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 Patterns of genetic variation of a species can be shaped by events that occur at wide temporal and geographic scales. Geophysical processes, such as continental glaciations, can affect species vicariance at wide scales whereas processes that act at finer scales, such as gene flow between populations, can have more localized effects. Recent studies have shown that contemporary population structure should be interpreted within the context of historical events, such as ice-age vicariance, due to the hierarchical nature of genetic variation found in many species. The thinhorn sheep ( Ovis dalli ) is a mountain specialist found in northwestern North America, from the Brooks Range in Alaska, east through Yukon to the Mackenzie Mountains of Northwest Territories and south to the Rocky and Coastal Mountains of British Columbia. In this study, we examined the population genetic structure of thinhorn sheep in light of genetic evidence regarding the glacier driven evolution of the two thinhorn sheep subspecies, O. d. dalli and O. d. stonei , using 153 biallelic single-nucleotide polymorphisms genotyped in over 2800 thinhorn rams. We found patterns of genetic variation to be generally consistent with genetic subspecies boundaries at the species-wide level, and mountain range and river valley boundaries at finer scales. By taking in account historical vicariance by conducting hierarchical analyses of population genetic structure, we revealed the presence of three previously unreported Stone’s sheep genetic clusters in the Stikine/Skeena, Cassiar and Rocky Mountains and identified a new geographic range for Stone’s sheep that is much more restricted than currently accepted subspecies maps indicate, and is almost exclusively confined within British Columbia. Our results indicate that contemporary patterns of genetic variation can be influenced by events acting over a range of spatial and temporal scales, and thus the importance of interpreting the findings of present-day genetic structure in light of the phylogeographical history of the species in question. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The distribution of genetic variation in a species is driven by a number of factors at different timescales and over different geographic scales that are typically the outcome of vicariant and dispersal processes. Large-scale historical events, such as continental wide glaciation, can influence genetic differentiation at a species-wide level while the existence of barriers to gene flow at a landscape level can have more localized effects (Avise 2000 ; Shafer et al. 2010 ). Together, these factors shape the structure and genetic diversity of a species. Therefore, any attempts to study the contemporary genetic structure of a species should take into account its evolutionary history since the signals of historical events, such as glacial vicariance, and present day dispersal can be confounding (Zink et al. 2000 ). Alpine species that are widely distributed make ideal subjects to study the relative effects of historical vicariance and gene flow since their lack of dispersal can result in the retention of the signatures of historical events while such signals may be masked in more vagile species due to gene flow between historically isolated lineages. The continent of North America underwent repeated glaciations during the Pleistocene epoch and vicariance due to ice-sheet advance has been shown to have driven much of broad-scale genetic differentiation among many of its native species (Shafer et al. 2010 ). One such species is the thinhorn sheep ( Ovis dalli ). The thinhorn sheep is an alpine ungulate endemic to the mountains of northwestern North America, from the Brooks Range in Alaska (AK), east through Yukon (YK) to the Mackenzie Mountains of Northwest Territories (NWT) and south to the Rocky and Coastal Mountains of British Columbia (BC) (Valdez and Krausman 1999 ). Currently, thinhorn sheep are classified into two subspecies based on pelage colour: (1) the white coated and northerly Dall’s sheep ( O. d. dalli ) and (2) the dark coated and southerly Stone’s sheep ( O. d. stonei ). This colour-based classification of subspecies is the source of some debate (Geist 1971 ; Worley et al. 2004 ; Loehr et al. 2006 ; Sim et al. 2016 ) since coat colour shows complete intergradation from pure white Dall’s sheep types through shades of gray/brown to dark brown Stone’s sheep types (Sheldon 1911 ). No clear break in coat colour exists between the subspecies and coat colours are often not uniform within a population (Demarchi and Hartwig 2004 ). Sheep with intermediate colouration, informally referred to as Fannin’s sheep, are most commonly found in the Ogilvie Mountains (YK) as well as the Pelly (YK) and Casssiar Moutains (YK/BC) although grey saddled Dall’s sheep have been known to exist even as far north as the Brooks Range in AK (Heimer pers. comm.). There have also been past attempts to designate sheep inhabiting the Kenai Peninsula of AK as a subspecies, O. d. kenaiensis , based on skull morphology (Allen 1902 ). Thinhorn sheep have substantial ecological, economic and cultural value, and they are a vital component of the natural heritage of North America (Jex et al. 2016 ), being highly valued by both sport and subsistence hunters, and by non-consumptive users alike. Wildlife agencies generally focus management toward protecting the long-term viability of the species and localized sub-populations, while providing opportunities for resource use. Effective conservation of thinhorn sheep populations relies on the establishment of biologically meaningful population units for management and protection of important seasonal habitats and movement corridors between those habitats. At present, management units can be based on subspecies designation, administrative boundaries, pelage colour, topology and biogeography. However, these measures may be imprecise and uninformative for determining sustainable harvest limits or in determining informed risk or sensitivity ratings associated with resource development. The delineation of more precise population boundaries and data regarding the degree of connectivity between populations are necessary to inform resource development decision-making processes as well as habitat and landscape management, so that the viability of herds, local and broad scale ecology, and options for sustainable human uses are maintained and protected. The use of molecular markers to", "role": "user" }, { "content": "The already-rare Stone's sheep of the Yukon is 20 per cent less common than previously thought, according to new research by University of Alberta biologists. The study examined 123 different DNA markers in approximately 2,800 thinhorn sheep in British Columbia and the Yukon, with the goal of mapping population boundaries. Results show significant overestimation of certain subspecies of thinhorn sheep, like Stone's sheep, due to misclassification. \"That means that population surveys, which are based on current maps, have been over-counting the number of Stone's sheep in Canada,\" explained Zijian Sim, Ph.D. student in the Department of Biological Sciences. \"When correctly classified as Dall's sheep, our results show that the rarer subspecies is even rarer than we once thought, about 20 per cent less than previously thought.\" Part of the problem stems from wildlife management units that are bound by traditional political, cultural, and geographical criteria, which do not necessarily line up with biological population boundaries. Mistaken identity \"The use of DNA markers allows us to directly measure the genetic differentiation between populations, essentially allowing the sheep themselves to tell us where these populations' boundaries are,\" said Sim, who conducted this research under the supervision of Professor David Coltman. \"Unfortunately, we found that sheep tend to ignore our neat political and geographical lines.\" The findings have implications for wildlife management and conservation efforts, highlighting the need for inter-jurisdictional planning where thinhorn sheep population straddle political and geographical boundaries, such as provincial borders or mountains. \"In fact, our study has already prompted discussions of co-management between relevant regulatory agencies in British Columbia and Yukon for cross-border herds,\" added Sim. The study stems from previous research on the misclassification of Stone's sheep based on coat colour. ", "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 Patterns of genetic variation of a species can be shaped by events that occur at wide temporal and geographic scales. Geophysical processes, such as continental glaciations, can affect species vicariance at wide scales whereas processes that act at finer scales, such as gene flow between populations, can have more localized effects. Recent studies have shown that contemporary population structure should be interpreted within the context of historical events, such as ice-age vicariance, due to the hierarchical nature of genetic variation found in many species. The thinhorn sheep ( Ovis dalli ) is a mountain specialist found in northwestern North America, from the Brooks Range in Alaska, east through Yukon to the Mackenzie Mountains of Northwest Territories and south to the Rocky and Coastal Mountains of British Columbia. In this study, we examined the population genetic structure of thinhorn sheep in light of genetic evidence regarding the glacier driven evolution of the two thinhorn sheep subspecies, O. d. dalli and O. d. stonei , using 153 biallelic single-nucleotide polymorphisms genotyped in over 2800 thinhorn rams. We found patterns of genetic variation to be generally consistent with genetic subspecies boundaries at the species-wide level, and mountain range and river valley boundaries at finer scales. By taking in account historical vicariance by conducting hierarchical analyses of population genetic structure, we revealed the presence of three previously unreported Stone’s sheep genetic clusters in the Stikine/Skeena, Cassiar and Rocky Mountains and identified a new geographic range for Stone’s sheep that is much more restricted than currently accepted subspecies maps indicate, and is almost exclusively confined within British Columbia. Our results indicate that contemporary patterns of genetic variation can be influenced by events acting over a range of spatial and temporal scales, and thus the importance of interpreting the findings of present-day genetic structure in light of the phylogeographical history of the species in question. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The distribution of genetic variation in a species is driven by a number of factors at different timescales and over different geographic scales that are typically the outcome of vicariant and dispersal processes. Large-scale historical events, such as continental wide glaciation, can influence genetic differentiation at a species-wide level while the existence of barriers to gene flow at a landscape level can have more localized effects (Avise 2000 ; Shafer et al. 2010 ). Together, these factors shape the structure and genetic diversity of a species. Therefore, any attempts to study the contemporary genetic structure of a species should take into account its evolutionary history since the signals of historical events, such as glacial vicariance, and present day dispersal can be confounding (Zink et al. 2000 ). Alpine species that are widely distributed make ideal subjects to study the relative effects of historical vicariance and gene flow since their lack of dispersal can result in the retention of the signatures of historical events while such signals may be masked in more vagile species due to gene flow between historically isolated lineages. The continent of North America underwent repeated glaciations during the Pleistocene epoch and vicariance due to ice-sheet advance has been shown to have driven much of broad-scale genetic differentiation among many of its native species (Shafer et al. 2010 ). One such species is the thinhorn sheep ( Ovis dalli ). The thinhorn sheep is an alpine ungulate endemic to the mountains of northwestern North America, from the Brooks Range in Alaska (AK), east through Yukon (YK) to the Mackenzie Mountains of Northwest Territories (NWT) and south to the Rocky and Coastal Mountains of British Columbia (BC) (Valdez and Krausman 1999 ). Currently, thinhorn sheep are classified into two subspecies based on pelage colour: (1) the white coated and northerly Dall’s sheep ( O. d. dalli ) and (2) the dark coated and southerly Stone’s sheep ( O. d. stonei ). This colour-based classification of subspecies is the source of some debate (Geist 1971 ; Worley et al. 2004 ; Loehr et al. 2006 ; Sim et al. 2016 ) since coat colour shows complete intergradation from pure white Dall’s sheep types through shades of gray/brown to dark brown Stone’s sheep types (Sheldon 1911 ). No clear break in coat colour exists between the subspecies and coat colours are often not uniform within a population (Demarchi and Hartwig 2004 ). Sheep with intermediate colouration, informally referred to as Fannin’s sheep, are most commonly found in the Ogilvie Mountains (YK) as well as the Pelly (YK) and Casssiar Moutains (YK/BC) although grey saddled Dall’s sheep have been known to exist even as far north as the Brooks Range in AK (Heimer pers. comm.). There have also been past attempts to designate sheep inhabiting the Kenai Peninsula of AK as a subspecies, O. d. kenaiensis , based on skull morphology (Allen 1902 ). Thinhorn sheep have substantial ecological, economic and cultural value, and they are a vital component of the natural heritage of North America (Jex et al. 2016 ), being highly valued by both sport and subsistence hunters, and by non-consumptive users alike. Wildlife agencies generally focus management toward protecting the long-term viability of the species and localized sub-populations, while providing opportunities for resource use. Effective conservation of thinhorn sheep populations relies on the establishment of biologically meaningful population units for management and protection of important seasonal habitats and movement corridors between those habitats. At present, management units can be based on subspecies designation, administrative boundaries, pelage colour, topology and biogeography. However, these measures may be imprecise and uninformative for determining sustainable harvest limits or in determining informed risk or sensitivity ratings associated with resource development. The delineation of more precise population boundaries and data regarding the degree of connectivity between populations are necessary to inform resource development decision-making processes as well as habitat and landscape management, so that the viability of herds, local and broad scale ecology, and options for sustainable human uses are maintained and protected. The use of molecular markers to<|im_end|> <|im_start|>assistant The already-rare Stone's sheep of the Yukon is 20 per cent less common than previously thought, according to new research by University of Alberta biologists. The study examined 123 different DNA markers in approximately 2,800 thinhorn sheep in British Columbia and the Yukon, with the goal of mapping population boundaries. Results show significant overestimation of certain subspecies of thinhorn sheep, like Stone's sheep, due to misclassification. "That means that population surveys, which are based on current maps, have been over-counting the number of Stone's sheep in Canada," explained Zijian Sim, Ph.D. student in the Department of Biological Sciences. "When correctly classified as Dall's sheep, our results show that the rarer subspecies is even rarer than we once thought, about 20 per cent less than previously thought." Part of the problem stems from wildlife management units that are bound by traditional political, cultural, and geographical criteria, which do not necessarily line up with biological population boundaries. Mistaken identity "The use of DNA markers allows us to directly measure the genetic differentiation between populations, essentially allowing the sheep themselves to tell us where these populations' boundaries are," said Sim, who conducted this research under the supervision of Professor David Coltman. "Unfortunately, we found that sheep tend to ignore our neat political and geographical lines." The findings have implications for wildlife management and conservation efforts, highlighting the need for inter-jurisdictional planning where thinhorn sheep population straddle political and geographical boundaries, such as provincial borders or mountains. "In fact, our study has already prompted discussions of co-management between relevant regulatory agencies in British Columbia and Yukon for cross-border herds," added Sim. The study stems from previous research on the misclassification of Stone's sheep based on coat colour. <|im_end|>

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1,699

[ { "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 do fungi navigate through the complex microscopic maze-like structures found in the soil? Fungal behaviour, especially at the hyphal scale, is largely unknown and challenging to study in natural habitats such as the opaque soil matrix. We monitored hyphal growth behaviour and strategies of seven Basidiomycete litter decomposing species in a micro-fabricated “Soil Chip” system that simulates principal aspects of the soil pore space and its micro-spatial heterogeneity. The hyphae were faced with micrometre constrictions, sharp turns and protruding obstacles, and the species examined were found to have profoundly different responses in terms of foraging range and persistence, spatial exploration and ability to pass obstacles. Hyphal behaviour was not predictable solely based on ecological assumptions, and our results obtained a level of trait information at the hyphal scale that cannot be fully explained using classical concepts of space exploration and exploitation such as the phalanx/guerrilla strategies. Instead, we propose a multivariate trait analysis, acknowledging the complex trade-offs and microscale strategies that fungal mycelia exhibit. Our results provide novel insights about hyphal behaviour, as well as an additional understanding of fungal habitat colonisation, their foraging strategies and niche partitioning in the soil environment. Introduction Fungi are fascinating organisms; Despite being classified as microbes, their mycelia can grow to form some of the largest organisms on earth [ 1 ] and their interlinked mycelial morphology can give insight into modern network theories [ 2 ]. Fungal ecology is believed to play a crucial role in shaping Earth’s ecosystems because of fungi’s ability to recycle nutrients in the system as decomposers [ 3 ], provide resources as symbionts of the majority of land plants [ 4 ], and impact the success and dynamics of other organisms as pathogens [ 5 , 6 ]. All these functions ultimately depend on interactions between individual hyphal tips and their immediate environment. Fungi live and interact with their environment mainly at the microscopic scale; their hyphae are very motile and can adjust their morphology in response to stimuli and changes in the environment [ 7 , 8 ]. This type of phenotypic plasticity has also previously been used to describe plant behaviour [ 9 , 10 ], particularly pertaining to plants’ ability to forage for resources [ 11 , 12 ]. How hyphae respond to and interact with different types of environments at the microscopic scale still represents a significant missing piece of the puzzle in our understanding of fungal ecology. Inspiration to describe fungal growth patterns at the mycelial scale can be drawn from plant ecology, especially from the descriptions of clonal plant growth. The different ways in which clonal plants colonise new territory has been conceptualised as guerrilla and phalanx growth forms [ 13 , 14 ]—terms that can also be used to describe fungal mycelial growth patterns [ 15 , 16 , 17 ] (Fig. 1 ). A guerrilla growth form fungus is characterised by opportunistic, far-reaching explorative hyphae; a short lifespan; and low competitive ability [ 15 ]—a beneficial strategy in a patchy, ephemeral resource landscape [ 17 ]. In contrast, a phalanx growth form fungus colonises new territories by short-range foraging, growing dense mats of hyphae and advancing slowly as a united front [ 15 ]. This strategy would be expected among specialists that exploit more complex and long-lasting substrates by investing in the production of large amounts of extra-cellular enzymes to break them down and antibiotics to fend off competitors [ 17 ]. Mycelia may also switch between phalanx- and guerrilla-type growth. For example, finding a nutrient-rich path could induce profuse branching and transition the fungi from guerrilla to phalanx growth form [ 17 ]. Understanding how fungal foraging strategies differ between species is important for being able to draw conclusions about their co-existence and spatial niche partitioning in the environment [ 18 ]. Fig. 1: Summary of hyphal growth behaviour in the context of the ecological concept of phalanx- and guerrilla-type foraging. This concept originates from plant ecology and is used to describe growth patterns of clonal plants, where Fragaria (strawberry; guerrilla, left) and Festuca (phalanx, right) are typical examples of the concept. Guerrilla-type foraging in fungi has been defined by infrequent branching, fast growth, leading hyphae, long-range foraging and sparse growth (listed to the left), whereas phalanx-type foraging has been defined by the opposite set of characteristics: frequent branching, slow growth, a front of hyphae advancing in synchrony, short-range foraging and dense growth [ 15 , 17 ]. The seven examined species were hypothetically placed along the continuum of the phalanx and guerrilla division based on assumptions associated with what type of litter the different species have been found to grow on (Table S1 ) (above), and further placed along the continuums of their defining trait components based on the results of this study (below). Based on our results, none of the examined species fell clearly into one of the categories, or even at a comparable location within the continuum for all trait axes. Instead, we saw that species could be typical guerrilla for one trait and typical phalanx for another. Full size image The fungal filamentous growth form is well adapted to the heterogeneity of the soil habitat [ 19 ]. The soil pore space constitutes a 3D labyrinth of channels and hidden corners that the fungi need to navigate [ 20 ] and organic matter—the most important nutrient source for soil microorganisms—is very patchily and ephemerally distributed in the soil. Soil is impenetrable to light, preventing direct visual observation, and therefore little is known about how fungal hyphae behave in their natural environment. In experimental settings, fungi are often cultured and propagated on structurally homogenous, typically nutrient-rich media in which the effect of small-scale structural heterogeneity on fungi’s ability to locate, consume, store and transport nutrients in the soil may be misjudged. Studying fungi in their natural soil substrate is notoriously difficult and involves slicing the colonised soil to later reconstruct spatial context [ 21 , 22 ]. To assess ecological questions concerning how fungi", "role": "user" }, { "content": "Researchers at Lund University in Sweden have discovered the individual traits of fungi, and how their hyphae—that is, the fungal threads that grow in soil—behave very differently as they navigate through the earth's microscopic labyrinths. The study was performed in a lab environment, and the underground system constructed synthetically from silicone. Using a microscope, researchers were able to follow seven species and compare their behavior. How do they react when the maze they grow in turns sharply and forces the hyphae to grow in the direction it came from? What happens when a large space opens up in front of them? \"Under a microscope, their behavior becomes much more personal than you can ever imagine. They become individual characters,\" says Edith Hammer, one of the researchers behind the study. The research team discovered that the fungi use different strategies when they grow and form their structures, the so-called mycelium. The different characteristics have led the researchers to give the various fungi nicknames such as 'the soldier,' the 'marathon runner' and 'the snake.' The soldier gained its name because it grows with great force, and plows down obstacles in its path, yet it does not get very far. The marathon runner, on the other hand, sends out hypha that act like 'lone fighters,' and grow quite far before giving up their search for food. However, this requires that they do not encounter tough obstacles, as this is their weak spot. Unlike the marathon runner, the snake specializes in weaving and growing around obstacles. Obstacle 2: Maze-like structure made by the researchers. Credit: Kristin Aleklett Kadish Examples of obstacles that the hyphae may encounter, and that can delay and confuse them, are zigzag patterns, sharp angles and rounded corners. The study shows that some species simply stop when they end up in a corner. The research is unique because it is the first time that the behavior of individual hyphae in multiple species has been studied in parallel and in detail. Previous studies have often focused on the mycelium as a whole, as they have not been able to distinguish the behavior of individual hyphae. So far, however, important pieces of the puzzle are missing on how microscopic soil structures affect the behavior of fungi, in order for the research to have practical applications in agriculture. ", "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 do fungi navigate through the complex microscopic maze-like structures found in the soil? Fungal behaviour, especially at the hyphal scale, is largely unknown and challenging to study in natural habitats such as the opaque soil matrix. We monitored hyphal growth behaviour and strategies of seven Basidiomycete litter decomposing species in a micro-fabricated “Soil Chip” system that simulates principal aspects of the soil pore space and its micro-spatial heterogeneity. The hyphae were faced with micrometre constrictions, sharp turns and protruding obstacles, and the species examined were found to have profoundly different responses in terms of foraging range and persistence, spatial exploration and ability to pass obstacles. Hyphal behaviour was not predictable solely based on ecological assumptions, and our results obtained a level of trait information at the hyphal scale that cannot be fully explained using classical concepts of space exploration and exploitation such as the phalanx/guerrilla strategies. Instead, we propose a multivariate trait analysis, acknowledging the complex trade-offs and microscale strategies that fungal mycelia exhibit. Our results provide novel insights about hyphal behaviour, as well as an additional understanding of fungal habitat colonisation, their foraging strategies and niche partitioning in the soil environment. Introduction Fungi are fascinating organisms; Despite being classified as microbes, their mycelia can grow to form some of the largest organisms on earth [ 1 ] and their interlinked mycelial morphology can give insight into modern network theories [ 2 ]. Fungal ecology is believed to play a crucial role in shaping Earth’s ecosystems because of fungi’s ability to recycle nutrients in the system as decomposers [ 3 ], provide resources as symbionts of the majority of land plants [ 4 ], and impact the success and dynamics of other organisms as pathogens [ 5 , 6 ]. All these functions ultimately depend on interactions between individual hyphal tips and their immediate environment. Fungi live and interact with their environment mainly at the microscopic scale; their hyphae are very motile and can adjust their morphology in response to stimuli and changes in the environment [ 7 , 8 ]. This type of phenotypic plasticity has also previously been used to describe plant behaviour [ 9 , 10 ], particularly pertaining to plants’ ability to forage for resources [ 11 , 12 ]. How hyphae respond to and interact with different types of environments at the microscopic scale still represents a significant missing piece of the puzzle in our understanding of fungal ecology. Inspiration to describe fungal growth patterns at the mycelial scale can be drawn from plant ecology, especially from the descriptions of clonal plant growth. The different ways in which clonal plants colonise new territory has been conceptualised as guerrilla and phalanx growth forms [ 13 , 14 ]—terms that can also be used to describe fungal mycelial growth patterns [ 15 , 16 , 17 ] (Fig. 1 ). A guerrilla growth form fungus is characterised by opportunistic, far-reaching explorative hyphae; a short lifespan; and low competitive ability [ 15 ]—a beneficial strategy in a patchy, ephemeral resource landscape [ 17 ]. In contrast, a phalanx growth form fungus colonises new territories by short-range foraging, growing dense mats of hyphae and advancing slowly as a united front [ 15 ]. This strategy would be expected among specialists that exploit more complex and long-lasting substrates by investing in the production of large amounts of extra-cellular enzymes to break them down and antibiotics to fend off competitors [ 17 ]. Mycelia may also switch between phalanx- and guerrilla-type growth. For example, finding a nutrient-rich path could induce profuse branching and transition the fungi from guerrilla to phalanx growth form [ 17 ]. Understanding how fungal foraging strategies differ between species is important for being able to draw conclusions about their co-existence and spatial niche partitioning in the environment [ 18 ]. Fig. 1: Summary of hyphal growth behaviour in the context of the ecological concept of phalanx- and guerrilla-type foraging. This concept originates from plant ecology and is used to describe growth patterns of clonal plants, where Fragaria (strawberry; guerrilla, left) and Festuca (phalanx, right) are typical examples of the concept. Guerrilla-type foraging in fungi has been defined by infrequent branching, fast growth, leading hyphae, long-range foraging and sparse growth (listed to the left), whereas phalanx-type foraging has been defined by the opposite set of characteristics: frequent branching, slow growth, a front of hyphae advancing in synchrony, short-range foraging and dense growth [ 15 , 17 ]. The seven examined species were hypothetically placed along the continuum of the phalanx and guerrilla division based on assumptions associated with what type of litter the different species have been found to grow on (Table S1 ) (above), and further placed along the continuums of their defining trait components based on the results of this study (below). Based on our results, none of the examined species fell clearly into one of the categories, or even at a comparable location within the continuum for all trait axes. Instead, we saw that species could be typical guerrilla for one trait and typical phalanx for another. Full size image The fungal filamentous growth form is well adapted to the heterogeneity of the soil habitat [ 19 ]. The soil pore space constitutes a 3D labyrinth of channels and hidden corners that the fungi need to navigate [ 20 ] and organic matter—the most important nutrient source for soil microorganisms—is very patchily and ephemerally distributed in the soil. Soil is impenetrable to light, preventing direct visual observation, and therefore little is known about how fungal hyphae behave in their natural environment. In experimental settings, fungi are often cultured and propagated on structurally homogenous, typically nutrient-rich media in which the effect of small-scale structural heterogeneity on fungi’s ability to locate, consume, store and transport nutrients in the soil may be misjudged. Studying fungi in their natural soil substrate is notoriously difficult and involves slicing the colonised soil to later reconstruct spatial context [ 21 , 22 ]. To assess ecological questions concerning how fungi<|im_end|> <|im_start|>assistant Researchers at Lund University in Sweden have discovered the individual traits of fungi, and how their hyphae—that is, the fungal threads that grow in soil—behave very differently as they navigate through the earth's microscopic labyrinths. The study was performed in a lab environment, and the underground system constructed synthetically from silicone. Using a microscope, researchers were able to follow seven species and compare their behavior. How do they react when the maze they grow in turns sharply and forces the hyphae to grow in the direction it came from? What happens when a large space opens up in front of them? "Under a microscope, their behavior becomes much more personal than you can ever imagine. They become individual characters," says Edith Hammer, one of the researchers behind the study. The research team discovered that the fungi use different strategies when they grow and form their structures, the so-called mycelium. The different characteristics have led the researchers to give the various fungi nicknames such as 'the soldier,' the 'marathon runner' and 'the snake.' The soldier gained its name because it grows with great force, and plows down obstacles in its path, yet it does not get very far. The marathon runner, on the other hand, sends out hypha that act like 'lone fighters,' and grow quite far before giving up their search for food. However, this requires that they do not encounter tough obstacles, as this is their weak spot. Unlike the marathon runner, the snake specializes in weaving and growing around obstacles. Obstacle 2: Maze-like structure made by the researchers. Credit: Kristin Aleklett Kadish Examples of obstacles that the hyphae may encounter, and that can delay and confuse them, are zigzag patterns, sharp angles and rounded corners. The study shows that some species simply stop when they end up in a corner. The research is unique because it is the first time that the behavior of individual hyphae in multiple species has been studied in parallel and in detail. Previous studies have often focused on the mycelium as a whole, as they have not been able to distinguish the behavior of individual hyphae. So far, however, important pieces of the puzzle are missing on how microscopic soil structures affect the behavior of fungi, in order for the research to have practical applications in agriculture. <|im_end|>

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1,813

[ { "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 Laser material deposition based restoration of high-value components can be a revolutionary technology in remanufacturing. The deposition process induces residual stresses due to thermomechanical behavior and metallurgical transformations. The presence of tensile residual stresses in the deposited layer will compromise the fatigue life of the restored component. We have developed a novel fully coupled metallurgical, thermal and mechanical (metallo-thermomechanical) model to predict residual stresses and identified a critical deposition height, which ensures compressive residual stresses in the deposited layer. Any lower deposition height will result in tensile residual stresses and higher deposition height will result in excessive dilution (substrate melting). We have validated the model using neutron and micro-focus X-ray diffraction measurements. This study highlights that the critical deposition height corresponds to the minimum cooling rate during solidification. It addresses one of the major outstanding problems of additive manufacturing and paves a way for “science-enabled-technology” solutions for sustainable restoration/remanufacturing. Introduction Transformation of the global industrial ecology is essential to ensure the stability of the climate-sensitive tipping elements of the Earth System 1 , 2 , 3 , 4 , 5 while maintaining sustainable industrial growth. For such a transformation, reorganizing the manufactured capital infrastructure towards repair and remanufacture of industrial products will reduce human impact on the environment as well as increase economic growth 4 , 6 , 7 , 8 . In this regard, the importance of maintenance, repair and overhaul (MRO) in the aerospace and automotive sectors can be understood from the fact that these sectors significantly leverage other sectors of a nation’s economy 9 . Even by conservative estimates ~18% increase by 2024 10 is predicted for the automotive collision repair industry and aircraft MRO market 10 , 11 . Central to these efforts for sustainable development in the automotive and aerospace sectors is extending the service life of molds/dies, engine parts and important structural components using energy efficient Directed Energy Deposition (DED) processes such as laser additive manufacturing 12 . Laser additive manufacturing provides numerous advantages over the traditional restoration techniques based on thermal spraying or welding, which are imprecise and ad hoc 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . The precise and controlled deposition in these processes produces a relatively narrow dilution and heat affected zone 15 , 16 , 17 , 19 , 26 . However, it induces residual stresses (locked in post processing stresses). Note that the nature of the residual stresses (compressive or tensile) is the most important factor affecting the integrity and quality of the processed components as it directly affects the service life 16 , 17 , 19 , 20 , 26 , 27 . The residual stresses develop due to strains induced by thermomechanical effects and metallurgical transformations 28 , 29 , 30 . The deposition of the hot molten material on a relatively cold substrate and subsequent conduction-driven cooling results in differential thermal expansion and contraction between the deposited and substrate layers 21 , 30 , 31 , 32 , 33 . The thermomechanical strains depend on the temperature distribution, the coefficients of thermal expansion and the elastoplastic behavior of the clad and the substrate materials. In addition, the high rate of cooling can result in metallurgical transformations which contribute to the development of additional strains due to transformation induced plasticity and volumetric dilation 34 , 35 , 36 , 37 , 38 , 39 . It may be noted that the deposited layer is often the most critical region and tensile residual stresses in this region can aid in crack propagation 17 , 18 , 27 , 30 , 31 , 40 , 41 . One of the greatest challenges in laser additive manufacturing today is to determine a critical deposition height to ensure compressive residual stress in the clad (from the surface of the clad to the clad-substrate interface region). Finite element (FE) models provide viable alternatives to expensive experiments for predicting the transient temperature field, the residual stresses and the microstructural transformations developed during the process 15 , 16 , 17 , 19 , 26 , 27 , 35 , 42 , 43 , 44 , 45 . Most of the finite element models reported in the literature for predicting the residual stresses use sequential coupling between the metallurgical and thermomechanical phenomena 37 , 39 , 46 , 47 . It may be noted that a fully coupled model can consider the effect of metallurgical transformations on the in-process stress evolution and can better predict the residual stress profile. Moreover, the existing models do not take into consideration of the shape of the deposited layer. In this work, we have investigated the residual stress distribution across a laser deposited layer on a substrate via a 3D fully coupled metallo-thermomechanical finite element model. Gaussian distribution of powder with uniform intensity moving heat source is considered in this analysis 22 , 48 . To experimentally validate the model, laser cladding (deposition) experiments were conducted on H13 tool steel with Crucible Particle Metallurgy (CPM) steel powders with high Vanadium content. It is known that dies and molds of H13 tool steel are repaired using CPM9V 18 , 22 , 23 , 24 , 49 , 50 . The residual stresses predicted by the model have been compared with the results obtained from micro-focus X-ray diffraction for micro-scale local residual stress measurements at IIT Bombay, and neutron diffraction experiments for determining volume averaged residual stresses at ANSTO, Sydney, Australia. The following sections describe the formulation of the fully coupled 3D metallo-thermomechanical model and experimental details. Methodology Metallo-thermomechanical modeling of residual stresses The 3D fully coupled metallo-thermomechanical finite element model utilizes various user-defined subroutines in the commercial finite element software ABAQUS ® to model the complex interactions between the thermal, mechanical and metallurgical phenomena involved in laser cladding. Figure 1 describes the algorithm for the metallo-thermomechanical model along with the computational domain with details of mesh size and loading-boundary conditions.", "role": "user" }, { "content": "Neutron diffraction strain scanning measurements at ANSTO have validated a new theoretical model that successfully predicts the residual stresses and critical deposition heights for laser additive manufacturing. The model, which was developed by Prof Ramesh Singh's group from the Indian Institute of Technology Bombay in association with Prof Wenyi Yan from Monash University, accounts for both thermomechanical behaviour and metallurgical transformation that takes place by direct energy deposition techniques, such as laser cladding. \"To collaborate with ANSTO and use the world-class facilities there can definitely enhance our research quality. This work, just published in Scientific Reports, is just one good example,\" said Yan. ''This research was completed through a joint Ph.D. training program between the Indian Institute of Technology Bombay and Monash University. The first author Santanu Paul has finished his Ph.D. study and is now working in an international company to develop software for additive manufacturing, ''said Yan. Laser cladding is used widely in the maintenance, repair and overhaul of parts and structural components in the automotive and aerospace industries because it improves material properties. \"Directed energy deposition methods have a huge potential in repair and re-manufacturing of aerospace components, dies and moulds which undergo damage due to cyclic thermomechanical loading. However, the presence of tensile residual stresses in the deposited layer will reduce the fatigue life of restored component. Comparison of residual stress predicted by finite element models with measured using Neutron and X-ray diffraction. Credit: Australian Nuclear Science and Technology Organisation (ANSTO) The fully coupled thermomechanical and metallurgical model developed in this collaborative work has been used to determine the critical deposition height which ensures compressive residual stresses in the deposited layer for sustainable restoration.\" said Singh. \"Working with ANSTO team on experimental measurements of residual stresses was a great pleasure and learning experience and this paper is just the beginning of a long term collaboration,\" said Singh. In the paper, the investigators reported that variation in residual stress across a cross section of laser clad steel, predicted by their metallo-thermomechanical model, demonstrated the existence of a critical deposition height. The critical height of deposition corresponds to the layer thickness, which, when deposited, would maximise beneficial compressive residual stresses in the deposited layer and substrate. Deposition that is lower than the critical height would produce detrimental tensile residual stresses at the interface while deposition that is higher than the critical height would result in excessive dilution. The research also found that at the critical height of deposition, the solidification rate was at a minimum. The Kowari residual stress diffractometer was used to measure macroscale residual stresses in a sample of H13 steel that was laser cladded with crucible particle metallurgy steel powders with a high vanadium content. The three-dimensional measurements of residual stresses on Kowari are highly accurate and non-destructive. \"A model is only as good as its validation. Using strain scanning instrument—Kowari we were able to identify triaxial residual stresses in the deposited layers, which verified the locations predicted by the model ,\" said Research Scientist and Industrial Liaison Manager Dr. Anna Paradowska, who is a co-author of the paper with Dr. Mark Reid. Laser cladding, which involves depositing molten metal on a relatively cold substrate of steel, creates a complex residual stress profile. Theoretical models based on thermomechanical properties, which are commonly used, were shown to overestimate tensile residual stresses and underestimates compressive residual stresses in the substrate and interface. The team used surface X-ray diffraction at the Indian Institute of Technology for measurements of residual stresses in one direction. However it was important to have an independent fully non-destructive bulk measurements to also validate the in-house measurements procedure. Both diffraction techniques showed the presence of tensile residual stresses near the melt front and compressive stresses in the deposited layer and interface regions. \"Understanding the stresses and being able to predict them is very important for additive manufacturing industry. Validated model is very beneficial as further optimalisation of the manufacturing process using this model will be cost effective and saves time,\" said Paradowska. \"The model allows you to calculate the laser position rate to achieve a specific height of deposition while minimising the effect of detrimental stresses and maximise the beneficial compressive stresses.\" The study authors suggested demonstrated a science-enable technology solution that could lead to an improvement in the quality, safety and economics of components manufactured with laser additive processes. ", "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 Laser material deposition based restoration of high-value components can be a revolutionary technology in remanufacturing. The deposition process induces residual stresses due to thermomechanical behavior and metallurgical transformations. The presence of tensile residual stresses in the deposited layer will compromise the fatigue life of the restored component. We have developed a novel fully coupled metallurgical, thermal and mechanical (metallo-thermomechanical) model to predict residual stresses and identified a critical deposition height, which ensures compressive residual stresses in the deposited layer. Any lower deposition height will result in tensile residual stresses and higher deposition height will result in excessive dilution (substrate melting). We have validated the model using neutron and micro-focus X-ray diffraction measurements. This study highlights that the critical deposition height corresponds to the minimum cooling rate during solidification. It addresses one of the major outstanding problems of additive manufacturing and paves a way for “science-enabled-technology” solutions for sustainable restoration/remanufacturing. Introduction Transformation of the global industrial ecology is essential to ensure the stability of the climate-sensitive tipping elements of the Earth System 1 , 2 , 3 , 4 , 5 while maintaining sustainable industrial growth. For such a transformation, reorganizing the manufactured capital infrastructure towards repair and remanufacture of industrial products will reduce human impact on the environment as well as increase economic growth 4 , 6 , 7 , 8 . In this regard, the importance of maintenance, repair and overhaul (MRO) in the aerospace and automotive sectors can be understood from the fact that these sectors significantly leverage other sectors of a nation’s economy 9 . Even by conservative estimates ~18% increase by 2024 10 is predicted for the automotive collision repair industry and aircraft MRO market 10 , 11 . Central to these efforts for sustainable development in the automotive and aerospace sectors is extending the service life of molds/dies, engine parts and important structural components using energy efficient Directed Energy Deposition (DED) processes such as laser additive manufacturing 12 . Laser additive manufacturing provides numerous advantages over the traditional restoration techniques based on thermal spraying or welding, which are imprecise and ad hoc 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . The precise and controlled deposition in these processes produces a relatively narrow dilution and heat affected zone 15 , 16 , 17 , 19 , 26 . However, it induces residual stresses (locked in post processing stresses). Note that the nature of the residual stresses (compressive or tensile) is the most important factor affecting the integrity and quality of the processed components as it directly affects the service life 16 , 17 , 19 , 20 , 26 , 27 . The residual stresses develop due to strains induced by thermomechanical effects and metallurgical transformations 28 , 29 , 30 . The deposition of the hot molten material on a relatively cold substrate and subsequent conduction-driven cooling results in differential thermal expansion and contraction between the deposited and substrate layers 21 , 30 , 31 , 32 , 33 . The thermomechanical strains depend on the temperature distribution, the coefficients of thermal expansion and the elastoplastic behavior of the clad and the substrate materials. In addition, the high rate of cooling can result in metallurgical transformations which contribute to the development of additional strains due to transformation induced plasticity and volumetric dilation 34 , 35 , 36 , 37 , 38 , 39 . It may be noted that the deposited layer is often the most critical region and tensile residual stresses in this region can aid in crack propagation 17 , 18 , 27 , 30 , 31 , 40 , 41 . One of the greatest challenges in laser additive manufacturing today is to determine a critical deposition height to ensure compressive residual stress in the clad (from the surface of the clad to the clad-substrate interface region). Finite element (FE) models provide viable alternatives to expensive experiments for predicting the transient temperature field, the residual stresses and the microstructural transformations developed during the process 15 , 16 , 17 , 19 , 26 , 27 , 35 , 42 , 43 , 44 , 45 . Most of the finite element models reported in the literature for predicting the residual stresses use sequential coupling between the metallurgical and thermomechanical phenomena 37 , 39 , 46 , 47 . It may be noted that a fully coupled model can consider the effect of metallurgical transformations on the in-process stress evolution and can better predict the residual stress profile. Moreover, the existing models do not take into consideration of the shape of the deposited layer. In this work, we have investigated the residual stress distribution across a laser deposited layer on a substrate via a 3D fully coupled metallo-thermomechanical finite element model. Gaussian distribution of powder with uniform intensity moving heat source is considered in this analysis 22 , 48 . To experimentally validate the model, laser cladding (deposition) experiments were conducted on H13 tool steel with Crucible Particle Metallurgy (CPM) steel powders with high Vanadium content. It is known that dies and molds of H13 tool steel are repaired using CPM9V 18 , 22 , 23 , 24 , 49 , 50 . The residual stresses predicted by the model have been compared with the results obtained from micro-focus X-ray diffraction for micro-scale local residual stress measurements at IIT Bombay, and neutron diffraction experiments for determining volume averaged residual stresses at ANSTO, Sydney, Australia. The following sections describe the formulation of the fully coupled 3D metallo-thermomechanical model and experimental details. Methodology Metallo-thermomechanical modeling of residual stresses The 3D fully coupled metallo-thermomechanical finite element model utilizes various user-defined subroutines in the commercial finite element software ABAQUS ® to model the complex interactions between the thermal, mechanical and metallurgical phenomena involved in laser cladding. Figure 1 describes the algorithm for the metallo-thermomechanical model along with the computational domain with details of mesh size and loading-boundary conditions.<|im_end|> <|im_start|>assistant Neutron diffraction strain scanning measurements at ANSTO have validated a new theoretical model that successfully predicts the residual stresses and critical deposition heights for laser additive manufacturing. The model, which was developed by Prof Ramesh Singh's group from the Indian Institute of Technology Bombay in association with Prof Wenyi Yan from Monash University, accounts for both thermomechanical behaviour and metallurgical transformation that takes place by direct energy deposition techniques, such as laser cladding. "To collaborate with ANSTO and use the world-class facilities there can definitely enhance our research quality. This work, just published in Scientific Reports, is just one good example," said Yan. ''This research was completed through a joint Ph.D. training program between the Indian Institute of Technology Bombay and Monash University. The first author Santanu Paul has finished his Ph.D. study and is now working in an international company to develop software for additive manufacturing, ''said Yan. Laser cladding is used widely in the maintenance, repair and overhaul of parts and structural components in the automotive and aerospace industries because it improves material properties. "Directed energy deposition methods have a huge potential in repair and re-manufacturing of aerospace components, dies and moulds which undergo damage due to cyclic thermomechanical loading. However, the presence of tensile residual stresses in the deposited layer will reduce the fatigue life of restored component. Comparison of residual stress predicted by finite element models with measured using Neutron and X-ray diffraction. Credit: Australian Nuclear Science and Technology Organisation (ANSTO) The fully coupled thermomechanical and metallurgical model developed in this collaborative work has been used to determine the critical deposition height which ensures compressive residual stresses in the deposited layer for sustainable restoration." said Singh. "Working with ANSTO team on experimental measurements of residual stresses was a great pleasure and learning experience and this paper is just the beginning of a long term collaboration," said Singh. In the paper, the investigators reported that variation in residual stress across a cross section of laser clad steel, predicted by their metallo-thermomechanical model, demonstrated the existence of a critical deposition height. The critical height of deposition corresponds to the layer thickness, which, when deposited, would maximise beneficial compressive residual stresses in the deposited layer and substrate. Deposition that is lower than the critical height would produce detrimental tensile residual stresses at the interface while deposition that is higher than the critical height would result in excessive dilution. The research also found that at the critical height of deposition, the solidification rate was at a minimum. The Kowari residual stress diffractometer was used to measure macroscale residual stresses in a sample of H13 steel that was laser cladded with crucible particle metallurgy steel powders with a high vanadium content. The three-dimensional measurements of residual stresses on Kowari are highly accurate and non-destructive. "A model is only as good as its validation. Using strain scanning instrument—Kowari we were able to identify triaxial residual stresses in the deposited layers, which verified the locations predicted by the model ," said Research Scientist and Industrial Liaison Manager Dr. Anna Paradowska, who is a co-author of the paper with Dr. Mark Reid. Laser cladding, which involves depositing molten metal on a relatively cold substrate of steel, creates a complex residual stress profile. Theoretical models based on thermomechanical properties, which are commonly used, were shown to overestimate tensile residual stresses and underestimates compressive residual stresses in the substrate and interface. The team used surface X-ray diffraction at the Indian Institute of Technology for measurements of residual stresses in one direction. However it was important to have an independent fully non-destructive bulk measurements to also validate the in-house measurements procedure. Both diffraction techniques showed the presence of tensile residual stresses near the melt front and compressive stresses in the deposited layer and interface regions. "Understanding the stresses and being able to predict them is very important for additive manufacturing industry. Validated model is very beneficial as further optimalisation of the manufacturing process using this model will be cost effective and saves time," said Paradowska. "The model allows you to calculate the laser position rate to achieve a specific height of deposition while minimising the effect of detrimental stresses and maximise the beneficial compressive stresses." The study authors suggested demonstrated a science-enable technology solution that could lead to an improvement in the quality, safety and economics of components manufactured with laser additive processes. <|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 observational fear (OF) paradigm in rodents, in which the subject is exposed to a distressed conspecific, elicits contextual fear learning and enhances future passive avoidance learning, which may model certain behavioral traits resulting from traumatic experiences in humans. As these behaviors affected by the OF require dorso-medial prefrontal cortex (dmPFC), we searched for synaptic adaptations in dmPFC resulting from OF in mice by recording synaptic responses in dmPFC layer V pyramidal neurons elicited by repeated 5 Hz electrical stimulation of dmPFC layer I or by optogenetic stimulation of specific interneurons ex vivo 1 day after OF. OF increased depression of inhibitory postsynaptic currents (IPSCs) along IPSC trains evoked by the 5 Hz electrical stimulation, but, surprisingly, decreased depression of dendritic IPSCs isolated after blocking GABAa receptor on the soma. Subsequent optogenetic analyses revealed increased depression of IPSCs originating from perisomatically projecting parvalbumin interneurons (PV-IPSCs), but decreased depression of IPSCs from dendritically projecting somatostatin cells (SOM-IPSCs). These changes were no longer detectable in the presence of a GABAb receptor antagonist CGP52432. Meanwhile, OF decreased the sensitivity of SOM-IPSCs, but not PV-IPSCs to a GABAb receptor agonist baclofen. Thus, OF causes opposing changes in GABAb receptor mediated suppression of GABA release from PV-positive and SOM-positive interneurons. Such adaptations may alter dmPFC connectivity with brain areas that target its deep vs superficial layers and thereby contribute to the behavioral consequences of the aversive experiences. Introduction Traumatic experiences, even those without physical pain, are a risk factor for mental disorders ( Cougle et al, 2009 ; Resnick et al, 1995 ), but how they alter relevant neuronal circuits remains unknown. The observational fear (OF) paradigm in rodent models certain components of socially induced trauma without physical pain or physical discomfort. The subject observer animal is exposed once to a conspecific demonstrator receiving electrical footshocks and emitting distress signals via multiple modalities. The distress signals act as an unconditional stimulus and lead to memorization of the associated cues and context ( Chen et al, 2009 ; Jeon et al, 2010 ; Yusufishaq and Rosenkranz, 2013 ). We have recently shown that OF also enhances future learning in the passive avoidance (PA) task and causes the formation of silent synapses in the input from the dorso-medial prefrontal cortex (dmPFC) to the basolateral amygdala ( Ito et al, 2015 ). As dmPFC is involved in Pavlovian conditioning ( Malin et al, 2007 ; Malin and McGaugh, 2006 ) and undergoes synaptic remodeling during contextual fear learning ( Bero et al, 2014 ), we hypothesized that OF also elicits plastic changes within dmPFC, which could potentially underlie the fear learning during OF, or the stronger PA learning in the future. We searched for changes at synapses that target pyramidal cells (PCs) in dmPFC layer V. These cells belong to dmPFC major output neurons. They innervate multiple targets including the cortex, amygdala, striatum, thalamus, brainstem nuclei and spinal cord ( Gabbott et al, 2005 ; Hirai et al, 2012 ; Shepherd, 2013 ). As their apical dendrites extend towards the superficial layer of dmPFC, the layer V PC are positioned to integrate information from all cortical layers by receiving inputs from local neurons and remote projections from all over the brain ( Ramaswamy and Markram, 2015 ). Our analysis suggests that OF redistributes flow of that information by reorganizing inhibitory control of inputs to the layer V neurons by two types of interneurons that are distinguished by expression of parvalbumin (PV) and somatostatin (SOM). Materials and methods Animals C57BL/6N males were crossed with 129SvEv females to obtain wild-type mice or with homozygous 129SvEv interneuron-specific Cre-driver females for interneuron-specific expression of ChR2. Male pups were housed two littermates per cage (Allentown, NJ) since weaning as detailed in Ito et al (2015) . All experiments were approved by Virginia Tech IACUC and followed the NIH Guide for the Care and Use of Laboratory Animals. Viral Injection Surgery ChR2-AAV pseudo-type 1 virus containing Cre-activated ChR2 gene was prepared by the University of North Carolina Gene Therapy Vector Core (Chapel Hill, NC) using a plasmid pAAV- EF1a -double floxed- hChR2 (H134R)-EYFP (Addgene 20298). Heterozygous male Pvalb tm1(cre)Arbr ( Hippenmeyer et al, 2005 ) or Sst tm2.1(cre)Zjh ( Taniguchi et al, 2011 ) transgenic mice were injected bilaterally with 0.5 μl of the viral solution (10 8 viral particles) per hemisphere in dmPFC at 1.3 mm anterior, 0.4 mm lateral from the bregma, and 1.3 mm ventral from brain surface, as described ( Ito et al, 2015 ). Previous studies have demonstrated specific expression of ChR2 in SOM-INs and PV interneurons (PV-INs) of dmPFC using these lines and AAV vector ( Kim et al, 2016 ; Sohal et al, 2009 ). Behavior OF procedure ( Jeon et al, 2010 ) was performed at age of p60–75 during light phase of the day cycle in a fear conditioning chamber (Med Associates, St Albans, VT), divided into two unequal compartments by a transparent Plexiglas wall with 7 mm diameter holes, spaced at 2 cm interval, to allow auditory and olfactory cues and whisker-to-whisker interaction. In the larger 26 × 20 × 26 cm (depth, width, height) compartment, a stainless-steel rod floor was covered with a white plastic sheet. In the smaller 26 × 9 × 26 cm compartment, the rod floor was exposed. Cagemates observer and demonstrator were placed in the larger and the smaller compartments, respectively. After 5 min acclimation, 24 footshocks (1 mA, 2 s, every 10 s) were delivered to the demonstrator. In the control procedure, demonstrators did not receive footshocks. The observers (OF or controls) were returned to the home cage and housed alone until preparation of brain slices for physiology on the next day. Electrophysiology Next day after OF training, under deep isoflurane anesthesia, animals were decapitated. Brains were immersed in an ice-cooled cutting solution containing (in mM) 110 Choline Cl, 2.5 KCl, 1.2 NaH 2 PO 4 , 2.5 NaHCO 3 , 20 glucose, 0.5 CaCl 2 , and 5 MgSO 4 , and bubbled with a 95%", "role": "user" }, { "content": "Scientists at the Virginia Tech Carilion Research Institute have discovered that observing fear in others may change how information flows in the brain. The results of their study were scheduled for advance online publication today (Jan. 4, 2017) in Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology. \"Negative emotional experience leaves a trace in the brain, which makes us more vulnerable,\" said Alexei Morozov, an assistant professor at the Virginia Tech Carilion Research Institute and lead author of the study. \"Traumatic experiences, even those without physical pain, are a risk factor for mental disorders.\" Post-traumatic stress disorder, also called PTSD, is an anxiety disorder that can develop in some people after they experience a shocking, scary, or dangerous event, according to the National Institute of Mental Health. Most people who live through dangerous events do not develop the disorder, but about 7 or 8 out of every 100 people will experience post-traumatic stress disorder at some point in their lives, according to the U.S. Department of Veterans Affairs' National Center for PTSD. \"PTSD doesn't stop at direct victims of illness, injury, or a terrorist attack; it can also affect their loved ones, caregivers, even bystanders - the people who witness or learn about others' suffering,\" said Morozov, who is also a faculty member in the Department of Biomedical Engineering and Mechanics in Virginia Tech's College of Engineering. He also noted that while a traumatic event may not immediately lead to the disorder, it increases odds of developing the disorder. \"There's evidence that children who watched media coverage of the Sept. 11 terrorist attacks are more likely to develop PTSD later in life when subjected to another adverse event,\" Morozov said. According to a 2008 RAND Corp. assessment of multiple studies of post-traumatic stress and depression in previously deployed service members, people who heard about a serious incident—such as a gunfire exchange— were just as likely to develop post-traumatic stress disorder as the people who actually lived through the incident. In previous studies, Morozov with Wataru Ito, a research assistant professor at the Virginia Tech Carilion Research Institute, found that rodents who witnessed stress in their counterparts but did not experience it firsthand formed stronger than normal memories of their own fear experiences—a behavioral trait relevant to some humans who experience traumatic stress. Based on these findings, the researchers investigated whether the part of the brain responsible for empathizing and understanding the mental state of others, called the prefrontal cortex, physically changes after witnessing fear in another. Lei Liu, a postdoctoral researcher in the lab, measured transmission through inhibitory synapses that regulate strength of the signals arriving in the prefrontal cortex from other parts of the brain in mice who had witnessed a stressful event in another mouse. \"Liu's measures suggest that observational fear physically redistributes the flow of information,\" Morozov said. \"And this redistribution is achieved by stress, not just observed, but communicated through social cues, such as body language, sound, and smell.\" According to Morozov, this shift may potentially enable more communications via the synapses in the deep cellular layers of the cerebral cortex, but less so in the superficial ones. It's not yet clear exactly how the circuits have altered, only that they have indeed changed. \"That's the next step,\" Morozov said. \"Once we understand the mechanism of this change in the brain in the person who has these experiences, we could potentially know how something like post-traumatic stress disorder is caused.\" ", "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 observational fear (OF) paradigm in rodents, in which the subject is exposed to a distressed conspecific, elicits contextual fear learning and enhances future passive avoidance learning, which may model certain behavioral traits resulting from traumatic experiences in humans. As these behaviors affected by the OF require dorso-medial prefrontal cortex (dmPFC), we searched for synaptic adaptations in dmPFC resulting from OF in mice by recording synaptic responses in dmPFC layer V pyramidal neurons elicited by repeated 5 Hz electrical stimulation of dmPFC layer I or by optogenetic stimulation of specific interneurons ex vivo 1 day after OF. OF increased depression of inhibitory postsynaptic currents (IPSCs) along IPSC trains evoked by the 5 Hz electrical stimulation, but, surprisingly, decreased depression of dendritic IPSCs isolated after blocking GABAa receptor on the soma. Subsequent optogenetic analyses revealed increased depression of IPSCs originating from perisomatically projecting parvalbumin interneurons (PV-IPSCs), but decreased depression of IPSCs from dendritically projecting somatostatin cells (SOM-IPSCs). These changes were no longer detectable in the presence of a GABAb receptor antagonist CGP52432. Meanwhile, OF decreased the sensitivity of SOM-IPSCs, but not PV-IPSCs to a GABAb receptor agonist baclofen. Thus, OF causes opposing changes in GABAb receptor mediated suppression of GABA release from PV-positive and SOM-positive interneurons. Such adaptations may alter dmPFC connectivity with brain areas that target its deep vs superficial layers and thereby contribute to the behavioral consequences of the aversive experiences. Introduction Traumatic experiences, even those without physical pain, are a risk factor for mental disorders ( Cougle et al, 2009 ; Resnick et al, 1995 ), but how they alter relevant neuronal circuits remains unknown. The observational fear (OF) paradigm in rodent models certain components of socially induced trauma without physical pain or physical discomfort. The subject observer animal is exposed once to a conspecific demonstrator receiving electrical footshocks and emitting distress signals via multiple modalities. The distress signals act as an unconditional stimulus and lead to memorization of the associated cues and context ( Chen et al, 2009 ; Jeon et al, 2010 ; Yusufishaq and Rosenkranz, 2013 ). We have recently shown that OF also enhances future learning in the passive avoidance (PA) task and causes the formation of silent synapses in the input from the dorso-medial prefrontal cortex (dmPFC) to the basolateral amygdala ( Ito et al, 2015 ). As dmPFC is involved in Pavlovian conditioning ( Malin et al, 2007 ; Malin and McGaugh, 2006 ) and undergoes synaptic remodeling during contextual fear learning ( Bero et al, 2014 ), we hypothesized that OF also elicits plastic changes within dmPFC, which could potentially underlie the fear learning during OF, or the stronger PA learning in the future. We searched for changes at synapses that target pyramidal cells (PCs) in dmPFC layer V. These cells belong to dmPFC major output neurons. They innervate multiple targets including the cortex, amygdala, striatum, thalamus, brainstem nuclei and spinal cord ( Gabbott et al, 2005 ; Hirai et al, 2012 ; Shepherd, 2013 ). As their apical dendrites extend towards the superficial layer of dmPFC, the layer V PC are positioned to integrate information from all cortical layers by receiving inputs from local neurons and remote projections from all over the brain ( Ramaswamy and Markram, 2015 ). Our analysis suggests that OF redistributes flow of that information by reorganizing inhibitory control of inputs to the layer V neurons by two types of interneurons that are distinguished by expression of parvalbumin (PV) and somatostatin (SOM). Materials and methods Animals C57BL/6N males were crossed with 129SvEv females to obtain wild-type mice or with homozygous 129SvEv interneuron-specific Cre-driver females for interneuron-specific expression of ChR2. Male pups were housed two littermates per cage (Allentown, NJ) since weaning as detailed in Ito et al (2015) . All experiments were approved by Virginia Tech IACUC and followed the NIH Guide for the Care and Use of Laboratory Animals. Viral Injection Surgery ChR2-AAV pseudo-type 1 virus containing Cre-activated ChR2 gene was prepared by the University of North Carolina Gene Therapy Vector Core (Chapel Hill, NC) using a plasmid pAAV- EF1a -double floxed- hChR2 (H134R)-EYFP (Addgene 20298). Heterozygous male Pvalb tm1(cre)Arbr ( Hippenmeyer et al, 2005 ) or Sst tm2.1(cre)Zjh ( Taniguchi et al, 2011 ) transgenic mice were injected bilaterally with 0.5 μl of the viral solution (10 8 viral particles) per hemisphere in dmPFC at 1.3 mm anterior, 0.4 mm lateral from the bregma, and 1.3 mm ventral from brain surface, as described ( Ito et al, 2015 ). Previous studies have demonstrated specific expression of ChR2 in SOM-INs and PV interneurons (PV-INs) of dmPFC using these lines and AAV vector ( Kim et al, 2016 ; Sohal et al, 2009 ). Behavior OF procedure ( Jeon et al, 2010 ) was performed at age of p60–75 during light phase of the day cycle in a fear conditioning chamber (Med Associates, St Albans, VT), divided into two unequal compartments by a transparent Plexiglas wall with 7 mm diameter holes, spaced at 2 cm interval, to allow auditory and olfactory cues and whisker-to-whisker interaction. In the larger 26 × 20 × 26 cm (depth, width, height) compartment, a stainless-steel rod floor was covered with a white plastic sheet. In the smaller 26 × 9 × 26 cm compartment, the rod floor was exposed. Cagemates observer and demonstrator were placed in the larger and the smaller compartments, respectively. After 5 min acclimation, 24 footshocks (1 mA, 2 s, every 10 s) were delivered to the demonstrator. In the control procedure, demonstrators did not receive footshocks. The observers (OF or controls) were returned to the home cage and housed alone until preparation of brain slices for physiology on the next day. Electrophysiology Next day after OF training, under deep isoflurane anesthesia, animals were decapitated. Brains were immersed in an ice-cooled cutting solution containing (in mM) 110 Choline Cl, 2.5 KCl, 1.2 NaH 2 PO 4 , 2.5 NaHCO 3 , 20 glucose, 0.5 CaCl 2 , and 5 MgSO 4 , and bubbled with a 95%<|im_end|> <|im_start|>assistant Scientists at the Virginia Tech Carilion Research Institute have discovered that observing fear in others may change how information flows in the brain. The results of their study were scheduled for advance online publication today (Jan. 4, 2017) in Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology. "Negative emotional experience leaves a trace in the brain, which makes us more vulnerable," said Alexei Morozov, an assistant professor at the Virginia Tech Carilion Research Institute and lead author of the study. "Traumatic experiences, even those without physical pain, are a risk factor for mental disorders." Post-traumatic stress disorder, also called PTSD, is an anxiety disorder that can develop in some people after they experience a shocking, scary, or dangerous event, according to the National Institute of Mental Health. Most people who live through dangerous events do not develop the disorder, but about 7 or 8 out of every 100 people will experience post-traumatic stress disorder at some point in their lives, according to the U.S. Department of Veterans Affairs' National Center for PTSD. "PTSD doesn't stop at direct victims of illness, injury, or a terrorist attack; it can also affect their loved ones, caregivers, even bystanders - the people who witness or learn about others' suffering," said Morozov, who is also a faculty member in the Department of Biomedical Engineering and Mechanics in Virginia Tech's College of Engineering. He also noted that while a traumatic event may not immediately lead to the disorder, it increases odds of developing the disorder. "There's evidence that children who watched media coverage of the Sept. 11 terrorist attacks are more likely to develop PTSD later in life when subjected to another adverse event," Morozov said. According to a 2008 RAND Corp. assessment of multiple studies of post-traumatic stress and depression in previously deployed service members, people who heard about a serious incident—such as a gunfire exchange— were just as likely to develop post-traumatic stress disorder as the people who actually lived through the incident. In previous studies, Morozov with Wataru Ito, a research assistant professor at the Virginia Tech Carilion Research Institute, found that rodents who witnessed stress in their counterparts but did not experience it firsthand formed stronger than normal memories of their own fear experiences—a behavioral trait relevant to some humans who experience traumatic stress. Based on these findings, the researchers investigated whether the part of the brain responsible for empathizing and understanding the mental state of others, called the prefrontal cortex, physically changes after witnessing fear in another. Lei Liu, a postdoctoral researcher in the lab, measured transmission through inhibitory synapses that regulate strength of the signals arriving in the prefrontal cortex from other parts of the brain in mice who had witnessed a stressful event in another mouse. "Liu's measures suggest that observational fear physically redistributes the flow of information," Morozov said. "And this redistribution is achieved by stress, not just observed, but communicated through social cues, such as body language, sound, and smell." According to Morozov, this shift may potentially enable more communications via the synapses in the deep cellular layers of the cerebral cortex, but less so in the superficial ones. It's not yet clear exactly how the circuits have altered, only that they have indeed changed. "That's the next step," Morozov said. "Once we understand the mechanism of this change in the brain in the person who has these experiences, we could potentially know how something like post-traumatic stress disorder is caused." <|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 Cretaceous breakup of Gondwana strongly modified the global distribution of shallow tropical seas reshaping the geographic configuration of marine basins. However, the links between tropical reef availability, plate tectonic processes and marine biodiversity distribution patterns are still unknown. Here, we show that a spatial diversification model constrained by absolute plate motions for the past 140 million years predicts the emergence and movement of diversity hotspots on tropical reefs. The spatial dynamics of tropical reefs explains marine fauna diversification in the Tethyan Ocean during the Cretaceous and early Cenozoic, and identifies an eastward movement of ancestral marine lineages towards the Indo-Australian Archipelago in the Miocene. A mechanistic model based only on habitat-driven diversification and dispersal yields realistic predictions of current biodiversity patterns for both corals and fishes. As in terrestrial systems, we demonstrate that plate tectonics played a major role in driving tropical marine shallow reef biodiversity dynamics. Introduction Tropical shallow reefs support the world’s greatest diversity of marine organisms 1 and have experienced a long history of climate-driven habitat change 2 , 3 . Sea level and temperature fluctuations during the Quaternary have strongly shaped the distribution of coral reefs and their associated fish faunas 3 . Nevertheless, most of the diversification of tropical marine faunas predates the Quaternary 4 , arguing for a major role of older historical events 2 , 4 , 5 . Because plate tectonics modulate the distribution of seafloors through continental movement and collision over geological timescales 6 , they are potentially one of the main determinants of tropical marine biodiversity 2 , 5 . The fossil record indicates that the location of the major marine biodiversity hotspot has moved across the globe during the last 50 million years 2 , transitioning from the western Tethys during the Eocene (55–33 Ma), to the Arabian Peninsula and Western Indian Ocean during the Late Eocene and Oligocene (37–15 Ma), and finally to the Indo-Australian Archipelago (IAA) in the Miocene (15–5 Ma). This movement was primarily driven by successive closure of the Tethys followed by the collision of the Arabian and Indian plates with Eurasia. Yet, the role of plate tectonics in shaping diversification and dispersal processes of tropical marine biodiversity still remains elusive. Correlative approaches have had limited success in disentangling alternative hypotheses and mechanistic models may provide a clearer understanding of the processes shaping marine biogeographic patterns 7 , 8 . We coupled a mechanistic model of species diversification to a model of synthetic paleobathymetry estimates for the past 140 Myr. The gridded paleobathymetry model is based on global ocean paleo-age grids 6 merged with paleocoastline distributions for continental areas 9 . The model outlines the absolute position of continents over time and the associated distribution and residence time of shallow epicontinental seas. Using a novel dynamic model that simulates clade dispersal, speciation and extinction from a single ancestral species, bounded by a temporal sequence of habitat availability, we show that plate motions predict the emergence and movement of diversity hotspots on tropical reefs. Incipient species emerge within (that is, sympatric) or adjacent (that is, parapatric) to the geographical range of its ancestor 10 , 11 and disperse at a distance d during each time step. Parapatric speciation arises when a species range is split into one or more distinct areas separated by a distance d s , while sympatric speciation arises within a cell with a probability P s . Consistent with the speciation-area hypothesis 12 , species occupying a large area show higher sympatric speciation frequency S=P s × A . Regardless of the speciation mode, the models predict the emergence and movement from the western Tethys towards the IAA. The diversification model assumes that speciation and extinction are modulated exclusively by variations in habitat size and spatial distribution. The model is based on strict niche conservatism, but provides a realistic picture of the historical dynamic of marine reef fauna. Results and Discussion Hopping biodiversity hotspots We show that the spatial distribution of tropical reef habitats over time ( Fig. 1 ; Supplementary Fig. 1 ) explains the emergence and movement of coral reef biodiversity hotspots since the Cretaceous with both parapatric ( Supplementary Fig. 2 ) and sympatric ( Supplementary Fig. 3 ) speciation modes ( Fig. 2 ; Supplementary Fig. 4 ). The parapatric model ( d= 4, d s =5) provided better estimates of fossil biodiversity in the Eocene (40 Ma, R 2 =0.26) and the Miocene (20 Ma, R 2 =0.38) than the sympatric model ( d =5, P s =6e−5, 40 Ma: R 2 =0.12; 20 Ma: R 2 =0.13). The paleobathymetry model suggests that the Tethys contained extensive but disjointed reef habitats promoting both modes of speciation ( Supplementary Fig. 5 ), but the biodiversity peak in the Western Tethys is most consistent with parapatric speciation fuelled by waves of disconnection and reconnection of isolated reef regions ( Supplementary Fig. 6 ). The highly dynamic and complex tectonics of the Western Tethys 13 provided fertile ground for parapatric speciation. Modelled diversification, computed as speciation minus extinction rates, peaked at 85 Ma ( Supplementary Figs 7 and 8 ) when fragmentation was highest, underpinning the biodiversity hotspot in Western Tethys ( Supplementary Fig. 5 ). During the mid/late Eocene–Oligocene times, the closure of the Tethys was associated with a narrowing coastal corridor 14 , that allowed Tethyan biodiversity to move eastward ( Fig. 2 ), supporting the hypothesis of faunal migration into the IAA 2 , 15 . Since high faunal turnover is expected at the transition across the Cretaceous–Paleogene (K/Pg) 16 , 17 , which is not considered in our habitat reconstructions, a sensitivity analyses demonstrated the robustness of this dynamic to a high degree of forced extinction at 66 Ma (80%, Supplementary Fig. 9 ). In addition, our results showed robustness in regards to the choice of plate kinematic model used to reconstruct plate positions ( Supplementary Fig. 10 ). Together, these results indicate that the Tethys was a major diversification and emigration hotspot explaining", "role": "user" }, { "content": "Nowhere today is the biodiversity of corals and reef-inhabiting fish higher than in the tropical waters around Indonesia and its neighbouring countries in Southeast Asia. \"To understand the reason for this diversity, you have to look back 100 million years - to a time when present-day South America and Africa still formed a common supercontinent and today's India was an island in the Earth's southern hemisphere,\" says Loïc Pellissier, Professor of Landscape Ecology at ETH Zurich and the Swiss Federal Institute for Forest, Snow and Landscape Research WSL and, up until ten months ago, Lecturer at the University of Fribourg. For the first time ever, an international research team under his direction studied the geographical pattern by which new species of corals and reef fish evolved over the millions of years of evolutionary history using a computer model. The scientists were able to show that the drift of the continental plates was the likely driving force behind the emergence of new species. Combination of different models To arrive at this conclusion, the researchers combined different simulations and data. These included a simulation of geological changes to the seafloor during Earth history as well as information on the earlier expansion of the tropics based on fossil finds of tropical coral species. Thus, the scientists were able to create a dynamic spatial model that indicates where throughout the course of history shallow and warm waters were located, in which corals and other tropical organisms found a habitat. Into this model, they integrated a well-known evolution mechanism in which two new species are formed out of an existing one. By way of illustration, take any fish species that lived in a tropical reef ecosystem 100 million years ago. If its home reef is divided into two separate reefs due to plate tectonics, for example, the two populations in each patch would continue to evolve independently and eventually, over the following hundreds of thousands of years, become two distinct species. Hotspot in the prehistoric ocean Such a fragmentation of tropical reef habitats actually took place, as Pellissier and his colleagues showed in their model calculations. Their simulation begins 140 million years ago, when present-day South America, Africa, India and Australia together formed the supercontinent Gondwana. A huge, contiguous body of shallow water ran along its equatorial coasts. In the millions of years to follow, the supercontinent broke up; there were massive continental drifts and fragmentation of the tropical reefs. A particularly strong fragmentation took place about 50 to 60 million years ago, as Fabien Leprieur, Professor at the University of Montpellier and the study's first author, explains: \"At that time in the western part of Tethys, the prehistoric ocean between Africa and Eurasia, there was a complex seafloor structure with many disconnected reefs - a bona fide patchwork.\" The plate tectonic processes at that time separated and merged these waters. It was an extremely dynamic system that strongly favoured the emergence of new species. It was known from fossil finds that the Western Tethys region was a hotspot of species development back then. Fossil finds have also shown that this hotspot has shifted in the past 60 million years, from the Tethys to today's Southeast Asia. \"Now, for the first time, our models provide an explanation for this movement,\" says Pellissier. \"Because of the plate tectonic processes, new habitats emerged in different locations over the course of millions of years, while others merged or disappeared. These dynamic structures encouraged the relocation of the focal point of species diversity,\" says the landscape ecology professor. Unification of Australian and Asian fauna However, today's biodiversity in Southeast Asia cannot be explained solely by this relocation; rather, this was the region where, around 15 million years ago, the marine fauna of Tethys came together with that of Australia. This encounter was also the result of continental drift, in this case the shifting of the Australian continental plate in the direction of the equator, as Pellissier and his colleagues illustrate. \"It was already known that this Australasian encounter took place with terrestrial animals and plants. We've now shown that it happened with tropical marine life too.\" Coral reef ecosystems, which are the focus of this study, are sensitive to changes in temperature and are in danger worldwide due to global warming: the Great Barrier Reef in Australia is currently experiencing the largest coral bleaching in its history. Pellissier says: \"In this context, it's important to understand that today's reef ecosystems have a very long history. It took 100 million years to build this extraordinarily large biodiversity, but it might take less than 100 years to destroy it.\" ", "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 Cretaceous breakup of Gondwana strongly modified the global distribution of shallow tropical seas reshaping the geographic configuration of marine basins. However, the links between tropical reef availability, plate tectonic processes and marine biodiversity distribution patterns are still unknown. Here, we show that a spatial diversification model constrained by absolute plate motions for the past 140 million years predicts the emergence and movement of diversity hotspots on tropical reefs. The spatial dynamics of tropical reefs explains marine fauna diversification in the Tethyan Ocean during the Cretaceous and early Cenozoic, and identifies an eastward movement of ancestral marine lineages towards the Indo-Australian Archipelago in the Miocene. A mechanistic model based only on habitat-driven diversification and dispersal yields realistic predictions of current biodiversity patterns for both corals and fishes. As in terrestrial systems, we demonstrate that plate tectonics played a major role in driving tropical marine shallow reef biodiversity dynamics. Introduction Tropical shallow reefs support the world’s greatest diversity of marine organisms 1 and have experienced a long history of climate-driven habitat change 2 , 3 . Sea level and temperature fluctuations during the Quaternary have strongly shaped the distribution of coral reefs and their associated fish faunas 3 . Nevertheless, most of the diversification of tropical marine faunas predates the Quaternary 4 , arguing for a major role of older historical events 2 , 4 , 5 . Because plate tectonics modulate the distribution of seafloors through continental movement and collision over geological timescales 6 , they are potentially one of the main determinants of tropical marine biodiversity 2 , 5 . The fossil record indicates that the location of the major marine biodiversity hotspot has moved across the globe during the last 50 million years 2 , transitioning from the western Tethys during the Eocene (55–33 Ma), to the Arabian Peninsula and Western Indian Ocean during the Late Eocene and Oligocene (37–15 Ma), and finally to the Indo-Australian Archipelago (IAA) in the Miocene (15–5 Ma). This movement was primarily driven by successive closure of the Tethys followed by the collision of the Arabian and Indian plates with Eurasia. Yet, the role of plate tectonics in shaping diversification and dispersal processes of tropical marine biodiversity still remains elusive. Correlative approaches have had limited success in disentangling alternative hypotheses and mechanistic models may provide a clearer understanding of the processes shaping marine biogeographic patterns 7 , 8 . We coupled a mechanistic model of species diversification to a model of synthetic paleobathymetry estimates for the past 140 Myr. The gridded paleobathymetry model is based on global ocean paleo-age grids 6 merged with paleocoastline distributions for continental areas 9 . The model outlines the absolute position of continents over time and the associated distribution and residence time of shallow epicontinental seas. Using a novel dynamic model that simulates clade dispersal, speciation and extinction from a single ancestral species, bounded by a temporal sequence of habitat availability, we show that plate motions predict the emergence and movement of diversity hotspots on tropical reefs. Incipient species emerge within (that is, sympatric) or adjacent (that is, parapatric) to the geographical range of its ancestor 10 , 11 and disperse at a distance d during each time step. Parapatric speciation arises when a species range is split into one or more distinct areas separated by a distance d s , while sympatric speciation arises within a cell with a probability P s . Consistent with the speciation-area hypothesis 12 , species occupying a large area show higher sympatric speciation frequency S=P s × A . Regardless of the speciation mode, the models predict the emergence and movement from the western Tethys towards the IAA. The diversification model assumes that speciation and extinction are modulated exclusively by variations in habitat size and spatial distribution. The model is based on strict niche conservatism, but provides a realistic picture of the historical dynamic of marine reef fauna. Results and Discussion Hopping biodiversity hotspots We show that the spatial distribution of tropical reef habitats over time ( Fig. 1 ; Supplementary Fig. 1 ) explains the emergence and movement of coral reef biodiversity hotspots since the Cretaceous with both parapatric ( Supplementary Fig. 2 ) and sympatric ( Supplementary Fig. 3 ) speciation modes ( Fig. 2 ; Supplementary Fig. 4 ). The parapatric model ( d= 4, d s =5) provided better estimates of fossil biodiversity in the Eocene (40 Ma, R 2 =0.26) and the Miocene (20 Ma, R 2 =0.38) than the sympatric model ( d =5, P s =6e−5, 40 Ma: R 2 =0.12; 20 Ma: R 2 =0.13). The paleobathymetry model suggests that the Tethys contained extensive but disjointed reef habitats promoting both modes of speciation ( Supplementary Fig. 5 ), but the biodiversity peak in the Western Tethys is most consistent with parapatric speciation fuelled by waves of disconnection and reconnection of isolated reef regions ( Supplementary Fig. 6 ). The highly dynamic and complex tectonics of the Western Tethys 13 provided fertile ground for parapatric speciation. Modelled diversification, computed as speciation minus extinction rates, peaked at 85 Ma ( Supplementary Figs 7 and 8 ) when fragmentation was highest, underpinning the biodiversity hotspot in Western Tethys ( Supplementary Fig. 5 ). During the mid/late Eocene–Oligocene times, the closure of the Tethys was associated with a narrowing coastal corridor 14 , that allowed Tethyan biodiversity to move eastward ( Fig. 2 ), supporting the hypothesis of faunal migration into the IAA 2 , 15 . Since high faunal turnover is expected at the transition across the Cretaceous–Paleogene (K/Pg) 16 , 17 , which is not considered in our habitat reconstructions, a sensitivity analyses demonstrated the robustness of this dynamic to a high degree of forced extinction at 66 Ma (80%, Supplementary Fig. 9 ). In addition, our results showed robustness in regards to the choice of plate kinematic model used to reconstruct plate positions ( Supplementary Fig. 10 ). Together, these results indicate that the Tethys was a major diversification and emigration hotspot explaining<|im_end|> <|im_start|>assistant Nowhere today is the biodiversity of corals and reef-inhabiting fish higher than in the tropical waters around Indonesia and its neighbouring countries in Southeast Asia. "To understand the reason for this diversity, you have to look back 100 million years - to a time when present-day South America and Africa still formed a common supercontinent and today's India was an island in the Earth's southern hemisphere," says Loïc Pellissier, Professor of Landscape Ecology at ETH Zurich and the Swiss Federal Institute for Forest, Snow and Landscape Research WSL and, up until ten months ago, Lecturer at the University of Fribourg. For the first time ever, an international research team under his direction studied the geographical pattern by which new species of corals and reef fish evolved over the millions of years of evolutionary history using a computer model. The scientists were able to show that the drift of the continental plates was the likely driving force behind the emergence of new species. Combination of different models To arrive at this conclusion, the researchers combined different simulations and data. These included a simulation of geological changes to the seafloor during Earth history as well as information on the earlier expansion of the tropics based on fossil finds of tropical coral species. Thus, the scientists were able to create a dynamic spatial model that indicates where throughout the course of history shallow and warm waters were located, in which corals and other tropical organisms found a habitat. Into this model, they integrated a well-known evolution mechanism in which two new species are formed out of an existing one. By way of illustration, take any fish species that lived in a tropical reef ecosystem 100 million years ago. If its home reef is divided into two separate reefs due to plate tectonics, for example, the two populations in each patch would continue to evolve independently and eventually, over the following hundreds of thousands of years, become two distinct species. Hotspot in the prehistoric ocean Such a fragmentation of tropical reef habitats actually took place, as Pellissier and his colleagues showed in their model calculations. Their simulation begins 140 million years ago, when present-day South America, Africa, India and Australia together formed the supercontinent Gondwana. A huge, contiguous body of shallow water ran along its equatorial coasts. In the millions of years to follow, the supercontinent broke up; there were massive continental drifts and fragmentation of the tropical reefs. A particularly strong fragmentation took place about 50 to 60 million years ago, as Fabien Leprieur, Professor at the University of Montpellier and the study's first author, explains: "At that time in the western part of Tethys, the prehistoric ocean between Africa and Eurasia, there was a complex seafloor structure with many disconnected reefs - a bona fide patchwork." The plate tectonic processes at that time separated and merged these waters. It was an extremely dynamic system that strongly favoured the emergence of new species. It was known from fossil finds that the Western Tethys region was a hotspot of species development back then. Fossil finds have also shown that this hotspot has shifted in the past 60 million years, from the Tethys to today's Southeast Asia. "Now, for the first time, our models provide an explanation for this movement," says Pellissier. "Because of the plate tectonic processes, new habitats emerged in different locations over the course of millions of years, while others merged or disappeared. These dynamic structures encouraged the relocation of the focal point of species diversity," says the landscape ecology professor. Unification of Australian and Asian fauna However, today's biodiversity in Southeast Asia cannot be explained solely by this relocation; rather, this was the region where, around 15 million years ago, the marine fauna of Tethys came together with that of Australia. This encounter was also the result of continental drift, in this case the shifting of the Australian continental plate in the direction of the equator, as Pellissier and his colleagues illustrate. "It was already known that this Australasian encounter took place with terrestrial animals and plants. We've now shown that it happened with tropical marine life too." Coral reef ecosystems, which are the focus of this study, are sensitive to changes in temperature and are in danger worldwide due to global warming: the Great Barrier Reef in Australia is currently experiencing the largest coral bleaching in its history. Pellissier says: "In this context, it's important to understand that today's reef ecosystems have a very long history. It took 100 million years to build this extraordinarily large biodiversity, but it might take less than 100 years to destroy it." <|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 Neonicotinoid pesticides have been linked to global declines of beneficial insects such as bumblebees. Exposure to trace levels of these chemicals causes sub-lethal effects, such as reduced learning and foraging efficiency. Complex behaviours may be particularly vulnerable to the neurotoxic effects of neonicotinoids. Such behaviours may include buzz pollination (sonication), in which pollinators, usually bees, use innate and learned behaviours to generate high-frequency vibrations to release pollen from flowers with specialised anther morphologies. This study assesses the effect of field-realistic, chronic exposure to the widely-used neonicotinoid thiamethoxam on the development of sonication buzz characteristics over time, as well as the collection of pollen from buzz-pollinated flowers. We found that the pollen collection of exposed bees improved less with increasing experience than that of unexposed bees, with exposed bees collecting between 47% and 56% less pollen by the end of 10 trials. We also found evidence of two distinct strategies for maximising pollen collection: (1) extensions to the duration of individual buzzes and (2) extensions of the overall time spent buzzing. We find new complexities in buzz pollination, and conclude that the impacts of field-realistic exposure to a neonicotinoid pesticide may seriously compromise this important ecosystem service. Introduction Understanding the interactions between plants and their insect pollinators is of great practical and political relevance, being vital to efforts to ensure food security under rapid global change 1 . Increased production is often achieved through the deployment of pesticides but this can compromise sustainability by impacting beneficial insect pollinators. This conflict is exemplified by the controversy over neonicotinoid insecticides 2 , 3 . Neonicotinoids have become the most widely used insecticides in the world 4 but their use is causing widespread concern, with evidence linking them to the decline of beneficial species such as bumblebees 5 , 6 . Beneficial insects can be exposed to these insecticides when they forage on flowering crops, as well as wild plants growing on agricultural land 7 , 8 , 9 . This exposure to trace levels of neonicotinoids in nectar and pollen causes a range of sub-lethal effects in bees, such as reduced foraging efficiency 10 , 11 , 12 , impaired navigation 13 , a reduction in learning and memory 14 and reduced reproductive success 15 , 16 . These impacts may have substantial impacts at the population level 5 , 6 , 17 and therefore adversely affect the plants that rely on insects for pollination 18 . A type of pollination that may be particularly sensitive to impairment in learning and memory, due to exposure to pesticides, is buzz pollination 19 . Buzz pollination is a relatively complex biotic interaction, in which pollinators, usually bees, interact with flowers with specialised anther morphologies that require high frequency vibrations to release pollen 20 , 21 , 22 , 23 , 24 . Buzz pollination has evolved independently many times 25 and now occurs in approximately 20,000 plant species, including some of the world’s most important crops, such as tomatoes and potatoes 22 . During buzz-pollination, bees grab the anthers with their mandibles, curl their body around the anther cone and then, decoupling their wings from the indirect flight mechanism, they rapidly contract their thoracic muscles, which produces a vibration without the wings beating 21 , 26 , 27 . These vibrations, also called buzzes or sonications due to the audible sound they incidentally produce, are transmitted from the bee’s body to the anthers, causing the pollen grains to be released on to the bee, where they can be collected 24 . Previous work has shown that sonication has both innate and learned components 28 , 29 , 30 . These studies showed that naïve foragers are able to effectively sonicate on their first visit to a flower, showing the innateness of the behaviour. However, after a number of visits, the characteristics of the buzzes change. For instance, Morgan et al . 29 found that the peak frequency of sonication declined with experience, and Russell et al . 30 established that the length and amplitude of buzzes increased with experience, suggesting a learned component. It is important to note that neither of these previous studies determined experimentally whether change in sonication characteristics during learning affect the quantity of pollen that bees can remove from flowers. Therefore, to date, we do not know whether sonication learning is associated with increased pollen collection. The challenge of manipulating morphologically complex flowers through the deployment of a multifaceted behaviour potentially makes buzz pollination particularly sensitive to neurotoxic pesticides, such as neonicotinoids. We know very little about how the ability of bees to buzz-pollinate flowers may be affected by pesticide exposure. In the only study on this to date, Switzer and Combes 19 looked at buzz pollination behaviour before and after an acute dose of the neonicotinoid imidacloprid. The authors found that the lowest dose of 0.0515 ng did not result in any quantitative changes in the frequency and length of sonication buzzes of Bombus impatiens workers. Unfortunately, too few bees exposed to the higher doses (0.515 and 5.15 ng) resumed foraging, and it was therefore not possible to assess how these concentrations impact buzz pollination. Furthermore, the quantity of pollen collected by bees in the different treatments was not assessed. Therefore, the effects of field-realistic, chronic exposure to neonicotinoids on buzz pollination remains to be determined. The present study explores this highly topical subject and aims to determine the effect of the widely-used neonicotinoid thiamethoxam on (1) the characteristics of sonication buzzes and changes over time and (2) the collection of pollen from buzz-pollinated flowers. Materials and Methods Two commercial Bombus terrestris audax colonies were obtained from Biobest (Belgium) via Agralan Ltd (Swindon, UK); the first on 8 th June 2016 and the second on 20 th July 2016. The experiment was carried out with bumblebees from the first colony and then repeated with bumblebees from the second colony. On arrival the majority of workers from the colony were removed and randomly split into three groups, ensuring an approximately", "role": "user" }, { "content": "Pesticides significantly reduce the number of pollen grains a bumblebee is able to collect, a new University of Stirling study has found. The research, conducted by a team in the Faculty of Natural Sciences, found that field-realistic doses of a neonicotinoid pesticide affects the behaviour of bees - ultimately interfering with the type of vibrations they produce while collecting pollen. Dr Penelope Whitehorn, the University of Stirling Research Fellow who led the research, said: \"Our result is the first to demonstrate quantitative changes in the type of buzzes produced by bees exposed to field-realistic levels of neonicotinoid. \"We also show that buzz pollinating bees exposed to the pesticide also collect fewer pollen grains.\" Dr Whitehorn, working with Associate Professor Mario Vallejo-Marin, looked at a complex type of pollination, called buzz pollination, in which bees use vibrations to remove pollen from flowers. They studied captive colonies of bumblebees visiting buzz-pollinated flowers, monitoring their behaviour and collecting bee buzzes using microphones. The scientists then analysed the acoustic signal produced during buzz pollination to detect changes in buzzing behaviour through time. They found that chronic exposure to the pesticide, at similar levels to those found in agricultural fields, interfered with the vibrations of the bees as they collected pollen which, in turn, reduced the amount of pollen collected. Dr Whitehorn explained: \"We found that control bees, who were not exposed to the pesticide, improved their pollen collection as they gained experience, which we interpreted as an ability to learn to buzz pollinate better. \"However, bees that came into contact with pesticide did not collect more pollen as they gained more experience, and by the end of the experiment collected between 47% and 56% less pollen compared to the control bees.\" Dr Vallejo-Marin said: \"Our findings have implications for the effects of pesticides on bee populations as well as the pollination services they provide. They also suggest that pesticide exposure may impair bees' ability to perform complex behaviours, such as buzz pollination. \"The next step in this research would be to establish the mechanism by which the pesticide is affecting the bees. We think that pesticides may be affecting the memory and cognitive ability of bumblebees, which may be very important when conducting complex behaviours.\" The paper, Neonicotinoid pesticide limits improvement in buzz pollination by bumblebees, 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 Neonicotinoid pesticides have been linked to global declines of beneficial insects such as bumblebees. Exposure to trace levels of these chemicals causes sub-lethal effects, such as reduced learning and foraging efficiency. Complex behaviours may be particularly vulnerable to the neurotoxic effects of neonicotinoids. Such behaviours may include buzz pollination (sonication), in which pollinators, usually bees, use innate and learned behaviours to generate high-frequency vibrations to release pollen from flowers with specialised anther morphologies. This study assesses the effect of field-realistic, chronic exposure to the widely-used neonicotinoid thiamethoxam on the development of sonication buzz characteristics over time, as well as the collection of pollen from buzz-pollinated flowers. We found that the pollen collection of exposed bees improved less with increasing experience than that of unexposed bees, with exposed bees collecting between 47% and 56% less pollen by the end of 10 trials. We also found evidence of two distinct strategies for maximising pollen collection: (1) extensions to the duration of individual buzzes and (2) extensions of the overall time spent buzzing. We find new complexities in buzz pollination, and conclude that the impacts of field-realistic exposure to a neonicotinoid pesticide may seriously compromise this important ecosystem service. Introduction Understanding the interactions between plants and their insect pollinators is of great practical and political relevance, being vital to efforts to ensure food security under rapid global change 1 . Increased production is often achieved through the deployment of pesticides but this can compromise sustainability by impacting beneficial insect pollinators. This conflict is exemplified by the controversy over neonicotinoid insecticides 2 , 3 . Neonicotinoids have become the most widely used insecticides in the world 4 but their use is causing widespread concern, with evidence linking them to the decline of beneficial species such as bumblebees 5 , 6 . Beneficial insects can be exposed to these insecticides when they forage on flowering crops, as well as wild plants growing on agricultural land 7 , 8 , 9 . This exposure to trace levels of neonicotinoids in nectar and pollen causes a range of sub-lethal effects in bees, such as reduced foraging efficiency 10 , 11 , 12 , impaired navigation 13 , a reduction in learning and memory 14 and reduced reproductive success 15 , 16 . These impacts may have substantial impacts at the population level 5 , 6 , 17 and therefore adversely affect the plants that rely on insects for pollination 18 . A type of pollination that may be particularly sensitive to impairment in learning and memory, due to exposure to pesticides, is buzz pollination 19 . Buzz pollination is a relatively complex biotic interaction, in which pollinators, usually bees, interact with flowers with specialised anther morphologies that require high frequency vibrations to release pollen 20 , 21 , 22 , 23 , 24 . Buzz pollination has evolved independently many times 25 and now occurs in approximately 20,000 plant species, including some of the world’s most important crops, such as tomatoes and potatoes 22 . During buzz-pollination, bees grab the anthers with their mandibles, curl their body around the anther cone and then, decoupling their wings from the indirect flight mechanism, they rapidly contract their thoracic muscles, which produces a vibration without the wings beating 21 , 26 , 27 . These vibrations, also called buzzes or sonications due to the audible sound they incidentally produce, are transmitted from the bee’s body to the anthers, causing the pollen grains to be released on to the bee, where they can be collected 24 . Previous work has shown that sonication has both innate and learned components 28 , 29 , 30 . These studies showed that naïve foragers are able to effectively sonicate on their first visit to a flower, showing the innateness of the behaviour. However, after a number of visits, the characteristics of the buzzes change. For instance, Morgan et al . 29 found that the peak frequency of sonication declined with experience, and Russell et al . 30 established that the length and amplitude of buzzes increased with experience, suggesting a learned component. It is important to note that neither of these previous studies determined experimentally whether change in sonication characteristics during learning affect the quantity of pollen that bees can remove from flowers. Therefore, to date, we do not know whether sonication learning is associated with increased pollen collection. The challenge of manipulating morphologically complex flowers through the deployment of a multifaceted behaviour potentially makes buzz pollination particularly sensitive to neurotoxic pesticides, such as neonicotinoids. We know very little about how the ability of bees to buzz-pollinate flowers may be affected by pesticide exposure. In the only study on this to date, Switzer and Combes 19 looked at buzz pollination behaviour before and after an acute dose of the neonicotinoid imidacloprid. The authors found that the lowest dose of 0.0515 ng did not result in any quantitative changes in the frequency and length of sonication buzzes of Bombus impatiens workers. Unfortunately, too few bees exposed to the higher doses (0.515 and 5.15 ng) resumed foraging, and it was therefore not possible to assess how these concentrations impact buzz pollination. Furthermore, the quantity of pollen collected by bees in the different treatments was not assessed. Therefore, the effects of field-realistic, chronic exposure to neonicotinoids on buzz pollination remains to be determined. The present study explores this highly topical subject and aims to determine the effect of the widely-used neonicotinoid thiamethoxam on (1) the characteristics of sonication buzzes and changes over time and (2) the collection of pollen from buzz-pollinated flowers. Materials and Methods Two commercial Bombus terrestris audax colonies were obtained from Biobest (Belgium) via Agralan Ltd (Swindon, UK); the first on 8 th June 2016 and the second on 20 th July 2016. The experiment was carried out with bumblebees from the first colony and then repeated with bumblebees from the second colony. On arrival the majority of workers from the colony were removed and randomly split into three groups, ensuring an approximately<|im_end|> <|im_start|>assistant Pesticides significantly reduce the number of pollen grains a bumblebee is able to collect, a new University of Stirling study has found. The research, conducted by a team in the Faculty of Natural Sciences, found that field-realistic doses of a neonicotinoid pesticide affects the behaviour of bees - ultimately interfering with the type of vibrations they produce while collecting pollen. Dr Penelope Whitehorn, the University of Stirling Research Fellow who led the research, said: "Our result is the first to demonstrate quantitative changes in the type of buzzes produced by bees exposed to field-realistic levels of neonicotinoid. "We also show that buzz pollinating bees exposed to the pesticide also collect fewer pollen grains." Dr Whitehorn, working with Associate Professor Mario Vallejo-Marin, looked at a complex type of pollination, called buzz pollination, in which bees use vibrations to remove pollen from flowers. They studied captive colonies of bumblebees visiting buzz-pollinated flowers, monitoring their behaviour and collecting bee buzzes using microphones. The scientists then analysed the acoustic signal produced during buzz pollination to detect changes in buzzing behaviour through time. They found that chronic exposure to the pesticide, at similar levels to those found in agricultural fields, interfered with the vibrations of the bees as they collected pollen which, in turn, reduced the amount of pollen collected. Dr Whitehorn explained: "We found that control bees, who were not exposed to the pesticide, improved their pollen collection as they gained experience, which we interpreted as an ability to learn to buzz pollinate better. "However, bees that came into contact with pesticide did not collect more pollen as they gained more experience, and by the end of the experiment collected between 47% and 56% less pollen compared to the control bees." Dr Vallejo-Marin said: "Our findings have implications for the effects of pesticides on bee populations as well as the pollination services they provide. They also suggest that pesticide exposure may impair bees' ability to perform complex behaviours, such as buzz pollination. "The next step in this research would be to establish the mechanism by which the pesticide is affecting the bees. We think that pesticides may be affecting the memory and cognitive ability of bumblebees, which may be very important when conducting complex behaviours." The paper, Neonicotinoid pesticide limits improvement in buzz pollination by bumblebees, is published in Scientific Reports. <|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 Contact tracing is critical to controlling COVID-19, but most protocols only “forward-trace” to notify people who were recently exposed. Using a stochastic branching-process model, we find that “bidirectional” tracing to identify infector individuals and their other infectees robustly improves outbreak control. In our model, bidirectional tracing more than doubles the reduction in effective reproduction number ( R eff ) achieved by forward-tracing alone, while dramatically increasing resilience to low case ascertainment and test sensitivity. The greatest gains are realised by expanding the manual tracing window from 2 to 6 days pre-symptom-onset or, alternatively, by implementing high-uptake smartphone-based exposure notification; however, to achieve the performance of the former approach, the latter requires nearly all smartphones to detect exposure events. With or without exposure notification, our results suggest that implementing bidirectional tracing could dramatically improve COVID-19 control. Introduction Contact tracing, isolation, and testing are some of the most powerful public health interventions available. The nations that have most effectively controlled the ongoing COVID-19 pandemic are noteworthy for conducting comprehensive and sophisticated tracing and testing 1 . Current “forward-tracing” protocols seek to identify and isolate individuals who may have been infected by the known case, preventing continued transmission (Fig. 1a ). For example, the European Union and World Health Organization call for the identification of potential infectees starting 2 days prior to the development of symptoms 2 , 3 . Fig. 1: Forward-only and bidirectional contact tracing and digital exposure notification. a Notifying people exposed to known cases (black) and isolating them (green) can prevent further transmission, but will miss asymptomatic and undiagnosed cases (gray) and descendants. b Bidirectional tracing also notifies and tests potential infectors, enabling isolation of additional cases. c Manual contact tracing requires individuals to share recent contacts with health authorities. d In digital exposure notification, smartphones broadcast rotating pseudorandom “chirps” and record those emitted by nearby devices 48 . e Individuals diagnosed with COVID-19 can “opt-in” by uploading broadcasted chirps to a diagnosis server 48 . All devices frequently check the server and alert the user if the calculated exposure exceeds a threshold set by the local health authority. In hybrid manual+digital systems, human tracers would seek to identify contacts without smartphones. Full size image However, chains of SARS-CoV-2 transmission may persist despite excellent medical monitoring and forward-tracing programs due to substantial rates of undiagnosed or asymptomatic transmission 4 (Fig. 1a ). Asymptomatic carriers, who reportedly bear equivalent viral loads to patients exhibiting symptoms 5 , have been estimated to account for 18% 6 to 79% 7 of cases, with multiple population surveys indicating intermediate values around 45% 8 , 9 , 10 . Moreover, a large fraction of transmission is known to be driven by superspreading events 11 , suggesting that methods that preferentially identify, test and trace potential superspreaders would be especially valuable in reducing transmission. We hypothesized that “bidirectional” contact tracing could identify and isolate undiscovered branches of the transmission tree, preventing many additional cases—especially when asymptomatic carriers are common or case ascertainment rates are low (Fig. 1b ). Bidirectional contact tracing uses “reverse-tracing” to identify the parent case who infected a known case, then continues tracing to iteratively discover other cases related to the parent. It has been successfully used to identify clusters and community transmission in Japan 12 and Singapore 13 , 14 , but is otherwise uncommon. Previous studies of COVID-19 contact tracing have largely neglected the possibility of gains from bidirectional tracing, with most models designed such that only forward-tracing can occur. We further hypothesized that bidirectional tracing would be most effective using a “hybrid” system that supplements manual tracing (Fig. 1c ) with digital exposure notification. Numerous ongoing efforts aim to use smartphones emitting randomized Bluetooth and/or ultrasound “chirps” to notify people exposed to infected individuals (Fig. 1d, e ). Digital approaches theoretically offer considerable advantages in speed 15 , scale, efficacy 16 , and confidentiality 17 , suggesting that they may offer an effective method of implementing bidirectional tracing. However, their use in this context has not previously been investigated, and existing implementations primarily focus on “forward-notifying” cases exposed during the peak infectious window of the notifier 18 . To investigate the efficacy of bidirectional contact tracing and digital exposure notification, we adapted and extended a stochastic branching-process model of SARS-CoV-2 forward-tracing 19 and used it to explore the efficacy of different tracing strategies under plausible epidemiological scenarios. We find that either expanding the manual tracing window to enable more effective bidirectional tracing or implementing high-uptake bidirectional digital exposure notification could substantially improve COVID-19 control. Results In our model, each case generates a number of new cases drawn from a negative binomial distribution, with incubation and generation-time distributions based on the published literature (Table 1 and Supplementary Table 1 ). Cases could be identified and isolated based on symptoms alone or through contact tracing (Methods). We assumed that symptomatic cases required a positive test before initiating contact tracing, as is the case in the EU 2 and most US jurisdictions. Ninety percent of cases were assumed to comply with isolation, after which they generated no further child cases. Each outbreak was initialized with 20 index cases to minimize stochastic extinction and designated as “controlled” if it reached extinction (zero new cases) before reaching 10,000 cumulative cases. Effective reproduction numbers ( R eff ) were computed as the mean number of child cases produced per case. Table 1 Key parameters of the branching-process model. Full size table We began by investigating a median scenario in which 10% of transmission was assumed to be environmental (and therefore untraceable), 48% of transmission occurred pre-symptomatically, and 45% of cases were asymptomatic with 50% infectiousness. For the initial analysis we assumed a fixed basic reproduction number ( R 0 ) of 2.5, a 50% ascertainment rate for symptomatic cases, and a test sensitivity of 70%, but explored other values below. Bidirectional manual tracing with an expanded tracing window could more than double efficacy In our initial scenario, manual forward tracing and isolation of contacts", "role": "user" }, { "content": "Contact tracing is an important component of mitigating the spread of infections like COVID-19. Alun Lloyd, Drexel Professor of Mathematics at NC State, works with computational models to help us understand how diseases spread. Lloyd recently co-authored a study that found bidirectional contact tracing is twice as effective as forward tracing, the contact tracing method currently in use. Kevin Esvelt of MIT was corresponding author of the study, with other coauthors from Boston University and the Max Planck Institute for Biology of Aging. The work appears in Nature Communications. The Abstract sat down with Lloyd to talk about what bidirectional tracing is, how it works, and why it's a good way to get a clearer picture of how infection travels through a population. TA: What do we mean by \"bidirectional\" tracing as opposed to forward-tracing? Lloyd: Contact tracing is part of the \"test-trace-isolate\" approach for controlling infection. Potentially infected people are tested to confirm whether they are indeed infected, and then asked to isolate until they are no longer infectious. In turn, their contacts are tested and isolated, and so on. By identifying and isolating infectious people, this \"test-trace-isolate\" approach reduces ongoing transmission. Contact tracers ask an infected person—or focal person—about recent contacts. These represent occasions when transmission might have happened. Because of the timeline of infection, contacts of the focal person in the most recent few days represent occasions when he/she might have transmitted infection to someone else. We call this forward tracing: trying to find who our focal individual might have infected. If we ask about contacts further back in time, we might find the person from whom our focal person got infected: this would be backward tracing. [Note: the timeline of infection is exposure; then latent period, typically lasting a few days, in which the infected person is not yet infectious; then a few more days during which the infected person is infectious but is not yet symptomatic; and then maybe a day or two longer before a test confirms that someone is indeed infected. This timeline can vary considerably. For example, some people never display symptoms of infection.] If we just ask about recent contacts (for example those in the two days before onset of symptoms or a positive test), we can forward trace. If we ask about contacts over a longer period of time (e.g. six days before symptoms) we would trace both forward and backward: bidirectional tracing. TA: Why do most contact tracing programs only forward-trace? Were both approaches thought to be equally effective? Lloyd: Bidirectional tracing needs information about contacts over a longer period of time. A contact tracer has to be in touch with each of these people. Looking over a longer period of time means more people to contact, so it involves additional work, and possibly quite a lot of additional work (e.g. potentially three times as many contacts over a 6-day period than a 2-day period). Also, the further back in time you look, the less likely that contact is to still be infectious, so it wasn't clear whether finding those people would be helpful. TA: How much more effective is bidirectional contact tracing? Lloyd: In our model, bidirectional contact tracing achieves more than double the reduction in the effective reproduction number (\"the R number\") than does forward tracing. Why might bidirectional contact tracing be more effective? One reason is because of \"superspreading\": most infected people cause a relatively low number of secondary infections, while a few people cause many secondary infections. A randomly chosen infected person is unlikely to be a superspreader, so tracing from them will only save a few cases. Superspreaders cause a disproportionate fraction of all infections, so if you look at the person who infected me, that person is more likely to be a superspreader than a typical person. So looking backwards increases the chance of finding a superspreader. Here's a slightly exaggerated example to illustrate the idea: Let's say that 99% of people cause an average of one infection, but 1% of people cause an average of 50 infections. If I randomly choose an infected person, the probability that I find a superspreader is just 1%. But it turns out that, for these numbers, if I randomly choose an infected person and ask who infected them—i.e. I trace backwards—I have a 33% probability of finding a superspreader. Why? Looking at 100 randomly chosen people, they cause an average of 99*1 + 1*50 = 149 infections. 66% of those infections are due to \"regular\" people (99/149 = 66%), but 33% (50/149 = 33%) are due to the one superspreader. Despite being only one person out of 100, they are responsible for a third of cases. If I randomly choose an infected person and ask who infected that person—tracing backwards—I find a superspreader with a probability of 33%. Again, these numbers are exaggerated to help make the point. Combine this with the large fraction of COVID-19 infections that are asymptomatic—that would go unnoticed in the absence of regular testing across the entire population—and you see why backwards tracing can be beneficial. TA: What are the barriers to implementing this approach? Lloyd: It is a lot more labor intensive, because contact tracers have to be in touch with many more people. The workload could be reduced if automated contact tracing, e.g. using cellphone based apps, was widely adopted. Despite a lot of early hope and indeed hype, the use of cellphones and tracing apps has had lower uptake than needed to make a major dent. ", "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 Contact tracing is critical to controlling COVID-19, but most protocols only “forward-trace” to notify people who were recently exposed. Using a stochastic branching-process model, we find that “bidirectional” tracing to identify infector individuals and their other infectees robustly improves outbreak control. In our model, bidirectional tracing more than doubles the reduction in effective reproduction number ( R eff ) achieved by forward-tracing alone, while dramatically increasing resilience to low case ascertainment and test sensitivity. The greatest gains are realised by expanding the manual tracing window from 2 to 6 days pre-symptom-onset or, alternatively, by implementing high-uptake smartphone-based exposure notification; however, to achieve the performance of the former approach, the latter requires nearly all smartphones to detect exposure events. With or without exposure notification, our results suggest that implementing bidirectional tracing could dramatically improve COVID-19 control. Introduction Contact tracing, isolation, and testing are some of the most powerful public health interventions available. The nations that have most effectively controlled the ongoing COVID-19 pandemic are noteworthy for conducting comprehensive and sophisticated tracing and testing 1 . Current “forward-tracing” protocols seek to identify and isolate individuals who may have been infected by the known case, preventing continued transmission (Fig. 1a ). For example, the European Union and World Health Organization call for the identification of potential infectees starting 2 days prior to the development of symptoms 2 , 3 . Fig. 1: Forward-only and bidirectional contact tracing and digital exposure notification. a Notifying people exposed to known cases (black) and isolating them (green) can prevent further transmission, but will miss asymptomatic and undiagnosed cases (gray) and descendants. b Bidirectional tracing also notifies and tests potential infectors, enabling isolation of additional cases. c Manual contact tracing requires individuals to share recent contacts with health authorities. d In digital exposure notification, smartphones broadcast rotating pseudorandom “chirps” and record those emitted by nearby devices 48 . e Individuals diagnosed with COVID-19 can “opt-in” by uploading broadcasted chirps to a diagnosis server 48 . All devices frequently check the server and alert the user if the calculated exposure exceeds a threshold set by the local health authority. In hybrid manual+digital systems, human tracers would seek to identify contacts without smartphones. Full size image However, chains of SARS-CoV-2 transmission may persist despite excellent medical monitoring and forward-tracing programs due to substantial rates of undiagnosed or asymptomatic transmission 4 (Fig. 1a ). Asymptomatic carriers, who reportedly bear equivalent viral loads to patients exhibiting symptoms 5 , have been estimated to account for 18% 6 to 79% 7 of cases, with multiple population surveys indicating intermediate values around 45% 8 , 9 , 10 . Moreover, a large fraction of transmission is known to be driven by superspreading events 11 , suggesting that methods that preferentially identify, test and trace potential superspreaders would be especially valuable in reducing transmission. We hypothesized that “bidirectional” contact tracing could identify and isolate undiscovered branches of the transmission tree, preventing many additional cases—especially when asymptomatic carriers are common or case ascertainment rates are low (Fig. 1b ). Bidirectional contact tracing uses “reverse-tracing” to identify the parent case who infected a known case, then continues tracing to iteratively discover other cases related to the parent. It has been successfully used to identify clusters and community transmission in Japan 12 and Singapore 13 , 14 , but is otherwise uncommon. Previous studies of COVID-19 contact tracing have largely neglected the possibility of gains from bidirectional tracing, with most models designed such that only forward-tracing can occur. We further hypothesized that bidirectional tracing would be most effective using a “hybrid” system that supplements manual tracing (Fig. 1c ) with digital exposure notification. Numerous ongoing efforts aim to use smartphones emitting randomized Bluetooth and/or ultrasound “chirps” to notify people exposed to infected individuals (Fig. 1d, e ). Digital approaches theoretically offer considerable advantages in speed 15 , scale, efficacy 16 , and confidentiality 17 , suggesting that they may offer an effective method of implementing bidirectional tracing. However, their use in this context has not previously been investigated, and existing implementations primarily focus on “forward-notifying” cases exposed during the peak infectious window of the notifier 18 . To investigate the efficacy of bidirectional contact tracing and digital exposure notification, we adapted and extended a stochastic branching-process model of SARS-CoV-2 forward-tracing 19 and used it to explore the efficacy of different tracing strategies under plausible epidemiological scenarios. We find that either expanding the manual tracing window to enable more effective bidirectional tracing or implementing high-uptake bidirectional digital exposure notification could substantially improve COVID-19 control. Results In our model, each case generates a number of new cases drawn from a negative binomial distribution, with incubation and generation-time distributions based on the published literature (Table 1 and Supplementary Table 1 ). Cases could be identified and isolated based on symptoms alone or through contact tracing (Methods). We assumed that symptomatic cases required a positive test before initiating contact tracing, as is the case in the EU 2 and most US jurisdictions. Ninety percent of cases were assumed to comply with isolation, after which they generated no further child cases. Each outbreak was initialized with 20 index cases to minimize stochastic extinction and designated as “controlled” if it reached extinction (zero new cases) before reaching 10,000 cumulative cases. Effective reproduction numbers ( R eff ) were computed as the mean number of child cases produced per case. Table 1 Key parameters of the branching-process model. Full size table We began by investigating a median scenario in which 10% of transmission was assumed to be environmental (and therefore untraceable), 48% of transmission occurred pre-symptomatically, and 45% of cases were asymptomatic with 50% infectiousness. For the initial analysis we assumed a fixed basic reproduction number ( R 0 ) of 2.5, a 50% ascertainment rate for symptomatic cases, and a test sensitivity of 70%, but explored other values below. Bidirectional manual tracing with an expanded tracing window could more than double efficacy In our initial scenario, manual forward tracing and isolation of contacts<|im_end|> <|im_start|>assistant Contact tracing is an important component of mitigating the spread of infections like COVID-19. Alun Lloyd, Drexel Professor of Mathematics at NC State, works with computational models to help us understand how diseases spread. Lloyd recently co-authored a study that found bidirectional contact tracing is twice as effective as forward tracing, the contact tracing method currently in use. Kevin Esvelt of MIT was corresponding author of the study, with other coauthors from Boston University and the Max Planck Institute for Biology of Aging. The work appears in Nature Communications. The Abstract sat down with Lloyd to talk about what bidirectional tracing is, how it works, and why it's a good way to get a clearer picture of how infection travels through a population. TA: What do we mean by "bidirectional" tracing as opposed to forward-tracing? Lloyd: Contact tracing is part of the "test-trace-isolate" approach for controlling infection. Potentially infected people are tested to confirm whether they are indeed infected, and then asked to isolate until they are no longer infectious. In turn, their contacts are tested and isolated, and so on. By identifying and isolating infectious people, this "test-trace-isolate" approach reduces ongoing transmission. Contact tracers ask an infected person—or focal person—about recent contacts. These represent occasions when transmission might have happened. Because of the timeline of infection, contacts of the focal person in the most recent few days represent occasions when he/she might have transmitted infection to someone else. We call this forward tracing: trying to find who our focal individual might have infected. If we ask about contacts further back in time, we might find the person from whom our focal person got infected: this would be backward tracing. [Note: the timeline of infection is exposure; then latent period, typically lasting a few days, in which the infected person is not yet infectious; then a few more days during which the infected person is infectious but is not yet symptomatic; and then maybe a day or two longer before a test confirms that someone is indeed infected. This timeline can vary considerably. For example, some people never display symptoms of infection.] If we just ask about recent contacts (for example those in the two days before onset of symptoms or a positive test), we can forward trace. If we ask about contacts over a longer period of time (e.g. six days before symptoms) we would trace both forward and backward: bidirectional tracing. TA: Why do most contact tracing programs only forward-trace? Were both approaches thought to be equally effective? Lloyd: Bidirectional tracing needs information about contacts over a longer period of time. A contact tracer has to be in touch with each of these people. Looking over a longer period of time means more people to contact, so it involves additional work, and possibly quite a lot of additional work (e.g. potentially three times as many contacts over a 6-day period than a 2-day period). Also, the further back in time you look, the less likely that contact is to still be infectious, so it wasn't clear whether finding those people would be helpful. TA: How much more effective is bidirectional contact tracing? Lloyd: In our model, bidirectional contact tracing achieves more than double the reduction in the effective reproduction number ("the R number") than does forward tracing. Why might bidirectional contact tracing be more effective? One reason is because of "superspreading": most infected people cause a relatively low number of secondary infections, while a few people cause many secondary infections. A randomly chosen infected person is unlikely to be a superspreader, so tracing from them will only save a few cases. Superspreaders cause a disproportionate fraction of all infections, so if you look at the person who infected me, that person is more likely to be a superspreader than a typical person. So looking backwards increases the chance of finding a superspreader. Here's a slightly exaggerated example to illustrate the idea: Let's say that 99% of people cause an average of one infection, but 1% of people cause an average of 50 infections. If I randomly choose an infected person, the probability that I find a superspreader is just 1%. But it turns out that, for these numbers, if I randomly choose an infected person and ask who infected them—i.e. I trace backwards—I have a 33% probability of finding a superspreader. Why? Looking at 100 randomly chosen people, they cause an average of 99*1 + 1*50 = 149 infections. 66% of those infections are due to "regular" people (99/149 = 66%), but 33% (50/149 = 33%) are due to the one superspreader. Despite being only one person out of 100, they are responsible for a third of cases. If I randomly choose an infected person and ask who infected that person—tracing backwards—I find a superspreader with a probability of 33%. Again, these numbers are exaggerated to help make the point. Combine this with the large fraction of COVID-19 infections that are asymptomatic—that would go unnoticed in the absence of regular testing across the entire population—and you see why backwards tracing can be beneficial. TA: What are the barriers to implementing this approach? Lloyd: It is a lot more labor intensive, because contact tracers have to be in touch with many more people. The workload could be reduced if automated contact tracing, e.g. using cellphone based apps, was widely adopted. Despite a lot of early hope and indeed hype, the use of cellphones and tracing apps has had lower uptake than needed to make a major dent. <|im_end|>

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2,505

[ { "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 analysis of bone breakage has always been underrepresented in taphonomic studies. Analysts, thus, lose the opportunity to resolve an important part of the equifinality related to activities that hominins and different types of carnivores may produce. Recent studies have shown that the use of powerful machine learning (ML) algorithms allow the accurate classification of bone surface modifications (BSM). Here, we present an experimental study, applying these algorithms to the analysis of bone breakage patterns. This statistical methodology allows the correct classification of three different assemblages which have been generated anthropogenically and by the activity of carnivores (i.e., hyenas and wolves). ML algorithms applied to a multivariate set of properties of broken bone specimens yielded an accuracy of 95% and were higher in classifying agency without the need to include information from BSM. This paper proposes a methodological approach that opens the door to improve our understanding of referential frameworks regarding bone breakage and to determine agency in prehistoric bone breakage processes. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The analysis of bone surface modifications (BSM) has had a particularly strong predominance in most debates regarding the anthropogenic origin of archeofaunal assemblages. This can be seen in cases such as the “hunting-scavenging” debate (Domínguez-Rodrigo 2002 , e.g., Domínguez-Rodrigo 2015 ; Domínguez-Rodrigo et al. 2007 ; Egeland et al. 2007 ; Pante et al. 2012 ; James and Thompson 2015 ; Harris et al. 2017 ; Parkinson 2018 ). BSM analysis has, thus, been used as the main method in understanding how archeological faunal assemblages are generated and the interaction of agents. The existence of faunal assemblages with poor preservation conditions of cortical surfaces, however, leads to difficulties when attempting to identify anthropic/carnivore activity through the sole study of BSM (e.g., Domínguez-Rodrigo and Martínez-Navarro 2012 ; Yravedra et al. 2016 ; Pineda et al. 2017 , 2019 ; Pineda and Saladié 2018 ). Fortunately, BSM are not the only type of diagnostic taphonomic evidence for anthropic or carnivorous activity. Bone breakage is the result of accessing marrow from long bones by hominins and carnivores. This produces a series of characteristics that may also be the subject of taphonomic analysis. Marrow from long bones is an important resource that has been continuously used for consumption throughout human evolution, with evidence of anthropic bone breakage dated at least 2.6 m.a. (Domínguez-Rodrigo et al. 2005 ). Bone breakage patterns have been underused in faunal analysis, however, since few studies have been dedicated to developing and understanding this taphonomic variable, especially considering the equifinality produced by bone breakage patterns from hominins and carnivores in terms of how bones are broken while green (Brain 1981 ; Blumenschine and Selvaggio 1991 ; Villa and Mahieu 1991 ). Agency determination through bone breakage can be summarized through the analysis of bone impact flakes generated accidently during the process of accessing bone marrow (Galán et al. 2009 ), the presence of green fracture planes (Villa and Mahieu 1991 ; Alcántara García et al. 2006 ; Coil et al. 2017 ), and the presence of notches along fracture planes (Capaldo and Blumenschine 1994 ; Galán et al. 2009 ; Moclán and Domínguez-Rodrigo 2018 ). For the moment, impact flakes have been poorly studied, especially since systematic studies of their variability and typology are completely lacking (Domínguez-Rodrigo and Martínez-Navarro 2012 ). However, their absolute frequency of occurrence in different experiments seems to suggest that they can be a good marker for anthropic activity (Pickering and Egeland 2006 ; Galán et al. 2009 ). Fracture planes, on the other hand, have been studied by different authors with many different perspectives. Most classic studies try to systematize the typologies of fracture planes in order to compare their morphologies, seeking a differentiation between fracture planes generated on green bones and those produced diagenetically, mainly on dry bone (Villa and Mahieu 1991 ). Modern approaches have tried to approach the study of fracture planes using quantitative approaches, measuring the angle between the fracture plane with the cortical surface of the bone (Alcántara García et al. 2006 ; Coil et al. 2017 ). The combination of both methods of analysis seem to have shown satisfactory results when used to differentiate between agents; however, a high degree of equifinality is still present, thus complicating their application to the archeological record (Pickering et al. 2005 ). Several authors have analyzed notches that appear on fracture planes showing that there is a well-defined typology that allows the separation of anthropic faunal assemblages from those produced by carnivores (Capaldo and Blumenschine 1994 ; Pickering and Egeland 2006 ; Galán et al. 2009 ; Moclán and Domínguez-Rodrigo 2018 ). A fourth variable that has shown to be useful for comparing faunal assemblages generated by different types of carnivores are taphotypes. Wauthoz et al. ( 2003 ) initially defined “taphonotype” as a taphonomic morphology derived from the variability caused by taphonomic agents, while Domínguez-Rodrigo et al. ( 2015 ) developed this concept to include a series of stages in the morphological modification of long bones by carnivores. Taphotypes can be used to define the type of carnivore responsible for an accumulation. However, the main handicap for this method is its application to anthropic bone breakage and the limitation of its scope to long bone ends, which make up a minor part of archeofaunal records. The physical state of bones (e.g., green, dry, boiled, mineralized) and their environmental/chemical conditions (e.g., weathering) are also determining factors in bone breakage/fragmentation (Behrensmeyer 1978 ; Myers et al. 1980 ; Bunn 1983 ; Haynes 1983a ; White and Hannus 1983 ; Morlan 1984 ; Lyman 1994 ; Outram 2001 ; Cáceres et al. 2002 ; Outram et al. 2005 ; Karr and Outram 2012 ), complicating the understanding of bone breakage beyond the aforementioned concepts of equifinality. Until now, all these studies proposed statistical methods that failed to include the probability of inference or classification, simply describing results through graphically produced data (i.e., confidence bars) (Pickering et", "role": "user" }, { "content": "An experimental study led by researcher Abel Moclán, from the Centro Nacional de Investigación sobre la Evolución Humana (CENIEH), has just been published in the Archaeological and Anthropological Sciences journal, which proposes a new method to understand how the faunal assemblages were generated in archaeological sites, and how they could have interacted with groups of humans and carnivores in the places they occupied. This new method involves the use of artificial intelligence and machine learning algorithms to decipher whether faunal assemblages were generated by hominids or carnivores, specifically hyenas and/or wolves. \"Thanks to this method, we can discern among the acting agents with a certainty of over 95%,\" says Abel Moclán. To carry out this study, bone fractures have been analyzed in order to interpret whether they were fractured by human groups to consume the bone marrow, or if, on the contrary, the carnivores fractured the bones when trying to access this same resource. This method can be used as a starting point in Taphonomy when analyzing remains in sites whose preservation does not allow distinguishing who accumulated the assemblages through the analysis of the cut or tooth marks left on the surface of the bones. \"The future of Taphonomy involves using increasingly powerful statistical tools, like the ones we use here,\" says Abel Moclán. Manuel-Domínguez-Rodrigo of the Complutense University of Madrid (UCM) and the Institute of Evolution in Africa (IDEA), and José Yravedra of the Complutense University of Madrid (UCM) have also participated in this study, titled \"Classifying agency in bone breakage: an experimental analysis of fracture planes to differentiate between hominin and carnivore dynamic and static loading using machine learning (ML) algorithms.\" ", "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 analysis of bone breakage has always been underrepresented in taphonomic studies. Analysts, thus, lose the opportunity to resolve an important part of the equifinality related to activities that hominins and different types of carnivores may produce. Recent studies have shown that the use of powerful machine learning (ML) algorithms allow the accurate classification of bone surface modifications (BSM). Here, we present an experimental study, applying these algorithms to the analysis of bone breakage patterns. This statistical methodology allows the correct classification of three different assemblages which have been generated anthropogenically and by the activity of carnivores (i.e., hyenas and wolves). ML algorithms applied to a multivariate set of properties of broken bone specimens yielded an accuracy of 95% and were higher in classifying agency without the need to include information from BSM. This paper proposes a methodological approach that opens the door to improve our understanding of referential frameworks regarding bone breakage and to determine agency in prehistoric bone breakage processes. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The analysis of bone surface modifications (BSM) has had a particularly strong predominance in most debates regarding the anthropogenic origin of archeofaunal assemblages. This can be seen in cases such as the “hunting-scavenging” debate (Domínguez-Rodrigo 2002 , e.g., Domínguez-Rodrigo 2015 ; Domínguez-Rodrigo et al. 2007 ; Egeland et al. 2007 ; Pante et al. 2012 ; James and Thompson 2015 ; Harris et al. 2017 ; Parkinson 2018 ). BSM analysis has, thus, been used as the main method in understanding how archeological faunal assemblages are generated and the interaction of agents. The existence of faunal assemblages with poor preservation conditions of cortical surfaces, however, leads to difficulties when attempting to identify anthropic/carnivore activity through the sole study of BSM (e.g., Domínguez-Rodrigo and Martínez-Navarro 2012 ; Yravedra et al. 2016 ; Pineda et al. 2017 , 2019 ; Pineda and Saladié 2018 ). Fortunately, BSM are not the only type of diagnostic taphonomic evidence for anthropic or carnivorous activity. Bone breakage is the result of accessing marrow from long bones by hominins and carnivores. This produces a series of characteristics that may also be the subject of taphonomic analysis. Marrow from long bones is an important resource that has been continuously used for consumption throughout human evolution, with evidence of anthropic bone breakage dated at least 2.6 m.a. (Domínguez-Rodrigo et al. 2005 ). Bone breakage patterns have been underused in faunal analysis, however, since few studies have been dedicated to developing and understanding this taphonomic variable, especially considering the equifinality produced by bone breakage patterns from hominins and carnivores in terms of how bones are broken while green (Brain 1981 ; Blumenschine and Selvaggio 1991 ; Villa and Mahieu 1991 ). Agency determination through bone breakage can be summarized through the analysis of bone impact flakes generated accidently during the process of accessing bone marrow (Galán et al. 2009 ), the presence of green fracture planes (Villa and Mahieu 1991 ; Alcántara García et al. 2006 ; Coil et al. 2017 ), and the presence of notches along fracture planes (Capaldo and Blumenschine 1994 ; Galán et al. 2009 ; Moclán and Domínguez-Rodrigo 2018 ). For the moment, impact flakes have been poorly studied, especially since systematic studies of their variability and typology are completely lacking (Domínguez-Rodrigo and Martínez-Navarro 2012 ). However, their absolute frequency of occurrence in different experiments seems to suggest that they can be a good marker for anthropic activity (Pickering and Egeland 2006 ; Galán et al. 2009 ). Fracture planes, on the other hand, have been studied by different authors with many different perspectives. Most classic studies try to systematize the typologies of fracture planes in order to compare their morphologies, seeking a differentiation between fracture planes generated on green bones and those produced diagenetically, mainly on dry bone (Villa and Mahieu 1991 ). Modern approaches have tried to approach the study of fracture planes using quantitative approaches, measuring the angle between the fracture plane with the cortical surface of the bone (Alcántara García et al. 2006 ; Coil et al. 2017 ). The combination of both methods of analysis seem to have shown satisfactory results when used to differentiate between agents; however, a high degree of equifinality is still present, thus complicating their application to the archeological record (Pickering et al. 2005 ). Several authors have analyzed notches that appear on fracture planes showing that there is a well-defined typology that allows the separation of anthropic faunal assemblages from those produced by carnivores (Capaldo and Blumenschine 1994 ; Pickering and Egeland 2006 ; Galán et al. 2009 ; Moclán and Domínguez-Rodrigo 2018 ). A fourth variable that has shown to be useful for comparing faunal assemblages generated by different types of carnivores are taphotypes. Wauthoz et al. ( 2003 ) initially defined “taphonotype” as a taphonomic morphology derived from the variability caused by taphonomic agents, while Domínguez-Rodrigo et al. ( 2015 ) developed this concept to include a series of stages in the morphological modification of long bones by carnivores. Taphotypes can be used to define the type of carnivore responsible for an accumulation. However, the main handicap for this method is its application to anthropic bone breakage and the limitation of its scope to long bone ends, which make up a minor part of archeofaunal records. The physical state of bones (e.g., green, dry, boiled, mineralized) and their environmental/chemical conditions (e.g., weathering) are also determining factors in bone breakage/fragmentation (Behrensmeyer 1978 ; Myers et al. 1980 ; Bunn 1983 ; Haynes 1983a ; White and Hannus 1983 ; Morlan 1984 ; Lyman 1994 ; Outram 2001 ; Cáceres et al. 2002 ; Outram et al. 2005 ; Karr and Outram 2012 ), complicating the understanding of bone breakage beyond the aforementioned concepts of equifinality. Until now, all these studies proposed statistical methods that failed to include the probability of inference or classification, simply describing results through graphically produced data (i.e., confidence bars) (Pickering et<|im_end|> <|im_start|>assistant An experimental study led by researcher Abel Moclán, from the Centro Nacional de Investigación sobre la Evolución Humana (CENIEH), has just been published in the Archaeological and Anthropological Sciences journal, which proposes a new method to understand how the faunal assemblages were generated in archaeological sites, and how they could have interacted with groups of humans and carnivores in the places they occupied. This new method involves the use of artificial intelligence and machine learning algorithms to decipher whether faunal assemblages were generated by hominids or carnivores, specifically hyenas and/or wolves. "Thanks to this method, we can discern among the acting agents with a certainty of over 95%," says Abel Moclán. To carry out this study, bone fractures have been analyzed in order to interpret whether they were fractured by human groups to consume the bone marrow, or if, on the contrary, the carnivores fractured the bones when trying to access this same resource. This method can be used as a starting point in Taphonomy when analyzing remains in sites whose preservation does not allow distinguishing who accumulated the assemblages through the analysis of the cut or tooth marks left on the surface of the bones. "The future of Taphonomy involves using increasingly powerful statistical tools, like the ones we use here," says Abel Moclán. Manuel-Domínguez-Rodrigo of the Complutense University of Madrid (UCM) and the Institute of Evolution in Africa (IDEA), and José Yravedra of the Complutense University of Madrid (UCM) have also participated in this study, titled "Classifying agency in bone breakage: an experimental analysis of fracture planes to differentiate between hominin and carnivore dynamic and static loading using machine learning (ML) algorithms." <|im_end|>

