 28 , 29 . In addition, the ZnF4 domain of A20 was proposed to limit tumour necrosis factor receptor 1 (TNFR1) signalling by mediating K48-linked ubiquitination of RIPK1 29 . However, knock-in mice expressing A20 with mutated catalytic ovarian tumour or ZnF4 domains did not develop spontaneous inflammatory pathology, arguing that ubiquitin-chain degradation and ZnF4-dependent functions are not essential for the A20-mediated suppression of inflammation in vivo 28 , 30 , 31 . The capacity to bind to ubiquitin chains through its ZnF domains 4 and 7 has also been implicated in A20 function 32 , 33 , 34 , 35 , 36 . In particular, the ZnF7 of A20 was implicated in regulating TNFR1 signalling by binding specifically to linear ubiquitin chains 28 , 37 and inhibiting TNFR1-mediated apoptosis and necroptosis 35 , 37 . However, the in vivo function of the A20 ZnF7 remains unknown. We showed previously that mice with myeloid-cell-specific A20 deficiency (A20 MYC-KO ) spontaneously develop inflammatory joint pathology resembling rheumatoid arthritis 23 . Arthritis development in A20 MYC-KO mice requires NLR family pyrin domain containing 3 (NLRP3), caspase-1 and interleukin 1 receptor (IL-1R1) signalling, suggesting that the regulation of inflammasome activation is a key anti-inflammatory function of A20 23 , 38 . However, the mechanisms by which A20 limits inflammasome activation remain poorly understood. Excessive inflammasome priming through impaired A20-dependent negative regulation of NF-κB-mediated expression of NLRP3 and pro-IL-1β was suggested to contribute to inflammasome hyperactivation and arthritis development based on in vitro studies using macrophages from A20 MYC-KO mice 38 . In addition, A20 was reported to negatively regulate the ubiquitination of pro-IL-1β as well as components of the NLRP3–Caspase-1 inflammasome in a RIPK3-dependent, but cell death-independent manner, suggesting that A20 directly regulates inflammasome activity by deubiquitination 39 . Therefore, the pathways that are controlled by A20 and are critical for the inhibition of inflammation in vivo as well as the functional domains of A20 that regulate these activities remain elusive. Here we provide genetic and biochemical evidence that A20 prevents inflammasome activation and arthritis pathology indirectly by inhibiting macrophage necroptosis. Moreover, we show that knock-in mice expressing A20 with mutated ZnF7 develop spontaneous arthritis, revealing an indispensable function of ZnF7-mediated binding to linear ubiquitin chains in the A20-mediated suppression of inflammation in vivo. Together, these results identify the inhibition of necroptosis as a critical anti-inflammatory function of A20 in vivo and suggest that necroptosis inhibitors could be effective for the treatment of arthritis and other inflammatory pathologies associated with impaired A20 activity. Results Inflammasome activation in myeloid cells causes arthritis in A20 MYC-KO mice A20 MYC-KO mice spontaneously develop inflammatory joint pathology resembling rheumatoid arthritis, which is characterised by immune cell infiltration, bone erosion and cartilage destruction, and show splenomegaly and elevated numbers of blood monocytes and neutrophils 23 (Fig. 1a–c and Supplementary Fig. 1a ). We showed previously that crossing A20 MYC-KO mice with Nlpr3 −/− , Casp1/11 − / − or Il-1r1 −/− mice strongly ameliorated arthritis development, suggesting that NLRP3 inflammasome-mediated IL-1β production drives the pathology 23 , 38 . To assess whether cell-intrinsic inflammasome activation in A20-deficient myeloid<|im_end|> <|im_start|>assistant A collaborative study has identified a new molecular mechanism causing rheumatoid arthritis. The researchers found that death of macrophages, an immune cell type, can trigger the disease. Moreover, they discovered how the protein A20 prevents macrophage death and protects against arthritis. These findings open up new possibilities for the treatment of this debilitating disease. Understanding arthritis Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that affects the joints, causing a painful swelling that eventually results in bone erosion and joint deformity. It affects 1 to 2 percent of the population, is very painful and severely affects the patients' quality of life. There is no cure for RA, but the disease progression in most patients can be slowed down with anti-inflammatory drugs. The underlying molecular mechanisms that cause the disease have remained largely unclear. Understanding these mechanisms is very important and may help in developing new therapies to treat patients suffering from RA. Cell death and inflammation The collaboration involved Prof. Manolis Pasparakis and Dr. Apostolos Polykratis (University of Cologne), Dr. Marietta Armaka (BSRC "Alexander Fleming," Athens), Dr. Yoshitaka Shirasaki and Dr. Yoshifumi Yamaguchi (University of Tokyo), and Prof. Geert van Loo and Arne Martens (VIB-UGent). The study builds further upon earlier research at the VIB-UGent Center for Inflammation Research that demonstrated that the protein A20 suppressed arthritis by preventing inflammation. Now, the researchers show that the inflammatory response is caused by the fact that a fraction of specialized immune cells, macrophages, die by a specific inflammation-promoting type of cell death called necroptosis. The researchers were able to prevent the development of RA by blocking necroptosis. Prof. Geert van Loo (VIB-UGent) says, "We could also identify why these macrophages are dying, and could demonstrate the importance of a specific part in the protein A20 for the prevention of cell death and RA development." Dr. Marietta Armaka says, "We revealed how the particular type of macrophage demise shapes the activation of synovial fibroblasts, a key cell type that orchestrates the destruction of cartilage and bone tissue in RA." New therapies This study confirms the crucial importance of A20 in the control of inflammation, but now also shows that preventing cell death is a critical anti-inflammatory function of A20 to protect against arthritis. Prof. Manolis Pasparakis says, "From a therapeutic perspective, this is a very important finding, since it suggests that drugs inhibiting cell death could be effective in the treatment of RA, at least in a subset of patients where macrophage death could provide the underlying trigger." Several pharmaceutical companies are developing new drugs to inhibit cell death, which will hopefully help to treat patients suffering from inflammatory diseases, including rheumatoid arthritis. The study is published in Nature Cell Biology. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The decline of neuronal synapses is an established feature of ageing accompanied by the diminishment of neuronal function, and in the motor system at least, a reduction of behavioural capacity. Here, we have investigated Drosophila motor neuron synaptic terminals during ageing. We observed cumulative fragmentation of presynaptic structures accompanied by diminishment of both evoked and miniature neurotransmission occurring in tandem with reduced motor ability. Through discrete manipulation of each neurotransmission modality, we find that miniature but not evoked neurotransmission is required to maintain presynaptic architecture and that increasing miniature events can both preserve synaptic structures and prolong motor ability during ageing. Our results establish that miniature neurotransmission, formerly viewed as an epiphenomenon, is necessary for the long-term stability of synaptic connections. Introduction Diminishment of synaptic structures in the brain is a hallmark of ageing and correlated with the decline of many cognitive parameters including learning, memory and executive function 1 , 2 , 3 , 4 . Age-dependent alterations of synapses are also evident in the motor systems of both humans and rodents. Neuromuscular junction (NMJ) terminals have been described to shrink and partition with ageing, accompanied by reduced neurotransmission 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 and progressive diminution of motor ability 13 , 14 . However, establishing a causal relationship between age-dependent changes in synaptic structure, neurotransmission properties and behavioural curtailment has proven challenging 1 , 2 , 3 , 4 . Here, using a system to investigate the ageing of motor synapses in Drosophila , we find that analogous to mammals, Drosophila synaptic terminals fragment as ageing