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1193, 955, 315, 15439, 259, 1366, 48228, 6029, 369, 41416, 292, 477, 97733, 20857, 5820, 13, 46701, 1464, 425, 374, 279, 1121, 315, 32888, 83748, 505, 1317, 25896, 555, 5105, 258, 1354, 323, 97733, 4692, 13, 1115, 19159, 264, 4101, 315, 17910, 430, 1253, 1101, 387, 279, 3917, 315, 259, 1366, 48228, 6492, 13, 2947, 654, 505, 1317, 25896, 374, 459, 3062, 5211, 430, 706, 1027, 31978, 1511, 369, 15652, 6957, 3823, 15740, 11, 449, 6029, 315, 41416, 292, 17685, 1464, 425, 30105, 520, 3325, 220, 17, 13, 21, 296, 5973, 13, 320, 23658, 2483, 983, 28700, 11151, 347, 81, 7992, 1880, 453, 13, 220, 1049, 20, 7609, 46701, 1464, 425, 12912, 617, 1027, 1234, 2656, 304, 2267, 26663, 6492, 11, 4869, 11, 2533, 2478, 7978, 617, 1027, 12514, 311, 11469, 323, 8830, 420, 259, 1366, 48228, 3977, 11, 5423, 13126, 279, 3312, 333, 81877, 9124, 555, 17685, 1464, 425, 12912, 505, 5105, 258, 1354, 323, 97733, 4692, 304, 3878, 315, 1268, 25896, 527, 11102, 1418, 6307, 320, 66177, 220, 3753, 16, 2652, 2563, 372, 47845, 483, 323, 24082, 85, 35259, 220, 2550, 16, 2652, 37912, 323, 16566, 26235, 220, 2550, 16, 7609, 16784, 26314, 1555, 17685, 1464, 425, 649, 387, 69729, 1555, 279, 6492, 315, 17685, 5536, 82723, 8066, 11677, 398, 2391, 279, 1920, 315, 32888, 17685, 83748, 320, 53619, 11644, 1880, 453, 13, 220, 1049, 24, 7026, 279, 9546, 315, 6307, 59904, 25761, 320, 53, 6374, 323, 16566, 26235, 220, 2550, 16, 2652, 1708, 66, 86533, 5169, 85341, 1880, 453, 13, 220, 1049, 21, 2652, 68765, 1880, 453, 13, 220, 679, 22, 7026, 323, 279, 9546, 315, 539, 8696, 3235, 59904, 25761, 320, 13199, 40232, 323, 2563, 372, 47845, 483, 220, 2550, 19, 2652, 10845, 11644, 1880, 453, 13, 220, 1049, 24, 2652, 386, 62868, 11644, 323, 21414, 2483, 983, 28700, 11151, 347, 81, 7992, 220, 679, 23, 7609, 1789, 279, 4545, 11, 5536, 82723, 617, 1027, 31555, 20041, 11, 5423, 2533, 37538, 7978, 315, 872, 54709, 323, 3666, 2508, 527, 6724, 32161, 320, 23658, 2483, 983, 28700, 11151, 347, 81, 7992, 323, 8290, 2483, 55506, 12, 10304, 82301, 220, 679, 17, 7609, 4452, 11, 872, 10973, 11900, 315, 32659, 304, 2204, 21896, 5084, 311, 4284, 430, 814, 649, 387, 264, 1695, 11381, 369, 41416, 292, 5820, 320, 38053, 4776, 323, 39175, 18615, 220, 1049, 21, 2652, 10845, 11644, 1880, 453, 13, 220, 1049, 24, 7609, 2939, 533, 554, 25761, 11, 389, 279, 1023, 1450, 11, 617, 1027, 20041, 555, 2204, 12283, 449, 1690, 2204, 39555, 13, 7648, 11670, 7978, 1456, 311, 1887, 266, 553, 279, 3666, 9268, 315, 59904, 25761, 304, 2015, 311, 9616, 872, 27448, 9268, 11, 11125, 264, 60038, 1990, 59904, 25761, 8066, 389, 6307, 25896, 323, 1884, 9124, 1891, 8703, 37774, 11, 14918, 389, 9235, 17685, 320, 53, 6374, 323, 16566, 26235, 220, 2550, 16, 7609, 18766, 20414, 617, 6818, 311, 5603, 279, 4007, 315, 59904, 25761, 1701, 47616, 20414, 11, 30090, 279, 9392, 1990, 279, 59904, 11277, 449, 279, 83619, 7479, 315, 279, 17685, 320, 2149, 66, 86533, 5169, 85341, 1880, 453, 13, 220, 1049, 21, 2652, 68765, 1880, 453, 13, 220, 679, 22, 7609, 578, 10824, 315, 2225, 5528, 315, 6492, 2873, 311, 617, 6982, 58831, 3135, 994, 1511, 311, 54263, 1990, 13307, 26, 4869, 11, 264, 1579, 8547, 315, 3312, 333, 81877, 374, 2103, 3118, 11, 8617, 69226, 1113, 872, 3851, 311, 279, 802, 1557, 5848, 3335, 320, 38053, 4776, 1880, 453, 13, 220, 1049, 20, 7609, 26778, 12283, 617, 30239, 539, 8696, 430, 5101, 389, 59904, 25761, 9204, 430, 1070, 374, 264, 1664, 39817, 3666, 2508, 430, 6276, 279, 25768, 315, 41416, 292, 2267, 26663, 439, 28111, 1154, 505, 1884, 9124, 555, 97733, 4692, 320, 13199, 40232, 323, 2563, 372, 47845, 483, 220, 2550, 19, 2652, 20305, 4776, 323, 39175, 18615, 220, 1049, 21, 2652, 10845, 11644, 1880, 453, 13, 220, 1049, 24, 2652, 386, 62868, 11644, 323, 21414, 2483, 983, 28700, 11151, 347, 81, 7992, 220, 679, 23, 7609, 362, 11999, 3977, 430, 706, 6982, 311, 387, 5505, 369, 27393, 2267, 26663, 439, 28111, 1154, 8066, 555, 2204, 4595, 315, 97733, 4692, 527, 259, 1366, 22583, 13, 468, 3322, 9700, 1880, 453, 13, 320, 220, 1049, 18, 883, 15453, 4613, 1054, 83, 1366, 263, 4249, 863, 439, 264, 259, 1366, 48228, 79612, 14592, 505, 279, 54709, 9057, 555, 259, 1366, 48228, 13307, 11, 1418, 21414, 2483, 983, 28700, 11151, 347, 81, 7992, 1880, 453, 13, 320, 220, 679, 20, 883, 8040, 420, 7434, 311, 2997, 264, 4101, 315, 18094, 304, 279, 27448, 5848, 17466, 315, 1317, 25896, 555, 97733, 4692, 13, 350, 1366, 22583, 649, 387, 1511, 311, 7124, 279, 955, 315, 97733, 461, 8647, 369, 459, 46835, 13, 4452, 11, 279, 1925, 75379, 369, 420, 1749, 374, 1202, 3851, 311, 41416, 292, 17685, 1464, 425, 323, 279, 20893, 315, 1202, 7036, 311, 1317, 17685, 10548, 11, 902, 1304, 709, 264, 9099, 961, 315, 802, 1557, 1073, 64, 26663, 7576, 13, 578, 7106, 1614, 315, 25896, 320, 68, 1326, 2637, 6307, 11, 9235, 11, 66185, 11, 25107, 1534, 8, 323, 872, 12434, 14, 32056, 4787, 320, 68, 1326, 2637, 9282, 287, 8, 527, 1101, 26679, 9547, 304, 17685, 1464, 425, 14, 43302, 367, 320, 10226, 1466, 3647, 35472, 220, 4468, 23, 2652, 51323, 1880, 453, 13, 220, 3753, 15, 2652, 426, 15278, 220, 3753, 18, 2652, 18276, 4978, 220, 3753, 18, 64, 2652, 5929, 323, 28829, 355, 220, 3753, 18, 2652, 8613, 10946, 220, 3753, 19, 2652, 16333, 1543, 220, 2550, 19, 2652, 4470, 2453, 220, 1049, 16, 2652, 356, 1995, 3913, 288, 1880, 453, 13, 220, 1049, 17, 2652, 4470, 2453, 1880, 453, 13, 220, 1049, 20, 2652, 735, 1138, 323, 4470, 2453, 220, 679, 17, 7026, 69226, 1113, 279, 8830, 315, 17685, 1464, 425, 7953, 279, 46752, 19476, 315, 3312, 333, 81877, 13, 30070, 1457, 11, 682, 1521, 7978, 11223, 29564, 5528, 430, 4745, 311, 2997, 279, 19463, 315, 45478, 477, 24790, 11, 5042, 23524, 3135, 1555, 4876, 2740, 9124, 828, 320, 72, 1770, 2637, 12410, 16283, 8, 320, 38053, 4776, 1880, 128257, 198, 128256, 78191, 198, 2127, 22772, 4007, 6197, 555, 32185, 87949, 386, 62868, 11644, 11, 505, 279, 57674, 45689, 409, 33180, 5840, 15482, 1208, 10641, 78176, 20449, 3444, 320, 34, 965, 5484, 39, 705, 706, 1120, 1027, 4756, 304, 279, 66102, 5848, 323, 70384, 5848, 23199, 8486, 11, 902, 55725, 264, 502, 1749, 311, 3619, 1268, 279, 2267, 26663, 439, 28111, 1154, 1051, 8066, 304, 69637, 6732, 11, 323, 1268, 814, 1436, 617, 16681, 291, 449, 5315, 315, 12966, 323, 97733, 4692, 304, 279, 7634, 814, 25366, 13, 1115, 502, 1749, 18065, 279, 1005, 315, 21075, 11478, 323, 5780, 6975, 26249, 311, 75277, 3508, 2267, 26663, 439, 28111, 1154, 1051, 8066, 555, 5105, 258, 3447, 477, 97733, 4692, 11, 11951, 6409, 28043, 323, 5255, 56271, 13, 330, 12947, 311, 420, 1749, 11, 584, 649, 42645, 4315, 279, 15718, 13307, 449, 264, 44743, 315, 927, 220, 2721, 4, 1359, 2795, 87949, 386, 62868, 11644, 13, 2057, 6920, 704, 420, 4007, 11, 17685, 78332, 617, 1027, 30239, 304, 2015, 311, 14532, 3508, 814, 1051, 80208, 555, 3823, 5315, 311, 25024, 279, 17685, 83748, 11, 477, 422, 11, 389, 279, 26102, 11, 279, 97733, 4692, 80208, 279, 25896, 994, 4560, 311, 2680, 420, 1890, 5211, 13, 1115, 1749, 649, 387, 1511, 439, 264, 6041, 1486, 304, 350, 1366, 17404, 994, 42118, 8625, 304, 6732, 6832, 46643, 1587, 539, 2187, 86055, 889, 41165, 279, 439, 28111, 1154, 1555, 279, 6492, 315, 279, 4018, 477, 26588, 15785, 2163, 389, 279, 7479, 315, 279, 25896, 13, 330, 791, 3938, 315, 350, 1366, 17404, 18065, 1701, 15098, 8147, 29564, 7526, 11, 1093, 279, 6305, 584, 1005, 1618, 1359, 2795, 87949, 386, 62868, 11644, 13, 44681, 9607, 316, 2483, 983, 28700, 11151, 347, 81, 7992, 315, 279, 1219, 501, 332, 1137, 3907, 315, 25048, 320, 5576, 44, 8, 323, 279, 10181, 315, 38321, 304, 10384, 320, 12420, 32, 705, 323, 44365, 816, 81, 4234, 969, 315, 279, 1219, 501, 332, 1137, 3907, 315, 25048, 320, 5576, 44, 8, 617, 1101, 31408, 304, 420, 4007, 11, 25891, 330, 1999, 7922, 9266, 304, 17685, 1464, 425, 25, 459, 22772, 6492, 315, 59904, 25761, 311, 54263, 1990, 5105, 65544, 323, 97733, 461, 8915, 323, 1118, 8441, 1701, 5780, 6975, 320, 2735, 8, 26249, 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 Upon illumination, photosensitizer molecules produce reactive oxygen species that can be used for functional manipulation of living cells, including protein inactivation, targeted-damage introduction and cellular ablation. Photosensitizers used to date have been either exogenous, resulting in delivery and removal challenges, or genetically encoded proteins that form or bind a native photosensitizing molecule, resulting in a constitutively active photosensitizer inside the cell. We describe a genetically encoded fluorogen-activating protein (FAP) that binds a heavy atom−substituted fluorogenic dye, forming an 'on-demand' activated photosensitizer that produces singlet oxygen and fluorescence when activated with near-infrared light. This targeted and activated photosensitizer (TAPs) approach enables protein inactivation, targeted cell killing and rapid targeted lineage ablation in living larval and adult zebrafish. The near-infrared excitation and emission of this FAP-TAPs provides a new spectral range for photosensitizer proteins that could be useful for imaging, manipulation and cellular ablation deep within living organisms. Main Light provides precise spatiotemporal control of biological processes when combined with suitable genetic constructs or chemical reagents 1 , 2 , 3 . Photosensitizer dyes and proteins exploit absorbed light to create short-lived reactive oxygen species (ROS) that can mediate biological effects at the target site 4 , 5 . Traditional photosensitizers such as methylene blue have no selectivity, and off-target phototoxicity produced during light exposure limits the applications 6 , 7 . Photosensitizers with improved efficiency of ROS generation, photostability and near-infrared (NIR) light absorption enhance optical tissue penetration and allow real-time fluorescence visualization 8 . More recently, genetically targeted photosensitizers, such as FlAsH and ReAsH, KillerRed and MiniSOG 9 , 10 , 11 , 12 , have been developed to improve targeting and specificity in living cells. The genetic fusion approach allows the photosensitizing protein to produce ROS at the target, selectively inactivating it through chromophore-assisted light inactivation (CALI) of directly linked proteins. These photosensitizer proteins require a very high light dose to reach effective inactivation or cell killing, and the spectral properties of these sensitizers overlap with those of biological chromophores, resulting in some ROS generation even in the absence of the photosensitizer proteins. Photosensitizers with far-red and/or NIR light excitation wavelengths (>620 nm) are required for deep tissue applications and to avoid photosensitization by endogenous chromophores, yet no genetically targeted photosensitizers are available in this spectral range. Activation of a photosensitizer at a target site improves specificity by minimizing the damage to nontargeted tissues 13 . Current activatable photosensitizers either are responsive to local environmental changes, such as changes in pH, or contain a quenching group that is cleaved, increasing photosensitizer activity 14 , 15 , 16 . Although activation increases the ROS production by 10–50-fold, these tools still show some off-target effects from nonspecifically localized materials. Thus, selectively targeting and activating a photosensitizer remains an important goal. To target and activate an ROS-generating photosensitizer, we exploited a genetically targetable and efficient FAP 17 . Fluorogen-FAP complexes have been adapted to a number of applications such as single-molecule imaging 18 , physiological pH measurements 19 and protein detection as recombinant affinity probes 20 . FAP dL5** (previously MBIC5; referred to hereinafter as dL5**) is a 25-kDa binder for malachite green (MG) derivatives that functions throughout living cells with thousands-fold fluorescence activation and a low-picomolar dissociation constant 17 , 21 . We reasoned that suppression of the nonradiative relaxation, which enhances fluorescence in MG fluorogens, could be exploited to modify other photochemical properties, in particular intersystem crossing, when combined with chemically tailored fluorogens 22 . We prepared an iodine-substituted MG analog ( Supplementary Note 1 ) with low free fluorescence and ROS generation that binds to dL5**, producing an NIR light–excitable fluorescent complex with high singlet oxygen ( 1 O 2 ) quantum yield ( Fig. 1a ). We used the dye-protein complex to photo-inactivate fused proteins; to photosensitize cells expressing dL5** at the plasma membrane, cytosol, mitochondrial matrix or nucleus in culture; and to ablate cardiac cells in living larval and adult zebrafish expressing dL5** in the cytoplasm. The free dye showed no photosensitization in cells or zebrafish, indicating that the iodinated MG analog is a potent, NIR light–excitable FAP-TAPs. Figure 1: Characterization of ROS generation by FAP-TAPs. ( a ) Mechanism of ROS generation by FAP-TAPs. IC, internal conversion by molecule's free rotation; ISC, intersystem crossing. ( b ) Normalized excitation (dashed lines) and emission (solid lines) spectra of MG-ester and MG-2I binding to dL5**, where 500 nM fluorogen was complexed with 3 μM dL5** and the fluorescence intensity was individually normalized to the peak maxima. ( c ) 1 O 2 generation by MG-2I–dL5** assessed on the basis of ADPA bleaching, where bleaching of ADPA fluorescence was monitored at 374-nm excitation and 402-nm emission as a function of the duration of 669-nm light exposure. AlPcS 4 was used as standard for the 1 O 2 generation (Φ Δ = 0.34). Optically matched solutions of MG-2I–dL5** and AlPcS 4 at 669 nm were used. n = 4; data are shown as mean ± s.e.m.; in instances of very small s.e.m., error bars overlap points and may not be visible. Source data Full size image Results MG-2I–dL5** as a 1 O 2 -specific photosensitizer Heavy-atom substitutions at some sites on the MG chromophore, which are expected to increase intersystem crossing 23 , 24 , retained high-affinity dL5** binding and fluorescent properties ( Supplementary Fig. 1 ). A di-iodinated derivative of the cell-permeable MG-ester fluorogen (MG-2I) showed dramatically increased photogenerated 1 O 2 when bound to dL5** (FAP-TAPs). The iodination redshifted the major absorption band, moving the excitation maximum of the complex into the NIR light range (666 nm; Supplementary Table 1 and Fig. 1b ). We evaluated the generation of 1 O 2 via bleaching of anthracene-9,10-dipropionic acid (ADPA), a commonly used 1 O 2 scavenger 25 . Relative to aluminum phthalocyanine tetrasulfonate (AlPcS 4 ) 26 , the FAP-TAPs 1 O 2 quantum yield (Φ Δ ) was 0.13 ( Fig. 1c ), whereas generation of 1 O 2 from the MG-ester–dL5** or free TAPs dye was", "role": "user" }, { "content": "Researchers led by Carnegie Mellon University's Molecular and Biosensor Imaging Center (MBIC) Director Marcel Bruchez have re-engineered a fluorescent probe into a powerful optogenetic photosensitizer that can be used to manipulate cells. The technology could help researchers better understand the role certain cells and proteins play in everyday function and disease, and could possibly be used as a targeted therapy for cancer and other diseases. Their findings were published online today by Nature Methods. Optogenetics refers to a process in which light is used to control a biological function. Researchers do this by programming light-activated components into an organism's genetic code. When those components are exposed to light, they cause parts of the organism to function differently. Bruchez and his team have spent the past decade developing fluorescent probes called fluorogen-activating proteins (FAPs) that are used to monitor protein activity in living cells in real-time. A FAP is genetically expressed in a cell and can be linked to the particular protein researchers wish to study. When a FAP comes in contact with a fluorescent dye called a fluorogen, the complex lights up allowing researchers to view and track the protein. \"We realized that we didn't have to limit our technology to being an imaging tool,\" said Bruchez, who is an associate professor in the departments of Biological Sciences and Chemistry. \"With a few modifications, we could transform it into a tool for biological manipulation.\" Carnegie Mellon University's Molecular and Biosensor Imaging Center (MBIC) has re-engineered a fluorescent probe into a powerful optogenetic photosensitizer that can be used to manipulate cells. The technology could help researchers better understand the role certain cells and proteins play in everyday function and disease, and could possibly be used as a targeted therapy for cancer and other diseases. Credit: Carnegie Mellon To create their optogenetic tag, the researchers engineered a dye that would not only glow but also produce singlet oxygen—a toxic form of oxygen—when it bound to a FAP and was exposed to light. This FAP-Targeted and Activated PhotoSensitizer approach (FAP-TAPS) not only allows researchers to visualize the protein they are targeting, but also can be used to selectively inactivate the protein. Previous attempts at developing such photosensitizers have been limited by their inability to selectively bind to target proteins and their need for high doses of light at biologically damaging wavelengths. The FAP-TAPS complex overcomes these obstacles with the precise targeting features of FAPs and the use of light in the far-red or near-infrared spectrums. Light at these wavelengths is both tissue penetrating and biologically safe. The FAP-TAPS approach also requires significantly less light than other photosensitizers, like Killer Red. In addition, singlet oxygen is biologically reactive over a short range, so it doesn't harm proteins in other areas of the cell, or cells in other areas of the organism. In the paper, the researchers proved the effectiveness of the FAP-TAPS module in a population of zebrafish. They first created a fish that expressed the FAP module only in cardiac muscle cells. They then added the dye and exposed the fish to light. In larval fish, the effects were immediate—the heart stopped beating and the blood flow ceased. In adult fish, the fish displayed a cardio-toxic response, and began to transform cardiomyocytes into proliferating cells, which repaired the damage within days. In addition to the proof-of-concept, the results show that FAP-TAPS could be used to study cardiac regeneration in zebrafish. The researchers also believe that FAP-TAPS has the potential to be used for a variety of other purposes, both health-related and in basic research. Such areas include tumor ablation, reactive oxygen signaling and the manipulation of the nervous system. ", "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 Upon illumination, photosensitizer molecules produce reactive oxygen species that can be used for functional manipulation of living cells, including protein inactivation, targeted-damage introduction and cellular ablation. Photosensitizers used to date have been either exogenous, resulting in delivery and removal challenges, or genetically encoded proteins that form or bind a native photosensitizing molecule, resulting in a constitutively active photosensitizer inside the cell. We describe a genetically encoded fluorogen-activating protein (FAP) that binds a heavy atom−substituted fluorogenic dye, forming an 'on-demand' activated photosensitizer that produces singlet oxygen and fluorescence when activated with near-infrared light. This targeted and activated photosensitizer (TAPs) approach enables protein inactivation, targeted cell killing and rapid targeted lineage ablation in living larval and adult zebrafish. The near-infrared excitation and emission of this FAP-TAPs provides a new spectral range for photosensitizer proteins that could be useful for imaging, manipulation and cellular ablation deep within living organisms. Main Light provides precise spatiotemporal control of biological processes when combined with suitable genetic constructs or chemical reagents 1 , 2 , 3 . Photosensitizer dyes and proteins exploit absorbed light to create short-lived reactive oxygen species (ROS) that can mediate biological effects at the target site 4 , 5 . Traditional photosensitizers such as methylene blue have no selectivity, and off-target phototoxicity produced during light exposure limits the applications 6 , 7 . Photosensitizers with improved efficiency of ROS generation, photostability and near-infrared (NIR) light absorption enhance optical tissue penetration and allow real-time fluorescence visualization 8 . More recently, genetically targeted photosensitizers, such as FlAsH and ReAsH, KillerRed and MiniSOG 9 , 10 , 11 , 12 , have been developed to improve targeting and specificity in living cells. The genetic fusion approach allows the photosensitizing protein to produce ROS at the target, selectively inactivating it through chromophore-assisted light inactivation (CALI) of directly linked proteins. These photosensitizer proteins require a very high light dose to reach effective inactivation or cell killing, and the spectral properties of these sensitizers overlap with those of biological chromophores, resulting in some ROS generation even in the absence of the photosensitizer proteins. Photosensitizers with far-red and/or NIR light excitation wavelengths (>620 nm) are required for deep tissue applications and to avoid photosensitization by endogenous chromophores, yet no genetically targeted photosensitizers are available in this spectral range. Activation of a photosensitizer at a target site improves specificity by minimizing the damage to nontargeted tissues 13 . Current activatable photosensitizers either are responsive to local environmental changes, such as changes in pH, or contain a quenching group that is cleaved, increasing photosensitizer activity 14 , 15 , 16 . Although activation increases the ROS production by 10–50-fold, these tools still show some off-target effects from nonspecifically localized materials. Thus, selectively targeting and activating a photosensitizer remains an important goal. To target and activate an ROS-generating photosensitizer, we exploited a genetically targetable and efficient FAP 17 . Fluorogen-FAP complexes have been adapted to a number of applications such as single-molecule imaging 18 , physiological pH measurements 19 and protein detection as recombinant affinity probes 20 . FAP dL5** (previously MBIC5; referred to hereinafter as dL5**) is a 25-kDa binder for malachite green (MG) derivatives that functions throughout living cells with thousands-fold fluorescence activation and a low-picomolar dissociation constant 17 , 21 . We reasoned that suppression of the nonradiative relaxation, which enhances fluorescence in MG fluorogens, could be exploited to modify other photochemical properties, in particular intersystem crossing, when combined with chemically tailored fluorogens 22 . We prepared an iodine-substituted MG analog ( Supplementary Note 1 ) with low free fluorescence and ROS generation that binds to dL5**, producing an NIR light–excitable fluorescent complex with high singlet oxygen ( 1 O 2 ) quantum yield ( Fig. 1a ). We used the dye-protein complex to photo-inactivate fused proteins; to photosensitize cells expressing dL5** at the plasma membrane, cytosol, mitochondrial matrix or nucleus in culture; and to ablate cardiac cells in living larval and adult zebrafish expressing dL5** in the cytoplasm. The free dye showed no photosensitization in cells or zebrafish, indicating that the iodinated MG analog is a potent, NIR light–excitable FAP-TAPs. Figure 1: Characterization of ROS generation by FAP-TAPs. ( a ) Mechanism of ROS generation by FAP-TAPs. IC, internal conversion by molecule's free rotation; ISC, intersystem crossing. ( b ) Normalized excitation (dashed lines) and emission (solid lines) spectra of MG-ester and MG-2I binding to dL5**, where 500 nM fluorogen was complexed with 3 μM dL5** and the fluorescence intensity was individually normalized to the peak maxima. ( c ) 1 O 2 generation by MG-2I–dL5** assessed on the basis of ADPA bleaching, where bleaching of ADPA fluorescence was monitored at 374-nm excitation and 402-nm emission as a function of the duration of 669-nm light exposure. AlPcS 4 was used as standard for the 1 O 2 generation (Φ Δ = 0.34). Optically matched solutions of MG-2I–dL5** and AlPcS 4 at 669 nm were used. n = 4; data are shown as mean ± s.e.m.; in instances of very small s.e.m., error bars overlap points and may not be visible. Source data Full size image Results MG-2I–dL5** as a 1 O 2 -specific photosensitizer Heavy-atom substitutions at some sites on the MG chromophore, which are expected to increase intersystem crossing 23 , 24 , retained high-affinity dL5** binding and fluorescent properties ( Supplementary Fig. 1 ). A di-iodinated derivative of the cell-permeable MG-ester fluorogen (MG-2I) showed dramatically increased photogenerated 1 O 2 when bound to dL5** (FAP-TAPs). The iodination redshifted the major absorption band, moving the excitation maximum of the complex into the NIR light range (666 nm; Supplementary Table 1 and Fig. 1b ). We evaluated the generation of 1 O 2 via bleaching of anthracene-9,10-dipropionic acid (ADPA), a commonly used 1 O 2 scavenger 25 . Relative to aluminum phthalocyanine tetrasulfonate (AlPcS 4 ) 26 , the FAP-TAPs 1 O 2 quantum yield (Φ Δ ) was 0.13 ( Fig. 1c ), whereas generation of 1 O 2 from the MG-ester–dL5** or free TAPs dye was<|im_end|> <|im_start|>assistant Researchers led by Carnegie Mellon University's Molecular and Biosensor Imaging Center (MBIC) Director Marcel Bruchez have re-engineered a fluorescent probe into a powerful optogenetic photosensitizer that can be used to manipulate cells. The technology could help researchers better understand the role certain cells and proteins play in everyday function and disease, and could possibly be used as a targeted therapy for cancer and other diseases. Their findings were published online today by Nature Methods. Optogenetics refers to a process in which light is used to control a biological function. Researchers do this by programming light-activated components into an organism's genetic code. When those components are exposed to light, they cause parts of the organism to function differently. Bruchez and his team have spent the past decade developing fluorescent probes called fluorogen-activating proteins (FAPs) that are used to monitor protein activity in living cells in real-time. A FAP is genetically expressed in a cell and can be linked to the particular protein researchers wish to study. When a FAP comes in contact with a fluorescent dye called a fluorogen, the complex lights up allowing researchers to view and track the protein. "We realized that we didn't have to limit our technology to being an imaging tool," said Bruchez, who is an associate professor in the departments of Biological Sciences and Chemistry. "With a few modifications, we could transform it into a tool for biological manipulation." Carnegie Mellon University's Molecular and Biosensor Imaging Center (MBIC) has re-engineered a fluorescent probe into a powerful optogenetic photosensitizer that can be used to manipulate cells. The technology could help researchers better understand the role certain cells and proteins play in everyday function and disease, and could possibly be used as a targeted therapy for cancer and other diseases. Credit: Carnegie Mellon To create their optogenetic tag, the researchers engineered a dye that would not only glow but also produce singlet oxygen—a toxic form of oxygen—when it bound to a FAP and was exposed to light. This FAP-Targeted and Activated PhotoSensitizer approach (FAP-TAPS) not only allows researchers to visualize the protein they are targeting, but also can be used to selectively inactivate the protein. Previous attempts at developing such photosensitizers have been limited by their inability to selectively bind to target proteins and their need for high doses of light at biologically damaging wavelengths. The FAP-TAPS complex overcomes these obstacles with the precise targeting features of FAPs and the use of light in the far-red or near-infrared spectrums. Light at these wavelengths is both tissue penetrating and biologically safe. The FAP-TAPS approach also requires significantly less light than other photosensitizers, like Killer Red. In addition, singlet oxygen is biologically reactive over a short range, so it doesn't harm proteins in other areas of the cell, or cells in other areas of the organism. In the paper, the researchers proved the effectiveness of the FAP-TAPS module in a population of zebrafish. They first created a fish that expressed the FAP module only in cardiac muscle cells. They then added the dye and exposed the fish to light. In larval fish, the effects were immediate—the heart stopped beating and the blood flow ceased. In adult fish, the fish displayed a cardio-toxic response, and began to transform cardiomyocytes into proliferating cells, which repaired the damage within days. In addition to the proof-of-concept, the results show that FAP-TAPS could be used to study cardiac regeneration in zebrafish. The researchers also believe that FAP-TAPS has the potential to be used for a variety of other purposes, both health-related and in basic research. Such areas include tumor ablation, reactive oxygen signaling and the manipulation of the nervous system. <|im_end|>

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2,379

[ { "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 With advances in care, neonates undergoing cardiac repairs are surviving more frequently. Our objectives were to 1) estimate the prevalence of chronic kidney disease (CKD) and hypertension 6 years after neonatal congenital heart surgery and 2) determine if cardiac surgery-associated acute kidney injury (CS-AKI) is associated with these outcomes. Methods Two-center prospective, longitudinal single-visit cohort study including children with congenital heart disease surgery as neonates between January 2005 and December 2012. CKD (estimated glomerular filtration rate < 90 mL/min/1.73m 2 or albumin/creatinine ≥3 mg/mmol) and hypertension (systolic or diastolic blood pressure ≥ 95th percentile for age, sex, and height) prevalence 6 years after surgery was estimated. The association of CS-AKI (Kidney Disease: Improving Global Outcomes definition) with CKD and hypertension was determined using multiple regression. Results Fifty-eight children with median follow-up of 6 years were evaluated. CS-AKI occurred in 58%. CKD and hypertension prevalence were 17% and 30%, respectively; an additional 15% were classified as having elevated blood pressure. CS-AKI was not associated with CKD or hypertension. Classification as cyanotic postoperatively was the only independent predictor of CKD. Postoperative days in hospital predicted hypertension at follow-up. Conclusions The prevalence of CKD and hypertension is high in children having neonatal congenital heart surgery. This is important; early identification of CKD and hypertension can improve outcomes. These children should be systematically followed for the evolution of these negative outcomes. CS-AKI defined by current standards may not be a useful clinical tool to decide who needs follow-up and who does not. Working on a manuscript? Avoid the common mistakes Introduction Epidemiological studies have shown the prevalence of cardiac surgery-associated acute kidney injury (CS-AKI) to be as high as 50–60% in neonates [ 1 , 2 ]. While much is known about the short-term outcomes of these patients, including prolonged ventilation, prolonged intensive care admission, and longer hospital stay [ 1 , 3 ], there is less known about the long-term renal outcomes such as chronic kidney disease (CKD) and hypertension. Two recent studies of pediatric patients showed no association of CS-AKI (measured by changes in serum creatinine) with long-term renal outcomes [ 4 , 5 ]. However, these studies did not include neonates, who have a unique renal physiology compared with the general pediatric population and perhaps have different critical care risks [ 6 ]. With advances in care, neonates undergoing complex cardiac repairs are surviving more frequently, resulting in a markedly increasing number of adults with congenital heart disease [ 7 , 8 ]. Given the lack of knowledge of long-term renal function in neonates, there is a need to further elucidate the risk of CKD and the role of neonatal CS-AKI in this vulnerable patient population. Chronic kidney disease causes significant personal and economic healthcare burden and is associated with worse long-term outcome, quality of life, and well-being in the general population [ 9 ]. It is a condition where early identification and intervention to mitigate modifiable risks can delay progression. Currently, there are no evidence-based guidelines for the follow-up of neonates after congenital heart repair relevant to renal health. We hypothesized that CKD and hypertension are common in children who undergo neonatal congenital heart surgery and that CS-AKI increases long-term risk for CKD and hypertension. Our objectives were to 1) estimate the prevalence of CKD and hypertension 5–7 years after neonatal cardiac surgery and 2) determine if CS-AKI is a risk factor for later CKD and hypertension. Materials and methods Study cohort and recruitment This is a two-center, longitudinal, cohort study of neonates who underwent neonatal congenital heart surgery at the Montreal Children’s Hospital, Montreal, Canada, and the Stollery Children’s Hospital, Edmonton, Canada, between January 2005 and December 2012. Exclusion criteria were preoperative known kidney disease, already recruited into a longitudinal study, unwillingness to return to the study center for assessments, or lived too far away (> 3.5-h drive) from the center for home study visits. Institutional Research Ethics Board approval was obtained before initiating this study. Written informed consent was provided by parents/legal guardians prior to initiating study activities with participants. Study population source Patients were identified (via hospital databases), reviewed for eligibility, and mailed invitations to contact us for study information. Responders were contacted, re-reviewed for eligibility, and invited to participate. In addition, children attending cardiology clinics in both Edmonton and Montreal fitting eligibility criteria were invited to participate, and children previously consenting to future contact during prior studies were contacted by telephone. Study procedure A single standardized study visit was performed 5 to 7 years post-cardiac surgery at the clinic research center or the patient’s home. Study staff were blind to past AKI status. Blood (minimum 1.5 mL) and urine (minimum 5 mL) samples were collected. Three measures of height (by either SECA 217 stadiometer, SECA; standardized supine measurement; or measuring tape if limited mobility) and weight (UC-321 PL Precision Health scale, A&D Medical; barefoot; bulky clothing removed) were taken, and the average was calculated. Height and weight, age and gender-specific percentiles, and z-scores were calculated using Centers for Disease Control and Prevention growth charts [ 10 ]. Three automated blood pressure (BP) measurements were performed (Omron HEM-711AC, Omron Healthcare, Inc.; regularly calibrated) in a quiet setting (efforts to reduce anxiety; before blood work), seated, using size-appropriate cuffs on the right arm (unless contraindicated). The average of the two lowest blood pressure measurements was used to calculate the age, gender, and height-specific blood pressure percentile. Blood pressure percentiles were calculated according to the 2017 American Academy of Pediatrics blood pressure guideline [ 11 ]. Data was collected on the use of anti-hypertensive medications. Index cardiac surgery data Relevant clinical data from the index cardiac surgery admission were collected retrospectively by chart review. Preoperative variables collected included sex, gestational age (weeks), age (days), weight (kg) and length (cm) at surgery, baseline serum creatinine (SCr, defined as the last creatinine drawn before surgery), ventilated at the time of surgery, and use of preoperative extracorporeal membrane oxygenation (ECMO). Complexity of cardiac surgery was categorized using the risk adjustment", "role": "user" }, { "content": "Babies who have life-saving surgery for congenital heart problems within the first month of life face a lifelong risk of chronic kidney disease and high blood pressure, according to new research led by University of Alberta pediatric specialists. \"We know that kidneys, like all organs, have to last a lifetime,\" said Catherine Morgan, associate professor and interim divisional director of pediatric nephrology in the U of A's Faculty of Medicine & Dentistry. \"Most children who have had cardiac surgery as neonates will survive and are going to live a long time, so we need to look at what associated kidney damage during this critical time might mean for them throughout their lives. The numbers were quite significant and worrying, and really important for us in terms of thinking about followup.\" The researchers examined 58 six-year-old cardiac surgery survivors at Edmonton's Stollery Children's Hospital and the Montreal Children's Hospital. Seventeen percent of the children were found to have chronic kidney disease, compared with two percent of the general pediatric population in Canada. Thirty percent of the survivors had high blood pressure, compared with less than one percent overall. In a second study, the researchers found that only a third of the cardiac survivors had an assessment of their kidney function within the first six years of life. \"Up until now there has been really no data about the long-term impact of acute kidney injury after cardiac surgery as it relates to high blood pressure and chronic kidney disease in childhood,\" said Andrew Mackie, professor and Stollery Science Lab Distinguished Researcher. Mackie, a cardiologist with Western Canada's largest pediatric heart program, said 90 percent of children born with a heart defect survive to adulthood. \"This is a huge advance compared to 20 or 30 years ago,\" Mackie said. \"Now the focus in newborns with complex heart disease is less on survival and more on their long-term outcomes.\" New tests, better follow-up Mackie explained that patients of any age can experience acute injury to the kidneys during and after cardiac surgery because the organs are sensitive to blood flow from a bypass machine or a repaired heart that may not yet be fully functional. Some medications can also damage kidneys. \"We know in adults, other pediatric populations and also now in neonates, that if you have acute kidney injury in hospital, your outcomes are not as good, so the hospital stays are longer, they're ventilated longer, the risk of death is higher,\" Morgan said. Morgan estimated that 40 to 60 percent of neonatal heart surgery patients experience acute kidney injury, but noted it can be hard to detect because the only available test is not considered definitive, especially in infants. The blood creatinine test measures a muscle waste product that can be elevated if the kidneys are not working properly, but measurements can go up for other reasons as well and are highly variable, particularly in babies and in children in intensive care. \"We define kidney injury based on just one blood marker, which raises the question of whether that is a good enough way to define it,\" she said, adding that research is underway around the world to find better biomarkers to test for kidney injury. Unchecked, chronic kidney disease and high blood pressure can lead to more heart problems later in life. \"Being a survivor of a congenital heart defect equates to living with a chronic health condition and requires lifelong followup and screening for late complications, not just of the heart but other organ systems as well, and not only through childhood but into adulthood,\" said Mackie. Morgan said the research results, which were funded by the Canadian Institutes of Health Research, should lead to new clinical practice guidelines to ensure neonatal heart patients are monitored every year or two for chronic kidney disease and high blood pressure, and given treatment if necessary. \"The real driver for me is about improving the quality of care for these children as they grow into adulthood,\" 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 Background With advances in care, neonates undergoing cardiac repairs are surviving more frequently. Our objectives were to 1) estimate the prevalence of chronic kidney disease (CKD) and hypertension 6 years after neonatal congenital heart surgery and 2) determine if cardiac surgery-associated acute kidney injury (CS-AKI) is associated with these outcomes. Methods Two-center prospective, longitudinal single-visit cohort study including children with congenital heart disease surgery as neonates between January 2005 and December 2012. CKD (estimated glomerular filtration rate < 90 mL/min/1.73m 2 or albumin/creatinine ≥3 mg/mmol) and hypertension (systolic or diastolic blood pressure ≥ 95th percentile for age, sex, and height) prevalence 6 years after surgery was estimated. The association of CS-AKI (Kidney Disease: Improving Global Outcomes definition) with CKD and hypertension was determined using multiple regression. Results Fifty-eight children with median follow-up of 6 years were evaluated. CS-AKI occurred in 58%. CKD and hypertension prevalence were 17% and 30%, respectively; an additional 15% were classified as having elevated blood pressure. CS-AKI was not associated with CKD or hypertension. Classification as cyanotic postoperatively was the only independent predictor of CKD. Postoperative days in hospital predicted hypertension at follow-up. Conclusions The prevalence of CKD and hypertension is high in children having neonatal congenital heart surgery. This is important; early identification of CKD and hypertension can improve outcomes. These children should be systematically followed for the evolution of these negative outcomes. CS-AKI defined by current standards may not be a useful clinical tool to decide who needs follow-up and who does not. Working on a manuscript? Avoid the common mistakes Introduction Epidemiological studies have shown the prevalence of cardiac surgery-associated acute kidney injury (CS-AKI) to be as high as 50–60% in neonates [ 1 , 2 ]. While much is known about the short-term outcomes of these patients, including prolonged ventilation, prolonged intensive care admission, and longer hospital stay [ 1 , 3 ], there is less known about the long-term renal outcomes such as chronic kidney disease (CKD) and hypertension. Two recent studies of pediatric patients showed no association of CS-AKI (measured by changes in serum creatinine) with long-term renal outcomes [ 4 , 5 ]. However, these studies did not include neonates, who have a unique renal physiology compared with the general pediatric population and perhaps have different critical care risks [ 6 ]. With advances in care, neonates undergoing complex cardiac repairs are surviving more frequently, resulting in a markedly increasing number of adults with congenital heart disease [ 7 , 8 ]. Given the lack of knowledge of long-term renal function in neonates, there is a need to further elucidate the risk of CKD and the role of neonatal CS-AKI in this vulnerable patient population. Chronic kidney disease causes significant personal and economic healthcare burden and is associated with worse long-term outcome, quality of life, and well-being in the general population [ 9 ]. It is a condition where early identification and intervention to mitigate modifiable risks can delay progression. Currently, there are no evidence-based guidelines for the follow-up of neonates after congenital heart repair relevant to renal health. We hypothesized that CKD and hypertension are common in children who undergo neonatal congenital heart surgery and that CS-AKI increases long-term risk for CKD and hypertension. Our objectives were to 1) estimate the prevalence of CKD and hypertension 5–7 years after neonatal cardiac surgery and 2) determine if CS-AKI is a risk factor for later CKD and hypertension. Materials and methods Study cohort and recruitment This is a two-center, longitudinal, cohort study of neonates who underwent neonatal congenital heart surgery at the Montreal Children’s Hospital, Montreal, Canada, and the Stollery Children’s Hospital, Edmonton, Canada, between January 2005 and December 2012. Exclusion criteria were preoperative known kidney disease, already recruited into a longitudinal study, unwillingness to return to the study center for assessments, or lived too far away (> 3.5-h drive) from the center for home study visits. Institutional Research Ethics Board approval was obtained before initiating this study. Written informed consent was provided by parents/legal guardians prior to initiating study activities with participants. Study population source Patients were identified (via hospital databases), reviewed for eligibility, and mailed invitations to contact us for study information. Responders were contacted, re-reviewed for eligibility, and invited to participate. In addition, children attending cardiology clinics in both Edmonton and Montreal fitting eligibility criteria were invited to participate, and children previously consenting to future contact during prior studies were contacted by telephone. Study procedure A single standardized study visit was performed 5 to 7 years post-cardiac surgery at the clinic research center or the patient’s home. Study staff were blind to past AKI status. Blood (minimum 1.5 mL) and urine (minimum 5 mL) samples were collected. Three measures of height (by either SECA 217 stadiometer, SECA; standardized supine measurement; or measuring tape if limited mobility) and weight (UC-321 PL Precision Health scale, A&D Medical; barefoot; bulky clothing removed) were taken, and the average was calculated. Height and weight, age and gender-specific percentiles, and z-scores were calculated using Centers for Disease Control and Prevention growth charts [ 10 ]. Three automated blood pressure (BP) measurements were performed (Omron HEM-711AC, Omron Healthcare, Inc.; regularly calibrated) in a quiet setting (efforts to reduce anxiety; before blood work), seated, using size-appropriate cuffs on the right arm (unless contraindicated). The average of the two lowest blood pressure measurements was used to calculate the age, gender, and height-specific blood pressure percentile. Blood pressure percentiles were calculated according to the 2017 American Academy of Pediatrics blood pressure guideline [ 11 ]. Data was collected on the use of anti-hypertensive medications. Index cardiac surgery data Relevant clinical data from the index cardiac surgery admission were collected retrospectively by chart review. Preoperative variables collected included sex, gestational age (weeks), age (days), weight (kg) and length (cm) at surgery, baseline serum creatinine (SCr, defined as the last creatinine drawn before surgery), ventilated at the time of surgery, and use of preoperative extracorporeal membrane oxygenation (ECMO). Complexity of cardiac surgery was categorized using the risk adjustment<|im_end|> <|im_start|>assistant Babies who have life-saving surgery for congenital heart problems within the first month of life face a lifelong risk of chronic kidney disease and high blood pressure, according to new research led by University of Alberta pediatric specialists. "We know that kidneys, like all organs, have to last a lifetime," said Catherine Morgan, associate professor and interim divisional director of pediatric nephrology in the U of A's Faculty of Medicine & Dentistry. "Most children who have had cardiac surgery as neonates will survive and are going to live a long time, so we need to look at what associated kidney damage during this critical time might mean for them throughout their lives. The numbers were quite significant and worrying, and really important for us in terms of thinking about followup." The researchers examined 58 six-year-old cardiac surgery survivors at Edmonton's Stollery Children's Hospital and the Montreal Children's Hospital. Seventeen percent of the children were found to have chronic kidney disease, compared with two percent of the general pediatric population in Canada. Thirty percent of the survivors had high blood pressure, compared with less than one percent overall. In a second study, the researchers found that only a third of the cardiac survivors had an assessment of their kidney function within the first six years of life. "Up until now there has been really no data about the long-term impact of acute kidney injury after cardiac surgery as it relates to high blood pressure and chronic kidney disease in childhood," said Andrew Mackie, professor and Stollery Science Lab Distinguished Researcher. Mackie, a cardiologist with Western Canada's largest pediatric heart program, said 90 percent of children born with a heart defect survive to adulthood. "This is a huge advance compared to 20 or 30 years ago," Mackie said. "Now the focus in newborns with complex heart disease is less on survival and more on their long-term outcomes." New tests, better follow-up Mackie explained that patients of any age can experience acute injury to the kidneys during and after cardiac surgery because the organs are sensitive to blood flow from a bypass machine or a repaired heart that may not yet be fully functional. Some medications can also damage kidneys. "We know in adults, other pediatric populations and also now in neonates, that if you have acute kidney injury in hospital, your outcomes are not as good, so the hospital stays are longer, they're ventilated longer, the risk of death is higher," Morgan said. Morgan estimated that 40 to 60 percent of neonatal heart surgery patients experience acute kidney injury, but noted it can be hard to detect because the only available test is not considered definitive, especially in infants. The blood creatinine test measures a muscle waste product that can be elevated if the kidneys are not working properly, but measurements can go up for other reasons as well and are highly variable, particularly in babies and in children in intensive care. "We define kidney injury based on just one blood marker, which raises the question of whether that is a good enough way to define it," she said, adding that research is underway around the world to find better biomarkers to test for kidney injury. Unchecked, chronic kidney disease and high blood pressure can lead to more heart problems later in life. "Being a survivor of a congenital heart defect equates to living with a chronic health condition and requires lifelong followup and screening for late complications, not just of the heart but other organ systems as well, and not only through childhood but into adulthood," said Mackie. Morgan said the research results, which were funded by the Canadian Institutes of Health Research, should lead to new clinical practice guidelines to ensure neonatal heart patients are monitored every year or two for chronic kidney disease and high blood pressure, and given treatment if necessary. "The real driver for me is about improving the quality of care for these children as they grow into adulthood," she said. <|im_end|>

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2,191

[ { "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 Methane hydrate dissociation has long been considered as a mechanism for global carbon cycle perturbations, climate change and even mass extinctions in Earth’s history. However, direct evidence of hydrate destabilization and methane release coinciding with such events is scarce. Here we report the presence of diagnostic lipid biomarkers with depleted carbon isotopes from three sites in the Southern Ocean that are directly linked to methane release and subsequent oxidation across the Oligocene–Miocene boundary (23 million years ago). The biomarker evidence indicates that the hydrate destabilization was initiated during the peak of the Oligocene–Miocene boundary glaciation and sea-level low stand, consistent with our model results suggesting the decrease in hydrostatic pressure eroded the base of global methane hydrate stability zones. Aerobic oxidation of methane in seawater consumes oxygen and acidifies the ocean, acting as a negative feedback that perhaps facilitated the rapid and mysterious termination of glaciation in the early Miocene. Main Thousands of gigatons (10 15 g) of carbon is stored beneath the seafloor as marine methane hydrates, making it one of the largest readily exchangeable carbon reservoirs near Earth’s surface 1 . Small changes to boundary conditions (for example, temperature and pressure) could perturbate gas hydrates and lead to methane release into the ocean and, sometimes, the atmosphere 2 . Documenting the destabilization of marine methane hydrates associated with ocean warming, continental slope instability or sea-level fluctuations in Earth’s history could provide useful lessons towards understanding the relationships between hydrate stability, the global carbon cycle and climate. Various global change events are thought to be related to hydrate dissociation, such as (1) the deglaciation after the Neoproterozoic snowball Earth 3 , (2) the Permian–Triassic global warming and mass extinction 4 and (3) the rapid warming and ocean acidification during the Palaeocene–Eocene thermal maximum 5 . However, most of these inferred methane release events are either based on conceptual models or the stable carbon and oxygen isotopes of carbonates, which are susceptible to post-deposition diagenetic alteration 6 , 7 . Little direct evidence for methane hydrate dissociation has been identified at these key events. Lipid biomarkers linked to methane cycling The consumption of methane in the ocean is largely mediated by microbes. These microbes synthesize diagnostic lipid compounds (‘biomarkers’), which are preserved in sediments for millions of years. At present, ~90% of methane in marine sediments is oxidized anaerobically (anaerobic oxidation of methane (AOM); equation ( 1 )) by consortia of methanotrophic archaea (ANME groups) and sulfate-reducing bacteria 8 , 9 , but if methane bubbles reach the oxygen-laden pore water or seawater, the oxidation is aerobic (equation ( 2 )), carried out by methanotrophic bacteria 10 : $${{{\\mathrm{CH}}}}_{4} + {{{{\\mathrm{SO}}}}_{4}}^{2 - } \\to {{{{\\mathrm{HCO}}}}_{3}}^ {-} + {{{\\mathrm{HS}}}}^ {-} + {{{\\mathrm{H}}}}_{2}{{{\\mathrm{O}}}}$$ (1) $${{{\\mathrm{CH}}}}_{{{\\mathrm{4}}}}+{{{\\mathrm{2O}}}}_{{{\\mathrm{2}}}} \\to {{{\\mathrm{CO}}}}_{{{\\mathrm{2}}}}+{{{\\mathrm{2H}}}}_{{{\\mathrm{2}}}}{{{\\mathrm{O}}}}$$ (2) Studies on the lipid biomarkers of microorganisms tightly linked to methane cycling have shown that these ‘molecular fossils’ could provide direct evidence for ancient methane release 11 . For example, archaeal lipids, such as crocetane, PMI (2,6,10,15,19-pentamethylicosane), archaeol and hydroxyarchaeol, have been reported from both modern and ancient cold seep environments, with an ANME origin 12 , 13 . Also, bacterial aerobic methane oxidation is linked to hopanoids such as diploptene and diplopterol 14 , 15 . Finally, these lipid biomarkers synthesized by microorganisms performing assimilative methanotrophy are 13 C-depleted, with reported carbon isotope (δ 13 C) values ranging from −40 to −130‰ (refs. 11 , 12 , 15 , 16 ). More recently, a diagnostic combination of archaeal lipids called glycerol dialkyl glycerol tetraethers (GDGTs), represented by the methane index (MI) 16 , was added to the AOM biomarker toolbox. High MI values (>0.3–0.5) are linked to methanotrophy, based on the rationale that a major group of methanotrophic archaea (ANME-1) preferentially synthesize GDGTs with one to three cyclopentane rings. GDGTs are often measured from marine sediments because of the large number of palaeoclimate applications of TEX 86 , a sea surface temperature (SST) proxy also based on the relative composition of GDGTs 17 . For samples with published TEX 86 , MI values can also be calculated and are even reported. We therefore used MI to screen published and our newly measured GDGT data from the late Oligocene to early Miocene to provide the initial evidence of methane release, which was followed by additional biomarkers and their compound-specific δ 13 C measurements to further verify the presence of methane in the past. Oligocene–Miocene boundary climate change and methane release The Oligocene and Miocene epochs (34–5 million years ago; Ma) represent the transition from a greenhouse climate state of the early Cenozoic to the Quaternary ice house 18 . The late Oligocene to early Miocene period arguably represents some of the most prominent and enigmatic climatic shifts in Earth’s Cenozoic history. For example, the Oligocene–Miocene boundary (OMB, ~23 Ma) is characterized by ~1‰ positive excursion of the benthic foraminiferal oxygen isotope (δ 18 O), attributed to both temperature and high-latitude ice-sheet fluctuation 19 , 20 . Rapidly deposited glaciomarine sequences in the Ross Sea indicate ice-sheet expansion in East Antarctica during this ‘Mi-1’ glaciation 21 . However, unlike the Eocene–Oligocene transition (~34 Ma), when a comparable δ 18 O excursion marked the onset of the first continental-scale glaciation of East Antarctica, the Antarctic ice growth during Mi-1 glaciation was terminated in ~300 kyr. The benthic δ 18 O signature then returned to almost pre-event values 22 , 23 . The driver of this rapid climate swing is poorly understood, but existing evidence points towards the important role of the global carbon cycle. For example, recent atmospheric CO 2 reconstructions based on boron isotopes revealed an ~100 parts per million by volume (ppm) or ~40% increase during the deglacial phase of Mi-1 24 . However, the driver of the increased greenhouse gas level that contributed to the ephemeral nature of the Mi-1 glaciation is yet to be identified. To evaluate the potential role of the marine gas hydrate system in the global carbon cycle and climate, we analysed the lipid biomarkers of late Oligocene–early", "role": "user" }, { "content": "Sediment cores taken from the Southern Ocean dating back 23 million years are providing insight into how ancient methane escaping from the seafloor could have led to regional or global climate and environmental changes, according to a study from two Texas A&M University researchers. Yige Zhang, assistant professor in the Department of Oceanography at Texas A&M, and doctoral student Bumsoo Kim have had their work published in the current issue of Nature Geoscience. The oceanographers examined cores—sediment samples from deep parts of the ocean floor—from the Oligocene-Miocene era, roughly 23 million years ago, from areas near Tasmania and Antarctica in the Pacific sector of the Southern Ocean. There are billions of tons of carbon stored beneath the ocean floor as gas hydrates—ice-like crystals composed of water and natural gas. Past releases of methane are believed to be related to huge earth events, such as global warming and subsequent climate shifts. \"For a long time, people thought that methane released from the ocean floor could go into the atmosphere and directly contribute to the greenhouse effect, leading to rapid warming and even mass extinctions,\" Zhang said. \"But this idea is no longer popular in the last decade or so because we lack direct evidence of methane release in Earth's history. Also, modern observations show that even when methane gasses are released, they rarely make it to the atmosphere.\" However, Kim and Zhang are now able to document past methane release by using markers that consume methane. These \"methane-eating\" substances are preserved in sediments for tens of millions of years, the researchers said. They could provide direct evidence of methane release from different places in the Southern Ocean. \"We saw that a methane release occurred during a peak glaciation about 23 million years ago,\" Zhang said. Glaciation is the formation, movement and recession of glaciers, and the process mostly commonly occurs in Antarctica and Greenland. When large ice sheets form, they draw in a tremendous amount of water that could lower the sea-level by tens to hundreds of feet. Zhang added that the methane gas release and its after-effects led to ocean acidification and hypoxia (a lack of oxygen in the water), something that has been observed after the Deepwater Horizon incident in 2010, when large amounts of methane were released in the Gulf of Mexico. \"One implication of our study is that if gas hydrates start to decompose in the future due to ocean warming, places like the Gulf of Mexico could suffer severely from ocean acidification and expansion of the low oxygen 'dead zones',\" Kim 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 Methane hydrate dissociation has long been considered as a mechanism for global carbon cycle perturbations, climate change and even mass extinctions in Earth’s history. However, direct evidence of hydrate destabilization and methane release coinciding with such events is scarce. Here we report the presence of diagnostic lipid biomarkers with depleted carbon isotopes from three sites in the Southern Ocean that are directly linked to methane release and subsequent oxidation across the Oligocene–Miocene boundary (23 million years ago). The biomarker evidence indicates that the hydrate destabilization was initiated during the peak of the Oligocene–Miocene boundary glaciation and sea-level low stand, consistent with our model results suggesting the decrease in hydrostatic pressure eroded the base of global methane hydrate stability zones. Aerobic oxidation of methane in seawater consumes oxygen and acidifies the ocean, acting as a negative feedback that perhaps facilitated the rapid and mysterious termination of glaciation in the early Miocene. Main Thousands of gigatons (10 15 g) of carbon is stored beneath the seafloor as marine methane hydrates, making it one of the largest readily exchangeable carbon reservoirs near Earth’s surface 1 . Small changes to boundary conditions (for example, temperature and pressure) could perturbate gas hydrates and lead to methane release into the ocean and, sometimes, the atmosphere 2 . Documenting the destabilization of marine methane hydrates associated with ocean warming, continental slope instability or sea-level fluctuations in Earth’s history could provide useful lessons towards understanding the relationships between hydrate stability, the global carbon cycle and climate. Various global change events are thought to be related to hydrate dissociation, such as (1) the deglaciation after the Neoproterozoic snowball Earth 3 , (2) the Permian–Triassic global warming and mass extinction 4 and (3) the rapid warming and ocean acidification during the Palaeocene–Eocene thermal maximum 5 . However, most of these inferred methane release events are either based on conceptual models or the stable carbon and oxygen isotopes of carbonates, which are susceptible to post-deposition diagenetic alteration 6 , 7 . Little direct evidence for methane hydrate dissociation has been identified at these key events. Lipid biomarkers linked to methane cycling The consumption of methane in the ocean is largely mediated by microbes. These microbes synthesize diagnostic lipid compounds (‘biomarkers’), which are preserved in sediments for millions of years. At present, ~90% of methane in marine sediments is oxidized anaerobically (anaerobic oxidation of methane (AOM); equation ( 1 )) by consortia of methanotrophic archaea (ANME groups) and sulfate-reducing bacteria 8 , 9 , but if methane bubbles reach the oxygen-laden pore water or seawater, the oxidation is aerobic (equation ( 2 )), carried out by methanotrophic bacteria 10 : $${{{\mathrm{CH}}}}_{4} + {{{{\mathrm{SO}}}}_{4}}^{2 - } \to {{{{\mathrm{HCO}}}}_{3}}^ {-} + {{{\mathrm{HS}}}}^ {-} + {{{\mathrm{H}}}}_{2}{{{\mathrm{O}}}}$$ (1) $${{{\mathrm{CH}}}}_{{{\mathrm{4}}}}+{{{\mathrm{2O}}}}_{{{\mathrm{2}}}} \to {{{\mathrm{CO}}}}_{{{\mathrm{2}}}}+{{{\mathrm{2H}}}}_{{{\mathrm{2}}}}{{{\mathrm{O}}}}$$ (2) Studies on the lipid biomarkers of microorganisms tightly linked to methane cycling have shown that these ‘molecular fossils’ could provide direct evidence for ancient methane release 11 . For example, archaeal lipids, such as crocetane, PMI (2,6,10,15,19-pentamethylicosane), archaeol and hydroxyarchaeol, have been reported from both modern and ancient cold seep environments, with an ANME origin 12 , 13 . Also, bacterial aerobic methane oxidation is linked to hopanoids such as diploptene and diplopterol 14 , 15 . Finally, these lipid biomarkers synthesized by microorganisms performing assimilative methanotrophy are 13 C-depleted, with reported carbon isotope (δ 13 C) values ranging from −40 to −130‰ (refs. 11 , 12 , 15 , 16 ). More recently, a diagnostic combination of archaeal lipids called glycerol dialkyl glycerol tetraethers (GDGTs), represented by the methane index (MI) 16 , was added to the AOM biomarker toolbox. High MI values (>0.3–0.5) are linked to methanotrophy, based on the rationale that a major group of methanotrophic archaea (ANME-1) preferentially synthesize GDGTs with one to three cyclopentane rings. GDGTs are often measured from marine sediments because of the large number of palaeoclimate applications of TEX 86 , a sea surface temperature (SST) proxy also based on the relative composition of GDGTs 17 . For samples with published TEX 86 , MI values can also be calculated and are even reported. We therefore used MI to screen published and our newly measured GDGT data from the late Oligocene to early Miocene to provide the initial evidence of methane release, which was followed by additional biomarkers and their compound-specific δ 13 C measurements to further verify the presence of methane in the past. Oligocene–Miocene boundary climate change and methane release The Oligocene and Miocene epochs (34–5 million years ago; Ma) represent the transition from a greenhouse climate state of the early Cenozoic to the Quaternary ice house 18 . The late Oligocene to early Miocene period arguably represents some of the most prominent and enigmatic climatic shifts in Earth’s Cenozoic history. For example, the Oligocene–Miocene boundary (OMB, ~23 Ma) is characterized by ~1‰ positive excursion of the benthic foraminiferal oxygen isotope (δ 18 O), attributed to both temperature and high-latitude ice-sheet fluctuation 19 , 20 . Rapidly deposited glaciomarine sequences in the Ross Sea indicate ice-sheet expansion in East Antarctica during this ‘Mi-1’ glaciation 21 . However, unlike the Eocene–Oligocene transition (~34 Ma), when a comparable δ 18 O excursion marked the onset of the first continental-scale glaciation of East Antarctica, the Antarctic ice growth during Mi-1 glaciation was terminated in ~300 kyr. The benthic δ 18 O signature then returned to almost pre-event values 22 , 23 . The driver of this rapid climate swing is poorly understood, but existing evidence points towards the important role of the global carbon cycle. For example, recent atmospheric CO 2 reconstructions based on boron isotopes revealed an ~100 parts per million by volume (ppm) or ~40% increase during the deglacial phase of Mi-1 24 . However, the driver of the increased greenhouse gas level that contributed to the ephemeral nature of the Mi-1 glaciation is yet to be identified. To evaluate the potential role of the marine gas hydrate system in the global carbon cycle and climate, we analysed the lipid biomarkers of late Oligocene–early<|im_end|> <|im_start|>assistant Sediment cores taken from the Southern Ocean dating back 23 million years are providing insight into how ancient methane escaping from the seafloor could have led to regional or global climate and environmental changes, according to a study from two Texas A&M University researchers. Yige Zhang, assistant professor in the Department of Oceanography at Texas A&M, and doctoral student Bumsoo Kim have had their work published in the current issue of Nature Geoscience. The oceanographers examined cores—sediment samples from deep parts of the ocean floor—from the Oligocene-Miocene era, roughly 23 million years ago, from areas near Tasmania and Antarctica in the Pacific sector of the Southern Ocean. There are billions of tons of carbon stored beneath the ocean floor as gas hydrates—ice-like crystals composed of water and natural gas. Past releases of methane are believed to be related to huge earth events, such as global warming and subsequent climate shifts. "For a long time, people thought that methane released from the ocean floor could go into the atmosphere and directly contribute to the greenhouse effect, leading to rapid warming and even mass extinctions," Zhang said. "But this idea is no longer popular in the last decade or so because we lack direct evidence of methane release in Earth's history. Also, modern observations show that even when methane gasses are released, they rarely make it to the atmosphere." However, Kim and Zhang are now able to document past methane release by using markers that consume methane. These "methane-eating" substances are preserved in sediments for tens of millions of years, the researchers said. They could provide direct evidence of methane release from different places in the Southern Ocean. "We saw that a methane release occurred during a peak glaciation about 23 million years ago," Zhang said. Glaciation is the formation, movement and recession of glaciers, and the process mostly commonly occurs in Antarctica and Greenland. When large ice sheets form, they draw in a tremendous amount of water that could lower the sea-level by tens to hundreds of feet. Zhang added that the methane gas release and its after-effects led to ocean acidification and hypoxia (a lack of oxygen in the water), something that has been observed after the Deepwater Horizon incident in 2010, when large amounts of methane were released in the Gulf of Mexico. "One implication of our study is that if gas hydrates start to decompose in the future due to ocean warming, places like the Gulf of Mexico could suffer severely from ocean acidification and expansion of the low oxygen 'dead zones'," Kim 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 Nitrogen availability is a growth-limiting factor in many habitats 1 , and the global nitrogen cycle involves prokaryotes and eukaryotes competing for this precious resource. Only some bacteria and archaea can fix elementary nitrogen; all other organisms depend on the assimilation of mineral or organic nitrogen. The nitrogen-rich compound guanidine occurs widely in nature 2 , 3 , 4 , but its utilization is impeded by pronounced resonance stabilization 5 , and enzymes catalysing hydrolysis of free guanidine have not been identified. Here we describe the arginase family protein GdmH (Sll1077) from Synechocystis sp. PCC 6803 as a Ni 2+ -dependent guanidine hydrolase. GdmH is highly specific for free guanidine. Its activity depends on two accessory proteins that load Ni 2+ instead of the typical Mn 2+ ions into the active site. Crystal structures of GdmH show coordination of the dinuclear metal cluster in a geometry typical for arginase family enzymes and allow modelling of the bound substrate. A unique amino-terminal extension and a tryptophan residue narrow the substrate-binding pocket and identify homologous proteins in further cyanobacteria, several other bacterial taxa and heterokont algae as probable guanidine hydrolases. This broad distribution suggests notable ecological relevance of guanidine hydrolysis in aquatic habitats. Main Guanidine, as a strong base, is protonated in aqueous solution and occurs as a planar guanidinium cation that is stabilized by a highly symmetrical delocalized π-orbital, sometimes referred to as Y-aromaticity 5 . Its salts are widely used in explosives and propellants, as chaotropic agents for protein unfolding and as a slow-release nitrogen fertilizer in agriculture 6 . Guanidine was identified more than 150 years ago as a thermal decomposition product of guanine 7 and low levels have been detected in human blood and tissue and a variety of plant and environmental samples 2 , 3 , 4 . Enzymatic conversion of guanidine to urea and ammonia by fungi was observed in 1931 but did not receive further attention 8 . The recent discovery of four classes of guanidine-dependent riboswitches in bacteria has sparked new interest in the biology of guanidine 9 , 10 , 11 , 12 , 13 . These specific riboswitches induce guanidine exporters 11 , 14 , ATP-binding cassette (ABC)-type importers and enzymes involved in guanidine catabolism 15 , 16 . In many terrestrial and aquatic habitats, nitrogen is a growth-limiting nutrient and utilization of guanidine as a nitrogen source would be highly beneficial for many microorganisms. The analysis of riboswitch-regulated genes has recently revealed an ATP-dependent pathway for the use of guanidine as a nitrogen source for bacterial growth that relies on carboxylation and subsequent hydrolysis of carboxyguanidine 15 , 16 . However, to our knowledge, enzymes mediating the direct hydrolysis of free guanidine to urea and ammonia have not been described until now. Urea, which shows similar resonance stabilization to that of guanidine, can be degraded by urea carboxylase and subsequent hydrolysis as well as via direct hydrolysis by urease 17 , 18 . Urease contains two Ni 2+ ions in the catalytic centre that position a hydroxide ion for nucleophilic attack at urea 19 . We wondered whether a guanidine hydrolase capable of direct hydrolysis of guanidine to urea and ammonia exists as well. When examining further genes under the control of guanidine riboswitches, we noted a group of enzymes annotated as arginase family proteins (Pfam0049) prevalent in cyanobacteria and other bacteria. The arginase or ureohydrolase family is an ancient class of enzymes that typically release urea from arginine, agmatine or other substrates with a guanidine moiety. The active site of these enzymes consists of a cluster of two Mn 2+ ions that position a hydroxide ion for nucleophilic attack 20 . The coordination of the two metal ions by four Asp and two His residues is highly conserved within this protein family and can be used to identify new members. As proteins of the arginase family evolved independently in different branches of the tree of life, the prediction of substrate specificities of uncharacterized members is difficult 21 , 22 , 23 . Here we investigate an arginase family enzyme (Sll1077) controlled by a guanidine-I riboswitch in the model cyanobacterium Synechocystis sp. PCC6803, for which neither agmatinase nor arginase activity was detected 22 , 24 . Sll1077 is encoded in an operon together with an ABC-type importer (Sll1080–Sll1082) and two putative metal chaperones, annotated as hydrogenase-associated proteins A2 and B2 (Sll1078 and Sll1079) (Fig. 1a ). The related proteins HypA1 and HypB1 mediate the GTP-dependent insertion of Ni 2+ into the apoprotein of the Ni/Fe hydrogenases in Escherichia coli and Synechocystis , but it has been shown that Sll1078 and Sll1079 do not contribute to hydrogenase maturation in Synechocystis 25 , 26 . We show that Sll1077 is a specific guanidine hydrolase that converts free guanidine into urea and ammonia. Activity of the guanidine hydrolase depends on the presence of Sll1078, Sll1079 and two Ni 2+ ions in the active site (Fig. 1 ). We determined crystal structures of the guanidine hydrolase that explain the substrate specificity of this enzyme. Further, we investigate the distribution of guanidine hydrolase genes in the tree of life and show that Synechocystis sp. PCC 6803 depends on GdmH to use guanidine as the sole nitrogen source for growth. Fig. 1: GdmH (Sll1077) is a Ni 2+ -dependent guanidine hydrolase. a , The operon regulated by a guanidine-I riboswitch (RS) in Synechocystis sp. PCC 6803 comprises the guanidine hydrolase GdmH (Sll1077), two putative Ni 2+ -delivery proteins GhaA (Sll1078) and GhaB (Sll1079), and an ABC-type importer. b , Urea production from 10 mM guanidine in extracts of E. coli overexpressing GdmH alone (red columns) or together with GhaA and GhaB (blue columns). The extracts were supplemented with 10 µM of the indicated metal ions and 1 mM GTP where annotated. Columns represent the average of technical triplicates and consistent results were obtained with independent preparations. Error bars, s.d. c , 13 C-NMR spectra of 13 C 15 N-labelled guanidine after incubation overnight with soluble protein", "role": "user" }, { "content": "Guanidine is one of the most nitrogen-rich compounds. It could be a valuable source of organic nitrogen, but only very few organisms can access it. However, certain bacteria manage to obtain nitrogen from guanidine. A Konstanz-based research team led by chemist Professor Jörg Hartig and biologist Professor Olga Mayans has now discovered how this works. A newly discovered enzyme plays a key role—and, surprisingly, so does nickel. The research results were published on 9 March 2022 in the scientific journal Nature. No growth without nitrogen Nitrogen is an important component of all living organisms, and no growth is possible without nitrogen uptake. Although almost 80 percent of the atmosphere are nitrogen, the vast majority of life forms cannot access this reserve. They are thus dependent on chemically bound nitrogen, which is therefore also a pivotal component of fertilizers. However, where there is not enough nitrogen available, plants as well as many microorganisms quickly reach their limits. There are nitrogen reserves in nature that are barely utilized: Guanidine is a widespread nitrogen-rich compound that excels by particularly high chemical stability. Due to this stability, it is hardly possible for organisms to obtain the vital nitrogen from guanidine: They cannot \"crack the nut\", so to speak. Hence, many organisms are within reach of an abundant source of nitrogen—and yet cannot tap it. A Konstanz-based research network led by chemist Professor Jörg Hartig and biologist Professor Olga Mayans has now identified a biochemical mechanism that enables certain microorganisms to extract nitrogen from guanidine. In nitrate-poor environments, this is a decisive advantage over competing organisms. How the nitrogen mining works Cyanobacteria, also known as blue-green algae, use an enzyme from the arginase family to initiate degradation of guanidine in the form of hydrolysis. Hydrolysis initially means merely the splitting of a chemical compound by water. In the case of guanidine, however, contact with water alone is not enough: \"When guanidine is immersed in water, for hundreds of millennia virtually nothing will happen—because there is not enough energy to attack this compound,\" says Dr. Dietmar Funck, a biologist from Konstanz. The water therefore first needs to be \"primed\" in order to become chemically more active and be able to break down the guanidine. This is done by binding to nickel ions. The fact that, of all things, nickel is used as the catalyst came as a surprise to the research team. \"Nickel is special. Nickel is complicated. Very quickly you have either too little or too much of it,\" describes Jörg Hartig: \"We humans no longer have nickel-dependent enzymes in our bodies, because it is too complicated for the organism to provide the right amount.\" Nevertheless, the bacteria specifically resort to the tricky nickel to initiate the hydrolysis. \"Dealing with nickel is no trivial matter for the bacteria either,\" explains biochemist Dr. Malte Sinn, \"they need two auxiliary enzymes to incorporate nickel into the enzyme.\" The water \"primed\" by nickel ions in the active center of the enzyme attacks the guanidine and converts it into ammonia and urea. The urea can in turn be converted into ammonia by further enzymes. Both compounds can thus subsequently be exploited as nitrogen sources, making the nitrogen available for building new biomolecules. Structural images Olga Mayans's research team carried out structural analyses to investigate the process at the molecular level. The high specificity of the process was another surprise. The structural images show how precisely the enzyme encloses its substrate guanidine. \"It has a very beautiful structure, strikingly symmetrical. The active site is very small and perfect for holding the small guanidine molecule in the correct position for hydrolysis,\" explains biologist Dr. Jennifer Fleming from Olga Mayans's research team. For the research team, the current results are a first step towards understanding naturally occurring guanidine in more detail: how it is formed, what functions it has in nature, and which other organisms can utilize it. Despite its wide distribution, guanidine is still a blank spot on the biochemical map. ", "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 Nitrogen availability is a growth-limiting factor in many habitats 1 , and the global nitrogen cycle involves prokaryotes and eukaryotes competing for this precious resource. Only some bacteria and archaea can fix elementary nitrogen; all other organisms depend on the assimilation of mineral or organic nitrogen. The nitrogen-rich compound guanidine occurs widely in nature 2 , 3 , 4 , but its utilization is impeded by pronounced resonance stabilization 5 , and enzymes catalysing hydrolysis of free guanidine have not been identified. Here we describe the arginase family protein GdmH (Sll1077) from Synechocystis sp. PCC 6803 as a Ni 2+ -dependent guanidine hydrolase. GdmH is highly specific for free guanidine. Its activity depends on two accessory proteins that load Ni 2+ instead of the typical Mn 2+ ions into the active site. Crystal structures of GdmH show coordination of the dinuclear metal cluster in a geometry typical for arginase family enzymes and allow modelling of the bound substrate. A unique amino-terminal extension and a tryptophan residue narrow the substrate-binding pocket and identify homologous proteins in further cyanobacteria, several other bacterial taxa and heterokont algae as probable guanidine hydrolases. This broad distribution suggests notable ecological relevance of guanidine hydrolysis in aquatic habitats. Main Guanidine, as a strong base, is protonated in aqueous solution and occurs as a planar guanidinium cation that is stabilized by a highly symmetrical delocalized π-orbital, sometimes referred to as Y-aromaticity 5 . Its salts are widely used in explosives and propellants, as chaotropic agents for protein unfolding and as a slow-release nitrogen fertilizer in agriculture 6 . Guanidine was identified more than 150 years ago as a thermal decomposition product of guanine 7 and low levels have been detected in human blood and tissue and a variety of plant and environmental samples 2 , 3 , 4 . Enzymatic conversion of guanidine to urea and ammonia by fungi was observed in 1931 but did not receive further attention 8 . The recent discovery of four classes of guanidine-dependent riboswitches in bacteria has sparked new interest in the biology of guanidine 9 , 10 , 11 , 12 , 13 . These specific riboswitches induce guanidine exporters 11 , 14 , ATP-binding cassette (ABC)-type importers and enzymes involved in guanidine catabolism 15 , 16 . In many terrestrial and aquatic habitats, nitrogen is a growth-limiting nutrient and utilization of guanidine as a nitrogen source would be highly beneficial for many microorganisms. The analysis of riboswitch-regulated genes has recently revealed an ATP-dependent pathway for the use of guanidine as a nitrogen source for bacterial growth that relies on carboxylation and subsequent hydrolysis of carboxyguanidine 15 , 16 . However, to our knowledge, enzymes mediating the direct hydrolysis of free guanidine to urea and ammonia have not been described until now. Urea, which shows similar resonance stabilization to that of guanidine, can be degraded by urea carboxylase and subsequent hydrolysis as well as via direct hydrolysis by urease 17 , 18 . Urease contains two Ni 2+ ions in the catalytic centre that position a hydroxide ion for nucleophilic attack at urea 19 . We wondered whether a guanidine hydrolase capable of direct hydrolysis of guanidine to urea and ammonia exists as well. When examining further genes under the control of guanidine riboswitches, we noted a group of enzymes annotated as arginase family proteins (Pfam0049) prevalent in cyanobacteria and other bacteria. The arginase or ureohydrolase family is an ancient class of enzymes that typically release urea from arginine, agmatine or other substrates with a guanidine moiety. The active site of these enzymes consists of a cluster of two Mn 2+ ions that position a hydroxide ion for nucleophilic attack 20 . The coordination of the two metal ions by four Asp and two His residues is highly conserved within this protein family and can be used to identify new members. As proteins of the arginase family evolved independently in different branches of the tree of life, the prediction of substrate specificities of uncharacterized members is difficult 21 , 22 , 23 . Here we investigate an arginase family enzyme (Sll1077) controlled by a guanidine-I riboswitch in the model cyanobacterium Synechocystis sp. PCC6803, for which neither agmatinase nor arginase activity was detected 22 , 24 . Sll1077 is encoded in an operon together with an ABC-type importer (Sll1080–Sll1082) and two putative metal chaperones, annotated as hydrogenase-associated proteins A2 and B2 (Sll1078 and Sll1079) (Fig. 1a ). The related proteins HypA1 and HypB1 mediate the GTP-dependent insertion of Ni 2+ into the apoprotein of the Ni/Fe hydrogenases in Escherichia coli and Synechocystis , but it has been shown that Sll1078 and Sll1079 do not contribute to hydrogenase maturation in Synechocystis 25 , 26 . We show that Sll1077 is a specific guanidine hydrolase that converts free guanidine into urea and ammonia. Activity of the guanidine hydrolase depends on the presence of Sll1078, Sll1079 and two Ni 2+ ions in the active site (Fig. 1 ). We determined crystal structures of the guanidine hydrolase that explain the substrate specificity of this enzyme. Further, we investigate the distribution of guanidine hydrolase genes in the tree of life and show that Synechocystis sp. PCC 6803 depends on GdmH to use guanidine as the sole nitrogen source for growth. Fig. 1: GdmH (Sll1077) is a Ni 2+ -dependent guanidine hydrolase. a , The operon regulated by a guanidine-I riboswitch (RS) in Synechocystis sp. PCC 6803 comprises the guanidine hydrolase GdmH (Sll1077), two putative Ni 2+ -delivery proteins GhaA (Sll1078) and GhaB (Sll1079), and an ABC-type importer. b , Urea production from 10 mM guanidine in extracts of E. coli overexpressing GdmH alone (red columns) or together with GhaA and GhaB (blue columns). The extracts were supplemented with 10 µM of the indicated metal ions and 1 mM GTP where annotated. Columns represent the average of technical triplicates and consistent results were obtained with independent preparations. Error bars, s.d. c , 13 C-NMR spectra of 13 C 15 N-labelled guanidine after incubation overnight with soluble protein<|im_end|> <|im_start|>assistant Guanidine is one of the most nitrogen-rich compounds. It could be a valuable source of organic nitrogen, but only very few organisms can access it. However, certain bacteria manage to obtain nitrogen from guanidine. A Konstanz-based research team led by chemist Professor Jörg Hartig and biologist Professor Olga Mayans has now discovered how this works. A newly discovered enzyme plays a key role—and, surprisingly, so does nickel. The research results were published on 9 March 2022 in the scientific journal Nature. No growth without nitrogen Nitrogen is an important component of all living organisms, and no growth is possible without nitrogen uptake. Although almost 80 percent of the atmosphere are nitrogen, the vast majority of life forms cannot access this reserve. They are thus dependent on chemically bound nitrogen, which is therefore also a pivotal component of fertilizers. However, where there is not enough nitrogen available, plants as well as many microorganisms quickly reach their limits. There are nitrogen reserves in nature that are barely utilized: Guanidine is a widespread nitrogen-rich compound that excels by particularly high chemical stability. Due to this stability, it is hardly possible for organisms to obtain the vital nitrogen from guanidine: They cannot "crack the nut", so to speak. Hence, many organisms are within reach of an abundant source of nitrogen—and yet cannot tap it. A Konstanz-based research network led by chemist Professor Jörg Hartig and biologist Professor Olga Mayans has now identified a biochemical mechanism that enables certain microorganisms to extract nitrogen from guanidine. In nitrate-poor environments, this is a decisive advantage over competing organisms. How the nitrogen mining works Cyanobacteria, also known as blue-green algae, use an enzyme from the arginase family to initiate degradation of guanidine in the form of hydrolysis. Hydrolysis initially means merely the splitting of a chemical compound by water. In the case of guanidine, however, contact with water alone is not enough: "When guanidine is immersed in water, for hundreds of millennia virtually nothing will happen—because there is not enough energy to attack this compound," says Dr. Dietmar Funck, a biologist from Konstanz. The water therefore first needs to be "primed" in order to become chemically more active and be able to break down the guanidine. This is done by binding to nickel ions. The fact that, of all things, nickel is used as the catalyst came as a surprise to the research team. "Nickel is special. Nickel is complicated. Very quickly you have either too little or too much of it," describes Jörg Hartig: "We humans no longer have nickel-dependent enzymes in our bodies, because it is too complicated for the organism to provide the right amount." Nevertheless, the bacteria specifically resort to the tricky nickel to initiate the hydrolysis. "Dealing with nickel is no trivial matter for the bacteria either," explains biochemist Dr. Malte Sinn, "they need two auxiliary enzymes to incorporate nickel into the enzyme." The water "primed" by nickel ions in the active center of the enzyme attacks the guanidine and converts it into ammonia and urea. The urea can in turn be converted into ammonia by further enzymes. Both compounds can thus subsequently be exploited as nitrogen sources, making the nitrogen available for building new biomolecules. Structural images Olga Mayans's research team carried out structural analyses to investigate the process at the molecular level. The high specificity of the process was another surprise. The structural images show how precisely the enzyme encloses its substrate guanidine. "It has a very beautiful structure, strikingly symmetrical. The active site is very small and perfect for holding the small guanidine molecule in the correct position for hydrolysis," explains biologist Dr. Jennifer Fleming from Olga Mayans's research team. For the research team, the current results are a first step towards understanding naturally occurring guanidine in more detail: how it is formed, what functions it has in nature, and which other organisms can utilize it. Despite its wide distribution, guanidine is still a blank spot on the biochemical map. <|im_end|>

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2,449

[ { "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 Global emissions scenarios play a critical role in the assessment of strategies to mitigate climate change. The current scenarios, however, are criticized because they feature strategies with pronounced overshoot of the global temperature goal, requiring a long-term repair phase to draw temperatures down again through net-negative emissions. Some impacts might not be reversible. Hence, we explore a new set of net-zero CO 2 emissions scenarios with limited overshoot. We show that upfront investments are needed in the near term for limiting temperature overshoot but that these would bring long-term economic gains. Our study further identifies alternative configurations of net-zero CO 2 emissions systems and the roles of different sectors and regions for balancing sources and sinks. Even without net-negative emissions, CO 2 removal is important for accelerating near-term reductions and for providing an anthropogenic sink that can offset the residual emissions in sectors that are hard to abate. Main The Paris Agreement sets the framework for international climate action. Within that context, countries are aiming to hold warming well below 2 °C and pursue limiting it to 1.5 °C. How such global temperature outcomes can be achieved has been explored widely in the scientific literature 1 , 2 , 3 , 4 and assessed by the IPCC, for example, in its Fifth Assessment Report (AR5; ref. 5 ) and its Special Report on Global Warming of 1.5 °C (SR1.5; ref. 6 ). Studies explore aspects of the timing and costs of emissions reductions and the contribution of different sectors 3 , 7 , 8 . However, there has been critique that, with the exception of a few notable studies 9 , 10 , 11 , 12 , the scenarios in the literature first exceed the prescribed temperature limits in the hope of recovering from this overshoot later through net-negative emissions 13 , 14 , 15 , 16 . Some pioneering studies 10 , 11 , 12 have explored implications of limiting overshoot through, for example, zero emissions goals, or have looked into the role of bioenergy with carbon capture and storage (BECCS) in reaching different temperature targets 9 . All these studies have relied on one or two models and/or a limited set of temperature targets. We bring together nine international modelling teams and conduct a comprehensive modelling intercomparison project (MIP) on this topic. Specifically, we explore mitigation pathways for reaching different temperature change targets with limited overshoot. We do this by adopting the scenario design from ref. 11 and contrast scenarios with a fixed remaining carbon budget until the time when net-zero CO 2 emissions (net-zero budget scenarios) are reached with scenarios that use an end-of-century budget design. The latter carbon budget for the full century permits the budget to be temporarily overspent, as long as net-negative CO 2 emissions (NNCE) bring back cumulative CO 2 emissions to within the budget by 2100. This approach dominates the current literature and leads to a temporary overshoot of the associated temperature target. Importantly, the earlier introduced ‘net-zero budget scenarios’ limit cumulative CO 2 to a maximum without exceeding the emissions budget. These scenarios thus keep global warming below a certain threshold (without exceeding it) and stabilize the temperature thereafter. The new pathways fill important knowledge gaps. First, they cover the range of carbon budgets consistent with low stabilization targets in a systematic way and across a wide range of diverse global models. The pathways thus explore important uncertainties, including the attainable scenario space across different models and target definitions. This information is critical for international assessments, such as those by the IPCC 17 . Secondly, we explore the impacts of the country pledges from the post-Paris process for the attainability of overshoot and non-overshoot targets. Thirdly, we investigate salient temporal trade-offs with respect to mitigation costs; and finally we explore distinct differences in terms of the possible regional and global designs of net-zero CO 2 emissions systems. The main narratives of the pathways and assumptions are provided in Table 1 . Table 1 Scenario narratives and the corresponding range of attainable 2030 CO 2 emissions and the attainable carbon budgets (2020–2100) Full size table Implications for emissions pathways Reaching stringent temperature targets with limited overshoot, requires a pronounced acceleration of the near-term transformation towards net-zero CO 2 emissions. Staying within a budget of 500 GtCO 2 (consistent with a median warming of 1.44–1.63 °C), for example, requires CO 2 emissions to reach net zero between 2045 and 2065 (range across models). When an ‘end-of-century’ carbon budget is used, the time of reaching net-zero CO 2 emissions is delayed between 5 and 15 years (to 2060–2070). This delay, combined with the higher emissions over that period, results in 0.08–0.16 °C higher peak temperatures compared to scenarios that are identical in all but their allowance to overshoot the carbon budget. A broad set of behavioural, biophysical, economic, geophysical, legal, political and technological factors render transformations to net zero more or less challenging 18 . The modelling exercise here informs primarily challenges related to economic, geophysical and technological feasibility. The lowest attainable net-zero CO 2 emissions budget (limiting overshoot) is 400–800 GtCO 2 across the models (assuming immediate implementation of ambitious policies and a middle-of-the-road socioeconomic development 19 ). This budget range corresponds to a median peak warming during the twenty-first century between 1.42 and 1.72 °C. Weak near-term policies that result in higher GHG emissions over the next decade, such as those implied by the current nationally determined contributions (NDCs), will affect the lowest attainable carbon budget. We estimate that the NDCs ( Methods ) will lead to GHG emissions of 46.8–56.3 GtCO 2 e by 2030, which is substantially higher than the range of cost-effective emissions pathways consistent with 2 °C (25–48.6 GtCO 2 e), let alone 1.5 °C, by 2030 (19.4–35.3 GtCO 2 e). We adopt the definition of 1.5 and 2 °C goals from the SR1.5 ( Methods ). Assuming NDCs are not tightened and comprehensive climate policies are thus delayed until after 2030, the lowest attainable net-zero CO", "role": "user" }, { "content": "A new international study coordinated by IIASA shows how near-term mitigation can help to prevent an overshoot in global temperatures, thereby reducing climate risks and bringing long-term economic gains. The Paris Agreement's goal is to hold global warming to well below 2 degrees Celsius, and pursue efforts to limit it to 1.5 degrees Celsius. But what path should the world take to reach this desirable destination? The study just published in Nature Climate Change led by IIASA Energy, Climate, and Environment Program Director, Keywan Riahi provides some answers. The study summarizes insights from nine leading integrated assessment research teams exploring how to design cost-effective and feasible pathways to meet the Paris goals. Scientists use integrated assessment models to explore options for climate policy. These look at the human activities driving emissions—forms of energy generation, efficiency measures, and changes in land use—and calculate the costs of deploying them over coming decades. Models adjust these factors to meet a given goal for the lowest cost. So far, most studies have focused on the distant future, requiring only that the Paris goals are achieved by the end of the 21st century. Consequently, almost all of the resulting scenarios allow global temperature to overshoot in mid-century, only later turning the dial back down again. In order to reverse the overshoot, they make a heavy demand: requiring the world to achieve net-negative emissions to reduce the amount of carbon dioxide in the atmosphere and thereby decrease the temperature level. Negative emissions on such a huge scale may however turn out not to be feasible; and even a temporary overshoot would increase hazards such as flooding and wildfires, and could cause permanent damage to the climate and fragile ecosystems. It would be much better not to stray into such dangerous territory. \"The study for the first time systematically compares scenarios that avoid overshoot across models. Rapid emissions cuts in the next few decades would mean that there is no need to go net-negative: instead, global temperatures would plateau at a given level around the time we reach net-zero emissions. We also found that models agree on many implications for regional energy systems like the rapid decarbonization of the power sector,\" says Christoph Bertram, a study coauthor from the Potsdam Institute for Climate Impact Research. As well as being safer for the planet, this turns out to have long-term economic benefits. The study projects that global GDP in 2100 would be up to 2% higher in scenarios that avoid overshoot. \"We show that up-front investment to achieve rapid transformations towards a global net-zero system will pay off in the long term,\" says Riahi. \"In fact, the benefit is likely to be greater still, as this calculation does not include the economic impacts of climate change, which would be more severe in overshoot scenarios,\" adds coauthor Laurent Drouet from the Euro-Mediterranean Center on Climate Change (CMCC) in Italy who led another paper in the same issue of Nature Climate Change, illustrating the benefits in terms of the avoided climate change impacts. \"Scenario results show consistently across models that the transportation sector will be the decarbonization laggard. Consequently, a 'mobility revolution' will be crucial to reducing dependence on net-negative-emissions technologies and to mitigate their risks and negative societal impacts,\" notes coauthor Daniel Huppmann, a researcher in the IIASA Integrated Assessment and Climate Change Research Group. The study by Riahi and colleagues also highlights the urgent need to improve climate ambition. It shows that if we follow existing Nationally Determined Contributions (NDCs—each country's stated aim for emissions to 2030), the 1.5 degrees Celsius threshold will be exceeded, in contrast to the stated ambition at the recent climate conference (COP26) in Glasgow. Following current pledges until 2030 imply a slow start to mitigation efforts, and the models simply cannot see a way to ramp up decarbonization fast enough after that to reach the Paris goals, no matter how hard we try. ", "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 Global emissions scenarios play a critical role in the assessment of strategies to mitigate climate change. The current scenarios, however, are criticized because they feature strategies with pronounced overshoot of the global temperature goal, requiring a long-term repair phase to draw temperatures down again through net-negative emissions. Some impacts might not be reversible. Hence, we explore a new set of net-zero CO 2 emissions scenarios with limited overshoot. We show that upfront investments are needed in the near term for limiting temperature overshoot but that these would bring long-term economic gains. Our study further identifies alternative configurations of net-zero CO 2 emissions systems and the roles of different sectors and regions for balancing sources and sinks. Even without net-negative emissions, CO 2 removal is important for accelerating near-term reductions and for providing an anthropogenic sink that can offset the residual emissions in sectors that are hard to abate. Main The Paris Agreement sets the framework for international climate action. Within that context, countries are aiming to hold warming well below 2 °C and pursue limiting it to 1.5 °C. How such global temperature outcomes can be achieved has been explored widely in the scientific literature 1 , 2 , 3 , 4 and assessed by the IPCC, for example, in its Fifth Assessment Report (AR5; ref. 5 ) and its Special Report on Global Warming of 1.5 °C (SR1.5; ref. 6 ). Studies explore aspects of the timing and costs of emissions reductions and the contribution of different sectors 3 , 7 , 8 . However, there has been critique that, with the exception of a few notable studies 9 , 10 , 11 , 12 , the scenarios in the literature first exceed the prescribed temperature limits in the hope of recovering from this overshoot later through net-negative emissions 13 , 14 , 15 , 16 . Some pioneering studies 10 , 11 , 12 have explored implications of limiting overshoot through, for example, zero emissions goals, or have looked into the role of bioenergy with carbon capture and storage (BECCS) in reaching different temperature targets 9 . All these studies have relied on one or two models and/or a limited set of temperature targets. We bring together nine international modelling teams and conduct a comprehensive modelling intercomparison project (MIP) on this topic. Specifically, we explore mitigation pathways for reaching different temperature change targets with limited overshoot. We do this by adopting the scenario design from ref. 11 and contrast scenarios with a fixed remaining carbon budget until the time when net-zero CO 2 emissions (net-zero budget scenarios) are reached with scenarios that use an end-of-century budget design. The latter carbon budget for the full century permits the budget to be temporarily overspent, as long as net-negative CO 2 emissions (NNCE) bring back cumulative CO 2 emissions to within the budget by 2100. This approach dominates the current literature and leads to a temporary overshoot of the associated temperature target. Importantly, the earlier introduced ‘net-zero budget scenarios’ limit cumulative CO 2 to a maximum without exceeding the emissions budget. These scenarios thus keep global warming below a certain threshold (without exceeding it) and stabilize the temperature thereafter. The new pathways fill important knowledge gaps. First, they cover the range of carbon budgets consistent with low stabilization targets in a systematic way and across a wide range of diverse global models. The pathways thus explore important uncertainties, including the attainable scenario space across different models and target definitions. This information is critical for international assessments, such as those by the IPCC 17 . Secondly, we explore the impacts of the country pledges from the post-Paris process for the attainability of overshoot and non-overshoot targets. Thirdly, we investigate salient temporal trade-offs with respect to mitigation costs; and finally we explore distinct differences in terms of the possible regional and global designs of net-zero CO 2 emissions systems. The main narratives of the pathways and assumptions are provided in Table 1 . Table 1 Scenario narratives and the corresponding range of attainable 2030 CO 2 emissions and the attainable carbon budgets (2020–2100) Full size table Implications for emissions pathways Reaching stringent temperature targets with limited overshoot, requires a pronounced acceleration of the near-term transformation towards net-zero CO 2 emissions. Staying within a budget of 500 GtCO 2 (consistent with a median warming of 1.44–1.63 °C), for example, requires CO 2 emissions to reach net zero between 2045 and 2065 (range across models). When an ‘end-of-century’ carbon budget is used, the time of reaching net-zero CO 2 emissions is delayed between 5 and 15 years (to 2060–2070). This delay, combined with the higher emissions over that period, results in 0.08–0.16 °C higher peak temperatures compared to scenarios that are identical in all but their allowance to overshoot the carbon budget. A broad set of behavioural, biophysical, economic, geophysical, legal, political and technological factors render transformations to net zero more or less challenging 18 . The modelling exercise here informs primarily challenges related to economic, geophysical and technological feasibility. The lowest attainable net-zero CO 2 emissions budget (limiting overshoot) is 400–800 GtCO 2 across the models (assuming immediate implementation of ambitious policies and a middle-of-the-road socioeconomic development 19 ). This budget range corresponds to a median peak warming during the twenty-first century between 1.42 and 1.72 °C. Weak near-term policies that result in higher GHG emissions over the next decade, such as those implied by the current nationally determined contributions (NDCs), will affect the lowest attainable carbon budget. We estimate that the NDCs ( Methods ) will lead to GHG emissions of 46.8–56.3 GtCO 2 e by 2030, which is substantially higher than the range of cost-effective emissions pathways consistent with 2 °C (25–48.6 GtCO 2 e), let alone 1.5 °C, by 2030 (19.4–35.3 GtCO 2 e). We adopt the definition of 1.5 and 2 °C goals from the SR1.5 ( Methods ). Assuming NDCs are not tightened and comprehensive climate policies are thus delayed until after 2030, the lowest attainable net-zero CO<|im_end|> <|im_start|>assistant A new international study coordinated by IIASA shows how near-term mitigation can help to prevent an overshoot in global temperatures, thereby reducing climate risks and bringing long-term economic gains. The Paris Agreement's goal is to hold global warming to well below 2 degrees Celsius, and pursue efforts to limit it to 1.5 degrees Celsius. But what path should the world take to reach this desirable destination? The study just published in Nature Climate Change led by IIASA Energy, Climate, and Environment Program Director, Keywan Riahi provides some answers. The study summarizes insights from nine leading integrated assessment research teams exploring how to design cost-effective and feasible pathways to meet the Paris goals. Scientists use integrated assessment models to explore options for climate policy. These look at the human activities driving emissions—forms of energy generation, efficiency measures, and changes in land use—and calculate the costs of deploying them over coming decades. Models adjust these factors to meet a given goal for the lowest cost. So far, most studies have focused on the distant future, requiring only that the Paris goals are achieved by the end of the 21st century. Consequently, almost all of the resulting scenarios allow global temperature to overshoot in mid-century, only later turning the dial back down again. In order to reverse the overshoot, they make a heavy demand: requiring the world to achieve net-negative emissions to reduce the amount of carbon dioxide in the atmosphere and thereby decrease the temperature level. Negative emissions on such a huge scale may however turn out not to be feasible; and even a temporary overshoot would increase hazards such as flooding and wildfires, and could cause permanent damage to the climate and fragile ecosystems. It would be much better not to stray into such dangerous territory. "The study for the first time systematically compares scenarios that avoid overshoot across models. Rapid emissions cuts in the next few decades would mean that there is no need to go net-negative: instead, global temperatures would plateau at a given level around the time we reach net-zero emissions. We also found that models agree on many implications for regional energy systems like the rapid decarbonization of the power sector," says Christoph Bertram, a study coauthor from the Potsdam Institute for Climate Impact Research. As well as being safer for the planet, this turns out to have long-term economic benefits. The study projects that global GDP in 2100 would be up to 2% higher in scenarios that avoid overshoot. "We show that up-front investment to achieve rapid transformations towards a global net-zero system will pay off in the long term," says Riahi. "In fact, the benefit is likely to be greater still, as this calculation does not include the economic impacts of climate change, which would be more severe in overshoot scenarios," adds coauthor Laurent Drouet from the Euro-Mediterranean Center on Climate Change (CMCC) in Italy who led another paper in the same issue of Nature Climate Change, illustrating the benefits in terms of the avoided climate change impacts. "Scenario results show consistently across models that the transportation sector will be the decarbonization laggard. Consequently, a 'mobility revolution' will be crucial to reducing dependence on net-negative-emissions technologies and to mitigate their risks and negative societal impacts," notes coauthor Daniel Huppmann, a researcher in the IIASA Integrated Assessment and Climate Change Research Group. The study by Riahi and colleagues also highlights the urgent need to improve climate ambition. It shows that if we follow existing Nationally Determined Contributions (NDCs—each country's stated aim for emissions to 2030), the 1.5 degrees Celsius threshold will be exceeded, in contrast to the stated ambition at the recent climate conference (COP26) in Glasgow. Following current pledges until 2030 imply a slow start to mitigation efforts, and the models simply cannot see a way to ramp up decarbonization fast enough after that to reach the Paris goals, no matter how hard we try. <|im_end|>

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4235, 8848, 15, 8, 8797, 1404, 2007, 14727, 10939, 369, 20748, 44014, 1050, 12092, 70099, 9499, 11811, 449, 7347, 66571, 1944, 11, 7612, 264, 38617, 31903, 315, 279, 3221, 9860, 18475, 7119, 4272, 38029, 7432, 220, 17, 20748, 13, 800, 17718, 2949, 264, 8199, 315, 220, 2636, 480, 83, 8445, 220, 17, 320, 79499, 449, 264, 23369, 24808, 315, 220, 16, 13, 2096, 4235, 16, 13, 5495, 37386, 34, 705, 369, 3187, 11, 7612, 7432, 220, 17, 20748, 311, 5662, 4272, 7315, 1990, 220, 7854, 20, 323, 220, 11056, 20, 320, 9866, 4028, 4211, 570, 3277, 459, 3451, 408, 8838, 34457, 529, 12782, 8199, 374, 1511, 11, 279, 892, 315, 19261, 4272, 38029, 7432, 220, 17, 20748, 374, 23540, 1990, 220, 20, 323, 220, 868, 1667, 320, 998, 220, 11056, 15, 4235, 12060, 15, 570, 1115, 7781, 11, 11093, 449, 279, 5190, 20748, 927, 430, 4261, 11, 3135, 304, 220, 15, 13, 2318, 4235, 15, 13, 845, 37386, 34, 5190, 16557, 20472, 7863, 311, 26350, 430, 527, 20086, 304, 682, 719, 872, 41458, 311, 66571, 1944, 279, 12782, 8199, 13, 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3063, 311, 48584, 38, 20748, 315, 220, 2790, 13, 23, 4235, 3487, 13, 18, 480, 83, 8445, 220, 17, 384, 555, 220, 9639, 15, 11, 902, 374, 32302, 5190, 1109, 279, 2134, 315, 2853, 53421, 20748, 44014, 13263, 449, 220, 17, 37386, 34, 320, 914, 4235, 2166, 13, 21, 480, 83, 8445, 220, 17, 384, 705, 1095, 7636, 220, 16, 13, 20, 37386, 34, 11, 555, 220, 9639, 15, 320, 777, 13, 19, 4235, 1758, 13, 18, 480, 83, 8445, 220, 17, 384, 570, 1226, 11142, 279, 7419, 315, 220, 16, 13, 20, 323, 220, 17, 37386, 34, 9021, 505, 279, 21550, 16, 13, 20, 320, 19331, 7609, 65064, 452, 5744, 82, 527, 539, 85820, 323, 16195, 10182, 10396, 527, 8617, 23540, 3156, 1306, 220, 9639, 15, 11, 279, 15821, 36861, 481, 4272, 38029, 7432, 128257, 198, 128256, 78191, 198, 32, 502, 6625, 4007, 47672, 555, 8105, 80692, 5039, 1268, 3221, 9860, 66860, 649, 1520, 311, 5471, 459, 66571, 1944, 304, 3728, 20472, 11, 28592, 18189, 10182, 15635, 323, 12967, 1317, 9860, 7100, 20192, 13, 578, 12366, 23314, 596, 5915, 374, 311, 3412, 3728, 24808, 311, 1664, 3770, 220, 17, 12628, 62447, 11, 323, 23564, 9045, 311, 4017, 433, 311, 220, 16, 13, 20, 12628, 62447, 13, 2030, 1148, 1853, 1288, 279, 1917, 1935, 311, 5662, 420, 35946, 9284, 30, 578, 4007, 1120, 4756, 304, 22037, 31636, 10604, 6197, 555, 8105, 80692, 12634, 11, 31636, 11, 323, 11847, 6826, 10783, 11, 5422, 16965, 432, 689, 6151, 5825, 1063, 11503, 13, 578, 4007, 94594, 26793, 505, 11888, 6522, 18751, 15813, 3495, 7411, 24919, 1268, 311, 2955, 2853, 53421, 323, 43303, 44014, 311, 3449, 279, 12366, 9021, 13, 57116, 1005, 18751, 15813, 4211, 311, 13488, 2671, 369, 10182, 4947, 13, 4314, 1427, 520, 279, 3823, 7640, 10043, 20748, 2345, 10008, 315, 4907, 9659, 11, 15374, 11193, 11, 323, 4442, 304, 4363, 1005, 17223, 11294, 279, 7194, 315, 61417, 1124, 927, 5108, 11026, 13, 27972, 7652, 1521, 9547, 311, 3449, 264, 2728, 5915, 369, 279, 15821, 2853, 13, 2100, 3117, 11, 1455, 7978, 617, 10968, 389, 279, 29827, 3938, 11, 23537, 1193, 430, 279, 12366, 9021, 527, 17427, 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505, 279, 20026, 5364, 3671, 618, 33561, 5955, 389, 31636, 10604, 320, 10190, 3791, 8, 304, 15704, 889, 6197, 2500, 5684, 304, 279, 1890, 4360, 315, 22037, 31636, 10604, 11, 94012, 279, 7720, 304, 3878, 315, 279, 31890, 10182, 2349, 25949, 13, 330, 55131, 3135, 1501, 21356, 4028, 4211, 430, 279, 18386, 10706, 690, 387, 279, 1654, 52745, 2065, 326, 16094, 569, 13, 53123, 11, 264, 364, 35035, 1429, 14110, 6, 690, 387, 16996, 311, 18189, 44393, 389, 4272, 62035, 37612, 16935, 14645, 323, 311, 50460, 872, 15635, 323, 8389, 59529, 25949, 1359, 8554, 1080, 3170, 15469, 473, 455, 5298, 1036, 11, 264, 32185, 304, 279, 8105, 80692, 50521, 37357, 323, 31636, 10604, 8483, 5856, 13, 578, 4007, 555, 432, 689, 6151, 323, 18105, 1101, 22020, 279, 34771, 1205, 311, 7417, 10182, 45715, 13, 1102, 5039, 430, 422, 584, 1833, 6484, 17671, 750, 36007, 291, 97104, 320, 45, 5744, 82, 2345, 9739, 3224, 596, 11224, 9395, 369, 20748, 311, 220, 9639, 15, 705, 279, 220, 16, 13, 20, 12628, 62447, 12447, 690, 387, 34908, 11, 304, 13168, 311, 279, 11224, 45715, 520, 279, 3293, 10182, 10017, 320, 34, 3143, 1627, 8, 304, 43997, 13, 23548, 1510, 79118, 3156, 220, 9639, 15, 34608, 264, 6435, 1212, 311, 66860, 9045, 11, 323, 279, 4211, 5042, 4250, 1518, 264, 1648, 311, 23091, 709, 1654, 52745, 2065, 5043, 3403, 1306, 430, 311, 5662, 279, 12366, 9021, 11, 912, 5030, 1268, 2653, 584, 1456, 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 Although cannabis-based products for medicinal use are now legal in the UK, it is still challenging for patients to gain access, and only very few National Health Service prescriptions have been written to date. This paper attempts to make sense of why the UK lags behind so many other countries which also have legalised medical cannabis. From consulting with parents and patients, prescribers, pharmacists and decision-makers it seems that there are a series of distinct barriers to prescribing that need to be overcome in order to improve patient access to medical cannabis in the UK. These include concerns about the perceived lack of scientific evidence. To alleviate these concerns, we highlight the importance of patient-centred approaches including patient-reported outcomes, pharmacoepidemiology and n=1 trials, which can contribute to the development of the evidence base for medical cannabis. We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current situation which is detrimental to patients. public health qualitative research statistics & research methods This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 13 news outlets Blogged by 2 Tweeted by 113 On 5 Facebook pages Reddited by 1 63 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 public health qualitative research statistics & research methods Strengths and limitations of this study There are a series of distinct barriers to prescribing medical cannabis that need to be overcome in order to improve patient access in the UK. Concerns about the perceived lack of randomised controlled trial evidence are misplaced as many patient-centred approaches including patient-reported outcomes, pharmacoepidemiology and n=1 trials can be applied. Thousands of UK patients self-medicating with illicit cannabis-based products for medicinal use and the international database evidence suggest this new class of drugs offers a significant advance in treatment for many in whom current medicines are either ineffective or poorly tolerated. We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current unsatisfactory situation. Introduction In November 2018 when the UK made cannabis-based products for medicinal use (CBPMs) legal most people assumed these would immediately be made available to patients, but they were wrong. In the year since almost no National Health Service (NHS) prescriptions have been issued 1 and less than a hundred have been made available from private providers at a cost of at least £1000 a month. 2 For these reasons, some parents of children with severe epilepsy continue to go overseas to get their children access to the only treatment which has proven to be effective for their condition, that is, a cannabinoid medication. Moreover, the vast majority of the estimated 1.4 million medical cannabis users 3 source from the black market with its problems of illegality, unknown quality, content and provenance. Given the substantial evidence of utility of CBPMs in many disorders as identified in the US National Academy of Sciences review in 2017 4 this failure of delivery in the UK seems odd and, to many, inexcusable. Concerns about perceived lack of evidence Statements such as ‘insufficient evidence of efficacy’ or ‘it is too dangerous’ are common and used even in the face of strong personal evidence from patients that CBPMs work and, in many cases, can be life-changing and well tolerated. Many doctors fail to include the evidence of the patient’s lived experience and cite the lack of placebo-controlled trials in every possible indication for their hesitation to prescribe. While tens of thousands of individual patient reports of the therapeutic value of CBPMs as in the Canadian and Minnesota databases 5 6 do not equate to the so-called gold-standard double-blind randomised controlled trial (RCT) level of proof, they are highly suggestive of a pattern of evidence which should be taken seriously rather than summarily dismissed. These large-scale databases could be further interrogated and systematically analysed to collate patient-reported outcomes (PROs) and other existing evidence for peer-reviewed publications. In the UK, Drug Science recently launched Project TWENTY21, the largest national medical cannabis registry in Europe, with the aim to create a structured body of evidence for the effectiveness and tolerability of medical cannabis for a broad range of conditions ( ). Moreover, Drug Science is also currently working on audits using existing data of patients with epilepsy prescribed medical cannabis, showing, for example, a clear reduction of seizures after medical cannabis use. The major criticism of the lack of placebo-controlled trials is misplaced. Prescribers often mistakenly state that without these they cannot prescribe. However, there are over 50 medicines or indications that have been licensed by Food and Drug Administration and/or European Medicines Agency between 1999 and 2014 without RCT data. 7 Moreover, the ex-head of National Institute for Health and Care Excellence (NICE) and the Medicines and Healthcare products Regulatory Agency, Sir Michael Rawlins, challenged this RCT preconception in the 2008 Harvean Oration, highlighting that: Randomised controlled trials (RCTs), long regarded at the ‘gold standard’ of evidence, have been put on an undeserved pedestal. Their appearance at the top of ‘hierarchies’ of evidence is inappropriate; and hierarchies, themselves, are illusory tools for assessing evidence. They should be replaced by a diversity of approaches that involve analysing the totality of the evidence-base. 8 Placebo-controlled double-blind", "role": "user" }, { "content": "Attitudes towards cannabis products for medicinal use need to change with much greater appropriate use of such products to help alleviate patients' pain, suggests research published in the journal BMJ Open. Researchers found that hundreds of thousands of UK patients were self-medicating with illegal cannabis-based products for medicinal use due to the fact that much of the medical and pharmacy professions have so far not embraced and prescribed legal cannabis-based products for their patients. In November 2018 when the UK made cannabis-based products for medicinal use (CBPMs) legal, most people assumed these would immediately be made available to patients, but this has not happened. In the year since then, almost no NHS prescriptions have been issued and less than a hundred have been made available from private providers at a cost of at least £1,000 a month. Consequently, some parents of children with severe epilepsy continue to go overseas to get their children access to the only treatment which has proven to be effective for their condition—cannabinoid medication. In addition, it is estimated that the vast majority of the estimated 1.4 million medical cannabis users source from the black market with its problems of illegality, unknown quality, content and provenance. This is despite that fact that there is existing substantial evidence of effectiveness with cannabis products for medicinal use in many disorders as identified in the US National Academy of Sciences review in 2017. Researchers from Imperial College London, London School of Economics and Drug Science (formerly known as the Independent Scientific Committee on Drugs), therefore, set out to understand why the UK was lagging behind so many other countries which also have legalised medical cannabis. They consulted with parents and patients, prescribers, pharmacists and decision makers. They found that there appeared to be a series of distinct barriers to prescribing that needed to be overcome in order to improve patient access to medical cannabis in the UK. These include concerns about a perceived lack of scientific evidence but the researchers said these concerns were misplaced because many patient-centred approaches including patient reported outcomes, pharmacoepidemiology (study of the uses and effects of drugs) and trials involving a single patient could be applied. International database evidence suggested this new class of drug offered a significant advance in treatment for many in whom current medicines were either ineffective or poorly tolerated. Various reasons to explain why there was resistance to use of these drugs were given, such as the fact the use of medicinal cannabis products were something being driven by patients and not doctors, which the latter group might resent. In addition, the current government insistence that medical cannabis be considered as a \"special' product, meant challenges for prescribers. For example, they faced additional organisational bureaucracy and the prescriber had to hold responsibility for any untold harm caused unlike any other product for which responsibility lay with the manufacturer. Another reason for the resistance to prescribing of these products was that for almost 50 years, the medical profession focused on the risks of cannabis with claims of harms, including male sterility, lung cancer and schizophrenia. Though these have now been largely debunked and were generally the result of recreational rather than prescribed medical use, many practitioners may not know this. The researchers say that the many thousands of UK patients self-medicating with non-regulated cannabis products for medicinal use and the international evidence suggested these new medical products offered an advance in treatment for many people. They also offered the potential of cost savings to the NHS in terms of reduced hospital stays and less prescribing of other medicines particularly opioids for chronic pain, they argued. They conclude: \"The failure of the medical and pharmacy professions to embrace CBPMs despite their being made 'legal' over 18 months ago is a great worry to patients\" and may, they say, have led to preventable deaths from conditions such as epilepsy. \"We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current highly unsatisfactory situation.\" ", "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 cannabis-based products for medicinal use are now legal in the UK, it is still challenging for patients to gain access, and only very few National Health Service prescriptions have been written to date. This paper attempts to make sense of why the UK lags behind so many other countries which also have legalised medical cannabis. From consulting with parents and patients, prescribers, pharmacists and decision-makers it seems that there are a series of distinct barriers to prescribing that need to be overcome in order to improve patient access to medical cannabis in the UK. These include concerns about the perceived lack of scientific evidence. To alleviate these concerns, we highlight the importance of patient-centred approaches including patient-reported outcomes, pharmacoepidemiology and n=1 trials, which can contribute to the development of the evidence base for medical cannabis. We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current situation which is detrimental to patients. public health qualitative research statistics & research methods This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 13 news outlets Blogged by 2 Tweeted by 113 On 5 Facebook pages Reddited by 1 63 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 public health qualitative research statistics & research methods Strengths and limitations of this study There are a series of distinct barriers to prescribing medical cannabis that need to be overcome in order to improve patient access in the UK. Concerns about the perceived lack of randomised controlled trial evidence are misplaced as many patient-centred approaches including patient-reported outcomes, pharmacoepidemiology and n=1 trials can be applied. Thousands of UK patients self-medicating with illicit cannabis-based products for medicinal use and the international database evidence suggest this new class of drugs offers a significant advance in treatment for many in whom current medicines are either ineffective or poorly tolerated. We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current unsatisfactory situation. Introduction In November 2018 when the UK made cannabis-based products for medicinal use (CBPMs) legal most people assumed these would immediately be made available to patients, but they were wrong. In the year since almost no National Health Service (NHS) prescriptions have been issued 1 and less than a hundred have been made available from private providers at a cost of at least £1000 a month. 2 For these reasons, some parents of children with severe epilepsy continue to go overseas to get their children access to the only treatment which has proven to be effective for their condition, that is, a cannabinoid medication. Moreover, the vast majority of the estimated 1.4 million medical cannabis users 3 source from the black market with its problems of illegality, unknown quality, content and provenance. Given the substantial evidence of utility of CBPMs in many disorders as identified in the US National Academy of Sciences review in 2017 4 this failure of delivery in the UK seems odd and, to many, inexcusable. Concerns about perceived lack of evidence Statements such as ‘insufficient evidence of efficacy’ or ‘it is too dangerous’ are common and used even in the face of strong personal evidence from patients that CBPMs work and, in many cases, can be life-changing and well tolerated. Many doctors fail to include the evidence of the patient’s lived experience and cite the lack of placebo-controlled trials in every possible indication for their hesitation to prescribe. While tens of thousands of individual patient reports of the therapeutic value of CBPMs as in the Canadian and Minnesota databases 5 6 do not equate to the so-called gold-standard double-blind randomised controlled trial (RCT) level of proof, they are highly suggestive of a pattern of evidence which should be taken seriously rather than summarily dismissed. These large-scale databases could be further interrogated and systematically analysed to collate patient-reported outcomes (PROs) and other existing evidence for peer-reviewed publications. In the UK, Drug Science recently launched Project TWENTY21, the largest national medical cannabis registry in Europe, with the aim to create a structured body of evidence for the effectiveness and tolerability of medical cannabis for a broad range of conditions ( ). Moreover, Drug Science is also currently working on audits using existing data of patients with epilepsy prescribed medical cannabis, showing, for example, a clear reduction of seizures after medical cannabis use. The major criticism of the lack of placebo-controlled trials is misplaced. Prescribers often mistakenly state that without these they cannot prescribe. However, there are over 50 medicines or indications that have been licensed by Food and Drug Administration and/or European Medicines Agency between 1999 and 2014 without RCT data. 7 Moreover, the ex-head of National Institute for Health and Care Excellence (NICE) and the Medicines and Healthcare products Regulatory Agency, Sir Michael Rawlins, challenged this RCT preconception in the 2008 Harvean Oration, highlighting that: Randomised controlled trials (RCTs), long regarded at the ‘gold standard’ of evidence, have been put on an undeserved pedestal. Their appearance at the top of ‘hierarchies’ of evidence is inappropriate; and hierarchies, themselves, are illusory tools for assessing evidence. They should be replaced by a diversity of approaches that involve analysing the totality of the evidence-base. 8 Placebo-controlled double-blind<|im_end|> <|im_start|>assistant Attitudes towards cannabis products for medicinal use need to change with much greater appropriate use of such products to help alleviate patients' pain, suggests research published in the journal BMJ Open. Researchers found that hundreds of thousands of UK patients were self-medicating with illegal cannabis-based products for medicinal use due to the fact that much of the medical and pharmacy professions have so far not embraced and prescribed legal cannabis-based products for their patients. In November 2018 when the UK made cannabis-based products for medicinal use (CBPMs) legal, most people assumed these would immediately be made available to patients, but this has not happened. In the year since then, almost no NHS prescriptions have been issued and less than a hundred have been made available from private providers at a cost of at least £1,000 a month. Consequently, some parents of children with severe epilepsy continue to go overseas to get their children access to the only treatment which has proven to be effective for their condition—cannabinoid medication. In addition, it is estimated that the vast majority of the estimated 1.4 million medical cannabis users source from the black market with its problems of illegality, unknown quality, content and provenance. This is despite that fact that there is existing substantial evidence of effectiveness with cannabis products for medicinal use in many disorders as identified in the US National Academy of Sciences review in 2017. Researchers from Imperial College London, London School of Economics and Drug Science (formerly known as the Independent Scientific Committee on Drugs), therefore, set out to understand why the UK was lagging behind so many other countries which also have legalised medical cannabis. They consulted with parents and patients, prescribers, pharmacists and decision makers. They found that there appeared to be a series of distinct barriers to prescribing that needed to be overcome in order to improve patient access to medical cannabis in the UK. These include concerns about a perceived lack of scientific evidence but the researchers said these concerns were misplaced because many patient-centred approaches including patient reported outcomes, pharmacoepidemiology (study of the uses and effects of drugs) and trials involving a single patient could be applied. International database evidence suggested this new class of drug offered a significant advance in treatment for many in whom current medicines were either ineffective or poorly tolerated. Various reasons to explain why there was resistance to use of these drugs were given, such as the fact the use of medicinal cannabis products were something being driven by patients and not doctors, which the latter group might resent. In addition, the current government insistence that medical cannabis be considered as a "special' product, meant challenges for prescribers. For example, they faced additional organisational bureaucracy and the prescriber had to hold responsibility for any untold harm caused unlike any other product for which responsibility lay with the manufacturer. Another reason for the resistance to prescribing of these products was that for almost 50 years, the medical profession focused on the risks of cannabis with claims of harms, including male sterility, lung cancer and schizophrenia. Though these have now been largely debunked and were generally the result of recreational rather than prescribed medical use, many practitioners may not know this. The researchers say that the many thousands of UK patients self-medicating with non-regulated cannabis products for medicinal use and the international evidence suggested these new medical products offered an advance in treatment for many people. They also offered the potential of cost savings to the NHS in terms of reduced hospital stays and less prescribing of other medicines particularly opioids for chronic pain, they argued. They conclude: "The failure of the medical and pharmacy professions to embrace CBPMs despite their being made 'legal' over 18 months ago is a great worry to patients" and may, they say, have led to preventable deaths from conditions such as epilepsy. "We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current highly unsatisfactory situation." <|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 The risk of hip fracture in women on plant-based diets is unclear. We aimed to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UK Women’s Cohort Study and to determine if potential associations between each diet group and hip fracture risk are modified by body mass index (BMI). Methods UK women, ages 35–69 years, were classified as regular meat-eaters (≥ 5 servings/week), occasional meat-eaters (< 5 servings/week), pescatarian (ate fish but not meat), or vegetarian (ate neither meat nor fish) based on a validated 217-item food frequency questionnaire completed in 1995–1998. Incident hip fractures were identified via linkage to Hospital Episode Statistics up to March 2019. Cox regression models were used to estimate the associations between each diet group and hip fracture risk over a median follow-up time of 22.3 years. Results Amongst 26,318 women, 822 hip fracture cases were observed (556,331 person-years). After adjustment for confounders, vegetarians (HR (95% CI) 1.33 (1.03, 1.71)) but not occasional meat-eaters (1.00 (0.85, 1.18)) or pescatarians (0.97 (0.75, 1.26)) had a greater risk of hip fracture than regular meat-eaters. There was no clear evidence of effect modification by BMI in any diet group ( p -interaction = 0.3). Conclusions Vegetarian women were at a higher risk of hip fracture compared to regular meat-eaters. Further research is needed to confirm this in men and non-European populations and to identify factors responsible for the observed risk difference. Further research exploring the role of BMI and nutrients abundant in animal-sourced foods is recommended. Trial registration ClinicalTrials.gov , NCT05081466 Peer Review reports Background Hip fractures are most common in elderly women [ 1 ] and are becoming increasingly prevalent in the UK and globally due to growing ageing populations [ 2 , 3 ]. Health-related quality of life declines after hip fracture and mortality increases [ 1 , 4 ]. Social and economic costs from hip fractures are also substantial [ 2 ], with an international average cost 12 months after the first hip fracture of $44,000 per patient [ 5 ]. There are growing concerns regarding bone health and fracture risk in individuals on meat-free diets [ 6 , 7 , 8 , 9 ], but associations between these diet groups and hip fracture risk remain unclear. An estimated 5% of the US population [ 10 ], 3% of the UK population [ 11 , 12 ], and 30% of India’s population follow vegetarian diets [ 13 ]. The number of vegetarians worldwide is increasing [ 7 ], possibly due to accumulating evidence of reduced risks of several chronic diseases, including diabetes [ 14 ], ischaemic heart disease, and cancer [ 15 ], and a lower environmental footprint of vegetarian diets compared to omnivorous diets [ 16 , 17 ]. Understanding hip fracture risk in vegetarians in particular is therefore becoming increasingly important to public health. Whilst diet quality varies among vegetarians [ 16 ], vegetarian diets are often characterised by a higher intake of fruits and vegetables including foods high in vegetable protein [ 8 ], which have been associated with a reduced hip fracture risk in adults in reviews of previous epidemiological studies [ 18 , 19 , 20 , 21 ]. However, vegetarian diets have also been characterised by lower dietary intakes of nutrients that have been positively associated with bone mineral density (BMD) and are more abundant in animal products than in plants. Examples include total protein, calcium, vitamin D, vitamin B12, and ω-3 fatty acids [ 6 , 22 ], though associations between these nutrients and hip fracture risk are unclear and complex [ 20 ]. Studies have also reported a lower average body mass index (BMI) in vegetarians and pescatarians compared to omnivores [ 8 , 23 ], which has been inversely associated with hip fracture risk [ 24 ]. Risk differences for hip fracture between vegetarians, pescatarians, and meat-eaters are therefore plausible, but evidence is limited in exploring these dietary patterns. Cross-sectional studies show lower BMD in vegetarians compared to non-vegetarians [ 25 , 26 ], but prospective studies comparing the risk of hip fracture in these diet groups over time are scarce and limited [ 8 , 9 ]. The recently published European Prospective Investigation into Cancer (EPIC)-Oxford cohort study of UK men and women showed a greater risk of hip fracture in pescatarians, vegetarians, and vegans compared to meat-eaters [ 8 ]. The Adventist Health Study-2 (AHS-2) also showed a greater risk of hip fracture in vegans but not vegetarians compared to meat-eaters in US women, but with outcome data based on self-administered questionnaires [ 9 ]. To our knowledge, no other prospective study has compared the risk of hip fracture in vegetarians and non-vegetarians; therefore, associations between these diet groups and hip fracture risk require further investigation. The United Kingdom Women’s Cohort Study (UKWCS) has been enriched with vegetarians and pescatarians, so is well-suited to study the risk of chronic diseases over time in these diet groups [ 27 ]. Our objectives were therefore to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in middle-aged UK women and to determine if potential associations between each diet group and hip fracture risk are modified by BMI. Methods We followed the Strengthening the Reporting of Observational Studies in Epidemiology – Nutritional Epidemiology (STROBE-nut) guidelines for the reporting of cohort studies (Additional file 1 : Table S1) [ 28 ]. Study design and participants The UKWCS has been described in detail elsewhere [ 27 ]. In brief, 500,000 women from England, Scotland, and Wales responded to a direct mail questionnaire from the World Cancer Research Fund (WCRF) between 1995 and 1998. Of the 75% that agreed to participate in a more detailed survey, those who identified as vegetarian or non-red meat-eaters, and were aged 35–69 years when completing the WCRF questionnaire, were eligible for inclusion in the UKWCS. For each vegetarian, the next non-vegetarian or red meat-eater who was", "role": "user" }, { "content": "A study of over 26,000 middle-aged UK women reveals those with a vegetarian diet had a 33% higher risk of hip fracture compared to regular meat-eaters. University of Leeds research, published Thursday, August 11 in the journal BMC Medicine, investigated the risk of hip fracture in occasional meat-eaters; pescatarians, people who eat fish but not meat; and vegetarians compared to regular meat-eaters. Among 26,318 women, 822 hip fracture cases were observed over roughly 20 years—that represented just over 3% of the sample population. After adjustment for factors such as smoking and age, vegetarians were the only diet group with an elevated risk of hip fracture. This study is one of very few studies to compare risk of hip fracture in vegetarians and meat-eaters where the occurrence of hip fracture was confirmed from hospital records. The scientists stress the need for more research into the exact causes of why vegetarians were at a greater risk of hip fracture. Vegetarian diets can be 'healthy or unhealthy' Study lead author James Webster, a doctoral researcher from the School of Food Science and Nutrition at Leeds, said, \"Our study highlights potential concerns regarding risk of hip fracture in women who have a vegetarian diet. However, it is not warning people to abandon vegetarian diets. As with any diet, it is important to understand personal circumstances and what nutrients are needed for a balanced healthy lifestyle. \"Vegetarian diets can vary widely from person to person and can be healthy or unhealthy, just like diets that include animal products. \"However, it is concerning that vegetarian diets often have lower intakes of nutrients that are linked with bone and muscle health. These types of nutrients generally are more abundant in meat and other animal products than in plants, such as protein, calcium, and other micronutrients. \"Low intake of these nutrients can lead to lower bone mineral density and muscle mass, which can make you more susceptible to hip fracture risk. This makes it especially important for further research to better understand factors driving the increased risk in vegetarians, whether it be particular nutrient deficiencies or weight management, so that we can help people to make healthy choices.\" Plant-based diets growing in popularity Vegetarian diets have gained popularity in recent years, with a 2021 YouGov survey putting the size of the UK vegetarian population at roughly 5-7%. It is often perceived as a healthier dietary option, with previous evidence that shows a vegetarian diet can reduce the risks of several chronic diseases, including diabetes, heart disease, and cancer compared to omnivorous diets. There is also a worldwide call for reducing the consumption of animal products in an effort to tackle climate change. Understanding hip fracture risk in vegetarians is therefore becoming increasingly important to public health. Study co-author Professor Janet Cade, leader of the Nutritional Epidemiology Group in the School of Food Science and Nutrition at Leeds, said, \"Hip fracture is a global health issue with high economic costs that causes loss of independence, reduces quality of life, and increases risk of other health issues. \"Plant-based diets have been linked with poor bone health, but there has been a lack of evidence on the links to hip fracture risk. This study is an important step in understanding the potential risk plant-based diets could present over the long-term and what can be done to mitigate those risks.\" The team used data from the UK Women's Cohort Study to investigate possible links between diet and hip fracture risk. The national cohort of middle-aged women was established at the University of Leeds to explore links between diet and chronic disease, encompassing a wide range of different eating patterns. Dietary information was collected using a food frequency questionnaire and was validated using a 4-day food diary in a subsample of women. At the time they were recruited into the cohort study, the women ranged in age from 35 to 69 years. Effect of low BMI The research team found that the average BMI among vegetarians was slightly lower than the average among the regular meat eaters. Previous research has shown a link between low BMI and a high risk of hip fracture. Lower BMI can indicate people are underweight, which can mean poorer bone and muscle health, and higher risk of hip fracture. Further investigation is needed to determine if low BMI is the reason for the observed higher risk in vegetarians. Study co-author Dr. Darren Greenwood, a biostatistician in the School of Medicine at Leeds, said, \"This study is just part of the wider picture of diet and healthy bones and muscles in older age. \"Further research is needed to confirm whether there could be similar results in men, to explore the role of body weight, and to identify the reasons for different outcomes in vegetarians and meat-eaters.\" ", "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 The risk of hip fracture in women on plant-based diets is unclear. We aimed to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UK Women’s Cohort Study and to determine if potential associations between each diet group and hip fracture risk are modified by body mass index (BMI). Methods UK women, ages 35–69 years, were classified as regular meat-eaters (≥ 5 servings/week), occasional meat-eaters (< 5 servings/week), pescatarian (ate fish but not meat), or vegetarian (ate neither meat nor fish) based on a validated 217-item food frequency questionnaire completed in 1995–1998. Incident hip fractures were identified via linkage to Hospital Episode Statistics up to March 2019. Cox regression models were used to estimate the associations between each diet group and hip fracture risk over a median follow-up time of 22.3 years. Results Amongst 26,318 women, 822 hip fracture cases were observed (556,331 person-years). After adjustment for confounders, vegetarians (HR (95% CI) 1.33 (1.03, 1.71)) but not occasional meat-eaters (1.00 (0.85, 1.18)) or pescatarians (0.97 (0.75, 1.26)) had a greater risk of hip fracture than regular meat-eaters. There was no clear evidence of effect modification by BMI in any diet group ( p -interaction = 0.3). Conclusions Vegetarian women were at a higher risk of hip fracture compared to regular meat-eaters. Further research is needed to confirm this in men and non-European populations and to identify factors responsible for the observed risk difference. Further research exploring the role of BMI and nutrients abundant in animal-sourced foods is recommended. Trial registration ClinicalTrials.gov , NCT05081466 Peer Review reports Background Hip fractures are most common in elderly women [ 1 ] and are becoming increasingly prevalent in the UK and globally due to growing ageing populations [ 2 , 3 ]. Health-related quality of life declines after hip fracture and mortality increases [ 1 , 4 ]. Social and economic costs from hip fractures are also substantial [ 2 ], with an international average cost 12 months after the first hip fracture of $44,000 per patient [ 5 ]. There are growing concerns regarding bone health and fracture risk in individuals on meat-free diets [ 6 , 7 , 8 , 9 ], but associations between these diet groups and hip fracture risk remain unclear. An estimated 5% of the US population [ 10 ], 3% of the UK population [ 11 , 12 ], and 30% of India’s population follow vegetarian diets [ 13 ]. The number of vegetarians worldwide is increasing [ 7 ], possibly due to accumulating evidence of reduced risks of several chronic diseases, including diabetes [ 14 ], ischaemic heart disease, and cancer [ 15 ], and a lower environmental footprint of vegetarian diets compared to omnivorous diets [ 16 , 17 ]. Understanding hip fracture risk in vegetarians in particular is therefore becoming increasingly important to public health. Whilst diet quality varies among vegetarians [ 16 ], vegetarian diets are often characterised by a higher intake of fruits and vegetables including foods high in vegetable protein [ 8 ], which have been associated with a reduced hip fracture risk in adults in reviews of previous epidemiological studies [ 18 , 19 , 20 , 21 ]. However, vegetarian diets have also been characterised by lower dietary intakes of nutrients that have been positively associated with bone mineral density (BMD) and are more abundant in animal products than in plants. Examples include total protein, calcium, vitamin D, vitamin B12, and ω-3 fatty acids [ 6 , 22 ], though associations between these nutrients and hip fracture risk are unclear and complex [ 20 ]. Studies have also reported a lower average body mass index (BMI) in vegetarians and pescatarians compared to omnivores [ 8 , 23 ], which has been inversely associated with hip fracture risk [ 24 ]. Risk differences for hip fracture between vegetarians, pescatarians, and meat-eaters are therefore plausible, but evidence is limited in exploring these dietary patterns. Cross-sectional studies show lower BMD in vegetarians compared to non-vegetarians [ 25 , 26 ], but prospective studies comparing the risk of hip fracture in these diet groups over time are scarce and limited [ 8 , 9 ]. The recently published European Prospective Investigation into Cancer (EPIC)-Oxford cohort study of UK men and women showed a greater risk of hip fracture in pescatarians, vegetarians, and vegans compared to meat-eaters [ 8 ]. The Adventist Health Study-2 (AHS-2) also showed a greater risk of hip fracture in vegans but not vegetarians compared to meat-eaters in US women, but with outcome data based on self-administered questionnaires [ 9 ]. To our knowledge, no other prospective study has compared the risk of hip fracture in vegetarians and non-vegetarians; therefore, associations between these diet groups and hip fracture risk require further investigation. The United Kingdom Women’s Cohort Study (UKWCS) has been enriched with vegetarians and pescatarians, so is well-suited to study the risk of chronic diseases over time in these diet groups [ 27 ]. Our objectives were therefore to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in middle-aged UK women and to determine if potential associations between each diet group and hip fracture risk are modified by BMI. Methods We followed the Strengthening the Reporting of Observational Studies in Epidemiology – Nutritional Epidemiology (STROBE-nut) guidelines for the reporting of cohort studies (Additional file 1 : Table S1) [ 28 ]. Study design and participants The UKWCS has been described in detail elsewhere [ 27 ]. In brief, 500,000 women from England, Scotland, and Wales responded to a direct mail questionnaire from the World Cancer Research Fund (WCRF) between 1995 and 1998. Of the 75% that agreed to participate in a more detailed survey, those who identified as vegetarian or non-red meat-eaters, and were aged 35–69 years when completing the WCRF questionnaire, were eligible for inclusion in the UKWCS. For each vegetarian, the next non-vegetarian or red meat-eater who was<|im_end|> <|im_start|>assistant A study of over 26,000 middle-aged UK women reveals those with a vegetarian diet had a 33% higher risk of hip fracture compared to regular meat-eaters. University of Leeds research, published Thursday, August 11 in the journal BMC Medicine, investigated the risk of hip fracture in occasional meat-eaters; pescatarians, people who eat fish but not meat; and vegetarians compared to regular meat-eaters. Among 26,318 women, 822 hip fracture cases were observed over roughly 20 years—that represented just over 3% of the sample population. After adjustment for factors such as smoking and age, vegetarians were the only diet group with an elevated risk of hip fracture. This study is one of very few studies to compare risk of hip fracture in vegetarians and meat-eaters where the occurrence of hip fracture was confirmed from hospital records. The scientists stress the need for more research into the exact causes of why vegetarians were at a greater risk of hip fracture. Vegetarian diets can be 'healthy or unhealthy' Study lead author James Webster, a doctoral researcher from the School of Food Science and Nutrition at Leeds, said, "Our study highlights potential concerns regarding risk of hip fracture in women who have a vegetarian diet. However, it is not warning people to abandon vegetarian diets. As with any diet, it is important to understand personal circumstances and what nutrients are needed for a balanced healthy lifestyle. "Vegetarian diets can vary widely from person to person and can be healthy or unhealthy, just like diets that include animal products. "However, it is concerning that vegetarian diets often have lower intakes of nutrients that are linked with bone and muscle health. These types of nutrients generally are more abundant in meat and other animal products than in plants, such as protein, calcium, and other micronutrients. "Low intake of these nutrients can lead to lower bone mineral density and muscle mass, which can make you more susceptible to hip fracture risk. This makes it especially important for further research to better understand factors driving the increased risk in vegetarians, whether it be particular nutrient deficiencies or weight management, so that we can help people to make healthy choices." Plant-based diets growing in popularity Vegetarian diets have gained popularity in recent years, with a 2021 YouGov survey putting the size of the UK vegetarian population at roughly 5-7%. It is often perceived as a healthier dietary option, with previous evidence that shows a vegetarian diet can reduce the risks of several chronic diseases, including diabetes, heart disease, and cancer compared to omnivorous diets. There is also a worldwide call for reducing the consumption of animal products in an effort to tackle climate change. Understanding hip fracture risk in vegetarians is therefore becoming increasingly important to public health. Study co-author Professor Janet Cade, leader of the Nutritional Epidemiology Group in the School of Food Science and Nutrition at Leeds, said, "Hip fracture is a global health issue with high economic costs that causes loss of independence, reduces quality of life, and increases risk of other health issues. "Plant-based diets have been linked with poor bone health, but there has been a lack of evidence on the links to hip fracture risk. This study is an important step in understanding the potential risk plant-based diets could present over the long-term and what can be done to mitigate those risks." The team used data from the UK Women's Cohort Study to investigate possible links between diet and hip fracture risk. The national cohort of middle-aged women was established at the University of Leeds to explore links between diet and chronic disease, encompassing a wide range of different eating patterns. Dietary information was collected using a food frequency questionnaire and was validated using a 4-day food diary in a subsample of women. At the time they were recruited into the cohort study, the women ranged in age from 35 to 69 years. Effect of low BMI The research team found that the average BMI among vegetarians was slightly lower than the average among the regular meat eaters. Previous research has shown a link between low BMI and a high risk of hip fracture. Lower BMI can indicate people are underweight, which can mean poorer bone and muscle health, and higher risk of hip fracture. Further investigation is needed to determine if low BMI is the reason for the observed higher risk in vegetarians. Study co-author Dr. Darren Greenwood, a biostatistician in the School of Medicine at Leeds, said, "This study is just part of the wider picture of diet and healthy bones and muscles in older age. "Further research is needed to confirm whether there could be similar results in men, to explore the role of body weight, and to identify the reasons for different outcomes in vegetarians and meat-eaters." <|im_end|>

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83571, 8997, 477, 2579, 13339, 5773, 977, 889, 574, 128257, 198, 128256, 78191, 198, 32, 4007, 315, 927, 220, 1627, 11, 931, 6278, 57859, 6560, 3278, 21667, 1884, 449, 264, 46482, 10173, 1047, 264, 220, 1644, 4, 5190, 5326, 315, 18638, 59904, 7863, 311, 5912, 13339, 5773, 11796, 13, 3907, 315, 52629, 3495, 11, 4756, 7950, 11, 6287, 220, 806, 304, 279, 8486, 82806, 19152, 11, 27313, 279, 5326, 315, 18638, 59904, 304, 28961, 13339, 5773, 11796, 26, 281, 3380, 266, 30627, 11, 1274, 889, 8343, 7795, 719, 539, 13339, 26, 323, 13294, 30627, 7863, 311, 5912, 13339, 5773, 11796, 13, 22395, 220, 1627, 11, 17592, 3278, 11, 220, 23105, 18638, 59904, 5157, 1051, 13468, 927, 17715, 220, 508, 1667, 41128, 15609, 1120, 927, 220, 18, 4, 315, 279, 6205, 7187, 13, 4740, 28174, 369, 9547, 1778, 439, 20149, 323, 4325, 11, 13294, 30627, 1051, 279, 1193, 10173, 1912, 449, 459, 32389, 5326, 315, 18638, 59904, 13, 1115, 4007, 374, 832, 315, 1633, 2478, 7978, 311, 9616, 5326, 315, 18638, 59904, 304, 13294, 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505, 279, 6560, 11215, 596, 84675, 371, 19723, 311, 19874, 3284, 7902, 1990, 10173, 323, 18638, 59904, 5326, 13, 578, 5426, 41944, 315, 6278, 57859, 3278, 574, 9749, 520, 279, 3907, 315, 52629, 311, 13488, 7902, 1990, 10173, 323, 21249, 8624, 11, 38632, 287, 264, 7029, 2134, 315, 2204, 12459, 12912, 13, 83808, 2038, 574, 14890, 1701, 264, 3691, 11900, 48964, 323, 574, 33432, 1701, 264, 220, 19, 11477, 3691, 47242, 304, 264, 5258, 1545, 315, 3278, 13, 2468, 279, 892, 814, 1051, 45425, 1139, 279, 41944, 4007, 11, 279, 3278, 41829, 304, 4325, 505, 220, 1758, 311, 220, 3076, 1667, 13, 13756, 315, 3428, 47224, 578, 3495, 2128, 1766, 430, 279, 5578, 47224, 4315, 13294, 30627, 574, 10284, 4827, 1109, 279, 5578, 4315, 279, 5912, 13339, 8343, 388, 13, 30013, 3495, 706, 6982, 264, 2723, 1990, 3428, 47224, 323, 264, 1579, 5326, 315, 18638, 59904, 13, 28636, 47224, 649, 13519, 1274, 527, 1234, 4870, 11, 902, 649, 3152, 66281, 17685, 323, 16124, 2890, 11, 323, 5190, 5326, 315, 18638, 59904, 13, 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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 Converging evidence from human and animal studies support an association between vitamin D deficiency and cognitive impairment. Previous studies have shown that hippocampal volume is reduced in adults with vitamin D deficiency as well as in a range of disorders, such as schizophrenia. The aim of the current study was to examine the effect of adult vitamin D (AVD) deficiency on hippocampal-dependent spatial learning, and hippocampal volume and connectivity in healthy adult mice. Ten-week-old male BALB/c mice were fed a control (vitamin D 1500 IU/kg) or vitamin D-depleted (vitamin D 0 IU/kg) diet for a minimum of 10 weeks. The mice were then tested for hippocampal-dependent spatial learning using active place avoidance (APA) and on tests of muscle and motor coordination (rotarod and grip strength). The mice were perfused and brains collected to acquire ex vivo structural and diffusion-weighted images using a 16.4 T MRI scanner. We also performed immunohistochemistry to quantify perineuronal nets (PNNs) and parvalbumin (PV) interneurons in various brain regions. AVD-deficient mice had a lower latency to enter the shock zone on APA, compared to control mice, suggesting impaired hippocampal-dependent spatial learning. There were no differences in rotarod or grip strength, indicating that AVD deficiency did not have an impact on muscle or motor coordination. AVD deficiency did not have an impact on hippocampal volume. However, AVD-deficient mice displayed a disrupted network centred on the right hippocampus with abnormal connectomes among 29 nodes. We found a reduction in PNN positive cells, but no change in PV, centred on the hippocampus. Our results provide compelling evidence to show that AVD deficiency in otherwise healthy adult mice may play a key role in hippocampal-dependent learning and memory formation. We suggest that the spatial learning deficits could be due to the disruption of right hippocampal structural connectivity. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Vitamin D plays an important role in the nervous system. For example, vitamin D exerts neuroprotective properties, facilitates neurotrophic function (Naveilhan et al. 1996 ; Brown et al. 2003 ) and regulates neuronal calcium homeostasis (Gezen-Ak et al. 2011 ). Epidemiological studies have shown that vitamin D deficiency is associated with a wide range of neuropsychiatric and neurological disorders, including schizophrenia (Cieslak et al. 2014 ; Chiang et al. 2016 ), autism (Fernell et al. 2015 ; Saad et al. 2016 ), depression (Spedding 2014 ; Brouwer-Brolsma et al. 2016 ), multiple sclerosis (Goral et al. 2015 ; Eskandari et al. 2015 ), dementia (Afzal et al. 2014 ) and Alzheimer’s disease (Balion et al. 2012 ). The association between lower serum vitamin D and cognitive impairment has also been reported in meta-analytic studies (Etgen et al. 2012 ; van Schoor et al. 2016 ), and is associated with various aspects of memory impairment, including visual, (Kuzma et al. 2016 ) and verbal memory (Vicente et al. 2015 ). However, a causal role of vitamin D deficiency on adult brain function has not been established. Several neuroimaging studies have examined the association between cognitive impairment, altered brain morphometry and vitamin D deficiency. However, the results have been inconsistent. For example, Annweiler et al. studied elderly individuals (> 65 years) and reported that the level of serum vitamin D may be associated with the size of the lateral cerebral ventricles (Annweiler et al. 2013 ), periventricular white matter abnormalities (Annweiler et al. 2014 ), intracranial volume (Annweiler et al. 2015 ) and brain volume (Hooshmand et al. 2014 ). In addition, the level of serum vitamin D was shown to be associated with impaired neuronal integrity, as measured by lower fractional anisotropy (FA) values in several brain regions of cognitively impaired elderly people (Moon et al. 2015 ). By contrast, no association was shown between serum vitamin D and neuroimaging abnormalities (Littlejohns et al. 2016 ). With respect to brain morphology, a lower hippocampal volume was observed in subjects with low serum 25-OHD (25-hydroxy vitamin D) (Karakis et al. 2016 ; Al-Amin et al. 2018 ), and a reduction of hippocampal grey matter volume in vitamin D-deficient patients with schizophrenia (Shivakumar et al. 2015 ). Because the hippocampus is an important brain region involved in memory processing, including the conversion of short-term to long-term memory formation (Virley et al. 1999 ; Cho et al. 2015 ), encoding and retrieval (Greicius et al. 2003 ; Lepage et al. 1998), these neuroimaging studies showed that hippocampal atrophy could be a basis of memory impairment associated with vitamin D deficiency. However, most of these studies were conducted on elderly people and the results may have been affected by many factors, such as changes in diet or outdoor activity that may confound the results and these studies cannot establish causality. Therefore, animal models of adult vitamin D (AVD) deficiency may be a feasible way to control for unknown confounding factors and examine the impact of vitamin D deficiency on hippocampal function and hippocampal microstructure. Animal studies have shown that vitamin D deficiency has an impact on learning and memory performance. However, the results have been inconsistent. For example, there was no effect of AVD deficiency in Sprague–Dawley rats on two-way active avoidance (Byrne et al. 2013 ), whereas impaired spatial learning was shown in the Morris water maze (Taghizadeh et al. 2013 ) and 8-Arm Radial Maze (Altemus et al. 1987 ). By contrast, AVD-deficient mice showed a reduced escape latency during acquisition and a decreased response score on a two-way active avoidance task, indicating improved performance compared to control mice (Groves et al. 2013 ). These findings suggest impaired hippocampal function, because hippocampal lesions typically lead to the seemingly paradoxical findings of reduced freezing and faster acquisition on active avoidance learning and impaired learning on place avoidance tasks (Black et al. 1977 ). The behavioural deficits in AVD deficiency could also be linked with altered brain neurochemistry. For example, AVD-deficient BALB/c, but not C57BL6/J, mice had increased levels of γ-aminobutyric acid (GABA) and reduced glutamine, glutamate (Groves et al. 2013", "role": "user" }, { "content": "University of Queensland research may explain why vitamin D is vital for brain health, and how deficiency leads to disorders including depression and schizophrenia. Associate Professor Thomas Burne at UQ's Queensland Brain Institute led the studies, which provide the groundwork for research into better prevention and treatments. \"Over a billion people worldwide are affected by vitamin D deficiency, and there is a well-established link between vitamin D deficiency and impaired cognition,\" Dr Burne said. \"Unfortunately, exactly how vitamin D influences brain structure and function is not well understood, so it has remained unclear why deficiency causes problems.\" Dr Burne's team found that vitamin D levels affect a type of 'scaffolding' in the brain, called perineuronal nets. \"These nets form a strong, supportive mesh around certain neurons, and in doing so they stabilise the contacts these cells make with other neurons,\" he said. Researchers removed vitamin D from the diet of a group of healthy adult mice, and after 20 weeks found a significant decline in their ability to remember and learn compared to a control group. Dr Burne said the vitamin D deficient group had a pronounced reduction in perineuronal nets in the hippocampus, the brain region crucial to memory formation. \"There was also a stark reduction in both the number and strength of connections between neurons in that region.\" Credit: University of Queensland Dr Burne's team propose that vitamin D plays an important role in keeping perineuronal nets stable, and that when vitamin D levels drop, this 'scaffolding' is more easily degraded by enzymes. \"As neurons in the hippocampus lose their supportive perineuronal nets, they have trouble maintaining connections, and this ultimately leads to a loss of cognitive function.\" Associate Professor Burne said the hippocampus may be most strongly affected by vitamin D deficiency because it is much more active than other brain regions. \"It's like the canary in the coalmine—it might fail first because its high energy requirement makes it more sensitive to the depletion of essential nutrients like vitamin D. \"Intriguingly, the right side of the hippocampus was more affected by vitamin D deficiency than the left side.\" Associate Professor Burne said loss of function in this area could be an important contributor to the hallmarks of schizophrenia, including severe memory deficits and a distorted perception of reality. \"The next step is to test this new hypothesis on the link between vitamin D deficiency, perineuronal nets and cognition,\" he said. \"We are also particularly excited to have discovered these nets can change in adult mice. \"I'm hoping that because they're dynamic there is a chance that we can rebuild them, and that could set the stage for new treatments.\" The research is published in Brain Structure and Function and Trends in Neuroscience. ", "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 Converging evidence from human and animal studies support an association between vitamin D deficiency and cognitive impairment. Previous studies have shown that hippocampal volume is reduced in adults with vitamin D deficiency as well as in a range of disorders, such as schizophrenia. The aim of the current study was to examine the effect of adult vitamin D (AVD) deficiency on hippocampal-dependent spatial learning, and hippocampal volume and connectivity in healthy adult mice. Ten-week-old male BALB/c mice were fed a control (vitamin D 1500 IU/kg) or vitamin D-depleted (vitamin D 0 IU/kg) diet for a minimum of 10 weeks. The mice were then tested for hippocampal-dependent spatial learning using active place avoidance (APA) and on tests of muscle and motor coordination (rotarod and grip strength). The mice were perfused and brains collected to acquire ex vivo structural and diffusion-weighted images using a 16.4 T MRI scanner. We also performed immunohistochemistry to quantify perineuronal nets (PNNs) and parvalbumin (PV) interneurons in various brain regions. AVD-deficient mice had a lower latency to enter the shock zone on APA, compared to control mice, suggesting impaired hippocampal-dependent spatial learning. There were no differences in rotarod or grip strength, indicating that AVD deficiency did not have an impact on muscle or motor coordination. AVD deficiency did not have an impact on hippocampal volume. However, AVD-deficient mice displayed a disrupted network centred on the right hippocampus with abnormal connectomes among 29 nodes. We found a reduction in PNN positive cells, but no change in PV, centred on the hippocampus. Our results provide compelling evidence to show that AVD deficiency in otherwise healthy adult mice may play a key role in hippocampal-dependent learning and memory formation. We suggest that the spatial learning deficits could be due to the disruption of right hippocampal structural connectivity. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Vitamin D plays an important role in the nervous system. For example, vitamin D exerts neuroprotective properties, facilitates neurotrophic function (Naveilhan et al. 1996 ; Brown et al. 2003 ) and regulates neuronal calcium homeostasis (Gezen-Ak et al. 2011 ). Epidemiological studies have shown that vitamin D deficiency is associated with a wide range of neuropsychiatric and neurological disorders, including schizophrenia (Cieslak et al. 2014 ; Chiang et al. 2016 ), autism (Fernell et al. 2015 ; Saad et al. 2016 ), depression (Spedding 2014 ; Brouwer-Brolsma et al. 2016 ), multiple sclerosis (Goral et al. 2015 ; Eskandari et al. 2015 ), dementia (Afzal et al. 2014 ) and Alzheimer’s disease (Balion et al. 2012 ). The association between lower serum vitamin D and cognitive impairment has also been reported in meta-analytic studies (Etgen et al. 2012 ; van Schoor et al. 2016 ), and is associated with various aspects of memory impairment, including visual, (Kuzma et al. 2016 ) and verbal memory (Vicente et al. 2015 ). However, a causal role of vitamin D deficiency on adult brain function has not been established. Several neuroimaging studies have examined the association between cognitive impairment, altered brain morphometry and vitamin D deficiency. However, the results have been inconsistent. For example, Annweiler et al. studied elderly individuals (> 65 years) and reported that the level of serum vitamin D may be associated with the size of the lateral cerebral ventricles (Annweiler et al. 2013 ), periventricular white matter abnormalities (Annweiler et al. 2014 ), intracranial volume (Annweiler et al. 2015 ) and brain volume (Hooshmand et al. 2014 ). In addition, the level of serum vitamin D was shown to be associated with impaired neuronal integrity, as measured by lower fractional anisotropy (FA) values in several brain regions of cognitively impaired elderly people (Moon et al. 2015 ). By contrast, no association was shown between serum vitamin D and neuroimaging abnormalities (Littlejohns et al. 2016 ). With respect to brain morphology, a lower hippocampal volume was observed in subjects with low serum 25-OHD (25-hydroxy vitamin D) (Karakis et al. 2016 ; Al-Amin et al. 2018 ), and a reduction of hippocampal grey matter volume in vitamin D-deficient patients with schizophrenia (Shivakumar et al. 2015 ). Because the hippocampus is an important brain region involved in memory processing, including the conversion of short-term to long-term memory formation (Virley et al. 1999 ; Cho et al. 2015 ), encoding and retrieval (Greicius et al. 2003 ; Lepage et al. 1998), these neuroimaging studies showed that hippocampal atrophy could be a basis of memory impairment associated with vitamin D deficiency. However, most of these studies were conducted on elderly people and the results may have been affected by many factors, such as changes in diet or outdoor activity that may confound the results and these studies cannot establish causality. Therefore, animal models of adult vitamin D (AVD) deficiency may be a feasible way to control for unknown confounding factors and examine the impact of vitamin D deficiency on hippocampal function and hippocampal microstructure. Animal studies have shown that vitamin D deficiency has an impact on learning and memory performance. However, the results have been inconsistent. For example, there was no effect of AVD deficiency in Sprague–Dawley rats on two-way active avoidance (Byrne et al. 2013 ), whereas impaired spatial learning was shown in the Morris water maze (Taghizadeh et al. 2013 ) and 8-Arm Radial Maze (Altemus et al. 1987 ). By contrast, AVD-deficient mice showed a reduced escape latency during acquisition and a decreased response score on a two-way active avoidance task, indicating improved performance compared to control mice (Groves et al. 2013 ). These findings suggest impaired hippocampal function, because hippocampal lesions typically lead to the seemingly paradoxical findings of reduced freezing and faster acquisition on active avoidance learning and impaired learning on place avoidance tasks (Black et al. 1977 ). The behavioural deficits in AVD deficiency could also be linked with altered brain neurochemistry. For example, AVD-deficient BALB/c, but not C57BL6/J, mice had increased levels of γ-aminobutyric acid (GABA) and reduced glutamine, glutamate (Groves et al. 2013<|im_end|> <|im_start|>assistant University of Queensland research may explain why vitamin D is vital for brain health, and how deficiency leads to disorders including depression and schizophrenia. Associate Professor Thomas Burne at UQ's Queensland Brain Institute led the studies, which provide the groundwork for research into better prevention and treatments. "Over a billion people worldwide are affected by vitamin D deficiency, and there is a well-established link between vitamin D deficiency and impaired cognition," Dr Burne said. "Unfortunately, exactly how vitamin D influences brain structure and function is not well understood, so it has remained unclear why deficiency causes problems." Dr Burne's team found that vitamin D levels affect a type of 'scaffolding' in the brain, called perineuronal nets. "These nets form a strong, supportive mesh around certain neurons, and in doing so they stabilise the contacts these cells make with other neurons," he said. Researchers removed vitamin D from the diet of a group of healthy adult mice, and after 20 weeks found a significant decline in their ability to remember and learn compared to a control group. Dr Burne said the vitamin D deficient group had a pronounced reduction in perineuronal nets in the hippocampus, the brain region crucial to memory formation. "There was also a stark reduction in both the number and strength of connections between neurons in that region." Credit: University of Queensland Dr Burne's team propose that vitamin D plays an important role in keeping perineuronal nets stable, and that when vitamin D levels drop, this 'scaffolding' is more easily degraded by enzymes. "As neurons in the hippocampus lose their supportive perineuronal nets, they have trouble maintaining connections, and this ultimately leads to a loss of cognitive function." Associate Professor Burne said the hippocampus may be most strongly affected by vitamin D deficiency because it is much more active than other brain regions. "It's like the canary in the coalmine—it might fail first because its high energy requirement makes it more sensitive to the depletion of essential nutrients like vitamin D. "Intriguingly, the right side of the hippocampus was more affected by vitamin D deficiency than the left side." Associate Professor Burne said loss of function in this area could be an important contributor to the hallmarks of schizophrenia, including severe memory deficits and a distorted perception of reality. "The next step is to test this new hypothesis on the link between vitamin D deficiency, perineuronal nets and cognition," he said. "We are also particularly excited to have discovered these nets can change in adult mice. "I'm hoping that because they're dynamic there is a chance that we can rebuild them, and that could set the stage for new treatments." The research is published in Brain Structure and Function and Trends in Neuroscience. <|im_end|>

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2,060

[ { "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 Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for collagen production by myofibroblasts. However, the molecular mechanisms regulating their ability to produce collagen remain poorly characterised. Here, we show that vestigial-like family member 3 (VGLL3) is specifically expressed in myofibroblasts from mouse and human fibrotic hearts and promotes collagen production. Further, substrate stiffness triggers VGLL3 translocation into the nucleus through the integrin β1-Rho-actin pathway. In the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac fibrosis after myocardial infarction is significantly attenuated in Vgll3 -deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts’ collagen production, representing a novel therapeutic target for tissue fibrosis. Introduction Fibrosis, the pathological deposition of extracellular matrix (ECM) proteins like collagens in the interstitium, can occur in almost all tissues 1 , 2 , 3 . During tissue injury, fibrosis is beneficial to the body as it rapidly compensates for tissue damage. However, excessive fibrosis caused by chronic inflammation or aging results in tissue dysfunction 2 . Fibrosis is involved in approximately 45% of all mortalities in developed countries 3 , but there are currently few effective therapies for fibrosis, and new therapeutic agents are needed for its alleviation. Myofibroblasts are responsible for excessive ECM synthesis and deposition in fibrotic tissues. Myofibroblasts are rare in normal tissues and are differentiated from multiple cell types such as resident fibroblasts, upon inflammation 4 , 5 . Their differentiation is triggered by humoral factors secreted by immune cells at the inflammation site 6 , like transforming growth factor (TGF)-β which activates Smad signalling 7 , 8 . Differentiated myofibroblasts produce excessive collagens, which accumulate in tissues and cause hardening. For example, the elastic modulus of a healthy rat heart is about 10 kPa, but in a fibrotic rat heart, it increases to about 50 kPa, resulting in decreased contractility 9 . Myofibroblasts recognise collagen-induced matrix stiffness through receptors like integrins, which activate Rho/Rho-associated protein kinase (ROCK) signalling and actin polymerisation 10 , 11 , 12 . Actin cytoskeletal formation promotes the expression of ECM proteins 13 , 14 . Thus, hardening plays an important role in maintaining myofibroblast differentiation, and generates feedback loops that accelerate collagen deposition 15 . However, the molecular mechanisms by which matrix stiffness increases fibrosis-related gene expression in myofibroblasts remain largely unknown. Liquid–liquid phase separation (LLPS) is a novel phenomenon that explains the dynamic binding of molecules containing RNA-binding proteins to membrane-free organelles and condensed bodies 16 . Condensates containing Non-POU domain containing octamer binding protein (NONO), an RNA-binding protein, are one of the biomolecular condensates formed by LLPS. Among the NONO condensates, the most well-known one is a paraspeckle, which is assembled from various RNA-binding proteins via LLPS, using an architectural lncRNA called nuclear paraspeckle assembly transcript 1 ( Neat1 ) as the backbone 17 , 18 , 19 , 20 . Paraspeckles have been reported to have various physiological functions and cause various pathological conditions 17 , 20 , 21 , 22 . On the other hand, it has been recently shown that non-paraspeckle NONO condensates also have biological functions 18 , 19 . However, the contribution of phase-separated condensates including NONO condensates to the pathogenesis of fibrosis remains unclear. Vestigial-like family member 3 (VGLL3) is a transcription cofactor 23 , 24 , 25 that binds TEA Domain (TEAD) transcription factors 24 . VGLL3 is involved in myogenesis 25 , cell proliferation 26 and female-biased autoimmune diseases 27 . However, the physiological and pathological roles of VGLL3 remain poorly understood. In this study, we reveal a role for VGLL3, which is specifically induced in cardiac and hepatic myofibroblasts, in collagen production during fibrosis. We show that VGLL3 is translocated to the nucleus by substrate stiffness and undergoes LLPS, which promotes collagen production. Results Substrate stiffness dictates myofibroblast differentiation in vitro During our previous study 28 , we accidentally found that cardiac myofibroblasts can be de-differentiated simply by culturing in suspension for several days, i.e. by removing physical stimuli. Further, we found that de-differentiated cells can re-differentiate into myofibroblasts only upon physical stimulus and adherent culture for several days. These results were consistent with previous reports demonstrating that myofibroblast differentiation is regulated by the surrounding ECM stiffness 10 , 15 . We thus hypothesised that comparing the gene expression of these cells, could reveal factors involved in myofibroblast differentiation by substrate stiffness and set up an experiment accordingly. Cardiac myofibroblasts were isolated from fibrotic mouse hearts after myocardial infarction (MI). In brief, we digested the fibrotic mouse hearts using enzymes and removed the erythrocytes. Then, the constituent cells were subjected to overnight culture on plastic plates. After that, the attached cells were collected and subjected to magnetic-activated cell sorting (MACS) separation using anti-CD45 antibody. CD45-negative cells were collected as myofibroblasts. Almost all the collected cells were positive for α-smooth muscle actin (αSMA), a myofibroblast marker protein (Supplementary Fig. 1a, b ). The purified cardiac myofibroblasts were cultured on polystyrene plates for 7 days; some of these cells were collected and designated as “adherent” myofibroblasts (Fig. 1a , Supplementary Fig. 1c, d ). The remaining myofibroblasts were transferred to ultra-low attachment plates, and cultured in suspension for 7 days, and designated “non-adherent” myofibroblasts (Fig. 1a ). These cells almost entirely lacked myofibroblast marker proteins such as αSMA encoded by Acta2 gene and periostin (Fig. 1b ). In addition, they lost the expression of fibroblast marker genes ( Thy1 , Tcf21 ) 29 (Supplementary Fig. 1e ). Instead, they exhibited increased expression of the stem cell marker Oct4 and mesenchymal stem cell marker genes ( Islr , Nt5e ) 30 , 31 (Supplementary Fig. 1e ), suggesting their de-differentiation. When non-adherent myofibroblasts were re-plated in a polystyrene plate and cultured for 7 days, myofibroblast marker protein expression in", "role": "user" }, { "content": "Researchers from Kyushu University have found how a single mechanosensitive protein induces the process that thickens and scars tissue, known as fibrosis. The protein, called VGLL3, was shown to contribute to fibrosis in multiple organs. The team hope their findings will lead to new treatments against fibrosis, a pathology that is attributed to 45% of all deaths in industrial nations. Their study was published in Nature Communications. In response to any injury, the body immediately begins a stream of events. Blood coagulates, the tissue begins to inflame, and the body begins to heal. In some cases that healing comes in the form of scaring and hardening. When an injury is on your skin, it shows up as a visible scar, but what happens when vital organs like your heart or liver are damaged and hardens? If left unchecked, it can lead to loss of mechanics and dangerous consequences. These changes in tissues are attributed to the extracellular matrix. The extracellular matrix is a web of proteins found in every cell in the body, and acts both like wires on a circuit that allow cells to communicate with each other, and the beams in a building, giving the organs its structure. Too much extracellular matrix makes the cell, and by extension the organ, tough and inflexible, a condition known as fibrosis. In simple terms, fibrosis is a stiffening of cells and tissue. Its health implications are profound, as it can lead to poor pumping by the heart or cirrhosis in the liver. \"Myofibroblasts are a group of cells that produce collagen, a common extracellular matrix protein. In diseased organs they are seen overproducing collagen. Once myofibroblasts appear in diseased organs, fibrosis proceeds in a snowball fashion,\" says Michio Nakaya Associate Professor at Kyushu University's Faculty of Pharmaceutical Sciences who led the study. \"At the same time, myofibroblasts are responsible for proper wound healing.\" To understand how myofibroblasts turn pathological, Nakaya and his colleagues looked at how different physical stimuli changes the expression of genes in these cells. They found consistent changes in the expression of one gene: VGLL3. Their study showed that after a heart attack, myofibroblasts in both mouse and human hearts express more VGLL3 protein which led to the production of collagen. VGLL3 was also expressed more in fibrotic mouse liver, suggesting it contributes to fibrosis in multiple organs. Conversely, preventing VGLL3 activation in mice led to far less fibrosis in these organs. \"We found that VGLL3 is translocated from the cytoplasm to the nucleus and begins to produce collage in response to mechanical stimuli. In mice without VGLL3, the fibrosis after a heart attack was reduced,\" noted Nakaya. The study further showed that the relationship between matrix stiffness and VGLL3 activation becomes a pathological positive feedback loop, in that a stiffer matrix triggers more VGLL3 activation, which triggers the cell to produce more collagen. Currently, there are only three drugs available for the treatment of fibrosis, and each has its limitations. Considering VGLL3's effects on cell stiffness, Nakaya believes research on treatments should give more attention to this protein. \"In the future, we expect to develop drugs and therapies for fibrosis by targeting VGLL3,\" concludes Nakaya. ", "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 Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for collagen production by myofibroblasts. However, the molecular mechanisms regulating their ability to produce collagen remain poorly characterised. Here, we show that vestigial-like family member 3 (VGLL3) is specifically expressed in myofibroblasts from mouse and human fibrotic hearts and promotes collagen production. Further, substrate stiffness triggers VGLL3 translocation into the nucleus through the integrin β1-Rho-actin pathway. In the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac fibrosis after myocardial infarction is significantly attenuated in Vgll3 -deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts’ collagen production, representing a novel therapeutic target for tissue fibrosis. Introduction Fibrosis, the pathological deposition of extracellular matrix (ECM) proteins like collagens in the interstitium, can occur in almost all tissues 1 , 2 , 3 . During tissue injury, fibrosis is beneficial to the body as it rapidly compensates for tissue damage. However, excessive fibrosis caused by chronic inflammation or aging results in tissue dysfunction 2 . Fibrosis is involved in approximately 45% of all mortalities in developed countries 3 , but there are currently few effective therapies for fibrosis, and new therapeutic agents are needed for its alleviation. Myofibroblasts are responsible for excessive ECM synthesis and deposition in fibrotic tissues. Myofibroblasts are rare in normal tissues and are differentiated from multiple cell types such as resident fibroblasts, upon inflammation 4 , 5 . Their differentiation is triggered by humoral factors secreted by immune cells at the inflammation site 6 , like transforming growth factor (TGF)-β which activates Smad signalling 7 , 8 . Differentiated myofibroblasts produce excessive collagens, which accumulate in tissues and cause hardening. For example, the elastic modulus of a healthy rat heart is about 10 kPa, but in a fibrotic rat heart, it increases to about 50 kPa, resulting in decreased contractility 9 . Myofibroblasts recognise collagen-induced matrix stiffness through receptors like integrins, which activate Rho/Rho-associated protein kinase (ROCK) signalling and actin polymerisation 10 , 11 , 12 . Actin cytoskeletal formation promotes the expression of ECM proteins 13 , 14 . Thus, hardening plays an important role in maintaining myofibroblast differentiation, and generates feedback loops that accelerate collagen deposition 15 . However, the molecular mechanisms by which matrix stiffness increases fibrosis-related gene expression in myofibroblasts remain largely unknown. Liquid–liquid phase separation (LLPS) is a novel phenomenon that explains the dynamic binding of molecules containing RNA-binding proteins to membrane-free organelles and condensed bodies 16 . Condensates containing Non-POU domain containing octamer binding protein (NONO), an RNA-binding protein, are one of the biomolecular condensates formed by LLPS. Among the NONO condensates, the most well-known one is a paraspeckle, which is assembled from various RNA-binding proteins via LLPS, using an architectural lncRNA called nuclear paraspeckle assembly transcript 1 ( Neat1 ) as the backbone 17 , 18 , 19 , 20 . Paraspeckles have been reported to have various physiological functions and cause various pathological conditions 17 , 20 , 21 , 22 . On the other hand, it has been recently shown that non-paraspeckle NONO condensates also have biological functions 18 , 19 . However, the contribution of phase-separated condensates including NONO condensates to the pathogenesis of fibrosis remains unclear. Vestigial-like family member 3 (VGLL3) is a transcription cofactor 23 , 24 , 25 that binds TEA Domain (TEAD) transcription factors 24 . VGLL3 is involved in myogenesis 25 , cell proliferation 26 and female-biased autoimmune diseases 27 . However, the physiological and pathological roles of VGLL3 remain poorly understood. In this study, we reveal a role for VGLL3, which is specifically induced in cardiac and hepatic myofibroblasts, in collagen production during fibrosis. We show that VGLL3 is translocated to the nucleus by substrate stiffness and undergoes LLPS, which promotes collagen production. Results Substrate stiffness dictates myofibroblast differentiation in vitro During our previous study 28 , we accidentally found that cardiac myofibroblasts can be de-differentiated simply by culturing in suspension for several days, i.e. by removing physical stimuli. Further, we found that de-differentiated cells can re-differentiate into myofibroblasts only upon physical stimulus and adherent culture for several days. These results were consistent with previous reports demonstrating that myofibroblast differentiation is regulated by the surrounding ECM stiffness 10 , 15 . We thus hypothesised that comparing the gene expression of these cells, could reveal factors involved in myofibroblast differentiation by substrate stiffness and set up an experiment accordingly. Cardiac myofibroblasts were isolated from fibrotic mouse hearts after myocardial infarction (MI). In brief, we digested the fibrotic mouse hearts using enzymes and removed the erythrocytes. Then, the constituent cells were subjected to overnight culture on plastic plates. After that, the attached cells were collected and subjected to magnetic-activated cell sorting (MACS) separation using anti-CD45 antibody. CD45-negative cells were collected as myofibroblasts. Almost all the collected cells were positive for α-smooth muscle actin (αSMA), a myofibroblast marker protein (Supplementary Fig. 1a, b ). The purified cardiac myofibroblasts were cultured on polystyrene plates for 7 days; some of these cells were collected and designated as “adherent” myofibroblasts (Fig. 1a , Supplementary Fig. 1c, d ). The remaining myofibroblasts were transferred to ultra-low attachment plates, and cultured in suspension for 7 days, and designated “non-adherent” myofibroblasts (Fig. 1a ). These cells almost entirely lacked myofibroblast marker proteins such as αSMA encoded by Acta2 gene and periostin (Fig. 1b ). In addition, they lost the expression of fibroblast marker genes ( Thy1 , Tcf21 ) 29 (Supplementary Fig. 1e ). Instead, they exhibited increased expression of the stem cell marker Oct4 and mesenchymal stem cell marker genes ( Islr , Nt5e ) 30 , 31 (Supplementary Fig. 1e ), suggesting their de-differentiation. When non-adherent myofibroblasts were re-plated in a polystyrene plate and cultured for 7 days, myofibroblast marker protein expression in<|im_end|> <|im_start|>assistant Researchers from Kyushu University have found how a single mechanosensitive protein induces the process that thickens and scars tissue, known as fibrosis. The protein, called VGLL3, was shown to contribute to fibrosis in multiple organs. The team hope their findings will lead to new treatments against fibrosis, a pathology that is attributed to 45% of all deaths in industrial nations. Their study was published in Nature Communications. In response to any injury, the body immediately begins a stream of events. Blood coagulates, the tissue begins to inflame, and the body begins to heal. In some cases that healing comes in the form of scaring and hardening. When an injury is on your skin, it shows up as a visible scar, but what happens when vital organs like your heart or liver are damaged and hardens? If left unchecked, it can lead to loss of mechanics and dangerous consequences. These changes in tissues are attributed to the extracellular matrix. The extracellular matrix is a web of proteins found in every cell in the body, and acts both like wires on a circuit that allow cells to communicate with each other, and the beams in a building, giving the organs its structure. Too much extracellular matrix makes the cell, and by extension the organ, tough and inflexible, a condition known as fibrosis. In simple terms, fibrosis is a stiffening of cells and tissue. Its health implications are profound, as it can lead to poor pumping by the heart or cirrhosis in the liver. "Myofibroblasts are a group of cells that produce collagen, a common extracellular matrix protein. In diseased organs they are seen overproducing collagen. Once myofibroblasts appear in diseased organs, fibrosis proceeds in a snowball fashion," says Michio Nakaya Associate Professor at Kyushu University's Faculty of Pharmaceutical Sciences who led the study. "At the same time, myofibroblasts are responsible for proper wound healing." To understand how myofibroblasts turn pathological, Nakaya and his colleagues looked at how different physical stimuli changes the expression of genes in these cells. They found consistent changes in the expression of one gene: VGLL3. Their study showed that after a heart attack, myofibroblasts in both mouse and human hearts express more VGLL3 protein which led to the production of collagen. VGLL3 was also expressed more in fibrotic mouse liver, suggesting it contributes to fibrosis in multiple organs. Conversely, preventing VGLL3 activation in mice led to far less fibrosis in these organs. "We found that VGLL3 is translocated from the cytoplasm to the nucleus and begins to produce collage in response to mechanical stimuli. In mice without VGLL3, the fibrosis after a heart attack was reduced," noted Nakaya. The study further showed that the relationship between matrix stiffness and VGLL3 activation becomes a pathological positive feedback loop, in that a stiffer matrix triggers more VGLL3 activation, which triggers the cell to produce more collagen. Currently, there are only three drugs available for the treatment of fibrosis, and each has its limitations. Considering VGLL3's effects on cell stiffness, Nakaya believes research on treatments should give more attention to this protein. "In the future, we expect to develop drugs and therapies for fibrosis by targeting VGLL3," concludes Nakaya. <|im_end|>

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2,350

[ { "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 Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP. Methods Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only “vasculature-related” BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity. Results We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of “vasculature-related” BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation. Conclusions Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta. Peer Review reports Background The increasing prevalence of cardio-metabolic diseases leading to premature death is a raising concern [ 1 ]. Although major risk factors are lifestyle factors after birth, epidemiological studies have associated low birth weight (LBW) and/or fetal growth restriction (FGR) with hypertension, cardiovascular diseases, and type 2 diabetes, indicating the existence of prenatal risk factors [ 2 , 3 , 4 ]. However, the underlying mechanisms explaining the relationship between LBW/FGR and diseases in adulthood are not fully understood. It is suggested that maternal undernutrition and/or poor placental function could alter long-lasting body function and physiology, predisposing individuals to cardio-metabolic diseases [ 5 , 6 ]. To analyze the effect of such intrauterine environment on fetal growth, the maternal genotype has been used as a proxy for the intrauterine environment [ 7 , 8 ]. Maternal genetic factors may influence fetal growth directly through the alleles inherited by the fetus, or indirectly through the intrauterine environment, and this idea has been developed into the Mendelian Randomization (MR) approach in the framework of causal inference [ 7 , 8 , 9 , 10 ]. Recent MR studies have reported that maternal systolic blood pressure (SBP)-increasing polygenic score (PGS) causes lower birth weight through elevated maternal SBP, independently of direct fetal genetic effects [ 8 , 10 ]. However, the genetic estimate of the association between maternal SBP and birth weight was in the opposite direction to the observational estimate [ 8 ]. In addition, hypertension usually develops in late life. Therefore, it may not be appropriate to apply to pregnant women the estimates of lifelong BP risks in the MR approach. Thus, it remains unclear why higher maternal SBP-increasing PGS results in lower birth weight. FGR pathophysiology and etiology are complex, but most cases are thought to arise from placental dysfunction [ 4 , 11 ]. Generally, placental growth precedes fetal growth, with the placental growth rate decreasing from about 30 weeks, and the fetus/placenta growth ratio gradually increasing until 37–38 weeks [ 12 ]. Nearly 80% of FGR are late-onset (≥ 32 weeks) [ 13 ]. In addition, it has been highlighted that placental weight is an important determinant of fetal growth in the third trimester [ 14 ], and birth and placental weight highly correlate [ 14 , 15 ]. The placenta is a vascular organ, and recent GWAS uncovered numerous BP-associated genes involved in regulating the development and function of the vascular system [ 16 , 17 , 18 ]. Therefore, we hypothesized that BP-increasing maternal SNPs influence placental growth, which in turn affects birth weight. Since the mediating role of the placenta was never been examined, we investigated whether maternal SBP-increasing PGS is inversely associated with placental weight and whether the placental weight mediates the effect of maternal SBP PGS on birth weight. Furthermore, by constructing a genetic BP-increasing risk score composed exclusively of vasculature-related SNPs, we aimed to clarify that the role of placental weight in the effects of vasculature-related BP SNPs on birth weight. We also aimed to confirm by haplotype analysis that maternal transmitted and non-transmitted BP-increasing alleles, but not paternal transmitted alleles, are inversely associated with birth and placental weight. Lowering of birth weight can be caused by deceleration of fetal growth velocity during pregnancy. Motivated to understand the indirect effect of maternal SBP PGS on fetal growth velocity, reflecting the fact that placental growth precedes fetal growth, we aimed to determine that maternal SBP PGS significantly decreases fetal growth velocity at the very end of pregnancy. Thus, our study uncovered that maternal genetic risk of hypertension inhibits fetal growth through the intrauterine environment established by the placenta. Methods Study cohorts The characteristics of the two cohorts analyzed in this study are presented in Additional file 1 : Table S1. More details about the participants of these cohorts have been described previously [ 19 , 20 , 21 ]. The study population was comparable with the general Japanese pregnant", "role": "user" }, { "content": "Cardiovascular diseases are the leading cause of death worldwide. Although the development of these disorders is most commonly associated with lifestyle factors like obesity, increasing evidence suggests that events much earlier in one's life can also play a role. In a recent article published in BMC Medicine, a team led by researchers at Tokyo Medical and Dental University (TMDU) investigated how low birth weight and fetal growth restriction may result from the mother having certain variants of hypertension-related genes. Interestingly, these consequences can occur despite the mother not having high blood pressure during the course of the pregnancy. Genetic factors from the mother can affect her child through directly passing down certain alleles, but they can also do so indirectly via the intrauterine environment. Studies examining such phenomena have recently suggested that women having genes related to hypertension risk are more likely to give birth to children with low birth weight. Researchers and clinicians therefore assumed that mothers with higher systolic blood pressure would have lower weight newborns. However, no such association was observed. This caused the TMDU group to believe that the intrauterine environment plays more of a role in this case. They hypothesized that all of these observations were caused by effects on the placenta. \"We focused on the placenta because it is an extremely vascular organ. Placental weight also frequently correlates with birth weight,\" says Noriko Sato, Associate Professor in the Department of Molecular Epidemiology, who led the study. \"Genome-wide association studies have shown that many blood pressure-related genes are involved in vascular system development and function.\" The researchers examined fetal growth in a cohort of Japanese individuals. They used a person's genetic risk of developing hypertension over a lifetime, called a polygenic risk score, to examine how maternal genetic score influenced placental weight and birth weight. Then the mediating role of the placenta regarding influence on birth weight was formally verified by the method, called a causal mediation analysis. \"We also focused on genetic variants of vascular-related blood pressure genes to see if the impact on birth weight could be ultimately through influence on placental growth,\" explains senior author Naoyuki Miyasaka, Professor in Comprehensive Reproductive Medicine. \"Nearly 100% of the effect of \"vasculature-related\" genetic score on birth weight was indeed mediated by placental weight.\" The team also found an inverse association between maternal systolic blood pressure genetic risk score and the rate of fetal growth towards the end of pregnancy, specifically around 36 weeks of gestation. \"Our findings suggest that the maternal blood pressure-related genes are associated with undesirable fetal growth deceleration by affecting the placental growth,\" explains Sato. \"The intrauterine environment constructed by the placental vasculature is the primarily relevant factor here rather than the mother's blood pressure at the time of pregnancy.\" This study provides strong evidence that maternal genes that are associated with hypertension risk can indirectly affect fetal growth and cause long-term impacts on a child via effects on the placenta. Fetal growth restriction in late pregnancy occurs in more than a few percent of pregnancies, and it is mostly of unknown cause and difficult to predict. However, incorporating maternal genetic risk information into clinical practice could enable screening and improved perinatal management for mother–child health. Furthermore, the results contribute to the development of new therapeutic targets for the treatment and prevention of hypertension and cardiovascular diseases. These results are fascinating, because they provide data that can help prevent the development of disease decades before potential onset. ", "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 Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP. Methods Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only “vasculature-related” BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity. Results We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of “vasculature-related” BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation. Conclusions Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta. Peer Review reports Background The increasing prevalence of cardio-metabolic diseases leading to premature death is a raising concern [ 1 ]. Although major risk factors are lifestyle factors after birth, epidemiological studies have associated low birth weight (LBW) and/or fetal growth restriction (FGR) with hypertension, cardiovascular diseases, and type 2 diabetes, indicating the existence of prenatal risk factors [ 2 , 3 , 4 ]. However, the underlying mechanisms explaining the relationship between LBW/FGR and diseases in adulthood are not fully understood. It is suggested that maternal undernutrition and/or poor placental function could alter long-lasting body function and physiology, predisposing individuals to cardio-metabolic diseases [ 5 , 6 ]. To analyze the effect of such intrauterine environment on fetal growth, the maternal genotype has been used as a proxy for the intrauterine environment [ 7 , 8 ]. Maternal genetic factors may influence fetal growth directly through the alleles inherited by the fetus, or indirectly through the intrauterine environment, and this idea has been developed into the Mendelian Randomization (MR) approach in the framework of causal inference [ 7 , 8 , 9 , 10 ]. Recent MR studies have reported that maternal systolic blood pressure (SBP)-increasing polygenic score (PGS) causes lower birth weight through elevated maternal SBP, independently of direct fetal genetic effects [ 8 , 10 ]. However, the genetic estimate of the association between maternal SBP and birth weight was in the opposite direction to the observational estimate [ 8 ]. In addition, hypertension usually develops in late life. Therefore, it may not be appropriate to apply to pregnant women the estimates of lifelong BP risks in the MR approach. Thus, it remains unclear why higher maternal SBP-increasing PGS results in lower birth weight. FGR pathophysiology and etiology are complex, but most cases are thought to arise from placental dysfunction [ 4 , 11 ]. Generally, placental growth precedes fetal growth, with the placental growth rate decreasing from about 30 weeks, and the fetus/placenta growth ratio gradually increasing until 37–38 weeks [ 12 ]. Nearly 80% of FGR are late-onset (≥ 32 weeks) [ 13 ]. In addition, it has been highlighted that placental weight is an important determinant of fetal growth in the third trimester [ 14 ], and birth and placental weight highly correlate [ 14 , 15 ]. The placenta is a vascular organ, and recent GWAS uncovered numerous BP-associated genes involved in regulating the development and function of the vascular system [ 16 , 17 , 18 ]. Therefore, we hypothesized that BP-increasing maternal SNPs influence placental growth, which in turn affects birth weight. Since the mediating role of the placenta was never been examined, we investigated whether maternal SBP-increasing PGS is inversely associated with placental weight and whether the placental weight mediates the effect of maternal SBP PGS on birth weight. Furthermore, by constructing a genetic BP-increasing risk score composed exclusively of vasculature-related SNPs, we aimed to clarify that the role of placental weight in the effects of vasculature-related BP SNPs on birth weight. We also aimed to confirm by haplotype analysis that maternal transmitted and non-transmitted BP-increasing alleles, but not paternal transmitted alleles, are inversely associated with birth and placental weight. Lowering of birth weight can be caused by deceleration of fetal growth velocity during pregnancy. Motivated to understand the indirect effect of maternal SBP PGS on fetal growth velocity, reflecting the fact that placental growth precedes fetal growth, we aimed to determine that maternal SBP PGS significantly decreases fetal growth velocity at the very end of pregnancy. Thus, our study uncovered that maternal genetic risk of hypertension inhibits fetal growth through the intrauterine environment established by the placenta. Methods Study cohorts The characteristics of the two cohorts analyzed in this study are presented in Additional file 1 : Table S1. More details about the participants of these cohorts have been described previously [ 19 , 20 , 21 ]. The study population was comparable with the general Japanese pregnant<|im_end|> <|im_start|>assistant Cardiovascular diseases are the leading cause of death worldwide. Although the development of these disorders is most commonly associated with lifestyle factors like obesity, increasing evidence suggests that events much earlier in one's life can also play a role. In a recent article published in BMC Medicine, a team led by researchers at Tokyo Medical and Dental University (TMDU) investigated how low birth weight and fetal growth restriction may result from the mother having certain variants of hypertension-related genes. Interestingly, these consequences can occur despite the mother not having high blood pressure during the course of the pregnancy. Genetic factors from the mother can affect her child through directly passing down certain alleles, but they can also do so indirectly via the intrauterine environment. Studies examining such phenomena have recently suggested that women having genes related to hypertension risk are more likely to give birth to children with low birth weight. Researchers and clinicians therefore assumed that mothers with higher systolic blood pressure would have lower weight newborns. However, no such association was observed. This caused the TMDU group to believe that the intrauterine environment plays more of a role in this case. They hypothesized that all of these observations were caused by effects on the placenta. "We focused on the placenta because it is an extremely vascular organ. Placental weight also frequently correlates with birth weight," says Noriko Sato, Associate Professor in the Department of Molecular Epidemiology, who led the study. "Genome-wide association studies have shown that many blood pressure-related genes are involved in vascular system development and function." The researchers examined fetal growth in a cohort of Japanese individuals. They used a person's genetic risk of developing hypertension over a lifetime, called a polygenic risk score, to examine how maternal genetic score influenced placental weight and birth weight. Then the mediating role of the placenta regarding influence on birth weight was formally verified by the method, called a causal mediation analysis. "We also focused on genetic variants of vascular-related blood pressure genes to see if the impact on birth weight could be ultimately through influence on placental growth," explains senior author Naoyuki Miyasaka, Professor in Comprehensive Reproductive Medicine. "Nearly 100% of the effect of "vasculature-related" genetic score on birth weight was indeed mediated by placental weight." The team also found an inverse association between maternal systolic blood pressure genetic risk score and the rate of fetal growth towards the end of pregnancy, specifically around 36 weeks of gestation. "Our findings suggest that the maternal blood pressure-related genes are associated with undesirable fetal growth deceleration by affecting the placental growth," explains Sato. "The intrauterine environment constructed by the placental vasculature is the primarily relevant factor here rather than the mother's blood pressure at the time of pregnancy." This study provides strong evidence that maternal genes that are associated with hypertension risk can indirectly affect fetal growth and cause long-term impacts on a child via effects on the placenta. Fetal growth restriction in late pregnancy occurs in more than a few percent of pregnancies, and it is mostly of unknown cause and difficult to predict. However, incorporating maternal genetic risk information into clinical practice could enable screening and improved perinatal management for mother–child health. Furthermore, the results contribute to the development of new therapeutic targets for the treatment and prevention of hypertension and cardiovascular diseases. These results are fascinating, because they provide data that can help prevent the development of disease decades before potential onset. <|im_end|>

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11, 719, 1455, 5157, 527, 3463, 311, 31889, 505, 29960, 6430, 32403, 510, 220, 19, 1174, 220, 806, 21087, 44493, 11, 29960, 6430, 6650, 16599, 288, 63746, 6650, 11, 449, 279, 29960, 6430, 6650, 4478, 44649, 505, 922, 220, 966, 5672, 11, 323, 279, 76688, 11505, 582, 16985, 6650, 11595, 27115, 7859, 3156, 220, 1806, 4235, 1987, 5672, 510, 220, 717, 21087, 49669, 220, 1490, 4, 315, 435, 8796, 527, 3389, 10539, 751, 320, 120156, 220, 843, 5672, 8, 510, 220, 1032, 21087, 763, 5369, 11, 433, 706, 1027, 27463, 430, 29960, 6430, 4785, 374, 459, 3062, 88060, 315, 63746, 6650, 304, 279, 4948, 75110, 261, 510, 220, 975, 10881, 323, 7342, 323, 29960, 6430, 4785, 7701, 81584, 510, 220, 975, 1174, 220, 868, 21087, 578, 29960, 16985, 374, 264, 64603, 2942, 11, 323, 3293, 42353, 1950, 43522, 12387, 30167, 75968, 21389, 6532, 304, 58499, 279, 4500, 323, 734, 315, 279, 64603, 1887, 510, 220, 845, 1174, 220, 1114, 1174, 220, 972, 21087, 15636, 11, 584, 22601, 83979, 430, 30167, 3502, 76562, 50150, 18407, 21051, 10383, 29960, 6430, 6650, 11, 902, 304, 2543, 22223, 7342, 4785, 13, 8876, 279, 1812, 23747, 3560, 315, 279, 29960, 16985, 574, 2646, 1027, 25078, 11, 584, 27313, 3508, 50150, 26313, 47, 3502, 76562, 393, 16929, 374, 65683, 989, 5938, 449, 29960, 6430, 4785, 323, 3508, 279, 29960, 6430, 4785, 25098, 988, 279, 2515, 315, 50150, 26313, 47, 393, 16929, 389, 7342, 4785, 13, 24296, 11, 555, 50453, 264, 19465, 30167, 3502, 76562, 5326, 5573, 24306, 24121, 315, 44496, 3395, 1598, 14228, 18407, 21051, 11, 584, 20034, 311, 38263, 430, 279, 3560, 315, 29960, 6430, 4785, 304, 279, 6372, 315, 44496, 3395, 1598, 14228, 30167, 18407, 21051, 389, 7342, 4785, 13, 1226, 1101, 20034, 311, 7838, 555, 46900, 75, 4249, 6492, 430, 50150, 34699, 323, 2536, 39160, 5600, 30167, 3502, 76562, 98260, 11, 719, 539, 93367, 34699, 98260, 11, 527, 65683, 989, 5938, 449, 7342, 323, 29960, 6430, 4785, 13, 28636, 287, 315, 7342, 4785, 649, 387, 9057, 555, 1654, 8023, 367, 315, 63746, 6650, 15798, 2391, 20209, 13, 19514, 55786, 311, 3619, 279, 25636, 2515, 315, 50150, 26313, 47, 393, 16929, 389, 63746, 6650, 15798, 11, 42852, 279, 2144, 430, 29960, 6430, 6650, 16599, 288, 63746, 6650, 11, 584, 20034, 311, 8417, 430, 50150, 26313, 47, 393, 16929, 12207, 43154, 63746, 6650, 15798, 520, 279, 1633, 842, 315, 20209, 13, 14636, 11, 1057, 4007, 43522, 430, 50150, 19465, 5326, 315, 63308, 20747, 1220, 63746, 6650, 1555, 279, 50938, 29051, 483, 4676, 9749, 555, 279, 29960, 16985, 13, 19331, 19723, 90388, 578, 17910, 315, 279, 1403, 90388, 30239, 304, 420, 4007, 527, 10666, 304, 24086, 1052, 220, 16, 551, 6771, 328, 16, 13, 4497, 3649, 922, 279, 13324, 315, 1521, 90388, 617, 1027, 7633, 8767, 510, 220, 777, 1174, 220, 508, 1174, 220, 1691, 21087, 578, 4007, 7187, 574, 30139, 449, 279, 4689, 11002, 20895, 128257, 198, 128256, 78191, 198, 5889, 822, 33945, 19338, 527, 279, 6522, 5353, 315, 4648, 15603, 13, 10541, 279, 4500, 315, 1521, 24673, 374, 1455, 17037, 5938, 449, 19433, 9547, 1093, 33048, 11, 7859, 6029, 13533, 430, 4455, 1790, 6931, 304, 832, 596, 2324, 649, 1101, 1514, 264, 3560, 13, 763, 264, 3293, 4652, 4756, 304, 82806, 19152, 11, 264, 2128, 6197, 555, 12074, 520, 27286, 13235, 323, 48804, 3907, 320, 51, 6204, 52, 8, 27313, 1268, 3428, 7342, 4785, 323, 63746, 6650, 20020, 1253, 1121, 505, 279, 6691, 3515, 3738, 27103, 315, 63308, 14228, 21389, 13, 58603, 11, 1521, 16296, 649, 12446, 8994, 279, 6691, 539, 3515, 1579, 6680, 7410, 2391, 279, 3388, 315, 279, 20209, 13, 75226, 9547, 505, 279, 6691, 649, 7958, 1077, 1716, 1555, 6089, 12579, 1523, 3738, 98260, 11, 719, 814, 649, 1101, 656, 779, 46345, 4669, 279, 50938, 29051, 483, 4676, 13, 19241, 38936, 1778, 44247, 617, 6051, 12090, 430, 3278, 3515, 21389, 5552, 311, 63308, 5326, 527, 810, 4461, 311, 3041, 7342, 311, 2911, 449, 3428, 7342, 4785, 13, 59250, 323, 78545, 9093, 19655, 430, 27698, 449, 5190, 42345, 7918, 6680, 7410, 1053, 617, 4827, 4785, 46397, 82, 13, 4452, 11, 912, 1778, 15360, 574, 13468, 13, 1115, 9057, 279, 350, 6204, 52, 1912, 311, 4510, 430, 279, 50938, 29051, 483, 4676, 11335, 810, 315, 264, 3560, 304, 420, 1162, 13, 2435, 22601, 83979, 430, 682, 315, 1521, 24654, 1051, 9057, 555, 6372, 389, 279, 29960, 16985, 13, 330, 1687, 10968, 389, 279, 29960, 16985, 1606, 433, 374, 459, 9193, 64603, 2942, 13, 1856, 582, 6430, 4785, 1101, 14134, 97303, 449, 7342, 4785, 1359, 2795, 8170, 24551, 328, 4428, 11, 33468, 17054, 304, 279, 6011, 315, 60825, 88953, 2508, 11, 889, 6197, 279, 4007, 13, 330, 10172, 638, 25480, 15360, 7978, 617, 6982, 430, 1690, 6680, 7410, 14228, 21389, 527, 6532, 304, 64603, 1887, 4500, 323, 734, 1210, 578, 12074, 25078, 63746, 6650, 304, 264, 41944, 315, 11002, 7931, 13, 2435, 1511, 264, 1732, 596, 19465, 5326, 315, 11469, 63308, 927, 264, 19569, 11, 2663, 264, 10062, 89305, 5326, 5573, 11, 311, 21635, 1268, 50150, 19465, 5573, 28160, 29960, 6430, 4785, 323, 7342, 4785, 13, 5112, 279, 1812, 23747, 3560, 315, 279, 29960, 16985, 9002, 10383, 389, 7342, 4785, 574, 37402, 24884, 555, 279, 1749, 11, 2663, 264, 59557, 77673, 6492, 13, 330, 1687, 1101, 10968, 389, 19465, 27103, 315, 64603, 14228, 6680, 7410, 21389, 311, 1518, 422, 279, 5536, 389, 7342, 4785, 1436, 387, 13967, 1555, 10383, 389, 29960, 6430, 6650, 1359, 15100, 10195, 3229, 13106, 2303, 22227, 67559, 300, 13637, 11, 17054, 304, 67963, 3402, 299, 68243, 19152, 13, 330, 64445, 220, 1041, 4, 315, 279, 2515, 315, 330, 4378, 3395, 1598, 14228, 1, 19465, 5573, 389, 7342, 4785, 574, 13118, 78926, 555, 29960, 6430, 4785, 1210, 578, 2128, 1101, 1766, 459, 29049, 15360, 1990, 50150, 42345, 7918, 6680, 7410, 19465, 5326, 5573, 323, 279, 4478, 315, 63746, 6650, 7119, 279, 842, 315, 20209, 11, 11951, 2212, 220, 1927, 5672, 315, 13033, 367, 13, 330, 8140, 14955, 4284, 430, 279, 50150, 6680, 7410, 14228, 21389, 527, 5938, 449, 77344, 63746, 6650, 1654, 8023, 367, 555, 28987, 279, 29960, 6430, 6650, 1359, 15100, 328, 4428, 13, 330, 791, 50938, 29051, 483, 4676, 20968, 555, 279, 29960, 6430, 44496, 3395, 1598, 374, 279, 15871, 9959, 8331, 1618, 4856, 1109, 279, 6691, 596, 6680, 7410, 520, 279, 892, 315, 20209, 1210, 1115, 4007, 5825, 3831, 6029, 430, 50150, 21389, 430, 527, 5938, 449, 63308, 5326, 649, 46345, 7958, 63746, 6650, 323, 5353, 1317, 9860, 25949, 389, 264, 1716, 4669, 6372, 389, 279, 29960, 16985, 13, 435, 22029, 6650, 20020, 304, 3389, 20209, 13980, 304, 810, 1109, 264, 2478, 3346, 315, 82308, 11, 323, 433, 374, 10213, 315, 9987, 5353, 323, 5107, 311, 7168, 13, 4452, 11, 52913, 50150, 19465, 5326, 2038, 1139, 14830, 6725, 1436, 7431, 23061, 323, 13241, 824, 258, 4306, 6373, 369, 6691, 4235, 3124, 2890, 13, 24296, 11, 279, 3135, 17210, 311, 279, 4500, 315, 502, 37471, 11811, 369, 279, 6514, 323, 27344, 315, 63308, 323, 41713, 19338, 13, 4314, 3135, 527, 27387, 11, 1606, 814, 3493, 828, 430, 649, 1520, 5471, 279, 4500, 315, 8624, 11026, 1603, 4754, 42080, 13, 220, 128257, 198 ]

2,036

[ { "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 De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. Main Small (4–12 kDa) binding proteins have the potential to bridge the gap between monoclonal antibodies and small molecule drugs 1 , 2 , 3 , with advantages of stability and amenability to chemical synthesis over monoclonal antibodies, and of selectivity and designability over small molecules. Directed evolution, starting from naturally occurring small protein scaffolds, has previously been used to generate new binding proteins 4 . While powerful, such approaches have limitations: they cannot modify the overall shape of the starting scaffold protein(s), they can sample only a very small fraction of sequence space, and naturally occurring disulfide mini-proteins can be difficult to express. Computational protein design has the potential to overcome these limitations by efficiently sampling both shape and sequence space on a much larger scale, and by generating readily producible proteins, as recently demonstrated by the design of stapled mini-protein scaffolds with a wide range of shapes 5 . Despite this potential, the high cost of synthesizing genes for each designed protein has, until recently 6 , limited testing to small numbers (tens) of designs for any one application, which is too few to systematically explore the determinants of protein binding and folding and provide feedback to improve the computational model 7 , 8 . Here, we describe an integrated computational and experimental approach that enables the rapid design and testing of tens of thousands of de novo mini-protein binders. Our approach exploits advances in both DNA manufacturing and protein design that have led to a fortunate convergence between the upper limit of the size of oligonucleotides (230 bp) that can be synthesized as pools of 10,000 or larger 9 , 10 , and the lower limit of the size of genetically encodable computationally designed proteins (roughly 40 amino acids). To generate binders for a given target, we used Rosetta 11 to design thousands of protein scaffolds with varying shapes, dock these onto the target, optimize the residues at the interface for high-affinity binding, and identify, from the resulting pool of hundreds of thousands of designs, approximately 10,000 with high predicted stability and affinity. This large pool of computational designs, together with controls probing aspects of the design procedure, was then experimentally evaluated by encoding each individual sequence in a single oligonucleotide, manufacturing the oligonucleotides in parallel, sorting yeast libraries displaying the designs labelled with fluorescent targets, and using deep sequencing to identify the designs most enriched for binding ( Fig. 1 ). Figure 1: Massively parallel binding protein design. a , Hundreds of 37–43 residue mini-protein backbones with different secondary structure elements, orientations and loop lengths were matched with hotspot binding motifs for HA (HB1 and HB2) and BoNT (Bot) by identifying compatible mini-protein local backbone segments, superimposing them onto the hotspot motif–target complex, and discarding docks with mini-protein/target backbone clashes. Each topology included designs with many different disulfide configurations; several possibilities are illustrated. b , For each non-clashing dock of each scaffold onto each target, the monomer and interaction energies were optimized with Rosetta sequence design. Representative models are shown at the left of each column. Right columns show a top view of the target with the hotspot interaction areas coloured as above and new contact areas generated by Rosetta sequence design coloured yellow; the total number of unique designs generated is indicated at the bottom. c , Designed contacts substantially increase the interface buried surface area of the designs beyond the starting hotspot residues. d , Genes encoding 16,968 mini-protein designs, including 6,286 controls, were synthesized using DNA oligo pool synthesis (see Methods). e , The oligo pools were recombined into yeast display vectors and transformed into yeast (see Methods), and binding of the designs HA or BoNT at different concentrations was assessed by FACS. For each sorting condition, enriched designs were identified by comparing the frequencies in the original and sorted populations using deep sequencing. These data were used to guide improvement of the computational design model, and the entire design, synthesis and testing cycle was iterated. PowerPoint slide Full size image High-throughput computational design As targets, we selected Influenza A H1 haemagglutinin (HA), as this virus remains a serious public health concern 12 , and botulinum neurotoxin B (BoNT/B), which causes the acute neuroparalytic syndrome of botulism and is one of the most lethal natural toxins known (with a lethal dose of approximately 1 ng per kg) 13 . We generated virtual scaffold libraries with over 4,000 backbone geometries in five different topologies: HHH, EHEE, HEE, EEHE, and HEEH (where H indicates an α-helix and E a β-strand) with or without 5 , 6 diverse disulfide connectivities ( Fig. 1a ). To design binding interfaces, we superimposed helical segments of the scaffolds on interface helices in previously solved HA and BoNT/B complexes (the previously designed HA binders HB36.6 and HB80.4 14 , 15 , 16 , and the natural target of BoNT/B synaptotagmin-II (Syt-II) 17 ), seeded the newly formed interfaces with hotspot residues from these helices ( Extended Data Fig. 1 ) and designed the remainder of the residues to maximize binding affinity and monomer stability using", "role": "user" }, { "content": "Scientists have created a high-speed method to generate thousands of different, small, stable proteins from scratch that can be custom-designed to bind to specific therapeutic targets. Protection against infectious diseases, like the flu, and antidotes to nerve toxins are but two research goals of this approach. The method rapidly produces thousands of new drug candidates. These computer-designed proteins, which did not previous exist in nature, combine the stability and bioavailability of small molecule drugs with the specificity and potency of larger biologics. \"These mini-protein binders have the potential of becoming a new class of drugs that bridge the gap between small molecule drugs and biologics. Like monoclonal antibodies, they can be designed to bind to targets with high selectivity, but they are more stable and easier to produce and to administer,\" said David Baker, who led the multi-institutional research project. Baker is a professor of biochemistry at the University of Washington School of Medicine and director of the UW Institute for Protein Design. He is also a Howard Hughes Medical Institute investigator. Baker and his colleagues report their findings in article published online Sept. 27 by the journal Nature. Aaron Chevalier, Daniel-Adriano Silva and Gabriel J. Rocklin were the lead authors and were all senior fellows at the UW Institute for Protein Design at the time of the project. The method used a computer platform, called Rosetta, developed by Baker and colleagues at the University of Washington. They designed thousands of short proteins, about 40 amino acids in length, that the Rosetta program predicted would bind tightly to the molecular target. David Baker of the University of Washington Institute for Protein design discusses the creation of mini-protein binders as potential targeted therapeutics against neurotoxins, flu viruses, and other troublesome agents. A brief tour of his lab shows where computational design of new proteins takes place, and where the proteins are grown in yeast and tested. These so-called \"de novo\" proteins did not exist in nature until they were created in the lab. Credit: Randy Carnell/UW Medicine Because of their small size, these short proteins tend to be extremely stable. They can be stored without refrigeration. They also are more easily administered than large protein drugs, such as monoclonal antibodies. Previously, such short, protein-binder drugs were typically re-engineered versions of naturally occurring proteins. These, however, tended not to be significantly better than monoclonal antibodies. Because these mini-proteins binders are original designs, they can be tailored to fit their targets much more tightly and are simpler to modify and refine. In this study, the researchers sought to design two sets of these proteins: one set that would prevent the influenza virus from invading cells and another that would bind to and neutralize a deadly nerve toxin from botulism. This toxin is considered a potential bioweapon. The computer modeling identified the amino-acid sequences of thousands of short proteins that would fit into and bind to the influenza and botulinum targets. The researchers created short pieces of DNA that coded each of these proteins, grew the proteins in yeast cells, and then looked at how tightly they bound to their targets. The targets were Influenza H1 hemagglutinin and botulinum neurotoxin B. All told, the method allowed them to design and test 22,660 proteins in just a few months. More than than two-thousand of them bound to their targets with high affinity. Evaluation of the best candidates found that the anti-influenza proteins neutralized viruses in cell culture and other designed proteins prevented the botulinum toxin from entering brain cells. A nasal spray containing one of the custom-designed proteins completely protected mice from the flu if administered before or as much as 72 hours after exposure.. The protection that the treatment provides equaled or surpassed that seen with antibodies, the researchers report. Testing of a subset of the proteins showed that they were extremely stable and, unlike antibodies, did not become inactivated by high temperatures. The small proteins also triggered little or no immune response, a problem that often renders larger protein drugs ineffective. ", "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 De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. Main Small (4–12 kDa) binding proteins have the potential to bridge the gap between monoclonal antibodies and small molecule drugs 1 , 2 , 3 , with advantages of stability and amenability to chemical synthesis over monoclonal antibodies, and of selectivity and designability over small molecules. Directed evolution, starting from naturally occurring small protein scaffolds, has previously been used to generate new binding proteins 4 . While powerful, such approaches have limitations: they cannot modify the overall shape of the starting scaffold protein(s), they can sample only a very small fraction of sequence space, and naturally occurring disulfide mini-proteins can be difficult to express. Computational protein design has the potential to overcome these limitations by efficiently sampling both shape and sequence space on a much larger scale, and by generating readily producible proteins, as recently demonstrated by the design of stapled mini-protein scaffolds with a wide range of shapes 5 . Despite this potential, the high cost of synthesizing genes for each designed protein has, until recently 6 , limited testing to small numbers (tens) of designs for any one application, which is too few to systematically explore the determinants of protein binding and folding and provide feedback to improve the computational model 7 , 8 . Here, we describe an integrated computational and experimental approach that enables the rapid design and testing of tens of thousands of de novo mini-protein binders. Our approach exploits advances in both DNA manufacturing and protein design that have led to a fortunate convergence between the upper limit of the size of oligonucleotides (230 bp) that can be synthesized as pools of 10,000 or larger 9 , 10 , and the lower limit of the size of genetically encodable computationally designed proteins (roughly 40 amino acids). To generate binders for a given target, we used Rosetta 11 to design thousands of protein scaffolds with varying shapes, dock these onto the target, optimize the residues at the interface for high-affinity binding, and identify, from the resulting pool of hundreds of thousands of designs, approximately 10,000 with high predicted stability and affinity. This large pool of computational designs, together with controls probing aspects of the design procedure, was then experimentally evaluated by encoding each individual sequence in a single oligonucleotide, manufacturing the oligonucleotides in parallel, sorting yeast libraries displaying the designs labelled with fluorescent targets, and using deep sequencing to identify the designs most enriched for binding ( Fig. 1 ). Figure 1: Massively parallel binding protein design. a , Hundreds of 37–43 residue mini-protein backbones with different secondary structure elements, orientations and loop lengths were matched with hotspot binding motifs for HA (HB1 and HB2) and BoNT (Bot) by identifying compatible mini-protein local backbone segments, superimposing them onto the hotspot motif–target complex, and discarding docks with mini-protein/target backbone clashes. Each topology included designs with many different disulfide configurations; several possibilities are illustrated. b , For each non-clashing dock of each scaffold onto each target, the monomer and interaction energies were optimized with Rosetta sequence design. Representative models are shown at the left of each column. Right columns show a top view of the target with the hotspot interaction areas coloured as above and new contact areas generated by Rosetta sequence design coloured yellow; the total number of unique designs generated is indicated at the bottom. c , Designed contacts substantially increase the interface buried surface area of the designs beyond the starting hotspot residues. d , Genes encoding 16,968 mini-protein designs, including 6,286 controls, were synthesized using DNA oligo pool synthesis (see Methods). e , The oligo pools were recombined into yeast display vectors and transformed into yeast (see Methods), and binding of the designs HA or BoNT at different concentrations was assessed by FACS. For each sorting condition, enriched designs were identified by comparing the frequencies in the original and sorted populations using deep sequencing. These data were used to guide improvement of the computational design model, and the entire design, synthesis and testing cycle was iterated. PowerPoint slide Full size image High-throughput computational design As targets, we selected Influenza A H1 haemagglutinin (HA), as this virus remains a serious public health concern 12 , and botulinum neurotoxin B (BoNT/B), which causes the acute neuroparalytic syndrome of botulism and is one of the most lethal natural toxins known (with a lethal dose of approximately 1 ng per kg) 13 . We generated virtual scaffold libraries with over 4,000 backbone geometries in five different topologies: HHH, EHEE, HEE, EEHE, and HEEH (where H indicates an α-helix and E a β-strand) with or without 5 , 6 diverse disulfide connectivities ( Fig. 1a ). To design binding interfaces, we superimposed helical segments of the scaffolds on interface helices in previously solved HA and BoNT/B complexes (the previously designed HA binders HB36.6 and HB80.4 14 , 15 , 16 , and the natural target of BoNT/B synaptotagmin-II (Syt-II) 17 ), seeded the newly formed interfaces with hotspot residues from these helices ( Extended Data Fig. 1 ) and designed the remainder of the residues to maximize binding affinity and monomer stability using<|im_end|> <|im_start|>assistant Scientists have created a high-speed method to generate thousands of different, small, stable proteins from scratch that can be custom-designed to bind to specific therapeutic targets. Protection against infectious diseases, like the flu, and antidotes to nerve toxins are but two research goals of this approach. The method rapidly produces thousands of new drug candidates. These computer-designed proteins, which did not previous exist in nature, combine the stability and bioavailability of small molecule drugs with the specificity and potency of larger biologics. "These mini-protein binders have the potential of becoming a new class of drugs that bridge the gap between small molecule drugs and biologics. Like monoclonal antibodies, they can be designed to bind to targets with high selectivity, but they are more stable and easier to produce and to administer," said David Baker, who led the multi-institutional research project. Baker is a professor of biochemistry at the University of Washington School of Medicine and director of the UW Institute for Protein Design. He is also a Howard Hughes Medical Institute investigator. Baker and his colleagues report their findings in article published online Sept. 27 by the journal Nature. Aaron Chevalier, Daniel-Adriano Silva and Gabriel J. Rocklin were the lead authors and were all senior fellows at the UW Institute for Protein Design at the time of the project. The method used a computer platform, called Rosetta, developed by Baker and colleagues at the University of Washington. They designed thousands of short proteins, about 40 amino acids in length, that the Rosetta program predicted would bind tightly to the molecular target. David Baker of the University of Washington Institute for Protein design discusses the creation of mini-protein binders as potential targeted therapeutics against neurotoxins, flu viruses, and other troublesome agents. A brief tour of his lab shows where computational design of new proteins takes place, and where the proteins are grown in yeast and tested. These so-called "de novo" proteins did not exist in nature until they were created in the lab. Credit: Randy Carnell/UW Medicine Because of their small size, these short proteins tend to be extremely stable. They can be stored without refrigeration. They also are more easily administered than large protein drugs, such as monoclonal antibodies. Previously, such short, protein-binder drugs were typically re-engineered versions of naturally occurring proteins. These, however, tended not to be significantly better than monoclonal antibodies. Because these mini-proteins binders are original designs, they can be tailored to fit their targets much more tightly and are simpler to modify and refine. In this study, the researchers sought to design two sets of these proteins: one set that would prevent the influenza virus from invading cells and another that would bind to and neutralize a deadly nerve toxin from botulism. This toxin is considered a potential bioweapon. The computer modeling identified the amino-acid sequences of thousands of short proteins that would fit into and bind to the influenza and botulinum targets. The researchers created short pieces of DNA that coded each of these proteins, grew the proteins in yeast cells, and then looked at how tightly they bound to their targets. The targets were Influenza H1 hemagglutinin and botulinum neurotoxin B. All told, the method allowed them to design and test 22,660 proteins in just a few months. More than than two-thousand of them bound to their targets with high affinity. Evaluation of the best candidates found that the anti-influenza proteins neutralized viruses in cell culture and other designed proteins prevented the botulinum toxin from entering brain cells. A nasal spray containing one of the custom-designed proteins completely protected mice from the flu if administered before or as much as 72 hours after exposure.. The protection that the treatment provides equaled or surpassed that seen with antibodies, the researchers report. Testing of a subset of the proteins showed that they were extremely stable and, unlike antibodies, did not become inactivated by high temperatures. The small proteins also triggered little or no immune response, a problem that often renders larger protein drugs ineffective. <|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 semiconductors are studied intensively for applications in electronics and optics 1 , and even spin-based information technology, or spintronics 2 . Fundamental quantities in spintronics are the population relaxation time ( T 1 ) and the phase memory time ( T 2 ): T 1 measures the lifetime of a classical bit, in this case embodied by a spin oriented either parallel or antiparallel to an external magnetic field, and T 2 measures the corresponding lifetime of a quantum bit, encoded in the phase of the quantum state. Here we establish that these times are surprisingly long for a common, low-cost and chemically modifiable organic semiconductor, the blue pigment copper phthalocyanine 3 , in easily processed thin-film form of the type used for device fabrication. At 5 K, a temperature reachable using inexpensive closed-cycle refrigerators, T 1 and T 2 are respectively 59 ms and 2.6 μs, and at 80 K, which is just above the boiling point of liquid nitrogen, they are respectively 10 μs and 1 μs, demonstrating that the performance of thin-film copper phthalocyanine is superior to that of single-molecule magnets over the same temperature range 4 . T 2 is more than two orders of magnitude greater than the duration of the spin manipulation pulses, which suggests that copper phthalocyanine holds promise for quantum information processing, and the long T 1 indicates possibilities for medium-term storage of classical bits in all-organic devices on plastic substrates. Main The drive to develop spintronics, through precise control and read-out of electron spins, has provided impetus for both fundamental discoveries and practical devices. Whereas initial studies mainly considered solid-state inorganic materials, recent work has focused on more exotic species, in particular single-molecule magnets 5 , 6 , 7 , 8 . These tend to be large, complex molecules possessing many electron spins and magnetic nuclei that induce decoherence. Thus, the longest decoherence times are measured at ultralow temperatures with the single-molecule magnets isolated from each other by dilution into either diamagnetic isomorphous host crystals or in frozen solution 4 , 9 . The latter approach has also been used for other molecular materials, such as N@C 60 (atomic nitrogen inside a 60-atom carbon cage; ref. 10 ), that have intrinsically long decoherence times at ambient temperatures. However, when considering compatibility with current thin-film-based plastic electronic and optoelectronic technologies, and reliability of manufacturing and usage, the potential of simpler molecules, such as copper phthalocyanine (CuPc; Fig. 1a ), that can be produced on an industrial scale and readily processed in thin films both for solar energy 3 and molecular electronics 11 should be explored. Moreover, spin-bearing organic molecules often have low spin–orbit coupling, possess a large Hilbert space with many non-degenerate transitions, and can be customized by chemical modification. These positive attributes have led to newer research assessing the potential of macrocycle materials for both spintronics and quantum information processing 5 , 6 , 8 . Here we demonstrate that the decoherence times of CuPc are comparable or superior to those of the best molecular systems and can be maintained even in a device-like film configuration on a readily available plastic substrate, Kapton. We achieve this through organic-molecular-beam deposition, co-depositing CuPc with the structurally isomorphous but diamagnetic free base phthalocyanine (H 2 Pc), allowing the spin-carrying CuPc molecules to be spatially separated while still adopting a well-defined crystal α-phase 12 . Co-deposition reduces spin–spin interactions and therefore decreases the decoherence rates in the ensemble, the measurement of which is always performed as the first test of utility for quantum information processing 4 , 5 , 13 , 14 , 15 , 16 , 17 . To constrain the orientation of the CuPc molecules, and thereby reduce the spectral variation due to the powder averaging of the anisotropic CuPc g factor ( g ), we deposited the 400-nm-thick CuPc:H 2 Pc films onto a layer of perylene-3,4,9,20-tetracarboxylic dianhydride. This forces the CuPc and H 2 Pc molecules to lie nearly flat on the Kapton 18 , with the normal to the molecular plane almost perpendicular to the surface ( Fig. 1b ). Figure 1: Copper phthalocyanine films. a , Copper phthalocyanine molecule, containing copper (red), nitrogen (blue), carbon (grey) and hydrogen (yellow) atoms. b , Schematic representation of the dilute film, with dispersed electron spins depicted as arrows. For clarity, only a single molecular layer is shown; films used in experiments are 400 nm, or approximately 1,200 layers, thick. c , EDFSs collected at 5 K for different copper concentrations. d , Energy level structure of the spin Hamiltonian for a single CuPc molecule oriented perpendicular to the magnetic field, with two magnified views showing the copper hyperfine coupling and the nitrogen hyperfine coupling, respectively. PowerPoint slide Full size image Figure 1c shows the echo-detected field sweeps (EDFSs) of CuPc thin films for different copper spin concentrations. The EDFS is a measurement of the Hahn echo as a function of applied magnetic field 19 . The broadening of spectral features at higher CuPc concentrations results from the increased electronic dipolar interaction. The peak at approximately 325 mT is due to radicals in the Kapton film and oxygen-centred radicals in H 2 Pc (ref. 20 ). Figure 1d is a schematic of the energy levels that give rise to the EDFS spectra for a single molecular orientation, with the normal to the molecular plane parallel to the applied field, as in our measurements. These are simulated in EASYSPIN 21 using the Hamiltonian H = gμ B B S + Σ IAS (see Methods for details), the two terms of which respectively represent the Zeeman energy for the electrons within the external field B ( μ B , Bohr magneton) and the sum of the various hyperfine interactions 19 . Copper( ii ) complexes have been studied extensively 22 : for CuPc the electronic spin is S = 1/2 and for both naturally occurring copper isotopes ( 63 Cu and 65 Cu) the nuclear spin is I = 3/2. The hyperfine coupling", "role": "user" }, { "content": "A common blue pigment used in the £5 note could have an important role to play in the development of a quantum computer, according to a paper published today in the journal Nature. The pigment, copper phthalocyanine (CuPc), which is similar to the light harvesting section of the chlorophyll molecule, is a low-cost organic semiconductor that is found in many household products. Crucially, it can be processed into a thin film that can be readily used for device fabrication, a significant advantage over similar materials that have been studied previously. Now, researchers from the London Centre for Nanotechnology at UCL and the University of British Columbia have shown that the electrons in CuPc can remain in 'superposition' – an intrinsically quantum effect where the electron exists in two states at once - for surprisingly long times, showing this simple dye molecule has potential as a medium for quantum technologies. The development of quantum computing requires precise control of tiny individual \"qubits\", the quantum analogs of the classical binary bits, '0' and '1', which underpin all of our computation and communications technologies today. What distinguishes the \"qubits\" from classical bits is their ability to exist in superposition states. The decay time of such superpositions tells us how useful a candidate qubit could be in quantum technologies. If this time is long, quantum data storage, manipulation and transmission become possible. Lead author Marc Warner from the London Centre for Nanotechnology, said: \"In theory, a quantum computer can easily solve problems that a normal, classical, computer would not be able to answer in the lifetime of the universe. We just don't know how to build one yet. \"Our research shows that a common blue dye has more potential for quantum computing than many of the more exotic molecules that have been considered previously.\" CuPc possesses many other attributes that could exploit the spin of electrons, rather than their charge, to store and process information which are highly desirable in a more conventional quantum technology. For example, the pigment strongly absorbs visible light and is easy to modify chemically and physically, so its magnetic and electrical properties can be controlled. Dr Warner added: \"The properties of copper phthalocyanine make it of interest for the emerging field of quantum engineering, which seeks to exploit the quantum properties of matter to perform tasks like information processing or sensing more effectively than has ever been possible.\" ", "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 semiconductors are studied intensively for applications in electronics and optics 1 , and even spin-based information technology, or spintronics 2 . Fundamental quantities in spintronics are the population relaxation time ( T 1 ) and the phase memory time ( T 2 ): T 1 measures the lifetime of a classical bit, in this case embodied by a spin oriented either parallel or antiparallel to an external magnetic field, and T 2 measures the corresponding lifetime of a quantum bit, encoded in the phase of the quantum state. Here we establish that these times are surprisingly long for a common, low-cost and chemically modifiable organic semiconductor, the blue pigment copper phthalocyanine 3 , in easily processed thin-film form of the type used for device fabrication. At 5 K, a temperature reachable using inexpensive closed-cycle refrigerators, T 1 and T 2 are respectively 59 ms and 2.6 μs, and at 80 K, which is just above the boiling point of liquid nitrogen, they are respectively 10 μs and 1 μs, demonstrating that the performance of thin-film copper phthalocyanine is superior to that of single-molecule magnets over the same temperature range 4 . T 2 is more than two orders of magnitude greater than the duration of the spin manipulation pulses, which suggests that copper phthalocyanine holds promise for quantum information processing, and the long T 1 indicates possibilities for medium-term storage of classical bits in all-organic devices on plastic substrates. Main The drive to develop spintronics, through precise control and read-out of electron spins, has provided impetus for both fundamental discoveries and practical devices. Whereas initial studies mainly considered solid-state inorganic materials, recent work has focused on more exotic species, in particular single-molecule magnets 5 , 6 , 7 , 8 . These tend to be large, complex molecules possessing many electron spins and magnetic nuclei that induce decoherence. Thus, the longest decoherence times are measured at ultralow temperatures with the single-molecule magnets isolated from each other by dilution into either diamagnetic isomorphous host crystals or in frozen solution 4 , 9 . The latter approach has also been used for other molecular materials, such as N@C 60 (atomic nitrogen inside a 60-atom carbon cage; ref. 10 ), that have intrinsically long decoherence times at ambient temperatures. However, when considering compatibility with current thin-film-based plastic electronic and optoelectronic technologies, and reliability of manufacturing and usage, the potential of simpler molecules, such as copper phthalocyanine (CuPc; Fig. 1a ), that can be produced on an industrial scale and readily processed in thin films both for solar energy 3 and molecular electronics 11 should be explored. Moreover, spin-bearing organic molecules often have low spin–orbit coupling, possess a large Hilbert space with many non-degenerate transitions, and can be customized by chemical modification. These positive attributes have led to newer research assessing the potential of macrocycle materials for both spintronics and quantum information processing 5 , 6 , 8 . Here we demonstrate that the decoherence times of CuPc are comparable or superior to those of the best molecular systems and can be maintained even in a device-like film configuration on a readily available plastic substrate, Kapton. We achieve this through organic-molecular-beam deposition, co-depositing CuPc with the structurally isomorphous but diamagnetic free base phthalocyanine (H 2 Pc), allowing the spin-carrying CuPc molecules to be spatially separated while still adopting a well-defined crystal α-phase 12 . Co-deposition reduces spin–spin interactions and therefore decreases the decoherence rates in the ensemble, the measurement of which is always performed as the first test of utility for quantum information processing 4 , 5 , 13 , 14 , 15 , 16 , 17 . To constrain the orientation of the CuPc molecules, and thereby reduce the spectral variation due to the powder averaging of the anisotropic CuPc g factor ( g ), we deposited the 400-nm-thick CuPc:H 2 Pc films onto a layer of perylene-3,4,9,20-tetracarboxylic dianhydride. This forces the CuPc and H 2 Pc molecules to lie nearly flat on the Kapton 18 , with the normal to the molecular plane almost perpendicular to the surface ( Fig. 1b ). Figure 1: Copper phthalocyanine films. a , Copper phthalocyanine molecule, containing copper (red), nitrogen (blue), carbon (grey) and hydrogen (yellow) atoms. b , Schematic representation of the dilute film, with dispersed electron spins depicted as arrows. For clarity, only a single molecular layer is shown; films used in experiments are 400 nm, or approximately 1,200 layers, thick. c , EDFSs collected at 5 K for different copper concentrations. d , Energy level structure of the spin Hamiltonian for a single CuPc molecule oriented perpendicular to the magnetic field, with two magnified views showing the copper hyperfine coupling and the nitrogen hyperfine coupling, respectively. PowerPoint slide Full size image Figure 1c shows the echo-detected field sweeps (EDFSs) of CuPc thin films for different copper spin concentrations. The EDFS is a measurement of the Hahn echo as a function of applied magnetic field 19 . The broadening of spectral features at higher CuPc concentrations results from the increased electronic dipolar interaction. The peak at approximately 325 mT is due to radicals in the Kapton film and oxygen-centred radicals in H 2 Pc (ref. 20 ). Figure 1d is a schematic of the energy levels that give rise to the EDFS spectra for a single molecular orientation, with the normal to the molecular plane parallel to the applied field, as in our measurements. These are simulated in EASYSPIN 21 using the Hamiltonian H = gμ B B S + Σ IAS (see Methods for details), the two terms of which respectively represent the Zeeman energy for the electrons within the external field B ( μ B , Bohr magneton) and the sum of the various hyperfine interactions 19 . Copper( ii ) complexes have been studied extensively 22 : for CuPc the electronic spin is S = 1/2 and for both naturally occurring copper isotopes ( 63 Cu and 65 Cu) the nuclear spin is I = 3/2. The hyperfine coupling<|im_end|> <|im_start|>assistant A common blue pigment used in the £5 note could have an important role to play in the development of a quantum computer, according to a paper published today in the journal Nature. The pigment, copper phthalocyanine (CuPc), which is similar to the light harvesting section of the chlorophyll molecule, is a low-cost organic semiconductor that is found in many household products. Crucially, it can be processed into a thin film that can be readily used for device fabrication, a significant advantage over similar materials that have been studied previously. Now, researchers from the London Centre for Nanotechnology at UCL and the University of British Columbia have shown that the electrons in CuPc can remain in 'superposition' – an intrinsically quantum effect where the electron exists in two states at once - for surprisingly long times, showing this simple dye molecule has potential as a medium for quantum technologies. The development of quantum computing requires precise control of tiny individual "qubits", the quantum analogs of the classical binary bits, '0' and '1', which underpin all of our computation and communications technologies today. What distinguishes the "qubits" from classical bits is their ability to exist in superposition states. The decay time of such superpositions tells us how useful a candidate qubit could be in quantum technologies. If this time is long, quantum data storage, manipulation and transmission become possible. Lead author Marc Warner from the London Centre for Nanotechnology, said: "In theory, a quantum computer can easily solve problems that a normal, classical, computer would not be able to answer in the lifetime of the universe. We just don't know how to build one yet. "Our research shows that a common blue dye has more potential for quantum computing than many of the more exotic molecules that have been considered previously." CuPc possesses many other attributes that could exploit the spin of electrons, rather than their charge, to store and process information which are highly desirable in a more conventional quantum technology. For example, the pigment strongly absorbs visible light and is easy to modify chemically and physically, so its magnetic and electrical properties can be controlled. Dr Warner added: "The properties of copper phthalocyanine make it of interest for the emerging field of quantum engineering, which seeks to exploit the quantum properties of matter to perform tasks like information processing or sensing more effectively than has ever been possible." <|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 Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43. Working on a manuscript? Avoid the common mistakes Introduction Amyotrophic lateral sclerosis (ALS) is a rare, fatal neurodegenerative disease that progressively affects motor neurons (MNs) in the motor cortex, brainstem, and spinal cord [ 30 ]. The majority of ALS cases occur sporadically (sALS) and less than 10% are monogenic [ 30 ]. Nuclear loss, pathological cytoplasmic aggregation [ 4 , 48 ], and hyperphosphorylation of the RNA-binding protein (RBP) TDP-43 [ 47 ] are frequently present in spinal and cortical MNs in ALS patients at late stages of the disease. Underscoring its central role, pathogenic variants in the TARDBP gene that encodes for TDP-43, have also been discovered in ALS patients [ 61 ]. A prevailing hypothesis is that TDP-43 nuclear loss-of-function and a toxic cytoplasmic gain-of-function of TDP-43 in insoluble aggregates contribute to the neuronal vulnerability in TDP-43 proteinopathies [ 11 , 19 , 23 , 38 , 69 ]. Early studies, modeling the loss-of-function, utilized transcriptome-wide cross-linking and immunoprecipitation (CLIP) and RNA-seq and identified that TDP-43 mediates RNA splicing primarily by interacting with UG-rich intronic sequences [ 52 , 64 ]. Interestingly, aberrant alternative splicing (AS) is frequently observed in postmortem tissue of ALS patients [ 12 , 54 ]. Later studies further highlighted a subset of unannotated human exons (cryptic) normally repressed by TDP-43 in the nucleus [ 37 ]. Recently, inclusion of a human-specific cryptic exon in the transcript of the microtubule regulator Stathmin2 (STMN2) has been identified upon TDP-43 depletion, resulting in the generation of a nonsense mediated decay mRNA isoform [ 31 , 46 ]. These studies also show that this isoform of STMN2 is present in sALS patient samples [ 31 , 46 ]. Transient, non-lethal stress in induced pluripotent stem cell-derived motor neurons (iPSC-MN) was previously shown to induce the formation of cytoplasmic TDP-43 aggregates [ 21 ], leading to signs of aberrant TDP-43 function such as inclusion of the TDP-43-associated STMN2 cryptic exon [ 41 ]. In our previous work in patient iPSC-MN with pathogenic variants in hnRNP A2/B1 causing severe neurodegeneration, we found that chemical stress was required to induce hnRNP A2/B1 to move into the cytoplasm [ 44 ]. However, even in the absence of stress, abnormal AS changes in patient iPSC-MN were observed suggesting that aberrant AS is an early sign of disease while cytoplasmic localization of RBPs may be a secondary, end-stage feature [ 44 ]. These studies collectively suggest that perturbation of RBP-splicing networks is a key component of ALS and may be an early event preceding cytoplasmic localization and aggregation of abnormal RBP-RNA complexes. Here, we investigated the origins of altered AS in early stages of sporadic and familial ALS and discovered new aberrant RBP-splicing networks. We utilized mass spectrometry to identify RBPs that exhibit increased insolubility in iPSC-MNs from ALS patients compared to controls. Focusing on splicing factors NOVA1, NOVA2, and RBFOX2, we applied enhanced CLIP methodology and discovered an enriched frequency of RNA binding of these proteins proximal to ALS-associated AS events. Of these, deeper evaluation of NOVA1 revealed elevated protein levels in the cytoplasm of ALS MNs without TDP-43 pathology in postmortem tissue. Exogenous expression and genetic knock out of NOVA1 revealed a complex disruption of NOVA1 function, including events caused by a consistent loss of NOVA1 function at early disease stages where TDP-43 pathology has yet to be developed. Materials and methods Human samples for iPSC generation We reprogrammed fibroblasts of two sALS patients (further referred as sALS-1-1/2 and sALS-2-1/2), two age-matched controls (Ctrl-1-1/2 and Ctrl-2-1/2, respectively) and included two additional controls (CV-B and Ctrl-3-1/2) and 2 fALS (fALS-1-1 and fALS-2-1) cases with pathogenic variants in TDP-43 in this study. The study approval for cell lines originating from Ctrl-1, Ctrl-2, sALS-1 and sALS-2 was granted by the local ethics committee (No. 4485, FAU Erlangen-Nürnberg). The 2 sALS patients did not have a family history of ALS and did not harbor known ALS-causing mutations determined by C9ORF72 repeat length analysis and exome sequencing. Both patients were diagnosed with clinically definite ALS according to the revised El Escorial criteria [ 40 ]. Patient sALS-2 presented with cortical and spinal motor neuron involvement starting in the right arm. In the latest follow-up (11 years after onset), he had been on a ventilator for the past 6 years, presenting with a revised ALS functional rating scale (ALSFRSr) of 1/48. In contrast, patient sALS-1 exhibited slower progression and an ALSFRSr of 39/48 12 years after disease onset. The use of cell lines originating from Ctrl-3, fALS-1 and fALS-2 were approved by the Institutional Review Board of the University of California, San Diego. The CV-B iPSC line, originating from Craig Venter, is publicly available and has been previously described [ 24 ]. Ctrl-3 and fALS-1 have been described previously [ 32 ].", "role": "user" }, { "content": "Currently, there is no cure for amyotrophic lateral sclerosis (ALS). Things could soon change, however. Researchers at FAU and the University of California San Diego (UCSD) have identified a protein that already displays pathological characteristics at an early stage of the neurological disease. The team has published their discovery, which could lead to a new approach for treating the disease, in the journal Acta Neuropathologica. In summer 2014, amyotrophic lateral sclerosis, or ALS for short, received a lot of attention through a social media campaign. In the ice bucket challenge, millions of people across the globe emptied buckets of ice cold water over their heads to simulate a feeling of paralysis due to the extreme cold. In Germany, approximately 6,000 to 8,000 people are living with ALS, and approximately 2,000 new cases of the disease, which proves fatal within just a few years, are diagnosed every year. \"ALS is a motor neuron disease, that means it damages the nerve cells that control our muscles,\" explains Prof. Dr. Beate Winner. \"During the first phase, muscles become weaker, before wasting away and finally leaving patients unable to swallow or breathe independently.\" The social media campaign was used to raise money for research into ALS. Turning back the biological clock by reprogramming cells into stem cells Beate Winner is a professor for stem cell models for rare neural diseases at FAU, head of the Department of Stem Cell Biology, and speaker for the Center for Rate Diseases at Universitätsklinikum Erlangen. Her laboratory investigates what triggers neurodegenerative diseases of the nervous system such as ALS in the hope of discovering new treatment options as a result. \"We have known for roughly 15 years that during the end stage of ALS, the protein TDP-43 found in neurons becomes insoluble and starts to form clumps,\" explains Winner. \"It loses its normal functions and adopts toxic properties.\" Even though these pathological changes are not yet noticeable in patients, the fate of the nerve cells is already sealed. \"We wanted to know whether we could find causes for ALS at an early stage of development before the TDP-43 changes.\" She started her quest together with Prof. Dr. Jürgen Winkler and PD Dr. Martin Regensburger from the Department of Molecular Neurology at Universitätsklinikum Erlangen. The researchers used an innovative technique. They extracted a small skin sample from the upper arm of ALS patients and healthy people in a control group and reprogrammed it into what are known as induced pluripotent stem cells, cells that are equivalent to a very early stage of human development and that can in theory develop into any cell within the human body. These stem cells were then transformed into nerve cells. \"Basically, we turned the clock back and generated neurons imitating the developmental stage of a fetus,\" explains Winner. The fact that cells from adult people can be reprogrammed back into pluripotent stem cells was discovered by Shin'ya Yamanaka, who received the Nobel Prize for Medicine in recognition of his work. The protein NOVA1 displays pathological features from an early stage The Erlangen researchers searched for insoluble proteins in the cell samples using mass spectrometry, a high-throughput procedure. They were successful. In the nerve cells of ALS patients they discovered an RNA-binding protein named NOVA1. \"In the neurons, the protein demonstrated changes including a greatly increased degree of insolvency, but not yet the typical pathological characteristics of TDP-43,\" explains Dr. Florian Krach, member of the FAU team and lead author of the study. \"The cells in the control group did not display these changes.\" Armed with these findings, Krach moved to the laboratory of the renowned RNA biologist and bioinformatics specialist Prof. Gene Yeo at the University of California in San Diego (U.S.), funded by the Bavaria California Technology Center (BaCaTeC). Thanks to specialized experiments and computer-assisted analysis he was able to investigate what NOVA1 binds to in RNA molecules and what influence it has on alternative splicing in human neurons. \"Alternative splicing is an extremely complex and ingenious mechanism that humans use to multiply their repertoire of proteins,\" explains Krach. \"Sections of an RNA messenger molecule are either cut or added, thereby hindering, extending or changing the function of proteins altogether.\" The researchers hope their findings will help make an early diagnosis possible and open the door to new treatment concepts. It has been known for some time that the alternative splicing process is unregulated in ALS patients. It is also known that TDP-43 influences this process. The team of researchers from Erlangen suspected, however, that other RNA-binding proteins are responsible for the pathological processes in early stages of the disease before TDP-43 changes. This suspicion has now been confirmed with the discovery of the impaired functioning of NOVA1. \"We have made a pioneering discovery, but it is only one first step towards possibly being able to detect ALS in the early stages,\" says Beate Winner. \"Follow-up studies with larger cohorts could deepen our understanding of the importance of RNA-binding proteins.\" The researchers hope that their work will help contribute to developing new therapy concepts before neurons cross the point of no return. ", "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 Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43. Working on a manuscript? Avoid the common mistakes Introduction Amyotrophic lateral sclerosis (ALS) is a rare, fatal neurodegenerative disease that progressively affects motor neurons (MNs) in the motor cortex, brainstem, and spinal cord [ 30 ]. The majority of ALS cases occur sporadically (sALS) and less than 10% are monogenic [ 30 ]. Nuclear loss, pathological cytoplasmic aggregation [ 4 , 48 ], and hyperphosphorylation of the RNA-binding protein (RBP) TDP-43 [ 47 ] are frequently present in spinal and cortical MNs in ALS patients at late stages of the disease. Underscoring its central role, pathogenic variants in the TARDBP gene that encodes for TDP-43, have also been discovered in ALS patients [ 61 ]. A prevailing hypothesis is that TDP-43 nuclear loss-of-function and a toxic cytoplasmic gain-of-function of TDP-43 in insoluble aggregates contribute to the neuronal vulnerability in TDP-43 proteinopathies [ 11 , 19 , 23 , 38 , 69 ]. Early studies, modeling the loss-of-function, utilized transcriptome-wide cross-linking and immunoprecipitation (CLIP) and RNA-seq and identified that TDP-43 mediates RNA splicing primarily by interacting with UG-rich intronic sequences [ 52 , 64 ]. Interestingly, aberrant alternative splicing (AS) is frequently observed in postmortem tissue of ALS patients [ 12 , 54 ]. Later studies further highlighted a subset of unannotated human exons (cryptic) normally repressed by TDP-43 in the nucleus [ 37 ]. Recently, inclusion of a human-specific cryptic exon in the transcript of the microtubule regulator Stathmin2 (STMN2) has been identified upon TDP-43 depletion, resulting in the generation of a nonsense mediated decay mRNA isoform [ 31 , 46 ]. These studies also show that this isoform of STMN2 is present in sALS patient samples [ 31 , 46 ]. Transient, non-lethal stress in induced pluripotent stem cell-derived motor neurons (iPSC-MN) was previously shown to induce the formation of cytoplasmic TDP-43 aggregates [ 21 ], leading to signs of aberrant TDP-43 function such as inclusion of the TDP-43-associated STMN2 cryptic exon [ 41 ]. In our previous work in patient iPSC-MN with pathogenic variants in hnRNP A2/B1 causing severe neurodegeneration, we found that chemical stress was required to induce hnRNP A2/B1 to move into the cytoplasm [ 44 ]. However, even in the absence of stress, abnormal AS changes in patient iPSC-MN were observed suggesting that aberrant AS is an early sign of disease while cytoplasmic localization of RBPs may be a secondary, end-stage feature [ 44 ]. These studies collectively suggest that perturbation of RBP-splicing networks is a key component of ALS and may be an early event preceding cytoplasmic localization and aggregation of abnormal RBP-RNA complexes. Here, we investigated the origins of altered AS in early stages of sporadic and familial ALS and discovered new aberrant RBP-splicing networks. We utilized mass spectrometry to identify RBPs that exhibit increased insolubility in iPSC-MNs from ALS patients compared to controls. Focusing on splicing factors NOVA1, NOVA2, and RBFOX2, we applied enhanced CLIP methodology and discovered an enriched frequency of RNA binding of these proteins proximal to ALS-associated AS events. Of these, deeper evaluation of NOVA1 revealed elevated protein levels in the cytoplasm of ALS MNs without TDP-43 pathology in postmortem tissue. Exogenous expression and genetic knock out of NOVA1 revealed a complex disruption of NOVA1 function, including events caused by a consistent loss of NOVA1 function at early disease stages where TDP-43 pathology has yet to be developed. Materials and methods Human samples for iPSC generation We reprogrammed fibroblasts of two sALS patients (further referred as sALS-1-1/2 and sALS-2-1/2), two age-matched controls (Ctrl-1-1/2 and Ctrl-2-1/2, respectively) and included two additional controls (CV-B and Ctrl-3-1/2) and 2 fALS (fALS-1-1 and fALS-2-1) cases with pathogenic variants in TDP-43 in this study. The study approval for cell lines originating from Ctrl-1, Ctrl-2, sALS-1 and sALS-2 was granted by the local ethics committee (No. 4485, FAU Erlangen-Nürnberg). The 2 sALS patients did not have a family history of ALS and did not harbor known ALS-causing mutations determined by C9ORF72 repeat length analysis and exome sequencing. Both patients were diagnosed with clinically definite ALS according to the revised El Escorial criteria [ 40 ]. Patient sALS-2 presented with cortical and spinal motor neuron involvement starting in the right arm. In the latest follow-up (11 years after onset), he had been on a ventilator for the past 6 years, presenting with a revised ALS functional rating scale (ALSFRSr) of 1/48. In contrast, patient sALS-1 exhibited slower progression and an ALSFRSr of 39/48 12 years after disease onset. The use of cell lines originating from Ctrl-3, fALS-1 and fALS-2 were approved by the Institutional Review Board of the University of California, San Diego. The CV-B iPSC line, originating from Craig Venter, is publicly available and has been previously described [ 24 ]. Ctrl-3 and fALS-1 have been described previously [ 32 ].<|im_end|> <|im_start|>assistant Currently, there is no cure for amyotrophic lateral sclerosis (ALS). Things could soon change, however. Researchers at FAU and the University of California San Diego (UCSD) have identified a protein that already displays pathological characteristics at an early stage of the neurological disease. The team has published their discovery, which could lead to a new approach for treating the disease, in the journal Acta Neuropathologica. In summer 2014, amyotrophic lateral sclerosis, or ALS for short, received a lot of attention through a social media campaign. In the ice bucket challenge, millions of people across the globe emptied buckets of ice cold water over their heads to simulate a feeling of paralysis due to the extreme cold. In Germany, approximately 6,000 to 8,000 people are living with ALS, and approximately 2,000 new cases of the disease, which proves fatal within just a few years, are diagnosed every year. "ALS is a motor neuron disease, that means it damages the nerve cells that control our muscles," explains Prof. Dr. Beate Winner. "During the first phase, muscles become weaker, before wasting away and finally leaving patients unable to swallow or breathe independently." The social media campaign was used to raise money for research into ALS. Turning back the biological clock by reprogramming cells into stem cells Beate Winner is a professor for stem cell models for rare neural diseases at FAU, head of the Department of Stem Cell Biology, and speaker for the Center for Rate Diseases at Universitätsklinikum Erlangen. Her laboratory investigates what triggers neurodegenerative diseases of the nervous system such as ALS in the hope of discovering new treatment options as a result. "We have known for roughly 15 years that during the end stage of ALS, the protein TDP-43 found in neurons becomes insoluble and starts to form clumps," explains Winner. "It loses its normal functions and adopts toxic properties." Even though these pathological changes are not yet noticeable in patients, the fate of the nerve cells is already sealed. "We wanted to know whether we could find causes for ALS at an early stage of development before the TDP-43 changes." She started her quest together with Prof. Dr. Jürgen Winkler and PD Dr. Martin Regensburger from the Department of Molecular Neurology at Universitätsklinikum Erlangen. The researchers used an innovative technique. They extracted a small skin sample from the upper arm of ALS patients and healthy people in a control group and reprogrammed it into what are known as induced pluripotent stem cells, cells that are equivalent to a very early stage of human development and that can in theory develop into any cell within the human body. These stem cells were then transformed into nerve cells. "Basically, we turned the clock back and generated neurons imitating the developmental stage of a fetus," explains Winner. The fact that cells from adult people can be reprogrammed back into pluripotent stem cells was discovered by Shin'ya Yamanaka, who received the Nobel Prize for Medicine in recognition of his work. The protein NOVA1 displays pathological features from an early stage The Erlangen researchers searched for insoluble proteins in the cell samples using mass spectrometry, a high-throughput procedure. They were successful. In the nerve cells of ALS patients they discovered an RNA-binding protein named NOVA1. "In the neurons, the protein demonstrated changes including a greatly increased degree of insolvency, but not yet the typical pathological characteristics of TDP-43," explains Dr. Florian Krach, member of the FAU team and lead author of the study. "The cells in the control group did not display these changes." Armed with these findings, Krach moved to the laboratory of the renowned RNA biologist and bioinformatics specialist Prof. Gene Yeo at the University of California in San Diego (U.S.), funded by the Bavaria California Technology Center (BaCaTeC). Thanks to specialized experiments and computer-assisted analysis he was able to investigate what NOVA1 binds to in RNA molecules and what influence it has on alternative splicing in human neurons. "Alternative splicing is an extremely complex and ingenious mechanism that humans use to multiply their repertoire of proteins," explains Krach. "Sections of an RNA messenger molecule are either cut or added, thereby hindering, extending or changing the function of proteins altogether." The researchers hope their findings will help make an early diagnosis possible and open the door to new treatment concepts. It has been known for some time that the alternative splicing process is unregulated in ALS patients. It is also known that TDP-43 influences this process. The team of researchers from Erlangen suspected, however, that other RNA-binding proteins are responsible for the pathological processes in early stages of the disease before TDP-43 changes. This suspicion has now been confirmed with the discovery of the impaired functioning of NOVA1. "We have made a pioneering discovery, but it is only one first step towards possibly being able to detect ALS in the early stages," says Beate Winner. "Follow-up studies with larger cohorts could deepen our understanding of the importance of RNA-binding proteins." The researchers hope that their work will help contribute to developing new therapy concepts before neurons cross the point of no return. <|im_end|>

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2,648

[ { "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 Galaxy clusters are the most massive virialized structures in the Universe and are formed through the gravitational accretion of matter over cosmic time 1 . The discovery 2 of an evolved galaxy cluster at redshift z = 2, corresponding to a look-back time of 10.4 billion years, provides an opportunity to study its properties. The galaxy cluster XLSSC 122 was originally detected as a faint, extended X-ray source in the XMM Large Scale Structure survey and was revealed to be coincident with a compact over-density of galaxies 2 with photometric redshifts of 1.9 ± 0.2. Subsequent observations 3 at millimetre wavelengths detected a Sunyaev–Zel’dovich decrement along the line of sight to XLSSC 122, thus confirming the existence of hot intracluster gas, while deep imaging spectroscopy from the European Space Agency’s X-ray Multi-Mirror Mission (XMM-Newton) revealed 4 an extended, X-ray-bright gaseous atmosphere with a virial temperature of 60 million Kelvin, enriched with metals to the same extent as are local clusters. Here we report optical spectroscopic observations of XLSSC 122 and identify 37 member galaxies at a mean redshift of 1.98, corresponding to a look-back time of 10.4 billion years. We use photometry to determine a mean, dust-free stellar age of 2.98 billion years, indicating that star formation commenced in these galaxies at a mean redshift of 12, when the Universe was only 370 million years old. The full range of inferred formation redshifts, including the effects of dust, covers the interval from 7 to 13. These observations confirm that XLSSC 122 is a remarkably mature galaxy cluster with both evolved stellar populations in the member galaxies and a hot, metal-rich gas composing the intracluster medium. Main To further our understanding of this galaxy cluster, particularly the properties of its member galaxies, we undertook a series of observations of XLSSC 122 with the Hubble Space telescope (HST) Wide Field Camera 3 (WFC3). We obtained images of the cluster in two wavebands, F105W and F140W, and performed low-spectral-resolution slitless spectroscopy using the G141 grism (see Methods). These observations cover the observed frame wavelength interval 1.0–1.7 μm, corresponding to an interval of 0.33 μm to 0.57 μm in the rest frame of a galaxy at redshift z = 2. Figure 1 displays the F140W image of XLSSC 122 and shows a compact cluster of galaxies associated with the extended X-ray-emitting region. Fig. 1: HST image of the galaxy cluster XLSSC 122. The greyscale is the F140W image. Contours display X-ray emission corresponding to the 100-ks XMM-Newton image presented in ref. 4 . The dashed circle is drawn with a radius equal to the measured value of r 500 (the radius within which the average matter density is 500 times the critical density of the Universe). Spectroscopic ‘gold’ and ‘silver’ members (see Methods) of the z = 1.98 cluster are indicated by red and green circles, respectively. Members of the z = 1.93 foreground structure are indicated by blue circles. See text for further details. Full size image We extracted one-dimensional spectra of all galaxies identified within the dispersed G141 grism image of the field (see Methods) and computed redshifts using a galaxy template-fitting algorithm with redshift as a free parameter. Figure 2 displays the histogram of galaxy redshifts in the field of XLSSC 122 over the restricted interval 1.9 < z < 2.05. Inspection of this interval reveals a primary peak at z = 1.98 associated with the central, red galaxies closest to the X-ray peak, and a secondary redshift peak at z = 1.93 associated with a mixture of red and blue galaxies, located at larger projected cluster-centric distances (see Fig. 1 ). The line-of-sight separation between z = 1.93 and z = 1.98 is 76 co-moving megaparsecs, far larger than the size of the XLSSC 122 cluster, and the two structures are therefore physically distinct. As outlined in the Methods, we identify 37 galaxies as being members of the cluster and a further 13 galaxies identified as members of the foreground structure. Fig. 2: Redshift histogram of all galaxies along the line of sight to XLSSC 122. The histogram considers galaxies satisfying the magnitude measurement F140W Kron < 24. Galaxies classified as ‘gold’ members of the z = 1.98 cluster are shown in red, ‘silver’ members are shown in green and members of the z = 1.93 structure are shown in blue. Galaxies not classified as a member of either the z = 1.98 cluster or the z = 1.93 structure are shown in grey. The vertical dashed lines show the unweighted mean redshift of both the cluster and the foreground structure (see text for further details). Full size image We performed photometry of all galaxies within the HST field of view in both the F105W and F140W images (see Methods) and summarize this information in Fig. 3 . The galaxies identified at 1.9 < z < 2.05 form a clear bimodal distribution in colour with a well populated sequence of red galaxies (corresponding to larger values of F105W − F140W) clearly separated from a broader distribution of blue galaxies. Fig. 3: Colour–magnitude diagram of all galaxies within the HST/WFC3 field of view. Spectroscopically confirmed z = 1.98 ‘gold’ and ‘silver’ cluster members are indicated as red squares and green triangles, respectively. Members of the z = 1.93 structure are indicated as blue squares. Galaxies at z ≈ 2 yet which are not formal cluster members are shown as solid black squares, whereas potentially contaminated or confused spectroscopic sources are shown as open black squares. Galaxies with visually classified emission lines are marked using black circles (only z = 1.98 and z = 1.93 are marked in this manner). All other galaxies in the field are indicated by grey squares. Error bars indicate the 1-sigma measurement uncertainty. The spectroscopic completeness limits of F140W Kron = 24 and 24.5 are indicated by the vertical dashed and dotted lines, respectively. The horizontal dot-dashed line shows the lower colour limit for a source to be considered on the cluster’s red sequence. The angled", "role": "user" }, { "content": "Using high-powered telescopes including NASA's Hubble Space Telescope, scientists from Canada, the United States and Denmark have captured the clearest image known of a cluster of galaxies from 10 billion years ago in a discovery that provides clues the universe was more evolved than previously thought. The discovery is the best-case example found so far of the mature, evolved system, says Jon Willis, lead author of research published in Nature and astronomer at the University of Victoria. Willis studies the physical contents of the universe covering many aspects of cosmology and astrophysics. Q. What is a galaxy cluster and what can they tell us about the universe? A. A galaxy cluster can be likened to a great city of galaxies, though galaxies themselves are collections of billions of stars all held together by gravity. In simple terms, astrophysics is the study of our universe and our place in it. By studying the stars that make up the galaxies we can tell how old they are and when each galaxy first formed. Q. What did your team of scientists find? A. We've discovered what is the most ancient city of galaxies in the universe. It's the clearest snapshot yet of a galaxy cluster—it's like a Rosetta Stone. In the same way, the Rosetta Stone was a glimpse into ancient Egyptian history, this discovery provides clues to understanding the physics of what was going on in that environment billions of years ago. Astronomy is wonderful in that seeing is believing. I don't need to show you an equation; I don't need to show you a complex model. I can show you an image in the sky. Q. How unique is your discovery? A. It's the most concentrated, easiest to see and the most prominent out of what's been seen. To put it in context, the universe is 13 billion years old and so the cluster is an old object in a young universe. We are very surprised to see how early the universe produced something so mature. Finding a galaxy cluster so early in the development of the universe tells us that—wow—the universe is capable of amazing things. Q. Can you provide a simple analogy for this discovery? A. It's an equivalent of meeting a child who displays all the characteristics of an adult. We have met these young clusters—think the universe was just over three-billion-years old—so we've found it's quite a precocious object and it can teach us about how physics works in the early universe. Q. You've captured these images using high-powered telescopes. How do you gain access to these tools? A. Although the Hubble Space Telescope is the most recent telescope we used, which gave us these wonderful views of the cluster, we have used a number of telescopes to get to this discovery. These include the European Space Agency XMM-Newton space observatory, the Canada France Hawaii Telescope and the European Southern Observatory Very Large Telescope. Q. What's next? A. We are fortunate that NASA is planning to launch the James Webb Space Telescope, which is the successor to Hubble in late 2020 or early 2021. The first observing proposals are due in May 2020. Rest assured we'll be applying to study this cluster in much more detail. ", "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 Galaxy clusters are the most massive virialized structures in the Universe and are formed through the gravitational accretion of matter over cosmic time 1 . The discovery 2 of an evolved galaxy cluster at redshift z = 2, corresponding to a look-back time of 10.4 billion years, provides an opportunity to study its properties. The galaxy cluster XLSSC 122 was originally detected as a faint, extended X-ray source in the XMM Large Scale Structure survey and was revealed to be coincident with a compact over-density of galaxies 2 with photometric redshifts of 1.9 ± 0.2. Subsequent observations 3 at millimetre wavelengths detected a Sunyaev–Zel’dovich decrement along the line of sight to XLSSC 122, thus confirming the existence of hot intracluster gas, while deep imaging spectroscopy from the European Space Agency’s X-ray Multi-Mirror Mission (XMM-Newton) revealed 4 an extended, X-ray-bright gaseous atmosphere with a virial temperature of 60 million Kelvin, enriched with metals to the same extent as are local clusters. Here we report optical spectroscopic observations of XLSSC 122 and identify 37 member galaxies at a mean redshift of 1.98, corresponding to a look-back time of 10.4 billion years. We use photometry to determine a mean, dust-free stellar age of 2.98 billion years, indicating that star formation commenced in these galaxies at a mean redshift of 12, when the Universe was only 370 million years old. The full range of inferred formation redshifts, including the effects of dust, covers the interval from 7 to 13. These observations confirm that XLSSC 122 is a remarkably mature galaxy cluster with both evolved stellar populations in the member galaxies and a hot, metal-rich gas composing the intracluster medium. Main To further our understanding of this galaxy cluster, particularly the properties of its member galaxies, we undertook a series of observations of XLSSC 122 with the Hubble Space telescope (HST) Wide Field Camera 3 (WFC3). We obtained images of the cluster in two wavebands, F105W and F140W, and performed low-spectral-resolution slitless spectroscopy using the G141 grism (see Methods). These observations cover the observed frame wavelength interval 1.0–1.7 μm, corresponding to an interval of 0.33 μm to 0.57 μm in the rest frame of a galaxy at redshift z = 2. Figure 1 displays the F140W image of XLSSC 122 and shows a compact cluster of galaxies associated with the extended X-ray-emitting region. Fig. 1: HST image of the galaxy cluster XLSSC 122. The greyscale is the F140W image. Contours display X-ray emission corresponding to the 100-ks XMM-Newton image presented in ref. 4 . The dashed circle is drawn with a radius equal to the measured value of r 500 (the radius within which the average matter density is 500 times the critical density of the Universe). Spectroscopic ‘gold’ and ‘silver’ members (see Methods) of the z = 1.98 cluster are indicated by red and green circles, respectively. Members of the z = 1.93 foreground structure are indicated by blue circles. See text for further details. Full size image We extracted one-dimensional spectra of all galaxies identified within the dispersed G141 grism image of the field (see Methods) and computed redshifts using a galaxy template-fitting algorithm with redshift as a free parameter. Figure 2 displays the histogram of galaxy redshifts in the field of XLSSC 122 over the restricted interval 1.9 < z < 2.05. Inspection of this interval reveals a primary peak at z = 1.98 associated with the central, red galaxies closest to the X-ray peak, and a secondary redshift peak at z = 1.93 associated with a mixture of red and blue galaxies, located at larger projected cluster-centric distances (see Fig. 1 ). The line-of-sight separation between z = 1.93 and z = 1.98 is 76 co-moving megaparsecs, far larger than the size of the XLSSC 122 cluster, and the two structures are therefore physically distinct. As outlined in the Methods, we identify 37 galaxies as being members of the cluster and a further 13 galaxies identified as members of the foreground structure. Fig. 2: Redshift histogram of all galaxies along the line of sight to XLSSC 122. The histogram considers galaxies satisfying the magnitude measurement F140W Kron < 24. Galaxies classified as ‘gold’ members of the z = 1.98 cluster are shown in red, ‘silver’ members are shown in green and members of the z = 1.93 structure are shown in blue. Galaxies not classified as a member of either the z = 1.98 cluster or the z = 1.93 structure are shown in grey. The vertical dashed lines show the unweighted mean redshift of both the cluster and the foreground structure (see text for further details). Full size image We performed photometry of all galaxies within the HST field of view in both the F105W and F140W images (see Methods) and summarize this information in Fig. 3 . The galaxies identified at 1.9 < z < 2.05 form a clear bimodal distribution in colour with a well populated sequence of red galaxies (corresponding to larger values of F105W − F140W) clearly separated from a broader distribution of blue galaxies. Fig. 3: Colour–magnitude diagram of all galaxies within the HST/WFC3 field of view. Spectroscopically confirmed z = 1.98 ‘gold’ and ‘silver’ cluster members are indicated as red squares and green triangles, respectively. Members of the z = 1.93 structure are indicated as blue squares. Galaxies at z ≈ 2 yet which are not formal cluster members are shown as solid black squares, whereas potentially contaminated or confused spectroscopic sources are shown as open black squares. Galaxies with visually classified emission lines are marked using black circles (only z = 1.98 and z = 1.93 are marked in this manner). All other galaxies in the field are indicated by grey squares. Error bars indicate the 1-sigma measurement uncertainty. The spectroscopic completeness limits of F140W Kron = 24 and 24.5 are indicated by the vertical dashed and dotted lines, respectively. The horizontal dot-dashed line shows the lower colour limit for a source to be considered on the cluster’s red sequence. The angled<|im_end|> <|im_start|>assistant Using high-powered telescopes including NASA's Hubble Space Telescope, scientists from Canada, the United States and Denmark have captured the clearest image known of a cluster of galaxies from 10 billion years ago in a discovery that provides clues the universe was more evolved than previously thought. The discovery is the best-case example found so far of the mature, evolved system, says Jon Willis, lead author of research published in Nature and astronomer at the University of Victoria. Willis studies the physical contents of the universe covering many aspects of cosmology and astrophysics. Q. What is a galaxy cluster and what can they tell us about the universe? A. A galaxy cluster can be likened to a great city of galaxies, though galaxies themselves are collections of billions of stars all held together by gravity. In simple terms, astrophysics is the study of our universe and our place in it. By studying the stars that make up the galaxies we can tell how old they are and when each galaxy first formed. Q. What did your team of scientists find? A. We've discovered what is the most ancient city of galaxies in the universe. It's the clearest snapshot yet of a galaxy cluster—it's like a Rosetta Stone. In the same way, the Rosetta Stone was a glimpse into ancient Egyptian history, this discovery provides clues to understanding the physics of what was going on in that environment billions of years ago. Astronomy is wonderful in that seeing is believing. I don't need to show you an equation; I don't need to show you a complex model. I can show you an image in the sky. Q. How unique is your discovery? A. It's the most concentrated, easiest to see and the most prominent out of what's been seen. To put it in context, the universe is 13 billion years old and so the cluster is an old object in a young universe. We are very surprised to see how early the universe produced something so mature. Finding a galaxy cluster so early in the development of the universe tells us that—wow—the universe is capable of amazing things. Q. Can you provide a simple analogy for this discovery? A. It's an equivalent of meeting a child who displays all the characteristics of an adult. We have met these young clusters—think the universe was just over three-billion-years old—so we've found it's quite a precocious object and it can teach us about how physics works in the early universe. Q. You've captured these images using high-powered telescopes. How do you gain access to these tools? A. Although the Hubble Space Telescope is the most recent telescope we used, which gave us these wonderful views of the cluster, we have used a number of telescopes to get to this discovery. These include the European Space Agency XMM-Newton space observatory, the Canada France Hawaii Telescope and the European Southern Observatory Very Large Telescope. Q. What's next? A. We are fortunate that NASA is planning to launch the James Webb Space Telescope, which is the successor to Hubble in late 2020 or early 2021. The first observing proposals are due in May 2020. Rest assured we'll be applying to study this cluster in much more detail. <|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 realm of particle self-assembly, it is possible to reliably construct nearly arbitrary structures if all the pieces are distinct 1 , 2 , 3 , but systems with fewer flavours of building blocks have so far been limited to the assembly of exotic crystals 4 , 5 , 6 . Here we introduce a minimal model system of colloidal droplet chains 7 , with programmable DNA interactions that guide their downhill folding into specific geometries. Droplets are observed in real space and time, unravelling the rules of folding. Combining experiments, simulations and theory, we show that controlling the order in which interactions are switched on directs folding into unique structures, which we call colloidal foldamers 8 . The simplest alternating sequences (ABAB...) of up to 13 droplets yield 11 foldamers in two dimensions and one in three dimensions. Optimizing the droplet sequence and adding an extra flavour uniquely encodes more than half of the 619 possible two-dimensional geometries. Foldamers consisting of at least 13 droplets exhibit open structures with holes, offering porous design. Numerical simulations show that foldamers can further interact to make complex supracolloidal architectures, such as dimers, ribbons and mosaics. Our results are independent of the dynamics and therefore apply to polymeric materials with hierarchical interactions on all length scales, from organic molecules all the way to Rubik’s Snakes. This toolbox enables the encoding of large-scale design into sequences of short polymers, placing folding at the forefront of materials self-assembly. Main Self-assembly of materials currently requires a toolbox of building blocks with a given shape and a multitude of interaction flavours and strengths to ensure a unique product 9 , 10 , 11 . By contrast, achieving self-assembly of an arbitrary structure with high yield using a limited palette of flavours remains a key challenge. We therefore turn to the biological concept of self-assembly by the folding of linear chains, analogous to protein and RNA folding, and adapt it to materials science 12 , 13 , 14 . Our system consists of two flavours of colloidal droplets, labelled blue (A) and yellow (B), functionalized with complementary DNA strands (Methods). These droplets irreversibly bind with valence two to form the backbone of an alternating colloidomer 7 , 15 , as depicted in Fig. 1a,b . The droplets are dispersed in an aqueous ferrofluid and we apply an intermittent magnetic field to accelerate the chaining process, giving rise to an exponential distribution of chain lengths, as shown in Extended Data Fig. 1 . These chains are thermal and freely jointed because DNA diffuses on the surface even after the droplets are bound. Fig. 1: Colloidomer design and folding. a , Two flavours of droplets, A (blue) and B (yellow), are functionalized with complementary backbone strands of DNA to make alternating chains. They also carry weaker DNA interactions that mediate folding. The blue flavour carries two additional types of DNA, whereas the yellow flavour carries only one DNA strand that provides two distinct interactions. This 9 base pair (bp) DNA strand carries a consecutive complement to the 6 bp strand on the blue particle, activated at a melting temperature ( T m ) around 32 o C, and 6 intermittent bp that are palindromes activated at T m around 27 o C to mediate the yellow–yellow interaction (Methods). b , An emulsion first assembles into colloidomers using a magnetic field ( B ), after which a temperature ( T ) protocol triggers folding into diverse geometries. c , Fluorescent images show colloidomers of different lengths that undergo folding over time. Scale bar, 20 μm. d , A temperature protocol gives rise to stepwise folding, each step with a duration τ , of a decamer chain into the crown foldamer. Scale bar, 5 μm. Full size image To mediate folding, each droplet flavour is in addition functionalized with DNA strands that act as weaker secondary interactions. Droplets have the advantage that they freely rearrange after binding, facilitating folding 16 . If all interactions are all simultaneously switched on, one obtains a mixture of folded geometries as the final product 17 , 18 . The number of possible geometries is singular for chains shorter than hexamers, but then grows exponentially with chain length. For example, an octamer can fold into nine distinct geometries, four of which are shown in Fig. 1b . By choosing DNA strands with distinct binding energies and therefore different melting temperatures 10 (Methods), we establish a hierarchy of bonds that are switched on as the temperature is lowered, as shown in Fig. 1c,d . Because the melting transition is sharp, working a few degrees below it ensures irreversible bond formation and downhill folding. For example, the decamer chain in Fig. 1d folds into the crown in a stepwise manner. First, the blue–blue palindrome interaction forms a pentamer core at high temperature, followed by the sequential locking in of yellow–blue and yellow–yellow bonds at progressively lower temperatures. Other protocols with a different sequence of secondary interactions are mediated by the same DNA strands, but grafted on droplets in different combinations (Methods). Design of the folding landscape Along the folding process, each new bond that forms causes the chain to adopt a different configuration. Those configurations that have the same contact matrix, ignoring chirality, are here defined to belong to a given state. All possible states between the linear chain and the final geometries map out an energy landscape that can be represented in a tree form 19 . In the folding tree in Fig. 2a , each row shows states with the same number of secondary bonds, that is, the same potential energy. Two states are connected in the tree if one can topologically transform into the other by making or breaking a single bond. Designing folding protocols, or the order of secondary droplet interactions, enables us to funnel the landscape to one final folded state. Fig. 2: Folding pathways of a heptamer. a , All folding pathways of a four-blue, three-yellow droplet heptamer result in a", "role": "user" }, { "content": "A team of physicists has created a new way to self-assemble particles—an advance that offers new promise for building complex and innovative materials at the microscopic level. Self-assembly, introduced in the early 2000s, gives scientists a means to \"pre-program\" particles, allowing for the building of materials without further human intervention—the microscopic equivalent of Ikea furniture that can assemble itself. The breakthrough, reported in the journal Nature, centers on emulsions—droplets of oil immersed in water—and their use in the self-assembly of foldamers, which are unique shapes that can be theoretically predicted from the sequence of droplet interactions. The self-assembly process borrows from the field of biology, mimicking the folding of proteins and RNA using colloids. In the Nature work, the researchers created tiny, oil-based droplets in water, possessing an array of DNA sequences that served as assembly \"instructions.\" These droplets first assemble into flexible chains and then sequentially collapse, or fold, via sticky DNA molecules. This folding yields a dozen types of foldamers, and further specificity could encode more than half of 600 possible geometric shapes. Microscopy images show a chain of alternating blue and yellow droplets folding into a crown geometry through blue-blue, blue-yellow, and finally yellow-yellow interactions, mediated by sticky DNA strands. Microscopic droplets are programmed to interact via sticky DNA strands to uniquely fold into well-defined shapes, as shown here. Credit: Brujic Lab \"Being able to pre-program colloidal architectures gives us the means to create materials with intricate and innovative properties,\" explains Jasna Brujic, a professor in New York University's Department of Physics and one of the researchers. \"Our work shows how hundreds of self-assembled geometries can be uniquely created, offering new possibilities for the creation of the next generation of materials.\" The research also included Angus McMullen, a postdoctoral fellow in NYU's Department of Physics, as well as Maitane Muñoz Basagoiti and Zorana Zeravcic of ESPCI Paris. The scientists emphasize the counterintuitive, and pioneering, aspect of the method: Rather than requiring a large number of building blocks to encode precise shapes, its folding technique means only a few are necessary because each block can adopt a variety of forms. \"Unlike a jigsaw puzzle, in which every piece is different, our process uses only two types of particles, which greatly reduces the variety of building blocks needed to encode a particular shape,\" explains Brujic. \"The innovation lies in using folding similar to the way that proteins do, but on a length scale 1,000 times bigger—about one-tenth the width of a strand of hair. These particles first bind together to make a chain, which then folds according to preprogrammed interactions that guide the chain through complex pathways into a unique geometry.\" \"The ability to obtain a lexicon of shapes opens the path to further assembly into larger scale materials, just as proteins hierarchically aggregate to build cellular compartments in biology,\" she adds. ", "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 realm of particle self-assembly, it is possible to reliably construct nearly arbitrary structures if all the pieces are distinct 1 , 2 , 3 , but systems with fewer flavours of building blocks have so far been limited to the assembly of exotic crystals 4 , 5 , 6 . Here we introduce a minimal model system of colloidal droplet chains 7 , with programmable DNA interactions that guide their downhill folding into specific geometries. Droplets are observed in real space and time, unravelling the rules of folding. Combining experiments, simulations and theory, we show that controlling the order in which interactions are switched on directs folding into unique structures, which we call colloidal foldamers 8 . The simplest alternating sequences (ABAB...) of up to 13 droplets yield 11 foldamers in two dimensions and one in three dimensions. Optimizing the droplet sequence and adding an extra flavour uniquely encodes more than half of the 619 possible two-dimensional geometries. Foldamers consisting of at least 13 droplets exhibit open structures with holes, offering porous design. Numerical simulations show that foldamers can further interact to make complex supracolloidal architectures, such as dimers, ribbons and mosaics. Our results are independent of the dynamics and therefore apply to polymeric materials with hierarchical interactions on all length scales, from organic molecules all the way to Rubik’s Snakes. This toolbox enables the encoding of large-scale design into sequences of short polymers, placing folding at the forefront of materials self-assembly. Main Self-assembly of materials currently requires a toolbox of building blocks with a given shape and a multitude of interaction flavours and strengths to ensure a unique product 9 , 10 , 11 . By contrast, achieving self-assembly of an arbitrary structure with high yield using a limited palette of flavours remains a key challenge. We therefore turn to the biological concept of self-assembly by the folding of linear chains, analogous to protein and RNA folding, and adapt it to materials science 12 , 13 , 14 . Our system consists of two flavours of colloidal droplets, labelled blue (A) and yellow (B), functionalized with complementary DNA strands (Methods). These droplets irreversibly bind with valence two to form the backbone of an alternating colloidomer 7 , 15 , as depicted in Fig. 1a,b . The droplets are dispersed in an aqueous ferrofluid and we apply an intermittent magnetic field to accelerate the chaining process, giving rise to an exponential distribution of chain lengths, as shown in Extended Data Fig. 1 . These chains are thermal and freely jointed because DNA diffuses on the surface even after the droplets are bound. Fig. 1: Colloidomer design and folding. a , Two flavours of droplets, A (blue) and B (yellow), are functionalized with complementary backbone strands of DNA to make alternating chains. They also carry weaker DNA interactions that mediate folding. The blue flavour carries two additional types of DNA, whereas the yellow flavour carries only one DNA strand that provides two distinct interactions. This 9 base pair (bp) DNA strand carries a consecutive complement to the 6 bp strand on the blue particle, activated at a melting temperature ( T m ) around 32 o C, and 6 intermittent bp that are palindromes activated at T m around 27 o C to mediate the yellow–yellow interaction (Methods). b , An emulsion first assembles into colloidomers using a magnetic field ( B ), after which a temperature ( T ) protocol triggers folding into diverse geometries. c , Fluorescent images show colloidomers of different lengths that undergo folding over time. Scale bar, 20 μm. d , A temperature protocol gives rise to stepwise folding, each step with a duration τ , of a decamer chain into the crown foldamer. Scale bar, 5 μm. Full size image To mediate folding, each droplet flavour is in addition functionalized with DNA strands that act as weaker secondary interactions. Droplets have the advantage that they freely rearrange after binding, facilitating folding 16 . If all interactions are all simultaneously switched on, one obtains a mixture of folded geometries as the final product 17 , 18 . The number of possible geometries is singular for chains shorter than hexamers, but then grows exponentially with chain length. For example, an octamer can fold into nine distinct geometries, four of which are shown in Fig. 1b . By choosing DNA strands with distinct binding energies and therefore different melting temperatures 10 (Methods), we establish a hierarchy of bonds that are switched on as the temperature is lowered, as shown in Fig. 1c,d . Because the melting transition is sharp, working a few degrees below it ensures irreversible bond formation and downhill folding. For example, the decamer chain in Fig. 1d folds into the crown in a stepwise manner. First, the blue–blue palindrome interaction forms a pentamer core at high temperature, followed by the sequential locking in of yellow–blue and yellow–yellow bonds at progressively lower temperatures. Other protocols with a different sequence of secondary interactions are mediated by the same DNA strands, but grafted on droplets in different combinations (Methods). Design of the folding landscape Along the folding process, each new bond that forms causes the chain to adopt a different configuration. Those configurations that have the same contact matrix, ignoring chirality, are here defined to belong to a given state. All possible states between the linear chain and the final geometries map out an energy landscape that can be represented in a tree form 19 . In the folding tree in Fig. 2a , each row shows states with the same number of secondary bonds, that is, the same potential energy. Two states are connected in the tree if one can topologically transform into the other by making or breaking a single bond. Designing folding protocols, or the order of secondary droplet interactions, enables us to funnel the landscape to one final folded state. Fig. 2: Folding pathways of a heptamer. a , All folding pathways of a four-blue, three-yellow droplet heptamer result in a<|im_end|> <|im_start|>assistant A team of physicists has created a new way to self-assemble particles—an advance that offers new promise for building complex and innovative materials at the microscopic level. Self-assembly, introduced in the early 2000s, gives scientists a means to "pre-program" particles, allowing for the building of materials without further human intervention—the microscopic equivalent of Ikea furniture that can assemble itself. The breakthrough, reported in the journal Nature, centers on emulsions—droplets of oil immersed in water—and their use in the self-assembly of foldamers, which are unique shapes that can be theoretically predicted from the sequence of droplet interactions. The self-assembly process borrows from the field of biology, mimicking the folding of proteins and RNA using colloids. In the Nature work, the researchers created tiny, oil-based droplets in water, possessing an array of DNA sequences that served as assembly "instructions." These droplets first assemble into flexible chains and then sequentially collapse, or fold, via sticky DNA molecules. This folding yields a dozen types of foldamers, and further specificity could encode more than half of 600 possible geometric shapes. Microscopy images show a chain of alternating blue and yellow droplets folding into a crown geometry through blue-blue, blue-yellow, and finally yellow-yellow interactions, mediated by sticky DNA strands. Microscopic droplets are programmed to interact via sticky DNA strands to uniquely fold into well-defined shapes, as shown here. Credit: Brujic Lab "Being able to pre-program colloidal architectures gives us the means to create materials with intricate and innovative properties," explains Jasna Brujic, a professor in New York University's Department of Physics and one of the researchers. "Our work shows how hundreds of self-assembled geometries can be uniquely created, offering new possibilities for the creation of the next generation of materials." The research also included Angus McMullen, a postdoctoral fellow in NYU's Department of Physics, as well as Maitane Muñoz Basagoiti and Zorana Zeravcic of ESPCI Paris. The scientists emphasize the counterintuitive, and pioneering, aspect of the method: Rather than requiring a large number of building blocks to encode precise shapes, its folding technique means only a few are necessary because each block can adopt a variety of forms. "Unlike a jigsaw puzzle, in which every piece is different, our process uses only two types of particles, which greatly reduces the variety of building blocks needed to encode a particular shape," explains Brujic. "The innovation lies in using folding similar to the way that proteins do, but on a length scale 1,000 times bigger—about one-tenth the width of a strand of hair. These particles first bind together to make a chain, which then folds according to preprogrammed interactions that guide the chain through complex pathways into a unique geometry." "The ability to obtain a lexicon of shapes opens the path to further assembly into larger scale materials, just as proteins hierarchically aggregate to build cellular compartments in biology," she adds. <|im_end|>

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1,934

[ { "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 Visual abilities of the honey bee have been studied for more than 100 years, recently revealing unexpectedly sophisticated cognitive skills rivalling those of vertebrates. However, the physiological limits of the honey bee eye have been largely unaddressed and only studied in an unnatural, dark state. Using a bright display and intracellular recordings, we here systematically investigated the angular sensitivity across the light adapted eye of honey bee foragers. Angular sensitivity is a measure of photoreceptor receptive field size and thus small values indicate higher visual acuity. Our recordings reveal a fronto-ventral acute zone in which angular sensitivity falls below 1.9°, some 30% smaller than previously reported. By measuring receptor noise and responses to moving dark objects, we also obtained direct measures of the smallest features detectable by the retina. In the frontal eye, single photoreceptors respond to objects as small as 0.6° × 0.6°, with >99% reliability. This indicates that honey bee foragers possess significantly better resolution than previously reported or estimated behaviourally, and commonly assumed in modelling of bee acuity. Introduction The visual cognitive abilities of the honey bee, Apis mellifera , have few rivals among invertebrates. They can learn conceptual relations between stimuli, perform visual pattern categorization and even segregate the hierarchy of local versus global features within scenes 1 , 2 . Combined with the amenability of free-flying forager individuals for behavioural analysis, these abilities have contributed to bees becoming a major model for studying visual perception, learning and memory. Yet the physiological limits of achromatic vision in bees remain surprisingly unexplored 3 , 4 . Prior physiological studies of honey bee have only measured angular resolution from limited or poorly characterised regions of the retina, and in a dark adapted state 3 , 4 . These studies concluded that honey bees have a relatively modest average angular sensitivity of 2.6°. This value has been widely applied over the years when designing and interpreting behavioural experiments and ultimately for modelling flower perception 5 and the effect of blur on the honey bee’s view of their world 6 , 7 . Flower detectability and the smallest visual angle that a bee can perceive has also been investigated behaviourally, revealing that bees could not discriminate a dark object smaller than 3° when trained to fly to a sugar source in a double arm arena 6 , 7 , 8 . While these behavioural estimates for the lower limit to object detection seem to be reasonably well matched to prior physiological data, the fact that the latter were from eyes in a dark-adapted state might lead to underestimates of the true resolution 9 . For example, a widespread property of insect apposition eyes (including those of Hymenoptera) is the movement of pigment granules within the photoreceptors and/or pigment cells. These act together as a pupil that reduces the light flux upon light adaptation and also improves angular resolution 9 , 10 , 11 , 12 . We therefore recorded from photoreceptors adapted to bright light conditions, closer to those that foraging bees experience in nature (300 cd/m 2 ). We estimated both the angular sensitivity Δρ (a measure of the receptive field size of single receptors, which limits resolution) and the smallest object a single cell can detect. Our results show that honey bee foragers have 30% better resolution than previous physiological estimates and a 5 times lower limit for feature detectability than has yet been estimated behaviourally. Results Angular sensitivity estimates To measure light adapted acuity, we recorded intracellularly from single photoreceptors while adapting the eye to a bright LCD monitor. We obtained data primarily for green sensitive cells, characterized by responses to coloured bars (green, red, blue) swept through the receptive field ( Fig. 1a ). We targeted cells within equatorial frontal and lateral sub-regions of the visual field likely involved in visual behaviours such as pattern discrimination and optical flow analysis 13 , 14 ( Fig. 1b ). For each cell we estimated 2-dimensional receptive fields by recording responses to small, dark objects scanned raster fashion (left to right) across the receptive field. Resulting raw receptive field maps ( Fig. 1a ) served as input to a 2D Gaussian optical model that accounts for the size of the scanning feature 15 . This allowed estimation of Δρ, the full width at half maximum for horizontal and vertical components (Δρ h , Δρ v ) of the underlying angular sensitivity ( Fig. 1b ). Figure 1: Intracellular measures of resolution in light adapted honey bee photoreceptors. ( a ) Example responses to red, green or blue bars swept through the receptive field (width: 4°, length 90°, velocity 80°/s) against a black background (responses are normalized to maximum response, i.e. to the white bar). All photoreceptors included in further analysis displayed similar spectral sensitivity with maximal response to green features. (i.e. green-sensitive or long-wavelength photoreceptor type). The raw 2-dimensional receptive field of a frontal photoreceptor was obtained by scanning its receptive field horizontally with a black square target (3 deg 2 ) at a velocity of 32°/s across a vertical series of scan lines 0.13° apart. Colours show deflection in membrane potential in mV. ( b ) Estimates of individual photoreceptor receptive fields across the eye ( N = 18). Ellipses denote relative sizes of angular sensitivity. Arrows denote frontal and lateral body axes (F: 0° azimuth, 0° elevation, L: 90° azimuth, 0° elevation) and the dorsal pole. The grey shading indicates lateral and frontal subsets of photoreceptors. Coloured plots show example 2D Gaussian kernel fits that account for the individual receptive fields from one frontal and one lateral photoreceptor, together with the vertical (dotted line) and horizontal (unbroken line) components of the angular half-width, Δρ. ( c ) Horizontal ( ⦁ ) and vertical ( ⚬ ) estimates of angular sensitivity (Δρ) in photoreceptors recorded across the eye as in (b). Least-square regression lines are reported for horizontal (unbroken line) and vertical (dotted line) components. Both Δρ h and Δρ v increase with increasing eccentricity, calculated as", "role": "user" }, { "content": "Research conducted at the University of Adelaide has discovered that bees have much better vision than was previously known, offering new insights into the lives of honey bees, and new opportunities for translating this knowledge into fields such as robot vision. The findings come from \"eye tests\" given to western honey bees (also known as European honey bees, Apis mellifera) by postdoctoral researcher Dr Elisa Rigosi (Department of Biology, Lund University, Sweden) in the Adelaide Medical School, under the supervision of Dr Steven Wiederman (Adelaide Medical School, University of Adelaide) and Professor David O'Carroll (Department of Biology, Lund University, Sweden). The results of their work are published today in the Nature journal Scientific Reports. Bee vision has been studied ever since the pioneering research of Dr Karl von Frisch in 1914, which reported bees' ability to see colors through a clever set of training experiments. \"Today, honey bees are still a fascinating model among scientists, in particular neuroscientists,\" Dr Rigosi says. \"Among other things, honey bees help to answer questions such as: how can a tiny brain of less than a million neurons achieve complex processes, and what are its utmost limits? In the last few decades it has been shown that bees can see and categorize objects and learn concepts through vision, such as the concept of 'symmetric' and 'above and below'. \"But one basic question that has only been partially addressed is: what actually is the visual acuity of the honey bee eye? Just how good is a bee's eyesight?\" Dr Wiederman says: \"Previous researchers have measured the visual acuity of bees, but most of these experiments have been conducted in the dark. Bright daylight and dark laboratories are two completely different environments, resulting in anatomical and physiological changes in the resolution of the eye. \"Photoreceptors in the visual system detect variations in light intensity. There are eight photoreceptors beyond each hexagonal facet of a bee's compound eye, and their eyes are made out of thousands of facets! Naturally, we expected some differences in the quality of bees' eyesight from being tested in brightly lit conditions compared with dim light,\" he says. A western honey bee, also known as a European honey bee (Apis mellifera). Researchers at Lund University, Sweden, and the University of Adelaide, Australia, have shown that honey bees have much sharper eyesight than previously known. Credit: Dr Elisa Rigosi, Lund University. Dr Rigosi, Dr Wiederman and Professor O'Carroll set out to answer two specific questions: first, what is the smallest well-defined object that a bee can see? (ie, its object resolution); and second, how far away can a bee see an object, even if it can't see that object clearly? (ie, maximum detectability limit). To do so, the researchers took electrophysiological recordings of the neural responses occurring in single photoreceptors in a bee's eyes. The photoreceptors are detectors of light in the retina, and each time an object passes into the field of vision, it registers a neural response. Dr Rigosi says: \"We found that in the frontal part of the eye, where the resolution is maximized, honey bees can clearly see objects that are as small as 1.9° - that's approximately the width of your thumb when you stretch your arm out in front of you. \"This is 30% better eyesight than has been previously recorded,\" she says. \"In terms of the smallest object a bee can detect, but not clearly, this works out to be about 0.6° - that's one third of your thumb width at arm's length. This is about one third of what bees can clearly see and five times smaller than what has so far been detected in behavioral experiments. \"These new results suggest that bees have the chance to see a potential predator, and thus escape, far earlier than what we thought previously, or perceive landmarks in the environment better than we expected, which is useful for navigation and thus for survival,\" Dr Rigosi says. Dr Wiederman says this research offers new and useful information about insect vision more broadly as well as for honey bees. \"We've shown that the honey bee has higher visual acuity than previously reported. They can resolve finer details than we originally thought, which has important implications in interpreting their responses to a range of cognitive experiments scientists have been conducting with bees for years. \"Importantly, these findings could also be useful in our work on designing bio-inspired robotics and robot vision, and for basic research on bee biology,\" he 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 Visual abilities of the honey bee have been studied for more than 100 years, recently revealing unexpectedly sophisticated cognitive skills rivalling those of vertebrates. However, the physiological limits of the honey bee eye have been largely unaddressed and only studied in an unnatural, dark state. Using a bright display and intracellular recordings, we here systematically investigated the angular sensitivity across the light adapted eye of honey bee foragers. Angular sensitivity is a measure of photoreceptor receptive field size and thus small values indicate higher visual acuity. Our recordings reveal a fronto-ventral acute zone in which angular sensitivity falls below 1.9°, some 30% smaller than previously reported. By measuring receptor noise and responses to moving dark objects, we also obtained direct measures of the smallest features detectable by the retina. In the frontal eye, single photoreceptors respond to objects as small as 0.6° × 0.6°, with >99% reliability. This indicates that honey bee foragers possess significantly better resolution than previously reported or estimated behaviourally, and commonly assumed in modelling of bee acuity. Introduction The visual cognitive abilities of the honey bee, Apis mellifera , have few rivals among invertebrates. They can learn conceptual relations between stimuli, perform visual pattern categorization and even segregate the hierarchy of local versus global features within scenes 1 , 2 . Combined with the amenability of free-flying forager individuals for behavioural analysis, these abilities have contributed to bees becoming a major model for studying visual perception, learning and memory. Yet the physiological limits of achromatic vision in bees remain surprisingly unexplored 3 , 4 . Prior physiological studies of honey bee have only measured angular resolution from limited or poorly characterised regions of the retina, and in a dark adapted state 3 , 4 . These studies concluded that honey bees have a relatively modest average angular sensitivity of 2.6°. This value has been widely applied over the years when designing and interpreting behavioural experiments and ultimately for modelling flower perception 5 and the effect of blur on the honey bee’s view of their world 6 , 7 . Flower detectability and the smallest visual angle that a bee can perceive has also been investigated behaviourally, revealing that bees could not discriminate a dark object smaller than 3° when trained to fly to a sugar source in a double arm arena 6 , 7 , 8 . While these behavioural estimates for the lower limit to object detection seem to be reasonably well matched to prior physiological data, the fact that the latter were from eyes in a dark-adapted state might lead to underestimates of the true resolution 9 . For example, a widespread property of insect apposition eyes (including those of Hymenoptera) is the movement of pigment granules within the photoreceptors and/or pigment cells. These act together as a pupil that reduces the light flux upon light adaptation and also improves angular resolution 9 , 10 , 11 , 12 . We therefore recorded from photoreceptors adapted to bright light conditions, closer to those that foraging bees experience in nature (300 cd/m 2 ). We estimated both the angular sensitivity Δρ (a measure of the receptive field size of single receptors, which limits resolution) and the smallest object a single cell can detect. Our results show that honey bee foragers have 30% better resolution than previous physiological estimates and a 5 times lower limit for feature detectability than has yet been estimated behaviourally. Results Angular sensitivity estimates To measure light adapted acuity, we recorded intracellularly from single photoreceptors while adapting the eye to a bright LCD monitor. We obtained data primarily for green sensitive cells, characterized by responses to coloured bars (green, red, blue) swept through the receptive field ( Fig. 1a ). We targeted cells within equatorial frontal and lateral sub-regions of the visual field likely involved in visual behaviours such as pattern discrimination and optical flow analysis 13 , 14 ( Fig. 1b ). For each cell we estimated 2-dimensional receptive fields by recording responses to small, dark objects scanned raster fashion (left to right) across the receptive field. Resulting raw receptive field maps ( Fig. 1a ) served as input to a 2D Gaussian optical model that accounts for the size of the scanning feature 15 . This allowed estimation of Δρ, the full width at half maximum for horizontal and vertical components (Δρ h , Δρ v ) of the underlying angular sensitivity ( Fig. 1b ). Figure 1: Intracellular measures of resolution in light adapted honey bee photoreceptors. ( a ) Example responses to red, green or blue bars swept through the receptive field (width: 4°, length 90°, velocity 80°/s) against a black background (responses are normalized to maximum response, i.e. to the white bar). All photoreceptors included in further analysis displayed similar spectral sensitivity with maximal response to green features. (i.e. green-sensitive or long-wavelength photoreceptor type). The raw 2-dimensional receptive field of a frontal photoreceptor was obtained by scanning its receptive field horizontally with a black square target (3 deg 2 ) at a velocity of 32°/s across a vertical series of scan lines 0.13° apart. Colours show deflection in membrane potential in mV. ( b ) Estimates of individual photoreceptor receptive fields across the eye ( N = 18). Ellipses denote relative sizes of angular sensitivity. Arrows denote frontal and lateral body axes (F: 0° azimuth, 0° elevation, L: 90° azimuth, 0° elevation) and the dorsal pole. The grey shading indicates lateral and frontal subsets of photoreceptors. Coloured plots show example 2D Gaussian kernel fits that account for the individual receptive fields from one frontal and one lateral photoreceptor, together with the vertical (dotted line) and horizontal (unbroken line) components of the angular half-width, Δρ. ( c ) Horizontal ( ⦁ ) and vertical ( ⚬ ) estimates of angular sensitivity (Δρ) in photoreceptors recorded across the eye as in (b). Least-square regression lines are reported for horizontal (unbroken line) and vertical (dotted line) components. Both Δρ h and Δρ v increase with increasing eccentricity, calculated as<|im_end|> <|im_start|>assistant Research conducted at the University of Adelaide has discovered that bees have much better vision than was previously known, offering new insights into the lives of honey bees, and new opportunities for translating this knowledge into fields such as robot vision. The findings come from "eye tests" given to western honey bees (also known as European honey bees, Apis mellifera) by postdoctoral researcher Dr Elisa Rigosi (Department of Biology, Lund University, Sweden) in the Adelaide Medical School, under the supervision of Dr Steven Wiederman (Adelaide Medical School, University of Adelaide) and Professor David O'Carroll (Department of Biology, Lund University, Sweden). The results of their work are published today in the Nature journal Scientific Reports. Bee vision has been studied ever since the pioneering research of Dr Karl von Frisch in 1914, which reported bees' ability to see colors through a clever set of training experiments. "Today, honey bees are still a fascinating model among scientists, in particular neuroscientists," Dr Rigosi says. "Among other things, honey bees help to answer questions such as: how can a tiny brain of less than a million neurons achieve complex processes, and what are its utmost limits? In the last few decades it has been shown that bees can see and categorize objects and learn concepts through vision, such as the concept of 'symmetric' and 'above and below'. "But one basic question that has only been partially addressed is: what actually is the visual acuity of the honey bee eye? Just how good is a bee's eyesight?" Dr Wiederman says: "Previous researchers have measured the visual acuity of bees, but most of these experiments have been conducted in the dark. Bright daylight and dark laboratories are two completely different environments, resulting in anatomical and physiological changes in the resolution of the eye. "Photoreceptors in the visual system detect variations in light intensity. There are eight photoreceptors beyond each hexagonal facet of a bee's compound eye, and their eyes are made out of thousands of facets! Naturally, we expected some differences in the quality of bees' eyesight from being tested in brightly lit conditions compared with dim light," he says. A western honey bee, also known as a European honey bee (Apis mellifera). Researchers at Lund University, Sweden, and the University of Adelaide, Australia, have shown that honey bees have much sharper eyesight than previously known. Credit: Dr Elisa Rigosi, Lund University. Dr Rigosi, Dr Wiederman and Professor O'Carroll set out to answer two specific questions: first, what is the smallest well-defined object that a bee can see? (ie, its object resolution); and second, how far away can a bee see an object, even if it can't see that object clearly? (ie, maximum detectability limit). To do so, the researchers took electrophysiological recordings of the neural responses occurring in single photoreceptors in a bee's eyes. The photoreceptors are detectors of light in the retina, and each time an object passes into the field of vision, it registers a neural response. Dr Rigosi says: "We found that in the frontal part of the eye, where the resolution is maximized, honey bees can clearly see objects that are as small as 1.9° - that's approximately the width of your thumb when you stretch your arm out in front of you. "This is 30% better eyesight than has been previously recorded," she says. "In terms of the smallest object a bee can detect, but not clearly, this works out to be about 0.6° - that's one third of your thumb width at arm's length. This is about one third of what bees can clearly see and five times smaller than what has so far been detected in behavioral experiments. "These new results suggest that bees have the chance to see a potential predator, and thus escape, far earlier than what we thought previously, or perceive landmarks in the environment better than we expected, which is useful for navigation and thus for survival," Dr Rigosi says. Dr Wiederman says this research offers new and useful information about insect vision more broadly as well as for honey bees. "We've shown that the honey bee has higher visual acuity than previously reported. They can resolve finer details than we originally thought, which has important implications in interpreting their responses to a range of cognitive experiments scientists have been conducting with bees for years. "Importantly, these findings could also be useful in our work on designing bio-inspired robotics and robot vision, and for basic research on bee biology," he says. <|im_end|>