progresses, accompanied by a decline of both neurotransmission and motor ability. Surprisingly, through experiments designed to causally relate these phenomena, we find that vesicular neurotransmission is necessary to maintain synaptic structures during ageing. Moreover, using neurogenetic tools that allow individual interrogation of each vesicular neurotransmitter release modality, we discover that miniature events are singularly essential to preserve synaptic structures and maintain motor ability as animals age. Our results reveal that miniature neurotransmission is uniquely critical for the long-term structural and functional conservation of synapses during ageing. Results Motor synaptic terminals fragment, neurotransmission is reduced and motor ability declines with ageing To investigate the structural stability of adult Drosophila synapses as they age, we examined a subset of glutamatergic NMJ terminals produced by motor neurons that express the transcription factor HB9 15 . These include a small subset of motor neurons that form bilateral terminals innervating the musculi ventralis interni mediales (mvim) 16 muscles in abdominal segment A2, but do not include the majority of motor neurons in this segment or these motor neurons in more posterior segments (Fig. 1a, b ). Larval Drosophila abdominal muscles have tonic neuromuscular terminals which release only glutamate and also phasic terminals which release neuropeptides in addition to glutamate, each of which are produced by distinct neurons 17 , 18 . Similarly, we found adult mvim muscles had both tonic (mvim T ) and phasic (mvim P ) terminals which could be distinguished by vesicular monoamine transporter (VMAT) labelling of the phasic terminal (Supplementary Fig. 1a ). However, only the tonic mvim T terminal expressed the HB9 transcription factor (Supplementary Fig. 1a ). As is typical of Drosophila synapses 19 , the mvim T presynaptic terminal is composed of a chain of linked bouton varicosities each of which contains multiple active zones for vesicle release (Fig. 1b, c ). We examined the morphological characteristics of these terminals in young adult animals from 5 days after eclosion throughout lifespan (Fig. 1d–i ; Supplementary Tables 1 and 2 ). During this period postsynaptic muscle surface area did not significantly change at any timepoint (Supplementary Fig. 1b ). In contrast, presynaptic terminal area declined with ageing ( R 2 = 0.13, p < 0.001) (Supplementary Fig. 1c ) accompanied by an obvious progressive decline in synaptic bouton diameter ( R 2 = 0.28, p < 0.001) such that the average bouton diameter was 74% ( p < 0.001) smaller in old animals compared to young animals (Fig. 1j–p ). This morphological size reduction was accompanied by a change in the distribution of active zone synaptic vesicle release sites labelled by the marker Bruchpilot (Brp) 20 (Fig. 1j-o ), which increased in number until middle age before declining in older animals, consistent with prior observations in the central nervous system (CNS) (Fig. 1q ) 21 . Strikingly, boutons with only a single active zone which accounted for only 9% of the varicosities in young animals, steadily increased to 31% ( P < 0.001) of all boutons in the oldest animals ( R 2 = 0.48, p < 0.001) (Fig. 1r and Supplementary Table 2 ). This observation was consistent with larger multiple active zone synaptic boutons cleaving or fragmenting into smaller units with less active zones as animals aged, in the most extreme case being reduced to having only a single active zone. Consistent with this conclusion, the total number of morphologically distinct albeit smaller boutons increased steadily with ageing (Supplementary Fig. 1d ) even as total terminal area declined (Supplementary Fig. 1c ). Moreover, in young animals, we observed that individual presynaptic boutons were completely enveloped by a matching single postsynaptic membrane elaboration (Fig. 1s ). In contrast, in old animals, multiple smaller presynaptic boutons were surrounded by a single postsynaptic elaboration with interstitial gaps occupied by peripheral glia (Fig. 1s, t ). This observation was further supported by serial electron microscopy of young and old synaptic terminals (Fig. 1u, v ). Consistent with our light microscope observations, we observed the frequent presence of small synaptic boutons containing an active zone in the terminals of old animals connected by thin processes to other boutons within the terminal (Fig. 1v ), in marked contrast to the large boutons of young animals (Fig. 1u ). The connections between small boutons in old animals coupled with the presence of multiple presynaptic and postsynaptic proteins similar to those found in larger young boutons", "role": "user" }, { "content": "Neurons communicate through rapid electrical signals that regulate the release of neurotransmitters, the brain's chemical messengers. Once transmitted across a neuron, electrical signals cause the juncture with another neuron, known as a synapse, to release droplets filled with neurotransmitters that pass the information on to the next neuron. This type of neuron-to-neuron communication is known as evoked neurotransmission. However, some neurotransmitter-packed droplets are released at the synapse even in the absence of electrical impulses. These miniature release events—or minis—have long been regarded as 'background noise', says Brian McCabe, Director of the Laboratory of Neural Genetics and Disease and a Professor in the EPFL Brain Mind Institute. But several studies have suggested that minis do have a function—and an important one. In 2014, for example, McCabe and his team showed that minis are important for the development of synapses. If neurons in the brain were a network of computers, evoked releases would be packets of data through which the machines exchange information, whereas minis would be pings—brief electronic signals that determine if there is a connection between two computers, McCabe says. \"Minis are the pings that neurons use to say 'I am connected.'\" To assess whether minis could play a role in the mature nervous system, Soumya Banerjee, a postdoc in McCabe's group, and his colleagues set out to study a set of neurons that control movement in fruit flies. As the insects aged, their synapses started to break up into smaller fragments, the researchers found. (A similar process occurs in aging mammals, including people.) As nerve junctions broke down, both evoked and miniature neurotransmission were dampened, and the flies showed motor problems such as a reduced ability to climb the walls of a plastic vial. Brian McCabe, Director of the Laboratory of Neural Genetics and Disease and a Professor in the EPFL Brain Mind Institute. Credit: © Alain Herzog / EPFL Next, the team assessed the effects of stimulating or inhibiting evoked and miniature neurotransmission. When both types of neurotransmission were blocked, synapses aged prematurely, suggesting that during aging or in neurological diseases associated with old age, changes in neurotransmission happen before synapses start to crumble. This finding, McCabe says, upends a longstanding idea in neuroscience. \"The idea has long been that the structure of the synapse breaks down, and that causes a functional change in the synapse, but we found it is the other way around,\" he says. Stimulating evoked neurotransmission alone had no effect on aging synapses, the researchers found. However, increasing the frequency of minis kept synapses intact and preserved the motor ability of middle-aged flies at levels comparable to those of young flies. \"Motor ability declines in all aging animals, including humans, so it was a delightful surprise to see that we could change that,\" McCabe says. Adult Drosophila motor terminals (green) and muscles (red) progressively degenerate with age. Credit: © Laboratory of Neural Genetics and Disease / EPFL The findings, published in Nature Communications, could have important implications for human health: minis have been found at every type of synapse studied so far, and defects in miniature neurotransmission have been linked to range of neurodevelopmental disorders in children. Figuring out how a reduction in miniature neurotransmission changes the structure of synapses, and how that in turn affects behavior, could help to better understand neurodegenerative disorders and other brain conditions. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The decline of neuronal synapses is an established feature of ageing accompanied by the diminishment of neuronal function, and in the motor system at least, a reduction of behavioural capacity. Here, we have investigated Drosophila motor neuron synaptic terminals during ageing. We observed cumulative fragmentation of presynaptic structures accompanied by diminishment of both evoked and miniature neurotransmission occurring in tandem with reduced motor ability. Through discrete manipulation of each neurotransmission modality, we find that miniature but not evoked neurotransmission is required to maintain presynaptic architecture and that increasing miniature events can both preserve synaptic structures and prolong motor ability during ageing. Our results establish that miniature neurotransmission, formerly viewed as an epiphenomenon, is necessary for the long-term stability of synaptic connections. Introduction Diminishment of synaptic structures in the brain is a hallmark of ageing and correlated with the decline of many cognitive parameters including learning, memory and executive function 1 , 2 , 3 , 4 . Age-dependent alterations of synapses are also evident in the motor systems of both humans and rodents. Neuromuscular junction (NMJ) terminals have been described to shrink and partition with ageing, accompanied by reduced neurotransmission 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 and progressive diminution of motor ability 13 , 14 . However, establishing a causal relationship between age-dependent changes in synaptic structure, neurotransmission properties and behavioural curtailment has proven challenging 1 , 2 , 3 , 4 . Here, using a system to investigate the ageing of motor synapses in Drosophila , we find that analogous to mammals, Drosophila synaptic terminals fragment as ageing progresses, accompanied by a decline of both neurotransmission and motor ability. Surprisingly, through experiments designed to causally relate these phenomena, we find that vesicular neurotransmission is necessary to maintain synaptic structures during ageing. Moreover, using neurogenetic tools that allow individual interrogation of each vesicular neurotransmitter release modality, we discover that miniature events are singularly essential to preserve synaptic structures and maintain motor ability as animals age. Our results reveal that miniature neurotransmission is uniquely critical for the long-term structural and functional conservation of synapses during ageing. Results Motor synaptic terminals fragment, neurotransmission is reduced and motor ability declines with ageing To investigate the structural stability of adult Drosophila synapses as they age, we examined a subset of glutamatergic NMJ terminals produced by motor neurons that express the transcription factor HB9 15 . These include a small subset of motor neurons that form bilateral terminals innervating the musculi ventralis interni mediales (mvim) 16 muscles in abdominal segment A2, but do not include the majority of motor neurons in this segment or these motor neurons in more posterior segments (Fig. 1a, b ). Larval Drosophila abdominal muscles have tonic neuromuscular terminals which release only glutamate and also phasic terminals which release neuropeptides in addition to glutamate, each of which are produced by distinct neurons 17 , 18 . Similarly, we found adult mvim muscles had both tonic (mvim T ) and phasic (mvim P ) terminals which could be distinguished by vesicular monoamine transporter (VMAT) labelling of the phasic terminal (Supplementary Fig. 1a ). However, only the tonic mvim T terminal expressed the HB9 transcription factor (Supplementary Fig. 1a ). As is typical of Drosophila synapses 19 , the mvim T presynaptic terminal is composed of a chain of linked bouton varicosities each of which contains multiple active zones for vesicle release (Fig. 1b, c ). We examined the morphological characteristics of these terminals in young adult animals from 5 days after eclosion throughout lifespan (Fig. 1d–i ; Supplementary Tables 1 and 2 ). During this period postsynaptic muscle surface area did not significantly change at any timepoint (Supplementary Fig. 1b ). In contrast, presynaptic terminal area declined with ageing ( R 2 = 0.13, p < 0.001) (Supplementary Fig. 1c ) accompanied by an obvious progressive decline in synaptic bouton diameter ( R 2 = 0.28, p < 0.001) such that the average bouton diameter was 74% ( p < 0.001) smaller in old animals compared to young animals (Fig. 1j–p ). This morphological size reduction was accompanied by a change in the distribution of active zone synaptic vesicle release sites labelled by the marker Bruchpilot (Brp) 20 (Fig. 1j-o ), which increased in number until middle age before declining in older animals, consistent with prior observations in the central nervous system (CNS) (Fig. 1q ) 21 . Strikingly, boutons with only a single active zone which accounted for only 9% of the varicosities in young animals, steadily increased to 31% ( P < 0.001) of all boutons in the oldest animals ( R 2 = 0.48, p < 0.001) (Fig. 1r and Supplementary Table 2 ). This observation was consistent with larger multiple active zone synaptic boutons cleaving or fragmenting into smaller units with less active zones as animals aged, in the most extreme case being reduced to having only a single active zone. Consistent with this conclusion, the total number of morphologically distinct albeit smaller boutons increased steadily with ageing (Supplementary Fig. 1d ) even as total terminal area declined (Supplementary Fig. 1c ). Moreover, in young animals, we observed that individual presynaptic boutons were completely enveloped by a matching single postsynaptic membrane elaboration (Fig. 1s ). In contrast, in old animals, multiple smaller presynaptic boutons were surrounded by a single postsynaptic elaboration with interstitial gaps occupied by peripheral glia (Fig. 1s, t ). This observation was further supported by serial electron microscopy of young and old synaptic terminals (Fig. 1u, v ). Consistent with our light microscope observations, we observed the frequent presence of small synaptic boutons containing an active zone in the terminals of old animals connected by thin processes to other boutons within the terminal (Fig. 1v ), in marked contrast to the large boutons of young animals (Fig. 1u ). The connections between small boutons in old animals coupled with the presence of multiple presynaptic and postsynaptic proteins similar to those found in larger young boutons<|im_end|> <|im_start|>assistant Neurons communicate through rapid electrical signals that regulate the release of neurotransmitters, the brain's chemical messengers. Once transmitted across a neuron, electrical signals cause the juncture with another neuron, known as a synapse, to release droplets filled with neurotransmitters that pass the information on to the next neuron. This type of neuron-to-neuron communication is known as evoked neurotransmission. However, some neurotransmitter-packed droplets are released at the synapse even in the absence of electrical impulses. These miniature release events—or minis—have long been regarded as 'background noise', says Brian McCabe, Director of the Laboratory of Neural Genetics and Disease and a Professor in the EPFL Brain Mind Institute. But several studies have suggested that minis do have a function—and an important one. In 2014, for example, McCabe and his team showed that minis are important for the development of synapses. If neurons in the brain were a network of computers, evoked releases would be packets of data through which the machines exchange information, whereas minis would be pings—brief electronic signals that determine if there is a connection between two computers, McCabe says. "Minis are the pings that neurons use to say 'I am connected.'" To assess whether minis could play a role in the mature nervous system, Soumya Banerjee, a postdoc in McCabe's group, and his colleagues set out to study a set of neurons that control movement in fruit flies. As the insects aged, their synapses started to break up into smaller fragments, the researchers found. (A similar process occurs in aging mammals, including people.) As nerve junctions broke down, both evoked and miniature neurotransmission were dampened, and the flies showed motor problems such as a reduced ability to climb the walls of a plastic vial. Brian McCabe, Director of the Laboratory of Neural Genetics and Disease and a Professor in the EPFL Brain Mind Institute. Credit: © Alain Herzog / EPFL Next, the team assessed the effects of stimulating or inhibiting evoked and miniature neurotransmission. When both types of neurotransmission were blocked, synapses aged prematurely, suggesting that during aging or in neurological diseases associated with old age, changes in neurotransmission happen before synapses start to crumble. This finding, McCabe says, upends a longstanding idea in neuroscience. "The idea has long been that the structure of the synapse breaks down, and that causes a functional change in the synapse, but we found it is the other way around," he says. Stimulating evoked neurotransmission alone had no effect on aging synapses, the researchers found. However, increasing the frequency of minis kept synapses intact and preserved the motor ability of middle-aged flies at levels comparable to those of young flies. "Motor ability declines in all aging animals, including humans, so it was a delightful surprise to see that we could change that," McCabe says. Adult Drosophila motor terminals (green) and muscles (red) progressively degenerate with age. Credit: © Laboratory of Neural Genetics and Disease / EPFL The findings, published in Nature Communications, could have important implications for human health: minis have been found at every type of synapse studied so far, and defects in miniature neurotransmission have been linked to range of neurodevelopmental disorders in children. Figuring out how a reduction in miniature neurotransmission changes the structure of synapses, and how that in turn affects behavior, could help to better understand neurodegenerative disorders and other brain conditions. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free survival. Thus, rhIL-7-hyFc represents a tunable clinic-ready adjuvant for improving suboptimal CAR T cell activity. Introduction Chimeric antigen receptor (CAR) T cell therapy is transforming modern cancer therapy, with four anti-CD19 CAR T cell products Food and Drug Administration-approved for relapsed/refractory B cell malignancies 1 , 2 , 3 , 4 , and many other CAR T cells for a variety of tumors currently being tested in clinical trials. However, in clinical practice suboptimal CAR T cell efficacy often results in antigen-positive tumor escape and disease relapse 5 , 6 . As the expansion and persistence of CAR T cells correlate with clinical response, we reasoned that interleukin-7 (IL-7), a pro-lymphoid growth and survival factor involved in the development, maintenance, and proliferation of T cells, would promote CAR T cell efficacy and tumor cell killing in vivo. rhIL-7-hyFc (efineptakin alfa, NT-I7) is a homodimeric genetically modified IL-7 molecule fused to a stable hyFc platform 7 , which prevents complement activation while prolonging in vivo serum half-life, providing clear pharmacologic advantages to short-lived native recombinant human IL-7 (rhIL-7). In the first human trial with healthy volunteers (NCT02860715), a single-dose intramuscular injection of rhIL-7-hyFc (60 mcg/kg) resulted in a substantial increase in the number of CD4+ and CD8+ T cells, and no major adverse events or dose-limiting toxicities were reported 8 . Therefore, we decided to explore the potential of this reagent to augment the activity of CAR T cells. Here we show that rhIL-7-hyFc dramatically enhances CAR T cell expansion, persistence, and anti-tumor efficacy, resulting in significantly prolonged survival of mice in CD19 + lymphoma and CD33 + leukemia xenograft models treated with human CAR T cells, and in immunocompetent mice bearing CD19+ tumors treated with murine CAR T cells. Immunocompetent mice that received rhIL-7-hyFc with CAR T cells exhibited sustained B cell aplasia and were protected against tumor rechallenge. Functional studies and single-cell RNA-seq (scRNA-seq) reveal that rhIL-7-hyFc not only increases CAR T cell numbers but also improves T cell cytotoxicity and decreases exhaustion. Therefore, rhIL-7-hyFc has the potential to improve the outcomes of CAR T cell treatment in patients with refractory malignancies. Results rhIL-7-hyFc enhances the expansion of UCART19 in vitro and maintains CAR-T polyfunctionality To test the effects of rhIL-7-hyFc (Fig. 1a ) on CAR T cells in vitro, human TCR-deficient anti-CD19 CAR T cells (UCART19) were cultured with rhIL-7-hyFc in the presence of CD19+ tumor cells. We used TCR deleted human CAR T cells to eliminate the potential for xenogeneic graft versus host disease (GVHD) confounding future in vivo experiments. UCART19 was generated from human T cells derived from healthy donors activated with anti-CD3/anti-CD28 beads for two days before electroporation with Cas9 mRNA and a TRAC -targeted gRNA. T cells were then transduced with a lentivirus expressing a 3 rd generation anti-CD19 CAR (19-28-BBζ) containing a 2A-cleaved human CD34 extracellular domain, permitting ex vivo purification and identification of CAR + cells (Fig. 1b ). CRISPR/Cas9-mediated TRAC deletion efficiency was more than 97%, with an average 58% CAR transduction efficiency (Supplemental Fig. 1 ). Ramos, a CD19+ B-lymphoma cell line, transduced with click beetle red luciferase (CBR) and green fluorescent protein (GFP; hereafter, Ramos CBR-GFP ), was co-cultured with UCART19 at an effector to target (E:T) ratio of 2:1 in either vehicle control, rhIL-7 10 ng/ml, or rhIL-7-hyFc (10, 100 or 1000 ng/ml). Seven days later, UCART19 was replated in fresh media containing rhIL-7 or rhIL-7-hyFc, and re-challenged with Ramos CBR-GFP (Fig. 1c ). Vehicle only controls failed to expand over the 14-day assay period, while supplementation with either rhIL-7 or rhIL-7-hyFc at concentrations in excess of 10 ng/ml led to robust expansion of UCART19 (Fig. 1d ). Qualitative assessment of UCART19 on day 14 post co-culture with rhIL-7 or rhIL-7-hyFc revealed that even at the lowest concentration, rhIL-7-hyFc promoted UCART19 viability, prevented apoptosis, and increased proliferation to the same degree as rhIL-7 (Fig. 1e ). Fig. 1: rhIL-7-hyFc enhances UCART19 expansion and function in vitro. a rhIL-7-hyFc is an engineered IL-7 homodimer fused to IgD and IgG4 elements (hyFc©), promoting in vivo stability and reducing complement activation. b UCART19 was generated by activating human T cells with anti-CD3/CD28 beads, followed by CRISPR/Cas9 deletion of the human T cell receptor alpha subunit ( TRAC ), and lentiviral transduction of a third-generation anti-CD19 CAR. c – e UCART19 was incubated with CD19+ Ramos CBR-GFP at an effector to target (E:T) ratio of 2:1 in 10 ng/ml of rhIL-7 or the indicated concentrations of rhIL-7-hyFc. On day 7, UCART19 was replated with Ramos CBR-GFP at an E:T of 2:1 with the addition of fresh cytokines. UCART19 numbers and phenotypes were determined by serial counting and flow cytometry. Bar graphs represent median values, with each data point representing a different T cell donor. d Representative growth plot for a single donor (left) and compiled fold-expansion of all donors on day 14 (right, n = 3 donors for rhIL-7, 4 donors for all other groups). p Values were calculated by one-way ANOVA with Tukey’s multiple comparisons test (rhIL-7 10 vs. 0, p = 0.0055, rhIL-7-hyFc 10 vs. 0, p = 0.0246, rhIL-7 10 vs. rhIL-7-hyFc, p = 0.82). e UCART19 viability (%propidium iodide exclusion, rhIL-7 10 vs. 0: p < 0.0001; rhIL-7-hyFc 10 vs. 0: p < 0.0001; rhIL-7 10 vs. rhIL-7-hyFc: p = 0.9999), apoptosis (%annexinV+, rhIL-7 10 vs. 0: p = 0.0005; rhIL-7-hyFc 10 vs. 0: p = 0.0002;", "role": "user" }, { "content": "Advances in cellular immunotherapy that spur genetically modified T cells to attack cancer cells have revolutionized the treatment of certain blood cancers. Six such CAR-T cell therapies are approved by the Food and Drug Administration to treat certain types of leukemia, lymphoma and multiple myeloma. Still, some patients' tumors don't respond well to these therapies, and many patients who do well initially later see their cancers return. Now, a new study by researchers at Washington University School of Medicine in St. Louis shows that additional treatment with an immunity boosting protein called interleukin 7 (IL-7) after an infusion of these genetically modified T cells causes the cancer-fighting CAR-T cells to grow in number and become more effective at killing tumor cells. The mouse study—published June 13 in the journal Nature Communications—suggests promise for a phase 1 clinical trial at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. The clinical trial is investigating a long-acting genetically modified type of IL-7 in conjunction with CAR-T cells targeting CD19, a B cell antigen in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). Siteman is the coordinating center and one of four sites across the country participating in the trial. \"Many researchers are trying different strategies to enhance the function of CAR-T cells in treating blood cancers,\" said senior author John F. DiPersio, MD, Ph.D., the Virginia E. & Sam J. Golman Professor of Medicine and director of the Division of Oncology. \"We're interested in IL-7 because we know it is a major driver of T cell expansion. The body makes IL-7 naturally to ramp up the number of T cells when a person gets sick, for example. When we give a long-acting type of IL-7 to tumor-bearing immunodeficient mice soon after CAR-T cell treatment, we see a dramatic expansion of these CAR-T cells greater than ten-thousandfold compared to mice not receiving IL-7. These CAR-T cells also persist longer and show dramatically increased anti-tumor activity.