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13, 1115, 374, 922, 832, 4948, 315, 1148, 40558, 649, 9539, 1518, 323, 4330, 3115, 9333, 1109, 1148, 706, 779, 3117, 1027, 16914, 304, 36695, 21896, 13, 330, 9673, 502, 3135, 4284, 430, 40558, 617, 279, 6140, 311, 1518, 264, 4754, 68006, 11, 323, 8617, 12731, 11, 3117, 6931, 1109, 1148, 584, 3463, 8767, 11, 477, 45493, 61024, 304, 279, 4676, 2731, 1109, 584, 3685, 11, 902, 374, 5505, 369, 10873, 323, 8617, 369, 20237, 1359, 2999, 52632, 31824, 2795, 13, 2999, 468, 1142, 4858, 2795, 420, 3495, 6209, 502, 323, 5505, 2038, 922, 27080, 11376, 810, 44029, 439, 1664, 439, 369, 26828, 40558, 13, 330, 1687, 3077, 6982, 430, 279, 26828, 38328, 706, 5190, 9302, 1645, 35594, 1109, 8767, 5068, 13, 2435, 649, 9006, 73886, 3649, 1109, 584, 13517, 3463, 11, 902, 706, 3062, 25127, 304, 66744, 872, 14847, 311, 264, 2134, 315, 25702, 21896, 14248, 617, 1027, 31474, 449, 40558, 369, 1667, 13, 330, 11772, 18007, 11, 1521, 14955, 1436, 1101, 387, 5505, 304, 1057, 990, 389, 30829, 17332, 53161, 74706, 323, 12585, 11376, 11, 323, 369, 6913, 3495, 389, 38328, 34458, 1359, 568, 2795, 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 Introduction In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID. Objective Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls. Methods 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations. Results Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare. Conclusion We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort. arthritis rheumatoid COVID-19 vaccination tumor necrosis factor inhibitors Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data are under embargo by local authorities if not included into the manuscript. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 55 news outlets Blogged by 6 Tweeted by 335 On 3 Facebook pages On 1 videos 270 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 arthritis rheumatoid COVID-19 vaccination tumor necrosis factor inhibitors Key messages What is already known about this subject? Data on the efficacy and safety of mRNA vaccines in patients with immunosuppressive therapies is not available so far. What does this study add? In our cohort, mRNA vaccines against SARS-CoV-2 showed a considerable immunogenicity in patients. Side effects in patients were comparable with controls with systemic side effects being less frequent. No flares of the underlying inflammatory condition could be observed in the context of the vaccination. How might this impact on clinical practice or future developments? The data in this study indicate that mRNA vaccines against SARS-CoV-2 are immunogenic and safe in patients with chronic inflammatory diseases. Introduction The SARS-CoV-2 pandemic continues to threaten the health of patients worldwide. Patients receiving immunosuppressive medication, for example, in the context of transplantation or chronic inflammatory diseases (CID), are considered to be at a higher risk of severe manifestations of COVID-19. Generally, patients receiving immunosuppression are considered to have an increased risk for infections. However, registry data appear to indicate that in the context of SARS-CoV-2 not every immunosuppressed patient has an increased risk of severe COVID-19. Indeed, biological therapies have been identified as decreasing the risk for hospitalisation due to COVID-19 in cohorts of patients with rheumatic diseases, chronic inflammatory bowel diseases and psoriasis. 1–5 The most important factors associated with a higher risk of hospitalisation and death across multiple indications and forms of immunosuppression were found to be older age, high underlying disease activity as well as high glucocorticoid dosages (at dosages equivalent to prednisolone ≥10 mg). 1 6 7 Additionally, B cell depleting drugs, that is, rituximab, might represent a risk factor. 8 Until now, there is insufficient registry data for other drugs commonly used to treat patients with CID in terms of increased risk of severe COVID-19. 1 9 10 However, patients have minimised their risk by sheltering in place early and reducing infection contacts (own unpublished data). Several drugs used in the management of CID have been analysed as potential treatments for COVID-19, especially in attenuating the so-called cytokine storm, some of which have shown considerable benefit. 11 Vaccination against SARS-CoV-2 is now a reality for the most vulnerable and continues to spread to encompass patients receiving immunosuppressive therapies. However, patients with a higher risk being older, taking more steroids and having high underlying disease activity are known to respond less to vaccines. 12–15 Additionally, patients with CID and those taking anticytokine therapies or immunosuppression were excluded from the phase III trials for all vaccines approved by the European Medicins Agency (EMA) and US Food and Drug Administration (FDA). 16–18 The scarce data available on vaccine response under immunosuppression for other vaccines leaves many open questions in relation to SARS-CoV-2 vaccination. 15 19 As shown for several vaccines in patients with chronic inflammatory diseases and transplanted patients, antibody titres postvaccination may be decreased depending on the vaccine and the treatment (although this is not always the case). 15 19 20 In relation to SARS-CoV-2, it is currently unclear how immunosuppression for CID affects vaccine response. There are also additional concerns regarding reactivation of the inflammatory disease by new mRNA vaccines. We therefore provide for the first-time data comparing the immunogenicity and safety of SARS-CoV-2 mRNA vaccines in patients with CID undergoing", "role": "user" }, { "content": "Chronic inflammatory diseases, such as rheumatic diseases, psoriasis or chronic inflammatory bowel diseases are autoimmune diseases in which the immune system targets the body. This leads to misdirected inflammations in the body which flare up repeatedly. Many of these diseases are therefore kept under control with immunosuppressive therapy, i.e. a form of treatment that suppresses the immune response. People undergoing immunosuppressive therapy were excluded from the clinical trials for approval of the new mRNA vaccines against COVID-19. There has therefore been no data available to date on how the vaccination works in this particular group, what the side effects are, and whether they can possibly lead to new flares of inflammation. A Kiel research team from the Cluster of Excellence \"Precision Medicine in Chronic Inflammation\" (PMI) has investigated this and published their results now in the scientific journal Annals of the Rheumatic Diseases. The researchers show for the first time worldwide that the new mRNA vaccines against COVID-19 are effective and well tolerated for people with chronic inflammatory diseases and undergoing immunosuppressive therapy. \"There was a great deal of concern among many patients with chronic inflammatory diseases who are undergoing corresponding immunosuppressive therapy that the vaccination either does not work sufficiently because of the suppressed immune system, or could lead to new flares of inflammation,\" explained coordinating author Bimba Hoyer, professor of rheumatology at Kiel University (CAU) and head of the Comprehensive Center for Inflammation Medicine at the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel. \"We know from influenza vaccinations that they are effective in people undergoing immunosuppressive therapy and are well tolerated. However, for many other vaccines, there is little to no data on efficacy and safety for this particular group of patients. In addition, the new mRNA vaccines utilize a completely new mode of action that has not been used before, so there was an urgent need for research here,\" added Hoyer. The research team examined 25 patients with various chronic inflammatory diseases at different times after vaccination with an mRNA COVID-19 vaccine, and compared the reactions to those of healthy vaccinated patients. All patients were receiving immunosuppressive therapy and had low disease activity or none at all at the time of vaccination. The vaccination itself was not part of the study, as all participants were in priority group 1 and were therefore already vaccinated at the start of the governmental vaccination campaign in Germany. \"Vaccination with one of the mRNA vaccines did not lead to any disease activity in the patients in our study, and we could not detect any flares of inflammation by either clinical or molecular methods,\" said Dr. Ulf Geisen, first author of the study and scientist at the Department of Internal Medicine I, Rheumatology, UKSH, Campus Kiel. In addition, neither different nor more frequent side effects were observed in the group with chronic inflammatory diseases than in the control group or in the clinical trials for approval. In fact, no person in this group developed a fever, whereas this symptom occurred in some of the healthy participants. All people undergoing immunosuppressive therapy also showed a sufficient vaccine response to the vaccines, based on the current state of knowledge. However, in a few patients the levels of antibodies measured, which serve as markers of successful vaccination, were lower than in the control group. \"This may possibly be due to the higher age of these patients. Even in healthy elderly people, the antibody levels are usually lower after vaccination,\" explained Hoyer. \"The lower antibody levels could have an impact on how long the vaccination remains effective. We want to examine this in future studies. It is possible that the group of people undergoing immunosuppressive therapy may need a booster dose of the vaccine earlier than healthy people,\" said Hoyer. The group investigated consisted predominantly of patients with rheumatoid arthritis, but vaccinated people suffering from other rheumatic diseases, the chronic skin disease psoriasis or from chronic inflammatory bowel diseases such as Crohn's disease were also investigated. \"Some of these diseases differ significantly in their symptoms, because they affect very different areas of the body, like the joints, skin or intestines. At the same time, the underlying disease mechanisms are surprisingly similar, as we have demonstrated in numerous studies. Therefore, the drug groups used also overlap in these different diseases,\" explained co-author and cluster spokesperson Professor Stefan Schreiber, who is also director of the Department of Internal Medicine I at the UKSH, Campus Kiel, and director of the Institute of Clinical Molecular Biology (IKMB) at the CAU and UKSH. \"That is why we investigated patients with various diseases in this study, but subgroups receiving the same immunosuppressive therapy. So far, we have not seen any differences in the efficacy or tolerability of vaccinations between the various diseases and treatments studied,\" added Schreiber. ", "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 Introduction In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID. Objective Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls. Methods 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations. Results Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare. Conclusion We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort. arthritis rheumatoid COVID-19 vaccination tumor necrosis factor inhibitors Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data are under embargo by local authorities if not included into the manuscript. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 55 news outlets Blogged by 6 Tweeted by 335 On 3 Facebook pages On 1 videos 270 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 arthritis rheumatoid COVID-19 vaccination tumor necrosis factor inhibitors Key messages What is already known about this subject? Data on the efficacy and safety of mRNA vaccines in patients with immunosuppressive therapies is not available so far. What does this study add? In our cohort, mRNA vaccines against SARS-CoV-2 showed a considerable immunogenicity in patients. Side effects in patients were comparable with controls with systemic side effects being less frequent. No flares of the underlying inflammatory condition could be observed in the context of the vaccination. How might this impact on clinical practice or future developments? The data in this study indicate that mRNA vaccines against SARS-CoV-2 are immunogenic and safe in patients with chronic inflammatory diseases. Introduction The SARS-CoV-2 pandemic continues to threaten the health of patients worldwide. Patients receiving immunosuppressive medication, for example, in the context of transplantation or chronic inflammatory diseases (CID), are considered to be at a higher risk of severe manifestations of COVID-19. Generally, patients receiving immunosuppression are considered to have an increased risk for infections. However, registry data appear to indicate that in the context of SARS-CoV-2 not every immunosuppressed patient has an increased risk of severe COVID-19. Indeed, biological therapies have been identified as decreasing the risk for hospitalisation due to COVID-19 in cohorts of patients with rheumatic diseases, chronic inflammatory bowel diseases and psoriasis. 1–5 The most important factors associated with a higher risk of hospitalisation and death across multiple indications and forms of immunosuppression were found to be older age, high underlying disease activity as well as high glucocorticoid dosages (at dosages equivalent to prednisolone ≥10 mg). 1 6 7 Additionally, B cell depleting drugs, that is, rituximab, might represent a risk factor. 8 Until now, there is insufficient registry data for other drugs commonly used to treat patients with CID in terms of increased risk of severe COVID-19. 1 9 10 However, patients have minimised their risk by sheltering in place early and reducing infection contacts (own unpublished data). Several drugs used in the management of CID have been analysed as potential treatments for COVID-19, especially in attenuating the so-called cytokine storm, some of which have shown considerable benefit. 11 Vaccination against SARS-CoV-2 is now a reality for the most vulnerable and continues to spread to encompass patients receiving immunosuppressive therapies. However, patients with a higher risk being older, taking more steroids and having high underlying disease activity are known to respond less to vaccines. 12–15 Additionally, patients with CID and those taking anticytokine therapies or immunosuppression were excluded from the phase III trials for all vaccines approved by the European Medicins Agency (EMA) and US Food and Drug Administration (FDA). 16–18 The scarce data available on vaccine response under immunosuppression for other vaccines leaves many open questions in relation to SARS-CoV-2 vaccination. 15 19 As shown for several vaccines in patients with chronic inflammatory diseases and transplanted patients, antibody titres postvaccination may be decreased depending on the vaccine and the treatment (although this is not always the case). 15 19 20 In relation to SARS-CoV-2, it is currently unclear how immunosuppression for CID affects vaccine response. There are also additional concerns regarding reactivation of the inflammatory disease by new mRNA vaccines. We therefore provide for the first-time data comparing the immunogenicity and safety of SARS-CoV-2 mRNA vaccines in patients with CID undergoing<|im_end|> <|im_start|>assistant Chronic inflammatory diseases, such as rheumatic diseases, psoriasis or chronic inflammatory bowel diseases are autoimmune diseases in which the immune system targets the body. This leads to misdirected inflammations in the body which flare up repeatedly. Many of these diseases are therefore kept under control with immunosuppressive therapy, i.e. a form of treatment that suppresses the immune response. People undergoing immunosuppressive therapy were excluded from the clinical trials for approval of the new mRNA vaccines against COVID-19. There has therefore been no data available to date on how the vaccination works in this particular group, what the side effects are, and whether they can possibly lead to new flares of inflammation. A Kiel research team from the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) has investigated this and published their results now in the scientific journal Annals of the Rheumatic Diseases. The researchers show for the first time worldwide that the new mRNA vaccines against COVID-19 are effective and well tolerated for people with chronic inflammatory diseases and undergoing immunosuppressive therapy. "There was a great deal of concern among many patients with chronic inflammatory diseases who are undergoing corresponding immunosuppressive therapy that the vaccination either does not work sufficiently because of the suppressed immune system, or could lead to new flares of inflammation," explained coordinating author Bimba Hoyer, professor of rheumatology at Kiel University (CAU) and head of the Comprehensive Center for Inflammation Medicine at the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel. "We know from influenza vaccinations that they are effective in people undergoing immunosuppressive therapy and are well tolerated. However, for many other vaccines, there is little to no data on efficacy and safety for this particular group of patients. In addition, the new mRNA vaccines utilize a completely new mode of action that has not been used before, so there was an urgent need for research here," added Hoyer. The research team examined 25 patients with various chronic inflammatory diseases at different times after vaccination with an mRNA COVID-19 vaccine, and compared the reactions to those of healthy vaccinated patients. All patients were receiving immunosuppressive therapy and had low disease activity or none at all at the time of vaccination. The vaccination itself was not part of the study, as all participants were in priority group 1 and were therefore already vaccinated at the start of the governmental vaccination campaign in Germany. "Vaccination with one of the mRNA vaccines did not lead to any disease activity in the patients in our study, and we could not detect any flares of inflammation by either clinical or molecular methods," said Dr. Ulf Geisen, first author of the study and scientist at the Department of Internal Medicine I, Rheumatology, UKSH, Campus Kiel. In addition, neither different nor more frequent side effects were observed in the group with chronic inflammatory diseases than in the control group or in the clinical trials for approval. In fact, no person in this group developed a fever, whereas this symptom occurred in some of the healthy participants. All people undergoing immunosuppressive therapy also showed a sufficient vaccine response to the vaccines, based on the current state of knowledge. However, in a few patients the levels of antibodies measured, which serve as markers of successful vaccination, were lower than in the control group. "This may possibly be due to the higher age of these patients. Even in healthy elderly people, the antibody levels are usually lower after vaccination," explained Hoyer. "The lower antibody levels could have an impact on how long the vaccination remains effective. We want to examine this in future studies. It is possible that the group of people undergoing immunosuppressive therapy may need a booster dose of the vaccine earlier than healthy people," said Hoyer. The group investigated consisted predominantly of patients with rheumatoid arthritis, but vaccinated people suffering from other rheumatic diseases, the chronic skin disease psoriasis or from chronic inflammatory bowel diseases such as Crohn's disease were also investigated. "Some of these diseases differ significantly in their symptoms, because they affect very different areas of the body, like the joints, skin or intestines. At the same time, the underlying disease mechanisms are surprisingly similar, as we have demonstrated in numerous studies. Therefore, the drug groups used also overlap in these different diseases," explained co-author and cluster spokesperson Professor Stefan Schreiber, who is also director of the Department of Internal Medicine I at the UKSH, Campus Kiel, and director of the Institute of Clinical Molecular Biology (IKMB) at the CAU and UKSH. "That is why we investigated patients with various diseases in this study, but subgroups receiving the same immunosuppressive therapy. So far, we have not seen any differences in the efficacy or tolerability of vaccinations between the various diseases and treatments studied," added Schreiber. <|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 Cellular forces are crucial for many biological processes but current methods to image them have limitations with respect to data analysis, resolution and throughput. Here, we present a robust approach to measure mechanical cell–substrate interactions in diverse biological systems by interferometrically detecting deformations of an elastic micro-cavity. Elastic resonator interference stress microscopy (ERISM) yields stress maps with exceptional precision and large dynamic range (2 nm displacement resolution over a >1 μm range, translating into 1 pN force sensitivity). This enables investigation of minute vertical stresses (<1 Pa) involved in podosome protrusion, protein-specific cell–substrate interaction and amoeboid migration through spatial confinement in real time. ERISM requires no zero-force reference and avoids phototoxic effects, which facilitates force monitoring over multiple days and at high frame rates and eliminates the need to detach cells after measurements. This allows observation of slow processes such as differentiation and further investigation of cells, for example, by immunostaining. Main Cells sense mechanical cues and constantly probe the mechanical properties of their environment (mechanosensing) 1 . Mechanical stimuli at the cellular level play an important role in cell function, for example, migration and differentiation, as well as in tissue-level processes, for example, morphogenesis, tumour growth and immune response 2 , 3 , 4 , 5 , 6 , 7 . Forces exerted by cells are also fundamental for many other physiological processes such as locomotion (for example, during immune response or tumour metastasis), cell growth, wound healing, tissue formation and repair, and extracellular matrix deposition 8 , 9 , 10 , 11 , 12 , 13 , 14 . Mechanical interaction between a cell and its substrate can occur through various mechanisms. During mesenchymal migration, lateral mechanical forces generated by the cytoskeleton are transferred to the extracellular matrix via firm focal adhesion protein complexes 15 . In other cases, forces act perpendicularly to the substrate and there is rapidly increasing interest in the role these vertical forces play, for example, during the extension of special cellular processes such as podosomes 16 or during amoeboid migration in spatial confinement where nonspecific cell–substrate interactions such as friction and pushing are important 17 , 18 , 19 . The forces involved in these diverse mechanical interactions are expected to vary substantially in magnitude, spatial distribution and temporal evolution. Being able to monitor them in a robust and non-disruptive manner is thus critical to advancing our understanding. Early studies obtained semi-quantitative maps of forces by direct observation of wrinkles that cell-generated forces induce in elastomer substrates 20 , 21 . Currently, the most widely used methods for imaging cellular forces (that is, to record stress or force maps) are traction force microscopy (TFM) 22 , 23 , 24 , 25 , 26 , 27 , 28 and the use of micro-fabricated elastic micro-pillar arrays 8 , 29 , 30 . (See ref. 31 for a review on currently available methods.) TFM and micro-pillar arrays are based on tracking displacement of fluorescent particles in hydrogels and bending of individual elastic pillars, respectively. While being powerful, these methods are indirect; in most cases the data analysis requires zero-force reference images, particularly if cell-induced substrate deformations are <200 nm 29 , 32 . For these reference images cells have to be removed from the substrate, rendering them unavailable for further investigations. There have been attempts to obviate the need for disruptive cell removal in TFM by using highly regular meshes or grids to record cell-induced substrate deformations but even under optimized conditions these approaches are limited to detecting relatively large deformations and require rather involved sample preparation 32 , 33 , 34 . Furthermore, fluorescence microscopy is often needed, which can be associated with phototoxicity. Micro-pillar arrays and TFM also have limited sensitivity to vertical forces. For instance, measuring the weak vertically directed protrusive forces exerted by podosomes has necessitated a specialized detection scheme based on atomic force microscopy (AFM) 16 . What is currently missing is a more generally applicable method to image cellular forces that allows cells to be retained on the substrate for subsequent measurements and is capable of resolving weak forces with reasonable throughput. Here, we address this need by introducing elastic resonator interference stress microscopy (ERISM), an approach for direct, robust and non-destructive imaging of forces associated with various types of mechanical cell–substrate interaction. While most existing methods use localization microscopy or direct imaging of surface deformations, ERISM detects cell-induced substrate deformations interferometrically by using an elastic optical micro-resonator and thus provides unprecedented sensitivity. We are able to resolve not only forces exerted by cells that form firm focal adhesion contacts to the substrate but can also detect protein-specific cell–substrate interaction and quantify the much weaker vertical forces (down to piconewtons) associated with amoeboid-type cell migration through confined environments and with the protrusion of podosomes. ERISM requires no zero-force reference image, which eliminates the need to detach non-migrating cells after a measurement and enables continuous, long-term measurements of multiple cells on one substrate as well as further investigation of the cells, for example, by immunostaining. Being a wide-field imaging method, ERISM determines the local deformation at each point of the image simultaneously and requires only low light intensities, thus facilitating observation of multiple cells at once without inducing photo-damage to the cells. RESULTS Concept and validation of ERISM Cells were grown on a protein-coated elastic optical micro-cavity consisting of a layer of an ultra-soft siloxane-based elastomer (stiffness 1.3 kPa, thickness (8.0 ± 0.5) μm; unless stated otherwise) sandwiched between two thin and semi-transparent gold layers ( Fig. 1a, b ; see Supplementary Fig. 1a–d for details on the gold/elastomer interface). Forces applied by cells were mapped with the microscope set-up schematically shown in Fig. 1c . Cells of interest were identified by conventional phase-contrast or fluorescence microscopy ( Fig. 1d ). The reflection of the micro-cavity was then imaged under illumination with monochromatic light of a certain wavelength ( Fig. 1e and Supplementary Fig. 1e ). When a cell locally deformed the micro-cavity, a fringe pattern was formed. (At", "role": "user" }, { "content": "Scientists at the University of St Andrews have developed an advanced new microscopy technique that could revolutionise our understanding of how immune and cancer cells find their way through the body. Elastic Resonator Interference Stress Microscopy (ERISM) images the extremely weak mechanical forces that living cells apply when they move, divide, and probe their environment. As described in Nature Cell Biology today (Monday 19 June 2017), ERISM resolves the tiny forces applied by feet-like structures on the surface of human immune cells. These feet allow immune cells to find the fastest route to a site of infection in the body. Similar structures may be responsible for the invasion of cancer cells into healthy tissue and it is planned to use ERISM in the future to learn more about the mechanisms involved in cancer spreading. The physical effect giving soap bubbles their rainbow-like appearance is a phenomenon called thin-film interference. It is based on interaction of light reflected on either side of a soap film. The different colours that white light consists of interact with different local thicknesses of the thin film and generate the familiar rainbow patterns. Effectively the colours are an image of the film thickness at each point on the surface of the soap bubble. A similar effect can be used to determine the forces exerted by cells. Professor Malte Gather of the School of Physics and Astronomy at St Andrews explained: \"Our microscope records very high colour resolution images of the light reflected by a thin and soft probe. From these images, we then create a highly accurate map of the thickness of the probe – with a mind-blowing precision of one-billionth part of a metre. \"If cells apply forces to the probe, the probe thickness changes locally, thus providing information about the position and magnitude of the applied forces. \"Although researchers have recorded forces applied by cells before, our interference-based approach gives an unprecedented resolution and in addition provides an internal reference that makes our technique extremely robust and relatively easy to use.\" This robustness means that measuring cell forces could soon become a tool in clinical diagnostics. For example, doctors may find that the ERISM method can complement existing techniques to assess the invasiveness of cancer. Work to scale up ERISM for use in the clinic is now underway. ", "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 Cellular forces are crucial for many biological processes but current methods to image them have limitations with respect to data analysis, resolution and throughput. Here, we present a robust approach to measure mechanical cell–substrate interactions in diverse biological systems by interferometrically detecting deformations of an elastic micro-cavity. Elastic resonator interference stress microscopy (ERISM) yields stress maps with exceptional precision and large dynamic range (2 nm displacement resolution over a >1 μm range, translating into 1 pN force sensitivity). This enables investigation of minute vertical stresses (<1 Pa) involved in podosome protrusion, protein-specific cell–substrate interaction and amoeboid migration through spatial confinement in real time. ERISM requires no zero-force reference and avoids phototoxic effects, which facilitates force monitoring over multiple days and at high frame rates and eliminates the need to detach cells after measurements. This allows observation of slow processes such as differentiation and further investigation of cells, for example, by immunostaining. Main Cells sense mechanical cues and constantly probe the mechanical properties of their environment (mechanosensing) 1 . Mechanical stimuli at the cellular level play an important role in cell function, for example, migration and differentiation, as well as in tissue-level processes, for example, morphogenesis, tumour growth and immune response 2 , 3 , 4 , 5 , 6 , 7 . Forces exerted by cells are also fundamental for many other physiological processes such as locomotion (for example, during immune response or tumour metastasis), cell growth, wound healing, tissue formation and repair, and extracellular matrix deposition 8 , 9 , 10 , 11 , 12 , 13 , 14 . Mechanical interaction between a cell and its substrate can occur through various mechanisms. During mesenchymal migration, lateral mechanical forces generated by the cytoskeleton are transferred to the extracellular matrix via firm focal adhesion protein complexes 15 . In other cases, forces act perpendicularly to the substrate and there is rapidly increasing interest in the role these vertical forces play, for example, during the extension of special cellular processes such as podosomes 16 or during amoeboid migration in spatial confinement where nonspecific cell–substrate interactions such as friction and pushing are important 17 , 18 , 19 . The forces involved in these diverse mechanical interactions are expected to vary substantially in magnitude, spatial distribution and temporal evolution. Being able to monitor them in a robust and non-disruptive manner is thus critical to advancing our understanding. Early studies obtained semi-quantitative maps of forces by direct observation of wrinkles that cell-generated forces induce in elastomer substrates 20 , 21 . Currently, the most widely used methods for imaging cellular forces (that is, to record stress or force maps) are traction force microscopy (TFM) 22 , 23 , 24 , 25 , 26 , 27 , 28 and the use of micro-fabricated elastic micro-pillar arrays 8 , 29 , 30 . (See ref. 31 for a review on currently available methods.) TFM and micro-pillar arrays are based on tracking displacement of fluorescent particles in hydrogels and bending of individual elastic pillars, respectively. While being powerful, these methods are indirect; in most cases the data analysis requires zero-force reference images, particularly if cell-induced substrate deformations are <200 nm 29 , 32 . For these reference images cells have to be removed from the substrate, rendering them unavailable for further investigations. There have been attempts to obviate the need for disruptive cell removal in TFM by using highly regular meshes or grids to record cell-induced substrate deformations but even under optimized conditions these approaches are limited to detecting relatively large deformations and require rather involved sample preparation 32 , 33 , 34 . Furthermore, fluorescence microscopy is often needed, which can be associated with phototoxicity. Micro-pillar arrays and TFM also have limited sensitivity to vertical forces. For instance, measuring the weak vertically directed protrusive forces exerted by podosomes has necessitated a specialized detection scheme based on atomic force microscopy (AFM) 16 . What is currently missing is a more generally applicable method to image cellular forces that allows cells to be retained on the substrate for subsequent measurements and is capable of resolving weak forces with reasonable throughput. Here, we address this need by introducing elastic resonator interference stress microscopy (ERISM), an approach for direct, robust and non-destructive imaging of forces associated with various types of mechanical cell–substrate interaction. While most existing methods use localization microscopy or direct imaging of surface deformations, ERISM detects cell-induced substrate deformations interferometrically by using an elastic optical micro-resonator and thus provides unprecedented sensitivity. We are able to resolve not only forces exerted by cells that form firm focal adhesion contacts to the substrate but can also detect protein-specific cell–substrate interaction and quantify the much weaker vertical forces (down to piconewtons) associated with amoeboid-type cell migration through confined environments and with the protrusion of podosomes. ERISM requires no zero-force reference image, which eliminates the need to detach non-migrating cells after a measurement and enables continuous, long-term measurements of multiple cells on one substrate as well as further investigation of the cells, for example, by immunostaining. Being a wide-field imaging method, ERISM determines the local deformation at each point of the image simultaneously and requires only low light intensities, thus facilitating observation of multiple cells at once without inducing photo-damage to the cells. RESULTS Concept and validation of ERISM Cells were grown on a protein-coated elastic optical micro-cavity consisting of a layer of an ultra-soft siloxane-based elastomer (stiffness 1.3 kPa, thickness (8.0 ± 0.5) μm; unless stated otherwise) sandwiched between two thin and semi-transparent gold layers ( Fig. 1a, b ; see Supplementary Fig. 1a–d for details on the gold/elastomer interface). Forces applied by cells were mapped with the microscope set-up schematically shown in Fig. 1c . Cells of interest were identified by conventional phase-contrast or fluorescence microscopy ( Fig. 1d ). The reflection of the micro-cavity was then imaged under illumination with monochromatic light of a certain wavelength ( Fig. 1e and Supplementary Fig. 1e ). When a cell locally deformed the micro-cavity, a fringe pattern was formed. (At<|im_end|> <|im_start|>assistant Scientists at the University of St Andrews have developed an advanced new microscopy technique that could revolutionise our understanding of how immune and cancer cells find their way through the body. Elastic Resonator Interference Stress Microscopy (ERISM) images the extremely weak mechanical forces that living cells apply when they move, divide, and probe their environment. As described in Nature Cell Biology today (Monday 19 June 2017), ERISM resolves the tiny forces applied by feet-like structures on the surface of human immune cells. These feet allow immune cells to find the fastest route to a site of infection in the body. Similar structures may be responsible for the invasion of cancer cells into healthy tissue and it is planned to use ERISM in the future to learn more about the mechanisms involved in cancer spreading. The physical effect giving soap bubbles their rainbow-like appearance is a phenomenon called thin-film interference. It is based on interaction of light reflected on either side of a soap film. The different colours that white light consists of interact with different local thicknesses of the thin film and generate the familiar rainbow patterns. Effectively the colours are an image of the film thickness at each point on the surface of the soap bubble. A similar effect can be used to determine the forces exerted by cells. Professor Malte Gather of the School of Physics and Astronomy at St Andrews explained: "Our microscope records very high colour resolution images of the light reflected by a thin and soft probe. From these images, we then create a highly accurate map of the thickness of the probe – with a mind-blowing precision of one-billionth part of a metre. "If cells apply forces to the probe, the probe thickness changes locally, thus providing information about the position and magnitude of the applied forces. "Although researchers have recorded forces applied by cells before, our interference-based approach gives an unprecedented resolution and in addition provides an internal reference that makes our technique extremely robust and relatively easy to use." This robustness means that measuring cell forces could soon become a tool in clinical diagnostics. For example, doctors may find that the ERISM method can complement existing techniques to assess the invasiveness of cancer. Work to scale up ERISM for use in the clinic is now underway. <|im_end|>

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1,815

[ { "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 Recently developed DNA base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks 1 , 2 , 3 , but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA 4 , 5 , 6 , 7 , 8 , it is now clear that the deaminases that are integral to commonly used DNA base editors often bind to RNA 9 , 10 , 11 , 12 , 13 . For example, the cytosine deaminase APOBEC1—which is used in cytosine base editors (CBEs)—targets both DNA and RNA 12 , and the adenine deaminase TadA—which is used in adenine base editors (ABEs)—induces site-specific inosine formation on RNA 9 , 11 . However, any potential RNA mutations caused by DNA base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA base editors is of great concern 14 , 15 , 16 . Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine base editor BE3 and the adenine base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases. Main To evaluate the off-target effects of base editors at the RNA level, we transfected one type of CBE (BE3; APOBEC1–nCas9–UGI) or ABE (ABE7.10; TadA–TadA*–nCas9), together with GFP and with or without a single guide RNA (sgRNA) into cultured HEK293T cells (Fig. 1a , Extended Data Fig. 1 ). First, we validated the high on-target efficiency of DNA editing by both BE3 and ABE7.10 in these HEK293T cells using Sanger sequencing (Fig. 1b–e ). We next performed RNA sequencing (RNA-seq) at an average depth of 125× on these samples (Supplementary Table 1 ). RNA SNVs were called from the RNA-seq data in each replicate separately, and any SNV identified in a wild-type sample was filtered out (Fig. 1a ). Fig. 1: Base editors induce numerous off-target RNA SNVs. a , Scheme of the experimental design. b , c , DNA on-target efficiency of BE3–site 3 and BE3–RNF2. Note that APOBEC1 is the cytosine deaminase of BE3. d , e , DNA on-target efficiency of ABE7.10–site 1 and ABE7.10–site 2. Note that TadA–TadA* (wild-type TadA–evolved TadA heterodimer) is the adenine deaminase of ABE7.10, and evolved TadA is indicated by TadA*. f , g , Comparison of the off-target RNA SNVs for BE3 and ABE7.10 groups. h , Representative distributions of off-target RNA SNVs on human chromosomes for GFP, BE3 and ABE7.10. Chromosomes are indicated with different colours. Right, number of RNA SNVs for each chromosome. GFP group serves as control for all comparisons. WT, wild-type; GFP, GFP only; APOBEC1, APOBEC1 only; BE3, BE3 only; BE3–site 3, BE3 with sgRNA targeting site 3; BE3–RNF2, BE3 with sgRNA targeting RNF2; TadA–TadA*, TadA–TadA* only; ABE7.10, ABE7.10 only; ABE7.10–site 1, ABE7.10 with sgRNA targeting site 1; ABE7.10–site 2, ABE7.10 with sgRNA targeting site 2. All values are presented as mean ± s.e.m. Number above the bar indicates the number of biologically independent samples. * P < 0.05, ** P < 0.01, *** P < 0.001, two-sided unpaired t -test. Exact P values are provided in Supplementary Table 3 . Full size image We found 742 ± 113 (mean ± s.e.m.) RNA SNVs in the GFP-alone control cells (Fig. 1f–h , Supplementary Table 2 ), but observed notably higher numbers of RNA SNVs in cells from the following sample groups: APOBEC1, BE3 without sgRNA, and BE3 with either site 3 (see Methods) or ring finger protein 2 (RNF2) sgRNA (5–40 times that in GFP-only cells; Fig. 1f, h , Extended Data Fig. 2 , Supplementary Tables 2 , 3 ). Similarly, large numbers of RNA SNVs (5–10 times those in GFP-only cells) were also found in cells expressing only TadA–TadA*, ABE7.10 without sgRNA, and ABE7.10 with either site 1 or site 2 sgRNA (Fig. 1g, h , Extended Data Fig. 2 , Supplementary Tables 2 , 3 ). Notably, transfection of APOBEC1 or TadA–TadA* induced the greatest numbers of RNA SNVs compared to other transfected groups, which implies that increased SNVs in CBE- or ABE-treated cells are likely to be caused by overexpression of the deaminase APOBEC1 or TadA (Fig. 1f, g , Extended Data Fig. 2 , Supplementary Tables 2 , 3 ). Moreover, the number of off-target RNA SNVs was increased when higher levels of CBEs or ABEs were expressed (Extended Data Fig. 2 ). Notably, nearly 100% of the RNA SNVs identified in BE3-treated cells were mutations from G to A or C to U; this level is significantly higher than that in the GFP-alone control cells ( P = 2.03 × 10 −10 for BE3, P = 0.017 for BE3–site 3 and P = 5.90 × 10 −10 for BE3–RNF2) (Fig. 2a, c , Extended Data Fig. 3 ). This mutation bias was the same as that of APOBEC1 itself 2 , which indicates that these mutations were not spontaneous but rather were induced by BE3 or APOBEC1. Similarly, 95% of the ABE7.10-induced mutations were A to G or U to C, consistent with the action of TadA (Fig. 2b, c , Extended Data Fig. 3 ). We noted that the GFP group also exhibited bias towards A to G and U to C mutations (Fig. 2c ), probably owing to innate mutation preferences 17 , 18 , 19 . We observed 27.7 ± 3.6% (mean ± s.e.m.) or 51.0 ± 3.3% (mean ± s.e.m.) overlap between any", "role": "user" }, { "content": "In a study published in Nature on June 10, researchers from Dr. Yang Hui's Lab at the Institute of Neuroscience of the Chinese Academy of Sciences (CAS), and collaborators from the CAS-MPG Partner Institute for Computational Biology of CAS and Sichuan University demonstrated that DNA base editors generated tens of thousands of off-target RNA single nucleotide variants (SNVs) and these off-target SNVs could be eliminated by introducing point mutations to the deaminases. This study revealed a previously overlooked aspect of the risk of DNA base editors and further provided a solution to the problem by engineering deaminases. DNA base-editing methods have enabled direct point mutation correction in genomic DNA without generating any double-strand breaks (DSBs), but the potential off-target effects have limited the application of these methods. Adeno-associated viruses (AAV) are the most common delivery system for DNA editing gene therapies. Since these viruses can sustain long-term gene expression in vivo, the extent of potential RNA off-target effects induced by DNA base editors is of great concern for their clinical application. Several previous studies have evaluated off-target mutations in genomic DNA by DNA base editors. Meanwhile, the deaminases integral to commonly used DNA base editors often exhibit RNA binding activities. For example, the cytosine deaminase APOBEC1 used in cytosine base editors (CBEs) was found to target both DNA and RNA, and the adenine deaminase TadA used in adenine base editors (ABEs) was found to induce site-specific inosine formation on RNA. However, any potential RNA mutations caused by DNA base editors had not been evaluated. In order to evaluate the off-target effect of DNA base editors at the level of RNA, the researchers counted the off-target RNA SNVs in each replicate of CBE- or ABE-treated cells, and then explored the possibility of eliminating the off-target RNA SNVs by engineering deaminases of DNA base editors. They transfected one type of CBE, BE3 (APOBEC1-nCas9-UGI), or ABE, ABE7.10 (TadA-TadA*-nCas9), together with GFP and with or without single-guide RNA (sgRNA), into HEK293T-cultured cells. After validating the high on-target efficiency of DNA editing by both BE3 and ABE7.10 in these HEK293T cells, they performed RNA-seq at an average depth of 125X on these samples and quantitively evaluated the RNA SNVs in each replicate. The on-target editing efficiency was evaluated in each replicate of the CBE- or ABE-treated cells to guarantee efficient editing. Then the number of off-target RNA SNVs in CBE- and ABE-treated groups was compared with the GFP-only control group. They found strikingly higher numbers of RNA SNVs in DNA base editor-treated cells. Furthermore, the researchers found that the mutation bias in BE3- or ABE7.10-treated cells was the same as that of APOBEC1 or TadA, respectively, indicating the off-target effects were caused by the overexpression of DNA base editors. They also identified CBE- and ABE-specific motifs and genetic regions of these off-target RNA SNVs. To eliminate the RNA off-target activity of base editors, they examined the effect of introducing point mutations on APOBEC1 or TadA. Three high-fidelity variants, BE3W90Y+R126E, BE3 (hA3AR128A) and BE3 (hA3AY130F), reduced RNA off-target SNVs to the base level. Similarly, an ABE variant ABE7.10F148A also showed complete elimination of off-target effects. This study obtained both high-fidelity variants for both CBEs and ABEs by introducing point mutations to the deaminases and provided a proposed method using rational engineering to increase the specificity of base editors. ", "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 Recently developed DNA base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks 1 , 2 , 3 , but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA 4 , 5 , 6 , 7 , 8 , it is now clear that the deaminases that are integral to commonly used DNA base editors often bind to RNA 9 , 10 , 11 , 12 , 13 . For example, the cytosine deaminase APOBEC1—which is used in cytosine base editors (CBEs)—targets both DNA and RNA 12 , and the adenine deaminase TadA—which is used in adenine base editors (ABEs)—induces site-specific inosine formation on RNA 9 , 11 . However, any potential RNA mutations caused by DNA base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA base editors is of great concern 14 , 15 , 16 . Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine base editor BE3 and the adenine base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases. Main To evaluate the off-target effects of base editors at the RNA level, we transfected one type of CBE (BE3; APOBEC1–nCas9–UGI) or ABE (ABE7.10; TadA–TadA*–nCas9), together with GFP and with or without a single guide RNA (sgRNA) into cultured HEK293T cells (Fig. 1a , Extended Data Fig. 1 ). First, we validated the high on-target efficiency of DNA editing by both BE3 and ABE7.10 in these HEK293T cells using Sanger sequencing (Fig. 1b–e ). We next performed RNA sequencing (RNA-seq) at an average depth of 125× on these samples (Supplementary Table 1 ). RNA SNVs were called from the RNA-seq data in each replicate separately, and any SNV identified in a wild-type sample was filtered out (Fig. 1a ). Fig. 1: Base editors induce numerous off-target RNA SNVs. a , Scheme of the experimental design. b , c , DNA on-target efficiency of BE3–site 3 and BE3–RNF2. Note that APOBEC1 is the cytosine deaminase of BE3. d , e , DNA on-target efficiency of ABE7.10–site 1 and ABE7.10–site 2. Note that TadA–TadA* (wild-type TadA–evolved TadA heterodimer) is the adenine deaminase of ABE7.10, and evolved TadA is indicated by TadA*. f , g , Comparison of the off-target RNA SNVs for BE3 and ABE7.10 groups. h , Representative distributions of off-target RNA SNVs on human chromosomes for GFP, BE3 and ABE7.10. Chromosomes are indicated with different colours. Right, number of RNA SNVs for each chromosome. GFP group serves as control for all comparisons. WT, wild-type; GFP, GFP only; APOBEC1, APOBEC1 only; BE3, BE3 only; BE3–site 3, BE3 with sgRNA targeting site 3; BE3–RNF2, BE3 with sgRNA targeting RNF2; TadA–TadA*, TadA–TadA* only; ABE7.10, ABE7.10 only; ABE7.10–site 1, ABE7.10 with sgRNA targeting site 1; ABE7.10–site 2, ABE7.10 with sgRNA targeting site 2. All values are presented as mean ± s.e.m. Number above the bar indicates the number of biologically independent samples. * P < 0.05, ** P < 0.01, *** P < 0.001, two-sided unpaired t -test. Exact P values are provided in Supplementary Table 3 . Full size image We found 742 ± 113 (mean ± s.e.m.) RNA SNVs in the GFP-alone control cells (Fig. 1f–h , Supplementary Table 2 ), but observed notably higher numbers of RNA SNVs in cells from the following sample groups: APOBEC1, BE3 without sgRNA, and BE3 with either site 3 (see Methods) or ring finger protein 2 (RNF2) sgRNA (5–40 times that in GFP-only cells; Fig. 1f, h , Extended Data Fig. 2 , Supplementary Tables 2 , 3 ). Similarly, large numbers of RNA SNVs (5–10 times those in GFP-only cells) were also found in cells expressing only TadA–TadA*, ABE7.10 without sgRNA, and ABE7.10 with either site 1 or site 2 sgRNA (Fig. 1g, h , Extended Data Fig. 2 , Supplementary Tables 2 , 3 ). Notably, transfection of APOBEC1 or TadA–TadA* induced the greatest numbers of RNA SNVs compared to other transfected groups, which implies that increased SNVs in CBE- or ABE-treated cells are likely to be caused by overexpression of the deaminase APOBEC1 or TadA (Fig. 1f, g , Extended Data Fig. 2 , Supplementary Tables 2 , 3 ). Moreover, the number of off-target RNA SNVs was increased when higher levels of CBEs or ABEs were expressed (Extended Data Fig. 2 ). Notably, nearly 100% of the RNA SNVs identified in BE3-treated cells were mutations from G to A or C to U; this level is significantly higher than that in the GFP-alone control cells ( P = 2.03 × 10 −10 for BE3, P = 0.017 for BE3–site 3 and P = 5.90 × 10 −10 for BE3–RNF2) (Fig. 2a, c , Extended Data Fig. 3 ). This mutation bias was the same as that of APOBEC1 itself 2 , which indicates that these mutations were not spontaneous but rather were induced by BE3 or APOBEC1. Similarly, 95% of the ABE7.10-induced mutations were A to G or U to C, consistent with the action of TadA (Fig. 2b, c , Extended Data Fig. 3 ). We noted that the GFP group also exhibited bias towards A to G and U to C mutations (Fig. 2c ), probably owing to innate mutation preferences 17 , 18 , 19 . We observed 27.7 ± 3.6% (mean ± s.e.m.) or 51.0 ± 3.3% (mean ± s.e.m.) overlap between any<|im_end|> <|im_start|>assistant In a study published in Nature on June 10, researchers from Dr. Yang Hui's Lab at the Institute of Neuroscience of the Chinese Academy of Sciences (CAS), and collaborators from the CAS-MPG Partner Institute for Computational Biology of CAS and Sichuan University demonstrated that DNA base editors generated tens of thousands of off-target RNA single nucleotide variants (SNVs) and these off-target SNVs could be eliminated by introducing point mutations to the deaminases. This study revealed a previously overlooked aspect of the risk of DNA base editors and further provided a solution to the problem by engineering deaminases. DNA base-editing methods have enabled direct point mutation correction in genomic DNA without generating any double-strand breaks (DSBs), but the potential off-target effects have limited the application of these methods. Adeno-associated viruses (AAV) are the most common delivery system for DNA editing gene therapies. Since these viruses can sustain long-term gene expression in vivo, the extent of potential RNA off-target effects induced by DNA base editors is of great concern for their clinical application. Several previous studies have evaluated off-target mutations in genomic DNA by DNA base editors. Meanwhile, the deaminases integral to commonly used DNA base editors often exhibit RNA binding activities. For example, the cytosine deaminase APOBEC1 used in cytosine base editors (CBEs) was found to target both DNA and RNA, and the adenine deaminase TadA used in adenine base editors (ABEs) was found to induce site-specific inosine formation on RNA. However, any potential RNA mutations caused by DNA base editors had not been evaluated. In order to evaluate the off-target effect of DNA base editors at the level of RNA, the researchers counted the off-target RNA SNVs in each replicate of CBE- or ABE-treated cells, and then explored the possibility of eliminating the off-target RNA SNVs by engineering deaminases of DNA base editors. They transfected one type of CBE, BE3 (APOBEC1-nCas9-UGI), or ABE, ABE7.10 (TadA-TadA*-nCas9), together with GFP and with or without single-guide RNA (sgRNA), into HEK293T-cultured cells. After validating the high on-target efficiency of DNA editing by both BE3 and ABE7.10 in these HEK293T cells, they performed RNA-seq at an average depth of 125X on these samples and quantitively evaluated the RNA SNVs in each replicate. The on-target editing efficiency was evaluated in each replicate of the CBE- or ABE-treated cells to guarantee efficient editing. Then the number of off-target RNA SNVs in CBE- and ABE-treated groups was compared with the GFP-only control group. They found strikingly higher numbers of RNA SNVs in DNA base editor-treated cells. Furthermore, the researchers found that the mutation bias in BE3- or ABE7.10-treated cells was the same as that of APOBEC1 or TadA, respectively, indicating the off-target effects were caused by the overexpression of DNA base editors. They also identified CBE- and ABE-specific motifs and genetic regions of these off-target RNA SNVs. To eliminate the RNA off-target activity of base editors, they examined the effect of introducing point mutations on APOBEC1 or TadA. Three high-fidelity variants, BE3W90Y+R126E, BE3 (hA3AR128A) and BE3 (hA3AY130F), reduced RNA off-target SNVs to the base level. Similarly, an ABE variant ABE7.10F148A also showed complete elimination of off-target effects. This study obtained both high-fidelity variants for both CBEs and ABEs by introducing point mutations to the deaminases and provided a proposed method using rational engineering to increase the specificity of base editors. <|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 chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture. Main Natural products have provided critical starting points for the development of a majority of the antibacterial drugs listed as essential medicines by the World Health Organization. During the period from about 1940 to 1960, sometimes described as the golden age of antibiotics research, academic and industrial laboratories identified the natural products that went on to define many of the major classes of modern antibiotics 1 . Few if any natural products prove to be optimal for safety, efficacy or oral use in humans, however, for these were probably not evolutionary pressures for the microbes in which they developed. For six decades a primary tool by which new antibiotics have been discovered and manufactured is semisynthesis, or the chemical modification of natural products derived from fermentation. Semisynthesis is inherently limited because it is challenging to modify structurally complex natural products selectively, and typically few positions of any given scaffold can be modified effectively 2 , 3 . Macrolide antibiotics (macrocyclic lactones with one or more pendant glycosidic residues), which have proven to be safe and effective for use in treating human infectious diseases such as community-acquired bacterial pneumonia, gonorrhoea and others, provide a compelling case in point. Since the discovery of erythromycin from a Philippine soil sample in 1949 4 , in spite of extraordinary efforts leading to fully synthetic 5 , 6 , 7 , 8 and modified biosynthetic routes 9 , 10 , 11 , 12 to macrolide antibiotics, all members of this class approved or in clinical development for use in humans have been manufactured by chemically modifying erythromycin (erythromycin itself is unstable in the stomach, and rearranges to form a product with gastrointestinal side-effects) 13 . Thus, azithromycin is prepared from erythromycin in four steps 14 , clarithromycin requires six steps 15 , and the advanced clinical candidate solithromycin is currently produced from erythromycin by a 16-step linear sequence ( Fig. 1 ) 16 , 17 . New macrolides are badly needed, for resistance to approved macrolide antibiotics such as clarithromycin and azithromycin is now widespread in both hospitals and the community 18 , 19 , 20 . Here we present a practical, fully synthetic platform for the preparation of macrolide antibiotics, providing both a discovery engine for structurally novel antibiotic candidates that would be difficult or impossible to obtain from erythromycin, as well as a basis for their eventual manufacture. Using simple building blocks and a highly convergent assembly process, we have prepared more than 300 structurally diverse macrolide antibiotic candidates, as well as the approved drug telithromycin and the clinical candidate solithromycin. We have identified molecules with diverse macrocyclic scaffolds that exhibit potent activities against bacterial strains resistant to erythromycin, azithromycin and other current antibiotics of different classes. Figure 1: Summary of macrolide antibiotic development by semisynthesis. To date, all macrolide antibiotics are produced by chemical modification (semisynthesis) of erythromycin, a natural product produced on the ton scale by fermentation. Depicted are erythromycin and the approved semisynthetic macrolide antibiotics clarithromycin, azithromycin and telithromycin along with the dates of their FDA approval and the number of steps for their synthesis from erythromycin. The previous ketolide clinical candidate cethromycin and the current clinical candidate solithromycin are also depicted. It is evident that increasingly lengthy sequences are being employed in macrolide discovery efforts. PowerPoint slide Full size image Synthesis of 14-membered azaketolides To illustrate our approach to the synthesis of macrolide antibiotics, we begin by detailing a route to new and highly active hybrid antibiotics, 14-membered azaketolides ( Fig. 2 ), and then show how the approach can be easily expanded to subsume many other active macrolide scaffolds, with broad latitude for substitutional variation. Ketolides replace the C3-cladinose carbohydrate residue of erythromycin with a carbonyl group, a chemical modification that allows them to evade certain inducible forms of macrolide resistance 21 , 22 , whereas the azalide azithromycin incorporates a nitrogen atom within an expanded (15-membered) macrolactone ring, features that have been proposed to impart favourable pharmacological properties, including increased efficacy against certain Gram-negative pathogens 23 , 24 . The hybrid ‘azaketolides’, or macrolides that contain both a C3 carbonyl group and a nitrogen atom within the macrolactone ring, have been little explored; one such compound has been reported and was found to be essentially inactive 25 . We were particularly interested in 14-membered azaketolides that would arise from formal replacement of the carbonyl group at position C9 of ketolides with an amino group, a transformation that would not be feasible by semisynthesis. Figure 2: A convergent, fully synthetic route to the 14-membered azaketolide 25. a , Graphical representation of the convergent synthesis of azaketolide 25 from eight variable building blocks (represented by coloured spheres). Downward, ‘Y’-shaped arrows signify convergent coupling reactions. b , Synthesis of azaketolide 25 , reagents and conditions (subscripts L and R indicate left and right halves, respectively) as follows: (a L ) LiHMDS, LiCl, 98%; (b L ) Et i Pr 2 N, COCl 2 ; (c L ) i PrMgCl, CH 3 Li, 76% over 2 steps, 92% of", "role": "user" }, { "content": "(Phys.org)—A team of researchers at Harvard University has found a way to create new macrolides—a class of drugs used to fight bacterial infections. In their paper published in the journal Nature, the team describes their approach and why they believe it might be useful in keeping ahead of bacterial resistance until something more revolutionary comes along. Ming Yan and Phil Baran with The Scripps Research Institute, offer a News & Views article outlining the work done by the team and why they believe the new technique may help medical researchers keep up with bacterial evolution. For many years, the go-to drugs of choice for treating a variety of bacterial infections has been macrolides, which are all drugs that have been created by altering a natural form of erythromycin—but in recent years, bacteria have become resistant to many of the drugs that have been developed. New ones have been slow in coming, due to the difficulty in finding new ways to alter the original bacteria which means R&D costs have been rising. This development has led to near-panic in the health community as it appears that if something does not change soon, the arsenal of weapons used to fight many infections will be vastly depleted. In this new effort, the researchers report that they have found a new way to create new variations of macrolides that does not require using native erythromycin as a source—instead, they create them from scratch. This development means that many more variants can be created at far lower cost, helping to keep ahead of bacterial resistance. To create new macrolides, the team reports, they used a method that allows for modular building, which they liken to the way cell phones are made—they start by building small-chemical blocks and then \"weld\" them together using a process that requires very few steps. They report also that the technique can be applied on a multigram scale, which means enough can be created at a time for use in experiments geared towards testing the results in killing bacteria. To date, the team has produced 300 macrolides using their technique, which include some that have had already been created using the original method. They report that some have already been tested to see how well they fight bacteria and have met with some initial success. They acknowledge that a lot more work needs to be done to find out if drugs produced using the method are truly effective in fighting bacterial infections and if so, if they will prove to be safe for use 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 The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture. Main Natural products have provided critical starting points for the development of a majority of the antibacterial drugs listed as essential medicines by the World Health Organization. During the period from about 1940 to 1960, sometimes described as the golden age of antibiotics research, academic and industrial laboratories identified the natural products that went on to define many of the major classes of modern antibiotics 1 . Few if any natural products prove to be optimal for safety, efficacy or oral use in humans, however, for these were probably not evolutionary pressures for the microbes in which they developed. For six decades a primary tool by which new antibiotics have been discovered and manufactured is semisynthesis, or the chemical modification of natural products derived from fermentation. Semisynthesis is inherently limited because it is challenging to modify structurally complex natural products selectively, and typically few positions of any given scaffold can be modified effectively 2 , 3 . Macrolide antibiotics (macrocyclic lactones with one or more pendant glycosidic residues), which have proven to be safe and effective for use in treating human infectious diseases such as community-acquired bacterial pneumonia, gonorrhoea and others, provide a compelling case in point. Since the discovery of erythromycin from a Philippine soil sample in 1949 4 , in spite of extraordinary efforts leading to fully synthetic 5 , 6 , 7 , 8 and modified biosynthetic routes 9 , 10 , 11 , 12 to macrolide antibiotics, all members of this class approved or in clinical development for use in humans have been manufactured by chemically modifying erythromycin (erythromycin itself is unstable in the stomach, and rearranges to form a product with gastrointestinal side-effects) 13 . Thus, azithromycin is prepared from erythromycin in four steps 14 , clarithromycin requires six steps 15 , and the advanced clinical candidate solithromycin is currently produced from erythromycin by a 16-step linear sequence ( Fig. 1 ) 16 , 17 . New macrolides are badly needed, for resistance to approved macrolide antibiotics such as clarithromycin and azithromycin is now widespread in both hospitals and the community 18 , 19 , 20 . Here we present a practical, fully synthetic platform for the preparation of macrolide antibiotics, providing both a discovery engine for structurally novel antibiotic candidates that would be difficult or impossible to obtain from erythromycin, as well as a basis for their eventual manufacture. Using simple building blocks and a highly convergent assembly process, we have prepared more than 300 structurally diverse macrolide antibiotic candidates, as well as the approved drug telithromycin and the clinical candidate solithromycin. We have identified molecules with diverse macrocyclic scaffolds that exhibit potent activities against bacterial strains resistant to erythromycin, azithromycin and other current antibiotics of different classes. Figure 1: Summary of macrolide antibiotic development by semisynthesis. To date, all macrolide antibiotics are produced by chemical modification (semisynthesis) of erythromycin, a natural product produced on the ton scale by fermentation. Depicted are erythromycin and the approved semisynthetic macrolide antibiotics clarithromycin, azithromycin and telithromycin along with the dates of their FDA approval and the number of steps for their synthesis from erythromycin. The previous ketolide clinical candidate cethromycin and the current clinical candidate solithromycin are also depicted. It is evident that increasingly lengthy sequences are being employed in macrolide discovery efforts. PowerPoint slide Full size image Synthesis of 14-membered azaketolides To illustrate our approach to the synthesis of macrolide antibiotics, we begin by detailing a route to new and highly active hybrid antibiotics, 14-membered azaketolides ( Fig. 2 ), and then show how the approach can be easily expanded to subsume many other active macrolide scaffolds, with broad latitude for substitutional variation. Ketolides replace the C3-cladinose carbohydrate residue of erythromycin with a carbonyl group, a chemical modification that allows them to evade certain inducible forms of macrolide resistance 21 , 22 , whereas the azalide azithromycin incorporates a nitrogen atom within an expanded (15-membered) macrolactone ring, features that have been proposed to impart favourable pharmacological properties, including increased efficacy against certain Gram-negative pathogens 23 , 24 . The hybrid ‘azaketolides’, or macrolides that contain both a C3 carbonyl group and a nitrogen atom within the macrolactone ring, have been little explored; one such compound has been reported and was found to be essentially inactive 25 . We were particularly interested in 14-membered azaketolides that would arise from formal replacement of the carbonyl group at position C9 of ketolides with an amino group, a transformation that would not be feasible by semisynthesis. Figure 2: A convergent, fully synthetic route to the 14-membered azaketolide 25. a , Graphical representation of the convergent synthesis of azaketolide 25 from eight variable building blocks (represented by coloured spheres). Downward, ‘Y’-shaped arrows signify convergent coupling reactions. b , Synthesis of azaketolide 25 , reagents and conditions (subscripts L and R indicate left and right halves, respectively) as follows: (a L ) LiHMDS, LiCl, 98%; (b L ) Et i Pr 2 N, COCl 2 ; (c L ) i PrMgCl, CH 3 Li, 76% over 2 steps, 92% of<|im_end|> <|im_start|>assistant (Phys.org)—A team of researchers at Harvard University has found a way to create new macrolides—a class of drugs used to fight bacterial infections. In their paper published in the journal Nature, the team describes their approach and why they believe it might be useful in keeping ahead of bacterial resistance until something more revolutionary comes along. Ming Yan and Phil Baran with The Scripps Research Institute, offer a News & Views article outlining the work done by the team and why they believe the new technique may help medical researchers keep up with bacterial evolution. For many years, the go-to drugs of choice for treating a variety of bacterial infections has been macrolides, which are all drugs that have been created by altering a natural form of erythromycin—but in recent years, bacteria have become resistant to many of the drugs that have been developed. New ones have been slow in coming, due to the difficulty in finding new ways to alter the original bacteria which means R&D costs have been rising. This development has led to near-panic in the health community as it appears that if something does not change soon, the arsenal of weapons used to fight many infections will be vastly depleted. In this new effort, the researchers report that they have found a new way to create new variations of macrolides that does not require using native erythromycin as a source—instead, they create them from scratch. This development means that many more variants can be created at far lower cost, helping to keep ahead of bacterial resistance. To create new macrolides, the team reports, they used a method that allows for modular building, which they liken to the way cell phones are made—they start by building small-chemical blocks and then "weld" them together using a process that requires very few steps. They report also that the technique can be applied on a multigram scale, which means enough can be created at a time for use in experiments geared towards testing the results in killing bacteria. To date, the team has produced 300 macrolides using their technique, which include some that have had already been created using the original method. They report that some have already been tested to see how well they fight bacteria and have met with some initial success. They acknowledge that a lot more work needs to be done to find out if drugs produced using the method are truly effective in fighting bacterial infections and if so, if they will prove to be safe for use in humans. <|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 Despite global warming and Arctic sea-ice loss, on average the Antarctic sea-ice extent has not declined since 1979 when satellite data became available. In contrast, climate model simulations tend to exhibit strong negative sea-ice trends for the same period. This Antarctic sea-ice paradox leads to low confidence in 21st-century sea-ice projections. Here we present multi-resolution climate change projections that account for Southern Ocean mesoscale eddies. The high-resolution configuration simulates stable September Antarctic sea-ice extent that is not projected to decline until the mid-21st century. We argue that one reason for this finding is a more realistic ocean circulation that increases the equatorward heat transport response to global warming. As a result, the ocean becomes more efficient at moderating the anthropogenic warming around Antarctica and hence at delaying sea-ice decline. Our study suggests that explicitly simulating Southern Ocean eddies is necessary for providing Antarctic sea-ice projections with higher confidence. Introduction Climate models that participated in the Coupled Model Intercomparison Project Phase 5 (CMIP5) 1 simulate a strong decline of September Antarctic sea-ice extent (SIE) for recent decades (Supplementary Fig. 1 ). In contrast, satellite data show a much more stable sea-ice cover on average, with a slight (albeit statistically non-significant) multi-decadal positive trend of +0.11 million km 2 per decade 2 in September for the same period (1979–2018). This supports the notion of a possible delayed sea-ice decline in the Antarctic compared to that in the Arctic. In the few years from 2016 onwards, there has been significantly lower Antarctic SIE 3 , 4 , 5 , 6 , 7 , 8 , which one could consider harbingers of imminent change. However, others 9 have argued that SIE is expected to regress to the near-neutral decadal trend in the near future; and indeed data for 2020/2021 seem to support this view 8 . To explain the lack of long-term Antarctic sea-ice decline since 1979, previous studies have proposed various mechanisms such as decadal wind trends associated with the Southern Annular Mode (SAM) 10 and variability of the Amundsen Sea Low 11 , 12 , dynamic sea-ice transport changes 13 , 14 , 15 , 16 , recent absence of deep open-ocean convection 17 , 18 , additional meltwater from the Antarctic ice sheet and ice shelves 19 , 20 , 21 , and internal variability of tropical origin 22 , 23 . While some of these factors are likely to contribute to the slightly positive real-world trend, here we argue that mesoscale dynamical processes in the ocean play a critical role for explaining a delayed Antarctic sea-ice decline. Due to the contrasting trends between observations and existing climate models (Supplementary Fig. 1 ), in which mesoscale oceanic processes are parameterized, as well as due to a lack of consensus regarding possible explanations for these differences 24 , the Intergovernmental Panel on Climate Change (IPCC) concludes that our confidence in projections of Antarctic sea ice is low 24 , 25 , 26 , 27 , 28 . It has been suggested that models with a faithful representation of mesoscale ocean eddies in the Antarctic Circumpolar Current (ACC) are needed in order to better represent the behaviour of the Southern Ocean 29 . In fact, realistically representing the Southern Ocean circulation and its response to global warming is known to be a challenging task in coarse-resolution models 30 , requiring parameterizations (e.g. for the effect of ocean eddies) that are sensitive to how they are tuned. In particular, changes in forcing can be compensated via eddy compensation and saturation 31 , resulting in a notably insensitive transport of the ACC through Drake Passage. Both changes in mesoscale transient eddies and changes in meandering flows 32 (standing eddies) may contribute to these phenomena, and the degree to which eddy compensation and saturation is realized in simulations thus depends on parameterizations in low-resolution (LR) models. There is some level of arbitrariness involved due to necessary choices being made for individual implementations of parameterizations in climate models. Although the development of eddy parameterizations is still an active field of research, it is increasingly being recognized that explicitly simulating mesoscale processes is often more accurate 33 . Therefore, an alternative way is to develop and use high-resolution (HR) sea ice-ocean models 34 that employ more of the laws of physics by explicitly simulating rather than parameterizing the effects of ocean eddies. Compared to LR simulations for the Southern Ocean, earlier studies using HR ocean components have reported changes in the hydrography 35 as well as of the overturning and ocean heat transport in idealized climate change simulations 32 , 35 . Here, we show the impact of explicitly simulating mesoscale processes in the ocean on Antarctic sea-ice trends in comprehensive CMIP-type projections using a high-emission scenario. Our HR climate model configuration simulates stable September Antarctic SIE that is not projected to decline until the mid-twenty-first century. This is in stark contrast to typical CMIP models and our complementary LR configuration. From additional mixed-resolution experiments, in which only the atmosphere or ocean is highly resolved, we attribute this delayed decline to the HR ocean. Our study provides support for the hypothesis that ocean models that permit or resolve eddies are necessary to increase the trustworthiness of climate projections of the Southern Ocean, and it thus constitutes a step towards providing Antarctic sea-ice projections with higher confidence. Results Resolution dependence of sea-ice trends in climate models When considering the CMIP5 ensemble of models, we find evidence that simulated historical (1979–2018) sea-ice trends depend on the resolution of the ocean model used in the Southern Ocean. Even in the low spatial resolution range of 35–200 km available from CMIP5, models with higher resolution tend to show positive or moderate negative SIE trends ≥ −0.2 million km 2 per decade; the coarsest models, on the other hand, show negative trends amounting to as much as −0.8 million km 2 per decade (Fig. 1 b). Particularly, the one CMIP5 model with the highest spatial ocean resolution in the Southern Ocean (35", "role": "user" }, { "content": "Despite global warming and the sea-ice loss in the Arctic, the Antarctic sea-ice extent has remained largely unchanged since 1979. However, existing climate model-based simulations indicate significant sea-ice loss, contrary to actual observations. As experts from the Alfred Wegener Institute have now shown, the ocean may weaken warming around Antarctica and delay sea-ice retreat. Given that many models are not capable of accurately reflecting this factor and the role of ocean eddies, the study, which was just published in the journal Nature Communications, provides the basis for improved simulations and forecasts of the future development of the Antarctic. Global warming is progressing rapidly, producing effects that can be felt around the world. The impacts of climate change are especially dramatic in the Arctic: since the beginning of satellite observation in 1979, the sea ice has declined massively in the face of rising global temperatures. According to the latest simulations, the Arctic could be consistently ice-free in summer before 2050, and in some years even before 2030. Yet on the other side of the planet, in Antarctica, the sea ice seems to have evaded the global warming trend. Since 2010, there have been more interannual fluctuations than in the previous period. However, apart from a significant negative excursion in the years 2016 to 2019, the long-term mean sea-ice cover around the Antarctic continent has remained stable since 1979. As such, the observable reality does not match the majority of scientific simulations, which show a significant sea-ice loss over the same timeframe. \"This so-called Antarctic sea-ice paradox has preoccupied the scientific community for some time now,\" says first author Thomas Rackow from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). \"The current models cannot yet correctly describe the behavior of the Antarctic sea ice; some key element seems to be missing. This also explains why the Intergovernmental Panel on Climate Change, IPCC, concludes that the confidence level for model-based projections of future Antarctic sea ice is low.\" In contrast, the models are already so reliable in the Arctic that the IPCC ascribes a high confidence level to their projections. \"With our study, we now provide a basis that could make future projections for Antarctica much more reliable.\" In the course of the study, the team applied the AWI Climate Model (AWI-CM). Unlike other climate models, the AWI-CM allows certain key regions like the Southern Ocean to be simulated in far more detail—or in other words, in high resolution. As a result, mixing processes in the ocean, caused by smaller ocean eddies with diameters of 10 to 20 kilometers, can also be directly included. \"We used a broad range of configurations for our simulations. In the process, it became clear that only those simulations with a high-resolution description of the Southern Ocean encircling the Antarctic produced delayed sea-ice loss similar to what we are seeing in reality,\" says Rackow. \"When we then extended the model into the future, even under a highly unfavorable greenhouse-gas scenario the Antarctic sea-ice cover remains largely stable until mid-century. After that point the sea ice retreats rather rapidly, just as the Arctic sea ice has been doing for decades.\" As such, the AWI study offers a potential explanation for why the behavior of the Antarctic sea ice does not follow the global warming trend. \"There could be a number of reasons for the paradoxical stability of the sea-ice cover. The theory that additional melt water from the Antarctic stabilizes the water column and thus also the ice by shielding the cool surface waters from the warmer deep waters is being discussed. According to another theory, the prime suspects are the westerlies blowing around the Antarctic, which have been strengthening under climate change. These winds could essentially spread out the ice like a thin pizza dough, so that it covers a greater area. In this scenario, the ice volume could already be declining, while the ice-covered areas would give the illusion of stability,\" Rackow explains. AWI's research efforts now bring ocean eddies into the focus. These could play a decisive part in dampening and thus delaying the effects of climate change in the Southern Ocean, allowing the ocean to transport additional heat taken up from the atmosphere north, toward the Equator. This northward heat transport is closely linked to the underlying overturning circulation in the upper about 1,000 meters of the ocean, which in the Southern Ocean is driven by the wind on the one hand but is also influenced by eddies. While the northward component of the circulation is growing due to stronger westerlies, the simplified eddies in low-resolution climate models often seem to overcompensate for this factor by a southward component toward Antarctica; the explicitly simulated eddies in the high-resolution model display a more neutral behavior. Taken together, a more pronounced northerly change in heat transport can be seen in the high-resolution model. As a result, the ocean surrounding the Antarctic warms more slowly and the ice cover remains stable for longer. \"Our study supports the hypothesis that climate models and projections of the Antarctic sea ice will be far more reliable as soon as they are capable of realistically simulating a high-resolution ocean, complete with eddies,\" says Rackow. \"Thanks to the ever-increasing performance of parallel supercomputers and new, more efficient models, next-generation climate models should make this a routine task.\" ", "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 Despite global warming and Arctic sea-ice loss, on average the Antarctic sea-ice extent has not declined since 1979 when satellite data became available. In contrast, climate model simulations tend to exhibit strong negative sea-ice trends for the same period. This Antarctic sea-ice paradox leads to low confidence in 21st-century sea-ice projections. Here we present multi-resolution climate change projections that account for Southern Ocean mesoscale eddies. The high-resolution configuration simulates stable September Antarctic sea-ice extent that is not projected to decline until the mid-21st century. We argue that one reason for this finding is a more realistic ocean circulation that increases the equatorward heat transport response to global warming. As a result, the ocean becomes more efficient at moderating the anthropogenic warming around Antarctica and hence at delaying sea-ice decline. Our study suggests that explicitly simulating Southern Ocean eddies is necessary for providing Antarctic sea-ice projections with higher confidence. Introduction Climate models that participated in the Coupled Model Intercomparison Project Phase 5 (CMIP5) 1 simulate a strong decline of September Antarctic sea-ice extent (SIE) for recent decades (Supplementary Fig. 1 ). In contrast, satellite data show a much more stable sea-ice cover on average, with a slight (albeit statistically non-significant) multi-decadal positive trend of +0.11 million km 2 per decade 2 in September for the same period (1979–2018). This supports the notion of a possible delayed sea-ice decline in the Antarctic compared to that in the Arctic. In the few years from 2016 onwards, there has been significantly lower Antarctic SIE 3 , 4 , 5 , 6 , 7 , 8 , which one could consider harbingers of imminent change. However, others 9 have argued that SIE is expected to regress to the near-neutral decadal trend in the near future; and indeed data for 2020/2021 seem to support this view 8 . To explain the lack of long-term Antarctic sea-ice decline since 1979, previous studies have proposed various mechanisms such as decadal wind trends associated with the Southern Annular Mode (SAM) 10 and variability of the Amundsen Sea Low 11 , 12 , dynamic sea-ice transport changes 13 , 14 , 15 , 16 , recent absence of deep open-ocean convection 17 , 18 , additional meltwater from the Antarctic ice sheet and ice shelves 19 , 20 , 21 , and internal variability of tropical origin 22 , 23 . While some of these factors are likely to contribute to the slightly positive real-world trend, here we argue that mesoscale dynamical processes in the ocean play a critical role for explaining a delayed Antarctic sea-ice decline. Due to the contrasting trends between observations and existing climate models (Supplementary Fig. 1 ), in which mesoscale oceanic processes are parameterized, as well as due to a lack of consensus regarding possible explanations for these differences 24 , the Intergovernmental Panel on Climate Change (IPCC) concludes that our confidence in projections of Antarctic sea ice is low 24 , 25 , 26 , 27 , 28 . It has been suggested that models with a faithful representation of mesoscale ocean eddies in the Antarctic Circumpolar Current (ACC) are needed in order to better represent the behaviour of the Southern Ocean 29 . In fact, realistically representing the Southern Ocean circulation and its response to global warming is known to be a challenging task in coarse-resolution models 30 , requiring parameterizations (e.g. for the effect of ocean eddies) that are sensitive to how they are tuned. In particular, changes in forcing can be compensated via eddy compensation and saturation 31 , resulting in a notably insensitive transport of the ACC through Drake Passage. Both changes in mesoscale transient eddies and changes in meandering flows 32 (standing eddies) may contribute to these phenomena, and the degree to which eddy compensation and saturation is realized in simulations thus depends on parameterizations in low-resolution (LR) models. There is some level of arbitrariness involved due to necessary choices being made for individual implementations of parameterizations in climate models. Although the development of eddy parameterizations is still an active field of research, it is increasingly being recognized that explicitly simulating mesoscale processes is often more accurate 33 . Therefore, an alternative way is to develop and use high-resolution (HR) sea ice-ocean models 34 that employ more of the laws of physics by explicitly simulating rather than parameterizing the effects of ocean eddies. Compared to LR simulations for the Southern Ocean, earlier studies using HR ocean components have reported changes in the hydrography 35 as well as of the overturning and ocean heat transport in idealized climate change simulations 32 , 35 . Here, we show the impact of explicitly simulating mesoscale processes in the ocean on Antarctic sea-ice trends in comprehensive CMIP-type projections using a high-emission scenario. Our HR climate model configuration simulates stable September Antarctic SIE that is not projected to decline until the mid-twenty-first century. This is in stark contrast to typical CMIP models and our complementary LR configuration. From additional mixed-resolution experiments, in which only the atmosphere or ocean is highly resolved, we attribute this delayed decline to the HR ocean. Our study provides support for the hypothesis that ocean models that permit or resolve eddies are necessary to increase the trustworthiness of climate projections of the Southern Ocean, and it thus constitutes a step towards providing Antarctic sea-ice projections with higher confidence. Results Resolution dependence of sea-ice trends in climate models When considering the CMIP5 ensemble of models, we find evidence that simulated historical (1979–2018) sea-ice trends depend on the resolution of the ocean model used in the Southern Ocean. Even in the low spatial resolution range of 35–200 km available from CMIP5, models with higher resolution tend to show positive or moderate negative SIE trends ≥ −0.2 million km 2 per decade; the coarsest models, on the other hand, show negative trends amounting to as much as −0.8 million km 2 per decade (Fig. 1 b). Particularly, the one CMIP5 model with the highest spatial ocean resolution in the Southern Ocean (35<|im_end|> <|im_start|>assistant Despite global warming and the sea-ice loss in the Arctic, the Antarctic sea-ice extent has remained largely unchanged since 1979. However, existing climate model-based simulations indicate significant sea-ice loss, contrary to actual observations. As experts from the Alfred Wegener Institute have now shown, the ocean may weaken warming around Antarctica and delay sea-ice retreat. Given that many models are not capable of accurately reflecting this factor and the role of ocean eddies, the study, which was just published in the journal Nature Communications, provides the basis for improved simulations and forecasts of the future development of the Antarctic. Global warming is progressing rapidly, producing effects that can be felt around the world. The impacts of climate change are especially dramatic in the Arctic: since the beginning of satellite observation in 1979, the sea ice has declined massively in the face of rising global temperatures. According to the latest simulations, the Arctic could be consistently ice-free in summer before 2050, and in some years even before 2030. Yet on the other side of the planet, in Antarctica, the sea ice seems to have evaded the global warming trend. Since 2010, there have been more interannual fluctuations than in the previous period. However, apart from a significant negative excursion in the years 2016 to 2019, the long-term mean sea-ice cover around the Antarctic continent has remained stable since 1979. As such, the observable reality does not match the majority of scientific simulations, which show a significant sea-ice loss over the same timeframe. "This so-called Antarctic sea-ice paradox has preoccupied the scientific community for some time now," says first author Thomas Rackow from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). "The current models cannot yet correctly describe the behavior of the Antarctic sea ice; some key element seems to be missing. This also explains why the Intergovernmental Panel on Climate Change, IPCC, concludes that the confidence level for model-based projections of future Antarctic sea ice is low." In contrast, the models are already so reliable in the Arctic that the IPCC ascribes a high confidence level to their projections. "With our study, we now provide a basis that could make future projections for Antarctica much more reliable." In the course of the study, the team applied the AWI Climate Model (AWI-CM). Unlike other climate models, the AWI-CM allows certain key regions like the Southern Ocean to be simulated in far more detail—or in other words, in high resolution. As a result, mixing processes in the ocean, caused by smaller ocean eddies with diameters of 10 to 20 kilometers, can also be directly included. "We used a broad range of configurations for our simulations. In the process, it became clear that only those simulations with a high-resolution description of the Southern Ocean encircling the Antarctic produced delayed sea-ice loss similar to what we are seeing in reality," says Rackow. "When we then extended the model into the future, even under a highly unfavorable greenhouse-gas scenario the Antarctic sea-ice cover remains largely stable until mid-century. After that point the sea ice retreats rather rapidly, just as the Arctic sea ice has been doing for decades." As such, the AWI study offers a potential explanation for why the behavior of the Antarctic sea ice does not follow the global warming trend. "There could be a number of reasons for the paradoxical stability of the sea-ice cover. The theory that additional melt water from the Antarctic stabilizes the water column and thus also the ice by shielding the cool surface waters from the warmer deep waters is being discussed. According to another theory, the prime suspects are the westerlies blowing around the Antarctic, which have been strengthening under climate change. These winds could essentially spread out the ice like a thin pizza dough, so that it covers a greater area. In this scenario, the ice volume could already be declining, while the ice-covered areas would give the illusion of stability," Rackow explains. AWI's research efforts now bring ocean eddies into the focus. These could play a decisive part in dampening and thus delaying the effects of climate change in the Southern Ocean, allowing the ocean to transport additional heat taken up from the atmosphere north, toward the Equator. This northward heat transport is closely linked to the underlying overturning circulation in the upper about 1,000 meters of the ocean, which in the Southern Ocean is driven by the wind on the one hand but is also influenced by eddies. While the northward component of the circulation is growing due to stronger westerlies, the simplified eddies in low-resolution climate models often seem to overcompensate for this factor by a southward component toward Antarctica; the explicitly simulated eddies in the high-resolution model display a more neutral behavior. Taken together, a more pronounced northerly change in heat transport can be seen in the high-resolution model. As a result, the ocean surrounding the Antarctic warms more slowly and the ice cover remains stable for longer. "Our study supports the hypothesis that climate models and projections of the Antarctic sea ice will be far more reliable as soon as they are capable of realistically simulating a high-resolution ocean, complete with eddies," says Rackow. "Thanks to the ever-increasing performance of parallel supercomputers and new, more efficient models, next-generation climate models should make this a routine task." <|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 Since 2017 the Juno spacecraft has observed a cyclone at the north pole of Jupiter surrounded by eight smaller cyclones arranged in a polygonal pattern. It is not clear why this configuration is so stable or how it is maintained. Here we use a time series of images obtained by the JIRAM mapping spectrometer on Juno to track the winds and measure the vorticity and horizontal divergence within and around the polar cyclone and two of the circumpolar ones. We find an anticyclonic ring between the polar cyclone and the surrounding cyclones, supporting the theory that such shielding is needed for the stability of the polygonal pattern. However, even at the smallest spatial scale (180 km) we do not find the expected signature of convection—a spatial correlation between divergence and anticyclonic vorticity—in contrast with a previous study using additional assumptions about the dynamics, which shows the correlation at scales from 20 to 200 km. We suggest that a smaller size, relative to atmospheric thickness, of Jupiter’s convective storms compared with Earth’s, can reconcile the two studies. Main At Jupiter’s north pole there are eight cyclones that form an octagon, with one cyclone at each vertex and one additional cyclone in the centre 1 , 2 . The centres of the cyclones are at latitudes of 83 ± 10°, which is about 8,700 km from the pole. Jupiter’s south pole is the same, except there are only five cyclones, which form a pentagon with one at the centre. The vertices are at latitudes of −83 ± 1°. The polygons and the individual vortices that comprise them have been stable for the 4 years since Juno discovered them 3 , 4 , 5 . The polygonal patterns rotate slowly, or not at all. The peak azimuthal wind speeds around each vortex range from 70 to 100 m s −1 , and the radial distance r from the peak to the vortex centre is about 1,000 km (ref. 6 ). In contrast, Saturn has only one vortex, a cyclone, at each pole 7 . The peak winds are 150 m s −1 , and the radius at the peak is 1,500 km (refs. 8 , 9 ). Saturn has a six-lobed meandering jet at 75°, but it has no cyclones associated with it. Both laboratory and theoretical models treat the hexagon as a stable wave-like pattern 10 , 11 , 12 , 13 , 14 . There have been a handful of theoretical studies that specifically address the origin of polar cyclones on Jupiter and Saturn 15 , 16 , 17 , 18 . They comprise one- and two-layer models that introduce small-scale motions either as an initial condition or as continuous forcing balanced by dissipation. The small-scale vortices merge and become the large-scale vortices. The cyclones drift polewards, and the anticyclones drift equatorwards, as they do on Earth. In some cases the cyclones merge into one big cyclone at the pole. In other cases, with different parameter settings, the cyclones wander about without forming polygons. Only one theoretical study obtained stable polygons from random initial conditions, and only when the wavelengths of the initial random disturbances are less than 300 km (ref. 19 ). A Fourier analysis of Juno data reveals that flows with wavelengths larger than 215 km are gaining energy from smaller-scale flows—an example of an upscale energy transfer 20 . Therefore, one goal of this Article is to measure vorticity and divergence at scales much smaller than the main cyclones and determine how the upscale energy transfer takes place. Another theoretical study 21 , which used shallow water equations, introduced cyclones that have the observed gross properties—maximum velocity and radius—and arranged them into different polygonal patterns around the pole to see which ones are stable. The stable ones have shielding (a ring of anticyclonic vorticity surrounding each of the cyclones) and the unstable ones do not. Some models with small-scale forcing develop shielding, but they do not organize into polygons 15 , 16 , 17 , 18 , 22 . So another goal of this Article is to measure the vorticity inside and outside the large cyclones and see whether they are shielded. The small-scale forcing in the one- and two-layer models is a crude representation of convection. There are 3D models that treat convection explicitly, in some cases with the Boussinesq (quasi-incompressible) approximation 23 , 24 , 25 and in other cases with density varying vertically by up to five scale heights 25 , 26 , 27 , 28 . Some treat fluid in a box with periodic boundary conditions, and others use full spherical geometry. All the 3D models have small-scale convective plumes. The convective plumes produce large-scale vortices by mergers, an upscale transfer of kinetic energy, and some of the vortices arrange themselves into polygonal patterns 23 , 28 . Although a relation between divergence and vorticity is not discussed in any of these models, a negative correlation is expected for convection on a rotating planet. Therefore, a third goal of this Article is to measure divergence and vorticity at scales down to 180 km and search for this signature of convection. Results Scale analysis At mid-latitudes one important parameter is the length, L β = ( U / β ) 1/2 , where U is a characteristic horizontal velocity and β = d f/ d y = 2 Ω sin θ / a is the latitudinal gradient of the planetary vorticity f = 2 Ω cos θ . Here θ is colatitude, y is the northward coordinate, and a and Ω are the planet’s radius and angular velocity, respectively. L β plays a role in the stability of the zonal jets. On both Jupiter and Saturn, 2π/ L β is approximately equal to the wavenumber of the zonal jet profile with respect to latitude when U is the root mean squared speed 29 , 30 , 31 , 32 , 33 . However, L β is infinite at the poles as β linearly approaches", "role": "user" }, { "content": "A team of space scientists affiliated with multiple institutions in the U.S., working with a colleague from Italy and another from France has used modeling to partially explain the resilience of cyclones circling Jupiter's poles. In their paper published in the journal Nature Astronomy, the group describes how they analyzed images captured by the Juno space probe and used what they learned to create shallow water models that might at least partly explain how the cyclones last so long. In 2016, NASA's Juno space probe entered an orbit around Jupiter. Unlike other such probes it has been circling the planet from pole to pole, rather than around its equator. As the probe began sending back pictures of the planet from this new perspective, researchers looking at them found a surprise. Not only was there a single cyclone sitting atop each of the poles, but both were surrounded by more cyclones. As time has passed, more pictures of the poles have arrived and the researchers studying them continue to be surprised by the stability of the cyclones—the original ones are still there today and have not even changed shape. Such behavior is of course unheard of here on Earth—cyclones take shape, travel around for awhile and then dissipate. Such behavior has left researchers scrambling to come up with a reasonable explanation for what they have observed. Photos of the planet's north pole show that there are eight cyclones surrounding the central cyclone directly over the pole. All eight are in close proximity and all are nearly equidistant from the central cyclone—and are arranged in an octagonal pattern. At this time, it is not clear if the cyclones rotate around the center. There is a similar arrangement at the southern pole, only there are just five cyclones, shaped as a pentagon. In this new effort, the researchers have tried a new approach to explaining how it is that the cyclones hold in place for so long, and how they do it without changing their position or shape. Vorticity and divergence derived from two independent determinations of the wind. Credit: Nature Astronomy (2022). DOI: 10.1038/s41550-022-01774-0 The work by the team involved analyzing pictures and other data from the Juno probe, looking specifically at wind speeds and direction. They then took what they learned and used it to create shallow water models and that led them to suggest that there is an \"anticyclonic ring\" of winds that move in the opposite direction of the cyclones, which is what keeps them in place. And while that may hold true, the team was unable to find signatures of convection, which would have helped to explain how heat was being used to fuel the cyclones. They acknowledge that much more work will need to be done to fully explain the behavior of Jupiter's cyclones. ", "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 Since 2017 the Juno spacecraft has observed a cyclone at the north pole of Jupiter surrounded by eight smaller cyclones arranged in a polygonal pattern. It is not clear why this configuration is so stable or how it is maintained. Here we use a time series of images obtained by the JIRAM mapping spectrometer on Juno to track the winds and measure the vorticity and horizontal divergence within and around the polar cyclone and two of the circumpolar ones. We find an anticyclonic ring between the polar cyclone and the surrounding cyclones, supporting the theory that such shielding is needed for the stability of the polygonal pattern. However, even at the smallest spatial scale (180 km) we do not find the expected signature of convection—a spatial correlation between divergence and anticyclonic vorticity—in contrast with a previous study using additional assumptions about the dynamics, which shows the correlation at scales from 20 to 200 km. We suggest that a smaller size, relative to atmospheric thickness, of Jupiter’s convective storms compared with Earth’s, can reconcile the two studies. Main At Jupiter’s north pole there are eight cyclones that form an octagon, with one cyclone at each vertex and one additional cyclone in the centre 1 , 2 . The centres of the cyclones are at latitudes of 83 ± 10°, which is about 8,700 km from the pole. Jupiter’s south pole is the same, except there are only five cyclones, which form a pentagon with one at the centre. The vertices are at latitudes of −83 ± 1°. The polygons and the individual vortices that comprise them have been stable for the 4 years since Juno discovered them 3 , 4 , 5 . The polygonal patterns rotate slowly, or not at all. The peak azimuthal wind speeds around each vortex range from 70 to 100 m s −1 , and the radial distance r from the peak to the vortex centre is about 1,000 km (ref. 6 ). In contrast, Saturn has only one vortex, a cyclone, at each pole 7 . The peak winds are 150 m s −1 , and the radius at the peak is 1,500 km (refs. 8 , 9 ). Saturn has a six-lobed meandering jet at 75°, but it has no cyclones associated with it. Both laboratory and theoretical models treat the hexagon as a stable wave-like pattern 10 , 11 , 12 , 13 , 14 . There have been a handful of theoretical studies that specifically address the origin of polar cyclones on Jupiter and Saturn 15 , 16 , 17 , 18 . They comprise one- and two-layer models that introduce small-scale motions either as an initial condition or as continuous forcing balanced by dissipation. The small-scale vortices merge and become the large-scale vortices. The cyclones drift polewards, and the anticyclones drift equatorwards, as they do on Earth. In some cases the cyclones merge into one big cyclone at the pole. In other cases, with different parameter settings, the cyclones wander about without forming polygons. Only one theoretical study obtained stable polygons from random initial conditions, and only when the wavelengths of the initial random disturbances are less than 300 km (ref. 19 ). A Fourier analysis of Juno data reveals that flows with wavelengths larger than 215 km are gaining energy from smaller-scale flows—an example of an upscale energy transfer 20 . Therefore, one goal of this Article is to measure vorticity and divergence at scales much smaller than the main cyclones and determine how the upscale energy transfer takes place. Another theoretical study 21 , which used shallow water equations, introduced cyclones that have the observed gross properties—maximum velocity and radius—and arranged them into different polygonal patterns around the pole to see which ones are stable. The stable ones have shielding (a ring of anticyclonic vorticity surrounding each of the cyclones) and the unstable ones do not. Some models with small-scale forcing develop shielding, but they do not organize into polygons 15 , 16 , 17 , 18 , 22 . So another goal of this Article is to measure the vorticity inside and outside the large cyclones and see whether they are shielded. The small-scale forcing in the one- and two-layer models is a crude representation of convection. There are 3D models that treat convection explicitly, in some cases with the Boussinesq (quasi-incompressible) approximation 23 , 24 , 25 and in other cases with density varying vertically by up to five scale heights 25 , 26 , 27 , 28 . Some treat fluid in a box with periodic boundary conditions, and others use full spherical geometry. All the 3D models have small-scale convective plumes. The convective plumes produce large-scale vortices by mergers, an upscale transfer of kinetic energy, and some of the vortices arrange themselves into polygonal patterns 23 , 28 . Although a relation between divergence and vorticity is not discussed in any of these models, a negative correlation is expected for convection on a rotating planet. Therefore, a third goal of this Article is to measure divergence and vorticity at scales down to 180 km and search for this signature of convection. Results Scale analysis At mid-latitudes one important parameter is the length, L β = ( U / β ) 1/2 , where U is a characteristic horizontal velocity and β = d f/ d y = 2 Ω sin θ / a is the latitudinal gradient of the planetary vorticity f = 2 Ω cos θ . Here θ is colatitude, y is the northward coordinate, and a and Ω are the planet’s radius and angular velocity, respectively. L β plays a role in the stability of the zonal jets. On both Jupiter and Saturn, 2π/ L β is approximately equal to the wavenumber of the zonal jet profile with respect to latitude when U is the root mean squared speed 29 , 30 , 31 , 32 , 33 . However, L β is infinite at the poles as β linearly approaches<|im_end|> <|im_start|>assistant A team of space scientists affiliated with multiple institutions in the U.S., working with a colleague from Italy and another from France has used modeling to partially explain the resilience of cyclones circling Jupiter's poles. In their paper published in the journal Nature Astronomy, the group describes how they analyzed images captured by the Juno space probe and used what they learned to create shallow water models that might at least partly explain how the cyclones last so long. In 2016, NASA's Juno space probe entered an orbit around Jupiter. Unlike other such probes it has been circling the planet from pole to pole, rather than around its equator. As the probe began sending back pictures of the planet from this new perspective, researchers looking at them found a surprise. Not only was there a single cyclone sitting atop each of the poles, but both were surrounded by more cyclones. As time has passed, more pictures of the poles have arrived and the researchers studying them continue to be surprised by the stability of the cyclones—the original ones are still there today and have not even changed shape. Such behavior is of course unheard of here on Earth—cyclones take shape, travel around for awhile and then dissipate. Such behavior has left researchers scrambling to come up with a reasonable explanation for what they have observed. Photos of the planet's north pole show that there are eight cyclones surrounding the central cyclone directly over the pole. All eight are in close proximity and all are nearly equidistant from the central cyclone—and are arranged in an octagonal pattern. At this time, it is not clear if the cyclones rotate around the center. There is a similar arrangement at the southern pole, only there are just five cyclones, shaped as a pentagon. In this new effort, the researchers have tried a new approach to explaining how it is that the cyclones hold in place for so long, and how they do it without changing their position or shape. Vorticity and divergence derived from two independent determinations of the wind. Credit: Nature Astronomy (2022). DOI: 10.1038/s41550-022-01774-0 The work by the team involved analyzing pictures and other data from the Juno probe, looking specifically at wind speeds and direction. They then took what they learned and used it to create shallow water models and that led them to suggest that there is an "anticyclonic ring" of winds that move in the opposite direction of the cyclones, which is what keeps them in place. And while that may hold true, the team was unable to find signatures of convection, which would have helped to explain how heat was being used to fuel the cyclones. They acknowledge that much more work will need to be done to fully explain the behavior of Jupiter's cyclones. <|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 Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS -mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors. Introduction Pharmacological doses of vitamin C (ascorbic acid) have been proposed as a potential anticancer therapy according to different pre-clinical and clinical trials 1 , 2 , 3 . Recent studies indicate that KRAS -mutant cancers may exhibit higher susceptibility to vitamin C antitumor effects, thus making this generally non-toxic compound a potential weapon against this aggressive tumor type 4 , 5 . High-dose vitamin C can exert its anticancer effects by pro-oxidant reactions, which cause the formation of hydrogen peroxide and hydroxyl radicals via Fenton chemistry. In turn, these reactive oxygen species (ROS) cause damage to macromolecules, thereby leading to cell death 3 , 4 , 6 , 7 , 8 . Vitamin C’s pro-oxidant action is strictly dependent on metal-ion redox chemistry. In particular, free iron was shown to be a key player in vitamin C-induced cytotoxic effects 3 , 9 . KRAS -mutant cancer cells rely on high levels of ROS and on a labile iron pool (LIP) to sustain their growth 10 , 11 , 12 . Increasing evidence supports the link between ROS production and free iron 10 , 13 , 14 . In particular, ROS could release iron from iron-containing proteins, thus expanding the LIP, which in turn could enhance ROS formation through redox chemistry 10 , 13 , 14 . Moreover, RAS oncogenic activation further increases cellular iron content by upregulating iron-uptake proteins, such as transferrin receptor (Trf1), and by downregulating iron export and storage proteins, in particular ferritin 10 , 11 , 12 . In this context, the stress inducible protein heme-oxygenase-1 (HO-1), regulates ferritin expression to avoid an excessive free iron content, which can damage macromolecules 15 . Although high-dose vitamin C could potentially be effective in treating patients with KRAS mutated cancers, it is unlikely that this treatment, when used as a monotherapy, would be sufficient to target the molecular heterogeneity and multiple escape mechanisms of these tumors 16 . Therefore, strategies to enhance and expand vitamin C activity in the treatment of KRAS mutated cancers are necessary. We have previously shown that fasting or a fasting-mimicking diet (FMD) reduce tumor progression and sensitize different types of cancer to chemotherapy, while protecting normal cells from chemo-toxic side effects 17 , 18 . These phenomena are known as “Differential Stress Sensitization” and “Differential Stress Resistance”, respectively 17 , 18 , 19 , 20 , 21 . The differential effects of fasting on normal (protection) and cancer (sensitization) cells can be mediated, at least in part, by its effects on the insulin-like growth factor 1 (IGF-1) signaling pathway and on glucose levels 19 , 20 , 21 , 22 . However, since fasting remains a challenging option for cancer patients, a more feasible and safer diet whose specific formulation mimics the effects of fasting was developed 23 , 24 . FMD refers to a plant-based, calorie-restricted, low sugar, low protein, and high-fat dietary composition administered cyclically and alternated with refeeding periods sufficient to prevent or minimize lean body mass loss (the caloric content of the FMD that we used for this study is indicated in the “Methods” session) 24 . To identify a highly effective but a low toxicity treatment for KRAS-mutant cancers, here we investigate the effect of FMD in potentiating the anticancer activity of vitamin C, alone or in combination with standard chemotherapy with a focus on colorectal cancer (CRC). Our findings reveal that FMD cycles selectively potentiate vitamin C anti-cancer effect against KRAS -mutant tumors, both in vitro and in vivo, by reverting the vitamin C mediated upregulation of HO-1. We also provide data showing that the toxic action exerted by FMD and vitamin C is further potentiated by chemotherapy. Together, our data support that cycles of FMD plus pharmacological doses of vitamin C could represent a promising therapeutic opportunity to be tested in the clinic for the treatment of KRAS mutated cancers. Results FMD enhances vitamin C toxicity in KRAS- mutant cancer cells We investigated whether the fasting/FMD potentiates the anti-cancer effect of vitamin C against different KRAS -mutant cancer models. Human (HCT116, DLD-1) and murine (CT26) KRAS -mutant CRC cell lines, as well as KRAS -mutant lung cancer (H23, H727) and pancreatic ductal adenocarcinoma (PANC1) cells, were grown in control medium (1 g/L glucose and 10% serum; CTR) or in a FMD-like medium (0.5 g/L glucose and 1% serum), here referred to as short-term starvation condition (STS), which mimics the reduction of extracellular glucose and growth factor concentrations that occurs during prolonged (>48 h) fasting or FMD in vivo, with or without pharmacological concentrations of vitamin C (≥0.3 mM). Consistent with recent findings 4 , KRAS -mutant tumor cells were more susceptible to vitamin C compared with KRAS -wild-type cancer cells (Fig. 1a, b ). When cancer cells were grown under STS conditions before and during treatment, vitamin C-mediated toxicity was strongly enhanced (Fig. 1a ). Conversely, KRAS -wild-type CRC (SW48, HT29), prostate cancer (PC-3), ovarian cancer (COV362) cell lines and a normal colon cell line (CCD841CoN) were resistant to vitamin C when used both as a single agent and in combination with STS", "role": "user" }, { "content": "Scientists from USC and the IFOM Cancer Institute in Milan have found that a fasting-mimicking diet could be more effective at treating some types of cancer when combined with vitamin C. In studies on mice, researchers found that the combination delayed tumor progression in multiple mouse models of colorectal cancer; in some mice, it caused disease regression. The results were published in the journal Nature Communications. \"For the first time, we have demonstrated how a completely non-toxic intervention can effectively treat an aggressive cancer,\" said Valter Longo, the study senior author and the director of the USC Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. \"We have taken two treatments that are studied extensively as interventions to delay aging— a fasting-mimicking diet and vitamin C—and combined them as a powerful treatment for cancer.\" The researchers said that while fasting remains a challenging option for cancer patients, a safer, more feasible option is a low-calorie, plant-based diet that causes cells to respond as if the body were fasting. Their findings suggest that a low-toxicity treatment of fasting-mimicking diet plus vitamin C has the potential to replace more toxic treatments. Results of prior research on the cancer-fighting potential of vitamin C have been mixed. Recent studies, though, are beginning to show some efficacy, especially in combination with chemotherapy. In this new study, the research team wanted to find out whether a fasting-mimicking diet could enhance the high-dose vitamin C tumor-fighting action by creating an environment that would be unsustainable for cancer cells but still safe for normal cells. \"Our first in vitro experiment showed remarkable effects,\" said Longo. \"When used alone, fasting-mimicking diet or vitamin C alone reduced cancer cell growth and caused a minor increase in cancer cell death. But when used together, they had a dramatic effect, killing almost all cancerous cells.\" Longo and his colleagues detected this strong effect only in cancer cells that had a mutation that is regarded as one of the most challenging targets in cancer research. These mutations in the KRAS gene signal the body is resisting most cancer-fighting treatments, and they reduce a patient's survival rate. KRAS mutations occur in approximately a quarter of all human cancers and are estimated to occur in up to half of all colorectal cancers. The study also provided clues about why previous studies of vitamin C as a potential anticancer therapy showed limited efficacy. By itself, a vitamin C treatment appears to trigger the KRAS-mutated cells to protect cancer cells by increasing levels of ferritin, a protein that binds iron. But by reducing levels of ferritin, the scientists managed to increase vitamin C's toxicity for the cancer cells. Amid this finding, the scientists also discovered that colorectal cancer patients with high levels of the iron-binding protein have a lower chance of survival. \"In this study, we observed how fasting-mimicking diet cycles are able to increase the effect of pharmacological doses of vitamin C against KRAS-mutated cancers,\" said Maira Di Tano, a study co-author at the IFOM, FIRC Institute of Molecular Oncology in Milan, Italy. \"This occurs through the regulation of the levels of iron and of the molecular mechanisms involved in oxidative stress. The results particularly pointed to a gene that regulates iron levels: heme-oxygenase-1.\" The research team's prior studies showed that fasting and a fasting-mimicking diet slow cancer's progression and make chemotherapy more effective in tumor cells, while protecting normal cells from chemotherapy-associated side effects. The combination enhances the immune system's anti-tumor response in breast cancer and melanoma mouse models. The scientists believe cancer will eventually be treated with low-toxicity drugs in a manner similar to how antibiotics are used to treat infections that kill particular bacteria, but which can be substituted by other drugs if the first is not effective. To move toward that goal, they say they needed to first test two hypotheses: that their non-toxic combination interventions would work in mice, and that it would look promising for human clinical trials. In this new study, they said that they've demonstrated both. At least five clinical trials, including one at USC on breast cancer and prostate cancer patients, are now investigating the effects of the fasting-mimicking diets in combination with different cancer-fighting drugs. ", "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 Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS -mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors. Introduction Pharmacological doses of vitamin C (ascorbic acid) have been proposed as a potential anticancer therapy according to different pre-clinical and clinical trials 1 , 2 , 3 . Recent studies indicate that KRAS -mutant cancers may exhibit higher susceptibility to vitamin C antitumor effects, thus making this generally non-toxic compound a potential weapon against this aggressive tumor type 4 , 5 . High-dose vitamin C can exert its anticancer effects by pro-oxidant reactions, which cause the formation of hydrogen peroxide and hydroxyl radicals via Fenton chemistry. In turn, these reactive oxygen species (ROS) cause damage to macromolecules, thereby leading to cell death 3 , 4 , 6 , 7 , 8 . Vitamin C’s pro-oxidant action is strictly dependent on metal-ion redox chemistry. In particular, free iron was shown to be a key player in vitamin C-induced cytotoxic effects 3 , 9 . KRAS -mutant cancer cells rely on high levels of ROS and on a labile iron pool (LIP) to sustain their growth 10 , 11 , 12 . Increasing evidence supports the link between ROS production and free iron 10 , 13 , 14 . In particular, ROS could release iron from iron-containing proteins, thus expanding the LIP, which in turn could enhance ROS formation through redox chemistry 10 , 13 , 14 . Moreover, RAS oncogenic activation further increases cellular iron content by upregulating iron-uptake proteins, such as transferrin receptor (Trf1), and by downregulating iron export and storage proteins, in particular ferritin 10 , 11 , 12 . In this context, the stress inducible protein heme-oxygenase-1 (HO-1), regulates ferritin expression to avoid an excessive free iron content, which can damage macromolecules 15 . Although high-dose vitamin C could potentially be effective in treating patients with KRAS mutated cancers, it is unlikely that this treatment, when used as a monotherapy, would be sufficient to target the molecular heterogeneity and multiple escape mechanisms of these tumors 16 . Therefore, strategies to enhance and expand vitamin C activity in the treatment of KRAS mutated cancers are necessary. We have previously shown that fasting or a fasting-mimicking diet (FMD) reduce tumor progression and sensitize different types of cancer to chemotherapy, while protecting normal cells from chemo-toxic side effects 17 , 18 . These phenomena are known as “Differential Stress Sensitization” and “Differential Stress Resistance”, respectively 17 , 18 , 19 , 20 , 21 . The differential effects of fasting on normal (protection) and cancer (sensitization) cells can be mediated, at least in part, by its effects on the insulin-like growth factor 1 (IGF-1) signaling pathway and on glucose levels 19 , 20 , 21 , 22 . However, since fasting remains a challenging option for cancer patients, a more feasible and safer diet whose specific formulation mimics the effects of fasting was developed 23 , 24 . FMD refers to a plant-based, calorie-restricted, low sugar, low protein, and high-fat dietary composition administered cyclically and alternated with refeeding periods sufficient to prevent or minimize lean body mass loss (the caloric content of the FMD that we used for this study is indicated in the “Methods” session) 24 . To identify a highly effective but a low toxicity treatment for KRAS-mutant cancers, here we investigate the effect of FMD in potentiating the anticancer activity of vitamin C, alone or in combination with standard chemotherapy with a focus on colorectal cancer (CRC). Our findings reveal that FMD cycles selectively potentiate vitamin C anti-cancer effect against KRAS -mutant tumors, both in vitro and in vivo, by reverting the vitamin C mediated upregulation of HO-1. We also provide data showing that the toxic action exerted by FMD and vitamin C is further potentiated by chemotherapy. Together, our data support that cycles of FMD plus pharmacological doses of vitamin C could represent a promising therapeutic opportunity to be tested in the clinic for the treatment of KRAS mutated cancers. Results FMD enhances vitamin C toxicity in KRAS- mutant cancer cells We investigated whether the fasting/FMD potentiates the anti-cancer effect of vitamin C against different KRAS -mutant cancer models. Human (HCT116, DLD-1) and murine (CT26) KRAS -mutant CRC cell lines, as well as KRAS -mutant lung cancer (H23, H727) and pancreatic ductal adenocarcinoma (PANC1) cells, were grown in control medium (1 g/L glucose and 10% serum; CTR) or in a FMD-like medium (0.5 g/L glucose and 1% serum), here referred to as short-term starvation condition (STS), which mimics the reduction of extracellular glucose and growth factor concentrations that occurs during prolonged (>48 h) fasting or FMD in vivo, with or without pharmacological concentrations of vitamin C (≥0.3 mM). Consistent with recent findings 4 , KRAS -mutant tumor cells were more susceptible to vitamin C compared with KRAS -wild-type cancer cells (Fig. 1a, b ). When cancer cells were grown under STS conditions before and during treatment, vitamin C-mediated toxicity was strongly enhanced (Fig. 1a ). Conversely, KRAS -wild-type CRC (SW48, HT29), prostate cancer (PC-3), ovarian cancer (COV362) cell lines and a normal colon cell line (CCD841CoN) were resistant to vitamin C when used both as a single agent and in combination with STS<|im_end|> <|im_start|>assistant Scientists from USC and the IFOM Cancer Institute in Milan have found that a fasting-mimicking diet could be more effective at treating some types of cancer when combined with vitamin C. In studies on mice, researchers found that the combination delayed tumor progression in multiple mouse models of colorectal cancer; in some mice, it caused disease regression. The results were published in the journal Nature Communications. "For the first time, we have demonstrated how a completely non-toxic intervention can effectively treat an aggressive cancer," said Valter Longo, the study senior author and the director of the USC Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. "We have taken two treatments that are studied extensively as interventions to delay aging— a fasting-mimicking diet and vitamin C—and combined them as a powerful treatment for cancer." The researchers said that while fasting remains a challenging option for cancer patients, a safer, more feasible option is a low-calorie, plant-based diet that causes cells to respond as if the body were fasting. Their findings suggest that a low-toxicity treatment of fasting-mimicking diet plus vitamin C has the potential to replace more toxic treatments. Results of prior research on the cancer-fighting potential of vitamin C have been mixed. Recent studies, though, are beginning to show some efficacy, especially in combination with chemotherapy. In this new study, the research team wanted to find out whether a fasting-mimicking diet could enhance the high-dose vitamin C tumor-fighting action by creating an environment that would be unsustainable for cancer cells but still safe for normal cells. "Our first in vitro experiment showed remarkable effects," said Longo. "When used alone, fasting-mimicking diet or vitamin C alone reduced cancer cell growth and caused a minor increase in cancer cell death. But when used together, they had a dramatic effect, killing almost all cancerous cells." Longo and his colleagues detected this strong effect only in cancer cells that had a mutation that is regarded as one of the most challenging targets in cancer research. These mutations in the KRAS gene signal the body is resisting most cancer-fighting treatments, and they reduce a patient's survival rate. KRAS mutations occur in approximately a quarter of all human cancers and are estimated to occur in up to half of all colorectal cancers. The study also provided clues about why previous studies of vitamin C as a potential anticancer therapy showed limited efficacy. By itself, a vitamin C treatment appears to trigger the KRAS-mutated cells to protect cancer cells by increasing levels of ferritin, a protein that binds iron. But by reducing levels of ferritin, the scientists managed to increase vitamin C's toxicity for the cancer cells. Amid this finding, the scientists also discovered that colorectal cancer patients with high levels of the iron-binding protein have a lower chance of survival. "In this study, we observed how fasting-mimicking diet cycles are able to increase the effect of pharmacological doses of vitamin C against KRAS-mutated cancers," said Maira Di Tano, a study co-author at the IFOM, FIRC Institute of Molecular Oncology in Milan, Italy. "This occurs through the regulation of the levels of iron and of the molecular mechanisms involved in oxidative stress. The results particularly pointed to a gene that regulates iron levels: heme-oxygenase-1." The research team's prior studies showed that fasting and a fasting-mimicking diet slow cancer's progression and make chemotherapy more effective in tumor cells, while protecting normal cells from chemotherapy-associated side effects. The combination enhances the immune system's anti-tumor response in breast cancer and melanoma mouse models. The scientists believe cancer will eventually be treated with low-toxicity drugs in a manner similar to how antibiotics are used to treat infections that kill particular bacteria, but which can be substituted by other drugs if the first is not effective. To move toward that goal, they say they needed to first test two hypotheses: that their non-toxic combination interventions would work in mice, and that it would look promising for human clinical trials. In this new study, they said that they've demonstrated both. At least five clinical trials, including one at USC on breast cancer and prostate cancer patients, are now investigating the effects of the fasting-mimicking diets in combination with different cancer-fighting drugs. <|im_end|>

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2,356

[ { "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 Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular–metabolic, neuropsychiatric, physiological–anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample ( N =112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer’s disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples. Introduction Cognitive functioning is positively associated with greater longevity and less physical and psychiatric morbidity, and negatively associated with many quantitative disease risk factors and indices. 1 Some specific associations between cognitive functions and health appear to arise because an illness has lowered prior levels of cognitive function. 2 , 3 For others, the direction of causation appears to be the reverse: there are many examples of associations between lower cognitive functions in youth, even childhood, and higher risk of later mental and physical illness and earlier death. 4 , 5 , 6 , 7 , 8 In some cases, it is not clear whether illness affects cognitive functioning or vice versa, or whether both are influenced by some common factors. Many examples of these phenotypic and cognitive–illness associations are shown in Supplementary Table 1 . Overall, the causes of these cognitive–health associations remain unknown and warrant further investigation. It is also well recognized that lower educational attainment is associated with adverse health outcomes, 9 and educational attainment has been used as a successful proxy for cognitive ability in genetic research. 10 , 11 A study that included three cohorts of twins indicated that the association between higher cognitive function and increased lifespan was mostly owing to common genetic effects. 12 The associations between cognitive and health and illness variables may, in part, reflect shared genetic influences. Cognitive functions show moderate heritability, 13 and so do many physical and mental illnesses and health-associated anthropometric measures. 14 Therefore, researchers have begun to examine pleiotropy between scores on tests of cognitive ability and health-related variables. 15 , 16 Pleiotropy is the overlap between the genetic architecture of two or more traits, perhaps owing to a variety of shared causal pathways. 17 Originally, the possibility of pleiotropy in cognitive–health associations was tested using family- and twin-based designs. 18 However, now data from single-nucleotide polymorphism (SNP) genotyping can assess pleiotropy, opening the possibility for larger-scale, population-generalizable studies. Multiple methods can be used to test for pleiotropy using SNP-based genetic data. Calculating genetic correlations between health measures using the summary results of previous genome-wide association studies (GWAS) has become possible using the method of linkage disequilibrium (LD) score regression. 19 In addition, the method of polygenic profile scoring 20 also uses summary GWAS data to test whether genetic liability to a given illness or health-related anthropometric measurement is associated with phenotypes such as cognitive test scores in a second independent data set. For example, lower cognitive functioning was associated significantly in healthy older people with higher polygenic risk for schizophrenia 21 and stroke, 22 but not for dementia. 23 However, most polygenic profile studies to date have been limited in the information they provide on this important topic: they have reported on single health outcomes, and have used relatively small cohorts with available cognitive data. Two recent papers, using polygenic profile scoring and/or LD score regression, have identified pleiotropy between a number of health-related traits and diseases, and educational attainment 15 and between a number of psychiatric disorders and cognitive traits, and behavioural traits. 16 We aimed to discover whether cognitive functioning is associated with many physical and mental health and health-related anthropometric measurements, in part, because of their shared genetic aetiology using the recently released UK Biobank genetic data ( ). 24 We curated GWAS meta-analyses for 24 health-related measures, and used them in two complementary methods to test for cognitive–health pleiotropy. First, we used LD score regression to derive genetic correlations between cognitive function and educational attainment traits measured in UK Biobank, and 24 health-related measures from the GWAS meta-analyses. Second, to provide a measure of the phenotypic variance that these genetic correlations account for, the summary data from GWAS meta-analyses were used to calculate polygenic profile scores in UK Biobank, which includes cognitive, educational and genome-wide SNP data on over 110 000 individuals. We calculated the associations between polygenic profile scores for the 24 health-related measures and the cognitive domains of memory, processing speed and verbal-numerical reasoning, and educational attainment in UK Biobank participants. These new data and results provide a substantial advance in understanding the aetiology of cognitive–health associations. Materials and methods Study design and participants This study includes baseline data from the UK Biobank Study ( ). 24 UK Biobank received ethical approval from the Research Ethics Committee. The Research Ethics Committee reference for UK Biobank is 11/NW/0382. UK Biobank is a health resource for researchers that aims to improve the prevention, diagnosis and treatment of a range of", "role": "user" }, { "content": "Genes that influence people's health also shape how effectively they think, a study shows. Scientists found that genes associated with diseases including Alzheimer's disease, schizophrenia, and autism also have an impact on some cognitive functions. They say the study will help understanding of some of the links between low levels of cognitive function and poor health. An international team, led by the University of Edinburgh, analysed data from around 100,000 people held in the UK Biobank. This national resource of health data can help researchers discover why some people develop particular diseases and others do not. When researchers compared each person's mental test data with their genome, they found that some traits linked to disease and thinking skills shared the same genetic influences. To test the findings, researchers gathered data from previous genetic studies of other mental and physical health factors—such as Alzheimer's disease, schizophrenia and autism. Professor Ian Deary, Director of the Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE) at the University of Edinburgh, who led the research, said: \"In addition to there being shared genetic influences between cognitive skills and some physical and mental health states, the study also found that cognitive skills share genetic influences with brain size, body shape and educational attainments.\" Researcher Saskia Hagenaars said: \"The study supports an existing theory which says that those with better overall health are likely to have higher levels of intelligence.\" Her colleague Dr Sarah Harris said: \"The research highlights the importance of investigating biological pathways that influence both cognitive function and health related traits.\" The study, published in Molecular Psychiatry, involved researchers in the UK, Germany and the US. The analysis was carried out at the University of Edinburgh's Centre for Cognitive Ageing and Epidemiology (CCACE). It was supported by the Medical Research Council (MRC) and the Biotechnology and Biological Research Council (BBSRC) as part of the Lifelong Health and Wellbeing programme, a collaboration between the UK's Research Councils. ", "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 Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular–metabolic, neuropsychiatric, physiological–anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample ( N =112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer’s disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples. Introduction Cognitive functioning is positively associated with greater longevity and less physical and psychiatric morbidity, and negatively associated with many quantitative disease risk factors and indices. 1 Some specific associations between cognitive functions and health appear to arise because an illness has lowered prior levels of cognitive function. 2 , 3 For others, the direction of causation appears to be the reverse: there are many examples of associations between lower cognitive functions in youth, even childhood, and higher risk of later mental and physical illness and earlier death. 4 , 5 , 6 , 7 , 8 In some cases, it is not clear whether illness affects cognitive functioning or vice versa, or whether both are influenced by some common factors. Many examples of these phenotypic and cognitive–illness associations are shown in Supplementary Table 1 . Overall, the causes of these cognitive–health associations remain unknown and warrant further investigation. It is also well recognized that lower educational attainment is associated with adverse health outcomes, 9 and educational attainment has been used as a successful proxy for cognitive ability in genetic research. 10 , 11 A study that included three cohorts of twins indicated that the association between higher cognitive function and increased lifespan was mostly owing to common genetic effects. 12 The associations between cognitive and health and illness variables may, in part, reflect shared genetic influences. Cognitive functions show moderate heritability, 13 and so do many physical and mental illnesses and health-associated anthropometric measures. 14 Therefore, researchers have begun to examine pleiotropy between scores on tests of cognitive ability and health-related variables. 15 , 16 Pleiotropy is the overlap between the genetic architecture of two or more traits, perhaps owing to a variety of shared causal pathways. 17 Originally, the possibility of pleiotropy in cognitive–health associations was tested using family- and twin-based designs. 18 However, now data from single-nucleotide polymorphism (SNP) genotyping can assess pleiotropy, opening the possibility for larger-scale, population-generalizable studies. Multiple methods can be used to test for pleiotropy using SNP-based genetic data. Calculating genetic correlations between health measures using the summary results of previous genome-wide association studies (GWAS) has become possible using the method of linkage disequilibrium (LD) score regression. 19 In addition, the method of polygenic profile scoring 20 also uses summary GWAS data to test whether genetic liability to a given illness or health-related anthropometric measurement is associated with phenotypes such as cognitive test scores in a second independent data set. For example, lower cognitive functioning was associated significantly in healthy older people with higher polygenic risk for schizophrenia 21 and stroke, 22 but not for dementia. 23 However, most polygenic profile studies to date have been limited in the information they provide on this important topic: they have reported on single health outcomes, and have used relatively small cohorts with available cognitive data. Two recent papers, using polygenic profile scoring and/or LD score regression, have identified pleiotropy between a number of health-related traits and diseases, and educational attainment 15 and between a number of psychiatric disorders and cognitive traits, and behavioural traits. 16 We aimed to discover whether cognitive functioning is associated with many physical and mental health and health-related anthropometric measurements, in part, because of their shared genetic aetiology using the recently released UK Biobank genetic data ( ). 24 We curated GWAS meta-analyses for 24 health-related measures, and used them in two complementary methods to test for cognitive–health pleiotropy. First, we used LD score regression to derive genetic correlations between cognitive function and educational attainment traits measured in UK Biobank, and 24 health-related measures from the GWAS meta-analyses. Second, to provide a measure of the phenotypic variance that these genetic correlations account for, the summary data from GWAS meta-analyses were used to calculate polygenic profile scores in UK Biobank, which includes cognitive, educational and genome-wide SNP data on over 110 000 individuals. We calculated the associations between polygenic profile scores for the 24 health-related measures and the cognitive domains of memory, processing speed and verbal-numerical reasoning, and educational attainment in UK Biobank participants. These new data and results provide a substantial advance in understanding the aetiology of cognitive–health associations. Materials and methods Study design and participants This study includes baseline data from the UK Biobank Study ( ). 24 UK Biobank received ethical approval from the Research Ethics Committee. The Research Ethics Committee reference for UK Biobank is 11/NW/0382. UK Biobank is a health resource for researchers that aims to improve the prevention, diagnosis and treatment of a range of<|im_end|> <|im_start|>assistant Genes that influence people's health also shape how effectively they think, a study shows. Scientists found that genes associated with diseases including Alzheimer's disease, schizophrenia, and autism also have an impact on some cognitive functions. They say the study will help understanding of some of the links between low levels of cognitive function and poor health. An international team, led by the University of Edinburgh, analysed data from around 100,000 people held in the UK Biobank. This national resource of health data can help researchers discover why some people develop particular diseases and others do not. When researchers compared each person's mental test data with their genome, they found that some traits linked to disease and thinking skills shared the same genetic influences. To test the findings, researchers gathered data from previous genetic studies of other mental and physical health factors—such as Alzheimer's disease, schizophrenia and autism. Professor Ian Deary, Director of the Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE) at the University of Edinburgh, who led the research, said: "In addition to there being shared genetic influences between cognitive skills and some physical and mental health states, the study also found that cognitive skills share genetic influences with brain size, body shape and educational attainments." Researcher Saskia Hagenaars said: "The study supports an existing theory which says that those with better overall health are likely to have higher levels of intelligence." Her colleague Dr Sarah Harris said: "The research highlights the importance of investigating biological pathways that influence both cognitive function and health related traits." The study, published in Molecular Psychiatry, involved researchers in the UK, Germany and the US. The analysis was carried out at the University of Edinburgh's Centre for Cognitive Ageing and Epidemiology (CCACE). It was supported by the Medical Research Council (MRC) and the Biotechnology and Biological Research Council (BBSRC) as part of the Lifelong Health and Wellbeing programme, a collaboration between the UK's Research Councils. <|im_end|>

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41416, 24264, 22323, 11, 304, 961, 11, 1606, 315, 872, 6222, 19465, 264, 295, 31226, 1701, 279, 6051, 6004, 6560, 12371, 677, 1201, 19465, 828, 320, 7609, 220, 1187, 1226, 58732, 42353, 1950, 8999, 19415, 278, 73279, 369, 220, 1187, 2890, 14228, 11193, 11, 323, 1511, 1124, 304, 1403, 58535, 5528, 311, 1296, 369, 25702, 4235, 12393, 7245, 11345, 18237, 13, 5629, 11, 584, 1511, 29977, 5573, 31649, 311, 43530, 19465, 69916, 1990, 25702, 734, 323, 16627, 93965, 25022, 17303, 304, 6560, 12371, 677, 1201, 11, 323, 220, 1187, 2890, 14228, 11193, 505, 279, 42353, 1950, 8999, 19415, 278, 73279, 13, 10657, 11, 311, 3493, 264, 6767, 315, 279, 14345, 37941, 292, 33373, 430, 1521, 19465, 69916, 2759, 369, 11, 279, 12399, 828, 505, 42353, 1950, 8999, 19415, 278, 73279, 1051, 1511, 311, 11294, 10062, 89305, 5643, 12483, 304, 6560, 12371, 677, 1201, 11, 902, 5764, 25702, 11, 16627, 323, 33869, 25480, 60418, 828, 389, 927, 220, 5120, 220, 931, 7931, 13, 1226, 16997, 279, 30257, 1990, 10062, 89305, 5643, 12483, 369, 279, 220, 1187, 2890, 14228, 11193, 323, 279, 25702, 31576, 315, 5044, 11, 8863, 4732, 323, 36870, 32294, 261, 950, 33811, 11, 323, 16627, 93965, 304, 6560, 12371, 677, 1201, 13324, 13, 4314, 502, 828, 323, 3135, 3493, 264, 12190, 12178, 304, 8830, 279, 264, 295, 31226, 315, 25702, 4235, 12393, 30257, 13, 32009, 323, 5528, 19723, 2955, 323, 13324, 1115, 4007, 5764, 26954, 828, 505, 279, 6560, 12371, 677, 1201, 19723, 320, 7609, 220, 1187, 6560, 12371, 677, 1201, 4036, 31308, 14765, 505, 279, 8483, 50281, 10554, 13, 578, 8483, 50281, 10554, 5905, 369, 6560, 12371, 677, 1201, 374, 220, 806, 20906, 54, 14, 24462, 17, 13, 6560, 12371, 677, 1201, 374, 264, 2890, 5211, 369, 12074, 430, 22262, 311, 7417, 279, 27344, 11, 23842, 323, 6514, 315, 264, 2134, 315, 128257, 198, 128256, 78191, 198, 10172, 288, 430, 10383, 1274, 596, 2890, 1101, 6211, 1268, 13750, 814, 1781, 11, 264, 4007, 5039, 13, 57116, 1766, 430, 21389, 5938, 449, 19338, 2737, 44531, 596, 8624, 11, 58533, 11, 323, 38281, 1101, 617, 459, 5536, 389, 1063, 25702, 5865, 13, 2435, 2019, 279, 4007, 690, 1520, 8830, 315, 1063, 315, 279, 7902, 1990, 3428, 5990, 315, 25702, 734, 323, 8009, 2890, 13, 1556, 6625, 2128, 11, 6197, 555, 279, 3907, 315, 41406, 11, 67458, 828, 505, 2212, 220, 1041, 11, 931, 1274, 5762, 304, 279, 6560, 12371, 677, 1201, 13, 1115, 5426, 5211, 315, 2890, 828, 649, 1520, 12074, 7142, 3249, 1063, 1274, 2274, 4040, 19338, 323, 3885, 656, 539, 13, 3277, 12074, 7863, 1855, 1732, 596, 10723, 1296, 828, 449, 872, 33869, 11, 814, 1766, 430, 1063, 25022, 10815, 311, 8624, 323, 7422, 7512, 6222, 279, 1890, 19465, 34453, 13, 2057, 1296, 279, 14955, 11, 12074, 20802, 828, 505, 3766, 19465, 7978, 315, 1023, 10723, 323, 7106, 2890, 9547, 2345, 21470, 439, 44531, 596, 8624, 11, 58533, 323, 38281, 13, 17054, 29335, 1611, 661, 11, 10783, 315, 279, 14821, 369, 73235, 13381, 287, 323, 73235, 88953, 2508, 320, 3791, 5693, 8, 520, 279, 3907, 315, 41406, 11, 889, 6197, 279, 3495, 11, 1071, 25, 330, 644, 5369, 311, 1070, 1694, 6222, 19465, 34453, 1990, 25702, 7512, 323, 1063, 7106, 323, 10723, 2890, 5415, 11, 279, 4007, 1101, 1766, 430, 25702, 7512, 4430, 19465, 34453, 449, 8271, 1404, 11, 2547, 6211, 323, 16627, 36861, 1392, 1210, 8483, 261, 49746, 689, 67639, 7304, 1590, 1071, 25, 330, 791, 4007, 11815, 459, 6484, 10334, 902, 2795, 430, 1884, 449, 2731, 8244, 2890, 527, 4461, 311, 617, 5190, 5990, 315, 11478, 1210, 6385, 37444, 2999, 21077, 21750, 1071, 25, 330, 791, 3495, 22020, 279, 12939, 315, 24834, 24156, 44014, 430, 10383, 2225, 25702, 734, 323, 2890, 5552, 25022, 1210, 578, 4007, 11, 4756, 304, 60825, 69244, 11, 6532, 12074, 304, 279, 6560, 11, 10057, 323, 279, 2326, 13, 578, 6492, 574, 11953, 704, 520, 279, 3907, 315, 41406, 596, 14821, 369, 73235, 13381, 287, 323, 88953, 2508, 320, 3791, 5693, 570, 1102, 574, 7396, 555, 279, 13235, 8483, 9251, 320, 44, 7532, 8, 323, 279, 12371, 52536, 323, 63711, 8483, 9251, 320, 33, 7497, 7532, 8, 439, 961, 315, 279, 65863, 39122, 6401, 323, 8489, 35214, 18629, 11, 264, 20632, 1990, 279, 6560, 596, 8483, 9251, 82, 13, 220, 128257, 198 ]

1,733

[ { "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 The Zc3h8 gene encodes a protein with three zinc finger motifs in the C-terminal region. The protein has been identified as a component of the Little Elongation Complex, involved in transcription of small nuclear RNAs. ZC3H8 is overexpressed in a number of human and mouse breast cancer cell lines, and elevated mRNA levels are associated with a poorer prognosis for women with breast cancer. Methods We used RNA silencing to decrease levels of expression in mouse mammary tumor cells and overexpression of ZC3H8 in cells derived from the normal mouse mammary gland. We measured characteristics of cell behavior in vitro, including proliferation, migration, invasion, growth in soft agar, and spheroid growth. We assessed the ability of these cells to form tumors in syngeneic BALB/c mice. ZC3H8 protein was visualized in cells using confocal microscopy. Results Tumor cells with lower ZC3H8 expression exhibited decreased proliferation rates, slower migration, reduced ability to invade through a basement membrane, and decreased anchorage independent growth in vitro. Cells with lower ZC3H8 levels formed fewer and smaller tumors in animals. Overexpression of ZC3H8 in non-tumorigenic COMMA-D cells led to an opposite effect. ZC3H8 protein localized to both PML bodies and Cajal bodies within the nucleus. ZC3H8 has a casein kinase 2 (CK2) phosphorylation site near the N-terminus, and a CK2 inhibitor caused the numerous PML bodies and ZC3H8 to coalesce to a few larger bodies. Removal of the inhibitor restored PML bodies to their original state. A mutant ZC3H8 lacking the predicted CK2 phosphorylation site showed localization and numbers of ZC3H8/PML bodies similar to wild type. In contrast, a mutant constructed with a glutamic acid in place of the phosphorylatable threonine showed dramatically increased numbers of smaller nuclear foci. Conclusions These experiments demonstrate that Zc3h8 expression contributes to aggressive tumor cell behavior in vitro and in vivo. Our studies show that ZC3H8 integrity is key to maintenance of PML bodies. The work provides a link between the Little Elongation Complex, PML bodies, and the cancer cell phenotype. Peer Review reports Background The zinc finger protein ZC3H8 was first identified as expressed in fetal liver [ 1 ], but moderate levels can be detected in a variety of tissues, and the gene is amplified in 2–6% of solid tumors of the breast [ 2 ]. The Zc3h8 gene encodes a protein of predicted molecular weight 34 kDa of unknown function. There are three predicted zinc fingers in the carboxy terminal domain, and a potential casein kinase 2 (CK2) phosphorylation site at threonine 32 [ 3 ] (Fig. 1a ). Zinc finger proteins of this arrangement (CCCH/C3H1) are found in eukaryotes including yeasts, trypanosomes, plants, and animals and have been shown to bind RNA and be involved in post-transcriptional regulatory processes in several cases [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. ZC3H8 specifically was identified in a cross-linking study of the human embryonic kidney cell proteome bound to mRNA [ 12 ]. Recent work has demonstrated that the zinc finger domains of some of the family members from disparate species are in fact, functionally interchangeable, thus suggesting a common strategy for binding RNA [ 13 ]. Fig. 1 ZC3H8 predicted structure and expression in tumors. a ) Domain map of ZC3H8 shows a putative CK2 phosphorylation site at amino acid T32 and three putative C3H1 zinc finger motifs in the c-terminus. b ) RT-qPCR survey of tumor cell lines derived from mouse mammary tissue expressing Zc3h8 . Experiments were performed in triplicate, error bars represent standard deviation. c ) Kaplan-Meier plot of disease-specific survival of breast cancer with high and low expression of ZC3H8, from Prognoscan data set GSE1456-GPL97, p value = 0.043377, hazard ratio 2.30, 95% CI = 0.85–6.24, Cox p value = 0.100218 [ 24 , 25 ] Full size image Hu et al. identified ZC3H8 as a component of the human little elongation complex (LEC), which functions in initiation and elongation of transcription of snRNA genes [ 14 ]. Knockdown of expression of the ICE1 subunit of the LEC led to decreased occupancy at U11 and U12 promoters, though knockdown of ZC3H8 had no effect on promoter binding [ 14 ]. Additionally, in a global analysis of snRNA expression, loss of ICE1 or ELL led to general defects in snRNA expression, while loss of ICE2 and ZC3H8 components did not affect snRNA expression [ 14 ]. Egloff et al. recently determined that ZC3H8 functions as a key component of the LEC, in combination with ICE1, ICE2, ELL, and the 7SK snRNP; when the RNA component was depleted, ZC3H8 association with the complex was abolished [ 15 ]. Takahashi et al., however, did not find evidence of ZC3H8 in complex with LEC recruited to snRNA genes by the mediator component MED26 [ 16 ], perhaps due to the existence of multiple forms of the LEC. This leaves the precise role of ZC3H8 in the LEC in question. Given the suggested role of CCCH zinc finger proteins in RNA binding, it is possible that ZC3H8 plays a role in processing or maturation of LEC transcription products rather than direct transcriptional events. Several studies have localized the ZC3H8 protein to distinct nuclear bodies. The LEC and associated proteins, including ZC3H8, were found in Cajal bodies, colocalized with COILIN, a marker for that structure [ 14 ]. MED26, a mediator component, has also been associated with the LEC in Cajal bodies, but ZC3H8 was not linked to the complex in this study [ 16 ]. However, Fong et al. performed genome scale profiling and tandem affinity-mass spectrometric analysis of a large number of proteins localized to distinct nuclear bodies, and found instead that ZC3H8, along with many other RNA binding proteins, was found in nuclear paraspeckles [ 17 ]. These subnuclear bodies are sites of retention of edited RNAs and long non-coding RNAs involved in regulation [ 18 , 19 ]. The noted amplification of ZC3H8 in human breast tumors, the potential regulatory effect of a known", "role": "user" }, { "content": "Villanova University biology professor Janice Knepper, PhD, and her students have discovered that a gene, previously poorly characterized, can be associated with breast cancer. Over the last eight years, Knepper and her students have been working with the gene, ZC3H8, simply known has Fliz1. The findings were recently published in BMC Cancer, a peer-reviewed open-source medical journal. Researchers and oncologists relentlessly study how genes affect cancer development and progression. When looking at individual genes in cancer, the genes either help promote it, which leads to more aggressive forms of cancer, or they help prevent it. The Villanova team discovered that Fliz1 can contribute to more aggressive behavior in cancer. However, this is just the start of the process. \"In terms of the impact on the medical field, this is step one,\" said Knepper. \"There are more than 20,000 genes in the human body and 70 are currently used to assess prognosis for breast cancer. We're not oncologists, but we certainly can see how down the road clinicians would be able to better identify disruptive genes in a breast cancer diagnosis. This gene was certainly not on their radar before.\" Fliz1 is an essential gene, one that cells cannot live without. The team is continuing additional tests and research to determine cellular effects as a result of alterations to the protein sequence. Similar to adjusting the volume on a speaker, they're looking to find out how much is too much or not enough that could damage the cell. \"We think this is the first major milestone and is just the tip of the iceberg,\" said John Schmidt, PhD, lead author and visiting assistant professor in Villanova's biology department. \"We don't quite yet have a grip on the mechanism of this protein, but this is certainly the start of something more. It opens up a new pathway in molecular biology.\" This new research involved former Villanova undergraduate students, five of whom are listed as co-authors on the research. They are: Emily R. Duffner, '17 College of Liberal Arts and Sciences (CLAS), Sara G. Radecki, '14 CLAS, Gerard T. Walker, '17 CLAS, Amber Shelton, '17 CLAS, '18 MS and Tianjiao Wang, '14 CLAS. The students began working in Dr. Knepper's lab during their sophomore or junior years. Former Villanova research associate professor Keith Danielson, PhD, was also involved in the research. \"It was a wonderful opportunity for our students, and they certainly rose to the occasion,\" said Knepper, noting that all five are currently working or doing postgraduate study in science or medical fields. ", "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 The Zc3h8 gene encodes a protein with three zinc finger motifs in the C-terminal region. The protein has been identified as a component of the Little Elongation Complex, involved in transcription of small nuclear RNAs. ZC3H8 is overexpressed in a number of human and mouse breast cancer cell lines, and elevated mRNA levels are associated with a poorer prognosis for women with breast cancer. Methods We used RNA silencing to decrease levels of expression in mouse mammary tumor cells and overexpression of ZC3H8 in cells derived from the normal mouse mammary gland. We measured characteristics of cell behavior in vitro, including proliferation, migration, invasion, growth in soft agar, and spheroid growth. We assessed the ability of these cells to form tumors in syngeneic BALB/c mice. ZC3H8 protein was visualized in cells using confocal microscopy. Results Tumor cells with lower ZC3H8 expression exhibited decreased proliferation rates, slower migration, reduced ability to invade through a basement membrane, and decreased anchorage independent growth in vitro. Cells with lower ZC3H8 levels formed fewer and smaller tumors in animals. Overexpression of ZC3H8 in non-tumorigenic COMMA-D cells led to an opposite effect. ZC3H8 protein localized to both PML bodies and Cajal bodies within the nucleus. ZC3H8 has a casein kinase 2 (CK2) phosphorylation site near the N-terminus, and a CK2 inhibitor caused the numerous PML bodies and ZC3H8 to coalesce to a few larger bodies. Removal of the inhibitor restored PML bodies to their original state. A mutant ZC3H8 lacking the predicted CK2 phosphorylation site showed localization and numbers of ZC3H8/PML bodies similar to wild type. In contrast, a mutant constructed with a glutamic acid in place of the phosphorylatable threonine showed dramatically increased numbers of smaller nuclear foci. Conclusions These experiments demonstrate that Zc3h8 expression contributes to aggressive tumor cell behavior in vitro and in vivo. Our studies show that ZC3H8 integrity is key to maintenance of PML bodies. The work provides a link between the Little Elongation Complex, PML bodies, and the cancer cell phenotype. Peer Review reports Background The zinc finger protein ZC3H8 was first identified as expressed in fetal liver [ 1 ], but moderate levels can be detected in a variety of tissues, and the gene is amplified in 2–6% of solid tumors of the breast [ 2 ]. The Zc3h8 gene encodes a protein of predicted molecular weight 34 kDa of unknown function. There are three predicted zinc fingers in the carboxy terminal domain, and a potential casein kinase 2 (CK2) phosphorylation site at threonine 32 [ 3 ] (Fig. 1a ). Zinc finger proteins of this arrangement (CCCH/C3H1) are found in eukaryotes including yeasts, trypanosomes, plants, and animals and have been shown to bind RNA and be involved in post-transcriptional regulatory processes in several cases [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. ZC3H8 specifically was identified in a cross-linking study of the human embryonic kidney cell proteome bound to mRNA [ 12 ]. Recent work has demonstrated that the zinc finger domains of some of the family members from disparate species are in fact, functionally interchangeable, thus suggesting a common strategy for binding RNA [ 13 ]. Fig. 1 ZC3H8 predicted structure and expression in tumors. a ) Domain map of ZC3H8 shows a putative CK2 phosphorylation site at amino acid T32 and three putative C3H1 zinc finger motifs in the c-terminus. b ) RT-qPCR survey of tumor cell lines derived from mouse mammary tissue expressing Zc3h8 . Experiments were performed in triplicate, error bars represent standard deviation. c ) Kaplan-Meier plot of disease-specific survival of breast cancer with high and low expression of ZC3H8, from Prognoscan data set GSE1456-GPL97, p value = 0.043377, hazard ratio 2.30, 95% CI = 0.85–6.24, Cox p value = 0.100218 [ 24 , 25 ] Full size image Hu et al. identified ZC3H8 as a component of the human little elongation complex (LEC), which functions in initiation and elongation of transcription of snRNA genes [ 14 ]. Knockdown of expression of the ICE1 subunit of the LEC led to decreased occupancy at U11 and U12 promoters, though knockdown of ZC3H8 had no effect on promoter binding [ 14 ]. Additionally, in a global analysis of snRNA expression, loss of ICE1 or ELL led to general defects in snRNA expression, while loss of ICE2 and ZC3H8 components did not affect snRNA expression [ 14 ]. Egloff et al. recently determined that ZC3H8 functions as a key component of the LEC, in combination with ICE1, ICE2, ELL, and the 7SK snRNP; when the RNA component was depleted, ZC3H8 association with the complex was abolished [ 15 ]. Takahashi et al., however, did not find evidence of ZC3H8 in complex with LEC recruited to snRNA genes by the mediator component MED26 [ 16 ], perhaps due to the existence of multiple forms of the LEC. This leaves the precise role of ZC3H8 in the LEC in question. Given the suggested role of CCCH zinc finger proteins in RNA binding, it is possible that ZC3H8 plays a role in processing or maturation of LEC transcription products rather than direct transcriptional events. Several studies have localized the ZC3H8 protein to distinct nuclear bodies. The LEC and associated proteins, including ZC3H8, were found in Cajal bodies, colocalized with COILIN, a marker for that structure [ 14 ]. MED26, a mediator component, has also been associated with the LEC in Cajal bodies, but ZC3H8 was not linked to the complex in this study [ 16 ]. However, Fong et al. performed genome scale profiling and tandem affinity-mass spectrometric analysis of a large number of proteins localized to distinct nuclear bodies, and found instead that ZC3H8, along with many other RNA binding proteins, was found in nuclear paraspeckles [ 17 ]. These subnuclear bodies are sites of retention of edited RNAs and long non-coding RNAs involved in regulation [ 18 , 19 ]. The noted amplification of ZC3H8 in human breast tumors, the potential regulatory effect of a known<|im_end|> <|im_start|>assistant Villanova University biology professor Janice Knepper, PhD, and her students have discovered that a gene, previously poorly characterized, can be associated with breast cancer. Over the last eight years, Knepper and her students have been working with the gene, ZC3H8, simply known has Fliz1. The findings were recently published in BMC Cancer, a peer-reviewed open-source medical journal. Researchers and oncologists relentlessly study how genes affect cancer development and progression. When looking at individual genes in cancer, the genes either help promote it, which leads to more aggressive forms of cancer, or they help prevent it. The Villanova team discovered that Fliz1 can contribute to more aggressive behavior in cancer. However, this is just the start of the process. "In terms of the impact on the medical field, this is step one," said Knepper. "There are more than 20,000 genes in the human body and 70 are currently used to assess prognosis for breast cancer. We're not oncologists, but we certainly can see how down the road clinicians would be able to better identify disruptive genes in a breast cancer diagnosis. This gene was certainly not on their radar before." Fliz1 is an essential gene, one that cells cannot live without. The team is continuing additional tests and research to determine cellular effects as a result of alterations to the protein sequence. Similar to adjusting the volume on a speaker, they're looking to find out how much is too much or not enough that could damage the cell. "We think this is the first major milestone and is just the tip of the iceberg," said John Schmidt, PhD, lead author and visiting assistant professor in Villanova's biology department. "We don't quite yet have a grip on the mechanism of this protein, but this is certainly the start of something more. It opens up a new pathway in molecular biology." This new research involved former Villanova undergraduate students, five of whom are listed as co-authors on the research. They are: Emily R. Duffner, '17 College of Liberal Arts and Sciences (CLAS), Sara G. Radecki, '14 CLAS, Gerard T. Walker, '17 CLAS, Amber Shelton, '17 CLAS, '18 MS and Tianjiao Wang, '14 CLAS. The students began working in Dr. Knepper's lab during their sophomore or junior years. Former Villanova research associate professor Keith Danielson, PhD, was also involved in the research. "It was a wonderful opportunity for our students, and they certainly rose to the occasion," said Knepper, noting that all five are currently working or doing postgraduate study in science or medical fields. <|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 // <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Robert A. Kazmierczak 1 , * , Bakul Dhagat-Mehta 1 , * , Elke Gulden 2 , Li Lee 3 , 4 , Lixin Ma 3 , 4 , Clintin P. Davis-Stober 5 , Austen A. Barnett 6 and Chiswili Yves Chabu 7 1 Cancer Research Center, Columbia, MO, USA 2 Department of Immunobiology, Yale University, New Haven, CT, USA 3 Department of Radiology and Department of Physics and Astronomy, University of Missouri, Columbia, MO, USA 4 Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA 5 Department of Psychological Sciences, Institute for Data Science & Informatics, University of Missouri, Columbia, MO, USA 6 Department of Biology, DeSales University, Center Valley, PA, USA 7 Division of Biological Sciences, University of Missouri, Columbia, MO, USA * These authors contributed equally to this work Correspondence to: Chiswili Yves Chabu, email: [email protected] Keywords: salmonella; cancer targeting; prostate cancer; immunotherapy; TRAMP Received: July 02, 2020 Accepted: September 24, 2020 Published: November 03, 2020 Copyright: © 2020 Kazmierczak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Conventional cancer chemotherapies are not fully efficacious and do not target tumors, leading to significant treatment-related morbidities. A number of genetically attenuated cancer-targeting bacteria are being developed to safely target tumors in vivo . Here we report the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer. CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals. In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable. Moreover, tumor-targeted CRC2631 generates an anti-tumor immune response. Combination of CRC2631 with checkpoint blockade reduces metastasis burden. Collectively, these findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies. x2o[53934661] begin <html> j2j[b747111] #content div.table-title * { font-family: Arial, sans-serif; font-size: 12px; text-transform: none !important; } #content div.table-title { font-family: Arial, sans-serif; font-size: 12px; text-transform: none !important; text-align: left; padding-left: 0.5em; padding-right: 0.5em; padding-top: 0.25em; padding-bottom: 0.25em; margin-top: 0.25em; } .OncoFigure.allow-scroll { overflow: auto; } #content div.table-container { display: block; text-align: center; margin-left: 0px; margin-right: auto; margin-bottom: 2em; margin-top: 2em; padding-right: 2em; background-color: #F6F6F9; border: 1px solid #E2E2E2; vertical-align: middle; width: 700px; -moz-box-shadow: 1px 1px 4px #888; -webkit-box-shadow: 1px 1px 4px #888; box-shadow: 1px 1px 4px #888; } #content div.table-body { width: 685px; padding-left: 5px; padding-right: 5px; overflow-x: auto; white-space: nowrap; } #content div.table-container img.inline-graphic { width:100%; margin:auto; } .BodyText table { background-color: #FFF; text-align: center; margin-left: auto; margin-right: auto; font-size: 12px; margin-top: 0.5em; margin-bottom: 0.5em; border-spacing: 1px; border-collapse: collapse; border-width: 1px 0 1px 0; border-style: solid; border-color: #000; } .BodyText table td { border: 1px solid #000; font-family: Arial, Helvetica, sans-serif; font-weight: normal; font-style: normal; font-size: 11px; line-height: 14px; text-decoration: none; font-variant: normal; text-indent: 2.16em; padding-left: 0.5em; padding-right: 0.5em; padding-top: 0.25em; padding-bottom: 0.25em; color: #221f22; margin: 0em; text-indent: 0; } sub { vertical-align: sub; font-size: x-small; line-height: 0px; } sup { vertical-align: super; font-size: x-small; line-height: 0px; } .OncoFigure * { text-transform: none !important; } .RedHeading, .section-container#Discussion > .SubHeading { color: #ac2b31 !important; } h3#Abbreviations { font-size: 1.1em !important; padding-bottom:0px; } Introduction Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities [ 1 , 2 ]. Efforts to develop cancer-targeted therapeutics include the use of cancer-targeting bacteria to achieve cancer-specific cell killing. However, it has been a challenge to transition these bacteria-based approaches to the clinic due to a lack of a bacteria strain that is both safe and efficacious. Several bacterial strains have been developed, including the Salmonella enterica serovar Typhimurium strain VNP20009, one of the most studied tumor-targeting strains. VNP20009 was first isolated in a genetic screen for hyperinvasion mutants using a library of mutant strains derived from ultraviolet and chemical mutagenesis of strain 14028 [ 3 ]. Additional targeted genetic mutations were introduced in the msb , lipid A, and purl loci to attenuate VNP20009 and generate purine auxotrophy, respectively [ 4 ]. The safety and efficacy of VNP20009 were demonstrated in a wide range of pre-clinical animal cancer models [ 4 – 6 ], ultimately leading to clinical trials on metastatic melanoma or renal cell carcinoma patients [ 7 ]. The majority of VNP20009 pre-clinical studies relied on data derived from minimally aggressive tumors in immune-compromised animals [ 4 – 6 ], raising translatability concerns. Indeed, VNP20009 showed moderate toxicity but no anti-tumor effect in the aforementioned clinical studies [ 7 ], presumably because it was rapidly cleared by patients’ immune system. These studies have provided significant clinical insights and have underscored the need for cancer-targeting biologics that are not only safe and efficacious, but also likely to translate to the clinic. We previously reported a tumor-targeting Salmonella typhimurium strain CRC2631 [ 8 ]. CRC2631 was derived from a parent strain (CRC1674) that was derived from the prototrophic wild-type Salmonella typhimurium LT2 strain [ 9 ] (Supplementary Table 1). CRC1674 was isolated in a genetic screen for mutants that selectively kill breast and prostate cancer cells in vitro using the Demerec collection [ 10 ]. This collection consists of mutant strains that arose naturally under nutrient-limiting conditions for over four decades, generating a wealth of genetically diverse and potentially attenuated strains [ 10 – 14 ]. CRC1674 was further attenuated by targeted deletion of rfaH and thyA genes. We also disrupted the aroA gene by Tn 10 d (Tc) transposon insertion. These modifications produced the attenuated strain CRC2631. rfaH is a positive transcriptional regulator of lipopolysaccharides (LPS) biosynthesis and its deletion [ 15 , 16 ] lowers the expression of core LPS genes. The aroA transposon insertion and thyA deletion introduced auxotrophy for aromatic amino acids and thymine respectively [ 17 – 19 ]. Here, we report the toxicological and in vivo tumor-targeting profiles of CRC2631 in the syngeneic and", "role": "user" }, { "content": "The body's immune system is the first line of defense against infections like bacteria, viruses or cancers. Some cancers, however, have developed the art of molecular deception to avoid destruction by the body's immune system. However, a University of Missouri researcher might have found a new way to help the body's immune system get past that deception and destroy the cancer. \"Normally, your body's immune cells are constantly on patrol to identify and destroy foreign entities in the body,\" said Yves Chabu, an assistant professor in the Division of Biological Sciences. \"Normal cells put up a 'don't-eat-me' molecular flag that is recognized by immune cells, thereby preventing destruction of normal tissues. But some cancers have also developed the ability to mimic normal cells and produce this 'don't eat me' signal. As a consequence, the immune system fails to recognize the cancer as a defective tissue and leaves it alone, which is bad news for the patient.\" Immunotherapies are cancer drugs that essentially block the \"don't-eat-me\" signal coming from the cancer and allow the immune system to kill it. Chabu, whose appointment is in the College of Arts and Science, said while these immunotherapies work for certain types of cancers, prostate cancer is highly immunosuppressive, meaning the cancer's physical and molecular environments simply overpower the body's immune system. But Chabu might have unlocked a solution with help from a more than 50-year-old strain of bacteria. Robert A. Kazmierczak with the Cancer Research Center helped developed a genetically distinct and non-toxic strain of salmonella called CRC2631 to select and kill cancer cells. Kazmierczak has a courtesy appointment with the Division of Biological Sciences at the University of Missouri. Credit: Courtesy of Cancer Research Center \"Cancers are different in one individual to the next, even when they affect the same tissue,\" Chabu said. \"These interpersonal differences contribute to whether or not a particular therapy will effectively kill the cancer and help the patient. The bacteria itself is genetically pliable, therefore it can be genetically modified to overcome patient-specific therapeutic limits. Imagine a patient whose cancer isn't responding to traditional therapies and has no other treatment options. One can envision genetically modifying the bacteria such that it can unload therapeutics that specifically exploit that cancer's unique vulnerabilities and kill it.\" In a previous study, scientists at the Cancer Research Center and the University of Missouri developed a genetically distinct and non-toxic strain of salmonella called CRC2631 to select and kill cancer cells. CRC2631 was derived from another strain of salmonella that had been stored at room temperature for more than half a century. Now, scientists like Chabu are demonstrating the ability for CRC2631, which enthusiastically targets cancerous tumors, to be used to unleash the body's immune system against prostate cancer. \"Because CRC2631 preferentially colonizes tumor cells, the effect is mainly localized to the tumor,\" Chabu said. \"The use of CRC2631 to design and deliver patient-tailored therapeutics foretells potential in precision medicine, or the ability to tailor a treatment to a specific patient.\" \"Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model,\" was published in Oncotarget. ", "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 // <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Robert A. Kazmierczak 1 , * , Bakul Dhagat-Mehta 1 , * , Elke Gulden 2 , Li Lee 3 , 4 , Lixin Ma 3 , 4 , Clintin P. Davis-Stober 5 , Austen A. Barnett 6 and Chiswili Yves Chabu 7 1 Cancer Research Center, Columbia, MO, USA 2 Department of Immunobiology, Yale University, New Haven, CT, USA 3 Department of Radiology and Department of Physics and Astronomy, University of Missouri, Columbia, MO, USA 4 Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA 5 Department of Psychological Sciences, Institute for Data Science & Informatics, University of Missouri, Columbia, MO, USA 6 Department of Biology, DeSales University, Center Valley, PA, USA 7 Division of Biological Sciences, University of Missouri, Columbia, MO, USA * These authors contributed equally to this work Correspondence to: Chiswili Yves Chabu, email: [email protected] Keywords: salmonella; cancer targeting; prostate cancer; immunotherapy; TRAMP Received: July 02, 2020 Accepted: September 24, 2020 Published: November 03, 2020 Copyright: © 2020 Kazmierczak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Conventional cancer chemotherapies are not fully efficacious and do not target tumors, leading to significant treatment-related morbidities. A number of genetically attenuated cancer-targeting bacteria are being developed to safely target tumors in vivo . Here we report the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer. CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals. In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable. Moreover, tumor-targeted CRC2631 generates an anti-tumor immune response. Combination of CRC2631 with checkpoint blockade reduces metastasis burden. Collectively, these findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies. x2o[53934661] begin <html> j2j[b747111] #content div.table-title * { font-family: Arial, sans-serif; font-size: 12px; text-transform: none !important; } #content div.table-title { font-family: Arial, sans-serif; font-size: 12px; text-transform: none !important; text-align: left; padding-left: 0.5em; padding-right: 0.5em; padding-top: 0.25em; padding-bottom: 0.25em; margin-top: 0.25em; } .OncoFigure.allow-scroll { overflow: auto; } #content div.table-container { display: block; text-align: center; margin-left: 0px; margin-right: auto; margin-bottom: 2em; margin-top: 2em; padding-right: 2em; background-color: #F6F6F9; border: 1px solid #E2E2E2; vertical-align: middle; width: 700px; -moz-box-shadow: 1px 1px 4px #888; -webkit-box-shadow: 1px 1px 4px #888; box-shadow: 1px 1px 4px #888; } #content div.table-body { width: 685px; padding-left: 5px; padding-right: 5px; overflow-x: auto; white-space: nowrap; } #content div.table-container img.inline-graphic { width:100%; margin:auto; } .BodyText table { background-color: #FFF; text-align: center; margin-left: auto; margin-right: auto; font-size: 12px; margin-top: 0.5em; margin-bottom: 0.5em; border-spacing: 1px; border-collapse: collapse; border-width: 1px 0 1px 0; border-style: solid; border-color: #000; } .BodyText table td { border: 1px solid #000; font-family: Arial, Helvetica, sans-serif; font-weight: normal; font-style: normal; font-size: 11px; line-height: 14px; text-decoration: none; font-variant: normal; text-indent: 2.16em; padding-left: 0.5em; padding-right: 0.5em; padding-top: 0.25em; padding-bottom: 0.25em; color: #221f22; margin: 0em; text-indent: 0; } sub { vertical-align: sub; font-size: x-small; line-height: 0px; } sup { vertical-align: super; font-size: x-small; line-height: 0px; } .OncoFigure * { text-transform: none !important; } .RedHeading, .section-container#Discussion > .SubHeading { color: #ac2b31 !important; } h3#Abbreviations { font-size: 1.1em !important; padding-bottom:0px; } Introduction Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities [ 1 , 2 ]. Efforts to develop cancer-targeted therapeutics include the use of cancer-targeting bacteria to achieve cancer-specific cell killing. However, it has been a challenge to transition these bacteria-based approaches to the clinic due to a lack of a bacteria strain that is both safe and efficacious. Several bacterial strains have been developed, including the Salmonella enterica serovar Typhimurium strain VNP20009, one of the most studied tumor-targeting strains. VNP20009 was first isolated in a genetic screen for hyperinvasion mutants using a library of mutant strains derived from ultraviolet and chemical mutagenesis of strain 14028 [ 3 ]. Additional targeted genetic mutations were introduced in the msb , lipid A, and purl loci to attenuate VNP20009 and generate purine auxotrophy, respectively [ 4 ]. The safety and efficacy of VNP20009 were demonstrated in a wide range of pre-clinical animal cancer models [ 4 – 6 ], ultimately leading to clinical trials on metastatic melanoma or renal cell carcinoma patients [ 7 ]. The majority of VNP20009 pre-clinical studies relied on data derived from minimally aggressive tumors in immune-compromised animals [ 4 – 6 ], raising translatability concerns. Indeed, VNP20009 showed moderate toxicity but no anti-tumor effect in the aforementioned clinical studies [ 7 ], presumably because it was rapidly cleared by patients’ immune system. These studies have provided significant clinical insights and have underscored the need for cancer-targeting biologics that are not only safe and efficacious, but also likely to translate to the clinic. We previously reported a tumor-targeting Salmonella typhimurium strain CRC2631 [ 8 ]. CRC2631 was derived from a parent strain (CRC1674) that was derived from the prototrophic wild-type Salmonella typhimurium LT2 strain [ 9 ] (Supplementary Table 1). CRC1674 was isolated in a genetic screen for mutants that selectively kill breast and prostate cancer cells in vitro using the Demerec collection [ 10 ]. This collection consists of mutant strains that arose naturally under nutrient-limiting conditions for over four decades, generating a wealth of genetically diverse and potentially attenuated strains [ 10 – 14 ]. CRC1674 was further attenuated by targeted deletion of rfaH and thyA genes. We also disrupted the aroA gene by Tn 10 d (Tc) transposon insertion. These modifications produced the attenuated strain CRC2631. rfaH is a positive transcriptional regulator of lipopolysaccharides (LPS) biosynthesis and its deletion [ 15 , 16 ] lowers the expression of core LPS genes. The aroA transposon insertion and thyA deletion introduced auxotrophy for aromatic amino acids and thymine respectively [ 17 – 19 ]. Here, we report the toxicological and in vivo tumor-targeting profiles of CRC2631 in the syngeneic and<|im_end|> <|im_start|>assistant The body's immune system is the first line of defense against infections like bacteria, viruses or cancers. Some cancers, however, have developed the art of molecular deception to avoid destruction by the body's immune system. However, a University of Missouri researcher might have found a new way to help the body's immune system get past that deception and destroy the cancer. "Normally, your body's immune cells are constantly on patrol to identify and destroy foreign entities in the body," said Yves Chabu, an assistant professor in the Division of Biological Sciences. "Normal cells put up a 'don't-eat-me' molecular flag that is recognized by immune cells, thereby preventing destruction of normal tissues. But some cancers have also developed the ability to mimic normal cells and produce this 'don't eat me' signal. As a consequence, the immune system fails to recognize the cancer as a defective tissue and leaves it alone, which is bad news for the patient." Immunotherapies are cancer drugs that essentially block the "don't-eat-me" signal coming from the cancer and allow the immune system to kill it. Chabu, whose appointment is in the College of Arts and Science, said while these immunotherapies work for certain types of cancers, prostate cancer is highly immunosuppressive, meaning the cancer's physical and molecular environments simply overpower the body's immune system. But Chabu might have unlocked a solution with help from a more than 50-year-old strain of bacteria. Robert A. Kazmierczak with the Cancer Research Center helped developed a genetically distinct and non-toxic strain of salmonella called CRC2631 to select and kill cancer cells. Kazmierczak has a courtesy appointment with the Division of Biological Sciences at the University of Missouri. Credit: Courtesy of Cancer Research Center "Cancers are different in one individual to the next, even when they affect the same tissue," Chabu said. "These interpersonal differences contribute to whether or not a particular therapy will effectively kill the cancer and help the patient. The bacteria itself is genetically pliable, therefore it can be genetically modified to overcome patient-specific therapeutic limits. Imagine a patient whose cancer isn't responding to traditional therapies and has no other treatment options. One can envision genetically modifying the bacteria such that it can unload therapeutics that specifically exploit that cancer's unique vulnerabilities and kill it." In a previous study, scientists at the Cancer Research Center and the University of Missouri developed a genetically distinct and non-toxic strain of salmonella called CRC2631 to select and kill cancer cells. CRC2631 was derived from another strain of salmonella that had been stored at room temperature for more than half a century. Now, scientists like Chabu are demonstrating the ability for CRC2631, which enthusiastically targets cancerous tumors, to be used to unleash the body's immune system against prostate cancer. "Because CRC2631 preferentially colonizes tumor cells, the effect is mainly localized to the tumor," Chabu said. "The use of CRC2631 to design and deliver patient-tailored therapeutics foretells potential in precision medicine, or the ability to tailor a treatment to a specific patient." "Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model," was published in Oncotarget. <|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 It has been more than 50 years since the discovery of dinucleoside polyphosphates (Np n Ns) and yet their roles and mechanisms of action remain unclear. Here, we show that both methylated and non-methylated Np n Ns serve as RNA caps in Escherichia coli . Np n Ns are excellent substrates for T7 and E. coli RNA polymerases (RNAPs) and efficiently initiate transcription. We demonstrate, that the E. coli enzymes RNA 5′-pyrophosphohydrolase (RppH) and bis(5′-nucleosyl)-tetraphosphatase (ApaH) are able to remove the Np n N-caps from RNA. ApaH is able to cleave all Np n N-caps, while RppH is unable to cleave the methylated forms suggesting that the methylation adds an additional layer to RNA stability regulation. Our work introduces a different perspective on the chemical structure of RNA in prokaryotes and on the role of RNA caps. We bring evidence that small molecules, such as Np n Ns are incorporated into RNA and may thus influence the cellular metabolism and RNA turnover. Introduction The role and chemical structure of the 5′-end of prokaryotic RNA is still unclear. The discovery of nicotinamide adenine dinucleotide (NAD) 1 , 2 and coenzyme A (CoA) 3 5′-RNA caps changed the perception of the RNA structure. 5′-caps are usually cleaved by NudiX enzymes 4 (NudC (refs. 1 , 5 , 6 ), RNA 5′-pyrophosphohydrolase (RppH) 7 , 8 ), which can, besides their decapping role (eukaryotic Nudt16 and Dcp2 (refs. 9 , 10 )), also cleave nucleoside diphosphates linked to another moiety (e.g., dinucleoside polyphosphates (Np n Ns) 11 , 12 ). Np n Ns are ubiquitous molecules 13 , 14 , 15 present in both prokaryotic and eukaryotic organisms.Their intracellular concentrations can increase from the μM to the mM range under stress conditions 11 , 16 , which is why they are often called alarmones. Nevertheless, the molecular targets of the alarm signaled by Np n Ns have not been identified yet. The main source of the Np n Ns is the back reaction of an aminoacyl adenylate with an acceptor nucleotide catalyzed by various aminoacyl-tRNA synthetases 17 . But there is evidence that e.g., the ubiquitinylation process can lead to Ap 4 A or Ap 3 A (ref. 18 ). Even though they have a similar chemical structure to known RNA caps, such as NAD (refs. 1 , 19 , 20 ) and the 7-methylguanylate cap 21 , they were never detected as a part of RNA. In this work, we show that Np n Ns can be accepted by two types of RNA polymerases (RNAPs; bacteriophage T7 and E. coli ) as non-canonical initiating nucleotides (NCINs) in in vitro transcription. To prove the existence of Np n N-RNA caps in vivo, we develop an liquid chromatography–mass spectrometry (LC–MS) technique for the detection of Np n Ns in isolated and digested RNA. We detect six previously unknown Np n N-caps (Ap 3 A, m 6 Ap 3 A, Ap 3 G, m 7 Gp 4 Gm, Ap 5 A, and mAp 5 G) in fractions of short RNA (sRNA) from Escherichia coli harvested in exponential phase and additional three Np n N-caps (mAp 4 G, mAp 5 A, and 2mAp 5 G) in late stationary phase. Some of the detected Np n N-caps are mono- or dimethylated. We identify two enzymes, RppH from the NudiX family and bis(5′-nucleosyl)-tetraphosphatase (ApaH), as decapping enzymes that can cleave Np n N-RNA. While the methylations of Np n N-caps protect the RNA from decapping by RppH, ApaH cleaves even the methylated forms of Np n N-caps. We propose that bacteria use methylated caps as protection against RNA degradation under starvation conditions. Results In vitro incorporation of Np n Ns into RNA To investigate whether Np n Ns (Fig. 1a ) can serve as NCINs similarly to NAD and CoA (ref. 22 ), we performed in vitro transcriptions in the presence of different Np n Ns (Ap 3-6 A, Ap 4-5 G, and Gp 4 G, Fig. 1b ) with T7 RNAP (single peptide chain enzyme, derived from an E. coli -infecting phage) and E. coli RNAP (multi-subunit enzyme). T7 RNAP was selected as a first tool to explore the capability of Np n Ns to be substrates of RNAPs as it was previously shown to be able to use comparably sized non-canonical initiating substrates 23 . Consistently, based on three-dimensional structures, the nucleotide-binding pockets for initiation phase of T7 (ref. 24 ) and E. coli 22 RNAP are spacious enough to accommodate such substrates. Fig. 1: Np n Ns are excellent substrates for RNAP. a The chemical structure of Np n Ns. b Scheme of the in vitro transcription with RNAP in the presence of Np n Ns and template DNA yielding RNA starting with A or G. The first step resulted in a mixture of capped and uncapped RNAs, which was then treated by 5′-polyphosphatase (P). In the third step, the 5′-p RNA was degraded by terminator exonuclease (T). c Polyacrylamide gel electrophoretic (PAGE—12%) analysis of the (α- 32 P GTP labeled) in vitro transcription products (35 nt) with T7 RNAP followed by P and/or T treatment (all experiments were performed in triplicates). If not specified, samples were treated with both P and T. d PAGE analysis of the in vitro transcription products with E. coli RNAP, and two templates with promoter rrnB P1 and rnaI , leading to A starting 144 nt long RNA ( rrnB P1) or 71 nt long RNA ( rnaI ), followed by P and/or T treatment (all experiments were performed in triplicates). e Percentage of different types of capped RNA produced by in vitro transcription with T7 RNAP calculated from PAGE analysis. The depth axis represents various concentrations of Np n Ns (0.2—red, 0.4—gray, 1—light blue, and 1.6 mM—dark blue) at a constant concentration of ATP (1 mM) and GTP (1 mM). The left panel shows the percentage of Ap 3–6 A and NAD-capped RNA, the right panel shows the percentage of Ap 4–5 G and Gp 4 G.", "role": "user" }, { "content": "The group of Dr. Hana Cahová of the Institute of Organic Chemistry and Biochemistry of the CAS, in collaboration with scientists from the Institute of Microbiology of the CAS, has discovered an entirely new class of dinucleoside polyphosphate 5'RNA caps in bacteria and described the function of alarmones and their mechanism of function. The discovery was recently published in the journal Nature Communications. Dinucleoside polyphosphates are small signaling molecules found in all types of organisms. They have been known for more than fifty years and are often called \"alarmones,\" as their concentration in cells increases under stress conditions. These molecules influence various cellular functions, but the mechanism of their action was as yet unknown. Hana Cahová and her colleagues noticed that the structure of these alarmones was similar to that of RNA and presumed that the alarmones were in fact part of the RNA in the form of so-called caps. Indeed, using mass spectrometry, they detected nine new types of these structures as part of RNA. \"As chemists, we noticed the glaring similarities of these alarmones with the RNA structure, so we were able to discover something that has been hidden from biologists for fifty years,\" says Hana Cahová, head of the junior research group at IOCB Prague. The researchers found that these molecules are accepted by RNA polymerases and used as the first building blocks in RNA synthesis. Moreover, they determined that dinucleoside polyphosphate capped RNA can be cleaved by two types of enzymes and thus degraded. Some of the dinucleoside polyphosphate RNA caps were methylated, and the researchers have shown that these methylations protected RNA from cleavage and further degradation. Hana Cahová Group, a junior research group at IOCB Prague. Credit: Jakub Stadler / IOCB Prague The amount of dinucleoside polyphosphate capped RNAs significantly increased under starvation conditions. Therefore, the authors propose that these caps protect RNA from degradation under starvation conditions when the cells do not have enough building blocks for creating such macromolecules as RNA. In such situations, the cell cannot flexibly react to the demands of the environment, but it can retain at least some RNA. Once the cell has enough nutrition again, the capped RNA is degraded by a specific enzyme, and the cell can build new RNA to reflect the current situation. This is the first work showing that the 5' end status of RNA depends on environment and stress. Moreover, the discovery of alarmones in RNA can explain the mechanism of their action. This work also provides the first evidence of small signaling molecules—dinucleoside polyphosphates—acting as parts of the RNA. The chemical biology group of Dr. Hana Cahová applies chemical methods to biological systems to better understand cellular processes. The team is especially interested in finding new RNA modifications in viruses and bacteria and understanding their role. ", "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 It has been more than 50 years since the discovery of dinucleoside polyphosphates (Np n Ns) and yet their roles and mechanisms of action remain unclear. Here, we show that both methylated and non-methylated Np n Ns serve as RNA caps in Escherichia coli . Np n Ns are excellent substrates for T7 and E. coli RNA polymerases (RNAPs) and efficiently initiate transcription. We demonstrate, that the E. coli enzymes RNA 5′-pyrophosphohydrolase (RppH) and bis(5′-nucleosyl)-tetraphosphatase (ApaH) are able to remove the Np n N-caps from RNA. ApaH is able to cleave all Np n N-caps, while RppH is unable to cleave the methylated forms suggesting that the methylation adds an additional layer to RNA stability regulation. Our work introduces a different perspective on the chemical structure of RNA in prokaryotes and on the role of RNA caps. We bring evidence that small molecules, such as Np n Ns are incorporated into RNA and may thus influence the cellular metabolism and RNA turnover. Introduction The role and chemical structure of the 5′-end of prokaryotic RNA is still unclear. The discovery of nicotinamide adenine dinucleotide (NAD) 1 , 2 and coenzyme A (CoA) 3 5′-RNA caps changed the perception of the RNA structure. 5′-caps are usually cleaved by NudiX enzymes 4 (NudC (refs. 1 , 5 , 6 ), RNA 5′-pyrophosphohydrolase (RppH) 7 , 8 ), which can, besides their decapping role (eukaryotic Nudt16 and Dcp2 (refs. 9 , 10 )), also cleave nucleoside diphosphates linked to another moiety (e.g., dinucleoside polyphosphates (Np n Ns) 11 , 12 ). Np n Ns are ubiquitous molecules 13 , 14 , 15 present in both prokaryotic and eukaryotic organisms.Their intracellular concentrations can increase from the μM to the mM range under stress conditions 11 , 16 , which is why they are often called alarmones. Nevertheless, the molecular targets of the alarm signaled by Np n Ns have not been identified yet. The main source of the Np n Ns is the back reaction of an aminoacyl adenylate with an acceptor nucleotide catalyzed by various aminoacyl-tRNA synthetases 17 . But there is evidence that e.g., the ubiquitinylation process can lead to Ap 4 A or Ap 3 A (ref. 18 ). Even though they have a similar chemical structure to known RNA caps, such as NAD (refs. 1 , 19 , 20 ) and the 7-methylguanylate cap 21 , they were never detected as a part of RNA. In this work, we show that Np n Ns can be accepted by two types of RNA polymerases (RNAPs; bacteriophage T7 and E. coli ) as non-canonical initiating nucleotides (NCINs) in in vitro transcription. To prove the existence of Np n N-RNA caps in vivo, we develop an liquid chromatography–mass spectrometry (LC–MS) technique for the detection of Np n Ns in isolated and digested RNA. We detect six previously unknown Np n N-caps (Ap 3 A, m 6 Ap 3 A, Ap 3 G, m 7 Gp 4 Gm, Ap 5 A, and mAp 5 G) in fractions of short RNA (sRNA) from Escherichia coli harvested in exponential phase and additional three Np n N-caps (mAp 4 G, mAp 5 A, and 2mAp 5 G) in late stationary phase. Some of the detected Np n N-caps are mono- or dimethylated. We identify two enzymes, RppH from the NudiX family and bis(5′-nucleosyl)-tetraphosphatase (ApaH), as decapping enzymes that can cleave Np n N-RNA. While the methylations of Np n N-caps protect the RNA from decapping by RppH, ApaH cleaves even the methylated forms of Np n N-caps. We propose that bacteria use methylated caps as protection against RNA degradation under starvation conditions. Results In vitro incorporation of Np n Ns into RNA To investigate whether Np n Ns (Fig. 1a ) can serve as NCINs similarly to NAD and CoA (ref. 22 ), we performed in vitro transcriptions in the presence of different Np n Ns (Ap 3-6 A, Ap 4-5 G, and Gp 4 G, Fig. 1b ) with T7 RNAP (single peptide chain enzyme, derived from an E. coli -infecting phage) and E. coli RNAP (multi-subunit enzyme). T7 RNAP was selected as a first tool to explore the capability of Np n Ns to be substrates of RNAPs as it was previously shown to be able to use comparably sized non-canonical initiating substrates 23 . Consistently, based on three-dimensional structures, the nucleotide-binding pockets for initiation phase of T7 (ref. 24 ) and E. coli 22 RNAP are spacious enough to accommodate such substrates. Fig. 1: Np n Ns are excellent substrates for RNAP. a The chemical structure of Np n Ns. b Scheme of the in vitro transcription with RNAP in the presence of Np n Ns and template DNA yielding RNA starting with A or G. The first step resulted in a mixture of capped and uncapped RNAs, which was then treated by 5′-polyphosphatase (P). In the third step, the 5′-p RNA was degraded by terminator exonuclease (T). c Polyacrylamide gel electrophoretic (PAGE—12%) analysis of the (α- 32 P GTP labeled) in vitro transcription products (35 nt) with T7 RNAP followed by P and/or T treatment (all experiments were performed in triplicates). If not specified, samples were treated with both P and T. d PAGE analysis of the in vitro transcription products with E. coli RNAP, and two templates with promoter rrnB P1 and rnaI , leading to A starting 144 nt long RNA ( rrnB P1) or 71 nt long RNA ( rnaI ), followed by P and/or T treatment (all experiments were performed in triplicates). e Percentage of different types of capped RNA produced by in vitro transcription with T7 RNAP calculated from PAGE analysis. The depth axis represents various concentrations of Np n Ns (0.2—red, 0.4—gray, 1—light blue, and 1.6 mM—dark blue) at a constant concentration of ATP (1 mM) and GTP (1 mM). The left panel shows the percentage of Ap 3–6 A and NAD-capped RNA, the right panel shows the percentage of Ap 4–5 G and Gp 4 G.<|im_end|> <|im_start|>assistant The group of Dr. Hana Cahová of the Institute of Organic Chemistry and Biochemistry of the CAS, in collaboration with scientists from the Institute of Microbiology of the CAS, has discovered an entirely new class of dinucleoside polyphosphate 5'RNA caps in bacteria and described the function of alarmones and their mechanism of function. The discovery was recently published in the journal Nature Communications. Dinucleoside polyphosphates are small signaling molecules found in all types of organisms. They have been known for more than fifty years and are often called "alarmones," as their concentration in cells increases under stress conditions. These molecules influence various cellular functions, but the mechanism of their action was as yet unknown. Hana Cahová and her colleagues noticed that the structure of these alarmones was similar to that of RNA and presumed that the alarmones were in fact part of the RNA in the form of so-called caps. Indeed, using mass spectrometry, they detected nine new types of these structures as part of RNA. "As chemists, we noticed the glaring similarities of these alarmones with the RNA structure, so we were able to discover something that has been hidden from biologists for fifty years," says Hana Cahová, head of the junior research group at IOCB Prague. The researchers found that these molecules are accepted by RNA polymerases and used as the first building blocks in RNA synthesis. Moreover, they determined that dinucleoside polyphosphate capped RNA can be cleaved by two types of enzymes and thus degraded. Some of the dinucleoside polyphosphate RNA caps were methylated, and the researchers have shown that these methylations protected RNA from cleavage and further degradation. Hana Cahová Group, a junior research group at IOCB Prague. Credit: Jakub Stadler / IOCB Prague The amount of dinucleoside polyphosphate capped RNAs significantly increased under starvation conditions. Therefore, the authors propose that these caps protect RNA from degradation under starvation conditions when the cells do not have enough building blocks for creating such macromolecules as RNA. In such situations, the cell cannot flexibly react to the demands of the environment, but it can retain at least some RNA. Once the cell has enough nutrition again, the capped RNA is degraded by a specific enzyme, and the cell can build new RNA to reflect the current situation. This is the first work showing that the 5' end status of RNA depends on environment and stress. Moreover, the discovery of alarmones in RNA can explain the mechanism of their action. This work also provides the first evidence of small signaling molecules—dinucleoside polyphosphates—acting as parts of the RNA. The chemical biology group of Dr. Hana Cahová applies chemical methods to biological systems to better understand cellular processes. The team is especially interested in finding new RNA modifications in viruses and bacteria and understanding their role. <|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 Modern challenges require new approaches to urban water management. One solution in the portfolio of potential strategies is the integration of distributed water infrastructure, practices, and technologies into existing systems. However, many practical barriers have prevented the widespread adoption of these systems in the US. The objective of this paper is to address these challenges by developing a conceptual model encompassing regulatory, financial, and governance components that can be used to incorporate new distributed water solutions into our current network. To construct the model, case studies of successfully implemented distributed electricity systems, specifically energy efficiency and renewable energy technologies, were examined to determine how these solutions have become prominent in recent years and what lessons can be applied to the water sector in a similar pursuit. The proposed model includes four action-oriented elements: catalyzing change, establishing funding sources, using resource pathways, and creating innovative governance structures. As illustrated in the model, the water sector should use suite of coordinated policies to promote change, engage end users through fiscal incentives, and encourage research, development and dissemination of new technologies over time. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Modern challenges including environmental degradation, climate change, urbanization, aging infrastructure, and ever increasing operation and maintenance costs are requiring new approaches to urban water management (Hering et al. 2013 ). One proposed solution in the suite of potential strategies addressing these challenges is the integration of distributed technologies, practices, and infrastructure into existing systems (Gleick 2003 ; Makropoulos and Butler 2010 ; Sharma et al. 2010 ; Bichai et al. 2015 ; Luthy and Sedlak 2015 ). These solutions manage all flows of the urban water cycle, including stormwater, potable water, and wastewater, more locally and at a smaller-scale than traditional centralized techniques (Makropoulos and Butler 2010 ). Distributed water solutions include a wide variety of practices and technologies such as green infrastructure designed to manage stormwater, demand-side management (DSM) measures that protect potable source water from waste, and decentralized wastewater and gray water treatment and reuse systems (Table 1 ). Incorporating distributed technologies and practices into existing water systems can be more economically, socially, and environmentally efficient than using centralized systems alone (Water Environment Research Foundation 2006 , Arora et al. 2015 ). While the benefits of distributed solutions are heterogeneous, these systems have the potential to increase network resilience and flexibility by reducing the load on aging infrastructure, eliminating or postponing the need to replace, expand, or build centralized systems, decreasing energy requirements for transportation, and offering alternative solutions if centralized infrastructure fails. Additionally, distributed solutions often have multiple benefits within the water sector and beyond; for example, green infrastructure not only provides flood control, but can also recharge groundwater, establish community recreational space, mitigate urban heat island effect, save building energy, and is linked with reduced crime (US Environmental Protection Agency 2010 ; Kondo et al. 2015 ; William et al. 2016 ). Table 1 Distributed water solutions Full size table Despite the potential benefits, many obstacles have prevented distributed water solutions from being adopted at a wide scale in the US (Sharma et al. 2010 ). One of the main barriers is financing—the economic landscape in the water sector is laden with problems that can make funding new projects difficult (Hanak et al. 2014 ), and these challenges can be exasperated for distributed solutions given their sometimes smaller project size and/or inclusion of innovative technologies that can be perceived as risky to investors (The Johnson Foundation at Wingspread 2014 ). For example, projects funded through the federal Water Infrastructure Finance and Innovation Act program must cost at least $20 million to be eligible for assistance, with the exception of projects in rural areas that can be a minimum of $5 million (Copeland 2015 ), a threshold still higher than the cost of many distributed water projects. Local funds often finance community-scale water projects (Hanak et al. 2014 ), however there is a gap between the financial needs of service providers and their abilities to locally generate funds (Mehan and Kline 2012 ; American Water Works Association 2015 ). Private investment that is difficult to secure for many conventional water projects can be even more challenging to acquire for distributed infrastructure and technologies (Mukheibir et al. 2014 ). Some studies have proposed fundraising methods to address the water sector’s growing needs, for example through alternative pricing schemes (Rogers et al. 2002 ; Hukka and Katko 2015 ) or by levying impact fees for financing specific infrastructure projects (Levinson 2002 ; Mantz and Thomas 2012 ). Yet, beyond additional funding, urban water reinvention and the integration of distributed solutions also requires the water sector to adopt new regulatory regimes and management techniques (Ajami et al. 2014 ; Wheater and Gober 2015 ; Dhakal and Chevalier 2016 ; Larsen et al. 2016 ). There is limited research that offers holistic analyzes of how to practically implement and finance new and non-traditional water projects. The goal of this paper is to address this gap by proposing a conceptual model encompassing potential policies, financing mechanisms, and governance structures that can be used to guide America’s water sector into a more sustainable future. To this end, we take a novel approach that draws lessons from the electricity sector, which has successfully overcome similar challenges in recent decades. Synergies between the Water and Electricity Sectors While some utilties, cities, and states in the US have already integrated distributed water infrastructure into their networks (Leurig and Brown 2014 ; Hornberger et al. 2015 ; Dhakal and Chevalier 2016 ), these solutions have yet to be adopted at a wide scale (Sharma et al. 2010 ). Looking at similar economic sectors, such as the electricity sector, can offer insight into novel practices. Over the past decade, innovation, and correspondingly the integration of distributed solutions, has advanced at a much faster rate in the electricity sector than in the water sector (Ajami et al. 2014 ). This paper aims", "role": "user" }, { "content": "Water utilities nationwide are grappling with aging infrastructure, environmental degradation and climate change. Existing water systems are also highly centralized and supported by old-fashioned financing models. But what if instead of simply replacing the physical infrastructure and financing mechanisms, the sector reinvented them? That was the approach California took to its electricity sector in recent decades, a success story that could be adapted to the water industry, according to a paper in Environmental Management. In the paper, Newsha Ajami, director of urban water policy at Stanford's Water in the West program, and her Stanford colleagues outlined four key elements to a potential plan. Step one: Water sector leaders must recognize that regulations and market drivers are essential to catalyzing change. For example, electricity utilities in California incorporated renewable energy sources into their systems mainly because regulations required them to do so, and while they were meeting these mandates, technology costs gradually decreased. The researchers see similar potential in the water sector, for example, if policies are enacted that require water utilities to diversify water supply systems or achieve certain water efficiency levels. Second, they say, water utilities must expand beyond traditional funding sources and rely on a diverse set of public and private funds to implement non-conventional water solutions. As part of this, policymakers and regulators must emulate the electricity sector's path, enacting policies that enable utilities to fund and finance projects in new ways. This approach could be adapted to the water sector through measures such as stormwater fee programs, tax credits or so-called green bonds, which are specifically earmarked for environmental and climate-related projects. Third, policymakers, regulators and decision makers must create pathways that enable cost-sharing or eliminate upfront costs in order to help see projects through. Study co-author Kim Quesnel, a graduate student in civil and environmental engineering, says this kind of thinking might encourage, for instance, the spread of graywater recycling systems. In such systems, a house, apartment building or office complex might channel all non-toilet wastewater—from sinks, showers and washing machines—back into some second on-site use, such as flushing water for toilets or irrigation for landscaping. Quesnel suggested that water providers could install such retrofits or upgrades in advance and recoup the cost by amortizing it over time on the monthly bill. This approach—called on-bill financing—is a decentralized way to encourage water reuse and has been used successfully in the electric utility world for residential solar panel installations. The fourth element of the framework concerns improving the governance of water projects. Developing and implementing distributed water systems doesn't just require money. New management strategies and a more diverse set of public and private actors are needed. One example is to bundle projects and pool funding sources, to decrease risk, improve management and give smaller projects better access to affordable financing while engaging a broader set of funders—a strategy successfully pursued in the electricity sector. Public benefit funds A related study, published in the Journal of the American Water Works Association, focuses on public benefit funds, a financing mechanism used in the electricity sector that Quesnel and Ajami see as particularly well suited for the water sector. Under this model, utilities added a use-based surcharge that usually worked out to $1 to $2 a month to ratepayers' electricity bills. The additional revenue went into a public benefit fund used for grants, loans, rebates and tax credits that encouraged energy efficiency and renewable energy production, such as by helping people buy and install solar panels. Some resources also went toward research, development and the funding of pilot-scale demonstration projects. In the water sector, Quesnel says, public benefit funds could be set aside for conservation and efficiency, green infrastructure, wastewater reuse projects and other efforts that modernize infrastructure, improve performance and increase innovation. Lessons for the water sector Ajami and Quesnel are part of a National Science Foundation engineering research center called ReNUWIt, short for Reinventing the Nation's Urban Water Infrastructure. To highlight the ideas and tools from their framework, they use an interactive map to present real-world examples of such innovations in the water sector. They see the map as a tool to expose leaders in different parts of the country to new ways to finance, govern and implement water projects. \"Over time this tool can help to change conventional ways of doing things and spur a transformation of America's aging water systems,\" Ajami 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 Modern challenges require new approaches to urban water management. One solution in the portfolio of potential strategies is the integration of distributed water infrastructure, practices, and technologies into existing systems. However, many practical barriers have prevented the widespread adoption of these systems in the US. The objective of this paper is to address these challenges by developing a conceptual model encompassing regulatory, financial, and governance components that can be used to incorporate new distributed water solutions into our current network. To construct the model, case studies of successfully implemented distributed electricity systems, specifically energy efficiency and renewable energy technologies, were examined to determine how these solutions have become prominent in recent years and what lessons can be applied to the water sector in a similar pursuit. The proposed model includes four action-oriented elements: catalyzing change, establishing funding sources, using resource pathways, and creating innovative governance structures. As illustrated in the model, the water sector should use suite of coordinated policies to promote change, engage end users through fiscal incentives, and encourage research, development and dissemination of new technologies over time. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Modern challenges including environmental degradation, climate change, urbanization, aging infrastructure, and ever increasing operation and maintenance costs are requiring new approaches to urban water management (Hering et al. 2013 ). One proposed solution in the suite of potential strategies addressing these challenges is the integration of distributed technologies, practices, and infrastructure into existing systems (Gleick 2003 ; Makropoulos and Butler 2010 ; Sharma et al. 2010 ; Bichai et al. 2015 ; Luthy and Sedlak 2015 ). These solutions manage all flows of the urban water cycle, including stormwater, potable water, and wastewater, more locally and at a smaller-scale than traditional centralized techniques (Makropoulos and Butler 2010 ). Distributed water solutions include a wide variety of practices and technologies such as green infrastructure designed to manage stormwater, demand-side management (DSM) measures that protect potable source water from waste, and decentralized wastewater and gray water treatment and reuse systems (Table 1 ). Incorporating distributed technologies and practices into existing water systems can be more economically, socially, and environmentally efficient than using centralized systems alone (Water Environment Research Foundation 2006 , Arora et al. 2015 ). While the benefits of distributed solutions are heterogeneous, these systems have the potential to increase network resilience and flexibility by reducing the load on aging infrastructure, eliminating or postponing the need to replace, expand, or build centralized systems, decreasing energy requirements for transportation, and offering alternative solutions if centralized infrastructure fails. Additionally, distributed solutions often have multiple benefits within the water sector and beyond; for example, green infrastructure not only provides flood control, but can also recharge groundwater, establish community recreational space, mitigate urban heat island effect, save building energy, and is linked with reduced crime (US Environmental Protection Agency 2010 ; Kondo et al. 2015 ; William et al. 2016 ). Table 1 Distributed water solutions Full size table Despite the potential benefits, many obstacles have prevented distributed water solutions from being adopted at a wide scale in the US (Sharma et al. 2010 ). One of the main barriers is financing—the economic landscape in the water sector is laden with problems that can make funding new projects difficult (Hanak et al. 2014 ), and these challenges can be exasperated for distributed solutions given their sometimes smaller project size and/or inclusion of innovative technologies that can be perceived as risky to investors (The Johnson Foundation at Wingspread 2014 ). For example, projects funded through the federal Water Infrastructure Finance and Innovation Act program must cost at least $20 million to be eligible for assistance, with the exception of projects in rural areas that can be a minimum of $5 million (Copeland 2015 ), a threshold still higher than the cost of many distributed water projects. Local funds often finance community-scale water projects (Hanak et al. 2014 ), however there is a gap between the financial needs of service providers and their abilities to locally generate funds (Mehan and Kline 2012 ; American Water Works Association 2015 ). Private investment that is difficult to secure for many conventional water projects can be even more challenging to acquire for distributed infrastructure and technologies (Mukheibir et al. 2014 ). Some studies have proposed fundraising methods to address the water sector’s growing needs, for example through alternative pricing schemes (Rogers et al. 2002 ; Hukka and Katko 2015 ) or by levying impact fees for financing specific infrastructure projects (Levinson 2002 ; Mantz and Thomas 2012 ). Yet, beyond additional funding, urban water reinvention and the integration of distributed solutions also requires the water sector to adopt new regulatory regimes and management techniques (Ajami et al. 2014 ; Wheater and Gober 2015 ; Dhakal and Chevalier 2016 ; Larsen et al. 2016 ). There is limited research that offers holistic analyzes of how to practically implement and finance new and non-traditional water projects. The goal of this paper is to address this gap by proposing a conceptual model encompassing potential policies, financing mechanisms, and governance structures that can be used to guide America’s water sector into a more sustainable future. To this end, we take a novel approach that draws lessons from the electricity sector, which has successfully overcome similar challenges in recent decades. Synergies between the Water and Electricity Sectors While some utilties, cities, and states in the US have already integrated distributed water infrastructure into their networks (Leurig and Brown 2014 ; Hornberger et al. 2015 ; Dhakal and Chevalier 2016 ), these solutions have yet to be adopted at a wide scale (Sharma et al. 2010 ). Looking at similar economic sectors, such as the electricity sector, can offer insight into novel practices. Over the past decade, innovation, and correspondingly the integration of distributed solutions, has advanced at a much faster rate in the electricity sector than in the water sector (Ajami et al. 2014 ). This paper aims<|im_end|> <|im_start|>assistant Water utilities nationwide are grappling with aging infrastructure, environmental degradation and climate change. Existing water systems are also highly centralized and supported by old-fashioned financing models. But what if instead of simply replacing the physical infrastructure and financing mechanisms, the sector reinvented them? That was the approach California took to its electricity sector in recent decades, a success story that could be adapted to the water industry, according to a paper in Environmental Management. In the paper, Newsha Ajami, director of urban water policy at Stanford's Water in the West program, and her Stanford colleagues outlined four key elements to a potential plan. Step one: Water sector leaders must recognize that regulations and market drivers are essential to catalyzing change. For example, electricity utilities in California incorporated renewable energy sources into their systems mainly because regulations required them to do so, and while they were meeting these mandates, technology costs gradually decreased. The researchers see similar potential in the water sector, for example, if policies are enacted that require water utilities to diversify water supply systems or achieve certain water efficiency levels. Second, they say, water utilities must expand beyond traditional funding sources and rely on a diverse set of public and private funds to implement non-conventional water solutions. As part of this, policymakers and regulators must emulate the electricity sector's path, enacting policies that enable utilities to fund and finance projects in new ways. This approach could be adapted to the water sector through measures such as stormwater fee programs, tax credits or so-called green bonds, which are specifically earmarked for environmental and climate-related projects. Third, policymakers, regulators and decision makers must create pathways that enable cost-sharing or eliminate upfront costs in order to help see projects through. Study co-author Kim Quesnel, a graduate student in civil and environmental engineering, says this kind of thinking might encourage, for instance, the spread of graywater recycling systems. In such systems, a house, apartment building or office complex might channel all non-toilet wastewater—from sinks, showers and washing machines—back into some second on-site use, such as flushing water for toilets or irrigation for landscaping. Quesnel suggested that water providers could install such retrofits or upgrades in advance and recoup the cost by amortizing it over time on the monthly bill. This approach—called on-bill financing—is a decentralized way to encourage water reuse and has been used successfully in the electric utility world for residential solar panel installations. The fourth element of the framework concerns improving the governance of water projects. Developing and implementing distributed water systems doesn't just require money. New management strategies and a more diverse set of public and private actors are needed. One example is to bundle projects and pool funding sources, to decrease risk, improve management and give smaller projects better access to affordable financing while engaging a broader set of funders—a strategy successfully pursued in the electricity sector. Public benefit funds A related study, published in the Journal of the American Water Works Association, focuses on public benefit funds, a financing mechanism used in the electricity sector that Quesnel and Ajami see as particularly well suited for the water sector. Under this model, utilities added a use-based surcharge that usually worked out to $1 to $2 a month to ratepayers' electricity bills. The additional revenue went into a public benefit fund used for grants, loans, rebates and tax credits that encouraged energy efficiency and renewable energy production, such as by helping people buy and install solar panels. Some resources also went toward research, development and the funding of pilot-scale demonstration projects. In the water sector, Quesnel says, public benefit funds could be set aside for conservation and efficiency, green infrastructure, wastewater reuse projects and other efforts that modernize infrastructure, improve performance and increase innovation. Lessons for the water sector Ajami and Quesnel are part of a National Science Foundation engineering research center called ReNUWIt, short for Reinventing the Nation's Urban Water Infrastructure. To highlight the ideas and tools from their framework, they use an interactive map to present real-world examples of such innovations in the water sector. They see the map as a tool to expose leaders in different parts of the country to new ways to finance, govern and implement water projects. "Over time this tool can help to change conventional ways of doing things and spur a transformation of America's aging water systems," Ajami 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 Reconstructions of Earth’s past climate strongly influence our understanding of the dynamics and sensitivity of the climate system. Yet global temperature has been reconstructed for only a few isolated windows of time 1 , 2 , and continuous reconstructions across glacial cycles remain elusive. Here I present a spatially weighted proxy reconstruction of global temperature over the past 2 million years estimated from a multi-proxy database of over 20,000 sea surface temperature point reconstructions. Global temperature gradually cooled until roughly 1.2 million years ago and cooling then stalled until the present. The cooling trend probably stalled before the beginning of the mid-Pleistocene transition 3 , and pre-dated the increase in the maximum size of ice sheets around 0.9 million years ago 4 , 5 , 6 . Thus, global cooling may have been a pre-condition for, but probably is not the sole causal mechanism of, the shift to quasi-100,000-year glacial cycles at the mid-Pleistocene transition. Over the past 800,000 years, polar amplification (the amplification of temperature change at the poles relative to global temperature change) has been stable over time, and global temperature and atmospheric greenhouse gas concentrations have been closely coupled across glacial cycles. A comparison of the new temperature reconstruction with radiative forcing from greenhouse gases estimates an Earth system sensitivity of 9 degrees Celsius (range 7 to 13 degrees Celsius, 95 per cent credible interval) change in global average surface temperature per doubling of atmospheric carbon dioxide over millennium timescales. This result suggests that stabilization at today’s greenhouse gas levels may already commit Earth to an eventual total warming of 5 degrees Celsius (range 3 to 7 degrees Celsius, 95 per cent credible interval) over the next few millennia as ice sheets, vegetation and atmospheric dust continue to respond to global warming. Main Reconstructions of several key climate variables are available with high temporal resolution across past glacial cycles, such as polar temperature, atmospheric greenhouse gas (GHG) concentrations, sea surface temperature (SST), deep-water temperature (DWT) and sea level (see, for example, Extended Data Tables 1 , 2 , 3 ). Yet global average surface temperature (GAST) has been reconstructed for only a few isolated windows of time 1 , 2 , and continuous reconstructions across glacial cycles remain elusive. The lack of continuous GAST reconstructions has constrained model–data comparisons to particular extreme points in time, such as the Last Glacial Maximum (LGM), but multiple time points are critical for characterizing the uncertainty in relationships estimated from palaeoclimate reconstructions 7 , 8 . The potential power of a continuous GAST record has been recently demonstrated 8 ; GAST was reconstructed for the past 22,000 years (kyr) and used to clarify carbon dioxide’s role in driving global climate change across glacial cycles. The present research creates a continuous record of GAST across a much longer timescale. Previous continuous reconstructions of GAST across glacial cycles used only a single proxy record that was scaled linearly 2 , 4 , 9 , 10 , 11 , 12 or modelled 13 to estimate global values. This Letter presents a spatially weighted proxy reconstruction of GAST over the past 2 million years ( Fig. 1a ), estimated using a multi-proxy database compilation of over 20,000 SST point reconstructions from 59 ocean sediment cores ( Extended Data Tables 1 , 2 ). This research uses probabilistic simulations across multiple sources of uncertainty to estimate credible intervals at 1-kyr intervals, and validates the new reconstruction against previous estimates. The new GAST reconstruction can provide key insights into several major palaeoclimate questions, including the magnitude and stability of polar amplification, the state dependence of Earth system sensitivity (ESS, see below), and the role of global temperature in the mid-Pleistocene transition (MPT). Figure 1: Reconstruction of global average surface temperature (GAST) over the past 2 million years compared to other key palaeoclimate variables. a , GAST as temperature deviation (in °C) from present (average over 0–5 ka) in blue. b , Stacked reconstruction of change in Antarctic temperature 14 (°C) in cyan. c , Stacked reconstruction of atmospheric CO 2 concentrations 18 (p.p.m.) in red. d , Stack of deep-sea oxygen isotopes 30 , δ 18 O (‰), in grey. In all panels, the solid black lines show the median estimate and the colour shaded areas show the 95% interval. PowerPoint slide Source data Full size image A comparison of GAST to Antarctic temperature reconstructions for the past 800 kyr finds that GAST and Antarctic temperature 14 are closely coupled across glacial cycles with a correlation of 0.72 (0.59–0.81, 95% credible interval, hereafter ‘interval’)—a high correlation given that the GAST reconstruction is estimated independently of the ice core records. There is a linear relationship of 0.61 °C (0.43–0.85 °C, 95% interval) change in GAST for every 1 °C change in Antarctic temperature ( Fig. 2a ) that does not significantly change over the past 800 kyr ( Extended Data Fig. 6a ). Some previous research on climate sensitivity over the past 800 kyr has assumed that changes in GAST are similar to half the magnitude of changes in Antarctic temperature 9 , 12 , 15 . On the basis of the new GAST reconstruction, there is an 87% probability that such an assumption underestimates global temperature and thus climate sensitivity. Figure 2: Relationship of changes in GAST to changes in Antarctic temperature and GHG radiative forcing over the past 800 kyr. a , b , Each point represents randomly sampled estimates from simulations of GAST plotted against Antarctic temperature 14 ( a ) and GHG radiative forcing 14 , 17 , 18 ( b ) over the past 800 kyr. The dashed black line shows the median estimated relationship in °C per °C in a and in °C per W m −2 in b . The red dashed line shows the median estimated quadratic relationship in b . PowerPoint slide Source data Full size image Polar amplification can be estimated as change in Antarctic temperature for every 1 °C change in GAST, here estimated as 1.6", "role": "user" }, { "content": "A new study paints a picture of an Earth that is warmer than it has been in about 120,000 years, and is locked into eventually hitting its hottest mark in more than 2 million years. As part of her doctoral dissertation at Stanford University, Carolyn Snyder , now a climate policy official at the U.S. Environmental Protection Agency, created a continuous 2 million year temperature record, much longer than a previous 22,000 year record. Snyder's temperature reconstruction, published Monday in the journal Nature , doesn't estimate temperature for a single year, but averages 5,000-year time periods going back a couple million years. Snyder based her reconstruction on 61 different sea surface temperature proxies from across the globe, such as ratios between magnesium and calcium, species makeup and acidity. But the further the study goes back in time, especially after half a million years, the fewer of those proxies are available, making the estimates less certain, she said. These are rough estimates with large margins of errors, she said. But she also found that the temperature changes correlated well to carbon dioxide levels. Temperatures averaged out over the most recent 5,000 years—which includes the last 125 years or so of industrial emissions of heat-trapping gases—are generally warmer than they have been since about 120,000 years ago or so, Snyder found. And two interglacial time periods, the one 120,000 years ago and another just about 2 million years ago, were the warmest Snyder tracked. They were about 3.6 degrees (2 degrees Celsius) warmer than the current 5,000-year average. With the link to carbon dioxide levels and taking into account other factors and past trends, Snyder calculated how much warming can be expected in the future. Snyder said if climate factors are the same as in the past—and that's a big if—Earth is already committed to another 7 degrees or so (about 4 degrees Celsius) of warming over the next few thousand years. \"This is based on what happened in the past,\" Snyder said. \"In the past it wasn't humans messing with the atmosphere.\" Scientists give various reasons for past changes in carbon dioxide and heat levels, including regular slight shifts in Earth's orbital tilt. Four outside scientists praised the study's tracking of past temperatures, with caveats about how less certain it is as it gets deeper in the past. Jeremy Shakun of Boston College said \"Snyder's work is a great contribution and future work should build on it.\" But many of the same scientists said Snyder's estimate of future warming seems too high. Shakun called it unrealistic and not matching historical time periods of similar carbon dioxide levels. A fifth scientist, Michael Mann of Pennsylvania State University, called the study provocative and interesting but said he remains skeptical until more research confirms it. He found the future temperature calculations \"so much higher than prevailing estimates that one has to consider it somewhat of an outlier.\" ", "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 Reconstructions of Earth’s past climate strongly influence our understanding of the dynamics and sensitivity of the climate system. Yet global temperature has been reconstructed for only a few isolated windows of time 1 , 2 , and continuous reconstructions across glacial cycles remain elusive. Here I present a spatially weighted proxy reconstruction of global temperature over the past 2 million years estimated from a multi-proxy database of over 20,000 sea surface temperature point reconstructions. Global temperature gradually cooled until roughly 1.2 million years ago and cooling then stalled until the present. The cooling trend probably stalled before the beginning of the mid-Pleistocene transition 3 , and pre-dated the increase in the maximum size of ice sheets around 0.9 million years ago 4 , 5 , 6 . Thus, global cooling may have been a pre-condition for, but probably is not the sole causal mechanism of, the shift to quasi-100,000-year glacial cycles at the mid-Pleistocene transition. Over the past 800,000 years, polar amplification (the amplification of temperature change at the poles relative to global temperature change) has been stable over time, and global temperature and atmospheric greenhouse gas concentrations have been closely coupled across glacial cycles. A comparison of the new temperature reconstruction with radiative forcing from greenhouse gases estimates an Earth system sensitivity of 9 degrees Celsius (range 7 to 13 degrees Celsius, 95 per cent credible interval) change in global average surface temperature per doubling of atmospheric carbon dioxide over millennium timescales. This result suggests that stabilization at today’s greenhouse gas levels may already commit Earth to an eventual total warming of 5 degrees Celsius (range 3 to 7 degrees Celsius, 95 per cent credible interval) over the next few millennia as ice sheets, vegetation and atmospheric dust continue to respond to global warming. Main Reconstructions of several key climate variables are available with high temporal resolution across past glacial cycles, such as polar temperature, atmospheric greenhouse gas (GHG) concentrations, sea surface temperature (SST), deep-water temperature (DWT) and sea level (see, for example, Extended Data Tables 1 , 2 , 3 ). Yet global average surface temperature (GAST) has been reconstructed for only a few isolated windows of time 1 , 2 , and continuous reconstructions across glacial cycles remain elusive. The lack of continuous GAST reconstructions has constrained model–data comparisons to particular extreme points in time, such as the Last Glacial Maximum (LGM), but multiple time points are critical for characterizing the uncertainty in relationships estimated from palaeoclimate reconstructions 7 , 8 . The potential power of a continuous GAST record has been recently demonstrated 8 ; GAST was reconstructed for the past 22,000 years (kyr) and used to clarify carbon dioxide’s role in driving global climate change across glacial cycles. The present research creates a continuous record of GAST across a much longer timescale. Previous continuous reconstructions of GAST across glacial cycles used only a single proxy record that was scaled linearly 2 , 4 , 9 , 10 , 11 , 12 or modelled 13 to estimate global values. This Letter presents a spatially weighted proxy reconstruction of GAST over the past 2 million years ( Fig. 1a ), estimated using a multi-proxy database compilation of over 20,000 SST point reconstructions from 59 ocean sediment cores ( Extended Data Tables 1 , 2 ). This research uses probabilistic simulations across multiple sources of uncertainty to estimate credible intervals at 1-kyr intervals, and validates the new reconstruction against previous estimates. The new GAST reconstruction can provide key insights into several major palaeoclimate questions, including the magnitude and stability of polar amplification, the state dependence of Earth system sensitivity (ESS, see below), and the role of global temperature in the mid-Pleistocene transition (MPT). Figure 1: Reconstruction of global average surface temperature (GAST) over the past 2 million years compared to other key palaeoclimate variables. a , GAST as temperature deviation (in °C) from present (average over 0–5 ka) in blue. b , Stacked reconstruction of change in Antarctic temperature 14 (°C) in cyan. c , Stacked reconstruction of atmospheric CO 2 concentrations 18 (p.p.m.) in red. d , Stack of deep-sea oxygen isotopes 30 , δ 18 O (‰), in grey. In all panels, the solid black lines show the median estimate and the colour shaded areas show the 95% interval. PowerPoint slide Source data Full size image A comparison of GAST to Antarctic temperature reconstructions for the past 800 kyr finds that GAST and Antarctic temperature 14 are closely coupled across glacial cycles with a correlation of 0.72 (0.59–0.81, 95% credible interval, hereafter ‘interval’)—a high correlation given that the GAST reconstruction is estimated independently of the ice core records. There is a linear relationship of 0.61 °C (0.43–0.85 °C, 95% interval) change in GAST for every 1 °C change in Antarctic temperature ( Fig. 2a ) that does not significantly change over the past 800 kyr ( Extended Data Fig. 6a ). Some previous research on climate sensitivity over the past 800 kyr has assumed that changes in GAST are similar to half the magnitude of changes in Antarctic temperature 9 , 12 , 15 . On the basis of the new GAST reconstruction, there is an 87% probability that such an assumption underestimates global temperature and thus climate sensitivity. Figure 2: Relationship of changes in GAST to changes in Antarctic temperature and GHG radiative forcing over the past 800 kyr. a , b , Each point represents randomly sampled estimates from simulations of GAST plotted against Antarctic temperature 14 ( a ) and GHG radiative forcing 14 , 17 , 18 ( b ) over the past 800 kyr. The dashed black line shows the median estimated relationship in °C per °C in a and in °C per W m −2 in b . The red dashed line shows the median estimated quadratic relationship in b . PowerPoint slide Source data Full size image Polar amplification can be estimated as change in Antarctic temperature for every 1 °C change in GAST, here estimated as 1.6<|im_end|> <|im_start|>assistant A new study paints a picture of an Earth that is warmer than it has been in about 120,000 years, and is locked into eventually hitting its hottest mark in more than 2 million years. As part of her doctoral dissertation at Stanford University, Carolyn Snyder , now a climate policy official at the U.S. Environmental Protection Agency, created a continuous 2 million year temperature record, much longer than a previous 22,000 year record. Snyder's temperature reconstruction, published Monday in the journal Nature , doesn't estimate temperature for a single year, but averages 5,000-year time periods going back a couple million years. Snyder based her reconstruction on 61 different sea surface temperature proxies from across the globe, such as ratios between magnesium and calcium, species makeup and acidity. But the further the study goes back in time, especially after half a million years, the fewer of those proxies are available, making the estimates less certain, she said. These are rough estimates with large margins of errors, she said. But she also found that the temperature changes correlated well to carbon dioxide levels. Temperatures averaged out over the most recent 5,000 years—which includes the last 125 years or so of industrial emissions of heat-trapping gases—are generally warmer than they have been since about 120,000 years ago or so, Snyder found. And two interglacial time periods, the one 120,000 years ago and another just about 2 million years ago, were the warmest Snyder tracked. They were about 3.6 degrees (2 degrees Celsius) warmer than the current 5,000-year average. With the link to carbon dioxide levels and taking into account other factors and past trends, Snyder calculated how much warming can be expected in the future. Snyder said if climate factors are the same as in the past—and that's a big if—Earth is already committed to another 7 degrees or so (about 4 degrees Celsius) of warming over the next few thousand years. "This is based on what happened in the past," Snyder said. "In the past it wasn't humans messing with the atmosphere." Scientists give various reasons for past changes in carbon dioxide and heat levels, including regular slight shifts in Earth's orbital tilt. Four outside scientists praised the study's tracking of past temperatures, with caveats about how less certain it is as it gets deeper in the past. Jeremy Shakun of Boston College said "Snyder's work is a great contribution and future work should build on it." But many of the same scientists said Snyder's estimate of future warming seems too high. Shakun called it unrealistic and not matching historical time periods of similar carbon dioxide levels. A fifth scientist, Michael Mann of Pennsylvania State University, called the study provocative and interesting but said he remains skeptical until more research confirms it. He found the future temperature calculations "so much higher than prevailing estimates that one has to consider it somewhat of an outlier." <|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 neural networks have revolutionized electronic computing. Similarly, molecular networks with neuromorphic architectures may enable molecular decision-making on a level comparable to gene regulatory networks 1 , 2 . Non-enzymatic networks could in principle support neuromorphic architectures, and seminal proofs-of-principle have been reported 3 , 4 . However, leakages (that is, the unwanted release of species), as well as issues with sensitivity, speed, preparation and the lack of strong nonlinear responses, make the composition of layers delicate, and molecular classifications equivalent to a multilayer neural network remain elusive (for example, the partitioning of a concentration space into regions that cannot be linearly separated). Here we introduce DNA-encoded enzymatic neurons with tuneable weights and biases, and which are assembled in multilayer architectures to classify nonlinearly separable regions. We first leverage the sharp decision margin of a neuron to compute various majority functions on 10 bits. We then compose neurons into a two-layer network and synthetize a parametric family of rectangular functions on a microRNA input. Finally, we connect neural and logical computations into a hybrid circuit that recursively partitions a concentration plane according to a decision tree in cell-sized droplets. This computational power and extreme miniaturization open avenues to query and manage molecular systems with complex contents, such as liquid biopsies or DNA databases. Main Synthetic DNA has emerged as a versatile polymer to store and process information at the molecular scale. It has powered a rich library of computational molecular devices ranging from logic circuits 5 , 6 , 7 , 8 to self-assembling automata 9 . Departing from the biological model of computation, most DNA computing devices imitate the Boolean paradigm of electronics. However, their computing power has fallen short of the exponential growth of Moore’s law: their size has been plateauing at around 5–10 logic gates for a decade 6 . In parallel, various groups have started looking at the brain, rather than the central processor unit (CPU), as an inspiration for computing with molecules 1 , 2 , 3 , 4 , 10 . This is because neuronal and chemical networks share striking similarities: massively parallel and recurrent architectures, analog and asynchronous operation, fault-tolerant and redundant computations (Supplementary Fig. 13 ). In 2018, Lopez et al. reported a DNA-based linear classifier 4 that performs all of its computations with a non-enzymatic mechanism: toehold-mediated strand displacement. Using similar DNA-only mechanisms on many more inputs and taking inspiration from competitive neural networks 1 , 2 , Cherry and Qian reported in a tour de force a DNA classifier for the MNIST database 3 . Together, these molecular classifiers showcased the benefits of neuromorphic networks over Boolean circuits: massive parallelism, handling of analog inputs and tolerance of corrupted patterns. However, these non-enzymatic classifiers had limited decision margins, that is, they could not discriminate between two similar inputs belonging to different classes. They also suffered from leaks that made the composition of layers delicate. Overall, fully molecular classification was only demonstrated on datasets that could be linearly separated by a wide margin. DNA-processing enzymes are the workhorses of biotechnology, synthetic biology and molecular biology. They perform an astounding variety of transactions on DNA: production, degradation, cleavage, ligation, scouting, cutting and pasting, and editing. In addition, enzymes are fast and processive, and their kinetic control is tight, making them prime candidates for powering DNA computing devices. Previous reports showcased the power of enzymatic networks for running advanced spatio-temporal dynamics like logic computation 11 , switches 12 , 13 , 14 , clocks 15 , 16 , 17 , predator–prey oscillators 18 , quorum sensing 19 , spatial waves 20 , maze pathfinders 21 and artificial morphogenesis 22 , 23 —many of which still resist implementation with strand displacement only. We set out to explore the potential of neuromorphic architectures combining the programmability of DNA with the efficiency of enzymatic processing. Linear classifier Our neuromorphic networks are built around a generic enzymatic neuron (Fig. 1 ) that emulates the perceptron proposed by Rosenblatt in 1958 24 . The neuron takes DNA or RNA strands as input. The state of the neuron is encoded by the concentration of a short DNA strand α (the signal sent by the neuron). The neuron computes a weighted sum of its inputs thanks to converter templates. They act like programmable-gain amplifiers in analog electronics, the gain being tuned by the composition of the templates (Fig. 1f ). The neuron then takes an ON state (yielding a high concentration of α) if the weighted sum of inputs exceeds a concentration threshold, and remains OFF otherwise (low concentration of α). In modern terms, this mimics a perceptron with a step function as the nonlinear activation function. The inputs here are two DNA analogues of the miR-21 and miR-31 microRNAS (miRNAs), which are involved in cancer 25 . The network is modular and can easily be rewired to accept different inputs or produce new outputs. Fig. 1: Architecture of DNA-encoded enzymatic neural networks. a , Multilayer neural networks can classify nonlinearly separable regions. b , Our individual neuron computes a weighted sum on its inputs and generates an output if the sum exceeds a threshold c (linear classification). c , Chemical architecture of the neuron. The autocatalytic amplification of the output strand α (red arrow) is triggered when the weighted activation (blue and orange) by input strands X i and X j overcomes the thresholding mechanism (purple). fluo., fluorescence. d , The chemical neuron is powered by three enzymes producing (polymerase), cutting (nickase) and degrading (exonuclease) DNA. e , Building blocks of the enzymatic neural networks. Positive and negative weights are computed by converter templates cT p and cT n . They produce species α or dT n whose steady-state concentration is proportional to the input X i . Weights can be independently tuned with fake templates (fT) that compete with cT for the inputs. The activation function—a step function—is encoded in a bistable switch composed of an amplification template (aT, which replicates the species α) and a drain template", "role": "user" }, { "content": "DNA can be used to reliably store a vast amount of digital data. However, retrieval or manipulation of specific data encoded in these molecules has hitherto been difficult. Now, researchers from the CNRS, the ESPCI Paris-PSL and the University of Tokyo have pioneered the application of a new method that harnesses enzymes, offering initial clues as to how these technical obstacles may be overcome. Their findings are reported in Nature, the October 20, 2022. Nature has indisputably invented the best solution for storing a massive amount of data: DNA. This understanding has inspired the use of DNA for the storage of digital data, converting binary (0 or 1) numbers into one of the four different DNA \"letters\" (A, T, C, or G). But how does one find a specific datum in the library of information stored as DNA? And how can calculations with DNA-encoded data be performed directly, without first converting them back into electronic data? These are the questions that teams from the LIMMS (CNRS / University of Tokyo) and Gulliver (CNRS / ESPCI Paris-PSL) research laboratories have sought to answer. They are testing a new approach using enzymes and applying the solutions of artificial neurons and neural networks for direct operations on DNA data. Specifically, the researchers have made use of the reactions of three enzymes to design chemical \"neurons\" that reproduce the network architecture and ability for complex calculations exhibited by true neurons. Their chemical neurons can execute calculations with data on DNA strands and express the results as fluorescent signals. The LIMMS and Gulliver teams have also innovated by assembling two layers of the artificial neurons in order to refine calculations. Precision is further enhanced through microfluidic miniaturization of reactions, allowing tens of thousands to take place. The fruit of a decade of cooperation between French biochemists and Japanese microfluidics engineers, these breakthroughs may eventually permit better screening for certain diseases as well as the manipulation of gigantic DNA-encoded databases. When kept away from water, air, and light, DNA can be preserved for hundreds of thousands of years, without any energy input. And stored in a capsule a few centimeters in diameter, it can hold up to 500 terabytes of digital data. By 2025, the total volume of digital data generated by humans is expected to reach 175 zettabytes1. Since current storage media are relatively bulky, fragile, and energy-intensive, DNA may provide a viable alternative—able to contain all existing data within the space of a shoebox. Facilitating DNA storage will be the PEPR MoleculArxiv goal, a priority research program provided last May by the CNRS. ", "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 neural networks have revolutionized electronic computing. Similarly, molecular networks with neuromorphic architectures may enable molecular decision-making on a level comparable to gene regulatory networks 1 , 2 . Non-enzymatic networks could in principle support neuromorphic architectures, and seminal proofs-of-principle have been reported 3 , 4 . However, leakages (that is, the unwanted release of species), as well as issues with sensitivity, speed, preparation and the lack of strong nonlinear responses, make the composition of layers delicate, and molecular classifications equivalent to a multilayer neural network remain elusive (for example, the partitioning of a concentration space into regions that cannot be linearly separated). Here we introduce DNA-encoded enzymatic neurons with tuneable weights and biases, and which are assembled in multilayer architectures to classify nonlinearly separable regions. We first leverage the sharp decision margin of a neuron to compute various majority functions on 10 bits. We then compose neurons into a two-layer network and synthetize a parametric family of rectangular functions on a microRNA input. Finally, we connect neural and logical computations into a hybrid circuit that recursively partitions a concentration plane according to a decision tree in cell-sized droplets. This computational power and extreme miniaturization open avenues to query and manage molecular systems with complex contents, such as liquid biopsies or DNA databases. Main Synthetic DNA has emerged as a versatile polymer to store and process information at the molecular scale. It has powered a rich library of computational molecular devices ranging from logic circuits 5 , 6 , 7 , 8 to self-assembling automata 9 . Departing from the biological model of computation, most DNA computing devices imitate the Boolean paradigm of electronics. However, their computing power has fallen short of the exponential growth of Moore’s law: their size has been plateauing at around 5–10 logic gates for a decade 6 . In parallel, various groups have started looking at the brain, rather than the central processor unit (CPU), as an inspiration for computing with molecules 1 , 2 , 3 , 4 , 10 . This is because neuronal and chemical networks share striking similarities: massively parallel and recurrent architectures, analog and asynchronous operation, fault-tolerant and redundant computations (Supplementary Fig. 13 ). In 2018, Lopez et al. reported a DNA-based linear classifier 4 that performs all of its computations with a non-enzymatic mechanism: toehold-mediated strand displacement. Using similar DNA-only mechanisms on many more inputs and taking inspiration from competitive neural networks 1 , 2 , Cherry and Qian reported in a tour de force a DNA classifier for the MNIST database 3 . Together, these molecular classifiers showcased the benefits of neuromorphic networks over Boolean circuits: massive parallelism, handling of analog inputs and tolerance of corrupted patterns. However, these non-enzymatic classifiers had limited decision margins, that is, they could not discriminate between two similar inputs belonging to different classes. They also suffered from leaks that made the composition of layers delicate. Overall, fully molecular classification was only demonstrated on datasets that could be linearly separated by a wide margin. DNA-processing enzymes are the workhorses of biotechnology, synthetic biology and molecular biology. They perform an astounding variety of transactions on DNA: production, degradation, cleavage, ligation, scouting, cutting and pasting, and editing. In addition, enzymes are fast and processive, and their kinetic control is tight, making them prime candidates for powering DNA computing devices. Previous reports showcased the power of enzymatic networks for running advanced spatio-temporal dynamics like logic computation 11 , switches 12 , 13 , 14 , clocks 15 , 16 , 17 , predator–prey oscillators 18 , quorum sensing 19 , spatial waves 20 , maze pathfinders 21 and artificial morphogenesis 22 , 23 —many of which still resist implementation with strand displacement only. We set out to explore the potential of neuromorphic architectures combining the programmability of DNA with the efficiency of enzymatic processing. Linear classifier Our neuromorphic networks are built around a generic enzymatic neuron (Fig. 1 ) that emulates the perceptron proposed by Rosenblatt in 1958 24 . The neuron takes DNA or RNA strands as input. The state of the neuron is encoded by the concentration of a short DNA strand α (the signal sent by the neuron). The neuron computes a weighted sum of its inputs thanks to converter templates. They act like programmable-gain amplifiers in analog electronics, the gain being tuned by the composition of the templates (Fig. 1f ). The neuron then takes an ON state (yielding a high concentration of α) if the weighted sum of inputs exceeds a concentration threshold, and remains OFF otherwise (low concentration of α). In modern terms, this mimics a perceptron with a step function as the nonlinear activation function. The inputs here are two DNA analogues of the miR-21 and miR-31 microRNAS (miRNAs), which are involved in cancer 25 . The network is modular and can easily be rewired to accept different inputs or produce new outputs. Fig. 1: Architecture of DNA-encoded enzymatic neural networks. a , Multilayer neural networks can classify nonlinearly separable regions. b , Our individual neuron computes a weighted sum on its inputs and generates an output if the sum exceeds a threshold c (linear classification). c , Chemical architecture of the neuron. The autocatalytic amplification of the output strand α (red arrow) is triggered when the weighted activation (blue and orange) by input strands X i and X j overcomes the thresholding mechanism (purple). fluo., fluorescence. d , The chemical neuron is powered by three enzymes producing (polymerase), cutting (nickase) and degrading (exonuclease) DNA. e , Building blocks of the enzymatic neural networks. Positive and negative weights are computed by converter templates cT p and cT n . They produce species α or dT n whose steady-state concentration is proportional to the input X i . Weights can be independently tuned with fake templates (fT) that compete with cT for the inputs. The activation function—a step function—is encoded in a bistable switch composed of an amplification template (aT, which replicates the species α) and a drain template<|im_end|> <|im_start|>assistant DNA can be used to reliably store a vast amount of digital data. However, retrieval or manipulation of specific data encoded in these molecules has hitherto been difficult. Now, researchers from the CNRS, the ESPCI Paris-PSL and the University of Tokyo have pioneered the application of a new method that harnesses enzymes, offering initial clues as to how these technical obstacles may be overcome. Their findings are reported in Nature, the October 20, 2022. Nature has indisputably invented the best solution for storing a massive amount of data: DNA. This understanding has inspired the use of DNA for the storage of digital data, converting binary (0 or 1) numbers into one of the four different DNA "letters" (A, T, C, or G). But how does one find a specific datum in the library of information stored as DNA? And how can calculations with DNA-encoded data be performed directly, without first converting them back into electronic data? These are the questions that teams from the LIMMS (CNRS / University of Tokyo) and Gulliver (CNRS / ESPCI Paris-PSL) research laboratories have sought to answer. They are testing a new approach using enzymes and applying the solutions of artificial neurons and neural networks for direct operations on DNA data. Specifically, the researchers have made use of the reactions of three enzymes to design chemical "neurons" that reproduce the network architecture and ability for complex calculations exhibited by true neurons. Their chemical neurons can execute calculations with data on DNA strands and express the results as fluorescent signals. The LIMMS and Gulliver teams have also innovated by assembling two layers of the artificial neurons in order to refine calculations. Precision is further enhanced through microfluidic miniaturization of reactions, allowing tens of thousands to take place. The fruit of a decade of cooperation between French biochemists and Japanese microfluidics engineers, these breakthroughs may eventually permit better screening for certain diseases as well as the manipulation of gigantic DNA-encoded databases. When kept away from water, air, and light, DNA can be preserved for hundreds of thousands of years, without any energy input. And stored in a capsule a few centimeters in diameter, it can hold up to 500 terabytes of digital data. By 2025, the total volume of digital data generated by humans is expected to reach 175 zettabytes1. Since current storage media are relatively bulky, fragile, and energy-intensive, DNA may provide a viable alternative—able to contain all existing data within the space of a shoebox. Facilitating DNA storage will be the PEPR MoleculArxiv goal, a priority research program provided last May by the CNRS. <|im_end|>

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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 The celebrated electronic properties of graphene 1 , 2 have opened the way for materials just one atom thick 3 to be used in the post-silicon electronic era 4 . An important milestone was the creation of heterostructures based on graphene and other two-dimensional crystals, which can be assembled into three-dimensional stacks with atomic layer precision 5 , 6 , 7 . Such layered structures have already demonstrated a range of fascinating physical phenomena 8 , 9 , 10 , 11 , and have also been used in demonstrating a prototype field-effect tunnelling transistor 12 , which is regarded to be a candidate for post-CMOS (complementary metal-oxide semiconductor) technology. The range of possible materials that could be incorporated into such stacks is very large. Indeed, there are many other materials with layers linked by weak van der Waals forces that can be exfoliated 3 , 13 and combined together to create novel highly tailored heterostructures. Here, we describe a new generation of field-effect vertical tunnelling transistors where two-dimensional tungsten disulphide serves as an atomically thin barrier between two layers of either mechanically exfoliated or chemical vapour deposition-grown graphene. The combination of tunnelling (under the barrier) and thermionic (over the barrier) transport allows for unprecedented current modulation exceeding 1 × 10 6 at room temperature and very high ON current. These devices can also operate on transparent and flexible substrates. Main The operation of a graphene-based field-effect tunnelling transistor (FETT) relies on the tunability of the effective height of the tunnelling barrier ( Δ ) via a shift in the Fermi level of the graphene and changes in the height and shape of the barrier. Previously, devices have been considered that have barriers comprising thin layers of hexagonal boron nitride 14 (hBN) or a silicon/graphene Schottky interface 15 . In this Letter, we demonstrate that by utilizing both the tunnelling and thermionic over-barrier currents in a tungsten disulphide (WS 2 )-based FETT, a dramatic improvement can be achieved in the device characteristics, to the extent that they satisfy the requirements for next-generation electronic devices. Bulk WS 2 is an indirect-bandgap (1.4 eV) semiconductor, but is expected to turn into a direct-bandgap (2.1 eV) material when exfoliated into the monolayer state 16 . Each single plane of WS 2 comprises a trilayer composed of a tungsten layer sandwiched between two sulphur layers in a trigonal prismatic coordination. Using barrier materials with a relatively small bandgap (such as WS 2 ) provides a viable method to increase the ON/OFF ratio of the FETT, because the changes in the Fermi level of the graphene (usually <0.5 eV, limited by the gate dielectric breakdown) will be of the order of or even exceed the barrier height. In contrast, hBN is a wide-bandgap insulator ( E g > 5 eV) and forms a high tunnelling barrier in graphene–hBN FETTs, so changes in the Fermi level of the graphene are therefore small compared to the barrier height. Being chemically stable and having only a weak impurity band, WS 2 also offers a distinct advantage over molybdenum disulphide (MoS 2 ) 12 , 17 , because it allows for switching between tunnelling and thermionic transport regimes, resulting in much better transistor characteristics and thus allowing for much higher ON/OFF ratios and much larger ON current. Figure 1 presents a schematic and band diagrams of our devices. The fabrication techniques are detailed in the Methods. Briefly, a standard dry transfer procedure was used to assemble heterostructures from individual flakes prepared by micromechanical exfoliation. The first layer of graphene (bottom contact), placed on hBN, was covered by a thin WS 2 flake. We used either graphene (mechanically exfoliated or grown by chemical vapour deposition, CVD), few-layer graphene, graphite or chromium/gold as the top contact. We studied more than a dozen graphene–WS 2 heterostructures, and observe qualitatively similar behaviour, regardless of the material used as the top contact. For simplicity, to illustrate the operation of the devices we discuss transistors with both bottom and top contacts composed of graphene layers. The highest ON/OFF ratio was obtained for four- to five-layer-thick WS 2 tunnelling barriers. Figure 1: Graphene–WS 2 heterotransistor. a , Optical image (scale bar, 10 µm). b , Cross-section high-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) image (scale bar, 5 nm). c , Bright-field STEM image (scale bar, 5 nm). d , Schematic of vertical architecture of transistor. e , Band diagram corresponding to no V g and applied V b . f , Negative V g shifts the Fermi level of the two graphene layers down from the neutrality point, increasing the potential barrier and switching the transistor OFF. g , Applying positive V g results in an increased current between Gr B and Gr T due to both thermionic (red arrow) and tunnelling (blue arrow) contributions. Full size image The principle of operation of our WS 2 -based FETT is illustrated by the series of band diagrams presented in Fig. 1 . Without a gate or bias voltage applied, the Fermi levels of the two graphene sheets are located near the bottom of the WS 2 conduction band ( Fig. 1 e). This is confirmed by the temperature dependence (see below). The gate voltage V g between the silicon substrate and the bottom graphene layer (Gr B ) changes the carrier concentration n in Gr B , shifting the Fermi level by . The sign of the Fermi level shift is determined by the polarity of the gate voltage. Accordingly, Fig. 1 f shows that a negative gate voltage shifts E F downwards, increasing the tunnelling barrier height by Δ E F and thus representing the ‘OFF’ state of the transistor. Positive gate voltage shifts the Fermi level into the conduction band, reducing the tunnelling barrier height or even resulting in an over-barrier thermionic current ( Fig. 1 g), thus representing the ‘ON’ state. In addition, because of the weak screening of the monolayer graphene, the electric field from the gate electrode penetrates through", "role": "user" }, { "content": "(Phys.org)—A new graphene-based transistor in which electrons travel both over a barrier and under it (by tunneling) has exhibited one of the highest performances of graphene-based transistors to date. The combination of the two types of transport enables the transistor to achieve a large difference between its on and off states, giving it a high on/off ratio, which has so far been difficult to achieve in graphene-based transistors. With this advantage, in addition to its ability to operate on transparent and flexible substrates, the new transistor could play a role in post-CMOS devices that are expected to be able to compute at much faster speeds than today's devices. The researchers from the University of Manchester in the UK, who designed the new graphene-based transistor, have published their study on the device in a recent issue of Nature Nanotechnology. As the researchers explain in their study, other graphene-based transistors have previously been demonstrated, many of which have a sandwich structure with atom-thick sheets of graphene forming the outer layers and a different ultrathin material forming the middle layer. This middle layer can consist of many possible materials. In the current study, the researchers used two-dimensional tungsten disulphide (WS2) as the middle layer, which served as an atomically thin barrier between the two layers of graphene. The biggest advantage of using WS2 compared to most other barrier materials is that WS2's chemical properties allow electrons to cross either by going over the barrier, as in thermionic transport, or under it, as in tunneling. In the off state, very few electrons can cross the barrier by either transport method, but they can cross by one or both methods in the on state. Switching between the two states involves changing the transistor's gate voltage. A negative gate voltage creates the off state, since it increases the tunneling barrier height so that few electrons can cross the barrier. A positive gate voltage switches the transistor to the on state by reducing the tunneling barrier height and—if the temperature is high enough—allowing over-barrier thermionic current as well. To make the on/off ratio as high as possible, the researchers took advantage of the way the tunneling current's dependence on the voltage changes for different voltage levels. At low voltages and low temperatures, the tunneling current varies linearly with voltage, but then grows exponentially with the voltage at higher voltages. At this point, thermionic current becomes the dominant transport mechanism. Using this information to their advantage, the researchers could tune the transistor to achieve an on/off ratio exceeding 1 x 106 at room temperature, which is competitive with the best graphene-based transistors with any barrier material. Furthermore, this level of performance satisfies the requirements to be a candidate for next-generation post-CMOS electronic devices. Because the new transistor is only a few atomic layers thick, it should be able to tolerate bending and could have potential applications in future flexible, transparent electronic devices. ", "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 celebrated electronic properties of graphene 1 , 2 have opened the way for materials just one atom thick 3 to be used in the post-silicon electronic era 4 . An important milestone was the creation of heterostructures based on graphene and other two-dimensional crystals, which can be assembled into three-dimensional stacks with atomic layer precision 5 , 6 , 7 . Such layered structures have already demonstrated a range of fascinating physical phenomena 8 , 9 , 10 , 11 , and have also been used in demonstrating a prototype field-effect tunnelling transistor 12 , which is regarded to be a candidate for post-CMOS (complementary metal-oxide semiconductor) technology. The range of possible materials that could be incorporated into such stacks is very large. Indeed, there are many other materials with layers linked by weak van der Waals forces that can be exfoliated 3 , 13 and combined together to create novel highly tailored heterostructures. Here, we describe a new generation of field-effect vertical tunnelling transistors where two-dimensional tungsten disulphide serves as an atomically thin barrier between two layers of either mechanically exfoliated or chemical vapour deposition-grown graphene. The combination of tunnelling (under the barrier) and thermionic (over the barrier) transport allows for unprecedented current modulation exceeding 1 × 10 6 at room temperature and very high ON current. These devices can also operate on transparent and flexible substrates. Main The operation of a graphene-based field-effect tunnelling transistor (FETT) relies on the tunability of the effective height of the tunnelling barrier ( Δ ) via a shift in the Fermi level of the graphene and changes in the height and shape of the barrier. Previously, devices have been considered that have barriers comprising thin layers of hexagonal boron nitride 14 (hBN) or a silicon/graphene Schottky interface 15 . In this Letter, we demonstrate that by utilizing both the tunnelling and thermionic over-barrier currents in a tungsten disulphide (WS 2 )-based FETT, a dramatic improvement can be achieved in the device characteristics, to the extent that they satisfy the requirements for next-generation electronic devices. Bulk WS 2 is an indirect-bandgap (1.4 eV) semiconductor, but is expected to turn into a direct-bandgap (2.1 eV) material when exfoliated into the monolayer state 16 . Each single plane of WS 2 comprises a trilayer composed of a tungsten layer sandwiched between two sulphur layers in a trigonal prismatic coordination. Using barrier materials with a relatively small bandgap (such as WS 2 ) provides a viable method to increase the ON/OFF ratio of the FETT, because the changes in the Fermi level of the graphene (usually <0.5 eV, limited by the gate dielectric breakdown) will be of the order of or even exceed the barrier height. In contrast, hBN is a wide-bandgap insulator ( E g > 5 eV) and forms a high tunnelling barrier in graphene–hBN FETTs, so changes in the Fermi level of the graphene are therefore small compared to the barrier height. Being chemically stable and having only a weak impurity band, WS 2 also offers a distinct advantage over molybdenum disulphide (MoS 2 ) 12 , 17 , because it allows for switching between tunnelling and thermionic transport regimes, resulting in much better transistor characteristics and thus allowing for much higher ON/OFF ratios and much larger ON current. Figure 1 presents a schematic and band diagrams of our devices. The fabrication techniques are detailed in the Methods. Briefly, a standard dry transfer procedure was used to assemble heterostructures from individual flakes prepared by micromechanical exfoliation. The first layer of graphene (bottom contact), placed on hBN, was covered by a thin WS 2 flake. We used either graphene (mechanically exfoliated or grown by chemical vapour deposition, CVD), few-layer graphene, graphite or chromium/gold as the top contact. We studied more than a dozen graphene–WS 2 heterostructures, and observe qualitatively similar behaviour, regardless of the material used as the top contact. For simplicity, to illustrate the operation of the devices we discuss transistors with both bottom and top contacts composed of graphene layers. The highest ON/OFF ratio was obtained for four- to five-layer-thick WS 2 tunnelling barriers. Figure 1: Graphene–WS 2 heterotransistor. a , Optical image (scale bar, 10 µm). b , Cross-section high-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) image (scale bar, 5 nm). c , Bright-field STEM image (scale bar, 5 nm). d , Schematic of vertical architecture of transistor. e , Band diagram corresponding to no V g and applied V b . f , Negative V g shifts the Fermi level of the two graphene layers down from the neutrality point, increasing the potential barrier and switching the transistor OFF. g , Applying positive V g results in an increased current between Gr B and Gr T due to both thermionic (red arrow) and tunnelling (blue arrow) contributions. Full size image The principle of operation of our WS 2 -based FETT is illustrated by the series of band diagrams presented in Fig. 1 . Without a gate or bias voltage applied, the Fermi levels of the two graphene sheets are located near the bottom of the WS 2 conduction band ( Fig. 1 e). This is confirmed by the temperature dependence (see below). The gate voltage V g between the silicon substrate and the bottom graphene layer (Gr B ) changes the carrier concentration n in Gr B , shifting the Fermi level by . The sign of the Fermi level shift is determined by the polarity of the gate voltage. Accordingly, Fig. 1 f shows that a negative gate voltage shifts E F downwards, increasing the tunnelling barrier height by Δ E F and thus representing the ‘OFF’ state of the transistor. Positive gate voltage shifts the Fermi level into the conduction band, reducing the tunnelling barrier height or even resulting in an over-barrier thermionic current ( Fig. 1 g), thus representing the ‘ON’ state. In addition, because of the weak screening of the monolayer graphene, the electric field from the gate electrode penetrates through<|im_end|> <|im_start|>assistant (Phys.org)—A new graphene-based transistor in which electrons travel both over a barrier and under it (by tunneling) has exhibited one of the highest performances of graphene-based transistors to date. The combination of the two types of transport enables the transistor to achieve a large difference between its on and off states, giving it a high on/off ratio, which has so far been difficult to achieve in graphene-based transistors. With this advantage, in addition to its ability to operate on transparent and flexible substrates, the new transistor could play a role in post-CMOS devices that are expected to be able to compute at much faster speeds than today's devices. The researchers from the University of Manchester in the UK, who designed the new graphene-based transistor, have published their study on the device in a recent issue of Nature Nanotechnology. As the researchers explain in their study, other graphene-based transistors have previously been demonstrated, many of which have a sandwich structure with atom-thick sheets of graphene forming the outer layers and a different ultrathin material forming the middle layer. This middle layer can consist of many possible materials. In the current study, the researchers used two-dimensional tungsten disulphide (WS2) as the middle layer, which served as an atomically thin barrier between the two layers of graphene. The biggest advantage of using WS2 compared to most other barrier materials is that WS2's chemical properties allow electrons to cross either by going over the barrier, as in thermionic transport, or under it, as in tunneling. In the off state, very few electrons can cross the barrier by either transport method, but they can cross by one or both methods in the on state. Switching between the two states involves changing the transistor's gate voltage. A negative gate voltage creates the off state, since it increases the tunneling barrier height so that few electrons can cross the barrier. A positive gate voltage switches the transistor to the on state by reducing the tunneling barrier height and—if the temperature is high enough—allowing over-barrier thermionic current as well. To make the on/off ratio as high as possible, the researchers took advantage of the way the tunneling current's dependence on the voltage changes for different voltage levels. At low voltages and low temperatures, the tunneling current varies linearly with voltage, but then grows exponentially with the voltage at higher voltages. At this point, thermionic current becomes the dominant transport mechanism. Using this information to their advantage, the researchers could tune the transistor to achieve an on/off ratio exceeding 1 x 106 at room temperature, which is competitive with the best graphene-based transistors with any barrier material. Furthermore, this level of performance satisfies the requirements to be a candidate for next-generation post-CMOS electronic devices. Because the new transistor is only a few atomic layers thick, it should be able to tolerate bending and could have potential applications in future flexible, transparent electronic devices. <|im_end|>

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1,998

[ { "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 early development of many organisms involves the folding of cell monolayers, but this behaviour is difficult to reproduce in vitro; therefore, both mechanistic causes and effects of local curvature remain unclear. Here we study epithelial cell monolayers on corrugated hydrogels engineered into wavy patterns, examining how concave and convex curvatures affect cellular and nuclear shape. We find that substrate curvature affects monolayer thickness, which is larger in valleys than crests. We show that this feature generically arises in a vertex model, leading to the hypothesis that cells may sense curvature by modifying the thickness of the tissue. We find that local curvature also affects nuclear morphology and positioning, which we explain by extending the vertex model to take into account membrane–nucleus interactions, encoding thickness modulation in changes to nuclear deformation and position. We propose that curvature governs the spatial distribution of yes-associated proteins via nuclear shape and density changes. We show that curvature also induces significant variations in lamins, chromatin condensation and cell proliferation rate in folded epithelial tissues. Together, this work identifies active cell mechanics and nuclear mechanoadaptation as the key players of the mechanistic regulation of epithelia to substrate curvature. Main Living tissues commonly adopt three-dimensional (3D) curved microstructures such as invaginations, folds or wavy morphologies, but the mechanisms underlying the relationship between curvature and biological function remain largely unexplored 1 , 2 . Despite numerous studies on the influence of cellular and subcellular-scale topography on cell fate 3 , 4 , 5 , few studies have investigated the effect of curvature on collective cell behaviour 6 , 7 , 8 , 9 , mainly due to limitations in engineering curved culture substrates 10 . It remains unclear whether and how curvatures at scales much larger than the cell size could be biologically sensed. Previous studies using glass fibres indicated that cells orient themselves along the line of minimal curvature to minimize cytoskeletal deformations 11 , 12 , 13 , and it was recently found that migration and preferred position of single adherent cells are affected by substrate curvature 14 , 15 . To understand the influence of curvature on confluent tissues, we combined experiments with Madin–Darby canine kidney (MDCK) cells grown on soft corrugated hydrogels with biophysical modelling. We show that local changes in monolayer thickness and cell density can be interpreted by energy minimization arising from the mechanics of apico-lateral tensions. We extended the vertex model to consider—in a minimal way—changes in nuclear morphology due to active tensions and cell shape, suggesting a simple mechanism with which thickness modulation couples to the experimentally observed changes in nuclear shape and positioning. We showed that these changes triggered by curvature also lead to high nuclear/cytoplasmic yes-associated protein (YAP) ratios, demonstrating YAP curvature sensing of epithelial tissues, which is inhibited at high cell density. Furthermore, we found that nuclear deformations resulting from adaptation to curvature involve the modulation of lamin A/C (LMAC) and lamin B1 (LMB1). Finally, we demonstrate that the matrix curvature can be considered as an important regulatory cue of epithelial tissues, leading to high levels of chromatin compaction and lower DNA synthesis rate in concave curvatures, which correspond to high-cell-density zones. Curvature does not change architecture of wavy epithelia To study how a monolayer of epithelial cells adapts to convex and concave cell-scale curvatures of their matrix (Fig. 1a ), we generated corrugated hydroxy-polyacrylamide (hydroxy-PAAm) hydrogels of 250 ± 30 kPa with various wavelengths, namely, 20 µm (λ20), 30 µm (λ30) and 50 µm (λ50), by photopolymerizing a hydroxy-PAAm solution at 360 nm through a chromium optical photomask (Supplementary Videos 1 – 3 and Methods). MDCK cells were then cultured at confluency on these wavy substrates. To determine whether curvature changes can affect epithelial thickness and nuclear organization (Fig. 1a ), we defined three zones of interest: crests, valleys and intermediate (interm.) zones. Convex (positive) curvature zones correspond to crests; concave (negative) curvature zones, valleys; and zero-curvature zones (corresponding to the junction between convex and concave zones), interm. zones (Extended Data Fig. 1a,b ). We determined the local maximal curvature values, amplitude ( β ) and wavelengths ( λ ) of convex and concave curvature zones using two-dimensional (2D) ( x – z ) profiles obtained from atomic force microscopy (AFM) and high-resolution confocal microscopy (Extended Data Fig. 1a,c and Extended Data Table 1 ). Fig. 1: Wavy epithelial monolayers on corrugated polyacrylamide hydrogels. a , Schematic of an epithelial monolayer grown on a corrugated hydrogel of amplitude β and wavelength λ . The corrugated profile is composed of crests (convex curvature), intermediate or interm. zones (zero curvature), and valleys (concave curvature). The balance between apical tension ( Γ a ; green), lateral tension ( Γ l ; red) and basal tension ( Γ b ; brown) leads to thickness modulation of the epithelial monolayer, changes in nuclear morphologies and nuclear offsets. b , Confocal volume rendering of an MDCK epithelial monolayer stained for F-actin (green) and nuclei (blue) grown on corrugated substrates of 20 µm (λ20; grey), 30 µm (λ30; red) and 50 µm (λ50; blue) wavelengths. Scale bars, 20 µm. c , Confocal volume rendering of the nuclei in epithelial monolayers grown on corrugated substrates of 20 µm (λ20; grey), 30 µm (λ30; red) and 50 µm (λ50; blue) wavelengths. The height in micrometres is colour coded. Scale bars, 20 µm. Full size image After 48 h, epithelial monolayers were immunostained with Alexa Fluor 488 for F-actin (Fig. 1b ) and with 4',6-diamidino-2-phenylindole (DAPI) for the nucleus (Fig. 1c ) and then imaged with a laser-scanning confocal microscope. Using Z -stack projections from the confocal scanning of F-actin (Extended Data Fig. 2a–c ), we found that the actin intensity was not substantially different between the flat and corrugated (λ20, λ30 and λ50) hydrogel monolayers (Extended Data Fig. 2d ), suggesting that matrix corrugations do not affect the global amount of F-actin in the epithelia. Furthermore, ß-catenin staining used to skeletonize cell outlines 16 showed that epithelial tissues remained cohesive on corrugated hydrogels", "role": "user" }, { "content": "Cells in your body cannot see, but they can sense their surroundings and their own shape. Scientists at the University of Mons and the Institute of Science and Technology (IST) Austria now showed via both—experiments and theory—how cells can sense the curvature of tissue around them and how this influences their inner workings. The study was published in Nature Physics. Curved surfaces are found everywhere in biological tissues. They provide for instance the increased surface area necessary for the absorption of nutrients in your intestine or for gas exchange in your lungs. More and more evidence suggests that cells are able to sense whether they are in flat or curved environments. Three-dimensional curvature can impact many processes such as the movement of cells, the development of stem cells, and even disease progression. However, the underlying mechanisms by which cells sense curvature and how it ultimately dictates their behavior are less clear. Now, a study in Nature Physics led by Ph.D. student Marine Luciano and Professor Sylvain Gabriele of the University of Mons in Belgium in cooperation with postdoc Shi-Lei Xue and Professor Edouard Hannezo at IST Austria has uncovered some new findings. The researchers found the mechanisms that regulate the cells' behavior depending on the change of the environment's curvature. Gabriele's team reproduced the folding patterns observed in living tissues in a very controlled way by developing a method to grow cells on curved surfaces using soft hydrogels—gels made of long molecules trapping water between them. This was important because it is very hard to clearly observe the effects of curvature in complex living tissues. They have many feedback loops depending on their own shape, making it difficult to distinguish cause and effect. These specially constructed surfaces have valleys and mountains with sizes from a hundredth to a tenth of a millimeter. The experiments showed that cells grown on these surfaces tend to spread thinly on the mountains and gather in the valleys. At IST Austria, Xue and Hannezo developed a key theoretical model that explains the experimental distribution of cells on the surfaces. They used the simple physical principle of energy minimization. Their cell model is inspired by the physics of foam and led to the understanding how the curvature governs the distribution of cells on the surface and therefore also their shape and density in an area. It was already known that cells could sense the density of other cells around them and that this governs their biochemical machinery. Therefore, biochemicals like the Yes-associated proteins (YAP)—key markers of stem cells—are influenced by the curvature via density sensing. This study identifies how curvature sensing influences multiple pathways in cell development. This kind of interdisciplinary study incorporating physical chemistry, cell biology, and theoretical physics once again sheds light on a cellular mechanism that has been poorly understood so far. ", "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 early development of many organisms involves the folding of cell monolayers, but this behaviour is difficult to reproduce in vitro; therefore, both mechanistic causes and effects of local curvature remain unclear. Here we study epithelial cell monolayers on corrugated hydrogels engineered into wavy patterns, examining how concave and convex curvatures affect cellular and nuclear shape. We find that substrate curvature affects monolayer thickness, which is larger in valleys than crests. We show that this feature generically arises in a vertex model, leading to the hypothesis that cells may sense curvature by modifying the thickness of the tissue. We find that local curvature also affects nuclear morphology and positioning, which we explain by extending the vertex model to take into account membrane–nucleus interactions, encoding thickness modulation in changes to nuclear deformation and position. We propose that curvature governs the spatial distribution of yes-associated proteins via nuclear shape and density changes. We show that curvature also induces significant variations in lamins, chromatin condensation and cell proliferation rate in folded epithelial tissues. Together, this work identifies active cell mechanics and nuclear mechanoadaptation as the key players of the mechanistic regulation of epithelia to substrate curvature. Main Living tissues commonly adopt three-dimensional (3D) curved microstructures such as invaginations, folds or wavy morphologies, but the mechanisms underlying the relationship between curvature and biological function remain largely unexplored 1 , 2 . Despite numerous studies on the influence of cellular and subcellular-scale topography on cell fate 3 , 4 , 5 , few studies have investigated the effect of curvature on collective cell behaviour 6 , 7 , 8 , 9 , mainly due to limitations in engineering curved culture substrates 10 . It remains unclear whether and how curvatures at scales much larger than the cell size could be biologically sensed. Previous studies using glass fibres indicated that cells orient themselves along the line of minimal curvature to minimize cytoskeletal deformations 11 , 12 , 13 , and it was recently found that migration and preferred position of single adherent cells are affected by substrate curvature 14 , 15 . To understand the influence of curvature on confluent tissues, we combined experiments with Madin–Darby canine kidney (MDCK) cells grown on soft corrugated hydrogels with biophysical modelling. We show that local changes in monolayer thickness and cell density can be interpreted by energy minimization arising from the mechanics of apico-lateral tensions. We extended the vertex model to consider—in a minimal way—changes in nuclear morphology due to active tensions and cell shape, suggesting a simple mechanism with which thickness modulation couples to the experimentally observed changes in nuclear shape and positioning. We showed that these changes triggered by curvature also lead to high nuclear/cytoplasmic yes-associated protein (YAP) ratios, demonstrating YAP curvature sensing of epithelial tissues, which is inhibited at high cell density. Furthermore, we found that nuclear deformations resulting from adaptation to curvature involve the modulation of lamin A/C (LMAC) and lamin B1 (LMB1). Finally, we demonstrate that the matrix curvature can be considered as an important regulatory cue of epithelial tissues, leading to high levels of chromatin compaction and lower DNA synthesis rate in concave curvatures, which correspond to high-cell-density zones. Curvature does not change architecture of wavy epithelia To study how a monolayer of epithelial cells adapts to convex and concave cell-scale curvatures of their matrix (Fig. 1a ), we generated corrugated hydroxy-polyacrylamide (hydroxy-PAAm) hydrogels of 250 ± 30 kPa with various wavelengths, namely, 20 µm (λ20), 30 µm (λ30) and 50 µm (λ50), by photopolymerizing a hydroxy-PAAm solution at 360 nm through a chromium optical photomask (Supplementary Videos 1 – 3 and Methods). MDCK cells were then cultured at confluency on these wavy substrates. To determine whether curvature changes can affect epithelial thickness and nuclear organization (Fig. 1a ), we defined three zones of interest: crests, valleys and intermediate (interm.) zones. Convex (positive) curvature zones correspond to crests; concave (negative) curvature zones, valleys; and zero-curvature zones (corresponding to the junction between convex and concave zones), interm. zones (Extended Data Fig. 1a,b ). We determined the local maximal curvature values, amplitude ( β ) and wavelengths ( λ ) of convex and concave curvature zones using two-dimensional (2D) ( x – z ) profiles obtained from atomic force microscopy (AFM) and high-resolution confocal microscopy (Extended Data Fig. 1a,c and Extended Data Table 1 ). Fig. 1: Wavy epithelial monolayers on corrugated polyacrylamide hydrogels. a , Schematic of an epithelial monolayer grown on a corrugated hydrogel of amplitude β and wavelength λ . The corrugated profile is composed of crests (convex curvature), intermediate or interm. zones (zero curvature), and valleys (concave curvature). The balance between apical tension ( Γ a ; green), lateral tension ( Γ l ; red) and basal tension ( Γ b ; brown) leads to thickness modulation of the epithelial monolayer, changes in nuclear morphologies and nuclear offsets. b , Confocal volume rendering of an MDCK epithelial monolayer stained for F-actin (green) and nuclei (blue) grown on corrugated substrates of 20 µm (λ20; grey), 30 µm (λ30; red) and 50 µm (λ50; blue) wavelengths. Scale bars, 20 µm. c , Confocal volume rendering of the nuclei in epithelial monolayers grown on corrugated substrates of 20 µm (λ20; grey), 30 µm (λ30; red) and 50 µm (λ50; blue) wavelengths. The height in micrometres is colour coded. Scale bars, 20 µm. Full size image After 48 h, epithelial monolayers were immunostained with Alexa Fluor 488 for F-actin (Fig. 1b ) and with 4',6-diamidino-2-phenylindole (DAPI) for the nucleus (Fig. 1c ) and then imaged with a laser-scanning confocal microscope. Using Z -stack projections from the confocal scanning of F-actin (Extended Data Fig. 2a–c ), we found that the actin intensity was not substantially different between the flat and corrugated (λ20, λ30 and λ50) hydrogel monolayers (Extended Data Fig. 2d ), suggesting that matrix corrugations do not affect the global amount of F-actin in the epithelia. Furthermore, ß-catenin staining used to skeletonize cell outlines 16 showed that epithelial tissues remained cohesive on corrugated hydrogels<|im_end|> <|im_start|>assistant Cells in your body cannot see, but they can sense their surroundings and their own shape. Scientists at the University of Mons and the Institute of Science and Technology (IST) Austria now showed via both—experiments and theory—how cells can sense the curvature of tissue around them and how this influences their inner workings. The study was published in Nature Physics. Curved surfaces are found everywhere in biological tissues. They provide for instance the increased surface area necessary for the absorption of nutrients in your intestine or for gas exchange in your lungs. More and more evidence suggests that cells are able to sense whether they are in flat or curved environments. Three-dimensional curvature can impact many processes such as the movement of cells, the development of stem cells, and even disease progression. However, the underlying mechanisms by which cells sense curvature and how it ultimately dictates their behavior are less clear. Now, a study in Nature Physics led by Ph.D. student Marine Luciano and Professor Sylvain Gabriele of the University of Mons in Belgium in cooperation with postdoc Shi-Lei Xue and Professor Edouard Hannezo at IST Austria has uncovered some new findings. The researchers found the mechanisms that regulate the cells' behavior depending on the change of the environment's curvature. Gabriele's team reproduced the folding patterns observed in living tissues in a very controlled way by developing a method to grow cells on curved surfaces using soft hydrogels—gels made of long molecules trapping water between them. This was important because it is very hard to clearly observe the effects of curvature in complex living tissues. They have many feedback loops depending on their own shape, making it difficult to distinguish cause and effect. These specially constructed surfaces have valleys and mountains with sizes from a hundredth to a tenth of a millimeter. The experiments showed that cells grown on these surfaces tend to spread thinly on the mountains and gather in the valleys. At IST Austria, Xue and Hannezo developed a key theoretical model that explains the experimental distribution of cells on the surfaces. They used the simple physical principle of energy minimization. Their cell model is inspired by the physics of foam and led to the understanding how the curvature governs the distribution of cells on the surface and therefore also their shape and density in an area. It was already known that cells could sense the density of other cells around them and that this governs their biochemical machinery. Therefore, biochemicals like the Yes-associated proteins (YAP)—key markers of stem cells—are influenced by the curvature via density sensing. This study identifies how curvature sensing influences multiple pathways in cell development. This kind of interdisciplinary study incorporating physical chemistry, cell biology, and theoretical physics once again sheds light on a cellular mechanism that has been poorly understood so far. <|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 Understanding SARS-CoV-2 transmission within and among communities is critical for tailoring public health policies to local context. However, analysis of community transmission is challenging due to a lack of high-resolution surveillance and testing data. Here, using contact tracing records for 644,029 cases and their contacts in New York City during the second pandemic wave, we provide a detailed characterization of the operational performance of contact tracing and reconstruct exposure and transmission networks at individual and ZIP code scales. We find considerable heterogeneity in reported close contacts and secondary infections and evidence of extensive transmission across ZIP code areas. Our analysis reveals the spatial pattern of SARS-CoV-2 spread and communities that are tightly interconnected by exposure and transmission. We find that locations with higher vaccination coverage and lower numbers of visitors to points-of-interest had reduced within- and cross-ZIP code transmission events, highlighting potential measures for curtailing SARS-CoV-2 spread in urban settings. Introduction Within metropolitan areas, infection risk and disease burden due to SARS-CoV-2, the causative agent of COVID-19, are characterized by spatial heterogeneity at neighborhood scales 1 , 2 , 3 . Communities with substantial local infections can sustain the spread of SARS-CoV-2, seed infections in interconnected neighborhoods, and spark resurgences of cases following the relaxation of non-pharmaceutical interventions (NPIs), such as masking and social distancing 4 . In densely populated urban settings, public health tactics may need to be uniquely tailored to specific geographic areas and/or communities that most support the persistence and spatial dispersion of SARS-CoV-2 infections. Development of such tailored tactics requires improved understanding of both transmission patterns at fine geographical scales and the factors shaping the intensity of community outbreaks. Examples of previously utilized targeted interventions include limiting indoor dining and gathering, increasing testing availability, encouraging home quarantine for exposed contacts, requiring face masks indoors, and closing nonessential businesses in high-risk communities. While the transmission patterns of SARS-CoV-2 at global, national, and regional levels have been reported 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , research on community-level transmission is often challenging due to limited availability of high-resolution surveillance and testing data, the lack of routine case interviews, and the difficulty identifying transmission events. In addition, the effect of public health interventions on community transmission of SARS-CoV-2 in metropolitan areas has not been well evaluated. Data collected through contact tracing efforts have provided valuable insights into the transmission dynamics of SARS-CoV-2; 14 , 15 , 16 , 17 , 18 however, most contact tracing during the early phase of the pandemic mainly focused on specific local outbreaks, which cannot support population-level analysis of community transmission. Here, we use detailed data from confirmed and probable cases 19 and case investigations during the second pandemic wave in New York City (NYC) to quantify community spread of COVID-19 at small spatial scales from October 2020 to May 2021. Unlike the initial outbreak during the spring of 2020, the second pandemic wave was fully captured by contact tracing. Additionally, contact tracing operation and individual protective measures such as mask-wearing and social distancing remained relatively stable during this period of the pandemic (in contrast with the post-Omicron era when protective measures were largely abandoned). As a result, data collected during the second pandemic wave may better inform understanding of SARS-CoV-2 community transmission in NYC and the operational performance of contact tracing during a public health emergency. Results Contact tracing in NYC The NYC Test & Trace Corps initiative was launched in June 2020 20 . Established as an operation to provide contact tracing, testing, and resources to support isolation and quarantine, the contact tracing program was integrated with a set of intervention efforts designed to limit morbidity and mortality from COVID-19 in NYC (Supplementary Information). Contact tracing was performed through phone calls and text messages, capable of reaching most residents of NYC. Specifically, contact tracers made phone calls to confirmed cases and symptomatic contacts to conduct a case investigation. For children under 18 years old, parents or legal guardians were contacted. Information about close contacts during the infectious period was elicited during the interview, and reported close contacts were then notified about their status of exposure through phone calls or text messages and are encouraged to get tested. Both confirmed/probably cases and their close contacts were monitored daily for the duration of their quarantine. We analyzed data obtained from case investigations and COVID-19 testing results (molecular and antigen) collected between 1 October 2020 and 10 May 2021 (Supplementary Fig. 1 , Supplementary Information). During this period, 691,834 confirmed and probable cases were reported to the New York City Department of Health and Mental Hygiene (DOHMH) 21 . The circulating strains of SARS-CoV-2 in NYC were dominated by the index virus strain; however, the Iota (B.1.526) and Alpha (B.1.1.7) variants gradually replaced the index virus during the spring of 2021 (Supplementary Fig. 2 ). After excluding cases residing in residential congregate settings, cases were sent to the NYC Test & Trace Corps for contact tracing. Among these cases, 644,029 were reached by tracers and 450,415 completed an interview. In total, 779,011 contacts with confirmed and probable cases were self-reported via case investigations, of whom 20.9% (162,659/779,011) were subsequently tested. The overall positivity rate among tested exposures is 55.8%. However, as infected individuals were more likely to seek tests, the actual secondary attack rate should be lower. We further disaggregated testing results for different exposure types (healthcare facility contact, home health aide, household member, intimate partner, large gathering contact, other close proximity, workplace contact) (Supplementary Fig. 3 ). The positivity rate was highest for household members and lowest for workplace contacts. The median time from specimen collection to reporting results to DOHMH was 2 days. 97% of index patients were called by tracers within two days of reporting to DOHMH (Fig. 1a ) and 68.4% of contacts were called the day of reporting to the Test & Trace team (Fig. 1b ). Among tested contacts, 66.6% sought testing within one week of notification", "role": "user" }, { "content": "A study led by researchers at Columbia University Mailman School of Public Health uses contract tracing data to produce a detailed map to date of SARS-CoV-2 spread in New York City. They found that the city's contact tracing program was efficient and produced data that can inform neighborhood-level interventions like vaccination and reactive restriction on business capacity. The study is published in the journal Nature Communications. The researchers analyzed contact tracing and testing records for 644,029 cases and their contacts in New York City during the second pandemic wave between October 1, 2020 and May 10, 2021. Data was collected by the NYC Test & Trace Corps and the Department of Health and Mental Hygiene. They found it was not possible to establish transmission chains at the individual level because more than 90 percent of self-reported close contacts were predominately household members and data on contacts outside home was incomplete. Instead, the researchers focused on how SARS-CoV-2 spread across communities and what the effects of control measures and vaccination on its spread. They also examined the operational performance of contact tracing. By reconstructing transmission chains, the authors found large heterogeneity in the number of reported close contacts and secondary infections. The transmission networks also reveal the spatial pattern of SARS-CoV-2 transmission across neighborhoods. The combination of vaccination and reactive, neighborhood-based interventions likely reduced the spread of COVID-19 during the second wave. Neighborhoods with many visitors, such those with a high density of businesses, were associated with elevated transmission levels within those areas and to other neighborhoods. Any future isolation measures should make allowances for front-line workers. \"Individuals working in essential businesses or emergency services may not be able to reduce movement, whereas individuals who travel long distances for resources might be better served by delivery or relocation of resources,\" says Sen Pei, Ph.D., assistant professor of environmental health sciences at Columbia Mailman School. Moreover, because communities with high test positivity are typically high-poverty areas, policymakers should provide supports for isolation and quarantine (food delivery, medication delivery, and access to safe isolation places), the researchers add. According to the study, the operation of contact tracing in New York City was very efficient with short turnaround times. The median time from specimen collection to reporting results to the Department of Health and Mental Hygiene was two days. Ninety-seven percent of index patients were called by tracers within two days of reporting to DOHMH and 68 percent of contacts were called the day of reporting to the Test & Trace team. Among tested contacts, two-thirds sought testing within one week of notification. For traced symptomatic infections, 87 percent were tested after symptom onset, and 13 percent were tested before symptom development. In the future, contract tracing could be improved through the integration of app-based services or Bluetooth which would provide information on contacts beyond of household members, the researchers say. However, to be effective, care must be taken to address privacy concerns. \"Contact tracing is useful information and could potentially become even more useful in the future, with COVID-19 or another infectious outbreak,\" says Pei. \"At the height of an outbreak, policymakers can see in real-time what neighborhoods are at greatest risk and direct resources to prevent infections.\" ", "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 Understanding SARS-CoV-2 transmission within and among communities is critical for tailoring public health policies to local context. However, analysis of community transmission is challenging due to a lack of high-resolution surveillance and testing data. Here, using contact tracing records for 644,029 cases and their contacts in New York City during the second pandemic wave, we provide a detailed characterization of the operational performance of contact tracing and reconstruct exposure and transmission networks at individual and ZIP code scales. We find considerable heterogeneity in reported close contacts and secondary infections and evidence of extensive transmission across ZIP code areas. Our analysis reveals the spatial pattern of SARS-CoV-2 spread and communities that are tightly interconnected by exposure and transmission. We find that locations with higher vaccination coverage and lower numbers of visitors to points-of-interest had reduced within- and cross-ZIP code transmission events, highlighting potential measures for curtailing SARS-CoV-2 spread in urban settings. Introduction Within metropolitan areas, infection risk and disease burden due to SARS-CoV-2, the causative agent of COVID-19, are characterized by spatial heterogeneity at neighborhood scales 1 , 2 , 3 . Communities with substantial local infections can sustain the spread of SARS-CoV-2, seed infections in interconnected neighborhoods, and spark resurgences of cases following the relaxation of non-pharmaceutical interventions (NPIs), such as masking and social distancing 4 . In densely populated urban settings, public health tactics may need to be uniquely tailored to specific geographic areas and/or communities that most support the persistence and spatial dispersion of SARS-CoV-2 infections. Development of such tailored tactics requires improved understanding of both transmission patterns at fine geographical scales and the factors shaping the intensity of community outbreaks. Examples of previously utilized targeted interventions include limiting indoor dining and gathering, increasing testing availability, encouraging home quarantine for exposed contacts, requiring face masks indoors, and closing nonessential businesses in high-risk communities. While the transmission patterns of SARS-CoV-2 at global, national, and regional levels have been reported 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , research on community-level transmission is often challenging due to limited availability of high-resolution surveillance and testing data, the lack of routine case interviews, and the difficulty identifying transmission events. In addition, the effect of public health interventions on community transmission of SARS-CoV-2 in metropolitan areas has not been well evaluated. Data collected through contact tracing efforts have provided valuable insights into the transmission dynamics of SARS-CoV-2; 14 , 15 , 16 , 17 , 18 however, most contact tracing during the early phase of the pandemic mainly focused on specific local outbreaks, which cannot support population-level analysis of community transmission. Here, we use detailed data from confirmed and probable cases 19 and case investigations during the second pandemic wave in New York City (NYC) to quantify community spread of COVID-19 at small spatial scales from October 2020 to May 2021. Unlike the initial outbreak during the spring of 2020, the second pandemic wave was fully captured by contact tracing. Additionally, contact tracing operation and individual protective measures such as mask-wearing and social distancing remained relatively stable during this period of the pandemic (in contrast with the post-Omicron era when protective measures were largely abandoned). As a result, data collected during the second pandemic wave may better inform understanding of SARS-CoV-2 community transmission in NYC and the operational performance of contact tracing during a public health emergency. Results Contact tracing in NYC The NYC Test & Trace Corps initiative was launched in June 2020 20 . Established as an operation to provide contact tracing, testing, and resources to support isolation and quarantine, the contact tracing program was integrated with a set of intervention efforts designed to limit morbidity and mortality from COVID-19 in NYC (Supplementary Information). Contact tracing was performed through phone calls and text messages, capable of reaching most residents of NYC. Specifically, contact tracers made phone calls to confirmed cases and symptomatic contacts to conduct a case investigation. For children under 18 years old, parents or legal guardians were contacted. Information about close contacts during the infectious period was elicited during the interview, and reported close contacts were then notified about their status of exposure through phone calls or text messages and are encouraged to get tested. Both confirmed/probably cases and their close contacts were monitored daily for the duration of their quarantine. We analyzed data obtained from case investigations and COVID-19 testing results (molecular and antigen) collected between 1 October 2020 and 10 May 2021 (Supplementary Fig. 1 , Supplementary Information). During this period, 691,834 confirmed and probable cases were reported to the New York City Department of Health and Mental Hygiene (DOHMH) 21 . The circulating strains of SARS-CoV-2 in NYC were dominated by the index virus strain; however, the Iota (B.1.526) and Alpha (B.1.1.7) variants gradually replaced the index virus during the spring of 2021 (Supplementary Fig. 2 ). After excluding cases residing in residential congregate settings, cases were sent to the NYC Test & Trace Corps for contact tracing. Among these cases, 644,029 were reached by tracers and 450,415 completed an interview. In total, 779,011 contacts with confirmed and probable cases were self-reported via case investigations, of whom 20.9% (162,659/779,011) were subsequently tested. The overall positivity rate among tested exposures is 55.8%. However, as infected individuals were more likely to seek tests, the actual secondary attack rate should be lower. We further disaggregated testing results for different exposure types (healthcare facility contact, home health aide, household member, intimate partner, large gathering contact, other close proximity, workplace contact) (Supplementary Fig. 3 ). The positivity rate was highest for household members and lowest for workplace contacts. The median time from specimen collection to reporting results to DOHMH was 2 days. 97% of index patients were called by tracers within two days of reporting to DOHMH (Fig. 1a ) and 68.4% of contacts were called the day of reporting to the Test & Trace team (Fig. 1b ). Among tested contacts, 66.6% sought testing within one week of notification<|im_end|> <|im_start|>assistant A study led by researchers at Columbia University Mailman School of Public Health uses contract tracing data to produce a detailed map to date of SARS-CoV-2 spread in New York City. They found that the city's contact tracing program was efficient and produced data that can inform neighborhood-level interventions like vaccination and reactive restriction on business capacity. The study is published in the journal Nature Communications. The researchers analyzed contact tracing and testing records for 644,029 cases and their contacts in New York City during the second pandemic wave between October 1, 2020 and May 10, 2021. Data was collected by the NYC Test & Trace Corps and the Department of Health and Mental Hygiene. They found it was not possible to establish transmission chains at the individual level because more than 90 percent of self-reported close contacts were predominately household members and data on contacts outside home was incomplete. Instead, the researchers focused on how SARS-CoV-2 spread across communities and what the effects of control measures and vaccination on its spread. They also examined the operational performance of contact tracing. By reconstructing transmission chains, the authors found large heterogeneity in the number of reported close contacts and secondary infections. The transmission networks also reveal the spatial pattern of SARS-CoV-2 transmission across neighborhoods. The combination of vaccination and reactive, neighborhood-based interventions likely reduced the spread of COVID-19 during the second wave. Neighborhoods with many visitors, such those with a high density of businesses, were associated with elevated transmission levels within those areas and to other neighborhoods. Any future isolation measures should make allowances for front-line workers. "Individuals working in essential businesses or emergency services may not be able to reduce movement, whereas individuals who travel long distances for resources might be better served by delivery or relocation of resources," says Sen Pei, Ph.D., assistant professor of environmental health sciences at Columbia Mailman School. Moreover, because communities with high test positivity are typically high-poverty areas, policymakers should provide supports for isolation and quarantine (food delivery, medication delivery, and access to safe isolation places), the researchers add. According to the study, the operation of contact tracing in New York City was very efficient with short turnaround times. The median time from specimen collection to reporting results to the Department of Health and Mental Hygiene was two days. Ninety-seven percent of index patients were called by tracers within two days of reporting to DOHMH and 68 percent of contacts were called the day of reporting to the Test & Trace team. Among tested contacts, two-thirds sought testing within one week of notification. For traced symptomatic infections, 87 percent were tested after symptom onset, and 13 percent were tested before symptom development. In the future, contract tracing could be improved through the integration of app-based services or Bluetooth which would provide information on contacts beyond of household members, the researchers say. However, to be effective, care must be taken to address privacy concerns. "Contact tracing is useful information and could potentially become even more useful in the future, with COVID-19 or another infectious outbreak," says Pei. "At the height of an outbreak, policymakers can see in real-time what neighborhoods are at greatest risk and direct resources to prevent infections." <|im_end|>