\" CAR-T cells are manufactured using the body's normal T cells, either from the patient or a donor. The CAR-T cells are genetically modified to specifically target a protein on the surface of the cancer cells. The targeting helps the CAR-T cells find the cancer cells, which are masters at evading immune attack. The therapy can be highly effective, but sometimes the CAR-T cells aren't able to expand enough to kill all of the cancer, or they become overstimulated, \"exhausting\" their ability to function, resulting in their loss of anti-tumor effectiveness. With these problems in mind, the researchers—including first author Miriam Y. Kim, MD, an assistant professor of medicine, and co-senior author Matthew L. Cooper, Ph.D., an adjunct assistant professor of medicine—were interested in whether they could harness the body's natural way of boosting T cell numbers to enhance the therapy. But natural IL-7 normally disappears from the body quickly. Therefore, DiPersio and his team tested a modified form of IL-7 that circulates in the body for weeks, making it much more effective at supporting the CAR-T cell expansion. Investigating two different models of B cell lymphoma in mice, the researchers showed that mice receiving CAR-T cells and long-acting IL-7 survived almost six times longer than mice receiving CAR-T cells alone. Mice treated with CAR-T cells alone survived for about one month after therapy. All mice that received long-acting IL-7 soon after the CAR-T cell treatment were still living at the end of an experimental time frame of 175 days. Further, tumor sizes in the mice that had received CAR-T cells and IL-7 were dramatically reduced, to the point of being undetectable in the majority of mice by day 35. \"In mice that received the CAR-T cells alone, the disease is controlled briefly,\" DiPersio said. \"But by week three, the tumor starts to return. And by week four, they start to look like the control mice that didn't receive any active therapy. But by adding long-acting IL-7, the numbers of CAR-T cells just explode, and those mice lived beyond the time frame we set for our experiment. Our study also suggests that it may be possible to fine-tune the expansion of the CAR-T cells by controlling the number of IL-7 doses that we give.\" Washington University research laid the groundwork for using IL-7 to boost the immune system to treat disease, including its use with CAR-T cells. In addition, Richard S. Hotchkiss, MD, a professor of anesthesiology, of medicine and of surgery, and his team have studied IL-7 for its use in stimulating T cells to fight sepsis, a life-threatening response to infection. Research from the Brain Tumor Center at Siteman also has shown promise for the use of long-acting IL-7 to enhance T cells in treating glioblastoma, an aggressive brain cancer. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free survival. Thus, rhIL-7-hyFc represents a tunable clinic-ready adjuvant for improving suboptimal CAR T cell activity. Introduction Chimeric antigen receptor (CAR) T cell therapy is transforming modern cancer therapy, with four anti-CD19 CAR T cell products Food and Drug Administration-approved for relapsed/refractory B cell malignancies 1 , 2 , 3 , 4 , and many other CAR T cells for a variety of tumors currently being tested in clinical trials. However, in clinical practice suboptimal CAR T cell efficacy often results in antigen-positive tumor escape and disease relapse 5 , 6 . As the expansion and persistence of CAR T cells correlate with clinical response, we reasoned that interleukin-7 (IL-7), a pro-lymphoid growth and survival factor involved in the development, maintenance, and proliferation of T cells, would promote CAR T cell efficacy and tumor cell killing in vivo. rhIL-7-hyFc (efineptakin alfa, NT-I7) is a homodimeric genetically modified IL-7 molecule fused to a stable hyFc platform 7 , which prevents complement activation while prolonging in vivo serum half-life, providing clear pharmacologic advantages to short-lived native recombinant human IL-7 (rhIL-7). In the first human trial with healthy volunteers (NCT02860715), a single-dose intramuscular injection of rhIL-7-hyFc (60 mcg/kg) resulted in a substantial increase in the number of CD4+ and CD8+ T cells, and no major adverse events or dose-limiting toxicities were reported 8 . Therefore, we decided to explore the potential of this reagent to augment the activity of CAR T cells. Here we show that rhIL-7-hyFc dramatically enhances CAR T cell expansion, persistence, and anti-tumor efficacy, resulting in significantly prolonged survival of mice in CD19 + lymphoma and CD33 + leukemia xenograft models treated with human CAR T cells, and in immunocompetent mice bearing CD19+ tumors treated with murine CAR T cells. Immunocompetent mice that received rhIL-7-hyFc with CAR T cells exhibited sustained B cell aplasia and were protected against tumor rechallenge. Functional studies and single-cell RNA-seq (scRNA-seq) reveal that rhIL-7-hyFc not only increases CAR T cell numbers but also improves T cell cytotoxicity and decreases exhaustion. Therefore, rhIL-7-hyFc has the potential to improve the outcomes of CAR T cell treatment in patients with refractory malignancies. Results rhIL-7-hyFc enhances the expansion of UCART19 in vitro and maintains CAR-T polyfunctionality To test the effects of rhIL-7-hyFc (Fig. 1a ) on CAR T cells in vitro, human TCR-deficient anti-CD19 CAR T cells (UCART19) were cultured with rhIL-7-hyFc in the presence of CD19+ tumor cells. We used TCR deleted human CAR T cells to eliminate the potential for xenogeneic graft versus host disease (GVHD) confounding future in vivo experiments. UCART19 was generated from human T cells derived from healthy donors activated with anti-CD3/anti-CD28 beads for two days before electroporation with Cas9 mRNA and a TRAC -targeted gRNA. T cells were then transduced with a lentivirus expressing a 3 rd generation anti-CD19 CAR (19-28-BBζ) containing a 2A-cleaved human CD34 extracellular domain, permitting ex vivo purification and identification of CAR + cells (Fig. 1b ). CRISPR/Cas9-mediated TRAC deletion efficiency was more than 97%, with an average 58% CAR transduction efficiency (Supplemental Fig. 1 ). Ramos, a CD19+ B-lymphoma cell line, transduced with click beetle red luciferase (CBR) and green fluorescent protein (GFP; hereafter, Ramos CBR-GFP ), was co-cultured with UCART19 at an effector to target (E:T) ratio of 2:1 in either vehicle control, rhIL-7 10 ng/ml, or rhIL-7-hyFc (10, 100 or 1000 ng/ml). Seven days later, UCART19 was replated in fresh media containing rhIL-7 or rhIL-7-hyFc, and re-challenged with Ramos CBR-GFP (Fig. 1c ). Vehicle only controls failed to expand over the 14-day assay period, while supplementation with either rhIL-7 or rhIL-7-hyFc at concentrations in excess of 10 ng/ml led to robust expansion of UCART19 (Fig. 1d ). Qualitative assessment of UCART19 on day 14 post co-culture with rhIL-7 or rhIL-7-hyFc revealed that even at the lowest concentration, rhIL-7-hyFc promoted UCART19 viability, prevented apoptosis, and increased proliferation to the same degree as rhIL-7 (Fig. 1e ). Fig. 1: rhIL-7-hyFc enhances UCART19 expansion and function in vitro. a rhIL-7-hyFc is an engineered IL-7 homodimer fused to IgD and IgG4 elements (hyFc©), promoting in vivo stability and reducing complement activation. b UCART19 was generated by activating human T cells with anti-CD3/CD28 beads, followed by