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2,011

[ { "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 While the effects of the Southern Annular Mode (SAM), a dominant climate variability mode in the Southern Ocean, on ocean acidification have been examined using models, no consensus has been reached. Using observational data from south of Tasmania, we show that during a period with positive SAM trends, surface water pH and aragonite saturation state at 60°–55° S (Antarctic Zone) decrease in austral summer at rates faster than those predicted from atmospheric CO 2 increase alone, whereas an opposite pattern is observed at 50°–45° S (Subantarctic Zone). Together with other processes, the enhanced acidification at 60°–55° S may be attributed to increased westerly winds that bring in more “acidified” waters from the higher latitudes via enhanced meridional Ekman transport and from the subsurface via increased vertical mixing. Our observations support climatic modulation of ocean acidification superimposed on the effect of increasing atmospheric CO 2 . Introduction The Southern Ocean has naturally low pH and saturation states of calcium carbonate (CaCO 3 ) due to cold temperatures and upwelling of CO 2 -enriched deep waters, and it is vulnerable to ocean acidification (OA) caused by increasing atmospheric CO 2 levels 1 , 2 , 3 , 4 . Surface waters of the Southern Ocean are predicted to become undersaturated with respect to aragonite (a more soluble form of CaCO 3 relative to calcite) as early as year 2030 if sea surface CO 2 increases in concert with atmospheric CO 2 (ref. 3 ). OA, defined as declining pH or CaCO 3 saturation states over decades or longer timescales 5 , affects many marine organisms and especially fragile Southern Ocean ecosystems 6 , 7 , 8 . Although global OA is due primarily to increasing atmospheric CO 2 by fossil fuel combustion and land use changes since the Industrial Revolution 2 , 9 , it may be enhanced by other processes such as upwelling, eutrophication, sea ice melt, and anomalous ocean circulation 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Such rapid acidification challenges the evolutionary adaptation capacity of organisms 18 . Therefore, understanding the processes or factors that modulate OA is important for projecting impacts on marine organisms and ecosystems. Climatically, the Southern Ocean is sensitive, particularly during austral summer, to the Southern Annular Mode (SAM) that is the dominant mode of climate variability in the extratropical Southern Hemisphere 19 , 20 . This mode is quantified by the SAM index as the difference in normalized mean sea level pressure between 40° and 65° S (ref. 20 ). In January, there was a positive SAM trend towards a high-index particularly since the 1980s, but this trend changed around 2000: the following decade exhibited decreased or no significant SAM trends (Fig. 1a ). A positive SAM trend is associated with increasing westerly winds at high-latitudes (south of 55° S, Fig. 1b ) resulting in increased equatorward Ekman transport and vertical mixing. Thus, “acidified” waters with lower pH and aragonite saturation state (Ω arag ) from the south and from deeper depths are likely to be transported to the surface further north. Therefore, enhanced surface OA in excess of the effect of increasing atmospheric CO 2 may be expected at high-latitudes during a period with positive SAM trends. Here we define enhanced OA as evidenced by declining rates of pH or Ω arag that are faster than rates predicted from increasing atmospheric CO 2 alone. Fig. 1 SAM index and change rates of zonal wind speed in the Southern Ocean. a SAM index in January 1983–2017 calculated by Marshall 20 . b , c Change rates of zonal wind speed in January 1991–2000 and January 2001–2011. In a , change rates of the SAM index (slope values) during the periods 1991–2000 (blue) and 2001–2011 (black) were determined using an ordinary least squares linear regression; slopes ( s ) and p -values of the regression analyses are also shown (differentiated with blue and black colors for the two periods). The gray line shows the weighted three-year running mean of the SAM index, which splits the data into two decades. In b , c , the red and blue lines show the mean positions of the subantarctic front (SAF) and the polar front (PF) 58 , respectively; the black rectangle delineates the study area south of Tasmania. Change rates of zonal wind speeds, which are based on the CCMP wind product, were calculated using an ordinary least squares linear regression in each grid (0.25° × 0.25°) Full size image However, due partly to lack of observational data, previous studies on the effects of SAM on OA in the Southern Ocean use models which yielded different and even opposite conclusions 18 , 21 , 22 , 23 . Therefore, it is necessary and important to further investigate the mechanistic role of the SAM on sea surface carbonate chemistry and OA. Also, it is important to ascertain whether OA responds to the SAM differently for different latitudinal zones as was shown for circulation and biology 24 , since the SAM measures a seesaw of atmospheric mass between the high-latitudes and mid-latitudes of the Southern Hemisphere 20 . Given that the region south of Tasmania is perhaps the only region where there is continuous observational CO 2 data since 1991 (Supplementary Fig. 1 ), we use observations from this area spanning two decades during 1991–2011, with contrasting SAM trends before and after 2000 (Fig. 1a and Supplementary Figs. 2 – 3 ) and show how changing wind patterns related to the SAM affect the rate of surface OA. We find that the SAM appears to have significant modulating effects on OA rates over different latitudinal zones. To account for the SAM modulation of OA rates, we examine mechanisms associated with wind-driven meridional Ekman transport and vertical mixing during austral summer when the upper ocean layers are stratified. Our work helps improve understanding of the mechanisms of OA in the Southern Ocean, thus providing observational constraints for the improvements of", "role": "user" }, { "content": "Antarctica has a current that circles the landmass as part of the Southern Ocean. This current is called the Antarctic Circumpolar Current. When the westerly winds strengthen during the Southern Hemisphere's summer, waters south of the current acidify faster than can be accounted for in carbon dioxide from the atmosphere alone. The opposite pattern was observed north of the current. Why does this happen and why does it matter? University of Delaware Professor Wei-Jun Cai co-wrote a paper that appeared in Nature Communications and addresses those questions. Researchers involved in the study say these effects are due to a combination of processes driven by these westerly winds—a theory that was borne out by two decades' worth of observational data from south of Tasmania. Understanding the factors that control ocean acidification is important for predicting the impact that the changing chemistry of the ocean will have on marine organisms and ecosystems in the future. The Southern Ocean, also known as the Antarctic Ocean, is a critical place to study these mechanisms because of its vast capacity to store carbon dioxide from the atmosphere, a crucial component of climate change. Data-driven results benefit future prediction models The fourth largest ocean, the Southern Ocean has a naturally low pH and saturation state for aragonite, a carbonate mineral that marine organisms need to build their shells. This is considered to be due to the Southern Ocean's cold temperatures, which average -2 to 7 degrees Celsius (approximately 28 to 45 degrees Fahrenheit), and strong vertical mixing throughout the water column. Because of these cold temperatures and deep mixing, the carbon dioxide absorbed at the water's surface can be quickly transferred to and stored in the deep regions of the Southern Ocean, unlike most lower latitude oceans where huge temperature differences prevent the surface water and the deep ocean from mixing. As atmospheric carbon dioxide levels continue to increase, however, surface waters in the Southern Ocean are expected to become increasingly vulnerable to ocean acidification. \"The Southern Ocean is a window to the deep ocean,\" said Cai, an expert in inorganic carbon chemistry and the Mary A.S. Lighthipe Chair of Earth, Ocean and Environment at UD. \" Better understanding the mechanisms of ocean acidification here can help improve prediction models for how much atmospheric carbon dioxide the ocean can take up here and elsewhere.\" \"The Southern Ocean is a window to the deep ocean\" said Wei-Jun Cai, an expert in inorganic carbon chemistry and the Mary A.S. Lighthipe Chair of Earth, Ocean and Environment at UD. Credit: Photos courtesy of Liang Xue/ University of Delaware In the southern hemisphere, the main way that the atmosphere varies is through what is known as the Southern Annual Mode (SAM). As this mode changes from one extreme to another, the pressure difference causes the belt of westerly winds (or jet stream) around Antarctica to move north or south. When the jet stream of air strengthens (a positive SAM trend), it contracts toward Antarctica. When the jet stream weakens (a negative SAM trend), it expands north toward the equator. In their study, the researchers explored how westerly winds regulate the rates of ocean acidification, using continuous data measurements of carbon dioxide from south of Tasmania recorded over two contrasting decades, 1991-2000 and 2001-2011. The researchers attributed the enhanced acidification to the westerly winds transporting more acidic waters horizontally from higher latitude locations toward the equator and vertically from the subsurface to the surface. \"When you have a pressure difference, you have a stronger wind and the wind always moves from high pressure to low pressure, driving the surface ocean currents from one point to another. In physical oceanography we call this wind-driven Ekman transport,\" said Cai. When westerly winds decrease, the result is the opposite and less acidic surface water is transferred toward the South Pole. \"Whether we study this in the Chesapeake Bay, the Gulf of Mexico or the Southern Ocean, it is all the same reason that another source of carbon dioxide or acidified water comes into the study area. But depending on the location, this mechanism can manifest itself differently,\" said Cai. This Southern Ocean mixing extends to a depth of approximately 300 to 400 meters (around 1,000 to 1,300 feet). This is far deeper than, say, in the Chesapeake Bay or oxygen-deficient Gulf of Mexico where the water's deepest regions might extend only 20 to 50 meters (54-164 feet deep). In theory, as atmospheric carbon dioxide increases, ocean carbon dioxide levels (i.e., ocean acidification) should increase in parallel. However, Cai explained that upwelling of deeper waters that contain more carbon dioxide combined with ocean circulation patterns, or mixing of different layers of the ocean, can cause the water's pH and carbonate saturation state to vary quite a lot. Cai said though there have been a few recent papers in this area, he and his colleagues are the first to show with direct data that this is caused by wind stress. \"There is a lot of debate on this issue, but when put together, the two decades' worth of data gave a consistent story that ocean circulation patterns really affect ocean acidification,\" said Cai. So, what does the Southern Ocean have to do with Delaware? \"The Southern Ocean is an area that really changes the deep ocean carbon dioxide signal because of this rapid mixing to the deep ocean,\" said Cai. \"Consequently, when wind speeds cause the layers of the water to mix and change circulation patterns, it really can drive changes that may be significant to the global ocean, and broadly, would eventually influence other areas, including the Atlantic 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 While the effects of the Southern Annular Mode (SAM), a dominant climate variability mode in the Southern Ocean, on ocean acidification have been examined using models, no consensus has been reached. Using observational data from south of Tasmania, we show that during a period with positive SAM trends, surface water pH and aragonite saturation state at 60°–55° S (Antarctic Zone) decrease in austral summer at rates faster than those predicted from atmospheric CO 2 increase alone, whereas an opposite pattern is observed at 50°–45° S (Subantarctic Zone). Together with other processes, the enhanced acidification at 60°–55° S may be attributed to increased westerly winds that bring in more “acidified” waters from the higher latitudes via enhanced meridional Ekman transport and from the subsurface via increased vertical mixing. Our observations support climatic modulation of ocean acidification superimposed on the effect of increasing atmospheric CO 2 . Introduction The Southern Ocean has naturally low pH and saturation states of calcium carbonate (CaCO 3 ) due to cold temperatures and upwelling of CO 2 -enriched deep waters, and it is vulnerable to ocean acidification (OA) caused by increasing atmospheric CO 2 levels 1 , 2 , 3 , 4 . Surface waters of the Southern Ocean are predicted to become undersaturated with respect to aragonite (a more soluble form of CaCO 3 relative to calcite) as early as year 2030 if sea surface CO 2 increases in concert with atmospheric CO 2 (ref. 3 ). OA, defined as declining pH or CaCO 3 saturation states over decades or longer timescales 5 , affects many marine organisms and especially fragile Southern Ocean ecosystems 6 , 7 , 8 . Although global OA is due primarily to increasing atmospheric CO 2 by fossil fuel combustion and land use changes since the Industrial Revolution 2 , 9 , it may be enhanced by other processes such as upwelling, eutrophication, sea ice melt, and anomalous ocean circulation 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Such rapid acidification challenges the evolutionary adaptation capacity of organisms 18 . Therefore, understanding the processes or factors that modulate OA is important for projecting impacts on marine organisms and ecosystems. Climatically, the Southern Ocean is sensitive, particularly during austral summer, to the Southern Annular Mode (SAM) that is the dominant mode of climate variability in the extratropical Southern Hemisphere 19 , 20 . This mode is quantified by the SAM index as the difference in normalized mean sea level pressure between 40° and 65° S (ref. 20 ). In January, there was a positive SAM trend towards a high-index particularly since the 1980s, but this trend changed around 2000: the following decade exhibited decreased or no significant SAM trends (Fig. 1a ). A positive SAM trend is associated with increasing westerly winds at high-latitudes (south of 55° S, Fig. 1b ) resulting in increased equatorward Ekman transport and vertical mixing. Thus, “acidified” waters with lower pH and aragonite saturation state (Ω arag ) from the south and from deeper depths are likely to be transported to the surface further north. Therefore, enhanced surface OA in excess of the effect of increasing atmospheric CO 2 may be expected at high-latitudes during a period with positive SAM trends. Here we define enhanced OA as evidenced by declining rates of pH or Ω arag that are faster than rates predicted from increasing atmospheric CO 2 alone. Fig. 1 SAM index and change rates of zonal wind speed in the Southern Ocean. a SAM index in January 1983–2017 calculated by Marshall 20 . b , c Change rates of zonal wind speed in January 1991–2000 and January 2001–2011. In a , change rates of the SAM index (slope values) during the periods 1991–2000 (blue) and 2001–2011 (black) were determined using an ordinary least squares linear regression; slopes ( s ) and p -values of the regression analyses are also shown (differentiated with blue and black colors for the two periods). The gray line shows the weighted three-year running mean of the SAM index, which splits the data into two decades. In b , c , the red and blue lines show the mean positions of the subantarctic front (SAF) and the polar front (PF) 58 , respectively; the black rectangle delineates the study area south of Tasmania. Change rates of zonal wind speeds, which are based on the CCMP wind product, were calculated using an ordinary least squares linear regression in each grid (0.25° × 0.25°) Full size image However, due partly to lack of observational data, previous studies on the effects of SAM on OA in the Southern Ocean use models which yielded different and even opposite conclusions 18 , 21 , 22 , 23 . Therefore, it is necessary and important to further investigate the mechanistic role of the SAM on sea surface carbonate chemistry and OA. Also, it is important to ascertain whether OA responds to the SAM differently for different latitudinal zones as was shown for circulation and biology 24 , since the SAM measures a seesaw of atmospheric mass between the high-latitudes and mid-latitudes of the Southern Hemisphere 20 . Given that the region south of Tasmania is perhaps the only region where there is continuous observational CO 2 data since 1991 (Supplementary Fig. 1 ), we use observations from this area spanning two decades during 1991–2011, with contrasting SAM trends before and after 2000 (Fig. 1a and Supplementary Figs. 2 – 3 ) and show how changing wind patterns related to the SAM affect the rate of surface OA. We find that the SAM appears to have significant modulating effects on OA rates over different latitudinal zones. To account for the SAM modulation of OA rates, we examine mechanisms associated with wind-driven meridional Ekman transport and vertical mixing during austral summer when the upper ocean layers are stratified. Our work helps improve understanding of the mechanisms of OA in the Southern Ocean, thus providing observational constraints for the improvements of<|im_end|> <|im_start|>assistant Antarctica has a current that circles the landmass as part of the Southern Ocean. This current is called the Antarctic Circumpolar Current. When the westerly winds strengthen during the Southern Hemisphere's summer, waters south of the current acidify faster than can be accounted for in carbon dioxide from the atmosphere alone. The opposite pattern was observed north of the current. Why does this happen and why does it matter? University of Delaware Professor Wei-Jun Cai co-wrote a paper that appeared in Nature Communications and addresses those questions. Researchers involved in the study say these effects are due to a combination of processes driven by these westerly winds—a theory that was borne out by two decades' worth of observational data from south of Tasmania. Understanding the factors that control ocean acidification is important for predicting the impact that the changing chemistry of the ocean will have on marine organisms and ecosystems in the future. The Southern Ocean, also known as the Antarctic Ocean, is a critical place to study these mechanisms because of its vast capacity to store carbon dioxide from the atmosphere, a crucial component of climate change. Data-driven results benefit future prediction models The fourth largest ocean, the Southern Ocean has a naturally low pH and saturation state for aragonite, a carbonate mineral that marine organisms need to build their shells. This is considered to be due to the Southern Ocean's cold temperatures, which average -2 to 7 degrees Celsius (approximately 28 to 45 degrees Fahrenheit), and strong vertical mixing throughout the water column. Because of these cold temperatures and deep mixing, the carbon dioxide absorbed at the water's surface can be quickly transferred to and stored in the deep regions of the Southern Ocean, unlike most lower latitude oceans where huge temperature differences prevent the surface water and the deep ocean from mixing. As atmospheric carbon dioxide levels continue to increase, however, surface waters in the Southern Ocean are expected to become increasingly vulnerable to ocean acidification. "The Southern Ocean is a window to the deep ocean," said Cai, an expert in inorganic carbon chemistry and the Mary A.S. Lighthipe Chair of Earth, Ocean and Environment at UD. " Better understanding the mechanisms of ocean acidification here can help improve prediction models for how much atmospheric carbon dioxide the ocean can take up here and elsewhere." "The Southern Ocean is a window to the deep ocean" said Wei-Jun Cai, an expert in inorganic carbon chemistry and the Mary A.S. Lighthipe Chair of Earth, Ocean and Environment at UD. Credit: Photos courtesy of Liang Xue/ University of Delaware In the southern hemisphere, the main way that the atmosphere varies is through what is known as the Southern Annual Mode (SAM). As this mode changes from one extreme to another, the pressure difference causes the belt of westerly winds (or jet stream) around Antarctica to move north or south. When the jet stream of air strengthens (a positive SAM trend), it contracts toward Antarctica. When the jet stream weakens (a negative SAM trend), it expands north toward the equator. In their study, the researchers explored how westerly winds regulate the rates of ocean acidification, using continuous data measurements of carbon dioxide from south of Tasmania recorded over two contrasting decades, 1991-2000 and 2001-2011. The researchers attributed the enhanced acidification to the westerly winds transporting more acidic waters horizontally from higher latitude locations toward the equator and vertically from the subsurface to the surface. "When you have a pressure difference, you have a stronger wind and the wind always moves from high pressure to low pressure, driving the surface ocean currents from one point to another. In physical oceanography we call this wind-driven Ekman transport," said Cai. When westerly winds decrease, the result is the opposite and less acidic surface water is transferred toward the South Pole. "Whether we study this in the Chesapeake Bay, the Gulf of Mexico or the Southern Ocean, it is all the same reason that another source of carbon dioxide or acidified water comes into the study area. But depending on the location, this mechanism can manifest itself differently," said Cai. This Southern Ocean mixing extends to a depth of approximately 300 to 400 meters (around 1,000 to 1,300 feet). This is far deeper than, say, in the Chesapeake Bay or oxygen-deficient Gulf of Mexico where the water's deepest regions might extend only 20 to 50 meters (54-164 feet deep). In theory, as atmospheric carbon dioxide increases, ocean carbon dioxide levels (i.e., ocean acidification) should increase in parallel. However, Cai explained that upwelling of deeper waters that contain more carbon dioxide combined with ocean circulation patterns, or mixing of different layers of the ocean, can cause the water's pH and carbonate saturation state to vary quite a lot. Cai said though there have been a few recent papers in this area, he and his colleagues are the first to show with direct data that this is caused by wind stress. "There is a lot of debate on this issue, but when put together, the two decades' worth of data gave a consistent story that ocean circulation patterns really affect ocean acidification," said Cai. So, what does the Southern Ocean have to do with Delaware? "The Southern Ocean is an area that really changes the deep ocean carbon dioxide signal because of this rapid mixing to the deep ocean," said Cai. "Consequently, when wind speeds cause the layers of the water to mix and change circulation patterns, it really can drive changes that may be significant to the global ocean, and broadly, would eventually influence other areas, including the Atlantic Ocean." <|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 Introduction of synthetic circuits into microbes creates competition between circuit and host genes for shared cellular resources, such as ribosomes. This can lead to the emergence of unwanted coupling between the expression of different circuit genes, complicating the design process and potentially leading to circuit failure. By expressing a synthetic 16S rRNA with altered specificity, we can partition the ribosome pool into host-specific and circuit-specific activities. We show mathematically and experimentally that the effects of resource competition can be alleviated by targeting genes to different ribosomal pools. This division of labour can be used to increase flux through a metabolic pathway. We develop a model of cell physiology which is able to capture these observations and use it to design a dynamic resource allocation controller. When implemented, this controller acts to decouple genes by increasing orthogonal ribosome production as the demand for translational resources by a synthetic circuit increases. Introduction A key goal of synthetic biology is the construction of novel information processing genetic circuits in microbes which can be used to guide cellular function and control metabolic processes 1 . However, many initial designs fail upon implementation in vivo due to unforeseen interactions between the host and synthetic circuit 2 . These often arise due to competition for shared cellular resources, such as RNA polymerases and ribosomes 3 , 4 . Previous experimental studies have shown that translational capacity, in the form of free ribosomes, limits microbial gene expression 3 , 5 , 6 , 7 , 8 and so is a key cause of these hidden interactions 4 . Previous work has shown that the non-regulatory coupling that emerges due to these hidden interactions can be reduced by careful design and selection of ribosome binding sites and plasmid copy numbers 3 , 4 , 6 . Additionally, incorporating negative feedback loops into the circuit can insulate genes 9 , 10 , 11 . These approaches, however, require significant re-design of the original synthetic circuit, and by incorporating additional regulatory interactions may make certain circuit behaviours unobtainable. In this work, we propose an alternative approach, based on the partitioning of the cell’s translational capacity, and show that it allows the decoupling of circuit genes without the need for extensive re-design. Previously, both transcription and protein degradation activities have been partitioned into circuit-specific and host-specific activities through the use of ‘orthogonal’ components. For example, the expression of RNA polymerases (RNAP) from bacteriophage T7 in Escherichia coli creates a circuit-specific transcription system 12 . Co-option of proteases from other bacteria has been used to create a circuit-specific degradation pathway 13 . Due to the universality and complexity of the cell’s translational machinery, there does not exist a sufficiently distinct ribosome which can be co-opted into E. coli to create a truly orthogonal ribosome pool. However, translational capacity can be divided into host- and circuit-specific functions by the use of synthetic ribosomal components to create a quasi-orthogonal ribosome (‘o-ribosome’) system 14 , 15 , 16 . The binding interactions between an mRNA and the 16S ribosomal RNA (rRNA) of the small ribosomal subunit are known to be a key regulator of translation initiation 17 , and thus o-ribosomes can be created by expressing a synthetic 16S rRNA. Evolving or designing the 5′ sequences at and around the ribosome binding site (RBS) of circuit mRNAs to interact with this synthetic sequence allows the creation of an orthogonal translation system 15 , 16 . For simplicity, we refer to this synthetic 5′ sequence as an orthogonal RBS (‘o-RBS’). These specialised o-ribosomes have previously been successfully used to probe various aspects of ribosome function 18 or for biocontainment 19 but their use in the creation of synthetic gene circuits and managing the distribution of translational activity has not yet been fully explored. In this paper, we demonstrate the use of orthogonal ribosomes for reducing coupling between the expression of different circuit genes. We use the division of translational activity provided by orthogonal ribosomes to design simple resource allocators, where circuit genes are targeted to either the host or orthogonal ribosome pools. We show that this can be used to relieve the effects of resource-mediated gene coupling and that by allocating circuit genes in this way flux though a metabolic pathway can be improved. We design a feedback controller that acts to dynamically increase o-ribosome production as demand for translational resources by the circuit genes increases. When implemented experimentally, this controller acts to reduce resource-mediated gene coupling by 50%. We develop a mathematical model of microbial growth, and show throughout that this can be used to assess how circuit genes should be allocated between different translational pools. Results Development of an o-ribosome model We initially developed a mathematical model to assess the feasibility of implementing and using an orthogonal translation system. Taking a host-aware modelling approach we based our model on that of microbial physiology developed by Weiße et al. 20 . This model captures the three fundamental trade-offs in bacterial gene expression: (i) internal anabolic capacity (‘energy’) is limited by substrate import and enzyme activity, (ii) finite translational capacity and (iii) finite proteome size. This model consists of a simple metabolism, transcriptome and proteome representing four main class of protein function: (i) metabolite transport ( T ), (ii) enzymes ( E ), (iii) ribosomes ( R ) and (iv) host proteins ( H ). We refer to these host genes as X ∈ { T , E , H , R }. Additional proteins representing circuit genes, the set Y , are included as described in Supplementary Note 1 . See Supplementary Fig. 1 for a simplified schematic. We fit our model to the growth rate and ribosomal mass fraction data as produced by Scott et al. 5 (Supplementary Fig. 2 ). We expanded on the original ribosome biosynthesis reaction to take account of both protein and rRNA components. We considered the production of a single large ribosomal protein to represent the small and large ribosomal subunits and other accessory protein complexes. We term", "role": "user" }, { "content": "Bacteria could be programmed to efficiently produce drugs, thanks to breakthrough research into synthetic biology using engineering principles, from the University of Warwick and the University of Surrey. Led by the Warwick Integrative Synthetic Biology Centre at Warwick's School of Engineering and the Faculty of Health and Medical Sciences at the University of Surrey, new research has discovered how to dynamically manage the allocation of essential resources inside engineered cells—advancing the potential of synthetically programming cells to combat disease and produce new drugs. The researchers have developed a way to efficiently control the distribution of ribosomes – microscopic 'factories' inside cells that build proteins that keep the cell alive and functional – to both the synthetic circuit and the host cell. Synthetic circuitry can be added to cells to enhance them and make them perform bespoke functions – providing vast new possibilities for the future of healthcare and pharmaceuticals, including the potential for cells specially programmed to produce novel antibiotics and other useful compounds. A cell only has a finite amount of ribosomes, and the synthetic circuit and host cell in which the circuitry is inserted both compete for this limited pool of resources. It is essential that there are enough ribosomes for both, so they can survive, multiply and thrive. Without enough ribosomes, either the circuit will fail, or the cell will die – or both. Using the engineering principal of a feedback control loop, commonly used in aircraft flight control systems, the researchers have developed and demonstrated a unique system through which ribosomes can be distributed dynamically—therefore, when the synthetic circuit requires more ribosomes to function properly, more will be allocated to it, and less allocated to the host cell, and vice versa. Declan Bates, Professor of Bioengineering at the University of Warwick's School of Engineering and Co-Director, Warwick Integrative Synthetic Biology Centre (WISB) commented: \"Synthetic Biology is about making cells easier to engineer so that we can address many of the most important challenges facing us today—from manufacturing new drugs and therapies to finding new biofuels and materials. It's been hugely exciting in this project to see an engineering idea, developed on a computer, being built in a lab and working inside a living cell.\" José Jiménez, Lecturer in Synthetic Biology at the University of Surrey's Faculty of Health and Medical Sciences: \"The ultimate goal of the selective manipulation of cellular functions like the one carried out in this project is to understand fundamental principles of biology itself. By learning about how cells operate and testing the constraints under which they evolve, we can come up with ways of engineering cells more efficiently for a wide range of applications in biotechnology\" Ribosomes live inside cells, and construct proteins when required for a cellular function. When a cell needs protein, the nucleus creates mRNA, which is sent to the ribosomes – which then synthesise the essential proteins by bonding the correct amino acids together in a chain. ", "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 Introduction of synthetic circuits into microbes creates competition between circuit and host genes for shared cellular resources, such as ribosomes. This can lead to the emergence of unwanted coupling between the expression of different circuit genes, complicating the design process and potentially leading to circuit failure. By expressing a synthetic 16S rRNA with altered specificity, we can partition the ribosome pool into host-specific and circuit-specific activities. We show mathematically and experimentally that the effects of resource competition can be alleviated by targeting genes to different ribosomal pools. This division of labour can be used to increase flux through a metabolic pathway. We develop a model of cell physiology which is able to capture these observations and use it to design a dynamic resource allocation controller. When implemented, this controller acts to decouple genes by increasing orthogonal ribosome production as the demand for translational resources by a synthetic circuit increases. Introduction A key goal of synthetic biology is the construction of novel information processing genetic circuits in microbes which can be used to guide cellular function and control metabolic processes 1 . However, many initial designs fail upon implementation in vivo due to unforeseen interactions between the host and synthetic circuit 2 . These often arise due to competition for shared cellular resources, such as RNA polymerases and ribosomes 3 , 4 . Previous experimental studies have shown that translational capacity, in the form of free ribosomes, limits microbial gene expression 3 , 5 , 6 , 7 , 8 and so is a key cause of these hidden interactions 4 . Previous work has shown that the non-regulatory coupling that emerges due to these hidden interactions can be reduced by careful design and selection of ribosome binding sites and plasmid copy numbers 3 , 4 , 6 . Additionally, incorporating negative feedback loops into the circuit can insulate genes 9 , 10 , 11 . These approaches, however, require significant re-design of the original synthetic circuit, and by incorporating additional regulatory interactions may make certain circuit behaviours unobtainable. In this work, we propose an alternative approach, based on the partitioning of the cell’s translational capacity, and show that it allows the decoupling of circuit genes without the need for extensive re-design. Previously, both transcription and protein degradation activities have been partitioned into circuit-specific and host-specific activities through the use of ‘orthogonal’ components. For example, the expression of RNA polymerases (RNAP) from bacteriophage T7 in Escherichia coli creates a circuit-specific transcription system 12 . Co-option of proteases from other bacteria has been used to create a circuit-specific degradation pathway 13 . Due to the universality and complexity of the cell’s translational machinery, there does not exist a sufficiently distinct ribosome which can be co-opted into E. coli to create a truly orthogonal ribosome pool. However, translational capacity can be divided into host- and circuit-specific functions by the use of synthetic ribosomal components to create a quasi-orthogonal ribosome (‘o-ribosome’) system 14 , 15 , 16 . The binding interactions between an mRNA and the 16S ribosomal RNA (rRNA) of the small ribosomal subunit are known to be a key regulator of translation initiation 17 , and thus o-ribosomes can be created by expressing a synthetic 16S rRNA. Evolving or designing the 5′ sequences at and around the ribosome binding site (RBS) of circuit mRNAs to interact with this synthetic sequence allows the creation of an orthogonal translation system 15 , 16 . For simplicity, we refer to this synthetic 5′ sequence as an orthogonal RBS (‘o-RBS’). These specialised o-ribosomes have previously been successfully used to probe various aspects of ribosome function 18 or for biocontainment 19 but their use in the creation of synthetic gene circuits and managing the distribution of translational activity has not yet been fully explored. In this paper, we demonstrate the use of orthogonal ribosomes for reducing coupling between the expression of different circuit genes. We use the division of translational activity provided by orthogonal ribosomes to design simple resource allocators, where circuit genes are targeted to either the host or orthogonal ribosome pools. We show that this can be used to relieve the effects of resource-mediated gene coupling and that by allocating circuit genes in this way flux though a metabolic pathway can be improved. We design a feedback controller that acts to dynamically increase o-ribosome production as demand for translational resources by the circuit genes increases. When implemented experimentally, this controller acts to reduce resource-mediated gene coupling by 50%. We develop a mathematical model of microbial growth, and show throughout that this can be used to assess how circuit genes should be allocated between different translational pools. Results Development of an o-ribosome model We initially developed a mathematical model to assess the feasibility of implementing and using an orthogonal translation system. Taking a host-aware modelling approach we based our model on that of microbial physiology developed by Weiße et al. 20 . This model captures the three fundamental trade-offs in bacterial gene expression: (i) internal anabolic capacity (‘energy’) is limited by substrate import and enzyme activity, (ii) finite translational capacity and (iii) finite proteome size. This model consists of a simple metabolism, transcriptome and proteome representing four main class of protein function: (i) metabolite transport ( T ), (ii) enzymes ( E ), (iii) ribosomes ( R ) and (iv) host proteins ( H ). We refer to these host genes as X ∈ { T , E , H , R }. Additional proteins representing circuit genes, the set Y , are included as described in Supplementary Note 1 . See Supplementary Fig. 1 for a simplified schematic. We fit our model to the growth rate and ribosomal mass fraction data as produced by Scott et al. 5 (Supplementary Fig. 2 ). We expanded on the original ribosome biosynthesis reaction to take account of both protein and rRNA components. We considered the production of a single large ribosomal protein to represent the small and large ribosomal subunits and other accessory protein complexes. We term<|im_end|> <|im_start|>assistant Bacteria could be programmed to efficiently produce drugs, thanks to breakthrough research into synthetic biology using engineering principles, from the University of Warwick and the University of Surrey. Led by the Warwick Integrative Synthetic Biology Centre at Warwick's School of Engineering and the Faculty of Health and Medical Sciences at the University of Surrey, new research has discovered how to dynamically manage the allocation of essential resources inside engineered cells—advancing the potential of synthetically programming cells to combat disease and produce new drugs. The researchers have developed a way to efficiently control the distribution of ribosomes – microscopic 'factories' inside cells that build proteins that keep the cell alive and functional – to both the synthetic circuit and the host cell. Synthetic circuitry can be added to cells to enhance them and make them perform bespoke functions – providing vast new possibilities for the future of healthcare and pharmaceuticals, including the potential for cells specially programmed to produce novel antibiotics and other useful compounds. A cell only has a finite amount of ribosomes, and the synthetic circuit and host cell in which the circuitry is inserted both compete for this limited pool of resources. It is essential that there are enough ribosomes for both, so they can survive, multiply and thrive. Without enough ribosomes, either the circuit will fail, or the cell will die – or both. Using the engineering principal of a feedback control loop, commonly used in aircraft flight control systems, the researchers have developed and demonstrated a unique system through which ribosomes can be distributed dynamically—therefore, when the synthetic circuit requires more ribosomes to function properly, more will be allocated to it, and less allocated to the host cell, and vice versa. Declan Bates, Professor of Bioengineering at the University of Warwick's School of Engineering and Co-Director, Warwick Integrative Synthetic Biology Centre (WISB) commented: "Synthetic Biology is about making cells easier to engineer so that we can address many of the most important challenges facing us today—from manufacturing new drugs and therapies to finding new biofuels and materials. It's been hugely exciting in this project to see an engineering idea, developed on a computer, being built in a lab and working inside a living cell." José Jiménez, Lecturer in Synthetic Biology at the University of Surrey's Faculty of Health and Medical Sciences: "The ultimate goal of the selective manipulation of cellular functions like the one carried out in this project is to understand fundamental principles of biology itself. By learning about how cells operate and testing the constraints under which they evolve, we can come up with ways of engineering cells more efficiently for a wide range of applications in biotechnology" Ribosomes live inside cells, and construct proteins when required for a cellular function. When a cell needs protein, the nucleus creates mRNA, which is sent to the ribosomes – which then synthesise the essential proteins by bonding the correct amino acids together in a chain. <|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 Metals have been mankind’s most essential materials for thousands of years; however, their use is affected by ecological and economical concerns. Alloys with higher strength and ductility could alleviate some of these concerns by reducing weight and improving energy efficiency. However, most metallurgical mechanisms for increasing strength lead to ductility loss, an effect referred to as the strength–ductility trade-off 1 , 2 . Here we present a metastability-engineering strategy in which we design nanostructured, bulk high-entropy alloys with multiple compositionally equivalent high-entropy phases. High-entropy alloys were originally proposed to benefit from phase stabilization through entropy maximization 3 , 4 , 5 , 6 . Yet here, motivated by recent work that relaxes the strict restrictions on high-entropy alloy compositions by demonstrating the weakness of this connection 7 , 8 , 9 , 10 , 11 , the concept is overturned. We decrease phase stability to achieve two key benefits: interface hardening due to a dual-phase microstructure (resulting from reduced thermal stability of the high-temperature phase 12 ); and transformation-induced hardening (resulting from the reduced mechanical stability of the room-temperature phase 13 ). This combines the best of two worlds: extensive hardening due to the decreased phase stability known from advanced steels 14 , 15 and massive solid-solution strengthening of high-entropy alloys 3 . In our transformation-induced plasticity-assisted, dual-phase high-entropy alloy (TRIP-DP-HEA), these two contributions lead respectively to enhanced trans-grain and inter-grain slip resistance, and hence, increased strength. Moreover, the increased strain hardening capacity that is enabled by dislocation hardening of the stable phase and transformation-induced hardening of the metastable phase produces increased ductility. This combined increase in strength and ductility distinguishes the TRIP-DP-HEA alloy from other recently developed structural materials 16 , 17 . This metastability-engineering strategy should thus usefully guide design in the near-infinite compositional space of high-entropy alloys. Main To realize the TRIP-DP-HEA concept, we switch from the equiatomic Fe 20 Mn 20 Ni 20 Co 20 Cr 20 (atomic per cent, at%) 6 system to the non-equiatomic Fe 80 − x Mn x Co 10 Cr 10 (at%) system, which exhibits partial martensitic transformation of the face-centred cubic (f.c.c.) to the hexagonal close-packed (h.c.p.) phase upon cooling from the high-temperature single-phase region. This change enables development of a dual-phase microstructure in which both phases obtain the maximum benefit of the solid-solution strengthening effect and one phase, owing to the decreased stacking fault energy 18 , undergoes deformation-induced displacive transformation. The partial martensitic transformation during quenching is the only possible approach that can lead to the formation of a DP-HEA with phases of identical chemical composition (that is, high-entropy phases). The alloys were synthesized with varying Mn contents in a vacuum induction furnace using pure metals, hot-rolled to 50% thickness at 900 °C, homogenized at 1,200 °C for 2 h in an Ar atmosphere, and water-quenched. Further grain refinement was achieved by cold-rolling (to 60% thickness) and 3-min annealing at 900 °C in an Ar atmosphere. The chemical composition of the HEAs measured by wet-chemical analysis is given in Extended Data Table 1 . Microstructure characterization down to 30-nm resolution reveals that the Fe 80 − x Mn x Co 10 Cr 10 (at%) system indeed demonstrates the targeted change in phase stability (see the X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) data in Fig. 1 ). A single f.c.c. phase structure was obtained when the Mn content was 45 at% and 40 at% (Fe 35 Mn 45 Co 10 Cr 10 and Fe 40 Mn 40 Co 10 Cr 10 , respectively). These two alloys demonstrate a transition in the deformation mechanisms from dislocation-dominated plasticity in the former 8 to twinning-induced plasticity (TWIP) in the latter 10 , confirming the targeted stability trend realized by tuning the stacking fault energy. A further decrease to 35 at% Mn leads to traces of h.c.p. phase (not captured by XRD). Finally, a decrease to 30 at% Mn (Fe 50 Mn 30 Co 10 Cr 10 ) successfully produces the desired dual-phase microstructure with ~28% h.c.p. phase. This alloy is analysed in more detail in the following. Figure 1: XRD patterns and EBSD phase maps of Fe 80 − x Mn x Co 10 Cr 10 ( x = 45 at%, 40 at%, 35 at% and 30 at%) HEAs. θ is the Bragg angle. The Mn content plays an important part in phase constitution, tuning phase stability for the activation of specific displacing transformation mechanisms, for example, enabling TWIP or TRIP effects. We note that the 35 at% Mn alloy has only trace amounts of the h.c.p. phase, and hence is not referred to as a DP-HEA. PowerPoint slide Source data Full size image The two phases constituting the as-quenched Fe 50 Mn 30 Co 10 Cr 10 (at%) alloy are the f.c.c. γ matrix (of ~45-μm grain size) and the h.c.p. ε phase laminate layers (ranging from several nanometres to 10 μm in thickness). In Fig. 2 , energy dispersive spectroscopy and atom probe tomography (APT) maps are also provided for the corresponding EBSD maps, respectively, to reveal the compositional distribution among the two phases. The energy dispersive spectroscopy maps in Fig. 2a show that all elements are uniformly distributed, suggesting that both phases benefit from the same level of solid solution strengthening. APT tips were lifted out from a phase boundary region (using the method outlined in ref. 19 ) shown in the EBSD phase map in Fig. 2b , to rule out the possibility of atomic-scale elemental partitioning between the f.c.c. and the h.c.p. phases. The analysis reveals that the investigated volume has an overall composition of Fe 48.6 Mn 27.6 Co 11.3 Cr 12.3 (at%), showing values near the nominal bulk composition. No apparent elemental segregations can be observed in the three-dimensional reconstructions ( Fig. 2b ) or from the statistical binomial frequency distribution analyses ( Extended Data Fig. 1 ), confirming the uniform distribution of all elements even at phase boundaries. This is different from Mn-containing steels, which show substantial chemical gradients across phase", "role": "user" }, { "content": "For centuries—in fact, since the Bronze Age began some 7,000 years ago—the creation of new metallic alloys has mostly been a trial-and-error process. Traditionally, one metal constituent was always dominant, with others making up a small fraction of the recipe. But a new study suggests a novel strategy that could help direct efforts to overturn this ancient lore, opening the way for new classes of alloys with previously unseen combinations of properties. The new approach is described in a paper this week in the journal Nature, by C. Cem Tasan, the Thomas B. King Career Development Professor of Metallurgy in MIT's Department of Materials Science and Engineering, and four others at the Max Planck Institute in Dusseldorf, Germany. The new approach, Tasan says, also challenges the conventional wisdom that improving the strength of a metal alloy is always a tradeoff that results in a loss of ductility—the property that allows a metal to deform without fracturing, for example when it is stamped to form the body panels of a car. \"We have lots of experience from hundreds of years, through trial and error, and we know very well that when you start mixing metals in roughly equal amounts, you do not have good mechanical properties in most cases, due to the presence of brittle intermetallic phases,\" Tasan explains. But in the last decade, there has been a renewed interest in exploring a category of metal mixtures known as high-entropy alloys (HEAs). These compounds contain multiple metallic elements in roughly equal amounts, which some materials scientists have proposed could yield single-phase microstructures and, in turn, improved mechanical strength and stability. While this field is attracting high research interest, however, with more than 300 papers published last year on HEAs, most of the compounds studied have not produced any significant improvements in their properties, and have still suffered from the strength-ductility tradeoff, Tasan says. The main focus of the previous work, he says, has been on evaluating the proposed single-phase stabilization concept in different alloy systems. But aiming for stable single-phase microstructures differs from the approach that has been taken with the most widely used metal of all—steel, of which 1,500 million tons are produced worldwide every year. One of the reasons for steel's ubiquity is that its various alloys can be tuned to have a wide range of different properties, depending on the specific application. Advanced steels often have phases that are stable, but also some that are metastable (having more than one stable configuration). Under stress, metastable phases can transform to stable configurations, which improves their ability to resist fracture. While the results reported so far for HEA materials have mostly not lived up to expectations, \"there are definitely interesting benefits of following this idea [of combining roughly equal portions of metallic elements],\" such as achieving a property called increased solid-solution hardening, Tasan says. \"So we thought, why not combine the strength of this concept with the strengths of steels, the most important structural material for humanity?\" The new finding now being reported by Tasan and his colleagues is that in HEAs it is metastability, rather than the usually sought-after stability, that produces the most promising new alloys. A new alloy designed with these principles, composed of iron, manganese, cobalt, and chromium, \"outperforms even the highest-performance, single-phase, high-entropy alloy,\" Tasan says. And, it offers exceptionally high values of both strength and ductility. \"It's like combining the best of two worlds: metastability, known from steels, and the solid-solution strengthening of HEAs,\" he says. But more important than the properties of this particular alloy, he says, is the underlying strategy used to produce it, which could open up new avenues for the design of alloys with novel properties. \"We think this is just one example of the kind of alloys that could be produced,\" he says. Hopefully, \"one could produce even better ones, since the new strategy is a generic tool for the design of new materials. I think this result will be very influential in guiding the HEA research community to achieve superior property combinations.\" Calling this work \"unique and creative,\" Ke Lu, professor and director of the Shenyang National Laboratory for Materials Science in China, who was not involved in this research, says: \"The authors utilized different strengthening mechanisms into an alloy system in a very smart way, leading to a simultaneous increase of strength and ductility that are often exclusive. While each individual mechanism is well documented in many different systems, a synergic application of these effects is novel and original. The properties achieved are impressive indeed.\" These findings could \"open up new dimensions of materials innovation and development,\" he adds. ", "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 Metals have been mankind’s most essential materials for thousands of years; however, their use is affected by ecological and economical concerns. Alloys with higher strength and ductility could alleviate some of these concerns by reducing weight and improving energy efficiency. However, most metallurgical mechanisms for increasing strength lead to ductility loss, an effect referred to as the strength–ductility trade-off 1 , 2 . Here we present a metastability-engineering strategy in which we design nanostructured, bulk high-entropy alloys with multiple compositionally equivalent high-entropy phases. High-entropy alloys were originally proposed to benefit from phase stabilization through entropy maximization 3 , 4 , 5 , 6 . Yet here, motivated by recent work that relaxes the strict restrictions on high-entropy alloy compositions by demonstrating the weakness of this connection 7 , 8 , 9 , 10 , 11 , the concept is overturned. We decrease phase stability to achieve two key benefits: interface hardening due to a dual-phase microstructure (resulting from reduced thermal stability of the high-temperature phase 12 ); and transformation-induced hardening (resulting from the reduced mechanical stability of the room-temperature phase 13 ). This combines the best of two worlds: extensive hardening due to the decreased phase stability known from advanced steels 14 , 15 and massive solid-solution strengthening of high-entropy alloys 3 . In our transformation-induced plasticity-assisted, dual-phase high-entropy alloy (TRIP-DP-HEA), these two contributions lead respectively to enhanced trans-grain and inter-grain slip resistance, and hence, increased strength. Moreover, the increased strain hardening capacity that is enabled by dislocation hardening of the stable phase and transformation-induced hardening of the metastable phase produces increased ductility. This combined increase in strength and ductility distinguishes the TRIP-DP-HEA alloy from other recently developed structural materials 16 , 17 . This metastability-engineering strategy should thus usefully guide design in the near-infinite compositional space of high-entropy alloys. Main To realize the TRIP-DP-HEA concept, we switch from the equiatomic Fe 20 Mn 20 Ni 20 Co 20 Cr 20 (atomic per cent, at%) 6 system to the non-equiatomic Fe 80 − x Mn x Co 10 Cr 10 (at%) system, which exhibits partial martensitic transformation of the face-centred cubic (f.c.c.) to the hexagonal close-packed (h.c.p.) phase upon cooling from the high-temperature single-phase region. This change enables development of a dual-phase microstructure in which both phases obtain the maximum benefit of the solid-solution strengthening effect and one phase, owing to the decreased stacking fault energy 18 , undergoes deformation-induced displacive transformation. The partial martensitic transformation during quenching is the only possible approach that can lead to the formation of a DP-HEA with phases of identical chemical composition (that is, high-entropy phases). The alloys were synthesized with varying Mn contents in a vacuum induction furnace using pure metals, hot-rolled to 50% thickness at 900 °C, homogenized at 1,200 °C for 2 h in an Ar atmosphere, and water-quenched. Further grain refinement was achieved by cold-rolling (to 60% thickness) and 3-min annealing at 900 °C in an Ar atmosphere. The chemical composition of the HEAs measured by wet-chemical analysis is given in Extended Data Table 1 . Microstructure characterization down to 30-nm resolution reveals that the Fe 80 − x Mn x Co 10 Cr 10 (at%) system indeed demonstrates the targeted change in phase stability (see the X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) data in Fig. 1 ). A single f.c.c. phase structure was obtained when the Mn content was 45 at% and 40 at% (Fe 35 Mn 45 Co 10 Cr 10 and Fe 40 Mn 40 Co 10 Cr 10 , respectively). These two alloys demonstrate a transition in the deformation mechanisms from dislocation-dominated plasticity in the former 8 to twinning-induced plasticity (TWIP) in the latter 10 , confirming the targeted stability trend realized by tuning the stacking fault energy. A further decrease to 35 at% Mn leads to traces of h.c.p. phase (not captured by XRD). Finally, a decrease to 30 at% Mn (Fe 50 Mn 30 Co 10 Cr 10 ) successfully produces the desired dual-phase microstructure with ~28% h.c.p. phase. This alloy is analysed in more detail in the following. Figure 1: XRD patterns and EBSD phase maps of Fe 80 − x Mn x Co 10 Cr 10 ( x = 45 at%, 40 at%, 35 at% and 30 at%) HEAs. θ is the Bragg angle. The Mn content plays an important part in phase constitution, tuning phase stability for the activation of specific displacing transformation mechanisms, for example, enabling TWIP or TRIP effects. We note that the 35 at% Mn alloy has only trace amounts of the h.c.p. phase, and hence is not referred to as a DP-HEA. PowerPoint slide Source data Full size image The two phases constituting the as-quenched Fe 50 Mn 30 Co 10 Cr 10 (at%) alloy are the f.c.c. γ matrix (of ~45-μm grain size) and the h.c.p. ε phase laminate layers (ranging from several nanometres to 10 μm in thickness). In Fig. 2 , energy dispersive spectroscopy and atom probe tomography (APT) maps are also provided for the corresponding EBSD maps, respectively, to reveal the compositional distribution among the two phases. The energy dispersive spectroscopy maps in Fig. 2a show that all elements are uniformly distributed, suggesting that both phases benefit from the same level of solid solution strengthening. APT tips were lifted out from a phase boundary region (using the method outlined in ref. 19 ) shown in the EBSD phase map in Fig. 2b , to rule out the possibility of atomic-scale elemental partitioning between the f.c.c. and the h.c.p. phases. The analysis reveals that the investigated volume has an overall composition of Fe 48.6 Mn 27.6 Co 11.3 Cr 12.3 (at%), showing values near the nominal bulk composition. No apparent elemental segregations can be observed in the three-dimensional reconstructions ( Fig. 2b ) or from the statistical binomial frequency distribution analyses ( Extended Data Fig. 1 ), confirming the uniform distribution of all elements even at phase boundaries. This is different from Mn-containing steels, which show substantial chemical gradients across phase<|im_end|> <|im_start|>assistant For centuries—in fact, since the Bronze Age began some 7,000 years ago—the creation of new metallic alloys has mostly been a trial-and-error process. Traditionally, one metal constituent was always dominant, with others making up a small fraction of the recipe. But a new study suggests a novel strategy that could help direct efforts to overturn this ancient lore, opening the way for new classes of alloys with previously unseen combinations of properties. The new approach is described in a paper this week in the journal Nature, by C. Cem Tasan, the Thomas B. King Career Development Professor of Metallurgy in MIT's Department of Materials Science and Engineering, and four others at the Max Planck Institute in Dusseldorf, Germany. The new approach, Tasan says, also challenges the conventional wisdom that improving the strength of a metal alloy is always a tradeoff that results in a loss of ductility—the property that allows a metal to deform without fracturing, for example when it is stamped to form the body panels of a car. "We have lots of experience from hundreds of years, through trial and error, and we know very well that when you start mixing metals in roughly equal amounts, you do not have good mechanical properties in most cases, due to the presence of brittle intermetallic phases," Tasan explains. But in the last decade, there has been a renewed interest in exploring a category of metal mixtures known as high-entropy alloys (HEAs). These compounds contain multiple metallic elements in roughly equal amounts, which some materials scientists have proposed could yield single-phase microstructures and, in turn, improved mechanical strength and stability. While this field is attracting high research interest, however, with more than 300 papers published last year on HEAs, most of the compounds studied have not produced any significant improvements in their properties, and have still suffered from the strength-ductility tradeoff, Tasan says. The main focus of the previous work, he says, has been on evaluating the proposed single-phase stabilization concept in different alloy systems. But aiming for stable single-phase microstructures differs from the approach that has been taken with the most widely used metal of all—steel, of which 1,500 million tons are produced worldwide every year. One of the reasons for steel's ubiquity is that its various alloys can be tuned to have a wide range of different properties, depending on the specific application. Advanced steels often have phases that are stable, but also some that are metastable (having more than one stable configuration). Under stress, metastable phases can transform to stable configurations, which improves their ability to resist fracture. While the results reported so far for HEA materials have mostly not lived up to expectations, "there are definitely interesting benefits of following this idea [of combining roughly equal portions of metallic elements]," such as achieving a property called increased solid-solution hardening, Tasan says. "So we thought, why not combine the strength of this concept with the strengths of steels, the most important structural material for humanity?" The new finding now being reported by Tasan and his colleagues is that in HEAs it is metastability, rather than the usually sought-after stability, that produces the most promising new alloys. A new alloy designed with these principles, composed of iron, manganese, cobalt, and chromium, "outperforms even the highest-performance, single-phase, high-entropy alloy," Tasan says. And, it offers exceptionally high values of both strength and ductility. "It's like combining the best of two worlds: metastability, known from steels, and the solid-solution strengthening of HEAs," he says. But more important than the properties of this particular alloy, he says, is the underlying strategy used to produce it, which could open up new avenues for the design of alloys with novel properties. "We think this is just one example of the kind of alloys that could be produced," he says. Hopefully, "one could produce even better ones, since the new strategy is a generic tool for the design of new materials. I think this result will be very influential in guiding the HEA research community to achieve superior property combinations." Calling this work "unique and creative," Ke Lu, professor and director of the Shenyang National Laboratory for Materials Science in China, who was not involved in this research, says: "The authors utilized different strengthening mechanisms into an alloy system in a very smart way, leading to a simultaneous increase of strength and ductility that are often exclusive. While each individual mechanism is well documented in many different systems, a synergic application of these effects is novel and original. The properties achieved are impressive indeed." These findings could "open up new dimensions of materials innovation and development," he adds. <|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 describe droplet-assisted RNA targeting by single-cell sequencing (DART-seq), a versatile technology that enables multiplexed amplicon sequencing and transcriptome profiling in single cells. We applied DART-seq to simultaneously characterize the non-A-tailed transcripts of a segmented dsRNA virus and the transcriptome of the infected cell. In addition, we used DART-seq to simultaneously determine the natively paired, variable region heavy and light chain amplicons and the transcriptome of B lymphocytes. Main Droplet microfluidics has made high-throughput single-cell RNA sequencing (scRNA-seq) accessible to more laboratories than ever before, but is restricted to capturing information from the ends of A-tailed messenger RNA transcripts 1 , 2 , 3 . Here we report DART-seq, a method that enables high-throughput targeted RNA amplicon sequencing and transcriptome profiling in single cells. DART-seq achieves this via a simple and inexpensive alteration of the Drop-seq strategy 1 . Drop-seq relies on co-encapsulation of single cells with barcoded primer beads that capture and prime reverse transcription of cellular mRNA 1 , 2 . The primers on Drop-seq beads comprise a common PCR sequence, a bead-specific cell barcode, a unique molecular identifier (UMI) and a poly(dT) sequence for mRNA reverse transcription priming. To enable simultaneous measurement of the transcriptome and multiplexed RNA amplicons in DART-seq, we devised a scheme to enzymatically attach custom primers to a subset of poly(dTs) on Drop-seq beads. This is achieved by first annealing a double-stranded toehold probe with a 3′ single-stranded DNA overhang that is complementary to the poly(dT) sequence, and then ligating the toehold using T4 DNA ligase (Supplementary Fig. 1 , Methods and Supplementary Protocol ). A variety of custom primers with different sequences can be attached to the same beads in a single reaction. We characterized the efficiency, tunability and variability of the ligation reaction using fluorescence hybridization assays (Fig. 1a and Supplementary Fig. 2 ). We found that the primer ligation reaction is highly efficient (25–40%), and the number of custom primers ligated to the beads is directly proportional to the number of primers included in the ligation reaction (Fig. 1a ). This was true for four primer sequences tested over a wide range of primer concentrations. The efficiency of probe ligation decreased for ligation reactions with more than 10 10 molecules per bead, indicating saturation of available oligonucleotide(dT)s. We compared the fluorescence hybridization signal across individual beads and found that the bead-to-bead variability in fluorescence signal was small (s.d. 3.0%; Fig. 1b ). Fig. 1: Characterization of DART-seq primer bead synthesis and reverse transcription priming. a , Number of fluorescence probes bound per bead as a function of the number of primers per bead included in the ligation reaction (four distinct primer sequences). Error bars, minimum and maximum of three replicate measurements; points indicate mean. Dotted line indicates expected values for 100% ligation efficiency. Schematic of fluorescence hybridization assay (inset). b , Bead-to-bead variability in fluorescence pixel intensity ( n = 741 beads, maximum pixel intensity is 255). Representative fluorescence microscopy image of beads (inset). A.U., arbitrary units. c , cDNA copies of reovirus RNA relative to Gapdh as a function of the number of custom primers included in the ligation reaction (bulk assay). Error bars, minimum and maximum of three replicates; points indicate mean. d , Enrichment of PCR amplicons relative to Gapdh in DART-seq versus Drop-seq libraries as a function of distance to the target locus. Measurement for two reovirus genes (S3 in green and L3 in violet). nt, nucleotide. Source Data Full size image After primer bead synthesis, DART-seq follows the Drop-seq workflow without modification. Cells and primer beads are co-encapsulated in droplets using microfluidics. Cellular RNA is captured by the beads and reverse transcribed. The DART-seq beads prime reverse transcription of both A-tailed mRNA and custom RNA amplicons. The resulting cDNA is PCR amplified, tagmented and again PCR amplified before sequencing. The cell of origin of mRNAs and RNA amplicons is identified by decoding of the cell barcodes. We assessed reverse transcription priming efficiency as a function of the number of custom primers ligated to DART-seq beads. We used quantitative PCR (qPCR) to measure the yield of cDNA copies of a non-A-tailed viral mRNA in reovirus-infected murine fibroblasts (L cells, Fig. 1c ). Two distinct primers were ligated, targeting the same viral genome segment (S2). The yield of cDNA copies of viral mRNA, relative to cDNA copies of a host transcript ( Gapdh ), increased with the number of primers included in the ligation reaction, and saturated for reactions with over 10 9 primers per bead (Fig. 1c ). Reverse transcription of Gapdh was not affected for DART-seq beads prepared with up to 10 10 primers per bead. Next, we evaluated the abundance of amplicons in sequencing libraries of reovirus-infected cells generated by Drop-seq and a DART-seq assay targeting all ten viral genome segments. We designed seven qPCR assays with amplicons distributed across two viral genome segments (S3 and L3). To account for assay-to-assay and sample-to-sample variability, we normalized the number of molecules detected in DART-seq and Drop-seq libraries to the number of Gapdh transcripts. We observed substantial enrichment upstream (5′ end), but not downstream (3′ end), of the custom primer sites (Fig. 1d ). Consistent with sequencing library preparation via tagmentation, we found that the degree of enrichment decreased with distance from the primer site. We applied DART-seq to investigate the heterogeneity of cellular phenotypes and viral genotypes during T3D reovirus infection. Recent studies have explored RNA virus infection biology in single cells 4 , 5 , 6 , but were limited by cell throughput or restricted to the analysis of polyadenylated viral mRNAs. We infected L cells at a high multiplicity of infection (value of 10), ensuring that nearly all cells were infected (Fig. 2a ). We performed Drop-seq and DART-seq experiments on infected and non-infected cells and implemented two DART-seq designs. The first targeted each viral genome segment with a single amplicon. The second consisted of seven amplicons distributed across the S2 segment (Fig. 2b ). Fig. 2: DART-seq reveals heterogeneity in viral", "role": "user" }, { "content": "Droplet microfluidics has revolutionized single-cell RNA sequencing, offering a low-cost, high-throughput method for single-cell genomics. However, this method has been limited in its ability to capture complete RNA transcription information. Researchers at Cornell—led by Iwijn De Vlaminck, assistant professor in the Meinig School of Biomedical Engineering—have come up with an elegant, low-cost method that solves that problem. And not only does it push single-cell genomics forward, it may allow for new avenues for studies of infection and immune biology. \"Simultaneous Multiplexed Amplicon Sequencing and Transcriptome Profiling in Single Cells\" was published recently in Nature Methods. Postdoctoral researcher Mridusmita Saikia and doctoral student Philip Burnham, both of the De Vlaminck lab, are lead authors. Also contributing were Charles Danko, assistant professor at the Baker Institute for Animal Health in the College of Veterinary Medicine, and John Parker, associate professor of virology in the Baker Institute. In 2015, researchers from Harvard University and the Massachusetts Institute of Technology introduced Drop-seq, a method to simultaneously and efficiently characterize the identities of thousands of cells, using nanoliter-scale droplets and attaching a unique identifier to each cell's RNA. \"Those technologies are very popular because they've lowered the cost of these types of analyses and sort of democratized them, made them very cheap and easy to do for many labs,\" De Vlaminck said. The drawback, however, is that they can only identify a certain type of messenger RNA (mRNA) molecule, which limits the potential scope of analyses. Messenger RNA carries the genetic information copied from DNA in the process of translation. De Vlaminck and his collaborators have come up with a simple, inexpensive twist to the existing Drop-seq protocol, and call their new method DART-seq (droplet-assisted RNA targeting by single-cell sequencing). In Drop-seq, individual cells are encapsulated with labeled microparticles that initiate reverse transcription of cellular mRNA. The De Vlaminck group devised an effective method to enzymatically customize the beads prior to performing conventional Drop-seq analysis, which allows for the recovery and analysis of a greater variety of molecules than are available through Drop-seq sequencing. In addition, this technology can identify virus-infected cells, and quantify viral and host gene expression, thus enabling examination of the host response to infection at single-cell level. \"A single virus species can be very diverse, and that diversity permits them to do extraordinary things,\" Burnham said. \"So if you can zoom down to the single-cell level, you can actually see how minor changes in the virus cause a potentially huge change in how the cell reacts to that small mutation.\" Saikia, who has a dual appointment with the veterinary college, thinks DART-seq will also help inform new approaches to cancer therapy. \"Cancer cells are a very heterogeneous population,\" she said, \"and when you don't look at them at the single-cell level, you often miss important information. So our technology also allows that.\" ", "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 describe droplet-assisted RNA targeting by single-cell sequencing (DART-seq), a versatile technology that enables multiplexed amplicon sequencing and transcriptome profiling in single cells. We applied DART-seq to simultaneously characterize the non-A-tailed transcripts of a segmented dsRNA virus and the transcriptome of the infected cell. In addition, we used DART-seq to simultaneously determine the natively paired, variable region heavy and light chain amplicons and the transcriptome of B lymphocytes. Main Droplet microfluidics has made high-throughput single-cell RNA sequencing (scRNA-seq) accessible to more laboratories than ever before, but is restricted to capturing information from the ends of A-tailed messenger RNA transcripts 1 , 2 , 3 . Here we report DART-seq, a method that enables high-throughput targeted RNA amplicon sequencing and transcriptome profiling in single cells. DART-seq achieves this via a simple and inexpensive alteration of the Drop-seq strategy 1 . Drop-seq relies on co-encapsulation of single cells with barcoded primer beads that capture and prime reverse transcription of cellular mRNA 1 , 2 . The primers on Drop-seq beads comprise a common PCR sequence, a bead-specific cell barcode, a unique molecular identifier (UMI) and a poly(dT) sequence for mRNA reverse transcription priming. To enable simultaneous measurement of the transcriptome and multiplexed RNA amplicons in DART-seq, we devised a scheme to enzymatically attach custom primers to a subset of poly(dTs) on Drop-seq beads. This is achieved by first annealing a double-stranded toehold probe with a 3′ single-stranded DNA overhang that is complementary to the poly(dT) sequence, and then ligating the toehold using T4 DNA ligase (Supplementary Fig. 1 , Methods and Supplementary Protocol ). A variety of custom primers with different sequences can be attached to the same beads in a single reaction. We characterized the efficiency, tunability and variability of the ligation reaction using fluorescence hybridization assays (Fig. 1a and Supplementary Fig. 2 ). We found that the primer ligation reaction is highly efficient (25–40%), and the number of custom primers ligated to the beads is directly proportional to the number of primers included in the ligation reaction (Fig. 1a ). This was true for four primer sequences tested over a wide range of primer concentrations. The efficiency of probe ligation decreased for ligation reactions with more than 10 10 molecules per bead, indicating saturation of available oligonucleotide(dT)s. We compared the fluorescence hybridization signal across individual beads and found that the bead-to-bead variability in fluorescence signal was small (s.d. 3.0%; Fig. 1b ). Fig. 1: Characterization of DART-seq primer bead synthesis and reverse transcription priming. a , Number of fluorescence probes bound per bead as a function of the number of primers per bead included in the ligation reaction (four distinct primer sequences). Error bars, minimum and maximum of three replicate measurements; points indicate mean. Dotted line indicates expected values for 100% ligation efficiency. Schematic of fluorescence hybridization assay (inset). b , Bead-to-bead variability in fluorescence pixel intensity ( n = 741 beads, maximum pixel intensity is 255). Representative fluorescence microscopy image of beads (inset). A.U., arbitrary units. c , cDNA copies of reovirus RNA relative to Gapdh as a function of the number of custom primers included in the ligation reaction (bulk assay). Error bars, minimum and maximum of three replicates; points indicate mean. d , Enrichment of PCR amplicons relative to Gapdh in DART-seq versus Drop-seq libraries as a function of distance to the target locus. Measurement for two reovirus genes (S3 in green and L3 in violet). nt, nucleotide. Source Data Full size image After primer bead synthesis, DART-seq follows the Drop-seq workflow without modification. Cells and primer beads are co-encapsulated in droplets using microfluidics. Cellular RNA is captured by the beads and reverse transcribed. The DART-seq beads prime reverse transcription of both A-tailed mRNA and custom RNA amplicons. The resulting cDNA is PCR amplified, tagmented and again PCR amplified before sequencing. The cell of origin of mRNAs and RNA amplicons is identified by decoding of the cell barcodes. We assessed reverse transcription priming efficiency as a function of the number of custom primers ligated to DART-seq beads. We used quantitative PCR (qPCR) to measure the yield of cDNA copies of a non-A-tailed viral mRNA in reovirus-infected murine fibroblasts (L cells, Fig. 1c ). Two distinct primers were ligated, targeting the same viral genome segment (S2). The yield of cDNA copies of viral mRNA, relative to cDNA copies of a host transcript ( Gapdh ), increased with the number of primers included in the ligation reaction, and saturated for reactions with over 10 9 primers per bead (Fig. 1c ). Reverse transcription of Gapdh was not affected for DART-seq beads prepared with up to 10 10 primers per bead. Next, we evaluated the abundance of amplicons in sequencing libraries of reovirus-infected cells generated by Drop-seq and a DART-seq assay targeting all ten viral genome segments. We designed seven qPCR assays with amplicons distributed across two viral genome segments (S3 and L3). To account for assay-to-assay and sample-to-sample variability, we normalized the number of molecules detected in DART-seq and Drop-seq libraries to the number of Gapdh transcripts. We observed substantial enrichment upstream (5′ end), but not downstream (3′ end), of the custom primer sites (Fig. 1d ). Consistent with sequencing library preparation via tagmentation, we found that the degree of enrichment decreased with distance from the primer site. We applied DART-seq to investigate the heterogeneity of cellular phenotypes and viral genotypes during T3D reovirus infection. Recent studies have explored RNA virus infection biology in single cells 4 , 5 , 6 , but were limited by cell throughput or restricted to the analysis of polyadenylated viral mRNAs. We infected L cells at a high multiplicity of infection (value of 10), ensuring that nearly all cells were infected (Fig. 2a ). We performed Drop-seq and DART-seq experiments on infected and non-infected cells and implemented two DART-seq designs. The first targeted each viral genome segment with a single amplicon. The second consisted of seven amplicons distributed across the S2 segment (Fig. 2b ). Fig. 2: DART-seq reveals heterogeneity in viral<|im_end|> <|im_start|>assistant Droplet microfluidics has revolutionized single-cell RNA sequencing, offering a low-cost, high-throughput method for single-cell genomics. However, this method has been limited in its ability to capture complete RNA transcription information. Researchers at Cornell—led by Iwijn De Vlaminck, assistant professor in the Meinig School of Biomedical Engineering—have come up with an elegant, low-cost method that solves that problem. And not only does it push single-cell genomics forward, it may allow for new avenues for studies of infection and immune biology. "Simultaneous Multiplexed Amplicon Sequencing and Transcriptome Profiling in Single Cells" was published recently in Nature Methods. Postdoctoral researcher Mridusmita Saikia and doctoral student Philip Burnham, both of the De Vlaminck lab, are lead authors. Also contributing were Charles Danko, assistant professor at the Baker Institute for Animal Health in the College of Veterinary Medicine, and John Parker, associate professor of virology in the Baker Institute. In 2015, researchers from Harvard University and the Massachusetts Institute of Technology introduced Drop-seq, a method to simultaneously and efficiently characterize the identities of thousands of cells, using nanoliter-scale droplets and attaching a unique identifier to each cell's RNA. "Those technologies are very popular because they've lowered the cost of these types of analyses and sort of democratized them, made them very cheap and easy to do for many labs," De Vlaminck said. The drawback, however, is that they can only identify a certain type of messenger RNA (mRNA) molecule, which limits the potential scope of analyses. Messenger RNA carries the genetic information copied from DNA in the process of translation. De Vlaminck and his collaborators have come up with a simple, inexpensive twist to the existing Drop-seq protocol, and call their new method DART-seq (droplet-assisted RNA targeting by single-cell sequencing). In Drop-seq, individual cells are encapsulated with labeled microparticles that initiate reverse transcription of cellular mRNA. The De Vlaminck group devised an effective method to enzymatically customize the beads prior to performing conventional Drop-seq analysis, which allows for the recovery and analysis of a greater variety of molecules than are available through Drop-seq sequencing. In addition, this technology can identify virus-infected cells, and quantify viral and host gene expression, thus enabling examination of the host response to infection at single-cell level. "A single virus species can be very diverse, and that diversity permits them to do extraordinary things," Burnham said. "So if you can zoom down to the single-cell level, you can actually see how minor changes in the virus cause a potentially huge change in how the cell reacts to that small mutation." Saikia, who has a dual appointment with the veterinary college, thinks DART-seq will also help inform new approaches to cancer therapy. "Cancer cells are a very heterogeneous population," she said, "and when you don't look at them at the single-cell level, you often miss important information. So our technology also allows that." <|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 Distributing entanglement over long distances using optical networks is an intriguing macroscopic quantum phenomenon with applications in quantum systems for advanced computing and secure communication 1 , 2 . Building quantum networks requires scalable quantum light–matter interfaces 1 based on atoms 3 , ions 4 or other optically addressable qubits. Solid-state emitters 5 , such as quantum dots and defects in diamond or silicon carbide 6 , 7 , 8 , 9 , 10 , have emerged as promising candidates for such interfaces. So far, it has not been possible to scale up these systems, motivating the development of alternative platforms. A central challenge is identifying emitters that exhibit coherent optical and spin transitions while coupled to photonic cavities that enhance the light–matter interaction and channel emission into optical fibres. Rare-earth ions in crystals are known to have highly coherent 4 f –4 f optical and spin transitions suited to quantum storage and transduction 11 , 12 , 13 , 14 , 15 , but only recently have single rare-earth ions been isolated 16 , 17 and coupled to nanocavities 18 , 19 . The crucial next steps towards using single rare-earth ions for quantum networks are realizing long spin coherence and single-shot readout in photonic resonators. Here we demonstrate spin initialization, coherent optical and spin manipulation, and high-fidelity single-shot optical readout of the hyperfine spin state of single 171 Yb 3+ ions coupled to a nanophotonic cavity fabricated in an yttrium orthovanadate host crystal. These ions have optical and spin transitions that are first-order insensitive to magnetic field fluctuations, enabling optical linewidths of less than one megahertz and spin coherence times exceeding thirty milliseconds for cavity-coupled ions, even at temperatures greater than one kelvin. The cavity-enhanced optical emission rate facilitates efficient spin initialization and single-shot readout with conditional fidelity greater than 95 per cent. These results showcase a solid-state platform based on single coherent rare-earth ions for the future quantum internet. Main This work is enabled by the unique properties of 171 Yb 3+ , the only paramagnetic rare-earth isotope with a nuclear spin of ½, which provides a favourable combination of a simple hyperfine structure that can be used as a qubit and clock transitions with long coherence times. Furthermore, in the crystal host yttrium orthovanadate (YVO 4 or YVO), 171 Yb 3+ directly substitutes for Y 3+ in a site that has non-polar symmetry ( D 2 d ), which results in no first-order d.c. Stark effect and thus reduces the sensitivity to electric field fluctuations that can cause optical decoherence. The relevant energy-level structure of 171 Yb 3+ in YVO is shown in Fig. 1a (see Supplementary Fig. 2 and ref. 20 for additional details). At zero applied magnetic field, the hyperfine interaction partially lifts the degeneracy of the ground state 2 F 7/2 (0), leading to coupled electron–nuclear spin states of the form $${|0\\rangle }_{{\\rm{g}}}=\\frac{|\\downarrow \\Uparrow \\rangle -|\\uparrow \\Downarrow \\rangle }{\\sqrt{2}},{|1\\rangle }_{{\\rm{g}}}=\\frac{|\\downarrow \\Uparrow \\rangle +|\\uparrow \\Downarrow \\rangle }{\\sqrt{2}}\\,{\\rm{a}}{\\rm{n}}{\\rm{d}}{|{\\rm{a}}{\\rm{u}}{\\rm{x}}\\rangle }_{{\\rm{g}}}=|\\uparrow \\Uparrow \\rangle ,|\\downarrow \\Downarrow \\rangle $$ Here we denote the electron spin as \$|\\uparrow \\rangle =|{S}_{z}=\\frac{1}{2}\\rangle \$ and \$|\\downarrow \\rangle =|{S}_{z}=-\\frac{1}{2}\\rangle \$ , and the nuclear spin as \$|\\Uparrow \\rangle =|{I}_{z}=\\frac{1}{2}\\rangle \$ and \$|\\Downarrow \\rangle =|{I}_{z}=-\\frac{1}{2}\\rangle \$ . We use the ground states \${|0\\rangle }_{{\\rm{g}}}\$ and \${|1\\rangle }_{{\\rm{g}}}\$ , which are separated by about 675 MHz, to form the spin qubit. The \${|0\\rangle }_{{\\rm{g}}}\$ and \${|1\\rangle }_{{\\rm{g}}}\$ states have zero net magnetic moment and as a result the \${|0\\rangle }_{{\\rm{g}}}\$ ↔ \${|1\\rangle }_{{\\rm{g}}}\$ transition is first-order insensitive to magnetic fluctuations that induce decoherence 12 , 21 . The \${|0\\rangle }_{{\\rm{g}}}\$ ↔ \${|1\\rangle }_{{\\rm{g}}}\$ transition retains the strength of an electron spin transition, which enables fast and efficient microwave manipulation. Fig. 1: Experimental platform. a , Zero-field energy level structure of 171 Yb 3+ :YVO. States \${|0\\rangle }_{{\\rm{g}}}\$ and \${|1\\rangle }_{{\\rm{g}}}\$ form the spin qubit. Red transitions A and E are coupled (co-polarized) to the cavity, while the blue transition F is cross-polarized to the cavity mode. b , Typical experimental sequence used to initialize the ion into the \${|0\\rangle }_{{\\rm{g}}}\$ state, manipulate the qubit and optically read out the spin state. c , Scanning electron microscope image of a photonic crystal cavity fabricated in YVO. Scale bar, 10 μm. d , Reflection spectrum of the cavity. e , Schematic of the experimental setup. The optical transitions are addressed using pulses generated from two frequency-stabilized continuous-wave (CW) lasers. The qubit is directly manipulated using microwave (MW) control pulses using a coplanar waveguide (CPW) next to the photonic crystal (PC) cavity, which is mounted in a dilution refrigerator. Light collected from the cavity is detected using a superconducting nanowire single-photon detector (SNSPD). Full size image A typical experimental sequence with spin initialization, control and readout is shown in Fig. 1b . The 171 Yb 3+ ions are coupled to a photonic crystal cavity with a large quality factor ( Q ≈ 1 × 10 4 ; Fig. 1c, d , Methods) and a small mode volume of about 1( λ / n YVO ) 3 , where λ is the wavelength of the optical transition and n YVO is the refractive index of YVO. This enhances the emission rate, collection efficiency and cyclicity of the optical transitions A and E via the Purcell effect 22 . The qubit is initialized into the \${|0\\rangle }_{{\\rm{g}}}\$ state by optical and microwave pumping on the F, A and f e transitions to empty the \${|{\\rm{aux}}\\rangle }_{{\\rm{g}}}\$ and \${|1\\rangle }_{{\\rm{g}}}\$ states, followed by cavity-enhanced decay into the \${|0\\rangle }_{{\\rm{g}}}\$ state via transition E (Fig. 1a ). A subsequent microwave π pulse applied on the f g transition optionally initializes the ion into the \${|1\\rangle }_{{\\rm{g}}}\$ state. The \${|1\\rangle }_{{\\rm{g}}}\$ state population is read out by excitation on the A transition and collection of the resulting ion fluorescence. Measurements are performed in a cryostat at 40 mK unless mentioned otherwise (see Methods for discussion of sample temperature). The ions are optically addressed using two frequency-stabilized continuous-wave lasers, while a microwave coplanar waveguide", "role": "user" }, { "content": "Engineers at Caltech have shown that atoms in optical cavities—tiny boxes for light—could be foundational to the creation of a quantum internet. Their work was published on March 30 by the journal Nature. Quantum networks would connect quantum computers through a system that also operates at a quantum, rather than classical, level. In theory, quantum computers will one day be able to perform certain functions faster than classical computers by taking advantage of the special properties of quantum mechanics, including superposition, which allows quantum bits to store information as a 1 and a 0 simultaneously. As they can with classical computers, engineers would like to be able to connect multiple quantum computers to share data and work together—creating a \"quantum internet.\" This would open the door to several applications, including solving computations that are too large to be handled by a single quantum computer and establishing unbreakably secure communications using quantum cryptography. In order to work, a quantum network needs to be able to transmit information between two points without altering the quantum properties of the information being transmitted. One current model works like this: a single atom or ion acts as a quantum bit (or \"qubit\") storing information via one if its quantum properties, such as spin. To read that information and transmit it elsewhere, the atom is excited with a pulse of light, causing it to emit a photon whose spin is entangled with the spin of the atom. The photon can then transmit the information entangled with the atom over a long distance via fiber optic cable. It is harder than it sounds, however. Finding atoms that you can control and measure, and that also aren't too sensitive to magnetic or electric field fluctuations that cause errors, or decoherence, is challenging. \"Solid-state emitters that interact well with light often fall victim to decoherence; that is, they stop storing information in a way that's useful from the prospective of quantum engineering,\" says Jon Kindem (MS '17, Ph.D. '19), lead author of the Nature paper. Meanwhile, atoms of rare-earth elements—which have properties that make the elements useful as qubits—tend to interact poorly with light. To overcome this challenge, researchers led by Caltech's Andrei Faraon (BS '04), professor of applied physics and electrical engineering, constructed a nanophotonic cavity, a beam that is about 10 microns in length with periodic nano-patterning, sculpted from a piece of crystal. They then identified a rare-earth ytterbium ion in the center of the beam. The optical cavity allows them to bounce light back and forth down the beam multiple times until it is finally absorbed by the ion. In the Nature paper, the team showed that the cavity modifies the environment of the ion such that whenever it emits a photon, more than 99 percent of the time that photon remains in the cavity, where scientists can then efficiently collect and detect that photon to measure the state of the ion. This results in an increase in the rate at which the ion can emit photons, improving the overall effectiveness of the system. In addition, the ytterbium ions are able to store information in their spin for 30 milliseconds. In this time, light could transmit information to travel across the continental United States. \"This checks most of the boxes. It's a rare-earth ion that absorbs and emits photons in exactly the way we'd need to create a quantum network,\" says Faraon, professor of applied physics and electrical engineering. \"This could form the backbone technology for the quantum internet.\" Currently, the team's focus is on creating the building blocks of a quantum network. Next, they hope to scale up their experiments and actually connect two quantum bits, Faraon says. Their paper is titled \"Control and single-shot readout of an ion embedded in a nanophotonic cavity.\" ", "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 Distributing entanglement over long distances using optical networks is an intriguing macroscopic quantum phenomenon with applications in quantum systems for advanced computing and secure communication 1 , 2 . Building quantum networks requires scalable quantum light–matter interfaces 1 based on atoms 3 , ions 4 or other optically addressable qubits. Solid-state emitters 5 , such as quantum dots and defects in diamond or silicon carbide 6 , 7 , 8 , 9 , 10 , have emerged as promising candidates for such interfaces. So far, it has not been possible to scale up these systems, motivating the development of alternative platforms. A central challenge is identifying emitters that exhibit coherent optical and spin transitions while coupled to photonic cavities that enhance the light–matter interaction and channel emission into optical fibres. Rare-earth ions in crystals are known to have highly coherent 4 f –4 f optical and spin transitions suited to quantum storage and transduction 11 , 12 , 13 , 14 , 15 , but only recently have single rare-earth ions been isolated 16 , 17 and coupled to nanocavities 18 , 19 . The crucial next steps towards using single rare-earth ions for quantum networks are realizing long spin coherence and single-shot readout in photonic resonators. Here we demonstrate spin initialization, coherent optical and spin manipulation, and high-fidelity single-shot optical readout of the hyperfine spin state of single 171 Yb 3+ ions coupled to a nanophotonic cavity fabricated in an yttrium orthovanadate host crystal. These ions have optical and spin transitions that are first-order insensitive to magnetic field fluctuations, enabling optical linewidths of less than one megahertz and spin coherence times exceeding thirty milliseconds for cavity-coupled ions, even at temperatures greater than one kelvin. The cavity-enhanced optical emission rate facilitates efficient spin initialization and single-shot readout with conditional fidelity greater than 95 per cent. These results showcase a solid-state platform based on single coherent rare-earth ions for the future quantum internet. Main This work is enabled by the unique properties of 171 Yb 3+ , the only paramagnetic rare-earth isotope with a nuclear spin of ½, which provides a favourable combination of a simple hyperfine structure that can be used as a qubit and clock transitions with long coherence times. Furthermore, in the crystal host yttrium orthovanadate (YVO 4 or YVO), 171 Yb 3+ directly substitutes for Y 3+ in a site that has non-polar symmetry ( D 2 d ), which results in no first-order d.c. Stark effect and thus reduces the sensitivity to electric field fluctuations that can cause optical decoherence. The relevant energy-level structure of 171 Yb 3+ in YVO is shown in Fig. 1a (see Supplementary Fig. 2 and ref. 20 for additional details). At zero applied magnetic field, the hyperfine interaction partially lifts the degeneracy of the ground state 2 F 7/2 (0), leading to coupled electron–nuclear spin states of the form $${|0\rangle }_{{\rm{g}}}=\frac{|\downarrow \Uparrow \rangle -|\uparrow \Downarrow \rangle }{\sqrt{2}},{|1\rangle }_{{\rm{g}}}=\frac{|\downarrow \Uparrow \rangle +|\uparrow \Downarrow \rangle }{\sqrt{2}}\,{\rm{a}}{\rm{n}}{\rm{d}}{|{\rm{a}}{\rm{u}}{\rm{x}}\rangle }_{{\rm{g}}}=|\uparrow \Uparrow \rangle ,|\downarrow \Downarrow \rangle $$ Here we denote the electron spin as $|\uparrow \rangle =|{S}_{z}=\frac{1}{2}\rangle $ and $|\downarrow \rangle =|{S}_{z}=-\frac{1}{2}\rangle $ , and the nuclear spin as $|\Uparrow \rangle =|{I}_{z}=\frac{1}{2}\rangle $ and $|\Downarrow \rangle =|{I}_{z}=-\frac{1}{2}\rangle $ . We use the ground states ${|0\rangle }_{{\rm{g}}}$ and ${|1\rangle }_{{\rm{g}}}$ , which are separated by about 675 MHz, to form the spin qubit. The ${|0\rangle }_{{\rm{g}}}$ and ${|1\rangle }_{{\rm{g}}}$ states have zero net magnetic moment and as a result the ${|0\rangle }_{{\rm{g}}}$ ↔ ${|1\rangle }_{{\rm{g}}}$ transition is first-order insensitive to magnetic fluctuations that induce decoherence 12 , 21 . The ${|0\rangle }_{{\rm{g}}}$ ↔ ${|1\rangle }_{{\rm{g}}}$ transition retains the strength of an electron spin transition, which enables fast and efficient microwave manipulation. Fig. 1: Experimental platform. a , Zero-field energy level structure of 171 Yb 3+ :YVO. States ${|0\rangle }_{{\rm{g}}}$ and ${|1\rangle }_{{\rm{g}}}$ form the spin qubit. Red transitions A and E are coupled (co-polarized) to the cavity, while the blue transition F is cross-polarized to the cavity mode. b , Typical experimental sequence used to initialize the ion into the ${|0\rangle }_{{\rm{g}}}$ state, manipulate the qubit and optically read out the spin state. c , Scanning electron microscope image of a photonic crystal cavity fabricated in YVO. Scale bar, 10 μm. d , Reflection spectrum of the cavity. e , Schematic of the experimental setup. The optical transitions are addressed using pulses generated from two frequency-stabilized continuous-wave (CW) lasers. The qubit is directly manipulated using microwave (MW) control pulses using a coplanar waveguide (CPW) next to the photonic crystal (PC) cavity, which is mounted in a dilution refrigerator. Light collected from the cavity is detected using a superconducting nanowire single-photon detector (SNSPD). Full size image A typical experimental sequence with spin initialization, control and readout is shown in Fig. 1b . The 171 Yb 3+ ions are coupled to a photonic crystal cavity with a large quality factor ( Q ≈ 1 × 10 4 ; Fig. 1c, d , Methods) and a small mode volume of about 1( λ / n YVO ) 3 , where λ is the wavelength of the optical transition and n YVO is the refractive index of YVO. This enhances the emission rate, collection efficiency and cyclicity of the optical transitions A and E via the Purcell effect 22 . The qubit is initialized into the ${|0\rangle }_{{\rm{g}}}$ state by optical and microwave pumping on the F, A and f e transitions to empty the ${|{\rm{aux}}\rangle }_{{\rm{g}}}$ and ${|1\rangle }_{{\rm{g}}}$ states, followed by cavity-enhanced decay into the ${|0\rangle }_{{\rm{g}}}$ state via transition E (Fig. 1a ). A subsequent microwave π pulse applied on the f g transition optionally initializes the ion into the ${|1\rangle }_{{\rm{g}}}$ state. The ${|1\rangle }_{{\rm{g}}}$ state population is read out by excitation on the A transition and collection of the resulting ion fluorescence. Measurements are performed in a cryostat at 40 mK unless mentioned otherwise (see Methods for discussion of sample temperature). The ions are optically addressed using two frequency-stabilized continuous-wave lasers, while a microwave coplanar waveguide<|im_end|> <|im_start|>assistant Engineers at Caltech have shown that atoms in optical cavities—tiny boxes for light—could be foundational to the creation of a quantum internet. Their work was published on March 30 by the journal Nature. Quantum networks would connect quantum computers through a system that also operates at a quantum, rather than classical, level. In theory, quantum computers will one day be able to perform certain functions faster than classical computers by taking advantage of the special properties of quantum mechanics, including superposition, which allows quantum bits to store information as a 1 and a 0 simultaneously. As they can with classical computers, engineers would like to be able to connect multiple quantum computers to share data and work together—creating a "quantum internet." This would open the door to several applications, including solving computations that are too large to be handled by a single quantum computer and establishing unbreakably secure communications using quantum cryptography. In order to work, a quantum network needs to be able to transmit information between two points without altering the quantum properties of the information being transmitted. One current model works like this: a single atom or ion acts as a quantum bit (or "qubit") storing information via one if its quantum properties, such as spin. To read that information and transmit it elsewhere, the atom is excited with a pulse of light, causing it to emit a photon whose spin is entangled with the spin of the atom. The photon can then transmit the information entangled with the atom over a long distance via fiber optic cable. It is harder than it sounds, however. Finding atoms that you can control and measure, and that also aren't too sensitive to magnetic or electric field fluctuations that cause errors, or decoherence, is challenging. "Solid-state emitters that interact well with light often fall victim to decoherence; that is, they stop storing information in a way that's useful from the prospective of quantum engineering," says Jon Kindem (MS '17, Ph.D. '19), lead author of the Nature paper. Meanwhile, atoms of rare-earth elements—which have properties that make the elements useful as qubits—tend to interact poorly with light. To overcome this challenge, researchers led by Caltech's Andrei Faraon (BS '04), professor of applied physics and electrical engineering, constructed a nanophotonic cavity, a beam that is about 10 microns in length with periodic nano-patterning, sculpted from a piece of crystal. They then identified a rare-earth ytterbium ion in the center of the beam. The optical cavity allows them to bounce light back and forth down the beam multiple times until it is finally absorbed by the ion. In the Nature paper, the team showed that the cavity modifies the environment of the ion such that whenever it emits a photon, more than 99 percent of the time that photon remains in the cavity, where scientists can then efficiently collect and detect that photon to measure the state of the ion. This results in an increase in the rate at which the ion can emit photons, improving the overall effectiveness of the system. In addition, the ytterbium ions are able to store information in their spin for 30 milliseconds. In this time, light could transmit information to travel across the continental United States. "This checks most of the boxes. It's a rare-earth ion that absorbs and emits photons in exactly the way we'd need to create a quantum network," says Faraon, professor of applied physics and electrical engineering. "This could form the backbone technology for the quantum internet." Currently, the team's focus is on creating the building blocks of a quantum network. Next, they hope to scale up their experiments and actually connect two quantum bits, Faraon says. Their paper is titled "Control and single-shot readout of an ion embedded in a nanophotonic cavity." <|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 People with specific health profiles and diseases (such as diabetes, lung and heart conditions) have been classified as ‘clinically vulnerable’ (CV) to COVID-19, that is, at higher risk of severe illness and mortality from COVID-19, and were targeted for shielding. However, there is as yet little evidence on how the pandemic and shielding impacted the health and social well-being of CV older people. Methods We used data from wave 9 (2018/2019) and the first COVID-19 substudy (June/July 2020) of the English Longitudinal Study of Ageing. Using logistic and linear regression models, we investigated associations between being CV and health and social well-being during the pandemic, while controlling for prepandemic levels of the outcome variables. We also explored the interactions between CV and age group (50s, 60s, 70s, 80+), and between CV and shielding. Results CV people were more likely to report worse health and social well-being outcomes during the pandemic, even taking into account prepandemic differences. However, changes in health were not uniform across different age groups, and CV respondents were generally at greater risks of deterioration in health and social well-being compared with those not CV in the same age group. CV respondents who were shielding reported worse outcomes compared with those not CV and not shielding. Conclusions While policies focusing on shielding CV older people reduce rates of hospitalisation and death from COVID-19, policymakers should also pay attention to understanding and addressing the wider needs of this group if their long-term health and social well-being are not to be compromised. COVID-19 ageing health status morbidity longitudinal studies Data availability statement Data are available in a public, open-access repository. ELSA data from all waves are available through the UK Data Service ( ) (SN 8688 and 5050). Data can be accessed via . More information on how to access ELSA and on the conditions of use can be found on both the ELSA website ( ) and the UK Data Service website. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 6 news outlets Blogged by 2 Referenced in 1 policy sources Tweeted by 14 56 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 COVID-19 ageing health status morbidity longitudinal studies Introduction Within a short time of the COVID-19 epidemic’s beginnings in Wuhan, China, clinical data revealed that the risk of severity of illness and death increased exponentially with age, and that a range of pre-existing health problems and chronic diseases all also correlated with age, predicted poor outcomes and mortality. 1–3 Multivariate analysis soon suggested that age, health and disease independently predicted severity of illness and mortality from COVID-19. 4–6 This led rapidly to the characterisation of populations who might be targeted for ‘shielding’ policies ranging from guidance to restrictions of movement. 7 In England, strict lockdown and orders to stay at home were announced by the UK Government on 23 March 2020. In particular, high-risk individuals (ie, clinically extremely vulnerable) were advised to ‘shield’, that is, not leave their homes, and within their homes to minimise all non-essential contact with other members of their household. This group at high risk included people who have had an organ transplant, those who are having treatments that can affect the immune system and those with serious heart or lung conditions. Similarly, all people over 70 and those with identified underlying health conditions (such as diabetes, asthma or hepatitis) were classified as ‘clinically vulnerable’ (CV; at moderate risk) and were also advised to stay indoors and limit their interactions with other people outside the household. Although these rules were somewhat relaxed in June, many restrictions remained in place, with vulnerable people advised to stay at home as much as possible and to take particular care to minimise contact with others outside their household. 8–11 Over the last few months, several studies have investigated mental health and health behaviours before and during the COVID-19 pandemic using representative samples and measuring changes either within individuals, across the population as a whole or across specific subgroups. 12–18 Results suggest that health deteriorated particularly among younger age groups, whereas older adults seem to have fared better during the pandemic. Yet, in these studies, older people have been portrayed and considered as a homogeneously vulnerable group, with analyses grouping together all people aged 55, 65 or 70 years and older and failing to acknowledge that older people are a diverse group. A recent report 19 which used the English Longitudinal Study of Ageing (ELSA) and focused specifically on older people suggests that those instructed by the National Health Service (NHS) or their general practitioner (GP) to shield were more likely to report poorer mental health and lower quality of life (QoL; even when prepandemic health measures were taken into account) as well as unhealthy behaviours during the pandemic compared with the remainder. Similar results were reported also among older individuals with multiple long-term health conditions. 20 Both reports provide an important contribution to the understanding of older people’s health during the initial lockdown and of the effect of social isolation and underlying health conditions. However, they are descriptive in nature and did not take into account important socioeconomic and demographic characteristics such as wealth, education and ethnicity, which are well known to be associated with both chronic conditions and health in later life. Moreover, to date,", "role": "user" }, { "content": "Older people who are clinically vulnerable to COVID-19 are at greater risk of deterioration in health and social well-being during the pandemic, according to a new study. The research, published in the Journal of Epidemiology and Community Health, found that older people were more likely to report worse health outcomes than those with no clinical vulnerabilities, including greater depression and anxiety and lower quality of life, even when taking into account pre-pandemic levels of health and social well-being. The findings highlight the need for policymakers to consider the mental and physical health consequences of the pandemic for those at higher risk from coronavirus, particularly for those asked to shield. Professor Debora Price from The University of Manchester and Dr. Giorgio Di Gessa from UCL compared data from 2020's English Longitudinal Study of Aging with data from the previous year. They analyzed responses from over 5000 people aged 52 and over in private households in England. The study revealed that during the pandemic, respondents classified as clinically vulnerable were more likely to report poor self-rated health, lower levels of physical activity, depression, anxiety, lower quality of life as well as loneliness and receipt of care, compared to those without clinical vulnerabilities. This was true within each age group. Among people in their 70s, the odds of being depressed and anxious for those clinically vulnerable were around 50% higher than for those without clinical vulnerabilities. Those in their 80s—regardless of clinical vulnerability—were much more likely to have unmet care needs and to have little contact with friends and family by text, email, or videocall. Although older adults' health and social well-being have been impacted by shielding, the researchers found that it was those who were clinically vulnerable and shielding who reported the most substantial rises in anxiety, depression, poor self-rated health and receipt of formal care, as well as decreases in well-being and physical activity. \"Older people with underlying health conditions, even before the pandemic, faced challenges in terms of access to healthcare services and social contact,\" said Professor Debora Price. \"They also experienced greater emotional distress, higher risk of loneliness and poorer quality of life than non-vulnerable individuals.\" \"While policies focusing on shielding clinically vulnerable older people reduce rates of hospitalization and death from COVID-19, policymakers need to acknowledge that there may be adverse consequences of this measure and address the wider needs of these vulnerable groups,\" added Dr. Giorgio Di Gessa. \"It's vital that policymakers are aware that when advised to stay at home, a host of health and social risks for this group, already poor, are likely to be exacerbated.\" ", "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 People with specific health profiles and diseases (such as diabetes, lung and heart conditions) have been classified as ‘clinically vulnerable’ (CV) to COVID-19, that is, at higher risk of severe illness and mortality from COVID-19, and were targeted for shielding. However, there is as yet little evidence on how the pandemic and shielding impacted the health and social well-being of CV older people. Methods We used data from wave 9 (2018/2019) and the first COVID-19 substudy (June/July 2020) of the English Longitudinal Study of Ageing. Using logistic and linear regression models, we investigated associations between being CV and health and social well-being during the pandemic, while controlling for prepandemic levels of the outcome variables. We also explored the interactions between CV and age group (50s, 60s, 70s, 80+), and between CV and shielding. Results CV people were more likely to report worse health and social well-being outcomes during the pandemic, even taking into account prepandemic differences. However, changes in health were not uniform across different age groups, and CV respondents were generally at greater risks of deterioration in health and social well-being compared with those not CV in the same age group. CV respondents who were shielding reported worse outcomes compared with those not CV and not shielding. Conclusions While policies focusing on shielding CV older people reduce rates of hospitalisation and death from COVID-19, policymakers should also pay attention to understanding and addressing the wider needs of this group if their long-term health and social well-being are not to be compromised. COVID-19 ageing health status morbidity longitudinal studies Data availability statement Data are available in a public, open-access repository. ELSA data from all waves are available through the UK Data Service ( ) (SN 8688 and 5050). Data can be accessed via . More information on how to access ELSA and on the conditions of use can be found on both the ELSA website ( ) and the UK Data Service website. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 6 news outlets Blogged by 2 Referenced in 1 policy sources Tweeted by 14 56 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 COVID-19 ageing health status morbidity longitudinal studies Introduction Within a short time of the COVID-19 epidemic’s beginnings in Wuhan, China, clinical data revealed that the risk of severity of illness and death increased exponentially with age, and that a range of pre-existing health problems and chronic diseases all also correlated with age, predicted poor outcomes and mortality. 1–3 Multivariate analysis soon suggested that age, health and disease independently predicted severity of illness and mortality from COVID-19. 4–6 This led rapidly to the characterisation of populations who might be targeted for ‘shielding’ policies ranging from guidance to restrictions of movement. 7 In England, strict lockdown and orders to stay at home were announced by the UK Government on 23 March 2020. In particular, high-risk individuals (ie, clinically extremely vulnerable) were advised to ‘shield’, that is, not leave their homes, and within their homes to minimise all non-essential contact with other members of their household. This group at high risk included people who have had an organ transplant, those who are having treatments that can affect the immune system and those with serious heart or lung conditions. Similarly, all people over 70 and those with identified underlying health conditions (such as diabetes, asthma or hepatitis) were classified as ‘clinically vulnerable’ (CV; at moderate risk) and were also advised to stay indoors and limit their interactions with other people outside the household. Although these rules were somewhat relaxed in June, many restrictions remained in place, with vulnerable people advised to stay at home as much as possible and to take particular care to minimise contact with others outside their household. 8–11 Over the last few months, several studies have investigated mental health and health behaviours before and during the COVID-19 pandemic using representative samples and measuring changes either within individuals, across the population as a whole or across specific subgroups. 12–18 Results suggest that health deteriorated particularly among younger age groups, whereas older adults seem to have fared better during the pandemic. Yet, in these studies, older people have been portrayed and considered as a homogeneously vulnerable group, with analyses grouping together all people aged 55, 65 or 70 years and older and failing to acknowledge that older people are a diverse group. A recent report 19 which used the English Longitudinal Study of Ageing (ELSA) and focused specifically on older people suggests that those instructed by the National Health Service (NHS) or their general practitioner (GP) to shield were more likely to report poorer mental health and lower quality of life (QoL; even when prepandemic health measures were taken into account) as well as unhealthy behaviours during the pandemic compared with the remainder. Similar results were reported also among older individuals with multiple long-term health conditions. 20 Both reports provide an important contribution to the understanding of older people’s health during the initial lockdown and of the effect of social isolation and underlying health conditions. However, they are descriptive in nature and did not take into account important socioeconomic and demographic characteristics such as wealth, education and ethnicity, which are well known to be associated with both chronic conditions and health in later life. Moreover, to date,<|im_end|> <|im_start|>assistant Older people who are clinically vulnerable to COVID-19 are at greater risk of deterioration in health and social well-being during the pandemic, according to a new study. The research, published in the Journal of Epidemiology and Community Health, found that older people were more likely to report worse health outcomes than those with no clinical vulnerabilities, including greater depression and anxiety and lower quality of life, even when taking into account pre-pandemic levels of health and social well-being. The findings highlight the need for policymakers to consider the mental and physical health consequences of the pandemic for those at higher risk from coronavirus, particularly for those asked to shield. Professor Debora Price from The University of Manchester and Dr. Giorgio Di Gessa from UCL compared data from 2020's English Longitudinal Study of Aging with data from the previous year. They analyzed responses from over 5000 people aged 52 and over in private households in England. The study revealed that during the pandemic, respondents classified as clinically vulnerable were more likely to report poor self-rated health, lower levels of physical activity, depression, anxiety, lower quality of life as well as loneliness and receipt of care, compared to those without clinical vulnerabilities. This was true within each age group. Among people in their 70s, the odds of being depressed and anxious for those clinically vulnerable were around 50% higher than for those without clinical vulnerabilities. Those in their 80s—regardless of clinical vulnerability—were much more likely to have unmet care needs and to have little contact with friends and family by text, email, or videocall. Although older adults' health and social well-being have been impacted by shielding, the researchers found that it was those who were clinically vulnerable and shielding who reported the most substantial rises in anxiety, depression, poor self-rated health and receipt of formal care, as well as decreases in well-being and physical activity. "Older people with underlying health conditions, even before the pandemic, faced challenges in terms of access to healthcare services and social contact," said Professor Debora Price. "They also experienced greater emotional distress, higher risk of loneliness and poorer quality of life than non-vulnerable individuals." "While policies focusing on shielding clinically vulnerable older people reduce rates of hospitalization and death from COVID-19, policymakers need to acknowledge that there may be adverse consequences of this measure and address the wider needs of these vulnerable groups," added Dr. Giorgio Di Gessa. "It's vital that policymakers are aware that when advised to stay at home, a host of health and social risks for this group, already poor, are likely to be exacerbated." <|im_end|>

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2536, 74144, 13, 3580, 25, 662, 48569, 1169, 351, 26808, 2615, 2993, 368, 314, 48569, 1169, 351, 8344, 446, 3013, 79, 26831, 12, 1331, 84, 5146, 18605, 25647, 505, 24610, 16282, 916, 3580, 810, 3649, 393, 19011, 709, 555, 220, 21, 3754, 28183, 14496, 3640, 555, 220, 17, 29734, 5886, 304, 220, 16, 4947, 8336, 26213, 291, 555, 220, 975, 220, 3487, 13016, 389, 386, 11178, 3258, 99371, 7384, 6274, 54457, 1442, 499, 6562, 311, 27068, 904, 477, 682, 315, 420, 4652, 4587, 1005, 279, 2723, 3770, 902, 690, 1935, 499, 311, 279, 3028, 93230, 5955, 753, 10734, 4026, 2532, 13, 1472, 690, 387, 3025, 311, 636, 264, 4062, 3430, 323, 9888, 8041, 311, 27068, 279, 2262, 304, 1690, 2204, 5627, 13, 949, 6591, 2373, 429, 16, 13, 15, 1, 11418, 429, 8729, 12, 23, 1, 949, 6274, 8709, 20562, 12, 777, 80043, 2890, 2704, 93144, 19025, 68102, 7978, 29438, 25218, 264, 2875, 892, 315, 279, 20562, 12, 777, 42620, 753, 67482, 304, 37230, 10118, 11, 5734, 11, 14830, 828, 10675, 430, 279, 5326, 315, 31020, 315, 17563, 323, 4648, 7319, 75251, 449, 4325, 11, 323, 430, 264, 2134, 315, 864, 50457, 2890, 5435, 323, 21249, 19338, 682, 1101, 49393, 449, 4325, 11, 19698, 8009, 20124, 323, 29528, 13, 220, 16, 4235, 18, 22950, 56522, 6492, 5246, 12090, 430, 4325, 11, 2890, 323, 8624, 29235, 19698, 31020, 315, 17563, 323, 29528, 505, 20562, 12, 777, 13, 220, 19, 4235, 21, 1115, 6197, 19019, 311, 279, 3752, 8082, 315, 22673, 889, 2643, 387, 17550, 369, 3451, 49052, 287, 529, 10396, 24950, 505, 19351, 311, 17294, 315, 7351, 13, 220, 22, 763, 9635, 11, 7452, 51235, 323, 10373, 311, 4822, 520, 2162, 1051, 7376, 555, 279, 6560, 10423, 389, 220, 1419, 5587, 220, 2366, 15, 13, 763, 4040, 11, 1579, 46570, 7931, 320, 648, 11, 70432, 9193, 20134, 8, 1051, 26160, 311, 3451, 49052, 20182, 430, 374, 11, 539, 5387, 872, 10632, 11, 323, 2949, 872, 10632, 311, 97087, 682, 2536, 12, 49582, 3729, 449, 1023, 3697, 315, 872, 14048, 13, 1115, 1912, 520, 1579, 5326, 5343, 1274, 889, 617, 1047, 459, 2942, 43929, 11, 1884, 889, 527, 3515, 22972, 430, 649, 7958, 279, 22852, 1887, 323, 1884, 449, 6129, 4851, 477, 21271, 4787, 13, 35339, 11, 682, 1274, 927, 220, 2031, 323, 1884, 449, 11054, 16940, 2890, 4787, 320, 21470, 439, 20335, 11, 51643, 477, 73975, 8, 1051, 21771, 439, 3451, 47681, 2740, 20134, 529, 320, 20161, 26, 520, 24070, 5326, 8, 323, 1051, 1101, 26160, 311, 4822, 55154, 323, 4017, 872, 22639, 449, 1023, 1274, 4994, 279, 14048, 13, 10541, 1521, 5718, 1051, 14738, 31467, 304, 5651, 11, 1690, 17294, 14958, 304, 2035, 11, 449, 20134, 1274, 26160, 311, 4822, 520, 2162, 439, 1790, 439, 3284, 323, 311, 1935, 4040, 2512, 311, 97087, 3729, 449, 3885, 4994, 872, 14048, 13, 220, 23, 4235, 806, 6193, 279, 1566, 2478, 4038, 11, 3892, 7978, 617, 27313, 10723, 2890, 323, 2890, 71177, 1603, 323, 2391, 279, 20562, 12, 777, 28522, 1701, 18740, 10688, 323, 30090, 4442, 3060, 2949, 7931, 11, 4028, 279, 7187, 439, 264, 4459, 477, 4028, 3230, 1207, 17171, 13, 220, 717, 4235, 972, 18591, 4284, 430, 2890, 39436, 660, 8104, 4315, 14992, 4325, 5315, 11, 20444, 9191, 12884, 2873, 311, 617, 282, 1636, 2731, 2391, 279, 28522, 13, 14968, 11, 304, 1521, 7978, 11, 9191, 1274, 617, 1027, 45877, 323, 6646, 439, 264, 5105, 34224, 7162, 20134, 1912, 11, 449, 29060, 50284, 3871, 682, 1274, 20330, 220, 2131, 11, 220, 2397, 477, 220, 2031, 1667, 323, 9191, 323, 22109, 311, 25670, 430, 9191, 1274, 527, 264, 17226, 1912, 13, 362, 3293, 1934, 220, 777, 902, 1511, 279, 6498, 5843, 13138, 992, 19723, 315, 13381, 287, 320, 2818, 7934, 8, 323, 10968, 11951, 389, 9191, 1274, 13533, 430, 1884, 42075, 555, 279, 5165, 6401, 5475, 320, 45, 12228, 8, 477, 872, 4689, 55472, 320, 25434, 8, 311, 20858, 1051, 810, 4461, 311, 1934, 66281, 10723, 2890, 323, 4827, 4367, 315, 2324, 320, 48, 78, 43, 26, 1524, 994, 22033, 438, 8274, 2890, 11193, 1051, 4529, 1139, 2759, 8, 439, 1664, 439, 53808, 71177, 2391, 279, 28522, 7863, 449, 279, 27410, 13, 22196, 3135, 1051, 5068, 1101, 4315, 9191, 7931, 449, 5361, 1317, 9860, 2890, 4787, 13, 220, 508, 11995, 6821, 3493, 459, 3062, 19035, 311, 279, 8830, 315, 9191, 1274, 753, 2890, 2391, 279, 2926, 51235, 323, 315, 279, 2515, 315, 3674, 31398, 323, 16940, 2890, 4787, 13, 4452, 11, 814, 527, 53944, 304, 7138, 323, 1550, 539, 1935, 1139, 2759, 3062, 80431, 323, 38462, 17910, 1778, 439, 12205, 11, 6873, 323, 57978, 11, 902, 527, 1664, 3967, 311, 387, 5938, 449, 2225, 21249, 4787, 323, 2890, 304, 3010, 2324, 13, 23674, 11, 311, 2457, 11, 128257, 198, 128256, 78191, 198, 18788, 261, 1274, 889, 527, 70432, 20134, 311, 20562, 12, 777, 527, 520, 7191, 5326, 315, 82189, 304, 2890, 323, 3674, 1664, 33851, 2391, 279, 28522, 11, 4184, 311, 264, 502, 4007, 13, 578, 3495, 11, 4756, 304, 279, 10139, 315, 88953, 2508, 323, 12332, 6401, 11, 1766, 430, 9191, 1274, 1051, 810, 4461, 311, 1934, 11201, 2890, 20124, 1109, 1884, 449, 912, 14830, 52227, 11, 2737, 7191, 18710, 323, 18547, 323, 4827, 4367, 315, 2324, 11, 1524, 994, 4737, 1139, 2759, 864, 2320, 438, 8274, 5990, 315, 2890, 323, 3674, 1664, 33851, 13, 578, 14955, 11415, 279, 1205, 369, 70978, 311, 2980, 279, 10723, 323, 7106, 2890, 16296, 315, 279, 28522, 369, 1884, 520, 5190, 5326, 505, 33333, 11, 8104, 369, 1884, 4691, 311, 20858, 13, 17054, 36561, 6347, 8650, 505, 578, 3907, 315, 19922, 323, 2999, 13, 15754, 1813, 822, 7923, 480, 26577, 505, 549, 3218, 7863, 828, 505, 220, 2366, 15, 596, 6498, 5843, 13138, 992, 19723, 315, 77188, 449, 828, 505, 279, 3766, 1060, 13, 2435, 30239, 14847, 505, 927, 220, 2636, 15, 1274, 20330, 220, 4103, 323, 927, 304, 879, 29939, 304, 9635, 13, 578, 4007, 10675, 430, 2391, 279, 28522, 11, 34281, 21771, 439, 70432, 20134, 1051, 810, 4461, 311, 1934, 8009, 659, 55985, 2890, 11, 4827, 5990, 315, 7106, 5820, 11, 18710, 11, 18547, 11, 4827, 4367, 315, 2324, 439, 1664, 439, 75040, 323, 23383, 315, 2512, 11, 7863, 311, 1884, 2085, 14830, 52227, 13, 1115, 574, 837, 2949, 1855, 4325, 1912, 13, 22395, 1274, 304, 872, 220, 2031, 82, 11, 279, 21448, 315, 1694, 42642, 323, 38100, 369, 1884, 70432, 20134, 1051, 2212, 220, 1135, 4, 5190, 1109, 369, 1884, 2085, 14830, 52227, 13, 13266, 304, 872, 220, 1490, 82, 2345, 1610, 30920, 315, 14830, 34104, 2345, 52898, 1790, 810, 4461, 311, 617, 653, 4150, 2512, 3966, 323, 311, 617, 2697, 3729, 449, 4885, 323, 3070, 555, 1495, 11, 2613, 11, 477, 23895, 511, 543, 13, 10541, 9191, 12884, 6, 2890, 323, 3674, 1664, 33851, 617, 1027, 40028, 555, 97776, 11, 279, 12074, 1766, 430, 433, 574, 1884, 889, 1051, 70432, 20134, 323, 97776, 889, 5068, 279, 1455, 12190, 38268, 304, 18547, 11, 18710, 11, 8009, 659, 55985, 2890, 323, 23383, 315, 16287, 2512, 11, 439, 1664, 439, 43154, 304, 1664, 33851, 323, 7106, 5820, 13, 330, 18788, 261, 1274, 449, 16940, 2890, 4787, 11, 1524, 1603, 279, 28522, 11, 17011, 11774, 304, 3878, 315, 2680, 311, 18985, 3600, 323, 3674, 3729, 1359, 1071, 17054, 36561, 6347, 8650, 13, 330, 7009, 1101, 10534, 7191, 14604, 35104, 11, 5190, 5326, 315, 75040, 323, 66281, 4367, 315, 2324, 1109, 2536, 8437, 94007, 7931, 1210, 330, 8142, 10396, 21760, 389, 97776, 70432, 20134, 9191, 1274, 8108, 7969, 315, 8952, 2065, 323, 4648, 505, 20562, 12, 777, 11, 70978, 1205, 311, 25670, 430, 1070, 1253, 387, 31959, 16296, 315, 420, 6767, 323, 2686, 279, 22622, 3966, 315, 1521, 20134, 5315, 1359, 3779, 2999, 13, 15754, 1813, 822, 7923, 480, 26577, 13, 330, 2181, 596, 16595, 430, 70978, 527, 8010, 430, 994, 26160, 311, 4822, 520, 2162, 11, 264, 3552, 315, 2890, 323, 3674, 15635, 369, 420, 1912, 11, 2736, 8009, 11, 527, 4461, 311, 387, 92541, 1210, 220, 128257, 198 ]

1,854

[ { "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 Nested concentric structures widely exist in nature and designed systems with circles, polygons, polyhedra, and spheres sharing the same center or axis. It still remains challenging to construct discrete nested architecture at (supra)molecular level. Herein, three generations ( G2 − G4 ) of giant nested supramolecules, or Kandinsky circles, have been designed and assembled with molecular weight 17,964, 27,713 and 38,352 Da, respectively. In the ligand preparation, consecutive condensation between precursors with primary amines and pyrylium salts is applied to modularize the synthesis. These discrete nested supramolecules are prone to assemble into tubular nanostructures through hierarchical self-assembly. Furthermore, nested supramolecules display high antimicrobial activity against Gram-positive pathogen methicillin-resistant Staphylococcus aureus (MRSA), and negligible toxicity to eukaryotic cells, while the corresponding ligands do not show potent antimicrobial activity. Introduction Nested concentric patterns are common throughout nature and designed systems within broad scales. Examples of nested structures in nature include onion, tree-rings, spider webs, Russian dolls, circular surface waves on the water, concentric hexagons at Saturn’s North Pole 1 , and so forth. In the art field, concentric rings are also known as Kandinsky circles named after Wassily Kandinsky, a pioneer in abstract art, because of his prominent and profound painting Color Study; Squares with Concentric Circles 2 . In addition to art and mathematics study 3 , chemists have been fascinated by nested architectures with discovery and/or creation of a significant number of two-dimensional (2D) and three-dimensional (3D) systems that display nested layer and shell arrangements of atoms, molecules, and materials. This is evident in the, for example, structure of Pariacoto virus 4 , light harvesting complexes in purple bacteria 5 , atomic organization of carbon onions 6 , concentric arrangement of multi-walled carbon nanotubes 7 , self-assembly of amphiphilic dendrimers 8 , block-copolymers 9 , and graphene onion rings 10 . It still remains, however, a formidable challenge to construct discrete nested structures at (supra)molecular level. Up to date, only a very few discrete nested supramolecules were reported but limited to DNA nanostructures 11 , 12 , porphyrin nanorings 13 , and complexes of carbon nanorings with fullerenes 14 , 15 . Nonetheless, precise control over the self-assembly toward discrete supramolecular nested structures is still one of the ultimate goals and challenges in the field. Inspired by Kandinsky circles, we focused our attention on seeking of an efficient (supra)molecular expression of the nested structure based on coordination-driven self-assembly. Since early 1990s 16 , coordination-driven self-assembly has witnessed an explosion in constructing various 2D and 3D supramolecular architectures 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 owing to the highly directional and predictable feature of coordination, as well as the structural information instilled in the building blocks. Benefiting from their precisely controlled structures, such supramolecules have found a myriad of applications 26 − 33 . With nested hexagons or Kandinsky circles as our target (Fig. 1a, b ), we should be able to create a series of discrete supramolecules, e.g., generations 1 to 4 ( G1 − G4 ) in the self-assembly of multitopic organic ligands with metal ions as bridging units. However, such design posed a substantial challenge in the synthesis of multitopic terpyridine (tpy) ligands given the increasing size and complexity of the target. In this study, we overcome the challenge through using modular pyrylium salts followed by consecutive condensation reaction with primary amines to prepare multitopic pyridinium salts ligands. As such, we successfully assemble giant discrete nested hexagons from G2 to G4 . Fig. 1 Synthesis and self-assembly of nested hexagon. a Molecular modeling of nested hexagons ( G2−G4 ). Alkyl chains were omitted for clarity in the molecular models. b Self-assembly of G1−G4 . In the self-assembly of L1 , a mixture of macrocycles was obtained instead of discrete hexagon. c Synthesis of the ligands L1−L4 based on pyrylium and pyridinium salts chemistry Full size image In addition to self-assembly of discrete nested hexagons, these giant multilayered supramolecules have a strong tendency to form tubular nanostructures through hierarchical self-assembly. We envision that these nested hexagons could interact with bacterial lipid membrane and form transmembrane channels owing to their desired shapes and sizes, cationic scaffolds with precise charge positioning, delicate balance of the overall hydrophobicity/hydrophilicity, and remarkable rigidity and stability. Indeed, these nested hexagons display highly potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and negligible toxicity to eukaryotic cells. It is worth noting that few synthetic ion channels based on metal-organic polyhydra and prism are reported, but none of them are active against bacteria 34 , 35 . Here we conduct a detailed study to address this antimicrobial mechanism, hopefully to shed light on fighting bacterial infections and antibiotic resistance. Results Synthesis and hierarchical assembly of supramolecular Kandinsky circles G2 − G4 Based on geometry and topology analysis along with detailed molecular dynamic simulation, we reasoned a series of nested hexagons could be assembled, e.g., G2 − G4 or even higher generation. In addition to the seeking of the chemical expression of the beautiful nested geometry, such architectures with increasing multivalent interaction 36 or high density of coordination sites 37 would advance the complexity and stability of 2D supramolecules. Moreover, the large and rigid scaffolds with all conjugated backbones may facilitate further packing of nested hexagons into tubular-like nanostructures through hierarchical self-assembly 38 . The major challenge posed in such design is the synthesis of multitopic ligands. This motivated us to exploit the synthesis of multitopic tpy ligand with the goal of developing a robust synthetic approach. We initially employed a synthetic strategy based on Suzuki coupling reaction on the dibromo-pyridinium salts as shown in Supplementary Figure 1 according to our recent study 39 . The synthesis and separation of singly charged tetratopic tpy ligand L2 was readily accomplished with good yield. In the preparation of L3 ; however, it was extremely difficult to isolate the doubly charged hexatopic ligand from the system, which contained multi-armed byproducts, e.g., pentatopic tpy component with very similar polarity and size", "role": "user" }, { "content": "Nested structures are commonly found throughout nature and art, whether they be in the form of tree rings, Russian dolls, or Wassily Kandinsky's famous 1913 abstract painting Color Study: Squares with Concentric Circles. Now in a new study, chemists have constructed giant nested supramolecules or \"supramolecular Kandinsky circles,\" some of which are more than 30,000 times heavier than a hydrogen atom. The scientists demonstrate that these supramolecules are highly toxic to methicillin-resistant Staphylococcus aureus (MRSA), potentially providing a new method for fighting these deadly pathogens. The researchers, Heng Wang, Xiamin Qian, and their coauthors at universities in China and the US, have published a paper on the antimicrobial supramolecular Kandinsky circles in a recent issue of Nature Communications. \"Biomaterials based on supramolecular Kandinsky circles pave a new avenue to the development of a new generation of antibiotics with novel mechanisms through the formation of unprecedented transmembrane channels with distinct pore size,\" coauthor Xiaopeng Li at the University of South Florida told Phys.org. Although called supramolecular Kandinsky circles, the supramolecules are composed of nested hexagons rather than circles, giving them the appearance of molecular spider webs. Constructing nested supramolecular structures has been a formidable challenge, which the researchers here address by using coordination-driven self-assembly. In this method, the supramolecules are composed of coordination complexes, which consist of a central metal ion surrounded by organic ligands that branch out to allow for the formation of multiple 2-D layers of nested hexagons. When observing these supramolecular structures with various imaging technologies, the researchers discovered that they have a strong tendency to curl up into tubular nanostructures. Partly for this reason, along with results from previous research, the scientists suspected that the new supramolecules may have antimicrobial properties. They tested the supramolecules on two types of bacteria, MRSA and E. coli, and found that the supramolecules were highly toxic to MRSA but unable to inhibit E. coli. This is likely due to the difference in the cell walls: E. coli, which is Gram-negative, has both an inner and an outer membrane, while MRSA, which is Gram-positive, has only an inner membrane and so is more susceptible to the supramolecules. Experiments showed that the antibacterial mechanism of the supramolecules arises from the nested hexagon structure, which curls into a tube, penetrates the inner membrane, and provides a channel through which the bacterial cell's cytoplasm leaks out. After a few hours, the leaking of the cytoplasmic contents results in cell death. On the other hand, the supramolecules exhibit negligible toxicity to red blood cells, which the researchers attribute to a weaker electrostatic attraction between the surfaces of the supramolecules and these cells, compared to the surface of the supramolecules and the bacteria. In the future, the supramolecular Kandinsky circles may provide a new defensive strategy against MRSA, with potential advantages that may include preventing the bacteria from developing antibiotic resistance, as well as reducing the toxicity to human cells. This is because the supramolecules have low minimum inhibitory concentrations (MICs), meaning less is needed to inhibit bacterial growth, compared to some other antimicrobial agents. One possibility is to combine the supramolecules with existing antibiotics in order to realize these advantages. Before then, the researchers plan to make further improvements on the supramolecules. \"We will increase the water solubility of the Kandinsky circles to further enhance their antibacterial activity,\" Li 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 Nested concentric structures widely exist in nature and designed systems with circles, polygons, polyhedra, and spheres sharing the same center or axis. It still remains challenging to construct discrete nested architecture at (supra)molecular level. Herein, three generations ( G2 − G4 ) of giant nested supramolecules, or Kandinsky circles, have been designed and assembled with molecular weight 17,964, 27,713 and 38,352 Da, respectively. In the ligand preparation, consecutive condensation between precursors with primary amines and pyrylium salts is applied to modularize the synthesis. These discrete nested supramolecules are prone to assemble into tubular nanostructures through hierarchical self-assembly. Furthermore, nested supramolecules display high antimicrobial activity against Gram-positive pathogen methicillin-resistant Staphylococcus aureus (MRSA), and negligible toxicity to eukaryotic cells, while the corresponding ligands do not show potent antimicrobial activity. Introduction Nested concentric patterns are common throughout nature and designed systems within broad scales. Examples of nested structures in nature include onion, tree-rings, spider webs, Russian dolls, circular surface waves on the water, concentric hexagons at Saturn’s North Pole 1 , and so forth. In the art field, concentric rings are also known as Kandinsky circles named after Wassily Kandinsky, a pioneer in abstract art, because of his prominent and profound painting Color Study; Squares with Concentric Circles 2 . In addition to art and mathematics study 3 , chemists have been fascinated by nested architectures with discovery and/or creation of a significant number of two-dimensional (2D) and three-dimensional (3D) systems that display nested layer and shell arrangements of atoms, molecules, and materials. This is evident in the, for example, structure of Pariacoto virus 4 , light harvesting complexes in purple bacteria 5 , atomic organization of carbon onions 6 , concentric arrangement of multi-walled carbon nanotubes 7 , self-assembly of amphiphilic dendrimers 8 , block-copolymers 9 , and graphene onion rings 10 . It still remains, however, a formidable challenge to construct discrete nested structures at (supra)molecular level. Up to date, only a very few discrete nested supramolecules were reported but limited to DNA nanostructures 11 , 12 , porphyrin nanorings 13 , and complexes of carbon nanorings with fullerenes 14 , 15 . Nonetheless, precise control over the self-assembly toward discrete supramolecular nested structures is still one of the ultimate goals and challenges in the field. Inspired by Kandinsky circles, we focused our attention on seeking of an efficient (supra)molecular expression of the nested structure based on coordination-driven self-assembly. Since early 1990s 16 , coordination-driven self-assembly has witnessed an explosion in constructing various 2D and 3D supramolecular architectures 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 owing to the highly directional and predictable feature of coordination, as well as the structural information instilled in the building blocks. Benefiting from their precisely controlled structures, such supramolecules have found a myriad of applications 26 − 33 . With nested hexagons or Kandinsky circles as our target (Fig. 1a, b ), we should be able to create a series of discrete supramolecules, e.g., generations 1 to 4 ( G1 − G4 ) in the self-assembly of multitopic organic ligands with metal ions as bridging units. However, such design posed a substantial challenge in the synthesis of multitopic terpyridine (tpy) ligands given the increasing size and complexity of the target. In this study, we overcome the challenge through using modular pyrylium salts followed by consecutive condensation reaction with primary amines to prepare multitopic pyridinium salts ligands. As such, we successfully assemble giant discrete nested hexagons from G2 to G4 . Fig. 1 Synthesis and self-assembly of nested hexagon. a Molecular modeling of nested hexagons ( G2−G4 ). Alkyl chains were omitted for clarity in the molecular models. b Self-assembly of G1−G4 . In the self-assembly of L1 , a mixture of macrocycles was obtained instead of discrete hexagon. c Synthesis of the ligands L1−L4 based on pyrylium and pyridinium salts chemistry Full size image In addition to self-assembly of discrete nested hexagons, these giant multilayered supramolecules have a strong tendency to form tubular nanostructures through hierarchical self-assembly. We envision that these nested hexagons could interact with bacterial lipid membrane and form transmembrane channels owing to their desired shapes and sizes, cationic scaffolds with precise charge positioning, delicate balance of the overall hydrophobicity/hydrophilicity, and remarkable rigidity and stability. Indeed, these nested hexagons display highly potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and negligible toxicity to eukaryotic cells. It is worth noting that few synthetic ion channels based on metal-organic polyhydra and prism are reported, but none of them are active against bacteria 34 , 35 . Here we conduct a detailed study to address this antimicrobial mechanism, hopefully to shed light on fighting bacterial infections and antibiotic resistance. Results Synthesis and hierarchical assembly of supramolecular Kandinsky circles G2 − G4 Based on geometry and topology analysis along with detailed molecular dynamic simulation, we reasoned a series of nested hexagons could be assembled, e.g., G2 − G4 or even higher generation. In addition to the seeking of the chemical expression of the beautiful nested geometry, such architectures with increasing multivalent interaction 36 or high density of coordination sites 37 would advance the complexity and stability of 2D supramolecules. Moreover, the large and rigid scaffolds with all conjugated backbones may facilitate further packing of nested hexagons into tubular-like nanostructures through hierarchical self-assembly 38 . The major challenge posed in such design is the synthesis of multitopic ligands. This motivated us to exploit the synthesis of multitopic tpy ligand with the goal of developing a robust synthetic approach. We initially employed a synthetic strategy based on Suzuki coupling reaction on the dibromo-pyridinium salts as shown in Supplementary Figure 1 according to our recent study 39 . The synthesis and separation of singly charged tetratopic tpy ligand L2 was readily accomplished with good yield. In the preparation of L3 ; however, it was extremely difficult to isolate the doubly charged hexatopic ligand from the system, which contained multi-armed byproducts, e.g., pentatopic tpy component with very similar polarity and size<|im_end|> <|im_start|>assistant Nested structures are commonly found throughout nature and art, whether they be in the form of tree rings, Russian dolls, or Wassily Kandinsky's famous 1913 abstract painting Color Study: Squares with Concentric Circles. Now in a new study, chemists have constructed giant nested supramolecules or "supramolecular Kandinsky circles," some of which are more than 30,000 times heavier than a hydrogen atom. The scientists demonstrate that these supramolecules are highly toxic to methicillin-resistant Staphylococcus aureus (MRSA), potentially providing a new method for fighting these deadly pathogens. The researchers, Heng Wang, Xiamin Qian, and their coauthors at universities in China and the US, have published a paper on the antimicrobial supramolecular Kandinsky circles in a recent issue of Nature Communications. "Biomaterials based on supramolecular Kandinsky circles pave a new avenue to the development of a new generation of antibiotics with novel mechanisms through the formation of unprecedented transmembrane channels with distinct pore size," coauthor Xiaopeng Li at the University of South Florida told Phys.org. Although called supramolecular Kandinsky circles, the supramolecules are composed of nested hexagons rather than circles, giving them the appearance of molecular spider webs. Constructing nested supramolecular structures has been a formidable challenge, which the researchers here address by using coordination-driven self-assembly. In this method, the supramolecules are composed of coordination complexes, which consist of a central metal ion surrounded by organic ligands that branch out to allow for the formation of multiple 2-D layers of nested hexagons. When observing these supramolecular structures with various imaging technologies, the researchers discovered that they have a strong tendency to curl up into tubular nanostructures. Partly for this reason, along with results from previous research, the scientists suspected that the new supramolecules may have antimicrobial properties. They tested the supramolecules on two types of bacteria, MRSA and E. coli, and found that the supramolecules were highly toxic to MRSA but unable to inhibit E. coli. This is likely due to the difference in the cell walls: E. coli, which is Gram-negative, has both an inner and an outer membrane, while MRSA, which is Gram-positive, has only an inner membrane and so is more susceptible to the supramolecules. Experiments showed that the antibacterial mechanism of the supramolecules arises from the nested hexagon structure, which curls into a tube, penetrates the inner membrane, and provides a channel through which the bacterial cell's cytoplasm leaks out. After a few hours, the leaking of the cytoplasmic contents results in cell death. On the other hand, the supramolecules exhibit negligible toxicity to red blood cells, which the researchers attribute to a weaker electrostatic attraction between the surfaces of the supramolecules and these cells, compared to the surface of the supramolecules and the bacteria. In the future, the supramolecular Kandinsky circles may provide a new defensive strategy against MRSA, with potential advantages that may include preventing the bacteria from developing antibiotic resistance, as well as reducing the toxicity to human cells. This is because the supramolecules have low minimum inhibitory concentrations (MICs), meaning less is needed to inhibit bacterial growth, compared to some other antimicrobial agents. One possibility is to combine the supramolecules with existing antibiotics in order to realize these advantages. Before then, the researchers plan to make further improvements on the supramolecules. "We will increase the water solubility of the Kandinsky circles to further enhance their antibacterial activity," Li 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 increasing animosity towards wolves ( Canis lupus ) by livestock-keeping nomads in Mongolia and the accompanying conflicts highlight the urgent need for knowledge about the feeding behavior of wolves, since information on the feeding ecology of wolves in Mongolia is rare, especially in the mountain taiga and mountain forest steppe regions of Northern Mongolia. Those regions are characterized by a relatively high wildlife diversity and are sparsely populated by humans. To face this problem, 137 wolf scats were collected in the Khentii Mountain range in Northern Mongolia between 2008 and 2012. Almost all wolf faeces contained remnants of wild ungulates, which made up 89% of the consumed biomass. Siberian roe deer ( Capreolus pygargus ) was the most important and positively selected prey species. It was followed by red deer ( Cervus elaphus ) and wild boar ( Sus scrofa ), which was negatively selected by wolves. Wolves also fed on buffer prey species such as lagomorphs and small mammals. No evidence of domestic ungulates was found in the wolf diet. Thus, near-natural habitats with a diverse fauna of wild animals are important to limit livestock depredation. Working on a manuscript? Avoid the common mistakes Throughout its range in Northern America and Europe, the wolf ( Canis lupus ) mainly feeds on wild ungulate species (Okarma 1995 ; Jędrzejewska and Jędrzejewski 1998 ; Peterson and Ciucci 2003 ; Mattioli et al. 2011 ; Lanszki et al. 2012 ; Wagner et al. 2012 ; Barber-Meyer and Mech 2016 ; Goldthorpe 2016 ; Newsome et al. 2016 ; Bassi et al. 2020 ; Figueiredo et al. 2020 ; Trbojević et al. 2020 ). In times of primary prey shortage, wolves switch to secondary “buffer” prey (Forbes and Theberge 1996 ; Sidorovich et al. 2003 ; Barber-Meyer and Mech 2016 ). Since the domestication of livestock came along with an impoverishment of wild ungulate species, wolves are more and more forced to change their feeding habits towards prevalently available domestic prey (Boitani 1995 ; Vos 2000 ; Peterson and Ciucci 2003 ; Capitani et al. 2004 ; Ciucci et al. 2018 ). This is particularly true in most parts of Southern Europe and Asia, where the availability of natural prey is low and poor husbandry techniques with weak prevention measures are prevailing (Janeiro-Otero et al. 2020 ; Lyngdoh et al. 2020 ). The consumption of livestock has been confirmed in several study areas in Southern Europe, where it constitutes the bulk of wolf diet (Torres et al. 2015 ; Petridou et al. 2019 ; Ciucci et al. 2020 ) or the second most consumed food category (Meriggi et al. 2015 ; Imbert et al. 2016 ; Ciucci et al. 2018 ; Trbojević et al. 2020 ). However, the studies by Meriggi et al. 2015 and Imbert et al. 2016 indicate a decreasing livestock predation with simultaneously increasing wildlife consumption by wolves, once wild ungulate restoration programs got established, that came along with an increase in forested areas and the implementation of depredation prevention techniques. Moreover, a high occurrence of livestock in wolf diet was reported for all over Asia, especially in Mongolia, China, Pakistan, and Iran (Goldthorpe 2016 ; Newsome et al. 2016 ; Janeiro-Otero et al. 2020 ; Lyngdoh et al. 2020 ). On the other hand, livestock consumption lies below two percent in several parts of Central Europe, where wildlife density is high and livestock is mostly kept protected (Ansorge et al. 2006 ; Nowak et al. 2011 ; Wagner et al. 2012 ). In Mongolia, an ongoing decline of wildlife populations has been recorded during the last decades. It is caused by unsustainable hunting due to an increasing wildlife trade as a consequence of Mongolia’s transition to a free market economy (Zahler et al. 2004 ; Wingard and Zahler 2006 ; Chimed-Ochir et al. 2010 ). At the same time, the amount of livestock increased from about 25 million to more than 40 million animals with a total population of only 2.8 million inhabitants (Erdenesan 2016 ). This led to a transformation of natural habitats into pasturelands, which cover more than one-third of the Mongolian territory. Livestock depredation plays a significant role in Mongolia, since livestock serves both as a food source and as source of income for more than 50% of the Mongolian population (Mijiddorj et al. 2018 ). Up-to-date information on livestock depredation rates in Mongolia is missing, since consistent recordings stopped after the Soviet Union collapse, but it is believed that rates are increasing (Eregdenedagva et al. 2016 ). However, only few studies on the feeding ecology of wolves were performed in Mongolia and all of them state a high consumption of livestock by wolves. Those studies were carried out in protected areas of Central Mongolia: Khustai National Park (Hovens and Tungalaktuja 2005 ; Van Duyne et al. 2009 ), Ikh Nart Nature Reserve (Davie et al. 2014 ) and Bogdkhan Mountain Strictly Protected Area (Nakazawa et al. 2008 ). Nevertheless, the diversity and density of large wild ungulates in all study areas were comparatively low, regarding the high amount of free-ranging livestock grazing in and around the protected areas. The studies were conducted mainly in steppe habitats of Central Mongolia, which commonly suffer from overgrazing, except for the protected areas itself. There is no information on the feeding habits of wolves in mountain taiga and mountain forest steppe regions of Northern Mongolia, where a relatively high wildlife diversity and sparse human presence is prevailing. Therefore, this study aims to investigate the diet composition and prey selection of wolves in a near-natural ecosystem and to contribute to a better description and understanding of wolf predation in Mongolia. Wolf scats were collected in an area of about 450 km 2 within the valley of Khonin Nuga (49°05′ N, 107°17′ E, elevation 900–1600 m), Selenge Aimag, which is located in the West Khentii Mountain range approximately 130 km north of the capital Ulaanbaatar. Khonin Nuga is situated in the buffer zone of the ‘Strictly Protected Area of", "role": "user" }, { "content": "When there is a choice, wolves in Mongolia prefer to feed on wild animals rather than grazing livestock. This is the discovery by a research team from the University of Göttingen and the Senckenberg Museum Görlitz. Previous studies had shown that the diet of wolves in inland Central Asia consists mainly of grazing livestock, which could lead to increasing conflict between nomadic livestock herders and wild predatory animals like wolves. The study has been published in the journal Mammalian Biology. Around three million people live in Mongolia, making it the most sparsely populated country in the world. In addition, there are more than 40 million grazing animals. These animals are not just a source of food but also the only source of income for more than half of the population. Livestock cultivation is leading to a massive change in Mongolia's landscape: areas close to nature are increasingly being converted into pastureland: in fact, one third of the country is now used for this purpose. This inevitably leads to conflict with the indigenous wild animals, especially large predators such as the wolf. Biologist and forest scientist Nina Tiralla from the University of Göttingen studied the feeding behavior of wolves for her Master's thesis. Together with colleagues from the Senckenberg Museum, she analyzed 137 wolf droppings collected during fieldwork in Mongolia between 2008 and 2012. \"We were able to show that 89 percent of the wolves' diet consisted of wild ungulates, predominantly Siberian roe deer,\" says Tiralla. \"The remaining 11 per cent consisted of small mammals such as hares or mice.\" Even remnants of insects and berries could be detected in the feces—but there was no trace of farmed animals. \"This was surprising for us because previous studies had shown grazing animals to be the main food source for wolves,\" says Tiralla. Nina Tiralla from the University of Göttingen follows a wolf trail in Mongolia. Credit: Nina Tiralla, University of Göttingen The key difference could lie in the situation of the animals: unlike the earlier studies on Mongolian wolves, the samples examined in this study come from near-natural regions with high species diversity. \"Although there is also a supply of grazing animals here, the wolves seem to prefer wild animals such as the Siberian roe deer as prey, possibly because they are easier and less dangerous to hunt,\" the authors explain. They conclude that if wolves live in a near-natural and species-rich landscape with sufficient prey, they pose only a very low threat to grazing livestock. This could apply not only in Mongolia, but in principle also to other countries. The Chentii Mountains in the north of Mongolia. Credit: Nina Tiralla, University of Göttingen ", "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 increasing animosity towards wolves ( Canis lupus ) by livestock-keeping nomads in Mongolia and the accompanying conflicts highlight the urgent need for knowledge about the feeding behavior of wolves, since information on the feeding ecology of wolves in Mongolia is rare, especially in the mountain taiga and mountain forest steppe regions of Northern Mongolia. Those regions are characterized by a relatively high wildlife diversity and are sparsely populated by humans. To face this problem, 137 wolf scats were collected in the Khentii Mountain range in Northern Mongolia between 2008 and 2012. Almost all wolf faeces contained remnants of wild ungulates, which made up 89% of the consumed biomass. Siberian roe deer ( Capreolus pygargus ) was the most important and positively selected prey species. It was followed by red deer ( Cervus elaphus ) and wild boar ( Sus scrofa ), which was negatively selected by wolves. Wolves also fed on buffer prey species such as lagomorphs and small mammals. No evidence of domestic ungulates was found in the wolf diet. Thus, near-natural habitats with a diverse fauna of wild animals are important to limit livestock depredation. Working on a manuscript? Avoid the common mistakes Throughout its range in Northern America and Europe, the wolf ( Canis lupus ) mainly feeds on wild ungulate species (Okarma 1995 ; Jędrzejewska and Jędrzejewski 1998 ; Peterson and Ciucci 2003 ; Mattioli et al. 2011 ; Lanszki et al. 2012 ; Wagner et al. 2012 ; Barber-Meyer and Mech 2016 ; Goldthorpe 2016 ; Newsome et al. 2016 ; Bassi et al. 2020 ; Figueiredo et al. 2020 ; Trbojević et al. 2020 ). In times of primary prey shortage, wolves switch to secondary “buffer” prey (Forbes and Theberge 1996 ; Sidorovich et al. 2003 ; Barber-Meyer and Mech 2016 ). Since the domestication of livestock came along with an impoverishment of wild ungulate species, wolves are more and more forced to change their feeding habits towards prevalently available domestic prey (Boitani 1995 ; Vos 2000 ; Peterson and Ciucci 2003 ; Capitani et al. 2004 ; Ciucci et al. 2018 ). This is particularly true in most parts of Southern Europe and Asia, where the availability of natural prey is low and poor husbandry techniques with weak prevention measures are prevailing (Janeiro-Otero et al. 2020 ; Lyngdoh et al. 2020 ). The consumption of livestock has been confirmed in several study areas in Southern Europe, where it constitutes the bulk of wolf diet (Torres et al. 2015 ; Petridou et al. 2019 ; Ciucci et al. 2020 ) or the second most consumed food category (Meriggi et al. 2015 ; Imbert et al. 2016 ; Ciucci et al. 2018 ; Trbojević et al. 2020 ). However, the studies by Meriggi et al. 2015 and Imbert et al. 2016 indicate a decreasing livestock predation with simultaneously increasing wildlife consumption by wolves, once wild ungulate restoration programs got established, that came along with an increase in forested areas and the implementation of depredation prevention techniques. Moreover, a high occurrence of livestock in wolf diet was reported for all over Asia, especially in Mongolia, China, Pakistan, and Iran (Goldthorpe 2016 ; Newsome et al. 2016 ; Janeiro-Otero et al. 2020 ; Lyngdoh et al. 2020 ). On the other hand, livestock consumption lies below two percent in several parts of Central Europe, where wildlife density is high and livestock is mostly kept protected (Ansorge et al. 2006 ; Nowak et al. 2011 ; Wagner et al. 2012 ). In Mongolia, an ongoing decline of wildlife populations has been recorded during the last decades. It is caused by unsustainable hunting due to an increasing wildlife trade as a consequence of Mongolia’s transition to a free market economy (Zahler et al. 2004 ; Wingard and Zahler 2006 ; Chimed-Ochir et al. 2010 ). At the same time, the amount of livestock increased from about 25 million to more than 40 million animals with a total population of only 2.8 million inhabitants (Erdenesan 2016 ). This led to a transformation of natural habitats into pasturelands, which cover more than one-third of the Mongolian territory. Livestock depredation plays a significant role in Mongolia, since livestock serves both as a food source and as source of income for more than 50% of the Mongolian population (Mijiddorj et al. 2018 ). Up-to-date information on livestock depredation rates in Mongolia is missing, since consistent recordings stopped after the Soviet Union collapse, but it is believed that rates are increasing (Eregdenedagva et al. 2016 ). However, only few studies on the feeding ecology of wolves were performed in Mongolia and all of them state a high consumption of livestock by wolves. Those studies were carried out in protected areas of Central Mongolia: Khustai National Park (Hovens and Tungalaktuja 2005 ; Van Duyne et al. 2009 ), Ikh Nart Nature Reserve (Davie et al. 2014 ) and Bogdkhan Mountain Strictly Protected Area (Nakazawa et al. 2008 ). Nevertheless, the diversity and density of large wild ungulates in all study areas were comparatively low, regarding the high amount of free-ranging livestock grazing in and around the protected areas. The studies were conducted mainly in steppe habitats of Central Mongolia, which commonly suffer from overgrazing, except for the protected areas itself. There is no information on the feeding habits of wolves in mountain taiga and mountain forest steppe regions of Northern Mongolia, where a relatively high wildlife diversity and sparse human presence is prevailing. Therefore, this study aims to investigate the diet composition and prey selection of wolves in a near-natural ecosystem and to contribute to a better description and understanding of wolf predation in Mongolia. Wolf scats were collected in an area of about 450 km 2 within the valley of Khonin Nuga (49°05′ N, 107°17′ E, elevation 900–1600 m), Selenge Aimag, which is located in the West Khentii Mountain range approximately 130 km north of the capital Ulaanbaatar. Khonin Nuga is situated in the buffer zone of the ‘Strictly Protected Area of<|im_end|> <|im_start|>assistant When there is a choice, wolves in Mongolia prefer to feed on wild animals rather than grazing livestock. This is the discovery by a research team from the University of Göttingen and the Senckenberg Museum Görlitz. Previous studies had shown that the diet of wolves in inland Central Asia consists mainly of grazing livestock, which could lead to increasing conflict between nomadic livestock herders and wild predatory animals like wolves. The study has been published in the journal Mammalian Biology. Around three million people live in Mongolia, making it the most sparsely populated country in the world. In addition, there are more than 40 million grazing animals. These animals are not just a source of food but also the only source of income for more than half of the population. Livestock cultivation is leading to a massive change in Mongolia's landscape: areas close to nature are increasingly being converted into pastureland: in fact, one third of the country is now used for this purpose. This inevitably leads to conflict with the indigenous wild animals, especially large predators such as the wolf. Biologist and forest scientist Nina Tiralla from the University of Göttingen studied the feeding behavior of wolves for her Master's thesis. Together with colleagues from the Senckenberg Museum, she analyzed 137 wolf droppings collected during fieldwork in Mongolia between 2008 and 2012. "We were able to show that 89 percent of the wolves' diet consisted of wild ungulates, predominantly Siberian roe deer," says Tiralla. "The remaining 11 per cent consisted of small mammals such as hares or mice." Even remnants of insects and berries could be detected in the feces—but there was no trace of farmed animals. "This was surprising for us because previous studies had shown grazing animals to be the main food source for wolves," says Tiralla. Nina Tiralla from the University of Göttingen follows a wolf trail in Mongolia. Credit: Nina Tiralla, University of Göttingen The key difference could lie in the situation of the animals: unlike the earlier studies on Mongolian wolves, the samples examined in this study come from near-natural regions with high species diversity. "Although there is also a supply of grazing animals here, the wolves seem to prefer wild animals such as the Siberian roe deer as prey, possibly because they are easier and less dangerous to hunt," the authors explain. They conclude that if wolves live in a near-natural and species-rich landscape with sufficient prey, they pose only a very low threat to grazing livestock. This could apply not only in Mongolia, but in principle also to other countries. The Chentii Mountains in the north of Mongolia. Credit: Nina Tiralla, University of Göttingen <|im_end|>

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2,037

[ { "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 mechanisms driving the variations in the centennial-scale East Asian summer monsoon (EASM) remain unclear. Here, we use the δ 18 O records from adult ostracode shells to reconstruct the EASM variations over the last 3 kyrs in southwestern Japan. A common variation with a 200 yr periodicity among the Asian monsoonal regions was recognized between BC 800 and BC 100. Since then, neither a correlation between the EASM variation and solar activity or a common EASM variation through EASM regions has been identified. The evidence reveals that solar activity dominantly affected the centennial-scale EASM variations throughout Asian monsoonal regions until BC 100. Furthermore, factors other than solar activity that varied and differed in specific regions controlled the EASM intensity due to decreasing summer solar insolation in the Northern Hemisphere after BC 100. These relations indicate that the dominant factor that affects the EASM variations shifts according to the solar insolation intensity. Introduction Climates in Asia are strongly controlled by monsoons that are linked to the global climate 1 , 2 . The East Asian monsoon, which is one of the largest monsoon systems, covers the regions including China, the Korean Peninsula and Japan 3 . The East Asian monsoon is composed of southeastern winds in summer and northwestern winds in winter. The summer monsoon transports a large volume of water vapour to the continents, providing important water resources. High-resolution speleothem records from caves have clarified the variations in the East Asian summer monsoon (EASM) and their relations to other climate and sun patterns. In particular, new records from various regions over the last two decades have improved the understanding of monsoon mechanisms and the driving forces during the Quaternary 4 , 5 . Numerous EASM records, particularly those from stalagmites in Chinese caves, have indicated that both the orbital-scale and millennial-scale EASM variations are mainly due to solar insolation 4 , 5 , 6 , 7 , 8 , 9 . In addition to sun activity, CO 2 concentrations 10 , the El Niño–Southern Oscillation (ENSO) 11 , and climate in the high latitudes of the Northern Hemisphere 4 , 12 have been proposed to be strongly linked to the intensity of the Asian summer monsoon. However, due to the small number of centennial-scale EASM records compared to the number of orbital- and millennial-scale records, coherent centennial-scale EASM variations and the relationships between the centennial-scale EASM variations and solar activity remain vague. Regardless of the significance and usefulness of the δ 18 O records in stalagmites, their inconsistencies between nearby caves have been recognized 7 , 13 . Furthermore, there are controversies that the δ 18 O records in stalagmites from southern China reflect the isotopic compositions of water vapour from the upstream source region and not the EASM intensity in southern China 12 , 14 , 15 , 16 , 17 . Thus, the EASM records derived from other materials are required. Ostracoda is a microcrustacea that inhabits aquatic environments throughout the world. The calcareous shells of Ostracoda are well preserved in the bottom sediments of freshwater lakes, brackish lakes and marine environments 18 . The δ 18 O of the adult shell of a brackish species Bicornucythere bisanensis has been used as a tool to reconstruct the past summer precipitation induced by the EASM in Lake Nakaumi, southwest Japan 19 (Fig. 1 ). According to the EASM records based on this method, centennial-scale EASM variations with periodicities of 300–500 yrs and no relationship with solar activity during the last 1.8 kyrs were defined. This result disagreed with the previous observations that the EASM was strongly linked to solar activities, as found in orbital- and millennial-scale EASM variations. In the present study, we reconstructed the centennial-scale EASM intensity over the last 3 kyrs to reveal the common EASM intensity and its relation to solar activity. Figure 1 Map showing East Asia and Lake Nakaumi. ( a ) The location of Lake Nakaumi and the regions where the EASM records were recognized. The dotted arrows show the window directions. ( b ) The locations of the N2015 (star) and X (filled circle) cores. The dotted lines indicate the directions of freshwater and seawater inflows. Full size image Results and Discussion Regional effect on ostracode δ 18 O values The δ 18 O values in the N2015 core from Lake Nakaumi fluctuated between 1.0 and −1.25 (Fig. 2 , Supplementary Table S1 ). The interval over which the δ 18 O records were obtained from the N2015 core overlapped to with the interval for the X core between AD 300 and 1100 19 . The 500 yr running mean values of the ostracode δ 18 O from the N2015 core were similar to those in the X core during the interval; moreover, a common gradually decreasing trend was also found. Overall, the long-term δ 18 O values gradually declined beginning in BC 900. This trend corresponds to a decrease in salinity induced by ostracode assemblage changes 18 , suggesting that the long-term trend in the δ 18 O records of ostracode shells was caused by a regional environmental shift accompanied by a gradual decrease in salinity (Fig. 2 ). Figure 2 The δ 18 O records from ostracode shells of Bicornucythere bisanensis . The data from the N2015 core (blue) were represented by adding the records from the X core (green) 19 . The coloured thick, thin and extra-thin lines suggest 500 yr and 50 yr running mean values and measurement values, respectively. Environmental changes were derived from fossil ostracode assemblages 18 . Full size image The standardized δ 18 O values between the two cores taken from Lake Nakaumi displayed anti-correlation between AD 300 and AD 1000 (Fig. 3 ). During this period, the reconstructed EASM intensity in the N2015 core showed a positive correlation with that in the δ 18 O records from stalagmites in Wanxiang Cave, China 20 , whereas there was a negative correlation with the records from the X core 19 . These anti-correlations", "role": "user" }, { "content": "The tiny shells at the bottom of Lake Nakaumi in southwest Japan may contain the secrets of the East Asia Summer Monsoon. This rainy season is fairly predictable, ushering in air and precipitation conducive to growing crops, but—sometimes without any hint—the pattern fails. Some areas of East Asia are left without rainfall, and their crops die. Other areas are inundated with rain, and their crops and homes flood. Ostracoda shells are smaller than the white wisp a fingernail grows over a month, yet they have recorded the effects of sunshine and climate shifts for almost 500 million years. A team of researchers dug into the lake and the rich historical record in the shells to better understand why East Asian summer monsoons vary at the centennial scale, which should hold relatively steady. They published their results on March 22, 2019, in Scientific Reports. \"The mechanisms driving the variations in East Asian summer monsoons remain unclear, so we used the oxygen isotopes from adult ostracode shells to reconstruct the variations over the last 3,000 years in southwestern Japan,\" said Katsura Yamada, paper author and a professor in the department of geology and faculty of science at Shinshu University. Yamada and the team cored sections of the lake, retrieving shells from present day to 3,000 years ago. The scientists analyzed the shells, measuring a specific ratio between slightly different versions of oxygen, called isotopes. The isotope ratio can offer a glimpse into the atmosphere's precise composition thousands of years ago. A higher rate of nitrogen in the atmosphere will produce a different isotope of oxygen than times when nitrogen is less abundant. Ostracod shells were collected from the bottom of the lake Nakaumi. Credit: Katsura Yamada, Shinshu University, Japan The researchers found that the primary factor of the centennial-scale variations in the East Asia summer monsoon was solar activity, also called insolation. \"Our results and compiled data propose that insolation variation was a primary factor of the centennial-scale East Asia summer monsoon variations,\" Yamada said. \"However, dominant factors affecting the variations can shift according to the solar insolation decreases.\" During sunny periods, the insolation dominates the East Asian monsoon pattern. During cooling off periods, usually around glacial ice ages, other factors—such as wind patterns—took over as the dominant influencer. \"Our next goal is to clarify the relationship between East Asian monsoon variations and other climatic phenomena,\" Yamada said. Ostracod shell fossils. Credit: Katsura Yamada, Shinshu University, Japan This work was supported by the Japan Society for the Promotion of Science and the cooperative research program for the Center for Advanced Marine Core Research at Kochi University. Other authors include Kazuma Kohara of the department of geology and Faculty of Science at Shinshu University; Minoru Ikehara of the Center for Advanced Marine Core Research at Kochi University; and Koji Seto of the Estuary Research Center at Shimane University. ", "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 mechanisms driving the variations in the centennial-scale East Asian summer monsoon (EASM) remain unclear. Here, we use the δ 18 O records from adult ostracode shells to reconstruct the EASM variations over the last 3 kyrs in southwestern Japan. A common variation with a 200 yr periodicity among the Asian monsoonal regions was recognized between BC 800 and BC 100. Since then, neither a correlation between the EASM variation and solar activity or a common EASM variation through EASM regions has been identified. The evidence reveals that solar activity dominantly affected the centennial-scale EASM variations throughout Asian monsoonal regions until BC 100. Furthermore, factors other than solar activity that varied and differed in specific regions controlled the EASM intensity due to decreasing summer solar insolation in the Northern Hemisphere after BC 100. These relations indicate that the dominant factor that affects the EASM variations shifts according to the solar insolation intensity. Introduction Climates in Asia are strongly controlled by monsoons that are linked to the global climate 1 , 2 . The East Asian monsoon, which is one of the largest monsoon systems, covers the regions including China, the Korean Peninsula and Japan 3 . The East Asian monsoon is composed of southeastern winds in summer and northwestern winds in winter. The summer monsoon transports a large volume of water vapour to the continents, providing important water resources. High-resolution speleothem records from caves have clarified the variations in the East Asian summer monsoon (EASM) and their relations to other climate and sun patterns. In particular, new records from various regions over the last two decades have improved the understanding of monsoon mechanisms and the driving forces during the Quaternary 4 , 5 . Numerous EASM records, particularly those from stalagmites in Chinese caves, have indicated that both the orbital-scale and millennial-scale EASM variations are mainly due to solar insolation 4 , 5 , 6 , 7 , 8 , 9 . In addition to sun activity, CO 2 concentrations 10 , the El Niño–Southern Oscillation (ENSO) 11 , and climate in the high latitudes of the Northern Hemisphere 4 , 12 have been proposed to be strongly linked to the intensity of the Asian summer monsoon. However, due to the small number of centennial-scale EASM records compared to the number of orbital- and millennial-scale records, coherent centennial-scale EASM variations and the relationships between the centennial-scale EASM variations and solar activity remain vague. Regardless of the significance and usefulness of the δ 18 O records in stalagmites, their inconsistencies between nearby caves have been recognized 7 , 13 . Furthermore, there are controversies that the δ 18 O records in stalagmites from southern China reflect the isotopic compositions of water vapour from the upstream source region and not the EASM intensity in southern China 12 , 14 , 15 , 16 , 17 . Thus, the EASM records derived from other materials are required. Ostracoda is a microcrustacea that inhabits aquatic environments throughout the world. The calcareous shells of Ostracoda are well preserved in the bottom sediments of freshwater lakes, brackish lakes and marine environments 18 . The δ 18 O of the adult shell of a brackish species Bicornucythere bisanensis has been used as a tool to reconstruct the past summer precipitation induced by the EASM in Lake Nakaumi, southwest Japan 19 (Fig. 1 ). According to the EASM records based on this method, centennial-scale EASM variations with periodicities of 300–500 yrs and no relationship with solar activity during the last 1.8 kyrs were defined. This result disagreed with the previous observations that the EASM was strongly linked to solar activities, as found in orbital- and millennial-scale EASM variations. In the present study, we reconstructed the centennial-scale EASM intensity over the last 3 kyrs to reveal the common EASM intensity and its relation to solar activity. Figure 1 Map showing East Asia and Lake Nakaumi. ( a ) The location of Lake Nakaumi and the regions where the EASM records were recognized. The dotted arrows show the window directions. ( b ) The locations of the N2015 (star) and X (filled circle) cores. The dotted lines indicate the directions of freshwater and seawater inflows. Full size image Results and Discussion Regional effect on ostracode δ 18 O values The δ 18 O values in the N2015 core from Lake Nakaumi fluctuated between 1.0 and −1.25 (Fig. 2 , Supplementary Table S1 ). The interval over which the δ 18 O records were obtained from the N2015 core overlapped to with the interval for the X core between AD 300 and 1100 19 . The 500 yr running mean values of the ostracode δ 18 O from the N2015 core were similar to those in the X core during the interval; moreover, a common gradually decreasing trend was also found. Overall, the long-term δ 18 O values gradually declined beginning in BC 900. This trend corresponds to a decrease in salinity induced by ostracode assemblage changes 18 , suggesting that the long-term trend in the δ 18 O records of ostracode shells was caused by a regional environmental shift accompanied by a gradual decrease in salinity (Fig. 2 ). Figure 2 The δ 18 O records from ostracode shells of Bicornucythere bisanensis . The data from the N2015 core (blue) were represented by adding the records from the X core (green) 19 . The coloured thick, thin and extra-thin lines suggest 500 yr and 50 yr running mean values and measurement values, respectively. Environmental changes were derived from fossil ostracode assemblages 18 . Full size image The standardized δ 18 O values between the two cores taken from Lake Nakaumi displayed anti-correlation between AD 300 and AD 1000 (Fig. 3 ). During this period, the reconstructed EASM intensity in the N2015 core showed a positive correlation with that in the δ 18 O records from stalagmites in Wanxiang Cave, China 20 , whereas there was a negative correlation with the records from the X core 19 . These anti-correlations<|im_end|> <|im_start|>assistant The tiny shells at the bottom of Lake Nakaumi in southwest Japan may contain the secrets of the East Asia Summer Monsoon. This rainy season is fairly predictable, ushering in air and precipitation conducive to growing crops, but—sometimes without any hint—the pattern fails. Some areas of East Asia are left without rainfall, and their crops die. Other areas are inundated with rain, and their crops and homes flood. Ostracoda shells are smaller than the white wisp a fingernail grows over a month, yet they have recorded the effects of sunshine and climate shifts for almost 500 million years. A team of researchers dug into the lake and the rich historical record in the shells to better understand why East Asian summer monsoons vary at the centennial scale, which should hold relatively steady. They published their results on March 22, 2019, in Scientific Reports. "The mechanisms driving the variations in East Asian summer monsoons remain unclear, so we used the oxygen isotopes from adult ostracode shells to reconstruct the variations over the last 3,000 years in southwestern Japan," said Katsura Yamada, paper author and a professor in the department of geology and faculty of science at Shinshu University. Yamada and the team cored sections of the lake, retrieving shells from present day to 3,000 years ago. The scientists analyzed the shells, measuring a specific ratio between slightly different versions of oxygen, called isotopes. The isotope ratio can offer a glimpse into the atmosphere's precise composition thousands of years ago. A higher rate of nitrogen in the atmosphere will produce a different isotope of oxygen than times when nitrogen is less abundant. Ostracod shells were collected from the bottom of the lake Nakaumi. Credit: Katsura Yamada, Shinshu University, Japan The researchers found that the primary factor of the centennial-scale variations in the East Asia summer monsoon was solar activity, also called insolation. "Our results and compiled data propose that insolation variation was a primary factor of the centennial-scale East Asia summer monsoon variations," Yamada said. "However, dominant factors affecting the variations can shift according to the solar insolation decreases." During sunny periods, the insolation dominates the East Asian monsoon pattern. During cooling off periods, usually around glacial ice ages, other factors—such as wind patterns—took over as the dominant influencer. "Our next goal is to clarify the relationship between East Asian monsoon variations and other climatic phenomena," Yamada said. Ostracod shell fossils. Credit: Katsura Yamada, Shinshu University, Japan This work was supported by the Japan Society for the Promotion of Science and the cooperative research program for the Center for Advanced Marine Core Research at Kochi University. Other authors include Kazuma Kohara of the department of geology and Faculty of Science at Shinshu University; Minoru Ikehara of the Center for Advanced Marine Core Research at Kochi University; and Koji Seto of the Estuary Research Center at Shimane University. <|im_end|>

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16805, 279, 4279, 469, 53684, 21261, 323, 1202, 12976, 311, 13238, 5820, 13, 19575, 220, 16, 5135, 9204, 6460, 13936, 323, 11940, 452, 13637, 25330, 13, 320, 264, 883, 578, 3813, 315, 11940, 452, 13637, 25330, 323, 279, 13918, 1405, 279, 469, 53684, 7576, 1051, 15324, 13, 578, 59201, 38057, 1501, 279, 3321, 18445, 13, 320, 293, 883, 578, 10687, 315, 279, 452, 679, 20, 320, 12134, 8, 323, 1630, 320, 28611, 12960, 8, 36804, 13, 578, 59201, 5238, 13519, 279, 18445, 315, 80744, 323, 67329, 977, 4704, 4336, 13, 8797, 1404, 2217, 18591, 323, 36613, 26361, 2515, 389, 67094, 582, 536, 70434, 220, 972, 507, 2819, 578, 70434, 220, 972, 507, 2819, 304, 279, 452, 679, 20, 6332, 505, 11940, 452, 13637, 25330, 39388, 13148, 1990, 220, 16, 13, 15, 323, 25173, 16, 13, 914, 320, 30035, 13, 220, 17, 1174, 99371, 6771, 328, 16, 7609, 578, 10074, 927, 902, 279, 70434, 220, 972, 507, 7576, 1051, 12457, 505, 279, 452, 679, 20, 6332, 29204, 5795, 311, 449, 279, 10074, 369, 279, 1630, 6332, 1990, 9827, 220, 3101, 323, 220, 5120, 15, 220, 777, 662, 578, 220, 2636, 43438, 4401, 3152, 2819, 315, 279, 67094, 582, 536, 70434, 220, 972, 507, 505, 279, 452, 679, 20, 6332, 1051, 4528, 311, 1884, 304, 279, 1630, 6332, 2391, 279, 10074, 26, 44643, 11, 264, 4279, 27115, 44649, 9327, 574, 1101, 1766, 13, 28993, 11, 279, 1317, 9860, 70434, 220, 972, 507, 2819, 27115, 19284, 7314, 304, 18531, 220, 7467, 13, 1115, 9327, 34310, 311, 264, 18979, 304, 4371, 13797, 36572, 555, 67094, 582, 536, 439, 28111, 425, 4442, 220, 972, 1174, 23377, 430, 279, 1317, 9860, 9327, 304, 279, 70434, 220, 972, 507, 7576, 315, 67094, 582, 536, 44054, 574, 9057, 555, 264, 15481, 12434, 6541, 24895, 555, 264, 53722, 18979, 304, 4371, 13797, 320, 30035, 13, 220, 17, 7609, 19575, 220, 17, 578, 70434, 220, 972, 507, 7576, 505, 67094, 582, 536, 44054, 315, 426, 51456, 1791, 88, 19041, 15184, 276, 87778, 662, 578, 828, 505, 279, 452, 679, 20, 6332, 320, 12481, 8, 1051, 15609, 555, 7999, 279, 7576, 505, 279, 1630, 6332, 320, 13553, 8, 220, 777, 662, 578, 58919, 12314, 11, 15792, 323, 5066, 7716, 258, 5238, 4284, 220, 2636, 43438, 323, 220, 1135, 43438, 4401, 3152, 2819, 323, 19179, 2819, 11, 15947, 13, 25027, 4442, 1051, 14592, 505, 31376, 67094, 582, 536, 439, 28111, 1154, 220, 972, 662, 8797, 1404, 2217, 578, 51114, 70434, 220, 972, 507, 2819, 1990, 279, 1403, 36804, 4529, 505, 11940, 452, 13637, 25330, 12882, 7294, 46713, 23013, 1990, 9827, 220, 3101, 323, 9827, 220, 1041, 15, 320, 30035, 13, 220, 18, 7609, 12220, 420, 4261, 11, 279, 83104, 469, 53684, 21261, 304, 279, 452, 679, 20, 6332, 8710, 264, 6928, 26670, 449, 430, 304, 279, 70434, 220, 972, 507, 7576, 505, 80576, 351, 92599, 304, 72118, 11927, 526, 50492, 11, 5734, 220, 508, 1174, 20444, 1070, 574, 264, 8389, 26670, 449, 279, 7576, 505, 279, 1630, 6332, 220, 777, 662, 4314, 7294, 46713, 66434, 128257, 198, 128256, 78191, 198, 791, 13987, 44054, 520, 279, 5740, 315, 11940, 452, 13637, 25330, 304, 54085, 6457, 1253, 6782, 279, 24511, 315, 279, 6460, 13936, 19367, 3206, 67156, 13, 1115, 63857, 3280, 374, 14470, 45207, 11, 64260, 287, 304, 3805, 323, 61050, 95561, 311, 7982, 31665, 11, 719, 2345, 57753, 2085, 904, 13310, 22416, 5497, 14865, 13, 4427, 5789, 315, 6460, 13936, 527, 2163, 2085, 53958, 11, 323, 872, 31665, 2815, 13, 7089, 5789, 527, 92629, 660, 449, 11422, 11, 323, 872, 31665, 323, 10632, 18197, 13, 507, 496, 582, 14320, 44054, 527, 9333, 1109, 279, 4251, 289, 13391, 264, 39827, 944, 607, 28815, 927, 264, 2305, 11, 3686, 814, 617, 12715, 279, 6372, 315, 52495, 323, 10182, 29735, 369, 4661, 220, 2636, 3610, 1667, 13, 362, 2128, 315, 12074, 44120, 1139, 279, 22553, 323, 279, 9257, 13970, 3335, 304, 279, 44054, 311, 2731, 3619, 3249, 6460, 14875, 7474, 1647, 708, 2439, 13592, 520, 279, 2960, 32331, 5569, 11, 902, 1288, 3412, 12309, 24981, 13, 2435, 4756, 872, 3135, 389, 5587, 220, 1313, 11, 220, 679, 24, 11, 304, 38130, 29140, 13, 330, 791, 24717, 10043, 279, 27339, 304, 6460, 14875, 7474, 1647, 708, 2439, 7293, 25420, 11, 779, 584, 1511, 279, 24463, 69551, 19031, 505, 6822, 67094, 582, 536, 44054, 311, 44928, 279, 27339, 927, 279, 1566, 220, 18, 11, 931, 1667, 304, 99911, 6457, 1359, 1071, 735, 1900, 5808, 34654, 2649, 11, 5684, 3229, 323, 264, 14561, 304, 279, 9476, 315, 3980, 2508, 323, 22291, 315, 8198, 520, 35549, 939, 84, 3907, 13, 34654, 2649, 323, 279, 2128, 272, 3093, 14491, 315, 279, 22553, 11, 49324, 44054, 505, 3118, 1938, 311, 220, 18, 11, 931, 1667, 4227, 13, 578, 14248, 30239, 279, 44054, 11, 30090, 264, 3230, 11595, 1990, 10284, 2204, 11028, 315, 24463, 11, 2663, 69551, 19031, 13, 578, 374, 51782, 11595, 649, 3085, 264, 40942, 1139, 279, 16975, 596, 24473, 18528, 9214, 315, 1667, 4227, 13, 362, 5190, 4478, 315, 47503, 304, 279, 16975, 690, 8356, 264, 2204, 374, 51782, 315, 24463, 1109, 3115, 994, 47503, 374, 2753, 44611, 13, 507, 496, 582, 347, 44054, 1051, 14890, 505, 279, 5740, 315, 279, 22553, 452, 13637, 25330, 13, 16666, 25, 735, 1900, 5808, 34654, 2649, 11, 35549, 939, 84, 3907, 11, 6457, 578, 12074, 1766, 430, 279, 6156, 8331, 315, 279, 2960, 32331, 13230, 27339, 304, 279, 6460, 13936, 7474, 1647, 67156, 574, 13238, 5820, 11, 1101, 2663, 1672, 36062, 13, 330, 8140, 3135, 323, 20276, 828, 30714, 430, 1672, 36062, 23851, 574, 264, 6156, 8331, 315, 279, 2960, 32331, 13230, 6460, 13936, 7474, 1647, 67156, 27339, 1359, 34654, 2649, 1071, 13, 330, 11458, 11, 25462, 9547, 28987, 279, 27339, 649, 6541, 4184, 311, 279, 13238, 1672, 36062, 43154, 1210, 12220, 40798, 18852, 11, 279, 1672, 36062, 83978, 279, 6460, 14875, 1647, 67156, 5497, 13, 12220, 28015, 1022, 18852, 11, 6118, 2212, 2840, 33211, 10054, 17051, 11, 1023, 9547, 2345, 21470, 439, 10160, 12912, 50617, 564, 927, 439, 279, 25462, 6791, 20099, 13, 330, 8140, 1828, 5915, 374, 311, 38263, 279, 5133, 1990, 6460, 14875, 1647, 67156, 27339, 323, 1023, 11323, 780, 44247, 1359, 34654, 2649, 1071, 13, 507, 496, 582, 347, 12811, 81473, 13, 16666, 25, 735, 1900, 5808, 34654, 2649, 11, 35549, 939, 84, 3907, 11, 6457, 1115, 990, 574, 7396, 555, 279, 6457, 13581, 369, 279, 57204, 315, 10170, 323, 279, 48566, 3495, 2068, 369, 279, 5955, 369, 21844, 23820, 9708, 8483, 520, 40593, 72, 3907, 13, 7089, 12283, 2997, 36074, 13722, 34975, 5169, 315, 279, 9476, 315, 3980, 2508, 323, 42904, 315, 10170, 520, 35549, 939, 84, 3907, 26, 30893, 84, 358, 71717, 5169, 315, 279, 5955, 369, 21844, 23820, 9708, 8483, 520, 40593, 72, 3907, 26, 323, 735, 28000, 2638, 78, 315, 279, 9589, 3620, 8483, 5955, 520, 54585, 2194, 3907, 13, 220, 128257, 198 ]

2,004

[ { "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 Circulating tumor cells (CTCs) carry a wealth of information on primary and metastatic tumors critical for precise cancer detection, monitoring, and treatment. Numerous microfluidic platforms have been developed in the past few years to capture these rare cells in patient bloodstream for deciphering the critical information needed. However, the practical need for a high-quality method of CTC isolation remains to be met. Herein, we demonstrate a novel multi-flow microfluidic device that is able to sensitively provide high purity (>87%) of separation outcome without labeling. Our device is constructed and configured based on the phenomenal effect of size-dependent inertial migration. The recovery rate of >93% has been achieved using spiked cancer cells at clinically relevant concentrations (10 cells per 5 mL and above). We have also successfully detected CTCs from 6 out of 8 non-small-cell-lung-cancer (NSCLC) patients, while none for 5 healthy control subjects. With these results, we envision our approach is a promising alternative for reliable CTC capture, and thus for facilitating the progress of extracting information from CTCs to personalize treatment strategies for solid tumor patients. Introduction Isolation of viable and intact circulating tumor cells (CTCs) is critical for implementing liquid biopsy which has shown their strong clinical implications as an alternative to tissue biopsy 1 , 2 . These cells serve as promising biomarkers for cancer prognostics, monitoring treatment response, drug screening, and personalized medicine 3 , 4 , 5 . Liquid biopsy continuously receives emphasis due to a number of advantages over traditional tissue biopsy, including readily accessibility and the potential for dynamic monitoring of cancer progression 6 , 7 . It is unrealistic to implement conventional invasive biopsy frequently and for some cancers, such as brain cancer and lung cancer, they are extremely difficult to biopsy due to the tumor location 6 , 8 . CTCs, on the other hand, can be easily accessed since they are tumor cells shed from primary and/or distant sites and circulate in the bloodstream 9 . These cells carry a wealth of information about specific mutations the tumor tissue may possess, allowing for targeted therapy approaches. Mechanisms of treatment resistance can also be investigated through the analysis of CTCs 10 . However, isolation of CTCs from blood is nontrivial, chiefly attributed to their extreme rarity as compared to surrounding blood cells 9 , 11 . Many technologies have been developed in the past decade to tackle the challenge of capturing CTCs. Although flow cytometry is capable of CTC isolation, its throughput is too low to be practical 12 . CellSearch TM system (Menarini Silicon Biosystems, Italy) is the only FDA-approved commercial product for CTC enumeration 2 . Nevertheless, its wide adoption in clinical settings is hindered by its shortcomings such as high cost, manual process, and false-positive/false-negative 13 . Recently, the burgeoning development of microfluidic technology has jump-started the search of alternative solutions for a greater CTC isolation. Numerous microfluidic platforms have been proposed to address the challenge. These systems can be roughly classified into two groups 14 . One major group is affinity-based methods that utilize surface markers, such as EpCAM, to distinguish CTCs from their surrounding blood cells 2 , 15 , 16 . While these methods show very good specificity, they are hindered from false-negatives due to downregulation of the expression of surface markers on some CTCs which are undergoing epithelial–mesenchymal-transition (EMT) 2 . The other group differentiates CTCs from blood cells based on the physical properties of CTCs, mainly the size and deformability differences of CTCs and white blood cells (WBCs) 2 , 14 . Due to the independence of surface markers, technologies of this group are deemed as critical complementary methods to affinity-based approaches for improved CTC isolation. These size-based, and thus label-free methods include acoustic and electrophoresis platforms 17 , 18 , hydrodynamic and cross-flow filtration 19 , 20 , micropore and micropost trapping 21 , 22 , 23 , deterministic lateral displacement (DLD) 24 , 25 , and inertial focusing systems 26 , 27 , 28 , 29 (including viscoelasticity aided method 30 ). Our recent work has also successfully demonstrated the separation of CTCs directly from patient whole blood based on cell size 31 . While many of these emerging systems have been tested using patient samples, they share a common shortcoming: their purity remains to be significantly improved 15 . High purity is in strong demand for CTC enumeration, molecular characterization, and functional assays with less background intervention from WBCs 9 . In this work, we report on a novel multi-flow microfluidic (MFM) system for the separation of CTCs with high purity. The microchannel takes advantage of inertial migration of cells 32 . The lateral migration of cells strongly depends on cell size in our microchannel, and label-free separation of CTCs from WBCs is thus achieved without sophisticated sample preparation steps and external controls required by affinity-based and active approaches. We conducted a thorough investigation on the effect of flow rate and flow rate ratio of sample and buffer flows on the channel performance prior to the tests of using clinical samples from non-small-cell-lung-cancer (NSCLC) patients. Our results with spiked samples show superb separation efficiency (>99%) and purity (>87%). We recovered >93% of spiked cancer cells for a concentration of 50 cells or above per 5 mL diluted blood and >83% for a concentration of 10 cells per 5 mL diluted blood. Samples of 8 NSCLC patients and of 5 healthy donors were processed through our microchannel. We isolated CTCs from samples of 6 patients with a maximum of 78 CTCs per mL blood and no CTCs were found in healthy control samples. We demonstrate a simple protocol as a promising alternative to existing methods for CTC isolation with high fidelity. Results and discussion Design and working principle Our separation microsystem is built upon the inertial migration of cells flowing in microchannels. From our earlier work 32 , cells are subjected to inertial forces that drive them toward equilibrium positions in two stages. First, cells migrate rapidly toward sidewalls of", "role": "user" }, { "content": "Researchers at the University of Illinois at Chicago and Queensland University of Technology of Australia, have developed a device that can isolate individual cancer cells from patient blood samples. The microfluidic device works by separating the various cell types found in blood by their size. The device may one day enable rapid, cheap liquid biopsies to help detect cancer and develop targeted treatment plans. The findings are reported in the journal Microsystems & Nanoengineering. \"This new microfluidics chip lets us separate cancer cells from whole blood or minimally-diluted blood,\" said Ian Papautsky, the Richard and Loan Hill Professor of Bioengineering in the UIC College of Engineering and corresponding author on the paper. \"While devices for detecting cancer cells circulating in the blood are becoming available, most are relatively expensive and are out of reach of many research labs or hospitals. Our device is cheap, and doesn't require much specimen preparation or dilution, making it fast and easy to use.\" The ability to successfully isolate cancer cells is a crucial step in enabling liquid biopsy where cancer could be detected through a simple blood draw. This would eliminate the discomfort and cost of tissue biopsies which use needles or surgical procedures as part of cancer diagnosis. Liquid biopsy could also be useful in tracking the efficacy of chemotherapy over the course of time, and for detecting cancer in organs difficult to access through traditional biopsy techniques, including the brain and lungs. However, isolating circulating tumor cells from the blood is no easy task, since they are present in extremely small quantities. For many cancers, circulating cells are present at levels close to one per 1 billion blood cells. \"A 7.5-milliliter tube of blood, which is a typical volume for a blood draw, might have ten cancer cells and 35-40 billion blood cells,\" said Papautsky. \"So we are really looking for a needle in a haystack.\" Microfluidic technologies present an alternative to traditional methods of cell detection in fluids. These devices either use markers to capture targeted cells as they float by, or they take advantage of the physical properties of targeted cells—mainly size—to separate them from other cells present in fluids. Cancer cell separating microfluidic device. Credit: Ian Papautsky Papautsky and his colleagues developed a device that uses size to separate tumor cells from blood. \"Using size differences to separate cell types within a fluid is much easier than affinity separation which uses 'sticky' tags that capture the right cell type as it goes by,\" said Papautsky. \"Affinity separation also requires a lot of advanced purification work which size separation techniques don't need.\" The device Papautsky and his colleagues developed capitalizes on the phenomena of inertial migration and shear-induced diffusion to separate cancer cells from blood as it passes through 'microchannels' formed in plastic. \"We are still investigating the physics behind these phenomena and their interplay in the device, but it separates cells based on tiny differences in size which dictate the cell's attraction to various locations within a column of liquid as it moves.\" Papautsky and his colleagues 'spiked' 5-milliliter samples of healthy blood with 10 small-cell-lung cancer cells and then ran the blood through their device. They were able to recover 93 percent of the cancer cells using the microfluidic device. Previously-developed microfluidics devices designed to separate circulating tumor cells from blood had recovery rates between 50 percent and 80 percent. When they ran eight samples of blood taken from patients diagnosed with non-small-cell lung cancer, they were able to separate cancer cells from six of the samples using the microfluidic device. In addition to the high efficiency and reliability of the devices, Papautsky said the fact that little dilution is needed is another plus. \"Without having to dilute, the time to run samples is shorter and so is preparation time.\" They used whole blood in their experiments as well as blood diluted just three times, which is low compared to other protocols for cell separation using devices based on inertial migration. Papautsky and colleague Dr. Alicia Hubert, assistant professor of surgery in the UIC College of Medicine, recently received a $125,000, one-year grant from the University of Illinois Cancer Center to develop a microfluidics device that can separate out circulating tumor cells as well as detect DNA from cancer cells in blood from lung cancer patients. They will use blood from patients being seen at the University of Illinois Cancer Center to test the efficacy of their prototype device. ", "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 Circulating tumor cells (CTCs) carry a wealth of information on primary and metastatic tumors critical for precise cancer detection, monitoring, and treatment. Numerous microfluidic platforms have been developed in the past few years to capture these rare cells in patient bloodstream for deciphering the critical information needed. However, the practical need for a high-quality method of CTC isolation remains to be met. Herein, we demonstrate a novel multi-flow microfluidic device that is able to sensitively provide high purity (>87%) of separation outcome without labeling. Our device is constructed and configured based on the phenomenal effect of size-dependent inertial migration. The recovery rate of >93% has been achieved using spiked cancer cells at clinically relevant concentrations (10 cells per 5 mL and above). We have also successfully detected CTCs from 6 out of 8 non-small-cell-lung-cancer (NSCLC) patients, while none for 5 healthy control subjects. With these results, we envision our approach is a promising alternative for reliable CTC capture, and thus for facilitating the progress of extracting information from CTCs to personalize treatment strategies for solid tumor patients. Introduction Isolation of viable and intact circulating tumor cells (CTCs) is critical for implementing liquid biopsy which has shown their strong clinical implications as an alternative to tissue biopsy 1 , 2 . These cells serve as promising biomarkers for cancer prognostics, monitoring treatment response, drug screening, and personalized medicine 3 , 4 , 5 . Liquid biopsy continuously receives emphasis due to a number of advantages over traditional tissue biopsy, including readily accessibility and the potential for dynamic monitoring of cancer progression 6 , 7 . It is unrealistic to implement conventional invasive biopsy frequently and for some cancers, such as brain cancer and lung cancer, they are extremely difficult to biopsy due to the tumor location 6 , 8 . CTCs, on the other hand, can be easily accessed since they are tumor cells shed from primary and/or distant sites and circulate in the bloodstream 9 . These cells carry a wealth of information about specific mutations the tumor tissue may possess, allowing for targeted therapy approaches. Mechanisms of treatment resistance can also be investigated through the analysis of CTCs 10 . However, isolation of CTCs from blood is nontrivial, chiefly attributed to their extreme rarity as compared to surrounding blood cells 9 , 11 . Many technologies have been developed in the past decade to tackle the challenge of capturing CTCs. Although flow cytometry is capable of CTC isolation, its throughput is too low to be practical 12 . CellSearch TM system (Menarini Silicon Biosystems, Italy) is the only FDA-approved commercial product for CTC enumeration 2 . Nevertheless, its wide adoption in clinical settings is hindered by its shortcomings such as high cost, manual process, and false-positive/false-negative 13 . Recently, the burgeoning development of microfluidic technology has jump-started the search of alternative solutions for a greater CTC isolation. Numerous microfluidic platforms have been proposed to address the challenge. These systems can be roughly classified into two groups 14 . One major group is affinity-based methods that utilize surface markers, such as EpCAM, to distinguish CTCs from their surrounding blood cells 2 , 15 , 16 . While these methods show very good specificity, they are hindered from false-negatives due to downregulation of the expression of surface markers on some CTCs which are undergoing epithelial–mesenchymal-transition (EMT) 2 . The other group differentiates CTCs from blood cells based on the physical properties of CTCs, mainly the size and deformability differences of CTCs and white blood cells (WBCs) 2 , 14 . Due to the independence of surface markers, technologies of this group are deemed as critical complementary methods to affinity-based approaches for improved CTC isolation. These size-based, and thus label-free methods include acoustic and electrophoresis platforms 17 , 18 , hydrodynamic and cross-flow filtration 19 , 20 , micropore and micropost trapping 21 , 22 , 23 , deterministic lateral displacement (DLD) 24 , 25 , and inertial focusing systems 26 , 27 , 28 , 29 (including viscoelasticity aided method 30 ). Our recent work has also successfully demonstrated the separation of CTCs directly from patient whole blood based on cell size 31 . While many of these emerging systems have been tested using patient samples, they share a common shortcoming: their purity remains to be significantly improved 15 . High purity is in strong demand for CTC enumeration, molecular characterization, and functional assays with less background intervention from WBCs 9 . In this work, we report on a novel multi-flow microfluidic (MFM) system for the separation of CTCs with high purity. The microchannel takes advantage of inertial migration of cells 32 . The lateral migration of cells strongly depends on cell size in our microchannel, and label-free separation of CTCs from WBCs is thus achieved without sophisticated sample preparation steps and external controls required by affinity-based and active approaches. We conducted a thorough investigation on the effect of flow rate and flow rate ratio of sample and buffer flows on the channel performance prior to the tests of using clinical samples from non-small-cell-lung-cancer (NSCLC) patients. Our results with spiked samples show superb separation efficiency (>99%) and purity (>87%). We recovered >93% of spiked cancer cells for a concentration of 50 cells or above per 5 mL diluted blood and >83% for a concentration of 10 cells per 5 mL diluted blood. Samples of 8 NSCLC patients and of 5 healthy donors were processed through our microchannel. We isolated CTCs from samples of 6 patients with a maximum of 78 CTCs per mL blood and no CTCs were found in healthy control samples. We demonstrate a simple protocol as a promising alternative to existing methods for CTC isolation with high fidelity. Results and discussion Design and working principle Our separation microsystem is built upon the inertial migration of cells flowing in microchannels. From our earlier work 32 , cells are subjected to inertial forces that drive them toward equilibrium positions in two stages. First, cells migrate rapidly toward sidewalls of<|im_end|> <|im_start|>assistant Researchers at the University of Illinois at Chicago and Queensland University of Technology of Australia, have developed a device that can isolate individual cancer cells from patient blood samples. The microfluidic device works by separating the various cell types found in blood by their size. The device may one day enable rapid, cheap liquid biopsies to help detect cancer and develop targeted treatment plans. The findings are reported in the journal Microsystems & Nanoengineering. "This new microfluidics chip lets us separate cancer cells from whole blood or minimally-diluted blood," said Ian Papautsky, the Richard and Loan Hill Professor of Bioengineering in the UIC College of Engineering and corresponding author on the paper. "While devices for detecting cancer cells circulating in the blood are becoming available, most are relatively expensive and are out of reach of many research labs or hospitals. Our device is cheap, and doesn't require much specimen preparation or dilution, making it fast and easy to use." The ability to successfully isolate cancer cells is a crucial step in enabling liquid biopsy where cancer could be detected through a simple blood draw. This would eliminate the discomfort and cost of tissue biopsies which use needles or surgical procedures as part of cancer diagnosis. Liquid biopsy could also be useful in tracking the efficacy of chemotherapy over the course of time, and for detecting cancer in organs difficult to access through traditional biopsy techniques, including the brain and lungs. However, isolating circulating tumor cells from the blood is no easy task, since they are present in extremely small quantities. For many cancers, circulating cells are present at levels close to one per 1 billion blood cells. "A 7.5-milliliter tube of blood, which is a typical volume for a blood draw, might have ten cancer cells and 35-40 billion blood cells," said Papautsky. "So we are really looking for a needle in a haystack." Microfluidic technologies present an alternative to traditional methods of cell detection in fluids. These devices either use markers to capture targeted cells as they float by, or they take advantage of the physical properties of targeted cells—mainly size—to separate them from other cells present in fluids. Cancer cell separating microfluidic device. Credit: Ian Papautsky Papautsky and his colleagues developed a device that uses size to separate tumor cells from blood. "Using size differences to separate cell types within a fluid is much easier than affinity separation which uses 'sticky' tags that capture the right cell type as it goes by," said Papautsky. "Affinity separation also requires a lot of advanced purification work which size separation techniques don't need." The device Papautsky and his colleagues developed capitalizes on the phenomena of inertial migration and shear-induced diffusion to separate cancer cells from blood as it passes through 'microchannels' formed in plastic. "We are still investigating the physics behind these phenomena and their interplay in the device, but it separates cells based on tiny differences in size which dictate the cell's attraction to various locations within a column of liquid as it moves." Papautsky and his colleagues 'spiked' 5-milliliter samples of healthy blood with 10 small-cell-lung cancer cells and then ran the blood through their device. They were able to recover 93 percent of the cancer cells using the microfluidic device. Previously-developed microfluidics devices designed to separate circulating tumor cells from blood had recovery rates between 50 percent and 80 percent. When they ran eight samples of blood taken from patients diagnosed with non-small-cell lung cancer, they were able to separate cancer cells from six of the samples using the microfluidic device. In addition to the high efficiency and reliability of the devices, Papautsky said the fact that little dilution is needed is another plus. "Without having to dilute, the time to run samples is shorter and so is preparation time." They used whole blood in their experiments as well as blood diluted just three times, which is low compared to other protocols for cell separation using devices based on inertial migration. Papautsky and colleague Dr. Alicia Hubert, assistant professor of surgery in the UIC College of Medicine, recently received a $125,000, one-year grant from the University of Illinois Cancer Center to develop a microfluidics device that can separate out circulating tumor cells as well as detect DNA from cancer cells in blood from lung cancer patients. They will use blood from patients being seen at the University of Illinois Cancer Center to test the efficacy of their prototype device. <|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 Helium is the second-most abundant element in the Universe after hydrogen and is one of the main constituents of gas-giant planets in our Solar System. Early theoretical models predicted helium to be among the most readily detectable species in the atmospheres of exoplanets, especially in extended and escaping atmospheres 1 . Searches for helium, however, have hitherto been unsuccessful 2 . Here we report observations of helium on an exoplanet, at a confidence level of 4.5 standard deviations. We measured the near-infrared transmission spectrum of the warm gas giant 3 WASP-107b and identified the narrow absorption feature of excited metastable helium at 10,833 angstroms. The amplitude of the feature, in transit depth, is 0.049 ± 0.011 per cent in a bandpass of 98 angstroms, which is more than five times greater than what could be caused by nominal stellar chromospheric activity. This large absorption signal suggests that WASP-107b has an extended atmosphere that is eroding at a total rate of 10 10 to 3 × 10 11 grams per second (0.1–4 per cent of its total mass per billion years), and may have a comet-like tail of gas shaped by radiation pressure. Main WASP-107b is one of the lowest-density planets known, with a radius (0.94 ± 0.02) R J similar to that of Jupiter but a much lower mass 3 , (0.12 ± 0.01) M J ; R J and M J are the radius and mass of Jupiter, respectively. It orbits an active K6 dwarf every 5.7 days at a distance of 0.055 ± 0.001 astronomical units. On 31 May 2017, we observed a primary transit of WASP-107b with Wide Field Camera 3 (WFC3), which is onboard the Hubble Space Telescope (HST). Our observations lasted 7 h and we acquired 84 time-series spectra with the G102 grism, which covers the 8,000–11,000 Å wavelength range. Further details about the observations and data reduction can be found in Methods. Each spectrum was integrated along the wavelength axis to first produce a ‘white’ light curve (Extended Data Fig. 1 ). In addition to the planetary transit signal, the resulting time series was affected by instrumental systematic errors caused by electron trapping in the WFC3 detector 5 . We fitted the white-light curve with a planetary transit model 4 multiplied by a linear baseline trend and a physically motivated WFC3 systematics model 5 . For the planetary transit model, we allowed the planet-to-star radius ratio ( R p /R s ) and the mid-transit time ( t 0 ) to vary as a free parameter, while holding the ratio of the orbital distance to the stellar radius ( a/R s ), the inclination ( i ), the eccentricity ( e ) and the period ( P ) fixed to previously determined values 6 , 7 . We assumed a quadratic limb-darkening profile for the star, holding the coefficients fixed to values determined from a model stellar spectrum 8 . Further details about this fit are provided in Methods. The results of the fit are reported in Extended Data Table 1 and Extended Data Fig. 1 . Two sets of spectroscopic light curves were constructed by summing each spectrum into broad- and narrowband bins. The first set consisted of 9 broadband channels spanning the 8,770–11,360 Å wavelength range, and the second set comprised 20 overlapping, narrowband channels spanning the 10,580–11,070 Å wavelength range. The narrowband channels covered the helium absorption triplet at 10,833 Å (vacuum wavelength; the air wavelength of this line is 10,830 Å). The widths of the broadband and narrowband channels were 294 Å (12-pixel columns) and 98 Å (4-pixel columns), respectively. We fitted both sets of spectroscopic light curves using the approach described above for the white-light curve. However, for the planetary transit signals, we only allowed R p /R s to vary as a free parameter, while holding t 0 , a/R s , i , e and P fixed to the values reported in Extended Data Table 1 . We fixed the limb-darkening coefficients in a similar way to the white-light curve fit. Additional details of the fitting procedure are given in Methods. The inferred values for the transit depth, ( R p /R s ) 2 , in each wavelength channel are shown in Fig. 1 and Extended Data Table 2 . These results constitute the atmospheric transmission spectrum. Fig. 1: Combined near-infrared transmission spectrum for WASP-107b with the helium absorption feature. a , Data are plotted on a linear scale. Points, with 1 σ error bars, are from a previous study (black) 9 and this work (light and dark blue), both corrected for stellar activity (see Methods ). The solid purple line is the best fit obtained with a lower-atmosphere retrieval model based on the Markov chain Monte Carlo technique, and the pink-shaded area encompasses 99.7% of the Markov chain Monte Carlo samples. The gold line is the best-fitting absorption profile for the 10,830-Å helium line, obtained by our 1D escaping-atmosphere model. b , Same as a , on a logarithmic scale. The dashed blue line shows the Roche radius. Full size image The broadband transmission spectrum is consistent with a previous transmission spectrum for WASP-107b, obtained using the WFC3 G141 grism, which covers the 11,000–16,000 Å wavelength range 9 . The latter exhibits a muted water absorption band centred at 14,000 Å, with an otherwise flat spectrum implying an opaque cloud deck. After applying a correction for stellar activity variations between the G102 and G141 observation epochs (see Methods ), the G102 spectrum aligns with the cloud deck level inferred from the G141 spectrum (Fig. 1 ). The helium triplet has an expected width of approximately 3 Å, whereas the resolution of the G102 grism is 67 Å (about 3 pixels) 10 at 10,400 Å. Therefore, to make a finely sampled transmission spectrum, we shifted each of the 20 narrowband channels by one pixel with respect to the adjacent channel along the wavelength axis. The narrowband transmission spectrum peaked at the channel most closely centred", "role": "user" }, { "content": "Astronomers have detected helium in the atmosphere of a planet that orbits a star far beyond our solar system for the very first time. An international team of researchers, led by Jessica Spake from the University of Exeter, discovered evidence of the inert gas on 'super-Neptune' exoplanet WASP-107b, found 200 light years from Earth and in the constellation of Virgo. The pivotal breakthrough, made from observations of the exoplanet using the Hubble Space Telescope, revealed an abundance of helium in the upper atmosphere of the exoplanet, which was only discovered in 2017. The strength of the helium signal detected was so large that scientists believe the planet's upper atmosphere extends tens of thousands of kilometres into space. Helium is the second most common element in the universe and it has long-since been predicted to be one of the most readily-detectable gases on giant exoplanets. However, this pioneering new research is the first time that the gas has been successfully found. Now, the research team believe that the ground-breaking study could pave the way for scientists to discover more atmospheres around Earth-sized exoplanets across the galaxy. The research is published in the leading scientific journal, Nature, on May 3, 2018. Jessica Spake, part of Exeter's Physics and Astronomy department said: \"We hope to use this technique with the upcoming James Webb Space Telescope, for example, to learn what kind of planets have large envelopes of hydrogen and helium, and how long planets can hold on to their atmospheres. By measuring infrared light, we can see further out into space than if we were using ultraviolet light.\" WASP-107b is a very low-density planet similar in size to Jupiter, but with only 12 per cent of its mass. Orbiting its host star every six days, it has one of the coolest atmospheres of any of the exoplanets discovered, although at 500 C is still radically hotter that Earth. By analysing the spectrum of light passing through the upper part of the exoplanet's atmosphere, the researchers were able to detect the presence of helium in an excited state. The significant strength of the signal measured exploited a new technique that doesn't rely on ultraviolet measurements which have historically been used to study upper exoplanet atmospheres. The team believe this new technique, which uses infrared light, could open up new paths to exploring the atmospheres of more Earth-sized exoplanets found in the further reaches of the universe. Tom Evans, a co-author also from the University of Exeter added: \"The helium we detected extends far out to space as a tenuous cloud surrounding the planet. If smaller, Earth-sized planets have similar helium clouds, this new technique offers an exciting means to study their upper atmospheres in the very near future..\" Helium was first detected as an unknown yellow spectral line signature in sunlight in 1868. Devon-based astronomer Norman Lockyer was the first to propose this line was due to a new element, and named it after the Greek Titan of the Sun, Helios. It has since been discovered to be one of the main constituents of the planets Jupiter and Saturn in our Solar System. ", "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 Helium is the second-most abundant element in the Universe after hydrogen and is one of the main constituents of gas-giant planets in our Solar System. Early theoretical models predicted helium to be among the most readily detectable species in the atmospheres of exoplanets, especially in extended and escaping atmospheres 1 . Searches for helium, however, have hitherto been unsuccessful 2 . Here we report observations of helium on an exoplanet, at a confidence level of 4.5 standard deviations. We measured the near-infrared transmission spectrum of the warm gas giant 3 WASP-107b and identified the narrow absorption feature of excited metastable helium at 10,833 angstroms. The amplitude of the feature, in transit depth, is 0.049 ± 0.011 per cent in a bandpass of 98 angstroms, which is more than five times greater than what could be caused by nominal stellar chromospheric activity. This large absorption signal suggests that WASP-107b has an extended atmosphere that is eroding at a total rate of 10 10 to 3 × 10 11 grams per second (0.1–4 per cent of its total mass per billion years), and may have a comet-like tail of gas shaped by radiation pressure. Main WASP-107b is one of the lowest-density planets known, with a radius (0.94 ± 0.02) R J similar to that of Jupiter but a much lower mass 3 , (0.12 ± 0.01) M J ; R J and M J are the radius and mass of Jupiter, respectively. It orbits an active K6 dwarf every 5.7 days at a distance of 0.055 ± 0.001 astronomical units. On 31 May 2017, we observed a primary transit of WASP-107b with Wide Field Camera 3 (WFC3), which is onboard the Hubble Space Telescope (HST). Our observations lasted 7 h and we acquired 84 time-series spectra with the G102 grism, which covers the 8,000–11,000 Å wavelength range. Further details about the observations and data reduction can be found in Methods. Each spectrum was integrated along the wavelength axis to first produce a ‘white’ light curve (Extended Data Fig. 1 ). In addition to the planetary transit signal, the resulting time series was affected by instrumental systematic errors caused by electron trapping in the WFC3 detector 5 . We fitted the white-light curve with a planetary transit model 4 multiplied by a linear baseline trend and a physically motivated WFC3 systematics model 5 . For the planetary transit model, we allowed the planet-to-star radius ratio ( R p /R s ) and the mid-transit time ( t 0 ) to vary as a free parameter, while holding the ratio of the orbital distance to the stellar radius ( a/R s ), the inclination ( i ), the eccentricity ( e ) and the period ( P ) fixed to previously determined values 6 , 7 . We assumed a quadratic limb-darkening profile for the star, holding the coefficients fixed to values determined from a model stellar spectrum 8 . Further details about this fit are provided in Methods. The results of the fit are reported in Extended Data Table 1 and Extended Data Fig. 1 . Two sets of spectroscopic light curves were constructed by summing each spectrum into broad- and narrowband bins. The first set consisted of 9 broadband channels spanning the 8,770–11,360 Å wavelength range, and the second set comprised 20 overlapping, narrowband channels spanning the 10,580–11,070 Å wavelength range. The narrowband channels covered the helium absorption triplet at 10,833 Å (vacuum wavelength; the air wavelength of this line is 10,830 Å). The widths of the broadband and narrowband channels were 294 Å (12-pixel columns) and 98 Å (4-pixel columns), respectively. We fitted both sets of spectroscopic light curves using the approach described above for the white-light curve. However, for the planetary transit signals, we only allowed R p /R s to vary as a free parameter, while holding t 0 , a/R s , i , e and P fixed to the values reported in Extended Data Table 1 . We fixed the limb-darkening coefficients in a similar way to the white-light curve fit. Additional details of the fitting procedure are given in Methods. The inferred values for the transit depth, ( R p /R s ) 2 , in each wavelength channel are shown in Fig. 1 and Extended Data Table 2 . These results constitute the atmospheric transmission spectrum. Fig. 1: Combined near-infrared transmission spectrum for WASP-107b with the helium absorption feature. a , Data are plotted on a linear scale. Points, with 1 σ error bars, are from a previous study (black) 9 and this work (light and dark blue), both corrected for stellar activity (see Methods ). The solid purple line is the best fit obtained with a lower-atmosphere retrieval model based on the Markov chain Monte Carlo technique, and the pink-shaded area encompasses 99.7% of the Markov chain Monte Carlo samples. The gold line is the best-fitting absorption profile for the 10,830-Å helium line, obtained by our 1D escaping-atmosphere model. b , Same as a , on a logarithmic scale. The dashed blue line shows the Roche radius. Full size image The broadband transmission spectrum is consistent with a previous transmission spectrum for WASP-107b, obtained using the WFC3 G141 grism, which covers the 11,000–16,000 Å wavelength range 9 . The latter exhibits a muted water absorption band centred at 14,000 Å, with an otherwise flat spectrum implying an opaque cloud deck. After applying a correction for stellar activity variations between the G102 and G141 observation epochs (see Methods ), the G102 spectrum aligns with the cloud deck level inferred from the G141 spectrum (Fig. 1 ). The helium triplet has an expected width of approximately 3 Å, whereas the resolution of the G102 grism is 67 Å (about 3 pixels) 10 at 10,400 Å. Therefore, to make a finely sampled transmission spectrum, we shifted each of the 20 narrowband channels by one pixel with respect to the adjacent channel along the wavelength axis. The narrowband transmission spectrum peaked at the channel most closely centred<|im_end|> <|im_start|>assistant Astronomers have detected helium in the atmosphere of a planet that orbits a star far beyond our solar system for the very first time. An international team of researchers, led by Jessica Spake from the University of Exeter, discovered evidence of the inert gas on 'super-Neptune' exoplanet WASP-107b, found 200 light years from Earth and in the constellation of Virgo. The pivotal breakthrough, made from observations of the exoplanet using the Hubble Space Telescope, revealed an abundance of helium in the upper atmosphere of the exoplanet, which was only discovered in 2017. The strength of the helium signal detected was so large that scientists believe the planet's upper atmosphere extends tens of thousands of kilometres into space. Helium is the second most common element in the universe and it has long-since been predicted to be one of the most readily-detectable gases on giant exoplanets. However, this pioneering new research is the first time that the gas has been successfully found. Now, the research team believe that the ground-breaking study could pave the way for scientists to discover more atmospheres around Earth-sized exoplanets across the galaxy. The research is published in the leading scientific journal, Nature, on May 3, 2018. Jessica Spake, part of Exeter's Physics and Astronomy department said: "We hope to use this technique with the upcoming James Webb Space Telescope, for example, to learn what kind of planets have large envelopes of hydrogen and helium, and how long planets can hold on to their atmospheres. By measuring infrared light, we can see further out into space than if we were using ultraviolet light." WASP-107b is a very low-density planet similar in size to Jupiter, but with only 12 per cent of its mass. Orbiting its host star every six days, it has one of the coolest atmospheres of any of the exoplanets discovered, although at 500 C is still radically hotter that Earth. By analysing the spectrum of light passing through the upper part of the exoplanet's atmosphere, the researchers were able to detect the presence of helium in an excited state. The significant strength of the signal measured exploited a new technique that doesn't rely on ultraviolet measurements which have historically been used to study upper exoplanet atmospheres. The team believe this new technique, which uses infrared light, could open up new paths to exploring the atmospheres of more Earth-sized exoplanets found in the further reaches of the universe. Tom Evans, a co-author also from the University of Exeter added: "The helium we detected extends far out to space as a tenuous cloud surrounding the planet. If smaller, Earth-sized planets have similar helium clouds, this new technique offers an exciting means to study their upper atmospheres in the very near future.." Helium was first detected as an unknown yellow spectral line signature in sunlight in 1868. Devon-based astronomer Norman Lockyer was the first to propose this line was due to a new element, and named it after the Greek Titan of the Sun, Helios. It has since been discovered to be one of the main constituents of the planets Jupiter and Saturn in our Solar System. <|im_end|>

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2,041

[ { "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 primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition. Main For almost all human diseases, individual susceptibility is, to some degree, influenced by genetic variation. Consequently, characterizing the relationship between sequence variation and disease predisposition provides a powerful tool for identifying processes fundamental to disease pathogenesis and highlighting novel strategies for prevention and treatment. Over the past 25 years, advances in technology and analytical approaches, often building on major community projects—such as those that generated the human genome sequence 1 and elaborated on that reference to capture sites of genetic variation 2 , 3 , 4 , 5 , 6 —have enabled many of the genes and variants that are causal for rare diseases to be identified and enabled a systematic dissection of the genetic basis of common multifactorial traits. There is growing momentum behind the application of this knowledge to drive innovation in clinical care, most obviously through developments in precision medicine. Genomic medicine, which was previously restricted to a few specific clinical indications, is poised to go mainstream. This Review charts recent milestones in the history of human disease genetics and provides an opportunity to reflect on lessons learned by the human genetics community. We focus first on the long-standing division between genetic discovery efforts targeting rare variants with large effects and those seeking alleles that influence predisposition to common diseases. We describe how this division, with its echoes of the century-old debate between Mendelian and biometric views of human genetics, has obscured the continuous spectrum of disease risk alleles—across the range of frequencies and effect sizes—observed in the population, and outline how genome-wide analyses in large biobanks are transforming genetic research by enabling a comprehensive perspective on genotype–phenotype relationships. We describe how the expansion in the scale and scope of strategies for enumerating the functional consequences of genetic variation is transforming the torrent of genetic discoveries from the past decade into mechanistic insights, and the ways in which this knowledge increasingly underpins advances in clinical care. Finally, we reflect on some of the challenges and opportunities that confront the field, and the principles that will, over the coming decade, drive the application of human genetics to enhance understanding of health and disease and maximize clinical benefit. Rare diseases, rare variants During the 1980s and 1990s, efforts to map disease genes were focused on rare, monogenic and syndromic diseases and were mostly driven by linkage analysis and fine mapping within large multiplex pedigrees. Localization of genetic signals was typically followed by Sanger sequencing of the genes found to map within the linked locus to identify disease-causing alleles. Assessments of pathogenicity, based on segregation of a putatively causal variant with disease across multiple families and evidence that the risk genotype was absent in healthy individuals, were typically followed by confirmatory functional studies in cellular and animal models. This path to gene identification was laborious; nevertheless, by 2000, around 1,000 of the estimated 7,000 single-gene inherited diseases had been characterized, including many with substantial biomedical impact, such as Huntington’s disease and cystic fibrosis 7 , 8 , 9 . Completion of the draft human genome sequence 1 reduced many of the obstacles to disease-gene mapping and propelled a fourfold increase in the genes implicated as causal for rare, single-gene disorders (Fig. 1 ). Microarray-based detection of structural variation 10 and exome- and genome-wide sequencing 11 , 12 have been pivotal, bolstered by in silico analysis and prioritization of the discovered genetic variants. Increasing availability of reference datasets cataloguing population genetic variation across diverse ethnic backgrounds has supported robust causal inference 2 , 3 , 5 , 6 . More recently, the adoption of high-throughput sequencing technologies has enabled the full range of causal genetic variation, from single mutations to large structural rearrangements, to be identified in a single assay. These technologies have extended from research into clinical usage, driving earlier and faster diagnosis for genetic disorders. Fig. 1: Growth in the discovery of disease-associated genetic variation. The cumulative numbers of genes harbouring variants causal for rare, monogenic diseases and traits and of significant GWAS associations implicated in common, complex diseases and traits are shown. Left, the advent of high-throughput sequencing technologies and availability of reference genomes from diverse populations has supported a fourfold increase in the discovery of rare disease-causing genes between 1999 and 2019. Right, international efforts such as the Human Genome Project and the HapMap Project, combined with GWAS and sequencing studies, have supported identification of more than 60,000 genetic associations across thousands of human diseases and traits. Centre, more recent developments have brought a synthesis of the rare- and common-variant approaches based around the combination of sequence-informed analyses in large cohorts. Key events contributing to these themes are depicted in the timeline. GA4GH, Global Alliance for Genomics and Health 160 ; ExAC, Exome Aggregation Consortium 5 . Full size image Reduced reliance on multiplex pedigrees in favour of collections of affected cases, often with parents 13 , has proven decisive in identifying new dominant disorders, many of which were previously considered recessive 14 . Increasingly, discovery of rare disease genes has transitioned from genetic characterization of small numbers of individuals with similar clinical presentations to genome-wide sequencing of larger cohorts of phenotypically diverse patients. This genotype-driven approach has revealed new disorders associated with more variable clinical presentation 15 , 16 . A more systematic approach to data sharing has been critical, both for the characterization of new disorders and diagnostic interpretation of potential", "role": "user" }, { "content": "Genetic discoveries over the past 25 years have substantially advanced understanding of both rare and common diseases, furthering the development of treatment and prevention for ailments ranging from inflammatory bowel diseases to diabetes, according to a study published in Nature in January. The paper, titled \"A brief history of human disease genetics,\" reviews breakthroughs in the association of specific genes with particular disorders, progress mostly driven by advances in technology and analytical approaches. The study also provides a framework for medical innovation to improve clinical care in the field. \"The future of medicine will increasingly focus on delivering care that is tailored to an individual's genetic makeup and patterns,\" says Judy H. Cho, MD, Dean of Translational Genetics at the Icahn School of Medicine at Mount Sinai, Director of The Charles Bronfman Institute for Personalized Medicine, and a co-author of the report. \"Applying this knowledge will help us to enhance personalized health and medicine for patients at The Mount Sinai Hospital now and for years to come.\" The study tracks advances in genomics over the past two decades through better technology, expanded access to vast and diverse data, and the development of other foundational resources and tools. The researchers also note the evolution of how diseases were discovered and identified. Another major advancement is the increasing availability of large prospective population-based cohorts, known as biobanks. These biobanks often include tissue samples from individuals of many ethnic backgrounds and provide access to a wide range of demographic, clinical, and lifestyle data. The study finds that systematic approaches to data sharing, such as global collaborative networks, are critical in characterizing new disorders. Today, genetic testing for individuals with symptoms and for at-risk relatives occurs routinely; it ranges from cancer screenings to noninvasive prenatal tests. But challenges remain, including the absence of evidence-based guidelines to support health care recommendations, disparities in testing across society, and the lack of experience in genomics by some health care professionals. The researchers say the biggest task in the coming decade will be to optimize and broadly implement strategies that use human genetics to enhance understanding of health and disease, and maximize the benefits of treatment. This will require joint efforts by the industry and academia to establish: comprehensive inventories of genotype-phenotype relationships across populations and environments;proactive measures to address entrenched disparities in scientific capacity and clinical opportunities that benefit individuals and societies across the world;a systematic assessment of variant and gene-level function across cell types, states, and exposures;improved strategies for turning basic knowledge from assessments into fully developed molecular, cellular, and physiological models of disease development; and application of these biological insights to drive new treatment and preventive options. ", "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 primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition. Main For almost all human diseases, individual susceptibility is, to some degree, influenced by genetic variation. Consequently, characterizing the relationship between sequence variation and disease predisposition provides a powerful tool for identifying processes fundamental to disease pathogenesis and highlighting novel strategies for prevention and treatment. Over the past 25 years, advances in technology and analytical approaches, often building on major community projects—such as those that generated the human genome sequence 1 and elaborated on that reference to capture sites of genetic variation 2 , 3 , 4 , 5 , 6 —have enabled many of the genes and variants that are causal for rare diseases to be identified and enabled a systematic dissection of the genetic basis of common multifactorial traits. There is growing momentum behind the application of this knowledge to drive innovation in clinical care, most obviously through developments in precision medicine. Genomic medicine, which was previously restricted to a few specific clinical indications, is poised to go mainstream. This Review charts recent milestones in the history of human disease genetics and provides an opportunity to reflect on lessons learned by the human genetics community. We focus first on the long-standing division between genetic discovery efforts targeting rare variants with large effects and those seeking alleles that influence predisposition to common diseases. We describe how this division, with its echoes of the century-old debate between Mendelian and biometric views of human genetics, has obscured the continuous spectrum of disease risk alleles—across the range of frequencies and effect sizes—observed in the population, and outline how genome-wide analyses in large biobanks are transforming genetic research by enabling a comprehensive perspective on genotype–phenotype relationships. We describe how the expansion in the scale and scope of strategies for enumerating the functional consequences of genetic variation is transforming the torrent of genetic discoveries from the past decade into mechanistic insights, and the ways in which this knowledge increasingly underpins advances in clinical care. Finally, we reflect on some of the challenges and opportunities that confront the field, and the principles that will, over the coming decade, drive the application of human genetics to enhance understanding of health and disease and maximize clinical benefit. Rare diseases, rare variants During the 1980s and 1990s, efforts to map disease genes were focused on rare, monogenic and syndromic diseases and were mostly driven by linkage analysis and fine mapping within large multiplex pedigrees. Localization of genetic signals was typically followed by Sanger sequencing of the genes found to map within the linked locus to identify disease-causing alleles. Assessments of pathogenicity, based on segregation of a putatively causal variant with disease across multiple families and evidence that the risk genotype was absent in healthy individuals, were typically followed by confirmatory functional studies in cellular and animal models. This path to gene identification was laborious; nevertheless, by 2000, around 1,000 of the estimated 7,000 single-gene inherited diseases had been characterized, including many with substantial biomedical impact, such as Huntington’s disease and cystic fibrosis 7 , 8 , 9 . Completion of the draft human genome sequence 1 reduced many of the obstacles to disease-gene mapping and propelled a fourfold increase in the genes implicated as causal for rare, single-gene disorders (Fig. 1 ). Microarray-based detection of structural variation 10 and exome- and genome-wide sequencing 11 , 12 have been pivotal, bolstered by in silico analysis and prioritization of the discovered genetic variants. Increasing availability of reference datasets cataloguing population genetic variation across diverse ethnic backgrounds has supported robust causal inference 2 , 3 , 5 , 6 . More recently, the adoption of high-throughput sequencing technologies has enabled the full range of causal genetic variation, from single mutations to large structural rearrangements, to be identified in a single assay. These technologies have extended from research into clinical usage, driving earlier and faster diagnosis for genetic disorders. Fig. 1: Growth in the discovery of disease-associated genetic variation. The cumulative numbers of genes harbouring variants causal for rare, monogenic diseases and traits and of significant GWAS associations implicated in common, complex diseases and traits are shown. Left, the advent of high-throughput sequencing technologies and availability of reference genomes from diverse populations has supported a fourfold increase in the discovery of rare disease-causing genes between 1999 and 2019. Right, international efforts such as the Human Genome Project and the HapMap Project, combined with GWAS and sequencing studies, have supported identification of more than 60,000 genetic associations across thousands of human diseases and traits. Centre, more recent developments have brought a synthesis of the rare- and common-variant approaches based around the combination of sequence-informed analyses in large cohorts. Key events contributing to these themes are depicted in the timeline. GA4GH, Global Alliance for Genomics and Health 160 ; ExAC, Exome Aggregation Consortium 5 . Full size image Reduced reliance on multiplex pedigrees in favour of collections of affected cases, often with parents 13 , has proven decisive in identifying new dominant disorders, many of which were previously considered recessive 14 . Increasingly, discovery of rare disease genes has transitioned from genetic characterization of small numbers of individuals with similar clinical presentations to genome-wide sequencing of larger cohorts of phenotypically diverse patients. This genotype-driven approach has revealed new disorders associated with more variable clinical presentation 15 , 16 . A more systematic approach to data sharing has been critical, both for the characterization of new disorders and diagnostic interpretation of potential<|im_end|> <|im_start|>assistant Genetic discoveries over the past 25 years have substantially advanced understanding of both rare and common diseases, furthering the development of treatment and prevention for ailments ranging from inflammatory bowel diseases to diabetes, according to a study published in Nature in January. The paper, titled "A brief history of human disease genetics," reviews breakthroughs in the association of specific genes with particular disorders, progress mostly driven by advances in technology and analytical approaches. The study also provides a framework for medical innovation to improve clinical care in the field. "The future of medicine will increasingly focus on delivering care that is tailored to an individual's genetic makeup and patterns," says Judy H. Cho, MD, Dean of Translational Genetics at the Icahn School of Medicine at Mount Sinai, Director of The Charles Bronfman Institute for Personalized Medicine, and a co-author of the report. "Applying this knowledge will help us to enhance personalized health and medicine for patients at The Mount Sinai Hospital now and for years to come." The study tracks advances in genomics over the past two decades through better technology, expanded access to vast and diverse data, and the development of other foundational resources and tools. The researchers also note the evolution of how diseases were discovered and identified. Another major advancement is the increasing availability of large prospective population-based cohorts, known as biobanks. These biobanks often include tissue samples from individuals of many ethnic backgrounds and provide access to a wide range of demographic, clinical, and lifestyle data. The study finds that systematic approaches to data sharing, such as global collaborative networks, are critical in characterizing new disorders. Today, genetic testing for individuals with symptoms and for at-risk relatives occurs routinely; it ranges from cancer screenings to noninvasive prenatal tests. But challenges remain, including the absence of evidence-based guidelines to support health care recommendations, disparities in testing across society, and the lack of experience in genomics by some health care professionals. The researchers say the biggest task in the coming decade will be to optimize and broadly implement strategies that use human genetics to enhance understanding of health and disease, and maximize the benefits of treatment. This will require joint efforts by the industry and academia to establish: comprehensive inventories of genotype-phenotype relationships across populations and environments;proactive measures to address entrenched disparities in scientific capacity and clinical opportunities that benefit individuals and societies across the world;a systematic assessment of variant and gene-level function across cell types, states, and exposures;improved strategies for turning basic knowledge from assessments into fully developed molecular, cellular, and physiological models of disease development; and application of these biological insights to drive new treatment and preventive options. <|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 Single-cell RNA sequencing (scRNA-seq) can determine gene expression in numerous individual cells simultaneously, promoting progress in the biomedical sciences. However, scRNA-seq data are high-dimensional with substantial technical noise, including dropouts. During analysis of scRNA-seq data, such noise engenders a statistical problem known as the curse of dimensionality (COD). Based on high-dimensional statistics, we herein formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), for high-dimensional data with random sampling noise. We show that RECODE consistently resolves COD in relevant scRNA-seq data with unique molecular identifiers. RECODE does not involve dimension reduction and recovers expression values for all genes, including lowly expressed genes, realizing precise delineation of cell fate transitions and identification of rare cells with all gene information. Compared with representative imputation methods, RECODE employs different principles and exhibits superior overall performance in cell-clustering, expression value recovery, and single-cell–level analysis. The RECODE algorithm is parameter-free, data-driven, deterministic, and high-speed, and its applicability can be predicted based on the variance normalization performance. We propose RECODE as a powerful strategy for preprocessing noisy high-dimensional data. Introduction Single-cell RNA sequencing (scRNA-seq) enables the determination of gene expression profiles in multiple individual cells simultaneously ( Tang et al, 2009 ). When used together with recently developed microfluidics platforms and cell index strategies, scRNA-seq permits the analysis of gene expression in thousands of single cells in parallel, accelerating progress in the biomedical sciences ( Regev et al, 2017 ; Cao et al, 2020 ). On the other hand, because of technical limitations, scRNA-seq detects only a fraction of the transcriptome in single cells (∼1–60%; on average: ∼ <10%), and there are large variations in the detection level of each transcript by scRNA-seq ( Grun et al, 2014 ; Kiselev et al, 2019 ). Thus, unlike conventional bulk RNA-sequencing, scRNA-seq, which is generally used to process numerous cells on automated platforms, provides a sparse representation of the true transcriptome of single cells, with detection failures (dropouts) and variations occurring randomly for most genes, particularly genes with low-expression levels ( Lähnemann et al, 2020 ). These drawbacks, collectively regarded as nonbiological technical noise, pose a key challenge in scRNA-seq data analysis and interpretation. To circumvent these drawbacks, preprocessing of scRNA-seq data, such as dimension reduction and normalization, is widely used ( Stegle et al, 2015 ; Kiselev et al, 2019 ). However, such preprocessing does not provide a fundamental solution, because it compresses the original data without separating the true information from the noise information and therefore cannot recover the true expression values. With a focus on mitigating the dropout effects and data sparsity and based on models for transcript/noise distributions as well as on the information from similar cells (“nearest neighbors”), many inventive methods for modifying scRNA-seq data have been proposed ( Bonnefoy et al, 2018 ; Li & Li, 2018 ; van Dijk et al, 2018 ; Zappia et al, 2018 ; Eraslan et al, 2019 ; Peng et al, 2019 ; Wagner et al, 2019 Preprint ; Wang et al, 2019 ). These “imputation” methods are classified into several categories, including model-based imputation, data smoothing, and data reconstruction, and appear to be successful in recovering dropped-out gene information ( Lähnemann et al, 2020 ). However, compared with no-imputation controls, most of these methods fail to substantially improve performance in downstream data analyses, such as clustering analyses and dimension reduction mappings; they also introduce “circularity,” thereby generating false positives and decreasing the reproducibility of specific gene expressions ( Andrews & Hemberg, 2018 ; Hou et al, 2020 ). Thus, imputations need to be used with appropriate caution and require further improvements. It is fundamental to note that scRNA-seq data are high-dimensional data (the dimension corresponds to the number of genes, i.e., > ∼10,000), with each feature (each gene expression level) bearing technical noise ( Grun et al, 2014 ). High-dimensional statistics theories demonstrate that such data, even when the noises are small, suffer from the “curse of dimensionality” (COD), which causes detrimental effects in downstream data analyses ( Hall et al, 2005 ). Specifically, COD causes impairments of close distances in true data structures, inconsistency of statistics such as contribution rates of principal components (PCs), and inconsistency of PCs, among other deleterious influences ( Yata & Aoshima, 2009 ; Aoshima et al, 2018 ) (see the Results section and Supplemental Data 1 for details; COD in this context is distinct from that in informatics, which refers to an exponential increase of computational complexity associated with a rise in data dimension). However, despite its significance, COD has not been explicitly addressed in the context of scRNA-seq data analysis, including imputations. Expand view - Supplemental Data 1. Supplemental Data 1. A mathematical formulation and theory of RECODE. [LSA-2022-01591_Supplemental_Data_1.pdf] Here, based on high-dimensional statistics ( Yata & Aoshima, 2010 ; 2012 ), we formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), which resolves COD in scRNA-seq data. RECODE is tailored to the scRNA-seq data with unique molecular identifiers (UMIs) because its mathematical formulation relies on the theory of random samplings, which are involved as noise in the copying and sequencing steps for generating scRNA-seq data with UMIs. We show that RECODE consistently resolves COD in the relevant scRNA-seq data. Significantly, RECODE does not involve dimension reduction, such as selection of highly variable genes (HVGs) and major principal components, for the downstream data analysis, but recovers expression values, even for lowly expressed genes, and thus enables the use of all the gene information and the distinguishing of close cell types/transient cell populations masked by COD. RECODE outperforms representative imputation methods, not only in the cluster level analysis but also in the expression value recovery and single-cell level analysis (e.g., the identification of rare cell types). The algorithm of RECODE is parameter-free, data-driven, deterministic, and high-speed, making the method practical, and notably, the applicability of RECODE is predictable. We propose the use of RECODE as a powerful strategy for preprocessing noisy high-dimensional data, including scRNA-seq data. Results COD The noise (technical noise)", "role": "user" }, { "content": "Since scientists first mapped the complete human genome, attention has now turned to the question of how cells use this master copy of genetic instructions. It is known that when genes are switched on, parts of the DNA sequences in the cell nucleus are copied into shorter string-like molecules, RNA, that deliver the molecules essential for survival and cell-specific functions. Understanding the profiles of RNA in a cell can show which genes are active and allow researchers to speculate what the cell is doing. The technology for measuring RNA by massively parallel DNA sequencer, RNA-sequencing, has become a standard technique over the past decade. More recently, rapid technological advances permit RNA sequencing at the single-cell level from thousands of cells in parallel, accelerating progress in the biomedical sciences. But quantifying RNAs from such a tiny material poses great technical challenges. Even with state-of-the-art equipment, data produced from single-cell RNA sequencing data contain large detection errors, including the so-called \"drop-out effect.\" Moreover, even small errors in the calculations for a large number of genes can quickly add up so that any useful information is lost among signal noise. Now, a team from the Kyoto University Institute for Advanced Study of Human Biology (WPI-ASHBi) has developed a new mathematical method that can eliminate the noise and thus enable the extraction of clear signals from single-cell RNA sequencing data. The new method successfully decreases random sampling noise in the data to enable a precise and complete understanding of a cell's activity. The research has recently been published in the journal Life Science Alliance. The lead author of the paper, Yusuke Imoto from ASHBi, explains, \"Each gene represents a different dimension in RNA sequencing data, which means that tens of thousands of dimensions must be collected across multiple cells and analyzed. Even the slightest noise in one dimension can majorly impact the downstream data analyses so that potentially important signals are lost. This is why we call this the 'curse of dimensionality.'\" To break the curse of dimensionality, the Kyoto team has developed a new noise reduction method, RECODE—standing for \"resolution of the curse of dimensionality\"—to remove the random sampling noise from single-cell RNA sequencing data. RECODE applies high-dimensional statistical theories to recover accurate results, even for genes expressed at very low levels. First, the team tested their method on data from a broadly well-studied cell population, human peripheral blood. They confirmed that RECODE successfully removes the curse of dimensionality to reveal expression patterns for individual genes close to their expected values. Next, when compared against other state-of-the-art analysis methods, RECODE outperformed the competition by giving much truer representations of gene activation. Moreover, RECODE is simpler to use than other methods, without relying on parameters or using machine learning for the calculations to work. Finally, the team tested RECODE on a complex dataset from mouse embryo cells containing many different types of cells with unique gene expression patterns. Whereas other methods blurred the results, RECODE clearly resolved gene expression levels, even for rare cell types. Imoto says, \"Single-cell RNA sequencing data analysis remains technically challenging and is a developing technique, but our RECODE algorithm is a step towards being able to reveal the true behaviors of single-cell structures. With our contribution, single-cell RNA sequencing data analysis could become a powerful research tool with massive implications across many biological fields.\" Another leading author Tomonori Nakamura, a biologist from ASHBi and The Hakubi Center for Advanced Study, Kyoto University, adds, \"By unlocking the true power of single-cell RNA sequencing, RECODE will enable researchers to discover unidentified rare cell types, leading to the development and establishment of the new research field in basic science as well as clinical application and drug discovery research.\" The paper is published in Life Science Alliance, and RECODE calculation programs (Python/R code, desktop application) are available on GitHub (https://github.com/yusuke-imoto-lab/RECODE). ", "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 Single-cell RNA sequencing (scRNA-seq) can determine gene expression in numerous individual cells simultaneously, promoting progress in the biomedical sciences. However, scRNA-seq data are high-dimensional with substantial technical noise, including dropouts. During analysis of scRNA-seq data, such noise engenders a statistical problem known as the curse of dimensionality (COD). Based on high-dimensional statistics, we herein formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), for high-dimensional data with random sampling noise. We show that RECODE consistently resolves COD in relevant scRNA-seq data with unique molecular identifiers. RECODE does not involve dimension reduction and recovers expression values for all genes, including lowly expressed genes, realizing precise delineation of cell fate transitions and identification of rare cells with all gene information. Compared with representative imputation methods, RECODE employs different principles and exhibits superior overall performance in cell-clustering, expression value recovery, and single-cell–level analysis. The RECODE algorithm is parameter-free, data-driven, deterministic, and high-speed, and its applicability can be predicted based on the variance normalization performance. We propose RECODE as a powerful strategy for preprocessing noisy high-dimensional data. Introduction Single-cell RNA sequencing (scRNA-seq) enables the determination of gene expression profiles in multiple individual cells simultaneously ( Tang et al, 2009 ). When used together with recently developed microfluidics platforms and cell index strategies, scRNA-seq permits the analysis of gene expression in thousands of single cells in parallel, accelerating progress in the biomedical sciences ( Regev et al, 2017 ; Cao et al, 2020 ). On the other hand, because of technical limitations, scRNA-seq detects only a fraction of the transcriptome in single cells (∼1–60%; on average: ∼ <10%), and there are large variations in the detection level of each transcript by scRNA-seq ( Grun et al, 2014 ; Kiselev et al, 2019 ). Thus, unlike conventional bulk RNA-sequencing, scRNA-seq, which is generally used to process numerous cells on automated platforms, provides a sparse representation of the true transcriptome of single cells, with detection failures (dropouts) and variations occurring randomly for most genes, particularly genes with low-expression levels ( Lähnemann et al, 2020 ). These drawbacks, collectively regarded as nonbiological technical noise, pose a key challenge in scRNA-seq data analysis and interpretation. To circumvent these drawbacks, preprocessing of scRNA-seq data, such as dimension reduction and normalization, is widely used ( Stegle et al, 2015 ; Kiselev et al, 2019 ). However, such preprocessing does not provide a fundamental solution, because it compresses the original data without separating the true information from the noise information and therefore cannot recover the true expression values. With a focus on mitigating the dropout effects and data sparsity and based on models for transcript/noise distributions as well as on the information from similar cells (“nearest neighbors”), many inventive methods for modifying scRNA-seq data have been proposed ( Bonnefoy et al, 2018 ; Li & Li, 2018 ; van Dijk et al, 2018 ; Zappia et al, 2018 ; Eraslan et al, 2019 ; Peng et al, 2019 ; Wagner et al, 2019 Preprint ; Wang et al, 2019 ). These “imputation” methods are classified into several categories, including model-based imputation, data smoothing, and data reconstruction, and appear to be successful in recovering dropped-out gene information ( Lähnemann et al, 2020 ). However, compared with no-imputation controls, most of these methods fail to substantially improve performance in downstream data analyses, such as clustering analyses and dimension reduction mappings; they also introduce “circularity,” thereby generating false positives and decreasing the reproducibility of specific gene expressions ( Andrews & Hemberg, 2018 ; Hou et al, 2020 ). Thus, imputations need to be used with appropriate caution and require further improvements. It is fundamental to note that scRNA-seq data are high-dimensional data (the dimension corresponds to the number of genes, i.e., > ∼10,000), with each feature (each gene expression level) bearing technical noise ( Grun et al, 2014 ). High-dimensional statistics theories demonstrate that such data, even when the noises are small, suffer from the “curse of dimensionality” (COD), which causes detrimental effects in downstream data analyses ( Hall et al, 2005 ). Specifically, COD causes impairments of close distances in true data structures, inconsistency of statistics such as contribution rates of principal components (PCs), and inconsistency of PCs, among other deleterious influences ( Yata & Aoshima, 2009 ; Aoshima et al, 2018 ) (see the Results section and Supplemental Data 1 for details; COD in this context is distinct from that in informatics, which refers to an exponential increase of computational complexity associated with a rise in data dimension). However, despite its significance, COD has not been explicitly addressed in the context of scRNA-seq data analysis, including imputations. Expand view - Supplemental Data 1. Supplemental Data 1. A mathematical formulation and theory of RECODE. [LSA-2022-01591_Supplemental_Data_1.pdf] Here, based on high-dimensional statistics ( Yata & Aoshima, 2010 ; 2012 ), we formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), which resolves COD in scRNA-seq data. RECODE is tailored to the scRNA-seq data with unique molecular identifiers (UMIs) because its mathematical formulation relies on the theory of random samplings, which are involved as noise in the copying and sequencing steps for generating scRNA-seq data with UMIs. We show that RECODE consistently resolves COD in the relevant scRNA-seq data. Significantly, RECODE does not involve dimension reduction, such as selection of highly variable genes (HVGs) and major principal components, for the downstream data analysis, but recovers expression values, even for lowly expressed genes, and thus enables the use of all the gene information and the distinguishing of close cell types/transient cell populations masked by COD. RECODE outperforms representative imputation methods, not only in the cluster level analysis but also in the expression value recovery and single-cell level analysis (e.g., the identification of rare cell types). The algorithm of RECODE is parameter-free, data-driven, deterministic, and high-speed, making the method practical, and notably, the applicability of RECODE is predictable. We propose the use of RECODE as a powerful strategy for preprocessing noisy high-dimensional data, including scRNA-seq data. Results COD The noise (technical noise)<|im_end|> <|im_start|>assistant Since scientists first mapped the complete human genome, attention has now turned to the question of how cells use this master copy of genetic instructions. It is known that when genes are switched on, parts of the DNA sequences in the cell nucleus are copied into shorter string-like molecules, RNA, that deliver the molecules essential for survival and cell-specific functions. Understanding the profiles of RNA in a cell can show which genes are active and allow researchers to speculate what the cell is doing. The technology for measuring RNA by massively parallel DNA sequencer, RNA-sequencing, has become a standard technique over the past decade. More recently, rapid technological advances permit RNA sequencing at the single-cell level from thousands of cells in parallel, accelerating progress in the biomedical sciences. But quantifying RNAs from such a tiny material poses great technical challenges. Even with state-of-the-art equipment, data produced from single-cell RNA sequencing data contain large detection errors, including the so-called "drop-out effect." Moreover, even small errors in the calculations for a large number of genes can quickly add up so that any useful information is lost among signal noise. Now, a team from the Kyoto University Institute for Advanced Study of Human Biology (WPI-ASHBi) has developed a new mathematical method that can eliminate the noise and thus enable the extraction of clear signals from single-cell RNA sequencing data. The new method successfully decreases random sampling noise in the data to enable a precise and complete understanding of a cell's activity. The research has recently been published in the journal Life Science Alliance. The lead author of the paper, Yusuke Imoto from ASHBi, explains, "Each gene represents a different dimension in RNA sequencing data, which means that tens of thousands of dimensions must be collected across multiple cells and analyzed. Even the slightest noise in one dimension can majorly impact the downstream data analyses so that potentially important signals are lost. This is why we call this the 'curse of dimensionality.'" To break the curse of dimensionality, the Kyoto team has developed a new noise reduction method, RECODE—standing for "resolution of the curse of dimensionality"—to remove the random sampling noise from single-cell RNA sequencing data. RECODE applies high-dimensional statistical theories to recover accurate results, even for genes expressed at very low levels. First, the team tested their method on data from a broadly well-studied cell population, human peripheral blood. They confirmed that RECODE successfully removes the curse of dimensionality to reveal expression patterns for individual genes close to their expected values. Next, when compared against other state-of-the-art analysis methods, RECODE outperformed the competition by giving much truer representations of gene activation. Moreover, RECODE is simpler to use than other methods, without relying on parameters or using machine learning for the calculations to work. Finally, the team tested RECODE on a complex dataset from mouse embryo cells containing many different types of cells with unique gene expression patterns. Whereas other methods blurred the results, RECODE clearly resolved gene expression levels, even for rare cell types. Imoto says, "Single-cell RNA sequencing data analysis remains technically challenging and is a developing technique, but our RECODE algorithm is a step towards being able to reveal the true behaviors of single-cell structures. With our contribution, single-cell RNA sequencing data analysis could become a powerful research tool with massive implications across many biological fields." Another leading author Tomonori Nakamura, a biologist from ASHBi and The Hakubi Center for Advanced Study, Kyoto University, adds, "By unlocking the true power of single-cell RNA sequencing, RECODE will enable researchers to discover unidentified rare cell types, leading to the development and establishment of the new research field in basic science as well as clinical application and drug discovery research." The paper is published in Life Science Alliance, and RECODE calculation programs (Python/R code, desktop application) are available on GitHub (https://github.com/yusuke-imoto-lab/RECODE). <|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 Across the periodic table the trans -influence operates, whereby tightly bonded ligands selectively lengthen mutually trans metal–ligand bonds. Conversely, in high oxidation state actinide complexes the inverse- trans -influence operates, where normally cis strongly donating ligands instead reside trans and actually reinforce each other. However, because the inverse- trans -influence is restricted to high-valent actinyls and a few uranium(V/VI) complexes, it has had limited scope in an area with few unifying rules. Here we report tetravalent cerium, uranium and thorium bis (carbene) complexes with trans C=M=C cores where experimental and theoretical data suggest the presence of an inverse- trans -influence. Studies of hypothetical praseodymium(IV) and terbium(IV) analogues suggest the inverse- trans -influence may extend to these ions but it also diminishes significantly as the 4 f orbitals are populated. This work suggests that the inverse- trans -influence may occur beyond high oxidation state 5 f metals and hence could encompass mid-range oxidation state actinides and lanthanides. Thus, the inverse- trans -influence might be a more general f -block principle. Introduction The trans -influence is a long-established, well-documented concept of broad relevance across inorganic chemistry 1 , 2 . This thermodynamic ground-state phenomenon classically occurs in square-planar and pseudo -octahedral d-block complexes where tightly bonded ligands selectively lengthen mutually trans metal–ligand bonds. The trans -influence is fundamentally important and underpins the trans -effect 3 , a kinetic rate effect where the order of substitution of ligands at a metal centre can be controlled; this is a key parameter to control, for example, the syntheses of cis- or trans -[PtCl 2 (NH 3 ) 2 ], whose isomerism is important regarding cancer treatment 4 . Although the bonding of lanthanide(III) and low/mid oxidation state early actinide ions is considered more ionic than in the d-block, there are crystallographic, and in some instances computationally supported, examples of complexes where metrical parameters are consistent with the presence of the trans -influence 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In high oxidation state actinide complexes the opposite phenomenon of the inverse- trans -influence (ITI) can be found 17 , 18 , 19 , 20 , 21 . Here, strongly donating ligands that normally adopt cis orientations to avoid destabilizing the respective metal–ligand bonds via the trans -influence in fact reside trans to one another and even mutually reinforce each other. The classical, dominant example of the ITI is the uranyl(VI) dication, {UO 2 } 2+ , that adopts a trans- linear geometry and is chemically robust because of strong, ITI-strengthened uranium–oxygen bonds 20 . Indeed, linear trans -dioxo actinyls {AnO 2 } n+ (An=U, Np, Pu) are well known and prevalent, but trans- dioxos in the d-block are unusual and require strong equatorial σ-donor ligands to weaken the metal-oxo linkages sufficiently to enable them to reside mutually trans . Two isostructural complexes that demonstrate the trans -influence and the ITI are [MoO 2 Cl 2 (OPPh 3 ) 2 ] ( I ) 22 and [UO 2 Cl 2 (OPPh 3 ) 2 ] ( II ) 23 , respectively ( Fig. 1 ); in the former the oxos are cis , whereas in the latter they are trans . The ITI often plays a structure-dictating role, but this is not a criterion that must be met to make invoking the ITI valid; there are examples of high valent uranium complexes where ligands are constrained by their own architecture such that they have no choice but to place donor groups trans to a strongly donating ligand like a nitride or oxo, but despite this they present very short metal–ligand distances despite their unfavourable bonding situation. For example, in the complexes [U(Tren TIPS )(E)] [Tren TIPS =N(CH 2 CH 2 NSiPr i 3 ) 3 ; E=N ( III ), O ( IV )] ( Fig. 1 ) 24 , 25 the U–N amine distances are short at 2.465(5) and 2.482(6) Å, respectively, despite being trans to nitride and oxo ligands, whereas such U–N amine distances are normally 2.5–2.7 Å (ref. 26 ). In these systems there is no ITI structure-dictating role, and as part of a polydentate Tren-ligand with minimal reorganization energy 27 the Tren amines are forced to be unfavourably trans to a nitride or oxo 28 , but the U–N amine distances are short, not long, that credibly invokes the ITI. Figure 1: Selected literature examples where the trans -influence and inverse- trans -influence are invoked. Complexes I and II are identical except for the metal ion and the molybdenum complex exhibits cis -oxos whereas the uranium complex has trans -oxos, consistent with the trans -influence and inverse- trans -influence, respectively. Complexes III and IV both exhibit short uranium–amine distances despite being trans to hard, charge-loaded nitride and oxo ligands that is not consistent with the trans -influence but conversely invokes the inverse- trans -influence. Full size image The origin of the ITI is complex, but is in part rationalized on the basis that in high oxidation state early actinides 6 p orbitals are semi-core and transfer electron density to vacant 5 f orbitals, creating an electron hole that is compensated for by additional donation of electron density from trans ligands 17 , 18 , 19 , 20 , 21 . For many years the ITI was limited to uranyl(VI) complexes 20 or structurally analogous complexes such as [UOCl 5 ] − (ref. 29 ), but in recent years a limited number of uranium(V) and (VI) ITI complexes have emerged 24 , 25 , 30 , 31 , 32 , 33 . The unifying theme has been high oxidation state (V or VI) metal complexes combined with hard, polarizing, charge-loaded oxo, imide and nitride ligands. Because it is limited to high oxidation state early actinides, the question of whether the ITI is a niche concept or in fact has a broader underpinning role for the f -block has remained unanswered for around a quarter of", "role": "user" }, { "content": "Researchers at The University of Manchester have entered the \"Wild West\" of the periodic table to finally solve a decades-old scientific challenge—and have revealed that an important but niche chemical bonding principle may be much more widely applicable than previously thought. The surprise discovery about this important bonding relationship - between a metal ion and a coordinated group known as a ligand—from a team led by Professor Steve Liddle, has potential implications from cancer treatments to the nuclear power industry. Their ground-breaking research has now been published in the leading multi-disciplinary journal Nature Communications. Professor Liddle explained: \"The arrangement of ligand groups at metal centres in metal-complexes is crucial to determining their reactivity. \"For example, the molecule known as cis-platin is very effective at treating cancerous tumours whereas trans-platin is ineffective. Both compounds have the same molecular formula with a central platinum ion bonded to two chloride and two ammonia ligands, all in the same plane and in the shape of a cross—but in the former the chlorides are next to each other and in the latter they are on opposite sides to each other. \"The arrangement of these ligands is therefore crucial to determining the reactivity of these complexes. The phenomenon that controls to a large extent the arrangement of ligands at metal centres is known as the trans-influence, which originates from the fact that some ligands bind to metals more strongly that others so ligands will avoid being opposite stronger donor ligands. This effect is observed right across the periodic table for most metals. \"Conversely, down at the bottom of the periodic table, things can be quite different and for heavy elements like uranium a phenomenon known as the inverse-trans-influence (ITI) operates. \"Here, ligands that would normally do everything they could to avoid being opposite each other at a metal, in fact, do everything they can to be oppositely disposed, and rather than this destabilising the ligands they actually mutually reinforce each other. \"However, the ITI was previously limited only to actinides in their maximum or close or maximum oxidation states. A good example of this is the uranyl, {UO2}2+ ion which is widely prevalent in the environment naturally and also nuclear waste where the two oxygen atoms reside opposite each other and are bonded very strongly to the uranium. \"This makes the uranyl moiety very important, but also the universal view that the ITI was a niche concept of limited applicability dominated because it was restricted to high oxidation state actinide metals like uranium. \"So whether this phenomenon was a niche rule or hinted at a broader underpinning concept, in an area that has few rules and is essentially the 'Wild West' of the periodic table, had been a question that had endured for decades. \"One reason this question had been difficult to tackle was the lack of structurally comparable families of molecules from which to conduct comparative studies where lower oxidation states of metal ions could be investigated.\" To address this problem, the research team prepared a new family of molecules with C=M=C cores where the metal was cerium [classed as a lanthanide] or thorium or uranium [which are classed as actinides] where two carbon atoms that are known to be strong donors were forced to be opposite to one another either side of the metal.\" Characterisation of this family of molecules required a team of researchers based at the Universities of Manchester, Lancaster, Nottingham, and Dresden, and the Rossendorf Beamline at Grenoble. Through this interdisciplinary effort the team was able to fully characterise the molecules and determine that the ITI operates in these molecules that contain metal ions in only the +4 oxidation state. The most notable observation is the fact that the two carbon atoms are bonded very closely to the metals, particularly for cerium, even though as strong donors they should be found at longer distances and this is a tell-tale sign of the ITI. Professor Liddle added: \"The combination of finding the ITI in +4 metal ion complexes, as well as for lanthanide as well as actinide complexes leads to the conclusion that this phenomenon is most likely of far broader reach than previously thought. \"Considering the prevalence of actinide elements in the environment naturally but also in nuclear waste, and that the structure of metal complexes is inherently linked to their reactivity, this research could help in waste clean-up 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 Across the periodic table the trans -influence operates, whereby tightly bonded ligands selectively lengthen mutually trans metal–ligand bonds. Conversely, in high oxidation state actinide complexes the inverse- trans -influence operates, where normally cis strongly donating ligands instead reside trans and actually reinforce each other. However, because the inverse- trans -influence is restricted to high-valent actinyls and a few uranium(V/VI) complexes, it has had limited scope in an area with few unifying rules. Here we report tetravalent cerium, uranium and thorium bis (carbene) complexes with trans C=M=C cores where experimental and theoretical data suggest the presence of an inverse- trans -influence. Studies of hypothetical praseodymium(IV) and terbium(IV) analogues suggest the inverse- trans -influence may extend to these ions but it also diminishes significantly as the 4 f orbitals are populated. This work suggests that the inverse- trans -influence may occur beyond high oxidation state 5 f metals and hence could encompass mid-range oxidation state actinides and lanthanides. Thus, the inverse- trans -influence might be a more general f -block principle. Introduction The trans -influence is a long-established, well-documented concept of broad relevance across inorganic chemistry 1 , 2 . This thermodynamic ground-state phenomenon classically occurs in square-planar and pseudo -octahedral d-block complexes where tightly bonded ligands selectively lengthen mutually trans metal–ligand bonds. The trans -influence is fundamentally important and underpins the trans -effect 3 , a kinetic rate effect where the order of substitution of ligands at a metal centre can be controlled; this is a key parameter to control, for example, the syntheses of cis- or trans -[PtCl 2 (NH 3 ) 2 ], whose isomerism is important regarding cancer treatment 4 . Although the bonding of lanthanide(III) and low/mid oxidation state early actinide ions is considered more ionic than in the d-block, there are crystallographic, and in some instances computationally supported, examples of complexes where metrical parameters are consistent with the presence of the trans -influence 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In high oxidation state actinide complexes the opposite phenomenon of the inverse- trans -influence (ITI) can be found 17 , 18 , 19 , 20 , 21 . Here, strongly donating ligands that normally adopt cis orientations to avoid destabilizing the respective metal–ligand bonds via the trans -influence in fact reside trans to one another and even mutually reinforce each other. The classical, dominant example of the ITI is the uranyl(VI) dication, {UO 2 } 2+ , that adopts a trans- linear geometry and is chemically robust because of strong, ITI-strengthened uranium–oxygen bonds 20 . Indeed, linear trans -dioxo actinyls {AnO 2 } n+ (An=U, Np, Pu) are well known and prevalent, but trans- dioxos in the d-block are unusual and require strong equatorial σ-donor ligands to weaken the metal-oxo linkages sufficiently to enable them to reside mutually trans . Two isostructural complexes that demonstrate the trans -influence and the ITI are [MoO 2 Cl 2 (OPPh 3 ) 2 ] ( I ) 22 and [UO 2 Cl 2 (OPPh 3 ) 2 ] ( II ) 23 , respectively ( Fig. 1 ); in the former the oxos are cis , whereas in the latter they are trans . The ITI often plays a structure-dictating role, but this is not a criterion that must be met to make invoking the ITI valid; there are examples of high valent uranium complexes where ligands are constrained by their own architecture such that they have no choice but to place donor groups trans to a strongly donating ligand like a nitride or oxo, but despite this they present very short metal–ligand distances despite their unfavourable bonding situation. For example, in the complexes [U(Tren TIPS )(E)] [Tren TIPS =N(CH 2 CH 2 NSiPr i 3 ) 3 ; E=N ( III ), O ( IV )] ( Fig. 1 ) 24 , 25 the U–N amine distances are short at 2.465(5) and 2.482(6) Å, respectively, despite being trans to nitride and oxo ligands, whereas such U–N amine distances are normally 2.5–2.7 Å (ref. 26 ). In these systems there is no ITI structure-dictating role, and as part of a polydentate Tren-ligand with minimal reorganization energy 27 the Tren amines are forced to be unfavourably trans to a nitride or oxo 28 , but the U–N amine distances are short, not long, that credibly invokes the ITI. Figure 1: Selected literature examples where the trans -influence and inverse- trans -influence are invoked. Complexes I and II are identical except for the metal ion and the molybdenum complex exhibits cis -oxos whereas the uranium complex has trans -oxos, consistent with the trans -influence and inverse- trans -influence, respectively. Complexes III and IV both exhibit short uranium–amine distances despite being trans to hard, charge-loaded nitride and oxo ligands that is not consistent with the trans -influence but conversely invokes the inverse- trans -influence. Full size image The origin of the ITI is complex, but is in part rationalized on the basis that in high oxidation state early actinides 6 p orbitals are semi-core and transfer electron density to vacant 5 f orbitals, creating an electron hole that is compensated for by additional donation of electron density from trans ligands 17 , 18 , 19 , 20 , 21 . For many years the ITI was limited to uranyl(VI) complexes 20 or structurally analogous complexes such as [UOCl 5 ] − (ref. 29 ), but in recent years a limited number of uranium(V) and (VI) ITI complexes have emerged 24 , 25 , 30 , 31 , 32 , 33 . The unifying theme has been high oxidation state (V or VI) metal complexes combined with hard, polarizing, charge-loaded oxo, imide and nitride ligands. Because it is limited to high oxidation state early actinides, the question of whether the ITI is a niche concept or in fact has a broader underpinning role for the f -block has remained unanswered for around a quarter of<|im_end|> <|im_start|>assistant Researchers at The University of Manchester have entered the "Wild West" of the periodic table to finally solve a decades-old scientific challenge—and have revealed that an important but niche chemical bonding principle may be much more widely applicable than previously thought. The surprise discovery about this important bonding relationship - between a metal ion and a coordinated group known as a ligand—from a team led by Professor Steve Liddle, has potential implications from cancer treatments to the nuclear power industry. Their ground-breaking research has now been published in the leading multi-disciplinary journal Nature Communications. Professor Liddle explained: "The arrangement of ligand groups at metal centres in metal-complexes is crucial to determining their reactivity. "For example, the molecule known as cis-platin is very effective at treating cancerous tumours whereas trans-platin is ineffective. Both compounds have the same molecular formula with a central platinum ion bonded to two chloride and two ammonia ligands, all in the same plane and in the shape of a cross—but in the former the chlorides are next to each other and in the latter they are on opposite sides to each other. "The arrangement of these ligands is therefore crucial to determining the reactivity of these complexes. The phenomenon that controls to a large extent the arrangement of ligands at metal centres is known as the trans-influence, which originates from the fact that some ligands bind to metals more strongly that others so ligands will avoid being opposite stronger donor ligands. This effect is observed right across the periodic table for most metals. "Conversely, down at the bottom of the periodic table, things can be quite different and for heavy elements like uranium a phenomenon known as the inverse-trans-influence (ITI) operates. "Here, ligands that would normally do everything they could to avoid being opposite each other at a metal, in fact, do everything they can to be oppositely disposed, and rather than this destabilising the ligands they actually mutually reinforce each other. "However, the ITI was previously limited only to actinides in their maximum or close or maximum oxidation states. A good example of this is the uranyl, {UO2}2+ ion which is widely prevalent in the environment naturally and also nuclear waste where the two oxygen atoms reside opposite each other and are bonded very strongly to the uranium. "This makes the uranyl moiety very important, but also the universal view that the ITI was a niche concept of limited applicability dominated because it was restricted to high oxidation state actinide metals like uranium. "So whether this phenomenon was a niche rule or hinted at a broader underpinning concept, in an area that has few rules and is essentially the 'Wild West' of the periodic table, had been a question that had endured for decades. "One reason this question had been difficult to tackle was the lack of structurally comparable families of molecules from which to conduct comparative studies where lower oxidation states of metal ions could be investigated." To address this problem, the research team prepared a new family of molecules with C=M=C cores where the metal was cerium [classed as a lanthanide] or thorium or uranium [which are classed as actinides] where two carbon atoms that are known to be strong donors were forced to be opposite to one another either side of the metal." Characterisation of this family of molecules required a team of researchers based at the Universities of Manchester, Lancaster, Nottingham, and Dresden, and the Rossendorf Beamline at Grenoble. Through this interdisciplinary effort the team was able to fully characterise the molecules and determine that the ITI operates in these molecules that contain metal ions in only the +4 oxidation state. The most notable observation is the fact that the two carbon atoms are bonded very closely to the metals, particularly for cerium, even though as strong donors they should be found at longer distances and this is a tell-tale sign of the ITI. Professor Liddle added: "The combination of finding the ITI in +4 metal ion complexes, as well as for lanthanide as well as actinide complexes leads to the conclusion that this phenomenon is most likely of far broader reach than previously thought. "Considering the prevalence of actinide elements in the environment naturally but also in nuclear waste, and that the structure of metal complexes is inherently linked to their reactivity, this research could help in waste clean-up in the future." <|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 global dispersal of forests and soils has been proposed as a cause for the Late Devonian mass extinctions of marine organisms, but detailed spatiotemporal records of forests and soils at that time remain lacking. We present data from microscopic and geochemical analyses of the Upper Devonian Chattanooga Shale (Famennian Stage). Plant residues (microfossils, vitrinite and inertinite) and biomarkers derived from terrestrial plants and wildfire occur throughout the stratigraphic section, suggesting widespread forest in the southern Appalachian Basin, a region with no macro plant fossil record during the Famennian. Inorganic geochemical results, as shown by increasing values of SiO 2 /Al 2 O 3 , Ti/Al, Zr/Al, and the Chemical Index of Alteration (CIA) upon time sequence, suggest enhanced continental weathering that may be attributed to the invasion of barren lands by rooted land plants. Our geochemical data collectively provide the oldest evidence of the influences of land plants from the southernmost Appalachian Basin. Our synthesis of vascular plant fossil record shows a more rapid process of afforestation and pedogenesis across south-central Euramerica during the Frasnian and Famennian than previously documented. Together, these results lead us to propose a new hypothesis that global floral dispersal had progressed southward along the Acadian landmass rapidly during the Late Devonian. Introduction The Late Devonian is known for the rapid and global radiation of early forests and soils such as spodosols and alfisols 1 , 2 , 3 . The development of land plants and soils is hypothesized to have been either a trigger or consequence of a series of global changes in the lithosphere (e.g., increased weathering and erosion), hydrosphere (e.g., anoxic oceans, global transgression and regression), atmosphere (e.g., global changes in O 2 and CO 2 ), and biosphere (i.e. mass extinctions of marine life) during the Middle to Late Devonian 4 , 5 , 6 , 7 , 8 , 9 , 10 . One compelling hypothesis is that forest radiation mobilized a tremendous amount of soils and associated nutrients (N and P) to coastal oceans for the first time in Earth’s history and led to dysoxic/anoxic oceans globally 4 , 11 , 12 , 13 . Testing this hypothesis, however, requires data on stratigraphic occurrences of soils and plants in specific paleogeographic areas. Current knowledge on the paleogeographic distribution of Devonian forests is largely based on macrofossils, such as tree trunks, stems, leaves, and roots, as well as some microfossils such as spores 14 , 15 , 16 , 17 . The oldest tree stems and stumps in the Euramerica are reported from the uppermost Givetian (Middle Devonian) strata of New York (i.e., Gilboa Park and Cairo) representing the central Euramerican landmass 18 (Fig. 1 ). To date, the record of Devonian trees and shrubs assigned to pteridophytes, which were likely the primary component for the first forest, is very limited from the southern Appalachian Basin along the southern Acadian landmass. Only a few uncertain remains have been reported as small wood fragments of possible Callixylon 19 and Foerstia 20 from Tennessee. In contrast, some tree or shrub fossils are known from the northern Appalachian Basin (e.g., New York, Pennsylvanian, West Virginia) and the Baltica and Avalonia landmasses (e.g., United Kingdom, Belgium) 21 , 22 , 23 , 24 , 25 , 26 , 27 . This gap in the paleogeographic occurrence between the northern and southern parts of the Appalachian Basin implies that forests originated from the central Euramerica in the late Middle Devonian and dispersed southward during the Late Devonian. Better understanding of the spatiotemporal occurrence of land plants in the southern Appalachian Basin will provide better understanding of the dispersal pattern of early land forest. Figure 1 Late Devonian paleogeography. Left: the global scale; right: south-central Euramerica. The yellow star indicates the study site (the present location of Alabama), which represents the southern part of the Chattanooga Sea (dashed elliptical area). Maps are adapted from original map (360 Ma) from Global Paleogeography and Tectonics in Deep Time Series by Ron Blakey [© 2016 Colorado Plateau Geosystems Inc.]. Full size image To date, fluvial sedimentary sequences are the most frequently reported units containing tree and shrub fossils (lycopsids, cladoxylopsids, progymnosperms, and possibly stem spermatophytes) and soils in the Appalachian Basin 1 , 18 , 28 , 29 . Those sandstone, siltstone, and limestone deposits are geographically distributed along the eastern side of the basin (close to the modern-day Appalachian Mountains) 30 . By comparison, very few tree fossils have been reported from the extensive Upper Devonian black shale deposits further offshore from the western margin of the Appalachian Basin, including the Ohio Shale, New Albany Shale, Cleveland Shale, Huron-Dunkirk shales, Millsboro Shale, and Chattanooga Shale. Typically, the preservation of land plant fossils in offshore marine deposits is not as common as that in nearshore environments (e.g., fluvial, deltaic), because plant remains can be easily broken into pieces and decomposed through taphonomic process. However, if information on the distribution of early forests could be obtained from the abundant and regionally extensive Upper Devonian marine black shales, it would significantly increase the amount of data on the occurrence of land plants available to geologists from the Paleozoic rock record. Such efforts would allow for the reconstruction of a far more spatially and stratigraphically detailed record of afforestation than is possible using the rarely preserved fluvial deposits alone. In the present study, we present identifiable signatures of forests and soils preserved in unfossiliferous black shales in the southernmost Appalachian Basin. We further demonstrate the potential of using these signatures to generate new understanding of the dispersal patterns of Famennian forest (land plant) and pedogenesis along the southern Acadian Orogen. We analyzed a complete section of the Chattanooga Shale in northeastern Alabama (Fig. 1 ). The Chattanooga Shale and other Upper Devonian black shale units in the Appalachian Basin are interpreted to have accumulated in a basin-like depositional environment further offshore than equivalent sandstone or siltstone dominated formations (i.e., alluvial plain or basin margin-like environment) 30 , 31 . Plant macrofossils", "role": "user" }, { "content": "Evidence from ancient rocks in north Alabama show the Earth's first forest spread rapidly, likely contributing to a mass extinction of shallow marine life some 370 million years ago. Findings outlined in Scientific Reports by researchers from The University of Alabama and their international colleagues provide geochemical evidence for the oldest forests in southeastern North America, meaning the first forest spread across the barren land of a super continent millions of years earlier than previously shown. The work sheds light on global extinctions 370 to 360 million years ago, giving credence to a theory that a lack of oxygen in the oceans killed off scores of marine life as early forests dumped nutrient-rich soils into the oceans. \"This story is, I think, ironic because today trees are the symbol of eco-friendly green life,\" said Dr. Takehito Ikejiri, a paleontologist with UA's Alabama Museum of Natural History who worked on this project. \"But, when they first appeared in Earth's history, they seemed to be harmful and caused big trouble for other life.\" During the period of Earth's history, known as the Devonian, there were three super continents, with present day North America meshed with Greenland and much of Europe. The first known large plants with wood tissue, trees, appeared in Euramerica, near present day New York, during the Middle Devonian, 393 to 382 million years ago, and spread across the continent. Not long, in geological time, after trees first appeared, massive numbers of marine animals living closer to land, such as trilobites, corals and plankton, died in two waves. The reason for these extinctions could be global cooling, extensive volcanism or asteroid impacts. It is not clear. Common marine animal fossils are shown in the rocks of Chattanooga Shale Formation in northeastern Alabama. Credit: T. Ikejiri One hypothesis is marine anoxia, a rapid drop of oxygen levels in the seas, stemming from erosion of soil and their nutrients created by deep-rooted trees. UA researchers set out to test this theory by analyzing black shale outcropping—above-ground exposures—from the period from northeastern Alabama, which represents the southernmost margin of the Appalachian Basin. Although tree fossils are scattered in the southern Appalachian Basin, geochemical and microscopic data show strong evidence that forests first appeared in the region, then the southern Euramerica landmass, 370 million years ago. Man Lu, a UA doctoral student in geological sciences and lead author on the paper, performed the geochemical and microscopic analyses of rock samples she collected from the shales. She discovered tiny wood fragments in this Devonian formation where no macro-fossils were reported previously. Geochemistry data further support that early forests became an important carbon source to these black shales during the Late Devonian. These geochemical data provide a clue to the timing of the early forest evolution in Earth's history. Ikejiri gathered and quantified global Devonian tree occurrences in the fossil record to determine the forest dispersal pattern. \"Our data show the global forestation occurred in a relatively short time,\" Ikejiri said. \"Trees spread rapidly in very large areas across the Euramerica continent and likely caused a series of drastic environmental changes.\" Dr. YueHan Lu, UA associate professor of geological sciences and corresponding author of the paper, believes the timing of this rapid forestation is interesting considering it occurs near the time of the marine life extinctions. ", "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 global dispersal of forests and soils has been proposed as a cause for the Late Devonian mass extinctions of marine organisms, but detailed spatiotemporal records of forests and soils at that time remain lacking. We present data from microscopic and geochemical analyses of the Upper Devonian Chattanooga Shale (Famennian Stage). Plant residues (microfossils, vitrinite and inertinite) and biomarkers derived from terrestrial plants and wildfire occur throughout the stratigraphic section, suggesting widespread forest in the southern Appalachian Basin, a region with no macro plant fossil record during the Famennian. Inorganic geochemical results, as shown by increasing values of SiO 2 /Al 2 O 3 , Ti/Al, Zr/Al, and the Chemical Index of Alteration (CIA) upon time sequence, suggest enhanced continental weathering that may be attributed to the invasion of barren lands by rooted land plants. Our geochemical data collectively provide the oldest evidence of the influences of land plants from the southernmost Appalachian Basin. Our synthesis of vascular plant fossil record shows a more rapid process of afforestation and pedogenesis across south-central Euramerica during the Frasnian and Famennian than previously documented. Together, these results lead us to propose a new hypothesis that global floral dispersal had progressed southward along the Acadian landmass rapidly during the Late Devonian. Introduction The Late Devonian is known for the rapid and global radiation of early forests and soils such as spodosols and alfisols 1 , 2 , 3 . The development of land plants and soils is hypothesized to have been either a trigger or consequence of a series of global changes in the lithosphere (e.g., increased weathering and erosion), hydrosphere (e.g., anoxic oceans, global transgression and regression), atmosphere (e.g., global changes in O 2 and CO 2 ), and biosphere (i.e. mass extinctions of marine life) during the Middle to Late Devonian 4 , 5 , 6 , 7 , 8 , 9 , 10 . One compelling hypothesis is that forest radiation mobilized a tremendous amount of soils and associated nutrients (N and P) to coastal oceans for the first time in Earth’s history and led to dysoxic/anoxic oceans globally 4 , 11 , 12 , 13 . Testing this hypothesis, however, requires data on stratigraphic occurrences of soils and plants in specific paleogeographic areas. Current knowledge on the paleogeographic distribution of Devonian forests is largely based on macrofossils, such as tree trunks, stems, leaves, and roots, as well as some microfossils such as spores 14 , 15 , 16 , 17 . The oldest tree stems and stumps in the Euramerica are reported from the uppermost Givetian (Middle Devonian) strata of New York (i.e., Gilboa Park and Cairo) representing the central Euramerican landmass 18 (Fig. 1 ). To date, the record of Devonian trees and shrubs assigned to pteridophytes, which were likely the primary component for the first forest, is very limited from the southern Appalachian Basin along the southern Acadian landmass. Only a few uncertain remains have been reported as small wood fragments of possible Callixylon 19 and Foerstia 20 from Tennessee. In contrast, some tree or shrub fossils are known from the northern Appalachian Basin (e.g., New York, Pennsylvanian, West Virginia) and the Baltica and Avalonia landmasses (e.g., United Kingdom, Belgium) 21 , 22 , 23 , 24 , 25 , 26 , 27 . This gap in the paleogeographic occurrence between the northern and southern parts of the Appalachian Basin implies that forests originated from the central Euramerica in the late Middle Devonian and dispersed southward during the Late Devonian. Better understanding of the spatiotemporal occurrence of land plants in the southern Appalachian Basin will provide better understanding of the dispersal pattern of early land forest. Figure 1 Late Devonian paleogeography. Left: the global scale; right: south-central Euramerica. The yellow star indicates the study site (the present location of Alabama), which represents the southern part of the Chattanooga Sea (dashed elliptical area). Maps are adapted from original map (360 Ma) from Global Paleogeography and Tectonics in Deep Time Series by Ron Blakey [© 2016 Colorado Plateau Geosystems Inc.]. Full size image To date, fluvial sedimentary sequences are the most frequently reported units containing tree and shrub fossils (lycopsids, cladoxylopsids, progymnosperms, and possibly stem spermatophytes) and soils in the Appalachian Basin 1 , 18 , 28 , 29 . Those sandstone, siltstone, and limestone deposits are geographically distributed along the eastern side of the basin (close to the modern-day Appalachian Mountains) 30 . By comparison, very few tree fossils have been reported from the extensive Upper Devonian black shale deposits further offshore from the western margin of the Appalachian Basin, including the Ohio Shale, New Albany Shale, Cleveland Shale, Huron-Dunkirk shales, Millsboro Shale, and Chattanooga Shale. Typically, the preservation of land plant fossils in offshore marine deposits is not as common as that in nearshore environments (e.g., fluvial, deltaic), because plant remains can be easily broken into pieces and decomposed through taphonomic process. However, if information on the distribution of early forests could be obtained from the abundant and regionally extensive Upper Devonian marine black shales, it would significantly increase the amount of data on the occurrence of land plants available to geologists from the Paleozoic rock record. Such efforts would allow for the reconstruction of a far more spatially and stratigraphically detailed record of afforestation than is possible using the rarely preserved fluvial deposits alone. In the present study, we present identifiable signatures of forests and soils preserved in unfossiliferous black shales in the southernmost Appalachian Basin. We further demonstrate the potential of using these signatures to generate new understanding of the dispersal patterns of Famennian forest (land plant) and pedogenesis along the southern Acadian Orogen. We analyzed a complete section of the Chattanooga Shale in northeastern Alabama (Fig. 1 ). The Chattanooga Shale and other Upper Devonian black shale units in the Appalachian Basin are interpreted to have accumulated in a basin-like depositional environment further offshore than equivalent sandstone or siltstone dominated formations (i.e., alluvial plain or basin margin-like environment) 30 , 31 . Plant macrofossils<|im_end|> <|im_start|>assistant Evidence from ancient rocks in north Alabama show the Earth's first forest spread rapidly, likely contributing to a mass extinction of shallow marine life some 370 million years ago. Findings outlined in Scientific Reports by researchers from The University of Alabama and their international colleagues provide geochemical evidence for the oldest forests in southeastern North America, meaning the first forest spread across the barren land of a super continent millions of years earlier than previously shown. The work sheds light on global extinctions 370 to 360 million years ago, giving credence to a theory that a lack of oxygen in the oceans killed off scores of marine life as early forests dumped nutrient-rich soils into the oceans. "This story is, I think, ironic because today trees are the symbol of eco-friendly green life," said Dr. Takehito Ikejiri, a paleontologist with UA's Alabama Museum of Natural History who worked on this project. "But, when they first appeared in Earth's history, they seemed to be harmful and caused big trouble for other life." During the period of Earth's history, known as the Devonian, there were three super continents, with present day North America meshed with Greenland and much of Europe. The first known large plants with wood tissue, trees, appeared in Euramerica, near present day New York, during the Middle Devonian, 393 to 382 million years ago, and spread across the continent. Not long, in geological time, after trees first appeared, massive numbers of marine animals living closer to land, such as trilobites, corals and plankton, died in two waves. The reason for these extinctions could be global cooling, extensive volcanism or asteroid impacts. It is not clear. Common marine animal fossils are shown in the rocks of Chattanooga Shale Formation in northeastern Alabama. Credit: T. Ikejiri One hypothesis is marine anoxia, a rapid drop of oxygen levels in the seas, stemming from erosion of soil and their nutrients created by deep-rooted trees. UA researchers set out to test this theory by analyzing black shale outcropping—above-ground exposures—from the period from northeastern Alabama, which represents the southernmost margin of the Appalachian Basin. Although tree fossils are scattered in the southern Appalachian Basin, geochemical and microscopic data show strong evidence that forests first appeared in the region, then the southern Euramerica landmass, 370 million years ago. Man Lu, a UA doctoral student in geological sciences and lead author on the paper, performed the geochemical and microscopic analyses of rock samples she collected from the shales. She discovered tiny wood fragments in this Devonian formation where no macro-fossils were reported previously. Geochemistry data further support that early forests became an important carbon source to these black shales during the Late Devonian. These geochemical data provide a clue to the timing of the early forest evolution in Earth's history. Ikejiri gathered and quantified global Devonian tree occurrences in the fossil record to determine the forest dispersal pattern. "Our data show the global forestation occurred in a relatively short time," Ikejiri said. "Trees spread rapidly in very large areas across the Euramerica continent and likely caused a series of drastic environmental changes." Dr. YueHan Lu, UA associate professor of geological sciences and corresponding author of the paper, believes the timing of this rapid forestation is interesting considering it occurs near the time of the marine life extinctions. <|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 Ribosome profiling has been used to predict thousands of short open reading frames (sORFs) in eukaryotic cells, but it suffers from substantial levels of noise. PRICE ( ) is a computational method that models experimental noise to enable researchers to accurately resolve overlapping sORFs and noncanonical translation initiation. We experimentally validated translation using major histocompatibility complex class I (MHC I) peptidomics and observed that sORF-derived peptides efficiently enter the MHC I presentation pathway and thus constitute a substantial fraction of the antigen repertoire. Main Ribosome profiling (Ribo-seq) is a powerful approach to measure translational activity in a genome-wide and quantitative manner with base-pair resolution 1 . It visualizes the triplet shifts of actively translating ribosomes and thereby allows the identification of codons and their corresponding open reading frames (ORFs) translated at the time of cell lysis. This has resulted in the prediction of thousands of sORFs, including upstream and upstream-overlapping ORFs (uORFs and uoORFs, respectively), thus revealing an important new layer of translational control in eukaryotic cells 2 . However, accurate and reliable identification of sORFs has remained difficult for overlapping ORFs and for initiation at noncanonical (non-AUG) start codons. In addition, the vast majority of these novel, cryptic gene products have remained virtually undetectable in whole cellular proteomes and thus are assumed to be highly unstable. Here we present a computational approach that allows accurate identification of sORFs from Ribo-seq data. It is based on computational modeling and subsequent removal of experimental noise from Ribo-seq data, and allows for improved statistical testing for active translation. On the basis of the accurate identification of thousands of sORFs, we show that although they are dramatically underrepresented in the cellular proteome, sORF-derived peptides do efficiently enter the MHC I presentation pathway and can be quantitatively recovered by MHC I peptidome analysis. MHC I peptidome analysis thus represents a potent method for large-scale validation of sORF translation. Ribosome footprints do not have a singular specific size. Instead, reads are the result of two stochastic RNase cleavage events. Thus, the use of deterministic rules (for example, using an offset of 12) to recover the codon located in the P site of the actively translating ribosome (signal) leads to mapping of reads to off-frame codons (noise). Depending on the combination of read lengths used to chart ribosome occupancy, signal may be sacrificed for the signal-to-noise ratio. Moreover, untemplated nucleotide additions frequently observed in Ribo-seq experiments further increase noise levels ( Supplementary Fig. 1 ). We developed probabilistic inference of codon activities by an EM algorithm (PRICE) to model the stochastic processes involved in Ribo-seq ( Fig. 1a ). For each individual experiment, all parameters are directly inferred from annotated, well-translated ORFs. Any codon located in the P site of a ribosome is able to produce several kinds of footprints, and their proportions depend on these inferred parameters. Our method determines the set of codons that generates the observed reads with maximum likelihood ( Supplementary Fig. 2 ). Figure 1: The PRICE approach. ( a ) Schematic of the approach. Left: the blue bars and the red bar represent the parameters of the probabilistic model. Center: translated codons are identified through solution of the inverse problem of the model. Right: calling of actively translated ORFs based on the generalized binomial distribution (details are available in the Online Methods ). H 0 , null hypothesis; k , b 1, b 2, b 3, number of codons exceeding the cutoff; p bg , background probability; n , total number of codons in ORF; pp , vector of background probabilities. ( b ) Comparison of approaches for mapping reads to codons with respect to signal (total number of reads mapped in-frame) and signal-to-noise ratio (noise: reads mapped out-of-frame to annotated ORFs) in the HSV-1 data set (ref. 13 ). Color-coded according to the key to indicate deterministic mapping of read classes defined by length and 5′ mismatch state and of combinations of read classes (basic, ignoring 5′ mismatches; extended, considering 5′ mismatches; top 4, combining the best read classes; see also Supplementary Fig. 4 ), and probabilistic mapping by PRICE. ( c ) Total amount of peptides detected in proteome and MHC I peptidome mass spectrometry experiments (MHC I peptidome data set 1; see Supplementary Fig. 9a for the other experiment). The 1% peptide-identification FDR is indicated by a dashed line. Gray bars represent the peptides from ORFs also identified by ORF-RATER or Rp-Bp (for PRICE) or ORFs also identified by PRICE (for ORF-RATER and Rp-Bp). ( d ) Validation rates of peptides from predicted ORFs with a minimal number of reads per codon (MHC I peptidome data set 2; see Supplementary Fig. 9b for the other experiment). Rates for all ORFs (solid lines) identified by the indicated methods and for ORFs predicted de novo (dashed lines) are shown. Source data Full size image After the assembly of identified codons into ORF candidates, potential start codons are predicted with high accuracy by a machine-learning model ( Supplementary Fig. 3 ). If available, samples treated with lactimidomycin or harringtonin for translation-start-site enrichment can also be integrated 3 , 4 . In principle, experimental noise in an ORF candidate can arise from (i) reads from overlapping ORFs, (ii) ribosome scanning or abortive translation events in the leader sequence, or (iii) non-ribosome-mediated mRNA protection from RNase treatment. To exclude candidate ORFs that reflect experimental noise, we used a hypothesis test based on the generalized binomial distribution that is specifically designed to also identify overlapping ORFs ( Fig. 1a ). We first compared the signal and noise levels obtained with PRICE to those observed with deterministic codon-mapping approaches used in prior studies 5 , 6 , 7 , 8 , 9 , 10 , 11 (while this manuscript was under review, an additional method for Ribo-seq data was published 12 ; however, it also uses the deterministic mapping strategy and does not address potentially overlapping ORFs). For Ribo-seq data obtained from herpes simplex virus 1 (HSV-1)-infected primary human fibroblasts 13 , about", "role": "user" }, { "content": "An infection with cytomegalovirus is usually harmless for adults. However, during pregnancy, the virus can be transmitted to the unborn baby and cause malformations. Once the viruses have invaded a human cell, they start to produce large amounts of viral proteins. This includes more than 500 proteins and peptides, including 200 previously unknown to science. This discovery was made possible by a new bioinformatics analysis method developed at the Department of Virology of Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany. The teams of Professor Lars Dölken and Professor Florian Erhard have published their method in the journal Nature Methods. The new technique is relevant for medical applications, because knowledge of the repertoire of viral proteins used to evade the immune system, for example, is crucial to fight infections or develop vaccines. The JMU development allows the ribosomal activities to be captured much more accurately than before. All proteins and peptides are assembled at the numerous ribosomes of a cell. During viral infection, the ribosomes also synthesize all proteins the virus needs to reproduce. The assembly instructions are delivered by special messenger molecules, the mRNAs. The researchers asked: which proteins and peptides are produced at the ribosomes of a cell, and in what amounts? How does this profile change due to the stress of viral infection? They addressed these questions using state-of-the-art high-throughput sequencing methods that use ribosomal profiling (Ribo-seq). These techniques visualize ribosomal activities, the so-called translation processes, as periodic patterns. \"Previously, a number of error sources often prevented the reliable detection of translation events when analysing Ribo-seq data,\" says Florian Erhard. What is more, in at least half of all mRNAs, shorter open reading frames (sORFs) precede the known open reading frames (ORFs). Very difficult to pinpoint in the measured data, they are however an important cellular regulating mechanism especially under stress. The new bioinformatics procedure, called PRICE, substantially improves the identification of translation events. \"Our method is capable of resolving even complex cases, for example overlapping ORFs or unusual start codons, with high accuracy. This has allowed us to determine all translated areas genome-wide with high accuracy for the first time,\" Professor Erhard explains. As a result, the JMU team discovered various new cellular and viral peptides. Moreover, the researchers observed that hundreds of sORF peptides are efficiently presented at the cell surface by MHC-I molecules. \"sORFs thus encode for a new class of antigens that can be recognized by our immune system,\" says Lars Dölken. \"We therefore assume that sORFs are involved in immunological control mechanisms especially during virus infections and stress responses.\" All these findings open up new possibilities to better understand the effects of viral infections on the organism. The PRICE method will have the strongest impact on fundamental research. Ribo-seq is a method that has been applied in almost all domains of biomedical research in recent years. \"PRICE now enables us to analyse all existing and future dataset in much greater depth and with substantially improved accuracy,\" Dölken says. He believes that the gain is so big that it justifies re-analysing all previously published data. To make this possible, the Würzburg scientists have provided their analysis tool as open-source software on the internet. They assume that their method will be used on a wide scale and become the international standard to analyse Ribo-seq experiments. They write, \"We are convinced that the enhanced data analysis will deliver essential new insights in many fields of biomedical research.\" In virology, the new method may contribute to getting a better understanding of cytomegalovirus. For example, it is still unknown why an infection with the pathogen causes severe damages in some unborn babies or transplant recipients, whereas others show no effects at all. ", "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 Ribosome profiling has been used to predict thousands of short open reading frames (sORFs) in eukaryotic cells, but it suffers from substantial levels of noise. PRICE ( ) is a computational method that models experimental noise to enable researchers to accurately resolve overlapping sORFs and noncanonical translation initiation. We experimentally validated translation using major histocompatibility complex class I (MHC I) peptidomics and observed that sORF-derived peptides efficiently enter the MHC I presentation pathway and thus constitute a substantial fraction of the antigen repertoire. Main Ribosome profiling (Ribo-seq) is a powerful approach to measure translational activity in a genome-wide and quantitative manner with base-pair resolution 1 . It visualizes the triplet shifts of actively translating ribosomes and thereby allows the identification of codons and their corresponding open reading frames (ORFs) translated at the time of cell lysis. This has resulted in the prediction of thousands of sORFs, including upstream and upstream-overlapping ORFs (uORFs and uoORFs, respectively), thus revealing an important new layer of translational control in eukaryotic cells 2 . However, accurate and reliable identification of sORFs has remained difficult for overlapping ORFs and for initiation at noncanonical (non-AUG) start codons. In addition, the vast majority of these novel, cryptic gene products have remained virtually undetectable in whole cellular proteomes and thus are assumed to be highly unstable. Here we present a computational approach that allows accurate identification of sORFs from Ribo-seq data. It is based on computational modeling and subsequent removal of experimental noise from Ribo-seq data, and allows for improved statistical testing for active translation. On the basis of the accurate identification of thousands of sORFs, we show that although they are dramatically underrepresented in the cellular proteome, sORF-derived peptides do efficiently enter the MHC I presentation pathway and can be quantitatively recovered by MHC I peptidome analysis. MHC I peptidome analysis thus represents a potent method for large-scale validation of sORF translation. Ribosome footprints do not have a singular specific size. Instead, reads are the result of two stochastic RNase cleavage events. Thus, the use of deterministic rules (for example, using an offset of 12) to recover the codon located in the P site of the actively translating ribosome (signal) leads to mapping of reads to off-frame codons (noise). Depending on the combination of read lengths used to chart ribosome occupancy, signal may be sacrificed for the signal-to-noise ratio. Moreover, untemplated nucleotide additions frequently observed in Ribo-seq experiments further increase noise levels ( Supplementary Fig. 1 ). We developed probabilistic inference of codon activities by an EM algorithm (PRICE) to model the stochastic processes involved in Ribo-seq ( Fig. 1a ). For each individual experiment, all parameters are directly inferred from annotated, well-translated ORFs. Any codon located in the P site of a ribosome is able to produce several kinds of footprints, and their proportions depend on these inferred parameters. Our method determines the set of codons that generates the observed reads with maximum likelihood ( Supplementary Fig. 2 ). Figure 1: The PRICE approach. ( a ) Schematic of the approach. Left: the blue bars and the red bar represent the parameters of the probabilistic model. Center: translated codons are identified through solution of the inverse problem of the model. Right: calling of actively translated ORFs based on the generalized binomial distribution (details are available in the Online Methods ). H 0 , null hypothesis; k , b 1, b 2, b 3, number of codons exceeding the cutoff; p bg , background probability; n , total number of codons in ORF; pp , vector of background probabilities. ( b ) Comparison of approaches for mapping reads to codons with respect to signal (total number of reads mapped in-frame) and signal-to-noise ratio (noise: reads mapped out-of-frame to annotated ORFs) in the HSV-1 data set (ref. 13 ). Color-coded according to the key to indicate deterministic mapping of read classes defined by length and 5′ mismatch state and of combinations of read classes (basic, ignoring 5′ mismatches; extended, considering 5′ mismatches; top 4, combining the best read classes; see also Supplementary Fig. 4 ), and probabilistic mapping by PRICE. ( c ) Total amount of peptides detected in proteome and MHC I peptidome mass spectrometry experiments (MHC I peptidome data set 1; see Supplementary Fig. 9a for the other experiment). The 1% peptide-identification FDR is indicated by a dashed line. Gray bars represent the peptides from ORFs also identified by ORF-RATER or Rp-Bp (for PRICE) or ORFs also identified by PRICE (for ORF-RATER and Rp-Bp). ( d ) Validation rates of peptides from predicted ORFs with a minimal number of reads per codon (MHC I peptidome data set 2; see Supplementary Fig. 9b for the other experiment). Rates for all ORFs (solid lines) identified by the indicated methods and for ORFs predicted de novo (dashed lines) are shown. Source data Full size image After the assembly of identified codons into ORF candidates, potential start codons are predicted with high accuracy by a machine-learning model ( Supplementary Fig. 3 ). If available, samples treated with lactimidomycin or harringtonin for translation-start-site enrichment can also be integrated 3 , 4 . In principle, experimental noise in an ORF candidate can arise from (i) reads from overlapping ORFs, (ii) ribosome scanning or abortive translation events in the leader sequence, or (iii) non-ribosome-mediated mRNA protection from RNase treatment. To exclude candidate ORFs that reflect experimental noise, we used a hypothesis test based on the generalized binomial distribution that is specifically designed to also identify overlapping ORFs ( Fig. 1a ). We first compared the signal and noise levels obtained with PRICE to those observed with deterministic codon-mapping approaches used in prior studies 5 , 6 , 7 , 8 , 9 , 10 , 11 (while this manuscript was under review, an additional method for Ribo-seq data was published 12 ; however, it also uses the deterministic mapping strategy and does not address potentially overlapping ORFs). For Ribo-seq data obtained from herpes simplex virus 1 (HSV-1)-infected primary human fibroblasts 13 , about<|im_end|> <|im_start|>assistant An infection with cytomegalovirus is usually harmless for adults. However, during pregnancy, the virus can be transmitted to the unborn baby and cause malformations. Once the viruses have invaded a human cell, they start to produce large amounts of viral proteins. This includes more than 500 proteins and peptides, including 200 previously unknown to science. This discovery was made possible by a new bioinformatics analysis method developed at the Department of Virology of Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany. The teams of Professor Lars Dölken and Professor Florian Erhard have published their method in the journal Nature Methods. The new technique is relevant for medical applications, because knowledge of the repertoire of viral proteins used to evade the immune system, for example, is crucial to fight infections or develop vaccines. The JMU development allows the ribosomal activities to be captured much more accurately than before. All proteins and peptides are assembled at the numerous ribosomes of a cell. During viral infection, the ribosomes also synthesize all proteins the virus needs to reproduce. The assembly instructions are delivered by special messenger molecules, the mRNAs. The researchers asked: which proteins and peptides are produced at the ribosomes of a cell, and in what amounts? How does this profile change due to the stress of viral infection? They addressed these questions using state-of-the-art high-throughput sequencing methods that use ribosomal profiling (Ribo-seq). These techniques visualize ribosomal activities, the so-called translation processes, as periodic patterns. "Previously, a number of error sources often prevented the reliable detection of translation events when analysing Ribo-seq data," says Florian Erhard. What is more, in at least half of all mRNAs, shorter open reading frames (sORFs) precede the known open reading frames (ORFs). Very difficult to pinpoint in the measured data, they are however an important cellular regulating mechanism especially under stress. The new bioinformatics procedure, called PRICE, substantially improves the identification of translation events. "Our method is capable of resolving even complex cases, for example overlapping ORFs or unusual start codons, with high accuracy. This has allowed us to determine all translated areas genome-wide with high accuracy for the first time," Professor Erhard explains. As a result, the JMU team discovered various new cellular and viral peptides. Moreover, the researchers observed that hundreds of sORF peptides are efficiently presented at the cell surface by MHC-I molecules. "sORFs thus encode for a new class of antigens that can be recognized by our immune system," says Lars Dölken. "We therefore assume that sORFs are involved in immunological control mechanisms especially during virus infections and stress responses." All these findings open up new possibilities to better understand the effects of viral infections on the organism. The PRICE method will have the strongest impact on fundamental research. Ribo-seq is a method that has been applied in almost all domains of biomedical research in recent years. "PRICE now enables us to analyse all existing and future dataset in much greater depth and with substantially improved accuracy," Dölken says. He believes that the gain is so big that it justifies re-analysing all previously published data. To make this possible, the Würzburg scientists have provided their analysis tool as open-source software on the internet. They assume that their method will be used on a wide scale and become the international standard to analyse Ribo-seq experiments. They write, "We are convinced that the enhanced data analysis will deliver essential new insights in many fields of biomedical research." In virology, the new method may contribute to getting a better understanding of cytomegalovirus. For example, it is still unknown why an infection with the pathogen causes severe damages in some unborn babies or transplant recipients, whereas others show no effects at all. <|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 0.1 parsecs of the Milky Way host a supermassive black hole identified with the position of the radio and infrared source Sagittarius A* (refs. 1 , 2 ), a cluster of young, massive stars (the S stars 3 ) and various gaseous features 4 , 5 . Recently, two unusual objects have been found to be closely orbiting Sagittarius A*: the so-called G sources, G1 and G2. These objects are unresolved (having a size of the order of 100 astronomical units, except at periapse, where the tidal interaction with the black hole stretches them along the orbit) and they show both thermal dust emission and line emission from ionized gas 6 , 7 , 8 , 9 , 10 . G1 and G2 have generated attention because they appear to be tidally interacting with the supermassive Galactic black hole, possibly enhancing its accretion activity. No broad consensus has yet been reached concerning their nature: the G objects show the characteristics of gas and dust clouds but display the dynamical properties of stellar-mass objects. Here we report observations of four additional G objects, all lying within 0.04 parsecs of the black hole and forming a class that is probably unique to this environment. The widely varying orbits derived for the six G objects demonstrate that they were commonly but separately formed. Main We used near-infrared (NIR) spectro-imaging data obtained over the past 13 years 11 at the W. M. Keck Observatory with the OSIRIS integral field spectrometer 12 , coupled with laser guide star adaptive optics wave front corrections 13 . OSIRIS data-cubes have two spatial dimensions—about 3 arcsec × 2 arcsec surrounding Sgr A* with a plate-scale of 35 mas—and one wavelength dimension that covers the Kn3 band, 2.121–2.229 µm, with a spectral resolution of R ≈ 3,800. We selected 24 data-cubes based on image quality and signal-to-noise ratio; see Methods section ‘Observations’. These cubes were processed through the OSIRIS pipeline 14 . We also removed the stellar continua to isolate emission features associated with interstellar gas ( Methods section ‘Continuum subtraction’). The reduced data-cubes were analysed with a three-dimensional visualization tool, OsrsVol 15 , that simultaneously displays all dimensions of the data-cube. This helps disentangle the many features of this crowded region, which are often superimposed in the spatial dimension but are separable in the wavelength dimension (Fig. 1 ). Fig. 1: 2006 OSIRIS data-cube visualized with OsrsVol. The spatial dimensions ( x − y ) cover the OSIRIS field of view. The wavelength dimension is centred around Brγ (±1,500 km s −1 ). G3, G4 and G6 are blueshifted, whereas G5 is redshifted. G1 and G2 are not visible here because they have larger velocities. The extended emission in the middle is near the rest wavelength and it arises from foreground or background gas (‘superimposed extended emission’). The emission extending the full length of the wavelength axis at a few positions (‘stellar continuum residuals’) is associated with continuum subtraction residuals. For this analysis, we only use sources that appear throughout the observed timeline. Full size image Analysing the data with OsrsVol as well as conventional two-dimensional (2D) and one-dimensional (1D) tools, we identify four new compact objects in Brackett-γ line emission (Brγ; 2.1661 µm rest wavelength) that consistently appear in the data across the observed timeline. In addition to Brγ, all four objects show two [Fe iii ] emission lines (at 2.1457 μm and 2.2184 μm; ref. 16 ). The four objects show many properties in common with G1 and G2 (compact Brγ emission and coherent orbital motion) and we therefore name them G3, G4, G5 and G6. G3 was previously identified (D2 7 , 17 ). For this work we independently identified G3 in Brγ emission, and G4, G5 and G6 are newly reported. Recently, G6 has been independently examined 18 , and interpreted as a bow shock source rather than a G object. We estimate that we are able to detect G objects having Brγ flux densities of at least 0.02 mJy, if they lie in a non-confused location. Several other infrared-excess sources have been identified with L′ and K′ observations (central wavelengths of 2.2 μm and 3.8 µm, respectively 7 , 17 , see Extended Data Fig. 1 ). We do not include these other sources in this work (except for G3/D2), either because they lie outside the OSIRIS field of view, or because they have not been detected in Brγ, or because they have not been consistently detected throughout the 13 years of data. We use Keck/NIRC2 L′ imaging data to investigate whether G3, G4, G5 and G6 have detectable L′ counterparts, as G1 and G2 do ( Methods section ‘L′ detection analysis’). No L′ counterpart was detected for G4, G5 and G6, with upper limits to the flux density of 0.4 mJy, 0.6 mJy and 0.5 mJy, respectively. G3 is detected in L′ with a dereddened flux density of 2.5 mJy, consistent with a previous report 17 . None of the G objects was detected in the K continuum. Our detection limit in the K continuum is 0.01 mJy in the OSIRIS spectra (Kn3 filter) and in the K′ broadband (2.12 μm central wavelength) a limit of 0.07 mJy was reported for G2 19 (but see ref. 20 ). The Brγ emission is a key defining feature of the G objects because it probably results from external ionization and does not depend on the mass of a putative central object, and hence its presence is independent of the nature of the G objects (low-mass cloud or extended stellar-mass object). The compactness of such emission is what distinguishes the G objects from other presumably short-lived gas blobs that have become detached from larger-scale interstellar structures. The dust heating can be attributed to some combination of the external radiation field and an internal stellar core, if present. Therefore, the lack of detection of the G objects in the L′ band does not necessarily have implications for the existence of a stellar object", "role": "user" }, { "content": "Astronomers from UCLA's Galactic Center Orbits Initiative have discovered a new class of bizarre objects at the center of our galaxy, not far from the supermassive black hole called Sagittarius A*. They published their research today in the journal Nature. \"These objects look like gas and behave like stars,\" said co-author Andrea Ghez, UCLA's Lauren B. Leichtman and Arthur E. Levine Professor of Astrophysics and director of the UCLA Galactic Center Group. The new objects look compact most of the time and stretch out when their orbits bring them closest to the black hole. Their orbits range from about 100 to 1,000 years, said lead author Anna Ciurlo, a UCLA postdoctoral researcher. Ghez's research group identified an unusual object at the center of our galaxy in 2005, which was later named G1. In 2012, astronomers in Germany made a puzzling discovery of a bizarre object named G2 in the center of the Milky Way that made a close approach to the supermassive black hole in 2014. Ghez and her research team believe that G2 is most likely two stars that had been orbiting the black hole in tandem and merged into an extremely large star, cloaked in unusually thick gas and dust. \"At the time of closest approach, G2 had a really strange signature,\" Ghez said. \"We had seen it before, but it didn't look too peculiar until it got close to the black hole and became elongated, and much of its gas was torn apart. It went from being a pretty innocuous object when it was far from the black hole to one that was really stretched out and distorted at its closest approach and lost its outer shell, and now it's getting more compact again.\" \"One of the things that has gotten everyone excited about the G objects is that the stuff that gets pulled off of them by tidal forces as they sweep by the central black hole must inevitably fall into the black hole,\" said co-author Mark Morris, UCLA professor of physics and astronomy. \"When that happens, it might be able to produce an impressive fireworks show since the material eaten by the black hole will heat up and emit copious radiation before it disappears across the event horizon.\" But are G2 and G1 outliers, or are they part of a larger class of objects? In answer to that question, Ghez's research group reports the existence of four more objects they are calling G3, G4, G5 and G6. The researchers have determined each of their orbits. While G1 and G2 have similar orbits, the four new objects have very different orbits. Ghez believes all six objects were binary stars—a system of two stars orbiting each other—that merged because of the strong gravitational force of the supermassive black hole. The merging of two stars takes more than 1 million years to complete, Ghez said. \"Mergers of stars may be happening in the universe more often than we thought, and likely are quite common,\" Ghez said. \"Black holes may be driving binary stars to merge. It's possible that many of the stars we've been watching and not understanding may be the end product of mergers that are calm now. We are learning how galaxies and black holes evolve. The way binary stars interact with each other and with the black hole is very different from how single stars interact with other single stars and with the black hole.\" Ciurlo noted that while the gas from G2's outer shell got stretched dramatically, its dust inside the gas did not get stretched much. \"Something must have kept it compact and enabled it to survive its encounter with the black hole,\" Ciurlo said. \"This is evidence for a stellar object inside G2.\" \"The unique dataset that Professor Ghez's group has gathered during more than 20 years is what allowed us to make this discovery,\" Ciurlo said. \"We now have a population of 'G' objects, so it is not a matter of explaining a 'one-time event' like G2.\" The researchers made observations from the W.M. Keck Observatory in Hawaii and used a powerful technology that Ghez helped pioneer, called adaptive optics, which corrects the distorting effects of the Earth's atmosphere in real time. They conducted a new analysis of 13 years of their UCLA Galactic Center Orbits Initiative data. In September 2019, Ghez's team reported that the black hole is getting hungrier and it is unclear why. The stretching of G2 in 2014 appeared to pull off gas that may recently have been swallowed by the black hole, said co-author Tuan Do, a UCLA research scientist and deputy director of the Galactic Center Group. The mergers of stars could feed the black hole. The team has already identified a few other candidates that may be part of this new class of objects, and are continuing to analyze them. Ghez noted the center of the Milky Way galaxy is an extreme environment, unlike our less hectic corner of the universe. \"The Earth is in the suburbs compared to the center of the galaxy, which is some 26,000 light-years away,\" Ghez said. \"The center of our galaxy has a density of stars 1 billion times higher than our part of the galaxy. The gravitational pull is so much stronger. The magnetic fields are more extreme. The center of the galaxy is where extreme astrophysics occurs—the X-sports of astrophysics.\" Ghez said this research will help to teach us what is happening in the majority of galaxies. Other co-authors include Randall Campbell, an astronomer with the W.M. Keck Observatory in Hawaii; Aurelien Hees, a former UCLA postdoctoral scholar, now a researcher at the Paris Observatory in France; and Smadar Naoz, a UCLA assistant professor of physics and astronomy. The research is funded by the National Science Foundation, W.M. Keck Foundation and Keck Visiting Scholars Program, the Gordon and Betty Moore Foundation, the Heising-Simons Foundation, Lauren Leichtman and Arthur Levine, Jim and Lori Keir, and Howard and Astrid Preston. In July 2019, Ghez's research team reported on the most comprehensive test of Einstein's iconic general theory of relativity near the black hole. They concluded that Einstein's theory passed the test and is correct, at least for now. ", "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 0.1 parsecs of the Milky Way host a supermassive black hole identified with the position of the radio and infrared source Sagittarius A* (refs. 1 , 2 ), a cluster of young, massive stars (the S stars 3 ) and various gaseous features 4 , 5 . Recently, two unusual objects have been found to be closely orbiting Sagittarius A*: the so-called G sources, G1 and G2. These objects are unresolved (having a size of the order of 100 astronomical units, except at periapse, where the tidal interaction with the black hole stretches them along the orbit) and they show both thermal dust emission and line emission from ionized gas 6 , 7 , 8 , 9 , 10 . G1 and G2 have generated attention because they appear to be tidally interacting with the supermassive Galactic black hole, possibly enhancing its accretion activity. No broad consensus has yet been reached concerning their nature: the G objects show the characteristics of gas and dust clouds but display the dynamical properties of stellar-mass objects. Here we report observations of four additional G objects, all lying within 0.04 parsecs of the black hole and forming a class that is probably unique to this environment. The widely varying orbits derived for the six G objects demonstrate that they were commonly but separately formed. Main We used near-infrared (NIR) spectro-imaging data obtained over the past 13 years 11 at the W. M. Keck Observatory with the OSIRIS integral field spectrometer 12 , coupled with laser guide star adaptive optics wave front corrections 13 . OSIRIS data-cubes have two spatial dimensions—about 3 arcsec × 2 arcsec surrounding Sgr A* with a plate-scale of 35 mas—and one wavelength dimension that covers the Kn3 band, 2.121–2.229 µm, with a spectral resolution of R ≈ 3,800. We selected 24 data-cubes based on image quality and signal-to-noise ratio; see Methods section ‘Observations’. These cubes were processed through the OSIRIS pipeline 14 . We also removed the stellar continua to isolate emission features associated with interstellar gas ( Methods section ‘Continuum subtraction’). The reduced data-cubes were analysed with a three-dimensional visualization tool, OsrsVol 15 , that simultaneously displays all dimensions of the data-cube. This helps disentangle the many features of this crowded region, which are often superimposed in the spatial dimension but are separable in the wavelength dimension (Fig. 1 ). Fig. 1: 2006 OSIRIS data-cube visualized with OsrsVol. The spatial dimensions ( x − y ) cover the OSIRIS field of view. The wavelength dimension is centred around Brγ (±1,500 km s −1 ). G3, G4 and G6 are blueshifted, whereas G5 is redshifted. G1 and G2 are not visible here because they have larger velocities. The extended emission in the middle is near the rest wavelength and it arises from foreground or background gas (‘superimposed extended emission’). The emission extending the full length of the wavelength axis at a few positions (‘stellar continuum residuals’) is associated with continuum subtraction residuals. For this analysis, we only use sources that appear throughout the observed timeline. Full size image Analysing the data with OsrsVol as well as conventional two-dimensional (2D) and one-dimensional (1D) tools, we identify four new compact objects in Brackett-γ line emission (Brγ; 2.1661 µm rest wavelength) that consistently appear in the data across the observed timeline. In addition to Brγ, all four objects show two [Fe iii ] emission lines (at 2.1457 μm and 2.2184 μm; ref. 16 ). The four objects show many properties in common with G1 and G2 (compact Brγ emission and coherent orbital motion) and we therefore name them G3, G4, G5 and G6. G3 was previously identified (D2 7 , 17 ). For this work we independently identified G3 in Brγ emission, and G4, G5 and G6 are newly reported. Recently, G6 has been independently examined 18 , and interpreted as a bow shock source rather than a G object. We estimate that we are able to detect G objects having Brγ flux densities of at least 0.02 mJy, if they lie in a non-confused location. Several other infrared-excess sources have been identified with L′ and K′ observations (central wavelengths of 2.2 μm and 3.8 µm, respectively 7 , 17 , see Extended Data Fig. 1 ). We do not include these other sources in this work (except for G3/D2), either because they lie outside the OSIRIS field of view, or because they have not been detected in Brγ, or because they have not been consistently detected throughout the 13 years of data. We use Keck/NIRC2 L′ imaging data to investigate whether G3, G4, G5 and G6 have detectable L′ counterparts, as G1 and G2 do ( Methods section ‘L′ detection analysis’). No L′ counterpart was detected for G4, G5 and G6, with upper limits to the flux density of 0.4 mJy, 0.6 mJy and 0.5 mJy, respectively. G3 is detected in L′ with a dereddened flux density of 2.5 mJy, consistent with a previous report 17 . None of the G objects was detected in the K continuum. Our detection limit in the K continuum is 0.01 mJy in the OSIRIS spectra (Kn3 filter) and in the K′ broadband (2.12 μm central wavelength) a limit of 0.07 mJy was reported for G2 19 (but see ref. 20 ). The Brγ emission is a key defining feature of the G objects because it probably results from external ionization and does not depend on the mass of a putative central object, and hence its presence is independent of the nature of the G objects (low-mass cloud or extended stellar-mass object). The compactness of such emission is what distinguishes the G objects from other presumably short-lived gas blobs that have become detached from larger-scale interstellar structures. The dust heating can be attributed to some combination of the external radiation field and an internal stellar core, if present. Therefore, the lack of detection of the G objects in the L′ band does not necessarily have implications for the existence of a stellar object<|im_end|> <|im_start|>assistant Astronomers from UCLA's Galactic Center Orbits Initiative have discovered a new class of bizarre objects at the center of our galaxy, not far from the supermassive black hole called Sagittarius A*. They published their research today in the journal Nature. "These objects look like gas and behave like stars," said co-author Andrea Ghez, UCLA's Lauren B. Leichtman and Arthur E. Levine Professor of Astrophysics and director of the UCLA Galactic Center Group. The new objects look compact most of the time and stretch out when their orbits bring them closest to the black hole. Their orbits range from about 100 to 1,000 years, said lead author Anna Ciurlo, a UCLA postdoctoral researcher. Ghez's research group identified an unusual object at the center of our galaxy in 2005, which was later named G1. In 2012, astronomers in Germany made a puzzling discovery of a bizarre object named G2 in the center of the Milky Way that made a close approach to the supermassive black hole in 2014. Ghez and her research team believe that G2 is most likely two stars that had been orbiting the black hole in tandem and merged into an extremely large star, cloaked in unusually thick gas and dust. "At the time of closest approach, G2 had a really strange signature," Ghez said. "We had seen it before, but it didn't look too peculiar until it got close to the black hole and became elongated, and much of its gas was torn apart. It went from being a pretty innocuous object when it was far from the black hole to one that was really stretched out and distorted at its closest approach and lost its outer shell, and now it's getting more compact again." "One of the things that has gotten everyone excited about the G objects is that the stuff that gets pulled off of them by tidal forces as they sweep by the central black hole must inevitably fall into the black hole," said co-author Mark Morris, UCLA professor of physics and astronomy. "When that happens, it might be able to produce an impressive fireworks show since the material eaten by the black hole will heat up and emit copious radiation before it disappears across the event horizon." But are G2 and G1 outliers, or are they part of a larger class of objects? In answer to that question, Ghez's research group reports the existence of four more objects they are calling G3, G4, G5 and G6. The researchers have determined each of their orbits. While G1 and G2 have similar orbits, the four new objects have very different orbits. Ghez believes all six objects were binary stars—a system of two stars orbiting each other—that merged because of the strong gravitational force of the supermassive black hole. The merging of two stars takes more than 1 million years to complete, Ghez said. "Mergers of stars may be happening in the universe more often than we thought, and likely are quite common," Ghez said. "Black holes may be driving binary stars to merge. It's possible that many of the stars we've been watching and not understanding may be the end product of mergers that are calm now. We are learning how galaxies and black holes evolve. The way binary stars interact with each other and with the black hole is very different from how single stars interact with other single stars and with the black hole." Ciurlo noted that while the gas from G2's outer shell got stretched dramatically, its dust inside the gas did not get stretched much. "Something must have kept it compact and enabled it to survive its encounter with the black hole," Ciurlo said. "This is evidence for a stellar object inside G2." "The unique dataset that Professor Ghez's group has gathered during more than 20 years is what allowed us to make this discovery," Ciurlo said. "We now have a population of 'G' objects, so it is not a matter of explaining a 'one-time event' like G2." The researchers made observations from the W.M. Keck Observatory in Hawaii and used a powerful technology that Ghez helped pioneer, called adaptive optics, which corrects the distorting effects of the Earth's atmosphere in real time. They conducted a new analysis of 13 years of their UCLA Galactic Center Orbits Initiative data. In September 2019, Ghez's team reported that the black hole is getting hungrier and it is unclear why. The stretching of G2 in 2014 appeared to pull off gas that may recently have been swallowed by the black hole, said co-author Tuan Do, a UCLA research scientist and deputy director of the Galactic Center Group. The mergers of stars could feed the black hole. The team has already identified a few other candidates that may be part of this new class of objects, and are continuing to analyze them. Ghez noted the center of the Milky Way galaxy is an extreme environment, unlike our less hectic corner of the universe. "The Earth is in the suburbs compared to the center of the galaxy, which is some 26,000 light-years away," Ghez said. "The center of our galaxy has a density of stars 1 billion times higher than our part of the galaxy. The gravitational pull is so much stronger. The magnetic fields are more extreme. The center of the galaxy is where extreme astrophysics occurs—the X-sports of astrophysics." Ghez said this research will help to teach us what is happening in the majority of galaxies. Other co-authors include Randall Campbell, an astronomer with the W.M. Keck Observatory in Hawaii; Aurelien Hees, a former UCLA postdoctoral scholar, now a researcher at the Paris Observatory in France; and Smadar Naoz, a UCLA assistant professor of physics and astronomy. The research is funded by the National Science Foundation, W.M. Keck Foundation and Keck Visiting Scholars Program, the Gordon and Betty Moore Foundation, the Heising-Simons Foundation, Lauren Leichtman and Arthur Levine, Jim and Lori Keir, and Howard and Astrid Preston. In July 2019, Ghez's research team reported on the most comprehensive test of Einstein's iconic general theory of relativity near the black hole. They concluded that Einstein's theory passed the test and is correct, at least for now. <|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 Strange-metal phenomena often develop at the border of antiferromagnetic order in strongly correlated metals 1 . Previous work established that they can originate from the fluctuations anchored by the quantum-critical point associated with a continuous quantum phase transition out of the antiferromagnetic order 2 , 3 , 4 . What is still unclear is how these phenomena can be associated with a potential new phase of matter at zero temperature. Here, we show that magnetic frustration of the 4 f local moments in the distorted kagome intermetallic compound cerium palladium aluminium gives rise to such a paramagnetic quantum-critical phase. Our discovery motivates a design principle for strongly correlated metallic states with unconventional excitations. Main Geometrical frustration in quantum spin systems gives rise to quantum fluctuations that may suppress long-range magnetic order and cause a quantum spin liquid ground state 5 . Traditionally, this notion was associated with insulating magnets only. More recently, there is increasing recognition that geometrical frustration is also important to bad metals that host local moments, such as strongly correlated f -electron metals 6 , 7 , 8 , 9 , 10 , which provide a prototype setting for magnetic quantum phase transitions (QPTs) 2 , 3 , 4 , 11 . From general theoretical considerations, the magnetic RKKY (Ruderman–Kittel–Kasuya–Yosida) interactions on a geometrically frustrated lattice generate quantum fluctuations that interplay with those produced by the competing Kondo interactions 8 , 9 , 10 , 12 . The QPT can then involve not only antiferromagnetic order and a paramagnetic heavy Fermi liquid, but also a potential metallic spin liquid phase. Although some have argued that the latter phase may exist in some Kondo systems 6 , 7 , 13 , 14 , how it develops from magnetic frustration in a Kondo lattice has not been demonstrated so far. The distorted kagome lattice system cerium palladium aluminium (CePdAl) with local quantum spins (effective spin S eff = ½) at temperatures below T ≈ 5 K is well suited for this study 15 , 16 . Due to geometrical frustration, only two-thirds of these local spins are involved in the magnetic ordering 17 , and in the temperature ( T )–magnetic field ( B ) phase diagram the frustration-assisted short-range order sets in at T m ( B ), substantially above the Néel temperature T N ( B ) (refs. 16 , 18 ), as shown in Fig. 1a . In the field-induced paramagnetic state, well separated from a first-order antiferromagnetic transition at the highest transition field B cp ≈ 4.2 T, a continuous QPT (or quantum-critical point (QCP)) was identified 18 at B 0 * ≈ 4.6 T; see also Supplementary Fig. 1 . At temperature T = 0 and on increasing the field through B 0 *, a partial delocalization of the 4 f states takes place, which corresponds to the T →0 extrapolation of a Mott-type (localization–delocalization) cross-over line B *( T ), as introduced in ref. 18 . In addition, B 0 * is the T →0 terminating point of two other cross-over lines, one into a Fermi liquid phase at B > B 0 *, and the other into a frustration-assisted metallic spin liquid state at B cp < B < B 0 *. At B = B 0 *, about 75% of the magnetization is already saturated 19 . In contrast to the behaviour of other antiferromagnetic Kondo systems 13 , 14 , non-Fermi liquid (NFL) phenomena reflecting quantum criticality could not be observed for CePdAl in the electrical resistivity, ρ , in the paramagnetic low-temperature phase near B 0 *. This was ascribed to the large Zeeman splitting of the crystal-field ground-state doublet of the cerium 4 f shell, which causes a correspondingly large reduction of spin flip scattering and an enhanced temperature dependence of the resistivity 18 . Fig. 1: Results at zero field illustrating the emerging quantum-critical phase. a , T – p phase diagram for B = 0 on top of a colour-coded map for the exponent n of Δ ρ ( T ) ∝ T n . T N and T m are derived from the inflection points and maxima, respectively, of the (real part of the) χ ′( T ) curves, shown in Supplementary Fig. 2b . Open circles mark the Néel temperatures derived from the d.c. susceptibility measurements from ref. 19 . Error bars reflect the standard deviations in determining T N and T m from the a.c./d.c. susceptibility data (see Supplementary Fig. 2b,c ). The phase space at T > 2 K is left white because ρ ( T ) was typically measured only up to 2 K in a dilution fridge. Inset: a sketch of the distorted kagome lattice of CePdAl. b , C 4 f / T as a function of T for CePd 1− x Ni x Al with x up to 0.4. The data for x = 0.2 and x = 0.4, which are beyond the critical concentration x ≈ 0.144 (ref. 23 ), were determined in this work, while the other curves are reproduced from ref. 24 . For x = 0.2, a logarithmic increase of C 4 f ( T )/ T exists down to 0.06 K. In contrast, we find a flat and large C 4 f ( T )/ T below 0.5 K for x = 0.4. This indicates heavy Fermi liquid behaviour, as documented by the large size of C 4 f ( T )/ T at low temperatures. Inset: Δ ρ versus T in a double-log scale; here, we observe Δ ρ ∝ T 1.6 for x = 0.2 and Δ ρ ∝ T 2 for x = 0.4. c , A and A ′ in Δ ρ ( T ) ∝ T n , with n = 2 and n < 2, respectively, as well as ρ 0 as a function of p . The large size of A provides evidence for a heavy Fermi liquid phase. Inset: n versus p estimated at", "role": "user" }, { "content": "Rice University physicist Qimiao Si began mapping quantum criticality more than a decade ago, and he's finally found a traveler that can traverse the final frontier. The traveler is an alloy of cerium palladium and aluminum, and its journey is described in a study published online this week in Nature Physics by Si, a theoretical physicist and director of the Rice Center for Quantum Materials (RCQM), and colleagues in China, Germany and Japan. Si's map is a graph called a phase diagram, a tool that condensed-matter physicists often use to interpret what happens when a material changes phase, as when a solid block of ice melts into liquid water. The regions on Si's map are areas where electrons follow different sets of rules, and the paper describes how the researchers used the geometric arrangement of atoms in the alloy in combination with various pressures and magnetic fields to alter the alloy's path and bring it into a region where physicists have only been able to speculate about the rules that govern electron behavior. \"That's the corner, or portion, of this road map that everybody really wants to access,\" Si said, pointing to the upper left side of the phase diagram, high up the vertical axis marked G. \"It has taken the community a huge amount of effort to look through candidate materials that have the feature of geometrical frustration, which is one way to realize this large G.\" The frustration stems from the arrangement of cerium atoms in the alloy in a series of equilateral triangles. The kagome lattice arrangement is so named because of its similarity to patterns in traditional Japanese kagome baskets, and the triangular arrangement ensures that spins, the magnetic states of electrons, cannot arrange themselves as they normally would under certain conditions. This frustration provided an experimental lever that Si and his collaborators could use to explore a new region of the phase diagram where the boundary between two well-studied and well-understood states—one marked by an orderly arrangement of electron spins and the other by disorder—diverged. Qimiao Si is the Harry C. and Olga K. Wiess Professor in Rice University's Department of Physics and Astronomy and director of RCQM, the Rice Center for Quantum Materials. Credit: Jeff Fitlow/Rice University \"If you start with an ordered, antiferromagnetic pattern of spins in an up-down, up-down arrangement, there are several ways of softening this hard pattern of the spins,\" said Si, the Harry C. and Olga K. Wiess Professor in Rice's Department of Physics and Astronomy. \"One way is through coupling to a background of conduction electrons, and as you change conditions to enhance this coupling, the spins get more and more scrambled. When the scrambling is strong enough, the ordered pattern is destroyed, and you end up with a non-ordered phase, a paramagnetic phase.\" Physicists can plot this journey from order to disorder as a line on a phase diagram. In the example above, the line would begin in a region marked \"AF\" for antiferromagnetic phase, and continue across one border into a neighboring region marked \"P\" for paramagnetic. The border crossing is the \"quantum critical point\" where billions upon trillions of electrons act in unison, adjusting their stances to conform to the rules of the regime they have just entered. Si is a leading proponent of quantum criticality, a theoretical framework that seeks to describe and predict the behavior of quantum materials in relation to these critical points and phase changes. \"What the geometrical frustration does is to extend the process where the spin order becomes more and more fragile so that it's no longer just a point that the system passes through on the way to being disordered,\" he said. \"In fact, that point sort of splits out into a separate region, with distinct borders on either side.\" Si said the team, which included co-corresponding authors and RCQM partners Frank Steglich of the Max Planck Institute for Chemical Physics of Solids in Dresden, Germany and Peijie Sun of the Chinese Academy of Sciences in Beijing, performed experiments that provided evidence that the cerium palladium aluminum alloy undergoes two border crossings. Physicists have conducted numerous experiments to see how various materials behave in the ordered phase where the alloy began its journey and in the disordered phase where it ended, but Si said these are the first experiments to trace a path through the intervening phase that is enabled by a high degree of geometrical frustration. He said measurements of the alloy's electronic properties as it passed through the region couldn't be explained by traditional theories that describe the behavior of metals, which means the alloy behaved as a \"strange\" metal in the mystery territory. \"The system acted as a kind of spin liquid, albeit a metallic one,\" he said. Si said the results demonstrate that geometrical frustration can be used as a design principle to create strange metals. \"That is significant because the unusual electronic excitations in strange metals are also the underlying exotic properties of other strongly correlated quantum materials, including most high-temperature superconductors,\" 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 Strange-metal phenomena often develop at the border of antiferromagnetic order in strongly correlated metals 1 . Previous work established that they can originate from the fluctuations anchored by the quantum-critical point associated with a continuous quantum phase transition out of the antiferromagnetic order 2 , 3 , 4 . What is still unclear is how these phenomena can be associated with a potential new phase of matter at zero temperature. Here, we show that magnetic frustration of the 4 f local moments in the distorted kagome intermetallic compound cerium palladium aluminium gives rise to such a paramagnetic quantum-critical phase. Our discovery motivates a design principle for strongly correlated metallic states with unconventional excitations. Main Geometrical frustration in quantum spin systems gives rise to quantum fluctuations that may suppress long-range magnetic order and cause a quantum spin liquid ground state 5 . Traditionally, this notion was associated with insulating magnets only. More recently, there is increasing recognition that geometrical frustration is also important to bad metals that host local moments, such as strongly correlated f -electron metals 6 , 7 , 8 , 9 , 10 , which provide a prototype setting for magnetic quantum phase transitions (QPTs) 2 , 3 , 4 , 11 . From general theoretical considerations, the magnetic RKKY (Ruderman–Kittel–Kasuya–Yosida) interactions on a geometrically frustrated lattice generate quantum fluctuations that interplay with those produced by the competing Kondo interactions 8 , 9 , 10 , 12 . The QPT can then involve not only antiferromagnetic order and a paramagnetic heavy Fermi liquid, but also a potential metallic spin liquid phase. Although some have argued that the latter phase may exist in some Kondo systems 6 , 7 , 13 , 14 , how it develops from magnetic frustration in a Kondo lattice has not been demonstrated so far. The distorted kagome lattice system cerium palladium aluminium (CePdAl) with local quantum spins (effective spin S eff = ½) at temperatures below T ≈ 5 K is well suited for this study 15 , 16 . Due to geometrical frustration, only two-thirds of these local spins are involved in the magnetic ordering 17 , and in the temperature ( T )–magnetic field ( B ) phase diagram the frustration-assisted short-range order sets in at T m ( B ), substantially above the Néel temperature T N ( B ) (refs. 16 , 18 ), as shown in Fig. 1a . In the field-induced paramagnetic state, well separated from a first-order antiferromagnetic transition at the highest transition field B cp ≈ 4.2 T, a continuous QPT (or quantum-critical point (QCP)) was identified 18 at B 0 * ≈ 4.6 T; see also Supplementary Fig. 1 . At temperature T = 0 and on increasing the field through B 0 *, a partial delocalization of the 4 f states takes place, which corresponds to the T →0 extrapolation of a Mott-type (localization–delocalization) cross-over line B *( T ), as introduced in ref. 18 . In addition, B 0 * is the T →0 terminating point of two other cross-over lines, one into a Fermi liquid phase at B > B 0 *, and the other into a frustration-assisted metallic spin liquid state at B cp < B < B 0 *. At B = B 0 *, about 75% of the magnetization is already saturated 19 . In contrast to the behaviour of other antiferromagnetic Kondo systems 13 , 14 , non-Fermi liquid (NFL) phenomena reflecting quantum criticality could not be observed for CePdAl in the electrical resistivity, ρ , in the paramagnetic low-temperature phase near B 0 *. This was ascribed to the large Zeeman splitting of the crystal-field ground-state doublet of the cerium 4 f shell, which causes a correspondingly large reduction of spin flip scattering and an enhanced temperature dependence of the resistivity 18 . Fig. 1: Results at zero field illustrating the emerging quantum-critical phase. a , T – p phase diagram for B = 0 on top of a colour-coded map for the exponent n of Δ ρ ( T ) ∝ T n . T N and T m are derived from the inflection points and maxima, respectively, of the (real part of the) χ ′( T ) curves, shown in Supplementary Fig. 2b . Open circles mark the Néel temperatures derived from the d.c. susceptibility measurements from ref. 19 . Error bars reflect the standard deviations in determining T N and T m from the a.c./d.c. susceptibility data (see Supplementary Fig. 2b,c ). The phase space at T > 2 K is left white because ρ ( T ) was typically measured only up to 2 K in a dilution fridge. Inset: a sketch of the distorted kagome lattice of CePdAl. b , C 4 f / T as a function of T for CePd 1− x Ni x Al with x up to 0.4. The data for x = 0.2 and x = 0.4, which are beyond the critical concentration x ≈ 0.144 (ref. 23 ), were determined in this work, while the other curves are reproduced from ref. 24 . For x = 0.2, a logarithmic increase of C 4 f ( T )/ T exists down to 0.06 K. In contrast, we find a flat and large C 4 f ( T )/ T below 0.5 K for x = 0.4. This indicates heavy Fermi liquid behaviour, as documented by the large size of C 4 f ( T )/ T at low temperatures. Inset: Δ ρ versus T in a double-log scale; here, we observe Δ ρ ∝ T 1.6 for x = 0.2 and Δ ρ ∝ T 2 for x = 0.4. c , A and A ′ in Δ ρ ( T ) ∝ T n , with n = 2 and n < 2, respectively, as well as ρ 0 as a function of p . The large size of A provides evidence for a heavy Fermi liquid phase. Inset: n versus p estimated at<|im_end|> <|im_start|>assistant Rice University physicist Qimiao Si began mapping quantum criticality more than a decade ago, and he's finally found a traveler that can traverse the final frontier. The traveler is an alloy of cerium palladium and aluminum, and its journey is described in a study published online this week in Nature Physics by Si, a theoretical physicist and director of the Rice Center for Quantum Materials (RCQM), and colleagues in China, Germany and Japan. Si's map is a graph called a phase diagram, a tool that condensed-matter physicists often use to interpret what happens when a material changes phase, as when a solid block of ice melts into liquid water. The regions on Si's map are areas where electrons follow different sets of rules, and the paper describes how the researchers used the geometric arrangement of atoms in the alloy in combination with various pressures and magnetic fields to alter the alloy's path and bring it into a region where physicists have only been able to speculate about the rules that govern electron behavior. "That's the corner, or portion, of this road map that everybody really wants to access," Si said, pointing to the upper left side of the phase diagram, high up the vertical axis marked G. "It has taken the community a huge amount of effort to look through candidate materials that have the feature of geometrical frustration, which is one way to realize this large G." The frustration stems from the arrangement of cerium atoms in the alloy in a series of equilateral triangles. The kagome lattice arrangement is so named because of its similarity to patterns in traditional Japanese kagome baskets, and the triangular arrangement ensures that spins, the magnetic states of electrons, cannot arrange themselves as they normally would under certain conditions. This frustration provided an experimental lever that Si and his collaborators could use to explore a new region of the phase diagram where the boundary between two well-studied and well-understood states—one marked by an orderly arrangement of electron spins and the other by disorder—diverged. Qimiao Si is the Harry C. and Olga K. Wiess Professor in Rice University's Department of Physics and Astronomy and director of RCQM, the Rice Center for Quantum Materials. Credit: Jeff Fitlow/Rice University "If you start with an ordered, antiferromagnetic pattern of spins in an up-down, up-down arrangement, there are several ways of softening this hard pattern of the spins," said Si, the Harry C. and Olga K. Wiess Professor in Rice's Department of Physics and Astronomy. "One way is through coupling to a background of conduction electrons, and as you change conditions to enhance this coupling, the spins get more and more scrambled. When the scrambling is strong enough, the ordered pattern is destroyed, and you end up with a non-ordered phase, a paramagnetic phase." Physicists can plot this journey from order to disorder as a line on a phase diagram. In the example above, the line would begin in a region marked "AF" for antiferromagnetic phase, and continue across one border into a neighboring region marked "P" for paramagnetic. The border crossing is the "quantum critical point" where billions upon trillions of electrons act in unison, adjusting their stances to conform to the rules of the regime they have just entered. Si is a leading proponent of quantum criticality, a theoretical framework that seeks to describe and predict the behavior of quantum materials in relation to these critical points and phase changes. "What the geometrical frustration does is to extend the process where the spin order becomes more and more fragile so that it's no longer just a point that the system passes through on the way to being disordered," he said. "In fact, that point sort of splits out into a separate region, with distinct borders on either side." Si said the team, which included co-corresponding authors and RCQM partners Frank Steglich of the Max Planck Institute for Chemical Physics of Solids in Dresden, Germany and Peijie Sun of the Chinese Academy of Sciences in Beijing, performed experiments that provided evidence that the cerium palladium aluminum alloy undergoes two border crossings. Physicists have conducted numerous experiments to see how various materials behave in the ordered phase where the alloy began its journey and in the disordered phase where it ended, but Si said these are the first experiments to trace a path through the intervening phase that is enabled by a high degree of geometrical frustration. He said measurements of the alloy's electronic properties as it passed through the region couldn't be explained by traditional theories that describe the behavior of metals, which means the alloy behaved as a "strange" metal in the mystery territory. "The system acted as a kind of spin liquid, albeit a metallic one," he said. Si said the results demonstrate that geometrical frustration can be used as a design principle to create strange metals. "That is significant because the unusual electronic excitations in strange metals are also the underlying exotic properties of other strongly correlated quantum materials, including most high-temperature superconductors," he said. <|im_end|>