CRISPR/Cas9 deletion of the human T cell receptor alpha subunit ( TRAC ), and lentiviral transduction of a third-generation anti-CD19 CAR. c – e UCART19 was incubated with CD19+ Ramos CBR-GFP at an effector to target (E:T) ratio of 2:1 in 10 ng/ml of rhIL-7 or the indicated concentrations of rhIL-7-hyFc. On day 7, UCART19 was replated with Ramos CBR-GFP at an E:T of 2:1 with the addition of fresh cytokines. UCART19 numbers and phenotypes were determined by serial counting and flow cytometry. Bar graphs represent median values, with each data point representing a different T cell donor. d Representative growth plot for a single donor (left) and compiled fold-expansion of all donors on day 14 (right, n = 3 donors for rhIL-7, 4 donors for all other groups). p Values were calculated by one-way ANOVA with Tukey’s multiple comparisons test (rhIL-7 10 vs. 0, p = 0.0055, rhIL-7-hyFc 10 vs. 0, p = 0.0246, rhIL-7 10 vs. rhIL-7-hyFc, p = 0.82). e UCART19 viability (%propidium iodide exclusion, rhIL-7 10 vs. 0: p < 0.0001; rhIL-7-hyFc 10 vs. 0: p < 0.0001; rhIL-7 10 vs. rhIL-7-hyFc: p = 0.9999), apoptosis (%annexinV+, rhIL-7 10 vs. 0: p = 0.0005; rhIL-7-hyFc 10 vs. 0: p = 0.0002;<|im_end|> <|im_start|>assistant Advances in cellular immunotherapy that spur genetically modified T cells to attack cancer cells have revolutionized the treatment of certain blood cancers. Six such CAR-T cell therapies are approved by the Food and Drug Administration to treat certain types of leukemia, lymphoma and multiple myeloma. Still, some patients' tumors don't respond well to these therapies, and many patients who do well initially later see their cancers return. Now, a new study by researchers at Washington University School of Medicine in St. Louis shows that additional treatment with an immunity boosting protein called interleukin 7 (IL-7) after an infusion of these genetically modified T cells causes the cancer-fighting CAR-T cells to grow in number and become more effective at killing tumor cells. The mouse study—published June 13 in the journal Nature Communications—suggests promise for a phase 1 clinical trial at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. The clinical trial is investigating a long-acting genetically modified type of IL-7 in conjunction with CAR-T cells targeting CD19, a B cell antigen in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). Siteman is the coordinating center and one of four sites across the country participating in the trial. "Many researchers are trying different strategies to enhance the function of CAR-T cells in treating blood cancers," said senior author John F. DiPersio, MD, Ph.D., the Virginia E. & Sam J. Golman Professor of Medicine and director of the Division of Oncology. "We're interested in IL-7 because we know it is a major driver of T cell expansion. The body makes IL-7 naturally to ramp up the number of T cells when a person gets sick, for example. When we give a long-acting type of IL-7 to tumor-bearing immunodeficient mice soon after CAR-T cell treatment, we see a dramatic expansion of these CAR-T cells greater than ten-thousandfold compared to mice not receiving IL-7. These CAR-T cells also persist longer and show dramatically increased anti-tumor activity." CAR-T cells are manufactured using the body's normal T cells, either from the patient or a donor. The CAR-T cells are genetically modified to specifically target a protein on the surface of the cancer cells. The targeting helps the CAR-T cells find the cancer cells, which are masters at evading immune attack. The therapy can be highly effective, but sometimes the CAR-T cells aren't able to expand enough to kill all of the cancer, or they become overstimulated, "exhausting" their ability to function, resulting in their loss of anti-tumor effectiveness. With these problems in mind, the researchers—including first author Miriam Y. Kim, MD, an assistant professor of medicine, and co-senior author Matthew L. Cooper, Ph.D., an adjunct assistant professor of medicine—were interested in whether they could harness the body's natural way of boosting T cell numbers to enhance the therapy. But natural IL-7 normally disappears from the body quickly. Therefore, DiPersio and his team tested a modified form of IL-7 that circulates in the body for weeks, making it much more effective at supporting the CAR-T cell expansion. Investigating two different models of B cell lymphoma in mice, the researchers showed that mice receiving CAR-T cells and long-acting IL-7 survived almost six times longer than mice receiving CAR-T cells alone. Mice treated with CAR-T cells alone survived for about one month after therapy. All mice that received long-acting IL-7 soon after the CAR-T cell treatment were still living at the end of an experimental time frame of 175 days. Further, tumor sizes in the mice that had received CAR-T cells and IL-7 were dramatically reduced, to the point of being undetectable in the majority of mice by day 35. "In mice that received the CAR-T cells alone, the disease is controlled briefly," DiPersio said. "But by week three, the tumor starts to return. And by week four, they start to look like the control mice that didn't receive any active therapy. But by adding long-acting IL-7, the numbers of CAR-T cells just explode, and those mice lived beyond the time frame we set for our experiment. Our study also suggests that it may be possible to fine-tune the expansion of the CAR-T cells by controlling the number of IL-7 doses that we give." Washington University research laid the groundwork for using IL-7 to boost the immune system to treat disease, including its use with CAR-T cells. In addition, Richard S. Hotchkiss, MD, a professor of anesthesiology, of medicine and of surgery, and his team have studied IL-7 for its use in stimulating T cells to fight sepsis, a life-threatening response to infection. Research from the Brain Tumor Center at Siteman also has shown promise for the use of long-acting IL-7 to enhance T cells in treating glioblastoma, an aggressive brain cancer. <|im_end|>

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2,811

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although blood-based liquid biopsy is a promising noninvasive technique to acquire a comprehensive molecular tumor profile by detecting cancer-specific biomarkers (e.g. DNA, RNA, and proteins), there has been limited progress for brain tumor application partially because the low permeability of the blood-brain barrier (BBB) hinders the release of tumor biomarkers. We previously demonstrated focused ultrasound-enabled liquid biopsy (FUS-LBx) that uses FUS to increase BBB permeability in murine glioblastoma models and thus enhance the release of tumor-specific biomarkers into the bloodstream. The objective of this study was to evaluate the feasibility and safety of FUS-LBx in the normal brain tissue of a porcine model. Increased BBB permeability was confirmed by the significant increase (p = 0.0053) in K trans (the transfer coefficient from blood to brain extravascular extracellular space) when comparing the FUS-sonicated brain area with the contralateral non-sonicated area. Meanwhile, there was a significant increase in the blood concentrations of glial fibrillary acidic protein (GFAP, p = 0.0074) and myelin basic protein (MBP, p = 0.0039) after FUS sonication as compared with before FUS. There was no detectable tissue damage by T 2 * -weighted MRI and histological analysis. Findings from this study suggest that FUS-LBx is a promising technique for noninvasive and localized diagnosis of the molecular profiles of brain diseases with the potential to translate to the clinic. Introduction Tissue biopsy has been used to characterize and track the tumor molecular landscape. However, tissue biopsy for brain tumor diagnosis requires invasive surgical procedures, which carry a 5–7% risk of major morbidity 1 . It may not be possible at all to perform this procedure on medically inoperable patients or patients with tumors in surgically inaccessible locations. Repeated tissue biopsies to assess treatment response and cancer recurrence are often not feasible given the increased risk for complications and morbidity. These challenges limit the timely diagnosis and selection of treatment options, hinder a better understanding of the disease, and impair the development of effective treatment approaches. Liquid biopsy (LBx), which refers to the detection of tumor-derived components in body fluids (e.g., blood, urine, saliva, ascitic fluid, cerebrospinal fluid, etc.), has been gaining enormous attention in both medical research and clinical applications 2 , 3 . Various substances from liquid biopsies have been found to be closely related to the stage of a tumor and might serve as biomarkers for cancer diagnosis and prognosis, such as circulating tumor cells, circulating tumor DNAs, RNAs, extracellular vesicles, and a series of cancer-related proteins 4 . Blood-based LBx enables physicians to noninvasively interrogate the dynamic evolution of a tumor and monitor a patient’s response to therapies through a simple blood test. Blood-based LBx-guided personalized therapy has already entered clinical practice in the management of several cancers. An important example of blood-based LBx clinical utility is the assessment of epidermal growth factor receptor (EGFR) mutations in circulating tumor DNA to guide the use of EGFR tyrosine kinase inhibitors in patients with advanced-stage non-small-cell lung carcinoma 5 , 6 . However, extending blood-based LBx to brain cancer remains challenging 2 . Brain tumor blood-based LBx not only faces the challenge of establishing sensitive and reliable biomarker detection methods but also the unique challenge from the blood-brain barrier (BBB) that hinders the release of tumor biomarkers into the blood circulation 1 . A number of publications have demonstrated the ability to detect circulating brain tumor biomarkers in patients with brain cancer. Yet, brain tumor-derived biomarkers are generally detected at low abundance and in a limited number of patients, which makes analysis difficult in routine clinical practice 2 , 7 , 8 , 9 . With current biomarker detection techniques, circulating tumor DNA is detectable in >75% of patients with advanced pancreatic, ovarian, colorectal bladder, melanoma, and head and neck cancer, but only in <10% of glioma patients 2 . Focused ultrasound (FUS) in combination with microbubbles has been established as a noninvasive BBB disruption technique for drug delivery (FUS-BBBD) 10 . Microbubbles, which are ultrasound contrast agents used in the clinic for ultrasound imaging, are intravenously injected into the blood circulation. FUS generated by an extracorporeal ultrasound transducer can penetrate through the skull and focus the ultrasound energy at a targeted brain location. When microbubbles pass through the FUS target brain region, the ultrasound waves induce microbubble cavitation (i.e., the expansion, contraction, and collapse of microbubbles in an acoustic field). The cavitating microbubbles localize and amplify the FUS acoustic energy and induce mechanical effects on the blood vessel wall 11 . Using optimized treatment parameters, FUS can transiently disrupt the BBB and increase its permeability without causing vascular damage. Successful applications of this technique have been demonstrated in not only various small animal models but also large animal models, such as nonhuman primates 12 , 13 , 14 , 15 , sheep 16 , and pigs 17 , 18 , 19 . Clinical trials are currently ongoing to evaluate the feasibility and safety of FUS-BBBD for brain drug delivery using magnetic resonance imaging (MRI)-guided FUS 20 , 21 , 22 . We proposed that FUS-induced BBB disruption enables a “two-way transfer” between the brain and blood circulation and introduced the FUS-enabled liquid biopsy technique (FUS-LBx) 23 . Although the use of ultrasound to amplify biomarker signals in the blood was proposed in 2009 24 , most previous studies used high-intensity focused ultrasound (HIFU) to induce permanent mechanical or thermal disruption of tumors outside the brain to liberate biomarkers from tumor cells 25 , 26 , 27 . Following the initial introduction of the ultrasound-mediated biomarker amplification concept by D’Souza et al . in 2009, several in vitro studies were reported over the next few years 28 , 29 , 30 , 31 . These studies showed that ultrasound combined with microbubble-induced sonoporation could liberate various cellular contents into the extracellular space, such as enhanced green fluorescence protein 28 , mammaglobin mRNA 28 , micro-RNA 21 29 , cancer antigens 125 and 19–9 30 , and small molecule calcein 31 . It was only after 2016 that", "role": "user" }, { "content": "Brain tumors are typically diagnosed using MRI imaging, as taking a sample for a tissue biopsy is risky and may not be possible due to tumor location or a patient's poor health conditions. Researchers at Washington University in St. Louis are developing a method to diagnose brain tumors without any incisions. The method is developed by a team led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine. It uses ultrasonic energy to target tumors deep in the brain. Once located, the researchers inject microbubbles into the blood that travel to the ultrasound-targeted tissue then pop, causing small tears of the blood-brain barrier. The ruptures allow biomarkers, such as DNA, RNA and proteins, from the tumor to pass through the blood-brain barrier and release into the blood, which can be tested with a blood draw, called a liquid biopsy. Chen and the team have been working on their focused ultrasound-enabled liquid biopsy (FUS-LBx) method for several years, conducting a feasibility study first in mice, followed by a safety evaluation study also in mice, and most recently, another study in young pigs, which have a similar skull thickness as humans. While blood-based liquid biopsy has been used in human patients with other cancers for personalized medicine, extending the method to brain cancer in humans remains challenging. Chen recently received a four-year, $2.5 million grant from the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health to pursue the study further. In a study published in Scientific Reports May 4, the team reported success in measuring two brain-specific biomarkers using FUS-LBx in seven of the eight pigs they used. They found no brain tissue damage in the pigs after the procedure. Brain tumors are typically diagnosed using MRI imaging, as taking a sample for a tissue biopsy is risky and may not be possible due to tumor location or a patient's poor health conditions. Researchers at Washington University in St. Louis are developing a method to diagnose brain tumors without any incisions. Credit: Chen Lab \"MRI only provides anatomic information about the brain tumor,\" said Chris Pacia, a third-year doctoral student in biomedical engineering and first author of the study. \"FUS-LBx may be integrated into future clinical practice as a complement to MRI and tissue biopsies to provide molecular information of the tumor.\" \"The potential impact of this technique could be huge, and not just for brain tumor diagnosis,\" Chen said. \"This method could be applied to the diagnosis of other brain diseases.\" Chen said the team wants to do more studies to better understand and optimize the technology as it prepares for clinical trials in humans. \"Our long-term goal is to transform the clinical management of patients with brain cancer by providing molecular signatures of the disease using noninvasive FUS-LBx,\" Chen said. \"Research with the new funding has the potential to radically advance the diagnosis and monitoring of brain cancer patients without surgery.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although blood-based liquid biopsy is a promising noninvasive technique to acquire a comprehensive molecular tumor profile by detecting cancer-specific biomarkers (e.g. DNA, RNA, and proteins), there has been limited progress for brain tumor application partially because the low permeability of the blood-brain barrier (BBB) hinders the release of tumor biomarkers. We previously demonstrated focused ultrasound-enabled liquid biopsy (FUS-LBx) that uses FUS to increase BBB permeability in murine glioblastoma models and thus enhance the release of tumor-specific biomarkers into the bloodstream. The objective of this study was to evaluate the feasibility and safety of FUS-LBx in the normal brain tissue of a porcine model. Increased BBB permeability was confirmed by the significant increase (p = 0.0053) in K trans (the transfer coefficient from blood to brain extravascular extracellular space) when comparing the FUS-sonicated brain area with the contralateral non-sonicated area. Meanwhile, there was a significant increase in the blood concentrations of glial fibrillary acidic protein (GFAP, p = 0.0074) and myelin basic protein (MBP, p = 0.0039) after FUS sonication as compared with before FUS. There was no detectable tissue damage by T 2 * -weighted MRI and histological analysis. Findings from this study suggest that FUS-LBx is a promising technique for noninvasive and localized diagnosis of the molecular profiles of brain diseases with the potential to translate to the clinic. Introduction Tissue biopsy has been used to characterize and track the tumor molecular landscape. However, tissue biopsy for brain tumor diagnosis requires invasive surgical procedures, which carry a 5–7% risk of major morbidity 1 . It may not be possible at all to perform this procedure on medically inoperable patients or patients with tumors in surgically inaccessible locations. Repeated tissue biopsies to assess treatment response and cancer recurrence are often not feasible given the increased risk for complications and morbidity. These challenges limit the timely diagnosis and selection of treatment options, hinder a better understanding of the disease, and impair the development of effective treatment approaches. Liquid biopsy (LBx), which refers to the detection of tumor-derived components in body fluids (e.g., blood, urine, saliva, ascitic fluid, cerebrospinal fluid, etc.), has been gaining enormous attention in both medical research and clinical applications 2 , 3 . Various substances from liquid biopsies have been found to be closely related to the stage of a tumor and might serve as biomarkers for cancer diagnosis and prognosis, such as circulating tumor cells, circulating tumor DNAs, RNAs, extracellular vesicles, and a series of cancer-related proteins 4 . Blood-based LBx enables physicians to noninvasively interrogate the dynamic evolution of a tumor and monitor a patient’s response to therapies through a simple blood test. Blood-based LBx-guided personalized therapy has already entered clinical practice in the management of several cancers. An important example of blood-based LBx clinical utility is the assessment of epidermal growth factor receptor (EGFR) mutations in circulating tumor DNA to guide the use of EGFR tyrosine kinase inhibitors in patients with advanced-stage non-small-cell lung carcinoma 5 , 6 . However, extending blood-based LBx to brain cancer remains challenging 2 . Brain tumor blood-based LBx not only faces the challenge of establishing sensitive and reliable biomarker detection methods but also the unique challenge from the blood-brain barrier (BBB) that hinders the release of tumor biomarkers into the blood circulation 1 . A number of publications have demonstrated the ability to detect circulating brain tumor biomarkers in patients with brain cancer. Yet, brain tumor-derived biomarkers are generally detected at low abundance and in a limited number of patients, which makes analysis difficult in routine clinical practice 2 , 7 , 8 , 9 . With current biomarker detection techniques, circulating tumor DNA is detectable in >75% of patients with advanced pancreatic, ovarian, colorectal bladder, melanoma, and head and neck cancer, but only in <10% of glioma patients 2 . Focused ultrasound (FUS) in combination with microbubbles has been established as a noninvasive BBB disruption technique for drug delivery (FUS-BBBD) 10 . Microbubbles, which are ultrasound contrast agents used in the clinic for ultrasound imaging, are intravenously injected into the blood circulation. FUS generated by an extracorporeal ultrasound transducer can penetrate through the skull and focus the ultrasound energy at a targeted brain location. When microbubbles pass through the FUS target brain region, the ultrasound waves induce microbubble cavitation (i.e., the expansion, contraction, and collapse of microbubbles in an acoustic field). The cavitating microbubbles localize and amplify the FUS acoustic energy and induce mechanical effects on the blood vessel wall 11 . Using optimized treatment parameters, FUS can transiently disrupt the BBB and increase its permeability without causing vascular damage. Successful applications of this technique have been demonstrated in not only various small animal models but also large animal models, such as nonhuman primates 12 , 13 , 14 , 15 , sheep 16 , and pigs 17 , 18 , 19 . Clinical trials are currently ongoing to evaluate the feasibility and safety of FUS-BBBD for brain drug delivery using magnetic resonance imaging (MRI)-guided FUS 20 , 21 , 22 . We proposed that FUS-induced BBB disruption enables a “two-way transfer” between the brain and blood circulation and introduced the FUS-enabled liquid biopsy technique (FUS-LBx) 23 . Although the use of ultrasound to amplify biomarker signals in the blood was proposed in 2009 24 , most previous studies used high-intensity focused ultrasound (HIFU) to induce permanent mechanical or thermal disruption of tumors outside the brain to liberate biomarkers from tumor cells 25 , 26 , 27 . Following the initial introduction of the ultrasound-mediated biomarker amplification concept by D’Souza et al . in 2009, several in vitro studies were reported over the next few years 28 , 29 , 30 , 31 . These studies showed that ultrasound combined with microbubble-induced sonoporation could liberate various cellular contents into the extracellular space, such as enhanced green fluorescence protein 28 , mammaglobin mRNA 28 , micro-RNA 21 29 , cancer antigens 125 and 19–9 30 , and small molecule calcein 31 . It was only after 2016 that<|im_end|> <|im_start|>assistant Brain tumors are typically diagnosed using MRI imaging, as taking a sample for a tissue biopsy is risky and may not be possible due to tumor location or a patient's poor health conditions. Researchers at Washington University in St. Louis are developing a method to diagnose brain tumors without any incisions. The method is developed by a team led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine. It uses ultrasonic energy to target tumors deep in the brain. Once located, the researchers inject microbubbles into the blood that travel to the ultrasound-targeted tissue then pop, causing small tears of the blood-brain barrier. The ruptures allow biomarkers, such as DNA, RNA and proteins, from the tumor to pass through the blood-brain barrier and release into the blood, which can be tested with a blood draw, called a liquid biopsy. Chen and the team have been working on their focused ultrasound-enabled liquid biopsy (FUS-LBx) method for several years, conducting a feasibility study first in mice, followed by a safety evaluation study also in mice, and most recently, another study in young pigs, which have a similar skull thickness as humans. While blood-based liquid biopsy has been used in human patients with other cancers for personalized medicine, extending the method to brain cancer in humans remains challenging. Chen recently received a four-year, $2.5 million grant from the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health to pursue the study further. In a study published in Scientific Reports May 4, the team reported success in measuring two brain-specific biomarkers using FUS-LBx in seven of the eight pigs they used. They found no brain tissue damage in the pigs after the procedure. Brain tumors are typically diagnosed using MRI imaging, as taking a sample for a tissue biopsy is risky and may not be possible due to tumor location or a patient's poor health conditions. Researchers at Washington University in St. Louis are developing a method to diagnose brain tumors without any incisions. Credit: Chen Lab "MRI only provides anatomic information about the brain tumor," said Chris Pacia, a third-year doctoral student in biomedical engineering and first author of the study. "FUS-LBx may be integrated into future clinical practice as a complement to MRI and tissue biopsies to provide molecular information of the tumor." "The potential impact of this technique could be huge, and not just for brain tumor diagnosis," Chen said. "This method could be applied to the diagnosis of other brain diseases." Chen said the team wants to do more studies to better understand and optimize the technology as it prepares for clinical trials in humans. "Our long-term goal is to transform the clinical management of patients with brain cancer by providing molecular signatures of the disease using noninvasive FUS-LBx," Chen said. "Research with the new funding has the potential to radically advance the diagnosis and monitoring of brain cancer patients without surgery." <|im_end|>

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