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2,421

[ { "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 Very low frequency communication systems (3 kHz–30 kHz) enable applications not feasible at higher frequencies. However, the highest radiation efficiency antennas require size at the scale of the wavelength (here, >1 km), making portable transmitters extremely challenging. Facilitating transmitters at the 10 cm scale, we demonstrate an ultra-low loss lithium niobate piezoelectric electric dipole driven at acoustic resonance that radiates with greater than 300x higher efficiency compared to the previous state of the art at a comparable electrical size. A piezoelectric radiating element eliminates the need for large impedance matching networks as it self-resonates at the acoustic wavelength. Temporal modulation of this resonance demonstrates a device bandwidth greater than 83x beyond the conventional Bode-Fano limit, thus increasing the transmitter bitrate while still minimizing losses. These results will open new applications for portable, electrically small antennas. Introduction The prevalence of human portable or autonomous vehicle platforms has significantly increased the demand for small, efficient transmitters 1 . Particularly attractive, very low frequency (VLF) signals attenuate <6 dB/1000 km within the Earth-ionosphere waveguide and can penetrate tens of meters into seawater or dirt. Conventional transmitter techniques are inadequate due to large size and high loss. We show that a strain-based, piezoelectric transmitter can overcome many of the fundamental limitations of conventional electrically small antennas (ESA). These transmitters can resonate in a very small footprint while exhibiting low losses 2 , 3 . Traditionally, a disadvantage of passive high-Q antennas was low bandwidth. Utilizing piezoelectricity as the radiating element allows us to dynamically shift the transmitter resonant frequency. Therefore, high total Q (low loss) no longer constrains the system bandwidth. These are our fundamental advancements: achieving an exceptionally high system Q with no external impedance matching network and an effective fractional bandwidth beyond the passive Bode-Fano limit 4 . Although demonstrated at VLF, this concept straightforwardly scales to other frequency bands. A significant challenge for ESAs with a wavenumber-length product much <1 is a high radiation Q, Q A , which considerably limits the radiation efficiency 5 , 6 . In a lossy antenna, the total Q is Q t = 1/(1/ Q m + 1/ Q A ) where Q m encompasses all non-radiation losses within the antenna system. If Q m is much less than Q A , then Q t is approximately equal to Q m and therefore, to maximize the transmitter efficiency, η = Q m / Q A , Q m must be maximized. Assuming a wavenumber-length product of 7.5 × 10 −5 , the minimum Q A 7 , 8 , 9 is between 3 × 10 12 and 3 × 10 13 (see methods). Therefore, to have a measurable increase of efficiency, Q m must be very large. Bulky impedance matching networks compound antenna inefficiency. Consider an electric dipole antenna made up of a copper wire normal to a ground plane. To impedance match to a 10-cm long, 10 mA m rms , 35.5 kHz antenna, a 10.5 H, 125 kV inductor is needed. The size and loss of this matching network, even assuming a Q of 1000, greatly exceed the antenna itself, making this technique non-viable. Active non-Foster matching networks, while shown to improve system bandwidth, are unwieldy at high voltages 10 , 11 , 12 . A potential solution is acoustically resonant transmitters 3 , 13 . Radiation has been measured from vibrating quartz resonators 14 , 15 , 16 and piezo-magnetic or multiferroic antennas have both improved ESAs 2 , 3 , 17 . An advantage of strain-based antennas is acoustic resonance in a device with physical dimensions much less than the electromagnetic wavelength, potentially removing the need for large, external impedance-matching elements. Passive, high Q transmitters have small fractional bandwidths, $$B = \\frac{1}{{Q_t}}\\left( {\\frac{{{\\mathrm{vswr}} - 1}}{{\\sqrt {{\\mathrm{vswr}}} }}} \\right),$$ (1) as they are bound by the Bode-Fano limit 4 . Here, the voltage standing wave ratio, vswr, is assumed to have a value of 2. A common metric for evaluating ESAs is the bandwidth-efficiency product 18 , 19 , $$B\\eta = \\frac{1}{{Q_t}}\\left( {\\frac{{{\\mathrm{vswr}} - 1}}{{\\sqrt {{\\mathrm{vswr}}} }}} \\right)\\left( {\\frac{{Q_t}}{{Q_{A,\\rm{min}}}}} \\right)$$ (2) For a passive antenna, this relationship simplifies to Bη = 1/( \$\\sqrt 2\$ Q A, min ) which is a function of Q A ,min , itself a function of the antenna electrical size. This implies that electrically small, low-loss transmitters are also low bandwidth and therefore, by the Shannon–Hartley theorem, have limited data bitrates 20 . Direct antenna modulation (DAM) decouples bandwidth from Q t 21 , 22 , 23 , 24 , 25 , 26 , 27 . In one embodiment, the resonant frequency is actively shifted coincident with changes in the input drive frequency. DAM enables operation at a frequency outside the fractional bandwidth of the passive antenna. In a frequency shift keying (FSK) modulation scheme, the carrier and hop frequencies each correspond to a different resonant frequency which changes at the FSK rate. Because an active transmitter is not a linear time-invariant system, the Bode-Fano limit does not constrain the bandwidth. If both the frequency separation, δf , and Q m are maximized, a larger bandwidth-efficiency product is possible, $$B_\\eta = \\left( {\\frac{{\\delta f}}{{f_c}}} \\right)\\left( {\\frac{{Q_m}}{{Q_A}}} \\right)$$ (3) As well as high bandwidth and efficiency, the radiated signal magnitude should be maximized. The electric dipole moment in a bulk piezoelectric resonator scales as ~ dT where d is the piezoelectric charge constant and T is stress. The effective d , allowable stress, and Q m should be maximized. The lumped Q m of the resonator system includes mounting losses, external dampening, and internal losses in the piezoelectric material itself 28 . The Y \$\\angle\$ 36° cut of single crystal lithium niobate (LN) is advantageous due to a yield stress >50 MPa as well as low intrinsic losses in bulk length-extensional modes, the second mode of which couples minimally to the mounting points. In this mode, thermoelastic dissipation and Akhiezer damping are low. Figure 1 shows the electric dipole moment and external electric fields of this vibration", "role": "user" }, { "content": "A new type of pocket-sized antenna, developed at the Department of Energy's SLAC National Accelerator Laboratory, could enable mobile communication in situations where conventional radios don't work, such as under water, through the ground and over very long distances through air. The device emits very low frequency (VLF) radiation with wavelengths of tens to hundreds of miles. These waves travel long distances beyond the horizon and can penetrate environments that would block radio waves with shorter wavelengths. While today's most powerful VLF technology requires gigantic emitters, this antenna is only four inches tall, so it could potentially be used for tasks that demand high mobility, including rescue and defense missions. \"Our device is also hundreds of times more efficient and can transmit data faster than previous devices of comparable size,\" said SLAC's Mark Kemp, the project's principal investigator. \"Its performance pushes the limits of what's technologically possible and puts portable VLF applications, like sending short text messages in challenging situations, within reach.\" The SLAC-led team reported their results today in Nature Communications. A sizable challenge In modern telecommunications, radio waves transport information through air for radio broadcasts, radar and navigation systems and other applications. But shorter-wavelength radio waves have their limits: The signal they transmit becomes weak over very long distances, can't travel through water and is easily blocked by layers of rock. A new compact antenna for very low frequency (VLF) transmissions, developed and tested at SLAC, consists of a 4-inch-long piezoelectric crystal (clear rod at center) that generates VLF radiation. Credit: Dawn Harmer/SLAC National Accelerator Laboratory In contrast, the longer wavelength of VLF radiation allows it to travel hundreds of feet through ground and water and thousands of miles beyond the horizon through air. However, VLF technology also comes with major challenges. An antenna is most efficient when its size is comparable to the wavelength it emits; VLF's long wavelength requires enormous antenna arrays that stretch for miles. Smaller VLF transmitters are much less efficient and can weigh hundreds of pounds, limiting their intended use as mobile devices. Another challenge is the low bandwidth of VLF communication, which limits the amount of data it can transmit. The new antenna was designed with these issues in mind. Its compact size could make it possible to build transmitters that weigh only a few pounds. In tests that sent signals from the transmitter to a receiver 100 feet away, the researchers demonstrated that their device produced VLF radiation 300 times more efficiently than previous compact antennas and transmitted data with almost 100 times greater bandwidth. \"There are many exciting potential applications for the technology,\" Kemp said. \"Our device is optimized for long-range communication through air, and our research is looking at the fundamental science behind the method to find ways to further enhance its capabilities.\" Principle of a new compact very low frequency (VLF) antenna. It consists of a rod-shaped crystal of a piezoelectric material, lithium niobate (center). An oscillating electric voltage (red wave) applied to the bottom of the rod makes it vibrate. This mechanical stress triggers an oscillating electric current (arrows) whose electromagnetic energy then gets emitted as VLF radiation (blue waves). The device can be switched during operations to tweak the wavelength of the emitted radiation and optimize the rate at which the device can transmit data. Credit: Greg Stewart/SLAC National Accelerator Laboratory A mechanical antenna To generate VLF radiation, the device exploits what is known as the piezoelectric effect, which converts mechanical stress to a buildup of electrical charge. The researchers used a rod-shaped crystal of a piezoelectric material, lithium niobate, as their antenna. When they applied an oscillating electric voltage to the rod it vibrated, alternately shrinking and expanding, and this mechanical stress triggered an oscillating electric current whose electromagnetic energy then got emitted as VLF radiation. The electric current stems from electric charges moving up and down the rod. In conventional antennas, these motions are close to the same size as the wavelength of the radiation they produce, and more compact designs typically require tuning units larger than the antenna itself. The new approach, on the other hand, \"allows us to efficiently excite electromagnetic waves with wavelengths that are much larger than the motions along the crystal and without large tuners, which is why this antenna is so compact,\" Kemp said. The researchers also found a clever way of tweaking the wavelength of the emitted radiation, he said: \"We repeatedly switch the wavelength during operation, which allows us to transmit with a large bandwidth. This is key to achieving data transfer rates of more than 100 bits per second—enough to send a simple text.\" ", "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 Very low frequency communication systems (3 kHz–30 kHz) enable applications not feasible at higher frequencies. However, the highest radiation efficiency antennas require size at the scale of the wavelength (here, >1 km), making portable transmitters extremely challenging. Facilitating transmitters at the 10 cm scale, we demonstrate an ultra-low loss lithium niobate piezoelectric electric dipole driven at acoustic resonance that radiates with greater than 300x higher efficiency compared to the previous state of the art at a comparable electrical size. A piezoelectric radiating element eliminates the need for large impedance matching networks as it self-resonates at the acoustic wavelength. Temporal modulation of this resonance demonstrates a device bandwidth greater than 83x beyond the conventional Bode-Fano limit, thus increasing the transmitter bitrate while still minimizing losses. These results will open new applications for portable, electrically small antennas. Introduction The prevalence of human portable or autonomous vehicle platforms has significantly increased the demand for small, efficient transmitters 1 . Particularly attractive, very low frequency (VLF) signals attenuate <6 dB/1000 km within the Earth-ionosphere waveguide and can penetrate tens of meters into seawater or dirt. Conventional transmitter techniques are inadequate due to large size and high loss. We show that a strain-based, piezoelectric transmitter can overcome many of the fundamental limitations of conventional electrically small antennas (ESA). These transmitters can resonate in a very small footprint while exhibiting low losses 2 , 3 . Traditionally, a disadvantage of passive high-Q antennas was low bandwidth. Utilizing piezoelectricity as the radiating element allows us to dynamically shift the transmitter resonant frequency. Therefore, high total Q (low loss) no longer constrains the system bandwidth. These are our fundamental advancements: achieving an exceptionally high system Q with no external impedance matching network and an effective fractional bandwidth beyond the passive Bode-Fano limit 4 . Although demonstrated at VLF, this concept straightforwardly scales to other frequency bands. A significant challenge for ESAs with a wavenumber-length product much <1 is a high radiation Q, Q A , which considerably limits the radiation efficiency 5 , 6 . In a lossy antenna, the total Q is Q t = 1/(1/ Q m + 1/ Q A ) where Q m encompasses all non-radiation losses within the antenna system. If Q m is much less than Q A , then Q t is approximately equal to Q m and therefore, to maximize the transmitter efficiency, η = Q m / Q A , Q m must be maximized. Assuming a wavenumber-length product of 7.5 × 10 −5 , the minimum Q A 7 , 8 , 9 is between 3 × 10 12 and 3 × 10 13 (see methods). Therefore, to have a measurable increase of efficiency, Q m must be very large. Bulky impedance matching networks compound antenna inefficiency. Consider an electric dipole antenna made up of a copper wire normal to a ground plane. To impedance match to a 10-cm long, 10 mA m rms , 35.5 kHz antenna, a 10.5 H, 125 kV inductor is needed. The size and loss of this matching network, even assuming a Q of 1000, greatly exceed the antenna itself, making this technique non-viable. Active non-Foster matching networks, while shown to improve system bandwidth, are unwieldy at high voltages 10 , 11 , 12 . A potential solution is acoustically resonant transmitters 3 , 13 . Radiation has been measured from vibrating quartz resonators 14 , 15 , 16 and piezo-magnetic or multiferroic antennas have both improved ESAs 2 , 3 , 17 . An advantage of strain-based antennas is acoustic resonance in a device with physical dimensions much less than the electromagnetic wavelength, potentially removing the need for large, external impedance-matching elements. Passive, high Q transmitters have small fractional bandwidths, $$B = \frac{1}{{Q_t}}\left( {\frac{{{\mathrm{vswr}} - 1}}{{\sqrt {{\mathrm{vswr}}} }}} \right),$$ (1) as they are bound by the Bode-Fano limit 4 . Here, the voltage standing wave ratio, vswr, is assumed to have a value of 2. A common metric for evaluating ESAs is the bandwidth-efficiency product 18 , 19 , $$B\eta = \frac{1}{{Q_t}}\left( {\frac{{{\mathrm{vswr}} - 1}}{{\sqrt {{\mathrm{vswr}}} }}} \right)\left( {\frac{{Q_t}}{{Q_{A,\rm{min}}}}} \right)$$ (2) For a passive antenna, this relationship simplifies to Bη = 1/( $\sqrt 2$ Q A, min ) which is a function of Q A ,min , itself a function of the antenna electrical size. This implies that electrically small, low-loss transmitters are also low bandwidth and therefore, by the Shannon–Hartley theorem, have limited data bitrates 20 . Direct antenna modulation (DAM) decouples bandwidth from Q t 21 , 22 , 23 , 24 , 25 , 26 , 27 . In one embodiment, the resonant frequency is actively shifted coincident with changes in the input drive frequency. DAM enables operation at a frequency outside the fractional bandwidth of the passive antenna. In a frequency shift keying (FSK) modulation scheme, the carrier and hop frequencies each correspond to a different resonant frequency which changes at the FSK rate. Because an active transmitter is not a linear time-invariant system, the Bode-Fano limit does not constrain the bandwidth. If both the frequency separation, δf , and Q m are maximized, a larger bandwidth-efficiency product is possible, $$B_\eta = \left( {\frac{{\delta f}}{{f_c}}} \right)\left( {\frac{{Q_m}}{{Q_A}}} \right)$$ (3) As well as high bandwidth and efficiency, the radiated signal magnitude should be maximized. The electric dipole moment in a bulk piezoelectric resonator scales as ~ dT where d is the piezoelectric charge constant and T is stress. The effective d , allowable stress, and Q m should be maximized. The lumped Q m of the resonator system includes mounting losses, external dampening, and internal losses in the piezoelectric material itself 28 . The Y $\angle$ 36° cut of single crystal lithium niobate (LN) is advantageous due to a yield stress >50 MPa as well as low intrinsic losses in bulk length-extensional modes, the second mode of which couples minimally to the mounting points. In this mode, thermoelastic dissipation and Akhiezer damping are low. Figure 1 shows the electric dipole moment and external electric fields of this vibration<|im_end|> <|im_start|>assistant A new type of pocket-sized antenna, developed at the Department of Energy's SLAC National Accelerator Laboratory, could enable mobile communication in situations where conventional radios don't work, such as under water, through the ground and over very long distances through air. The device emits very low frequency (VLF) radiation with wavelengths of tens to hundreds of miles. These waves travel long distances beyond the horizon and can penetrate environments that would block radio waves with shorter wavelengths. While today's most powerful VLF technology requires gigantic emitters, this antenna is only four inches tall, so it could potentially be used for tasks that demand high mobility, including rescue and defense missions. "Our device is also hundreds of times more efficient and can transmit data faster than previous devices of comparable size," said SLAC's Mark Kemp, the project's principal investigator. "Its performance pushes the limits of what's technologically possible and puts portable VLF applications, like sending short text messages in challenging situations, within reach." The SLAC-led team reported their results today in Nature Communications. A sizable challenge In modern telecommunications, radio waves transport information through air for radio broadcasts, radar and navigation systems and other applications. But shorter-wavelength radio waves have their limits: The signal they transmit becomes weak over very long distances, can't travel through water and is easily blocked by layers of rock. A new compact antenna for very low frequency (VLF) transmissions, developed and tested at SLAC, consists of a 4-inch-long piezoelectric crystal (clear rod at center) that generates VLF radiation. Credit: Dawn Harmer/SLAC National Accelerator Laboratory In contrast, the longer wavelength of VLF radiation allows it to travel hundreds of feet through ground and water and thousands of miles beyond the horizon through air. However, VLF technology also comes with major challenges. An antenna is most efficient when its size is comparable to the wavelength it emits; VLF's long wavelength requires enormous antenna arrays that stretch for miles. Smaller VLF transmitters are much less efficient and can weigh hundreds of pounds, limiting their intended use as mobile devices. Another challenge is the low bandwidth of VLF communication, which limits the amount of data it can transmit. The new antenna was designed with these issues in mind. Its compact size could make it possible to build transmitters that weigh only a few pounds. In tests that sent signals from the transmitter to a receiver 100 feet away, the researchers demonstrated that their device produced VLF radiation 300 times more efficiently than previous compact antennas and transmitted data with almost 100 times greater bandwidth. "There are many exciting potential applications for the technology," Kemp said. "Our device is optimized for long-range communication through air, and our research is looking at the fundamental science behind the method to find ways to further enhance its capabilities." Principle of a new compact very low frequency (VLF) antenna. It consists of a rod-shaped crystal of a piezoelectric material, lithium niobate (center). An oscillating electric voltage (red wave) applied to the bottom of the rod makes it vibrate. This mechanical stress triggers an oscillating electric current (arrows) whose electromagnetic energy then gets emitted as VLF radiation (blue waves). The device can be switched during operations to tweak the wavelength of the emitted radiation and optimize the rate at which the device can transmit data. Credit: Greg Stewart/SLAC National Accelerator Laboratory A mechanical antenna To generate VLF radiation, the device exploits what is known as the piezoelectric effect, which converts mechanical stress to a buildup of electrical charge. The researchers used a rod-shaped crystal of a piezoelectric material, lithium niobate, as their antenna. When they applied an oscillating electric voltage to the rod it vibrated, alternately shrinking and expanding, and this mechanical stress triggered an oscillating electric current whose electromagnetic energy then got emitted as VLF radiation. The electric current stems from electric charges moving up and down the rod. In conventional antennas, these motions are close to the same size as the wavelength of the radiation they produce, and more compact designs typically require tuning units larger than the antenna itself. The new approach, on the other hand, "allows us to efficiently excite electromagnetic waves with wavelengths that are much larger than the motions along the crystal and without large tuners, which is why this antenna is so compact," Kemp said. The researchers also found a clever way of tweaking the wavelength of the emitted radiation, he said: "We repeatedly switch the wavelength during operation, which allows us to transmit with a large bandwidth. This is key to achieving data transfer rates of more than 100 bits per second—enough to send a simple text." <|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 Rising sea temperatures and increasing pollution threaten the fate of coral reefs and millions of people who depend on them. Some reef-building corals respond to thermal stress and subsequent bleaching with increases in heterotrophy, which may increase the risk of ingesting microplastics. Whether this heterotrophic plasticity affects microplastics ingestion or whether ingesting microplastics affects heterotrophic feeding in corals is unknown. To determine this, two coral species, Montipora capitata and Pocillopora damicornis , were exposed to ambient (~27 °C) and increased (~30 °C) temperature and then fed microplastics, Artemia nauplii, or both. Following thermal stress, both species significantly reduced feeding on Artemia but no significant decrease in microplastics ingestion was observed. Interestingly, P . damicornis only ingested microplastics when Artemia were also present, providing evidence that microplastics are not selectively ingested by this species and are only incidentally ingested when food is available. As the first study to examine microplastics ingestion following thermal stress in corals, our results highlight the variability in the risk of microplastics ingestion among species and the importance of considering multiple drivers to project how corals will be affected by global change. Introduction Reef building corals (Scleractinia) are increasingly challenged by a suite of anthropogenic stressors including pollution and rising sea temperatures due to climate change 1 , 2 . These stressors threaten the fate of coral reefs and the ecosystem services they provide which support the livelihoods of tens of millions of people worldwide 3 . Model projections forecast that more than 75% of coral reefs will be subjected to annual severe bleaching before 2070 due to thermal stress alone 4 , but the fate of corals may be worsened when they face additional stressors 5 , 6 . Recent evidence suggests that microplastics (plastic particles or fibers <5 mm), may negatively affect corals 7 , 8 , 9 , 10 . To date, however, no studies have looked at the potential for thermal stress to affect microplastics ingestion by reef-building corals. Under normal conditions, most reef-building corals acquire the majority of their energy from a symbiotic partnership with photosynthetic dinoflagellates in the family Symbiodiniaceae 11 , while less energy is generally derived from heterotrophic feeding on zooplankton 12 , 13 , 14 . When thermally stressed, Symbiodiniaceae are expelled from corals (bleaching) leading to a net decrease in autotrophic energy acquisition 15 , 16 . If elevated temperatures persist, corals deplete their energy reserves and can starve, but if the temperature reduces before the corals’ energy reserves are exhausted, Symbiodiniaceae can be reacquired and the coral may recover 17 , 18 , 19 . Some corals respond to thermal stress and subsequent bleaching by increased heterotrophy which shifts the corals’ reliance from energy derived from photosynthesis to energy derived from zooplankton prey, an adaptation termed heterotrophic plasticity 14 , 20 , 21 , 22 , 23 . While the underlying mechanisms and timing of this response are still unclear, increased carbon acquisition from heterotrophy can help corals maintain daily metabolic costs until Symbiodiniaceae can be reacquired. In contrast, other corals decrease their feeding rate during, or following, thermal stress 22 , 23 , 24 which may negatively impact their resilience. For corals that display heterotrophic plasticity, increased feeding of zooplankton prey could potentially increase their risk of ingesting unwanted particles in the water, such as microplastics. Microplastics are considered ubiquitous in aquatic ecosystems worldwide and are negatively impacting marine life 25 . By 2014, there was an estimated 15 to 51 trillion microplastic particles in the oceans 26 , which are derived from direct manufacturing or break down from larger plastic debris due to abrasion, wave action, and UV radiation. Plastic waste entering the oceans is expected to increase 10-fold by 2025 27 leading to growing concerns about the potential for these pollutants to negatively affect marine organisms. Their similarity in shape and size to zooplankton make microplastics particularly problematic for planktivorous animals such as corals that can ingest them while feeding 8 . In some organisms, ingesting microplastics can lead to decreased feeding efficiency, growth and fecundity 9 , 28 , 29 but for corals these effects are still not fully understood. Further, there is increasing concern about the role of plastics, large and small, to act as vectors for diseases and contaminants 30 , 31 , 32 . Previous studies have demonstrated that ingesting, and exposure to, microplastics can have negative effects on corals. Corals that ingested microplastics tended to egest most of them within 48 h which limited the time microplastics could cause internal damage but is still thought to be energetically costly 7 , 8 , 9 . For some coral species, exposure to microplastics resulted in increased mucous production, bleaching, necrosis, changes in photosynthetic performance, and decreased growth and feeding rates 7 , 9 , 10 . One coral species, Astrangia poculata , appeared to selectively feed on clean microplastics when also offered bio-fouled particles, leading researchers to suggest that chemical cues released by plastics (i.e., chemoreception) drove ingestion 33 . Additional research also showed that A . poculata preferred to feed on microplastics over similar sized brine shrimp eggs, and that ingesting microplastics can inhibit later feeding on nutritious prey 32 . While we are beginning to understand the responses and mechanisms of microplastics ingestion by corals, we still do not know how this pervasive pollutant interacts with other stressors, such as rising sea temperatures. The objective of this study was to examine whether prior exposure to thermal stress affects microplastics ingestion and if microplastics exposure and ingestion affects the amount of prey ingested by reef-building corals. To determine this, we compared ingestion rates of corals exposed to microplastics (MP) only, Artemia only, or MP and Artemia following ambient and increased temperature treatments. We hypothesized that if Artemia ingestion changed due to thermal stress, we would also see a similar trend in MP ingestion rates. Additionally, if a chemical in microplastics makes them more appealing to corals 33 , then we hypothesized that corals exposed to microplastics would", "role": "user" }, { "content": "Tiny microplastic particles are about as common in the ocean today as plastic is in our daily lives. Synthetic clothing, containers, bottles, plastic bags and cosmetics all degrade and release microplastics into the environment. Corals and other marine organisms are eating microplastics that enter the waterway. Studies in this emerging field show some harmful effects, but it's largely unknown how this ubiquitous material is impacting ocean life. A new experiment by the University of Washington has found that some corals are more likely to eat microplastics when they are consuming other food, yet microplastics alone are undesirable. Two coral species tested responded differently to the synthetic material, suggesting variations in how corals are adapting to life with microplastics. The study was published Dec. 3 in the journal Scientific Reports. \"The more plastic we use, the more microplastics there are, and the more corals are going to be exposed,\" said lead author Jeremy Axworthy, a UW doctoral student in the School of Aquatic and Fishery Sciences. \"Our study found that some corals probably won't eat microplastics and will keep going about their daily business. But some might—and if they happen to be sensitive to warmer ocean temperatures or other stressors, this is just another compounding factor to be worried about.\" Corals are tiny animals that are rooted to the reef or rocks on the ocean floor. They use tentacle-like arms to sweep food into their mouths. Many rely on algae for energy, but most also consume drifting animals for survival. This study is the first to examine whether corals eat microplastics when exposed to warmer water, which is expected to accelerate with climate change. Rising ocean temperatures can be deadly for coral: warm water stresses them, causing corals to lose their symbiotic algae partner that undergoes photosynthesis and provides energy for them to survive. When this happens, coral bleaching and eventual death can occur. Jeremy Axworthy removes a young coral from a tank at the team's University of Washington lab. The two coral species shown here are Pocillopora damicornis (left), known as cauliflower coral, and Montipora capitatae (right), or rice coral. Cauliflower coral was more likely to ingest microplastics during the team's experiments. Credit: Dennis Wise/University of Washington But some corals have adapted to bleaching by shifting their diets to feed on tiny marine organisms called zooplankton, which provide an alternate energy source. As they munch on these small animals—often the same size as microplastics—the research team wondered whether they also were ingesting plastic fragments. The experiment shows corals do eat microplastics when they switch to a zooplankton diet, adding one more stressor for corals in a changing ocean environment. \"Microplastics are not as simple as a life-or-death threat for corals—it's not that black or white,\" said senior author Jacqueline Padilla-Gamiño, assistant professor at the UW School of Aquatic and Fishery Sciences. \"It's about total energy lost. If corals constantly are dealing with microplastics, it might not kill them, but there will be less energy for them to grow and to reproduce.\" The researchers collected two species of common corals off the east coast of Oahu, Hawaii, and exposed half of each species to warmer water for several weeks to induce stress and bleaching. Then they ran four different feeding experiments on both bleached and non-bleached corals: corals were fed only microplastics; only a type of zooplankton; microplastics and zooplankton; or nothing. After dissecting the coral polyps, researchers found that corals stressed by warmer temperatures actually ate much less than their counterparts in normal seawater. This was unexpected and possibly due to stress from high water temperatures. However, one of the two species, known for its voracious eating habits in the wild, consumed microplastics only while also eating zooplankton. Neither coral species ate microplastics alone. The researchers don't know why one species of coral readily ate microplastics in the presence of other food, but avoided microplastics when they were the only thing on the menu. They suspect that this species of coral can read certain chemical or physical cues from the plastics and the prey, but might not be able to distinguish between the two when both are present. Under a black light, fluorescent green microplastics are seen in the water during a small demonstration experiment. In the 2018 experiment described in the paper, cauliflower coral (above) ingested microplastics when prey was also present in the water, but avoided eating microplastics when no prey was there. Credit: Dennis Wise/University of Washington It's also possible the plastic used in this experiment is less desirable to corals, and that plastics with a different chemical makeup could, in fact, be tasty to corals. The researchers plan to test the \"tastiness\" of other types of microplastics, such as synthetic fibers from clothing. Ultimately, some coral species likely face greater risks from exposure to microplastics than others, the study found. The researchers will look next at impacts on the physiology of corals that are exposed over a longer period to microplastics. \"Knowing that will provide a lot more context to this work,\" Axworthy said. \"We need to know the full physiological impacts of chronic exposure to microplastics on corals, especially at increased temperatures, to understand how serious the problem is.\" In the meantime, the problem of microplastics isn't going away. A 2014 estimate found between 15 and 51 trillion microplastic particles in the oceans, and plastic waste entering the oceans is expected to increase tenfold between 2010 and 2025. \"It's important when talking about waste management to think big picture—what are we putting in the oceans?\" Padilla-Gamiño said. \"We don't know where plastic goes, where it stays, who grabs it, and what are the mechanisms by which we get it back. We are just at the tip of understanding these implications.\" ", "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 Rising sea temperatures and increasing pollution threaten the fate of coral reefs and millions of people who depend on them. Some reef-building corals respond to thermal stress and subsequent bleaching with increases in heterotrophy, which may increase the risk of ingesting microplastics. Whether this heterotrophic plasticity affects microplastics ingestion or whether ingesting microplastics affects heterotrophic feeding in corals is unknown. To determine this, two coral species, Montipora capitata and Pocillopora damicornis , were exposed to ambient (~27 °C) and increased (~30 °C) temperature and then fed microplastics, Artemia nauplii, or both. Following thermal stress, both species significantly reduced feeding on Artemia but no significant decrease in microplastics ingestion was observed. Interestingly, P . damicornis only ingested microplastics when Artemia were also present, providing evidence that microplastics are not selectively ingested by this species and are only incidentally ingested when food is available. As the first study to examine microplastics ingestion following thermal stress in corals, our results highlight the variability in the risk of microplastics ingestion among species and the importance of considering multiple drivers to project how corals will be affected by global change. Introduction Reef building corals (Scleractinia) are increasingly challenged by a suite of anthropogenic stressors including pollution and rising sea temperatures due to climate change 1 , 2 . These stressors threaten the fate of coral reefs and the ecosystem services they provide which support the livelihoods of tens of millions of people worldwide 3 . Model projections forecast that more than 75% of coral reefs will be subjected to annual severe bleaching before 2070 due to thermal stress alone 4 , but the fate of corals may be worsened when they face additional stressors 5 , 6 . Recent evidence suggests that microplastics (plastic particles or fibers <5 mm), may negatively affect corals 7 , 8 , 9 , 10 . To date, however, no studies have looked at the potential for thermal stress to affect microplastics ingestion by reef-building corals. Under normal conditions, most reef-building corals acquire the majority of their energy from a symbiotic partnership with photosynthetic dinoflagellates in the family Symbiodiniaceae 11 , while less energy is generally derived from heterotrophic feeding on zooplankton 12 , 13 , 14 . When thermally stressed, Symbiodiniaceae are expelled from corals (bleaching) leading to a net decrease in autotrophic energy acquisition 15 , 16 . If elevated temperatures persist, corals deplete their energy reserves and can starve, but if the temperature reduces before the corals’ energy reserves are exhausted, Symbiodiniaceae can be reacquired and the coral may recover 17 , 18 , 19 . Some corals respond to thermal stress and subsequent bleaching by increased heterotrophy which shifts the corals’ reliance from energy derived from photosynthesis to energy derived from zooplankton prey, an adaptation termed heterotrophic plasticity 14 , 20 , 21 , 22 , 23 . While the underlying mechanisms and timing of this response are still unclear, increased carbon acquisition from heterotrophy can help corals maintain daily metabolic costs until Symbiodiniaceae can be reacquired. In contrast, other corals decrease their feeding rate during, or following, thermal stress 22 , 23 , 24 which may negatively impact their resilience. For corals that display heterotrophic plasticity, increased feeding of zooplankton prey could potentially increase their risk of ingesting unwanted particles in the water, such as microplastics. Microplastics are considered ubiquitous in aquatic ecosystems worldwide and are negatively impacting marine life 25 . By 2014, there was an estimated 15 to 51 trillion microplastic particles in the oceans 26 , which are derived from direct manufacturing or break down from larger plastic debris due to abrasion, wave action, and UV radiation. Plastic waste entering the oceans is expected to increase 10-fold by 2025 27 leading to growing concerns about the potential for these pollutants to negatively affect marine organisms. Their similarity in shape and size to zooplankton make microplastics particularly problematic for planktivorous animals such as corals that can ingest them while feeding 8 . In some organisms, ingesting microplastics can lead to decreased feeding efficiency, growth and fecundity 9 , 28 , 29 but for corals these effects are still not fully understood. Further, there is increasing concern about the role of plastics, large and small, to act as vectors for diseases and contaminants 30 , 31 , 32 . Previous studies have demonstrated that ingesting, and exposure to, microplastics can have negative effects on corals. Corals that ingested microplastics tended to egest most of them within 48 h which limited the time microplastics could cause internal damage but is still thought to be energetically costly 7 , 8 , 9 . For some coral species, exposure to microplastics resulted in increased mucous production, bleaching, necrosis, changes in photosynthetic performance, and decreased growth and feeding rates 7 , 9 , 10 . One coral species, Astrangia poculata , appeared to selectively feed on clean microplastics when also offered bio-fouled particles, leading researchers to suggest that chemical cues released by plastics (i.e., chemoreception) drove ingestion 33 . Additional research also showed that A . poculata preferred to feed on microplastics over similar sized brine shrimp eggs, and that ingesting microplastics can inhibit later feeding on nutritious prey 32 . While we are beginning to understand the responses and mechanisms of microplastics ingestion by corals, we still do not know how this pervasive pollutant interacts with other stressors, such as rising sea temperatures. The objective of this study was to examine whether prior exposure to thermal stress affects microplastics ingestion and if microplastics exposure and ingestion affects the amount of prey ingested by reef-building corals. To determine this, we compared ingestion rates of corals exposed to microplastics (MP) only, Artemia only, or MP and Artemia following ambient and increased temperature treatments. We hypothesized that if Artemia ingestion changed due to thermal stress, we would also see a similar trend in MP ingestion rates. Additionally, if a chemical in microplastics makes them more appealing to corals 33 , then we hypothesized that corals exposed to microplastics would<|im_end|> <|im_start|>assistant Tiny microplastic particles are about as common in the ocean today as plastic is in our daily lives. Synthetic clothing, containers, bottles, plastic bags and cosmetics all degrade and release microplastics into the environment. Corals and other marine organisms are eating microplastics that enter the waterway. Studies in this emerging field show some harmful effects, but it's largely unknown how this ubiquitous material is impacting ocean life. A new experiment by the University of Washington has found that some corals are more likely to eat microplastics when they are consuming other food, yet microplastics alone are undesirable. Two coral species tested responded differently to the synthetic material, suggesting variations in how corals are adapting to life with microplastics. The study was published Dec. 3 in the journal Scientific Reports. "The more plastic we use, the more microplastics there are, and the more corals are going to be exposed," said lead author Jeremy Axworthy, a UW doctoral student in the School of Aquatic and Fishery Sciences. "Our study found that some corals probably won't eat microplastics and will keep going about their daily business. But some might—and if they happen to be sensitive to warmer ocean temperatures or other stressors, this is just another compounding factor to be worried about." Corals are tiny animals that are rooted to the reef or rocks on the ocean floor. They use tentacle-like arms to sweep food into their mouths. Many rely on algae for energy, but most also consume drifting animals for survival. This study is the first to examine whether corals eat microplastics when exposed to warmer water, which is expected to accelerate with climate change. Rising ocean temperatures can be deadly for coral: warm water stresses them, causing corals to lose their symbiotic algae partner that undergoes photosynthesis and provides energy for them to survive. When this happens, coral bleaching and eventual death can occur. Jeremy Axworthy removes a young coral from a tank at the team's University of Washington lab. The two coral species shown here are Pocillopora damicornis (left), known as cauliflower coral, and Montipora capitatae (right), or rice coral. Cauliflower coral was more likely to ingest microplastics during the team's experiments. Credit: Dennis Wise/University of Washington But some corals have adapted to bleaching by shifting their diets to feed on tiny marine organisms called zooplankton, which provide an alternate energy source. As they munch on these small animals—often the same size as microplastics—the research team wondered whether they also were ingesting plastic fragments. The experiment shows corals do eat microplastics when they switch to a zooplankton diet, adding one more stressor for corals in a changing ocean environment. "Microplastics are not as simple as a life-or-death threat for corals—it's not that black or white," said senior author Jacqueline Padilla-Gamiño, assistant professor at the UW School of Aquatic and Fishery Sciences. "It's about total energy lost. If corals constantly are dealing with microplastics, it might not kill them, but there will be less energy for them to grow and to reproduce." The researchers collected two species of common corals off the east coast of Oahu, Hawaii, and exposed half of each species to warmer water for several weeks to induce stress and bleaching. Then they ran four different feeding experiments on both bleached and non-bleached corals: corals were fed only microplastics; only a type of zooplankton; microplastics and zooplankton; or nothing. After dissecting the coral polyps, researchers found that corals stressed by warmer temperatures actually ate much less than their counterparts in normal seawater. This was unexpected and possibly due to stress from high water temperatures. However, one of the two species, known for its voracious eating habits in the wild, consumed microplastics only while also eating zooplankton. Neither coral species ate microplastics alone. The researchers don't know why one species of coral readily ate microplastics in the presence of other food, but avoided microplastics when they were the only thing on the menu. They suspect that this species of coral can read certain chemical or physical cues from the plastics and the prey, but might not be able to distinguish between the two when both are present. Under a black light, fluorescent green microplastics are seen in the water during a small demonstration experiment. In the 2018 experiment described in the paper, cauliflower coral (above) ingested microplastics when prey was also present in the water, but avoided eating microplastics when no prey was there. Credit: Dennis Wise/University of Washington It's also possible the plastic used in this experiment is less desirable to corals, and that plastics with a different chemical makeup could, in fact, be tasty to corals. The researchers plan to test the "tastiness" of other types of microplastics, such as synthetic fibers from clothing. Ultimately, some coral species likely face greater risks from exposure to microplastics than others, the study found. The researchers will look next at impacts on the physiology of corals that are exposed over a longer period to microplastics. "Knowing that will provide a lot more context to this work," Axworthy said. "We need to know the full physiological impacts of chronic exposure to microplastics on corals, especially at increased temperatures, to understand how serious the problem is." In the meantime, the problem of microplastics isn't going away. A 2014 estimate found between 15 and 51 trillion microplastic particles in the oceans, and plastic waste entering the oceans is expected to increase tenfold between 2010 and 2025. "It's important when talking about waste management to think big picture—what are we putting in the oceans?" Padilla-Gamiño said. "We don't know where plastic goes, where it stays, who grabs it, and what are the mechanisms by which we get it back. We are just at the tip of understanding these implications." <|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 How the coexistence of many species is maintained is a fundamental and unresolved question in ecology. Coexistence is a puzzle because we lack a mechanistic understanding of the variation in species presence and abundance. Whether variation in ecological communities is driven by deterministic or random processes is one of the most controversial issues in ecology. Here, I study the variation of species presence and abundance in microbial communities from a macroecological standpoint. I identify three macroecological laws that quantitatively characterize the fluctuation of species abundance across communities and over time. Using these three laws, one can predict species’ presence and absence, diversity, and commonly studied macroecological patterns. I show that a mathematical model based on environmental stochasticity, the stochastic logistic model, quantitatively predicts the three macroecological laws, as well as non-stationary properties of community dynamics. Introduction No two ecological communities are alike, as species composition and abundance vary widely. Surveys of microbial communities, mapping taxonomy from Arctic oceans to zebras’ guts, have shown the incredible diversity of these ecosystems. Often, we have a detailed understanding of which environmental factors affect community variability 1 , 2 , 3 , 4 and, sometimes, the genetic drivers determining the response to different environmental conditions 5 , 6 . This qualitative understanding of the correlates, and potential causes, of the observed variation does not parallel with a mechanistic understanding of its fundamental and general properties 7 , 8 , 9 . Recent experiments allowed to document the existence and quantify the effect of several ecological mechanisms driving diversity in vitro 10 , 11 , 12 , 13 , 14 . Sometimes, with counter-intuitive results. For instance, many species can coexist on a single supplied resource thanks to widespread cross-feeding 13 . Environmental modification can lead to ecological suicide when one species, in the absence of other ones, modify pH to such a degree that lead to extinction of the whole population 14 . These growing body of fundamental results in microbial ecology are made possible by the simplified nature of the experimental communities, which typically consist of an handful of interacting species. It is challenging to upscale the experimental setups to match the complex spatio-temporal conditions of natural communities, in order to characterize the processes shaping the variation of many coexisting species. Environmental fluctuations, competition, cross-feeding, environmental modification, demographic stochasticity, migration, and many other ecological forces shape microbial communities over time and space. The existence of such forces is not in doubt. Their quantitative strength and relative relevance in determining composition and variation in natural communities are unknown. It is in fact extremely challenging to disentangle the effect of multiple mechanisms in communities with thousands of species interacting. In such complex communities, mechanisms and microscopic forces manifest in emergent, macroscopic, properties. Macroecology, the study of ecological communities through patterns of abundance, diversity, and distribution 15 , is therefore a promising approach to study quantitatively variation in microbial communities 16 , 17 , 18 , and to provide quantification of mechanisms that are shaping them. The most studied pattern in (macro)ecology is the species abundance distribution (SAD) 19 , 20 , which is defined as the fraction of species with a given abundance. Multiple functional forms, and consequently multiple mechanisms, have been proposed to describe the empirical SAD in microbial communities 17 . While SADs are highly studied and characterized, it is often neglected that three distinct and independent sources of variation influence their shape: sampling noise, fluctuation of abundances of individual species, and variability in abundance across species. This work disentangles these sources of variation in three macroecological laws. Here, I show that three macroecological laws describe the fluctuations of abundance and diversity. These three ecological laws hold across biomes and for both cross-sectional and temporal data, and are fundamental, as they suffice to predict, without fitting any additional parameters, the scaling of diversity and other commonly studied macroecological patterns, such as the SAD. These laws allow to generate in silico ecological communities, providing a statistically sophisticated ground truth, that allows to test ecological theories, models, and mechanisms. Macroecological patterns are the bridges from uncharacterized variation to ecological processes and mechanisms. I show that the stochastic logistic growth model, which is based on environmental stochasticity, reproduces the three macroecological laws, as well as dynamic patterns in temporal data. Both data and model show that, at the taxonomic resolution commonly used, competitive exclusion is rare and variation of species presence and abundance is mostly due to environmental fluctuations. Results Abundance fluctuations are gamma distributed The first pattern I consider is the abundance fluctuation distribution (AFD), which is defined as the distribution of abundances of a species across communities (Fig. 1 a). Fig. 1: Laws of variation in microbial communities. a The species abundance distribution (SAD) describes the fluctuations of abundance across species in a community. b The Abundance Fluctuation Distribution (AFD) describes the distribution of abundances of a species across communities. I consider cross-sectional data from 9 data sets (colored symbols, see Methods). A Gamma distribution (solid black line) closely matches the AFD, here reported for the most abundant species (see Methods). The Gamma distribution describes the AFD of both abundant and rare species (Supplementary Note 1 and Supplementary Fig. 2 ). c The mean and variance of the abundance distribution are not independent across species, a relationship known as Taylor’s Law. The variance is, in fact, proportional to the square of the mean (solid line), implying that the coefficient of variation of the abundance fluctuations is constant across species (Supplementary Fig. 7 ). Taylor’s Law (together with a Gamma AFD) implies that a single parameter per species (the average abundance) recapitulates the distribution of fluctuations. d The Mean Abundance Distribution (MAD), defined as the distribution of mean abundance (obtained by averaging over communities) across species, is Lognormally distributed (black line, Supplementary Note 7 ). Full size image This quantity is strongly influenced by sampling errors, especially when, because of fluctuations, a species becomes rare. For the most abundant species, these sampling errors can", "role": "user" }, { "content": "The natural world is astonishingly complex. After centuries of study, scientists still have much to learn about how all the species in an ecosystem coexist, for example. New research on microbial communities published in Nature Communications helps light the way to answering this fundamental question in ecology. \"What I wanted to know is, sure communities are very complicated, there are many species interacting, but if we try to describe the most important forces shaping this community, what are they?\" says author Jacopo Grilli, a biological physicist at the International Center for Theoretical Physics in Trieste, Italy and a former Omidyar Fellow at the Santa Fe Institute in the U.S. Grilli, whose work focuses on understanding complex phenomena by using simple rules, knew that to begin to answer that question, he needed to focus on ecological communities from many different environments, and for which a wealth of data already existed. It's far easier to study a glass of ocean water or a spoonful of soil than a patch of forest, he explains. \"Ecology is traditionally a data-poor discipline. But in the case of microbial communities, it's much easier to get a lot of data on these communities, across several conditions,\" Grilli says. \"Microbial communities are everywhere. They are all around us, outside and inside us. So they contribute to many fundamental ecological processes around the world, and they determine in some part our health and well-being. Their impact on our lives and on our planet is immense.\" In parsing the abundance and diversity of bacteria in a variety of tiny worlds using a simple mathematical model, Grilli's research suggests that environmental variability is the main determinant of whether a species is present or absent in a microbial community, and that environmental change—such as a change in temperature or nutrients—is the primary driver of fluctuations in the abundance of a species. \"That sort of suggests the players are different—the species that are in our gut versus the species that are in the ocean are different—but the forces that shape them are the same,\" Grilli says. He also identified three key laws that help explain how the number of species in an ecosystem fluctuates over time. These laws can be used to predict a species presence or absence and the diversity in a system. While the size, complexity, and dearth of data for, say, a forest ecosystem makes it difficult to extrapolate the findings to other systems, Grilli says these laws can be used as a starting point for investigations of bigger ecosystems. \"When we look at these bacterial communities, the number of individuals is huge compared to the forest next to our backyard,\" he says. For example, the number of bacterial cells in our colon is ten times the number of trees in the world. \"So when we understand something about the ecology of bacteria, we are looking at the ecology of something that is at the spatial and temporal scale of our planet. Every hypothesis in the context of micro-communities provides a starting point for other communities. And it's obvious why, in a time when we see a huge decline in biodiversity at the global scale, understanding something more about ecology and in such a large scale is important.\" Grilli is now building on this work to better understand interactions among microbial species. Grilli adds that while he is the sole author of the paper, the research was informed by input from the many scientists from diverse disciplines he met while he was a fellow at SFI. \"If I didn't spend the time at SFI, where I had the opportunity to discuss and collaborate, I don't think this paper would have existed,\" he says. \"It's the result of many conversations and the environment.\" ", "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 the coexistence of many species is maintained is a fundamental and unresolved question in ecology. Coexistence is a puzzle because we lack a mechanistic understanding of the variation in species presence and abundance. Whether variation in ecological communities is driven by deterministic or random processes is one of the most controversial issues in ecology. Here, I study the variation of species presence and abundance in microbial communities from a macroecological standpoint. I identify three macroecological laws that quantitatively characterize the fluctuation of species abundance across communities and over time. Using these three laws, one can predict species’ presence and absence, diversity, and commonly studied macroecological patterns. I show that a mathematical model based on environmental stochasticity, the stochastic logistic model, quantitatively predicts the three macroecological laws, as well as non-stationary properties of community dynamics. Introduction No two ecological communities are alike, as species composition and abundance vary widely. Surveys of microbial communities, mapping taxonomy from Arctic oceans to zebras’ guts, have shown the incredible diversity of these ecosystems. Often, we have a detailed understanding of which environmental factors affect community variability 1 , 2 , 3 , 4 and, sometimes, the genetic drivers determining the response to different environmental conditions 5 , 6 . This qualitative understanding of the correlates, and potential causes, of the observed variation does not parallel with a mechanistic understanding of its fundamental and general properties 7 , 8 , 9 . Recent experiments allowed to document the existence and quantify the effect of several ecological mechanisms driving diversity in vitro 10 , 11 , 12 , 13 , 14 . Sometimes, with counter-intuitive results. For instance, many species can coexist on a single supplied resource thanks to widespread cross-feeding 13 . Environmental modification can lead to ecological suicide when one species, in the absence of other ones, modify pH to such a degree that lead to extinction of the whole population 14 . These growing body of fundamental results in microbial ecology are made possible by the simplified nature of the experimental communities, which typically consist of an handful of interacting species. It is challenging to upscale the experimental setups to match the complex spatio-temporal conditions of natural communities, in order to characterize the processes shaping the variation of many coexisting species. Environmental fluctuations, competition, cross-feeding, environmental modification, demographic stochasticity, migration, and many other ecological forces shape microbial communities over time and space. The existence of such forces is not in doubt. Their quantitative strength and relative relevance in determining composition and variation in natural communities are unknown. It is in fact extremely challenging to disentangle the effect of multiple mechanisms in communities with thousands of species interacting. In such complex communities, mechanisms and microscopic forces manifest in emergent, macroscopic, properties. Macroecology, the study of ecological communities through patterns of abundance, diversity, and distribution 15 , is therefore a promising approach to study quantitatively variation in microbial communities 16 , 17 , 18 , and to provide quantification of mechanisms that are shaping them. The most studied pattern in (macro)ecology is the species abundance distribution (SAD) 19 , 20 , which is defined as the fraction of species with a given abundance. Multiple functional forms, and consequently multiple mechanisms, have been proposed to describe the empirical SAD in microbial communities 17 . While SADs are highly studied and characterized, it is often neglected that three distinct and independent sources of variation influence their shape: sampling noise, fluctuation of abundances of individual species, and variability in abundance across species. This work disentangles these sources of variation in three macroecological laws. Here, I show that three macroecological laws describe the fluctuations of abundance and diversity. These three ecological laws hold across biomes and for both cross-sectional and temporal data, and are fundamental, as they suffice to predict, without fitting any additional parameters, the scaling of diversity and other commonly studied macroecological patterns, such as the SAD. These laws allow to generate in silico ecological communities, providing a statistically sophisticated ground truth, that allows to test ecological theories, models, and mechanisms. Macroecological patterns are the bridges from uncharacterized variation to ecological processes and mechanisms. I show that the stochastic logistic growth model, which is based on environmental stochasticity, reproduces the three macroecological laws, as well as dynamic patterns in temporal data. Both data and model show that, at the taxonomic resolution commonly used, competitive exclusion is rare and variation of species presence and abundance is mostly due to environmental fluctuations. Results Abundance fluctuations are gamma distributed The first pattern I consider is the abundance fluctuation distribution (AFD), which is defined as the distribution of abundances of a species across communities (Fig. 1 a). Fig. 1: Laws of variation in microbial communities. a The species abundance distribution (SAD) describes the fluctuations of abundance across species in a community. b The Abundance Fluctuation Distribution (AFD) describes the distribution of abundances of a species across communities. I consider cross-sectional data from 9 data sets (colored symbols, see Methods). A Gamma distribution (solid black line) closely matches the AFD, here reported for the most abundant species (see Methods). The Gamma distribution describes the AFD of both abundant and rare species (Supplementary Note 1 and Supplementary Fig. 2 ). c The mean and variance of the abundance distribution are not independent across species, a relationship known as Taylor’s Law. The variance is, in fact, proportional to the square of the mean (solid line), implying that the coefficient of variation of the abundance fluctuations is constant across species (Supplementary Fig. 7 ). Taylor’s Law (together with a Gamma AFD) implies that a single parameter per species (the average abundance) recapitulates the distribution of fluctuations. d The Mean Abundance Distribution (MAD), defined as the distribution of mean abundance (obtained by averaging over communities) across species, is Lognormally distributed (black line, Supplementary Note 7 ). Full size image This quantity is strongly influenced by sampling errors, especially when, because of fluctuations, a species becomes rare. For the most abundant species, these sampling errors can<|im_end|> <|im_start|>assistant The natural world is astonishingly complex. After centuries of study, scientists still have much to learn about how all the species in an ecosystem coexist, for example. New research on microbial communities published in Nature Communications helps light the way to answering this fundamental question in ecology. "What I wanted to know is, sure communities are very complicated, there are many species interacting, but if we try to describe the most important forces shaping this community, what are they?" says author Jacopo Grilli, a biological physicist at the International Center for Theoretical Physics in Trieste, Italy and a former Omidyar Fellow at the Santa Fe Institute in the U.S. Grilli, whose work focuses on understanding complex phenomena by using simple rules, knew that to begin to answer that question, he needed to focus on ecological communities from many different environments, and for which a wealth of data already existed. It's far easier to study a glass of ocean water or a spoonful of soil than a patch of forest, he explains. "Ecology is traditionally a data-poor discipline. But in the case of microbial communities, it's much easier to get a lot of data on these communities, across several conditions," Grilli says. "Microbial communities are everywhere. They are all around us, outside and inside us. So they contribute to many fundamental ecological processes around the world, and they determine in some part our health and well-being. Their impact on our lives and on our planet is immense." In parsing the abundance and diversity of bacteria in a variety of tiny worlds using a simple mathematical model, Grilli's research suggests that environmental variability is the main determinant of whether a species is present or absent in a microbial community, and that environmental change—such as a change in temperature or nutrients—is the primary driver of fluctuations in the abundance of a species. "That sort of suggests the players are different—the species that are in our gut versus the species that are in the ocean are different—but the forces that shape them are the same," Grilli says. He also identified three key laws that help explain how the number of species in an ecosystem fluctuates over time. These laws can be used to predict a species presence or absence and the diversity in a system. While the size, complexity, and dearth of data for, say, a forest ecosystem makes it difficult to extrapolate the findings to other systems, Grilli says these laws can be used as a starting point for investigations of bigger ecosystems. "When we look at these bacterial communities, the number of individuals is huge compared to the forest next to our backyard," he says. For example, the number of bacterial cells in our colon is ten times the number of trees in the world. "So when we understand something about the ecology of bacteria, we are looking at the ecology of something that is at the spatial and temporal scale of our planet. Every hypothesis in the context of micro-communities provides a starting point for other communities. And it's obvious why, in a time when we see a huge decline in biodiversity at the global scale, understanding something more about ecology and in such a large scale is important." Grilli is now building on this work to better understand interactions among microbial species. Grilli adds that while he is the sole author of the paper, the research was informed by input from the many scientists from diverse disciplines he met while he was a fellow at SFI. "If I didn't spend the time at SFI, where I had the opportunity to discuss and collaborate, I don't think this paper would have existed," he says. "It's the result of many conversations and the environment." <|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 classical nova occurs when material accreting onto the surface of a white dwarf in a close binary system ignites in a thermonuclear runaway 1 , 2 . Complex structures observed in the ejecta at late stages 3 , 4 , 5 could result from interactions with the companion during the common-envelope phase 6 , 7 . Alternatively, the explosion could be intrinsically bipolar, resulting from a localized ignition on the surface of the white dwarf 8 or as a consequence of rotational distortion 9 , 10 . Studying the structure of novae during the earliest phases is challenging because of the high spatial resolution needed to measure their small sizes 11 . Here we report near-infrared interferometric measurements of the angular size of Nova Delphini 2013, starting one day after the explosion and continuing with extensive time coverage during the first 43 days. Changes in the apparent expansion rate can be explained by an explosion model consisting of an optically thick core surrounded by a diffuse envelope. The optical depth of the ejected material changes as it expands. We detect an ellipticity in the light distribution, suggesting a prolate or bipolar structure that develops as early as the second day. Combining the angular expansion rate with radial velocity measurements, we derive a geometric distance to the nova of 4.54 ± 0.59 kiloparsecs from the Sun. Main Nova Delphini 2013 (also known as V339 Del) was discovered 12 by K. Itagaki on 14 August 2013 Universal Time ( ut ) at 14:01. We began an intensive observing campaign to measure the size of the nova with the CHARA Array 13 , an optical/infrared interferometer located on Mount Wilson, California. Our observations began within 15 h of the discovery and within 24 h of the detonation itself. We measured the size of the expanding ejecta as the nova rose to peak brightness and continued monitoring it for a total of 27 nights between ut 2013 August 15 and September 26. We measured the angular diameter of Nova Del 2013 by fitting a uniformly bright circle to the visibility amplitudes of the interference fringes recorded during each night ( Extended Data Table 1 ). We plot the expansion curve in Fig. 1 . The dotted line shows a linear fit to the angular diameters during the first 27 days after the explosion. The inset panel shows an apparent deceleration during the first four nights compared with lines of constant velocity. During the last week, the measurements show a large jump in the effective size of the nova compared with an extrapolation of the linear fit. For comparison, we show the visible and infrared light curves in Fig. 2 . Figure 1: Expansion curve of Nova Del 2013. The angular diameters were measured by fitting a circular disk to the interferometric data. The dotted line shows a linear fit for days 0–27. The inset panel zooms in during the first week and shows dotted lines with velocities 17 of 613 km s −1 and 2,500 km s −1 at a distance of 4.54 kpc. The apparent deceleration during the first week, along with the jump in size during the last week, can be explained by a two-component model consisting of a circular core surrounded by a ring where the flux ratio changes over time. The grey region shows the expansion rate of the core (lower edge) and the ring (upper edge). The solid line shows the effective size obtained by fitting the two-component model visibilities as a single circular disk. Error bars represent 1 σ uncertainties computed from a bootstrap analysis. PowerPoint slide Source data Full size image Figure 2: Infrared light curve of Nova Del 2013. The magnitudes and error bars were computed from the mean and standard deviation of counts recorded on the detector during each interferometric observation collected at the CHARA Array. The data were obtained in the H-band using two different beam combiners (blue squares and green diamonds) and in the K'-band (red triangles). For comparison, we plot daily averages of photometric measurements in the V-band downloaded from the American Association of Variable Star Observers (AAVSO; black circles). The rise to peak brightness was slower in the infrared compared to the visible. PowerPoint slide Source data Full size image The apparent changes in slope of the expansion curve can be explained by a two-component model consisting of an optically thick pseudo-photosphere surrounded by an optically thin halo. We approximated the intensity distribution projected on the sky using a uniformly bright, circular core surrounded by a circular ring. We fitted the two-component model to the interferometric visibilities and minimized the total χ 2 simultaneously across all nights. We fixed the time of detonation at modified Julian day t 0 = MJD 56518.277, computed by extrapolating the first two pre-discovery photometric measurements 14 back to the quiescent flux 15 , 16 . From our interferometric data, we measured an expansion rate of 0.156 ± 0.003 milli-arcseconds (mas) per day for the core diameter and a size ratio of 1.73 ± 0.02 between the outer ring and core. We allowed the flux ratio between the ring and core to vary on a nightly basis. Figure 3 shows how the percentage of light from the ring changes over time. During the first two nights, the core and ring have similar surface brightnesses. Therefore, at the earliest times, the nova can be approximated by a single uniform disk component where the optically thick pseudo-photosphere extends to the outermost, fastest-moving layers of the ejecta. After the peak in the visible light curve, the amount of flux in the ring drops, which indicates that the outer layers became optically thin and the pseudo-photosphere moved towards the inner, slower-moving, and denser layers. Therefore, the apparent deceleration in the expansion curve during the first few nights is probably caused by a diminishing contribution from the outer layers. Over the next few weeks, the absolute flux of both components decreased; however, the flux from the core dropped at", "role": "user" }, { "content": "The first images of a nova during its early fireball stage—when it ejects material, and gases expand and cool—show that this activity is more complicated than predicted. That is the conclusion, published in the current issue of Nature, from a research collaboration led by Georgia State University Astronomer Gail Schaefer that includes 37 researchers from 17 institutions. The researchers observed the expanding thermonuclear fireball from a nova that erupted last year in the constellation Delphinus. \"This is the first time astronomers have been able to witness an expanding fireball with such great detail, rather than as a tiny point of light way out in the galaxy,\" Schaefer said. \"It was amazing to see the material expanding outward each day after the explosion.\" A nova occurs after a thin layer of hydrogen builds up on the surface of a white dwarf—a highly evolved star with the mass of the sun packed into the volume of the Earth. A normal star accompanies the white dwarf in a binary star system, providing that hydrogen as the two stars orbit each other. The normal star sheds a small amount of its mass through a stream onto the white dwarf's surface that gradually builds up a hydrogen \"ocean.\" When that ocean is perhaps 200 meters (~650 feet) deep, the white dwarf's enormous surface gravity produces a pressure at the bottom of the hydrogen layer sufficient to trigger thermonuclear fusion, essentially a stellar H-bomb. Over ensuing weeks, the nova slowly fades as the fireball expands, cools and dissipates. Surprisingly, this seeming cataclysm on the white dwarf's surface has no real effect on the star or its companion, and the flow of material resumes so that the detonation will likely repeat at a future date. Because these objects are generally very far from the sun and faint until the explosion occurs, they do not appear on classical star maps. Instead, a \"new\" star suddenly appears where none was before. The famous 16th century Danish astronomer Tycho Brahe described this sudden appearance of stars in his 1572 book De Stella Nova, and the Latin nova for \"new\" became attached to this phenomenon, which also manifests itself through far more energetic processes that are destructive of the exploding star in a supernova. Nova Delphinus lights up Last year, on Aug. 14, the Japanese amateur astronomer Koichi Itagaki discovered a \"new\" star, promptly named Nova Delphinus 2013. Within 15 hours of discovery and within 24 hours of actual explosion, the NSF-funded Center for High Angular Resolution Astronomy (CHARA) and its Georgia State University astronomers pointed array telescopes, located at historic Mount Wilson Observatory in the San Gabriel Mountains of Southern California, toward Nova Del 2013 to image the fireball and measure it. They measured the nova on a total of 27 nights over two months; the first measurement represents the earliest size yet obtained for a nova event. The CHARA facility uses optical interferometry principles to combine light from six telescopes to create images with very high resolution, equivalent to that of a telescope with a diameter of more than 300 meters. This makes it capable of seeing details far smaller in angular extent than traditional telescopes on the ground or in space. To put it in perspective, it can resolve imagery the size of a U.S nickel on the top of the Eiffel tower in Paris from the distance of Los Angeles, Calif. \"Since novae can dim rapidly after their outburst, having sufficient brightness and resolution at the critical times is very challenging,\" said collaborator Dipankar Banerjee from the Indian Physical Research Laboratory. \"CHARA is one of the few instruments in the world that can do this.\" CHARA's measurement of angular expansion rate of the nova, combined with measurements of the expansion velocity from independent spectroscopic observations, allowed researchers to determine distance to the star. Nova Del 2013 was found to be 14,800 light years from the sun. This means that, while we witnessed this explosion here on Earth last August, it actually took place nearly 15,000 years ago. Knowing the nova's distance along with its angular size allows astronomers to determine the fireball's physical size at different times of observation. During the first observation on Aug. 15, the fireball was roughly the size of Earth's orbit. Two days later, it was already the size of Mars' orbit, and by day 12, the fireball surface would extend out to Jupiter's orbit. When last measured 43 days after detonation, it had expanded nearly 20-fold to nearly the size of Neptune's orbit. But it was the thermonuclear explosion back on the white dwarf's surface that fueled this remarkable expansion rate of more than 600 kilometers-per-second (over 1.3 million miles per hour). Catch a flying elliptical nova fireball The University of Michigan Infrared Beam Combiner (MIRC), an instrument that combines all six telescopes of the CHARA Array simultaneously, created the nova fireball's first images and showed that the explosion was not precisely spherical, and that the fireball actually had an ellipticity of 13 percent. This will help astronomers understand how material is ejected from a white dwarf during this kind of explosion. \"One remaining mystery here is how the shape of the explosion changed so much over just a few days,\" said John Monnier, MIRC principal investigator. \"I can't wait for the next big nova to happen soon to see what more we can learn about this dramatic process.\" The CHARA observations also showed that fireball outer layers became more diffuse and transparent as it expanded. After about 30 days, researchers saw evidence for a brightening in outer layers, potentially caused by dust grains forming in cooler, clumpy structures that emitted light at infrared wavelengths. \"This result is a dramatic illustration of the powerful new capability provided by optical interferometry,\" said Jim Neff, NSF astronomy program officer. \"And it also highlights the importance of rapid communication and cooperation among astronomers worldwide, both amateur and professional.\" It has been almost 350 years since Carthusian monk Pere Dom Anthelme discovered the first true nova in the constellation of Vulpecula in 1670. Since then thousands of novae have been discovered, but it is only in the last decade or so that it has become possible to image the earliest stages of the explosion due to interferometry's high resolution. The new CHARA measurements follow the expansion of Nova Del 2013 from its very early relatively compact stages until the fireball was nearly the size of our solar system. Studying how the structure of the nova changed at the earliest stages brings new insights to theoretical models of novae eruptions. ", "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 classical nova occurs when material accreting onto the surface of a white dwarf in a close binary system ignites in a thermonuclear runaway 1 , 2 . Complex structures observed in the ejecta at late stages 3 , 4 , 5 could result from interactions with the companion during the common-envelope phase 6 , 7 . Alternatively, the explosion could be intrinsically bipolar, resulting from a localized ignition on the surface of the white dwarf 8 or as a consequence of rotational distortion 9 , 10 . Studying the structure of novae during the earliest phases is challenging because of the high spatial resolution needed to measure their small sizes 11 . Here we report near-infrared interferometric measurements of the angular size of Nova Delphini 2013, starting one day after the explosion and continuing with extensive time coverage during the first 43 days. Changes in the apparent expansion rate can be explained by an explosion model consisting of an optically thick core surrounded by a diffuse envelope. The optical depth of the ejected material changes as it expands. We detect an ellipticity in the light distribution, suggesting a prolate or bipolar structure that develops as early as the second day. Combining the angular expansion rate with radial velocity measurements, we derive a geometric distance to the nova of 4.54 ± 0.59 kiloparsecs from the Sun. Main Nova Delphini 2013 (also known as V339 Del) was discovered 12 by K. Itagaki on 14 August 2013 Universal Time ( ut ) at 14:01. We began an intensive observing campaign to measure the size of the nova with the CHARA Array 13 , an optical/infrared interferometer located on Mount Wilson, California. Our observations began within 15 h of the discovery and within 24 h of the detonation itself. We measured the size of the expanding ejecta as the nova rose to peak brightness and continued monitoring it for a total of 27 nights between ut 2013 August 15 and September 26. We measured the angular diameter of Nova Del 2013 by fitting a uniformly bright circle to the visibility amplitudes of the interference fringes recorded during each night ( Extended Data Table 1 ). We plot the expansion curve in Fig. 1 . The dotted line shows a linear fit to the angular diameters during the first 27 days after the explosion. The inset panel shows an apparent deceleration during the first four nights compared with lines of constant velocity. During the last week, the measurements show a large jump in the effective size of the nova compared with an extrapolation of the linear fit. For comparison, we show the visible and infrared light curves in Fig. 2 . Figure 1: Expansion curve of Nova Del 2013. The angular diameters were measured by fitting a circular disk to the interferometric data. The dotted line shows a linear fit for days 0–27. The inset panel zooms in during the first week and shows dotted lines with velocities 17 of 613 km s −1 and 2,500 km s −1 at a distance of 4.54 kpc. The apparent deceleration during the first week, along with the jump in size during the last week, can be explained by a two-component model consisting of a circular core surrounded by a ring where the flux ratio changes over time. The grey region shows the expansion rate of the core (lower edge) and the ring (upper edge). The solid line shows the effective size obtained by fitting the two-component model visibilities as a single circular disk. Error bars represent 1 σ uncertainties computed from a bootstrap analysis. PowerPoint slide Source data Full size image Figure 2: Infrared light curve of Nova Del 2013. The magnitudes and error bars were computed from the mean and standard deviation of counts recorded on the detector during each interferometric observation collected at the CHARA Array. The data were obtained in the H-band using two different beam combiners (blue squares and green diamonds) and in the K'-band (red triangles). For comparison, we plot daily averages of photometric measurements in the V-band downloaded from the American Association of Variable Star Observers (AAVSO; black circles). The rise to peak brightness was slower in the infrared compared to the visible. PowerPoint slide Source data Full size image The apparent changes in slope of the expansion curve can be explained by a two-component model consisting of an optically thick pseudo-photosphere surrounded by an optically thin halo. We approximated the intensity distribution projected on the sky using a uniformly bright, circular core surrounded by a circular ring. We fitted the two-component model to the interferometric visibilities and minimized the total χ 2 simultaneously across all nights. We fixed the time of detonation at modified Julian day t 0 = MJD 56518.277, computed by extrapolating the first two pre-discovery photometric measurements 14 back to the quiescent flux 15 , 16 . From our interferometric data, we measured an expansion rate of 0.156 ± 0.003 milli-arcseconds (mas) per day for the core diameter and a size ratio of 1.73 ± 0.02 between the outer ring and core. We allowed the flux ratio between the ring and core to vary on a nightly basis. Figure 3 shows how the percentage of light from the ring changes over time. During the first two nights, the core and ring have similar surface brightnesses. Therefore, at the earliest times, the nova can be approximated by a single uniform disk component where the optically thick pseudo-photosphere extends to the outermost, fastest-moving layers of the ejecta. After the peak in the visible light curve, the amount of flux in the ring drops, which indicates that the outer layers became optically thin and the pseudo-photosphere moved towards the inner, slower-moving, and denser layers. Therefore, the apparent deceleration in the expansion curve during the first few nights is probably caused by a diminishing contribution from the outer layers. Over the next few weeks, the absolute flux of both components decreased; however, the flux from the core dropped at<|im_end|> <|im_start|>assistant The first images of a nova during its early fireball stage—when it ejects material, and gases expand and cool—show that this activity is more complicated than predicted. That is the conclusion, published in the current issue of Nature, from a research collaboration led by Georgia State University Astronomer Gail Schaefer that includes 37 researchers from 17 institutions. The researchers observed the expanding thermonuclear fireball from a nova that erupted last year in the constellation Delphinus. "This is the first time astronomers have been able to witness an expanding fireball with such great detail, rather than as a tiny point of light way out in the galaxy," Schaefer said. "It was amazing to see the material expanding outward each day after the explosion." A nova occurs after a thin layer of hydrogen builds up on the surface of a white dwarf—a highly evolved star with the mass of the sun packed into the volume of the Earth. A normal star accompanies the white dwarf in a binary star system, providing that hydrogen as the two stars orbit each other. The normal star sheds a small amount of its mass through a stream onto the white dwarf's surface that gradually builds up a hydrogen "ocean." When that ocean is perhaps 200 meters (~650 feet) deep, the white dwarf's enormous surface gravity produces a pressure at the bottom of the hydrogen layer sufficient to trigger thermonuclear fusion, essentially a stellar H-bomb. Over ensuing weeks, the nova slowly fades as the fireball expands, cools and dissipates. Surprisingly, this seeming cataclysm on the white dwarf's surface has no real effect on the star or its companion, and the flow of material resumes so that the detonation will likely repeat at a future date. Because these objects are generally very far from the sun and faint until the explosion occurs, they do not appear on classical star maps. Instead, a "new" star suddenly appears where none was before. The famous 16th century Danish astronomer Tycho Brahe described this sudden appearance of stars in his 1572 book De Stella Nova, and the Latin nova for "new" became attached to this phenomenon, which also manifests itself through far more energetic processes that are destructive of the exploding star in a supernova. Nova Delphinus lights up Last year, on Aug. 14, the Japanese amateur astronomer Koichi Itagaki discovered a "new" star, promptly named Nova Delphinus 2013. Within 15 hours of discovery and within 24 hours of actual explosion, the NSF-funded Center for High Angular Resolution Astronomy (CHARA) and its Georgia State University astronomers pointed array telescopes, located at historic Mount Wilson Observatory in the San Gabriel Mountains of Southern California, toward Nova Del 2013 to image the fireball and measure it. They measured the nova on a total of 27 nights over two months; the first measurement represents the earliest size yet obtained for a nova event. The CHARA facility uses optical interferometry principles to combine light from six telescopes to create images with very high resolution, equivalent to that of a telescope with a diameter of more than 300 meters. This makes it capable of seeing details far smaller in angular extent than traditional telescopes on the ground or in space. To put it in perspective, it can resolve imagery the size of a U.S nickel on the top of the Eiffel tower in Paris from the distance of Los Angeles, Calif. "Since novae can dim rapidly after their outburst, having sufficient brightness and resolution at the critical times is very challenging," said collaborator Dipankar Banerjee from the Indian Physical Research Laboratory. "CHARA is one of the few instruments in the world that can do this." CHARA's measurement of angular expansion rate of the nova, combined with measurements of the expansion velocity from independent spectroscopic observations, allowed researchers to determine distance to the star. Nova Del 2013 was found to be 14,800 light years from the sun. This means that, while we witnessed this explosion here on Earth last August, it actually took place nearly 15,000 years ago. Knowing the nova's distance along with its angular size allows astronomers to determine the fireball's physical size at different times of observation. During the first observation on Aug. 15, the fireball was roughly the size of Earth's orbit. Two days later, it was already the size of Mars' orbit, and by day 12, the fireball surface would extend out to Jupiter's orbit. When last measured 43 days after detonation, it had expanded nearly 20-fold to nearly the size of Neptune's orbit. But it was the thermonuclear explosion back on the white dwarf's surface that fueled this remarkable expansion rate of more than 600 kilometers-per-second (over 1.3 million miles per hour). Catch a flying elliptical nova fireball The University of Michigan Infrared Beam Combiner (MIRC), an instrument that combines all six telescopes of the CHARA Array simultaneously, created the nova fireball's first images and showed that the explosion was not precisely spherical, and that the fireball actually had an ellipticity of 13 percent. This will help astronomers understand how material is ejected from a white dwarf during this kind of explosion. "One remaining mystery here is how the shape of the explosion changed so much over just a few days," said John Monnier, MIRC principal investigator. "I can't wait for the next big nova to happen soon to see what more we can learn about this dramatic process." The CHARA observations also showed that fireball outer layers became more diffuse and transparent as it expanded. After about 30 days, researchers saw evidence for a brightening in outer layers, potentially caused by dust grains forming in cooler, clumpy structures that emitted light at infrared wavelengths. "This result is a dramatic illustration of the powerful new capability provided by optical interferometry," said Jim Neff, NSF astronomy program officer. "And it also highlights the importance of rapid communication and cooperation among astronomers worldwide, both amateur and professional." It has been almost 350 years since Carthusian monk Pere Dom Anthelme discovered the first true nova in the constellation of Vulpecula in 1670. Since then thousands of novae have been discovered, but it is only in the last decade or so that it has become possible to image the earliest stages of the explosion due to interferometry's high resolution. The new CHARA measurements follow the expansion of Nova Del 2013 from its very early relatively compact stages until the fireball was nearly the size of our solar system. Studying how the structure of the nova changed at the earliest stages brings new insights to theoretical models of novae eruptions. <|im_end|>

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2,672

[ { "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 Atmospheric ozone (O 3 ) is a pollutant produced through chemical chain reactions where volatile organic compounds (VOCs), carbon monoxide and methane are oxidized in the presence of oxides of nitrogen (NO x ). For decades, the controlling chain termination step has been used to separate regions into either ‘NO x limited’ (peroxyl-radical self-reactions dominate) or ‘VOC limited’ (hydroxyl radical (OH) + nitrogen dioxide (NO 2 ) reaction dominates). The controlling regime would then guide policies for reducing emissions and so O 3 concentrations. Using a chemical transport model, we show that a third ‘aerosol inhibited’ regime exists, where reactive uptake of hydroperoxyl radicals (HO 2 ) onto aerosol particles dominates. In 1970, 2% of the Northern Hemisphere population lived in an aerosol-inhibited regime, but by 2014 this had increased to 21%; 60% more than lived in a VOC-limited regime. Aerosol-inhibited chemistry suppressed surface O 3 concentrations in North America and Europe in the 1970s and is currently suppressing surface O 3 over Asia. This third photochemical O 3 regime leads to potential trade-off tensions between reducing particle pollution in Asia (a key current health policy and priority) and increasing surface O 3 , should O 3 precursors emissions not be reduced in tandem. Main Ozone (O 3 ) has well-documented detrimental impacts on human and ecosystem health, and in the mid to upper free troposphere is a greenhouse gas 1 , 2 . Since the mid-twentieth century, it has been known that O 3 is formed through complex radical chain-reaction chemistry involving the oxidation of volatile organic compounds (VOCs) in the presence of oxides of nitrogen (NO x ) (ref. 3 ). The chain reaction is initiated through the photolysis of photo-labile compounds such as O 3 , CH 2 O and HONO, propagated through the interconversion of peroxyl (HO 2 and RO 2 ) and hydroxyl (OH) radicals and terminated either through the self-reaction of peroxyl radicals to form longer-lived species (such as peroxides) or from the reaction of a hydroxyl radical with nitrogen dioxide (NO 2 ) to form nitric acid (HNO 3 ) 4 , 5 . From the perspective of reducing O 3 pollution, the dominant termination step is often used to identify whether reductions in the emissions of NO x or VOCs should be preferentially employed 6 . If peroxyl-radical self-reactions dominate (known as the ‘NO x limited’ regime), reductions in NO x emissions are most beneficial, whereas if the NO 2 + OH reaction dominates (known as the ‘VOC limited’ regime) reductions in organic emissions are most effective. The existence of these two well-defined O 3 production regimes has been used to guide national-, regional- and city-level air-quality policy choices for many decades 3 . Since the development of the NO x - versus VOC-limited model, understanding of atmospheric chemistry has advanced, with increased understanding of VOC chemistry 7 , aerosols 8 , halogens 9 and so on. In this study, we use a chemistry transport model with an advanced representation of atmospheric chemistry (GEOS-Chem 10 ) to diagnose the balance of termination steps. Notably, the model includes the uptake of HO 2 onto aerosol surfaces, which has been identified as an important process for chain termination over the past decades 8 , 11 , 12 , 13 , 14 , 15 . We compare the rate of radical termination by peroxyl-radical self-reactions, the OH + NO 2 reaction and the uptake of HO 2 onto aerosol in July for the Northern Hemisphere in the pre-industrial era (1750), 1970 and 2014 ( Methods ). Concentrations of key components calculated by the model are shown in Supplementary Figs. 1–6 . Chain termination Figure 1 shows the surface distribution of the relative chemical fluxes of these termination steps for July 1750, 1970 and 2014 (enlargements over North America, Europe and Asia are in Supplementary Figs. 8 – 10 ). Fig. 1: Map of the fractional contribution of each radical loss pathway for the years 1750, 1950 and 2014. Mean simulated July solar noon-time fraction of radical termination at the surface that occurs through OH + NO 2 (red), peroxyl-radical self-reactions (green) and aerosol uptake of HO 2 (blue) for 1750, 1970 and 2014. Enlargements of North America, Europe and Asia are shown in the Supplementary Information . Full size image In the pre-industrial era (1750), peroxyl-radical self-reactions (green) dominate. Biomass burning (forest fires) in Russia and Canada show termination by the uptake of HO 2 onto aerosol (blue), whereas fires over Kazakhstan show termination by OH + NO 2 (red) (Extended Data Fig. 1 shows a simulation with biomass burning switched off). This reflects the differing balance of NO x relative to particulates emitted by different fires 16 . Desert dust makes only a limited contribution to the aerosol surface area, leading to some increased contribution of HO 2 uptake over Mauritania, Oman and Iran, but overall the impact is minor (Extended Data Fig. 1 shows a simulation with no desert dust emissions). Some HO 2 uptake by sea salt occurs over the northern Atlantic/Pacific and over the Arabian sea (Extended Data Fig. 1 shows a simulation with no sea-salt emissions). In 1970, industrial and transport emissions over North America, Europe and Japan 17 have a profound impact on the radical termination processes. Many of the cities in North America, Europe and Japan are red, indicating NO 2 + OH as the dominant termination step. However, over Europe, large regions of the North Sea and eastern Germany are magenta (balance between OH + NO 2 and aerosol uptake), with much of eastern Europe being cyan (balance between peroxyl-radical self-reaction and aerosol uptake). Over North America, West Coast cities (Los Angeles, San Francisco and Seattle) show NO 2 + OH domination, while cities around the Great Lakes and those on the East Coast show large fractions of the radical termination being due to HO 2 uptake (magenta, cyan), reflecting the different industrial and transport sources in these regions. Most of Japan is red or yellow,", "role": "user" }, { "content": "Researchers from the University of York have discovered why reducing particle pollution is actually increasing surface ozone pollution in some emerging economies, negatively impacting health, ecosystems and agriculture. The findings, published in Nature Geoscience, challenge established methods for tackling air pollution, the researchers say. Surface ozone is the main component of \"smog\" and is created by chemical reactions between oxides of nitrogen (NOx) and volatile organic compounds (VOC). This happens when pollutants emitted by cars, power plants, industrial boilers, refineries, chemical plants, and other sources react in the presence of sunlight. In the last decade, when countries such as China improved air quality by reducing particle pollution—which is emitted from burning of coal, steel making, vehicles, and fires—the scientific community was surprised to see ozone pollution increase. Now, the study has shed new light on the relationship between these two pollutants. Policymakers have historically considered ozone and particles as separate problems, however the researchers have shown that in some regions they are closely linked. Some short-lived components necessary to make ozone (peroxy radicals) stick to particle pollution, preventing them from going on to form ozone. As the number of particles decreases, the peroxy radicals become available for reactions and ozone increases. The study modeled the effects of reducing particle pollution and found that it could cause an increase in ozone of 20-30% in some highly populated areas of India and China. If left unmanaged, this would have a significant negative impact on ecosystems and crop yield. The researchers are calling for new strategies that take this interaction between pollutants into account. The problem can be overcome by targeting reductions in a wider range of pollutants, particularly (VOCs) from chemicals and fuels and NOx from combustion. Co-lead author of the study, Professor Mathew Evans from the Department of Chemistry at the University of York said: \"Particle pollution and ozone pollution have been viewed by policy makers around the world as separate issues, but our study emphasizes the need to look at them together. For 40 years we have thought that ozone depended only on volatile organic compounds and nitrogen oxides and it's only now that we are putting the pieces of the puzzle together and seeing this relationship with particle pollution. Policy now needs to be adapted to this new knowledge. \"Tackling particulate matter in the atmosphere is rightly a priority because of the serious risk it poses to human health. However this study highlights the complex choices facing governments in how they invest to manage air pollution. Solutions are not straightforward and there can be hidden connections between different pollutants.\" The WHO estimates that 4.2 million die prematurely every year as the result of exposure to outdoor air pollution. Developing countries such as India, China and Africa are among the worst affected. The modeling study estimated that significant reductions in particle pollution in these areas would lead to the need to make dramatic reductions in the emissions of the NOx and VOCs—up to 50% in— order to keep ozone pollution in check. Co-lead author of the study, Professor Alastair Lewis from the National Center for Atmospheric Science added \"this study shows that there can be risks in focusing too narrowly on just one pollutant. There has been dramatic improvement in particle pollution in China over recent years, but emphasis only on particles can lead to unintended consequences. Action to accelerate the reduction in emissions of NOx and VOCs is now essential.\" \"Suppression of surface ozone by an aerosol-inhibited photochemical ozone regime\" is published in Nature Geoscience. ", "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 Atmospheric ozone (O 3 ) is a pollutant produced through chemical chain reactions where volatile organic compounds (VOCs), carbon monoxide and methane are oxidized in the presence of oxides of nitrogen (NO x ). For decades, the controlling chain termination step has been used to separate regions into either ‘NO x limited’ (peroxyl-radical self-reactions dominate) or ‘VOC limited’ (hydroxyl radical (OH) + nitrogen dioxide (NO 2 ) reaction dominates). The controlling regime would then guide policies for reducing emissions and so O 3 concentrations. Using a chemical transport model, we show that a third ‘aerosol inhibited’ regime exists, where reactive uptake of hydroperoxyl radicals (HO 2 ) onto aerosol particles dominates. In 1970, 2% of the Northern Hemisphere population lived in an aerosol-inhibited regime, but by 2014 this had increased to 21%; 60% more than lived in a VOC-limited regime. Aerosol-inhibited chemistry suppressed surface O 3 concentrations in North America and Europe in the 1970s and is currently suppressing surface O 3 over Asia. This third photochemical O 3 regime leads to potential trade-off tensions between reducing particle pollution in Asia (a key current health policy and priority) and increasing surface O 3 , should O 3 precursors emissions not be reduced in tandem. Main Ozone (O 3 ) has well-documented detrimental impacts on human and ecosystem health, and in the mid to upper free troposphere is a greenhouse gas 1 , 2 . Since the mid-twentieth century, it has been known that O 3 is formed through complex radical chain-reaction chemistry involving the oxidation of volatile organic compounds (VOCs) in the presence of oxides of nitrogen (NO x ) (ref. 3 ). The chain reaction is initiated through the photolysis of photo-labile compounds such as O 3 , CH 2 O and HONO, propagated through the interconversion of peroxyl (HO 2 and RO 2 ) and hydroxyl (OH) radicals and terminated either through the self-reaction of peroxyl radicals to form longer-lived species (such as peroxides) or from the reaction of a hydroxyl radical with nitrogen dioxide (NO 2 ) to form nitric acid (HNO 3 ) 4 , 5 . From the perspective of reducing O 3 pollution, the dominant termination step is often used to identify whether reductions in the emissions of NO x or VOCs should be preferentially employed 6 . If peroxyl-radical self-reactions dominate (known as the ‘NO x limited’ regime), reductions in NO x emissions are most beneficial, whereas if the NO 2 + OH reaction dominates (known as the ‘VOC limited’ regime) reductions in organic emissions are most effective. The existence of these two well-defined O 3 production regimes has been used to guide national-, regional- and city-level air-quality policy choices for many decades 3 . Since the development of the NO x - versus VOC-limited model, understanding of atmospheric chemistry has advanced, with increased understanding of VOC chemistry 7 , aerosols 8 , halogens 9 and so on. In this study, we use a chemistry transport model with an advanced representation of atmospheric chemistry (GEOS-Chem 10 ) to diagnose the balance of termination steps. Notably, the model includes the uptake of HO 2 onto aerosol surfaces, which has been identified as an important process for chain termination over the past decades 8 , 11 , 12 , 13 , 14 , 15 . We compare the rate of radical termination by peroxyl-radical self-reactions, the OH + NO 2 reaction and the uptake of HO 2 onto aerosol in July for the Northern Hemisphere in the pre-industrial era (1750), 1970 and 2014 ( Methods ). Concentrations of key components calculated by the model are shown in Supplementary Figs. 1–6 . Chain termination Figure 1 shows the surface distribution of the relative chemical fluxes of these termination steps for July 1750, 1970 and 2014 (enlargements over North America, Europe and Asia are in Supplementary Figs. 8 – 10 ). Fig. 1: Map of the fractional contribution of each radical loss pathway for the years 1750, 1950 and 2014. Mean simulated July solar noon-time fraction of radical termination at the surface that occurs through OH + NO 2 (red), peroxyl-radical self-reactions (green) and aerosol uptake of HO 2 (blue) for 1750, 1970 and 2014. Enlargements of North America, Europe and Asia are shown in the Supplementary Information . Full size image In the pre-industrial era (1750), peroxyl-radical self-reactions (green) dominate. Biomass burning (forest fires) in Russia and Canada show termination by the uptake of HO 2 onto aerosol (blue), whereas fires over Kazakhstan show termination by OH + NO 2 (red) (Extended Data Fig. 1 shows a simulation with biomass burning switched off). This reflects the differing balance of NO x relative to particulates emitted by different fires 16 . Desert dust makes only a limited contribution to the aerosol surface area, leading to some increased contribution of HO 2 uptake over Mauritania, Oman and Iran, but overall the impact is minor (Extended Data Fig. 1 shows a simulation with no desert dust emissions). Some HO 2 uptake by sea salt occurs over the northern Atlantic/Pacific and over the Arabian sea (Extended Data Fig. 1 shows a simulation with no sea-salt emissions). In 1970, industrial and transport emissions over North America, Europe and Japan 17 have a profound impact on the radical termination processes. Many of the cities in North America, Europe and Japan are red, indicating NO 2 + OH as the dominant termination step. However, over Europe, large regions of the North Sea and eastern Germany are magenta (balance between OH + NO 2 and aerosol uptake), with much of eastern Europe being cyan (balance between peroxyl-radical self-reaction and aerosol uptake). Over North America, West Coast cities (Los Angeles, San Francisco and Seattle) show NO 2 + OH domination, while cities around the Great Lakes and those on the East Coast show large fractions of the radical termination being due to HO 2 uptake (magenta, cyan), reflecting the different industrial and transport sources in these regions. Most of Japan is red or yellow,<|im_end|> <|im_start|>assistant Researchers from the University of York have discovered why reducing particle pollution is actually increasing surface ozone pollution in some emerging economies, negatively impacting health, ecosystems and agriculture. The findings, published in Nature Geoscience, challenge established methods for tackling air pollution, the researchers say. Surface ozone is the main component of "smog" and is created by chemical reactions between oxides of nitrogen (NOx) and volatile organic compounds (VOC). This happens when pollutants emitted by cars, power plants, industrial boilers, refineries, chemical plants, and other sources react in the presence of sunlight. In the last decade, when countries such as China improved air quality by reducing particle pollution—which is emitted from burning of coal, steel making, vehicles, and fires—the scientific community was surprised to see ozone pollution increase. Now, the study has shed new light on the relationship between these two pollutants. Policymakers have historically considered ozone and particles as separate problems, however the researchers have shown that in some regions they are closely linked. Some short-lived components necessary to make ozone (peroxy radicals) stick to particle pollution, preventing them from going on to form ozone. As the number of particles decreases, the peroxy radicals become available for reactions and ozone increases. The study modeled the effects of reducing particle pollution and found that it could cause an increase in ozone of 20-30% in some highly populated areas of India and China. If left unmanaged, this would have a significant negative impact on ecosystems and crop yield. The researchers are calling for new strategies that take this interaction between pollutants into account. The problem can be overcome by targeting reductions in a wider range of pollutants, particularly (VOCs) from chemicals and fuels and NOx from combustion. Co-lead author of the study, Professor Mathew Evans from the Department of Chemistry at the University of York said: "Particle pollution and ozone pollution have been viewed by policy makers around the world as separate issues, but our study emphasizes the need to look at them together. For 40 years we have thought that ozone depended only on volatile organic compounds and nitrogen oxides and it's only now that we are putting the pieces of the puzzle together and seeing this relationship with particle pollution. Policy now needs to be adapted to this new knowledge. "Tackling particulate matter in the atmosphere is rightly a priority because of the serious risk it poses to human health. However this study highlights the complex choices facing governments in how they invest to manage air pollution. Solutions are not straightforward and there can be hidden connections between different pollutants." The WHO estimates that 4.2 million die prematurely every year as the result of exposure to outdoor air pollution. Developing countries such as India, China and Africa are among the worst affected. The modeling study estimated that significant reductions in particle pollution in these areas would lead to the need to make dramatic reductions in the emissions of the NOx and VOCs—up to 50% in— order to keep ozone pollution in check. Co-lead author of the study, Professor Alastair Lewis from the National Center for Atmospheric Science added "this study shows that there can be risks in focusing too narrowly on just one pollutant. There has been dramatic improvement in particle pollution in China over recent years, but emphasis only on particles can lead to unintended consequences. Action to accelerate the reduction in emissions of NOx and VOCs is now essential." "Suppression of surface ozone by an aerosol-inhibited photochemical ozone regime" is published in Nature Geoscience. <|im_end|>

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24366, 1873, 13, 220, 128257, 198 ]

2,120

[ { "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 report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations. Main The Y chromosome bears a unique record of human history owing to its male-specific inheritance and the absence of crossover for most of its length, which together link it completely to male phenotype and behavior 1 . Previous studies have demonstrated the value of full sequences for characterizing and calibrating the human Y-chromosome phylogeny 2 , 3 . These studies have led to insights into male demography, but further work is needed to more comprehensively describe the range of Y-chromosome variation, including classes of variation more complex than single-nucleotide variants (SNVs); to investigate the mutational processes operating in the different classes; and to determine the relative roles of selection 4 and demography 5 in shaping Y-chromosome variation. The role of demography has risen to prominence with reports of male-specific bottlenecks in several geographical areas after 10 thousand years ago (kya) 5 , 6 , 7 , at times putatively associated with the spread of farming 5 or Bronze Age culture 6 . With improved calibration of the Y-chromosome SNV mutation rate 8 , 9 , 10 and, consequently, more secure dating of relevant features of the Y-chromosome phylogeny, it is now possible to hone such interpretations. We have conducted a comprehensive analysis of Y-chromosome variation using the largest extant sequence-based survey of global genetic variation—phase 3 of the 1000 Genomes Project 11 . We have documented the extent of and biological processes acting on five types of genetic variation, and we have generated new insights into the history of human males. Results Data set Our data set comprises 1,244 Y chromosomes sampled from 26 populations ( Supplementary Table 1 ) and sequenced to a median haploid coverage of 4.3×. Reads were mapped to the GRCh37 human reference assembly used by phase 3 of the 1000 Genomes Project 11 and to the GRCh38 reference for our analysis of short tandem repeats (STRs). We used multiple haploid-tailored methods to call variants and generate call sets containing more than 65,000 variants of five types, including SNVs ( Supplementary Fig. 1 and Supplementary Tables 2 and 3 ), multiple-nucleotide variants (MNVs), short insertions and deletions (indels), copy number variants (CNVs) ( Supplementary Figs. 2–12 ), and STRs ( Supplementary Tables 4–6 ). We also identified karyotype variation, which included one instance of 47,XXY and several mosaics of the karyotypes 46,XY and 45,X ( Supplementary Table 7 ). We applied stringent quality control to meet the Project's requirement of a false discovery rate (FDR) <5% for SNVs, indels and MNVs, and CNVs. In our validation analysis with independent data sets, the genotype concordance was greater than 99% for SNVs and was 86–97% for more complex variants ( Table 1 ). Table 1 Y-chromosome variants discovered in 1,244 males Full size table To construct a set of putative SNVs, we generated six distinct call sets, which we input to a consensus genotype caller. In an iterative process, we leveraged the phylogeny to tune the final genotype calling strategy. We used similar methods for MNVs and indels, and we ran HipSTR to call STRs ( Supplementary Note ). We discovered CNVs in the sequence data using two approaches, GenomeSTRiP 12 and CnvHitSeq 13 ( Supplementary Note ), and we validated calls using array comparative genomic hybridization (aCGH), supplemented by FISH on DNA fibers (fiber-FISH) in a few cases ( Supplementary Figs. 8 and 9 , and Supplementary Note ). In Figure 1 , we illustrate a representative large deletion, which we discovered in a single individual using GenomeSTRiP ( Fig. 1b ). We validated its presence by aCGH ( Fig. 1c ) and ascertained its structure with fiber-FISH ( Fig. 1d ). Notably, the event that gave rise to this variant was not a simple recombination between the segmental duplication elements it partially encompasses ( Fig. 1a,d ). Figure 1: Discovery and validation of a representative Y-chromosome CNV. ( a ) The GRCh37 reference sequence contains an inverted segmental duplication (yellow bars) within GRCh37 Y: 17,986,738–18,016,824 bp. We designed FISH probes to target the 3′ termini of the two segments (magenta and green bars labeled P1 and P3, respectively) and the unique region between them (light-blue bar labeled P2). A fourth probe used reference sequence BAC clone RP11-12J24 (dark-blue bar labeled P4). Unlabeled green and magenta bars represent expected cross-hybridization, and black bars represent CNV events called by GenomeSTRiP and aCGH. GenomeSTRiP called a 30-kb deletion that includes the duplicated segments and the unique spacer region, whereas aCGH lacks probes in the duplicated regions. ( b ) GenomeSTRiP discovery plot. The red curve indicates the normalized read depth for sample HG00183, as compared to the read depth for 1,232 other samples (gray) and the median depth (black). ( c ) Validation by aCGH. The intensity ratio for HG00183 (red) is shown relative to that for 1,233 other samples (gray) and the median ratio (black). ( d ) Fiber-FISH validation using the probes illustrated in a . The reference sample, HG00096, matches the human reference sequence, with green, magenta, light-blue, magenta, and green hybridizations occurring in sequence. In contrast, we observed just one green and one magenta hybridization in HG00183, indicating deletion of one copy of the segmental duplication and the central unique region. The coordinate scale that is consistent across a – c does not apply to d , and, although the BAC clone", "role": "user" }, { "content": "The largest ever study of global genetic variation in the human Y chromosome has uncovered the hidden history of men. Research published today (25 April) in Nature Genetics reveals explosions in male population numbers in five continents, occurring at times between 55 thousand and four thousand years ago. The study, led by Dr Chris Tyler-Smith of the Wellcome Trust Sanger Institute, analysed sequence differences between the Y chromosomes of more than 1200 men from 26 populations around the world using data generated by the 1000 Genomes Project. The work involved 42 scientists from four continents. Dr David Poznik, from Stanford University, California, first author on the paper, said: \"We identified more than 60,000 positions where one DNA letter was replaced by another in a man with modern descendants, and we discovered thousands of more complex DNA variants. These data constitute a rich and publicly available resource for further genealogical, historical and forensic studies.\" Analysing the Y chromosomes of modern men can tell us about the lives of our ancestors. The Y chromosome is only passed from father to son and so is wholly linked to male characteristics and behaviours. The team used the data to build a tree of these 1200 Y chromosomes; it shows how they are all related to one another. As expected, they all descend from a single man who lived approximately 190,000 years ago. The most intriguing and novel finding was that some parts of the tree were more like a bush than a tree, with many branches originating at the same point. Dr Yali Xue, lead author from the Wellcome Trust Sanger Institute, explained: \"This pattern tells us that there was an explosive increase in the number of men carrying a certain type of Y chromosome, within just a few generations. We only observed this phenomenon in males, and only in a few groups of men.\" The earliest explosive increases of male numbers occurred 50,000-55,000 years ago, across Asia and Europe, and 15,000 years ago in the Americas. There were also later expansions in sub-Saharan Africa, Western Europe, South Asia and East Asia, at times between 4,000 and 8,000 years ago. The team believes the earlier population increases resulted from the first peopling by modern humans of vast continents, where plenty of resources were available. The later expansions are more enigmatic. Dr Chris Tyler-Smith, from the Sanger Institute, added: \"The best explanation is that they may have resulted from advances in technology that could be controlled by small groups of men. Wheeled transport, metal working and organised warfare are all candidate explanations that can now be investigated further.\" All of the samples and data from the 1000 Genomes Project are freely available for use by other scientists and interested investigators. ", "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 report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations. Main The Y chromosome bears a unique record of human history owing to its male-specific inheritance and the absence of crossover for most of its length, which together link it completely to male phenotype and behavior 1 . Previous studies have demonstrated the value of full sequences for characterizing and calibrating the human Y-chromosome phylogeny 2 , 3 . These studies have led to insights into male demography, but further work is needed to more comprehensively describe the range of Y-chromosome variation, including classes of variation more complex than single-nucleotide variants (SNVs); to investigate the mutational processes operating in the different classes; and to determine the relative roles of selection 4 and demography 5 in shaping Y-chromosome variation. The role of demography has risen to prominence with reports of male-specific bottlenecks in several geographical areas after 10 thousand years ago (kya) 5 , 6 , 7 , at times putatively associated with the spread of farming 5 or Bronze Age culture 6 . With improved calibration of the Y-chromosome SNV mutation rate 8 , 9 , 10 and, consequently, more secure dating of relevant features of the Y-chromosome phylogeny, it is now possible to hone such interpretations. We have conducted a comprehensive analysis of Y-chromosome variation using the largest extant sequence-based survey of global genetic variation—phase 3 of the 1000 Genomes Project 11 . We have documented the extent of and biological processes acting on five types of genetic variation, and we have generated new insights into the history of human males. Results Data set Our data set comprises 1,244 Y chromosomes sampled from 26 populations ( Supplementary Table 1 ) and sequenced to a median haploid coverage of 4.3×. Reads were mapped to the GRCh37 human reference assembly used by phase 3 of the 1000 Genomes Project 11 and to the GRCh38 reference for our analysis of short tandem repeats (STRs). We used multiple haploid-tailored methods to call variants and generate call sets containing more than 65,000 variants of five types, including SNVs ( Supplementary Fig. 1 and Supplementary Tables 2 and 3 ), multiple-nucleotide variants (MNVs), short insertions and deletions (indels), copy number variants (CNVs) ( Supplementary Figs. 2–12 ), and STRs ( Supplementary Tables 4–6 ). We also identified karyotype variation, which included one instance of 47,XXY and several mosaics of the karyotypes 46,XY and 45,X ( Supplementary Table 7 ). We applied stringent quality control to meet the Project's requirement of a false discovery rate (FDR) <5% for SNVs, indels and MNVs, and CNVs. In our validation analysis with independent data sets, the genotype concordance was greater than 99% for SNVs and was 86–97% for more complex variants ( Table 1 ). Table 1 Y-chromosome variants discovered in 1,244 males Full size table To construct a set of putative SNVs, we generated six distinct call sets, which we input to a consensus genotype caller. In an iterative process, we leveraged the phylogeny to tune the final genotype calling strategy. We used similar methods for MNVs and indels, and we ran HipSTR to call STRs ( Supplementary Note ). We discovered CNVs in the sequence data using two approaches, GenomeSTRiP 12 and CnvHitSeq 13 ( Supplementary Note ), and we validated calls using array comparative genomic hybridization (aCGH), supplemented by FISH on DNA fibers (fiber-FISH) in a few cases ( Supplementary Figs. 8 and 9 , and Supplementary Note ). In Figure 1 , we illustrate a representative large deletion, which we discovered in a single individual using GenomeSTRiP ( Fig. 1b ). We validated its presence by aCGH ( Fig. 1c ) and ascertained its structure with fiber-FISH ( Fig. 1d ). Notably, the event that gave rise to this variant was not a simple recombination between the segmental duplication elements it partially encompasses ( Fig. 1a,d ). Figure 1: Discovery and validation of a representative Y-chromosome CNV. ( a ) The GRCh37 reference sequence contains an inverted segmental duplication (yellow bars) within GRCh37 Y: 17,986,738–18,016,824 bp. We designed FISH probes to target the 3′ termini of the two segments (magenta and green bars labeled P1 and P3, respectively) and the unique region between them (light-blue bar labeled P2). A fourth probe used reference sequence BAC clone RP11-12J24 (dark-blue bar labeled P4). Unlabeled green and magenta bars represent expected cross-hybridization, and black bars represent CNV events called by GenomeSTRiP and aCGH. GenomeSTRiP called a 30-kb deletion that includes the duplicated segments and the unique spacer region, whereas aCGH lacks probes in the duplicated regions. ( b ) GenomeSTRiP discovery plot. The red curve indicates the normalized read depth for sample HG00183, as compared to the read depth for 1,232 other samples (gray) and the median depth (black). ( c ) Validation by aCGH. The intensity ratio for HG00183 (red) is shown relative to that for 1,233 other samples (gray) and the median ratio (black). ( d ) Fiber-FISH validation using the probes illustrated in a . The reference sample, HG00096, matches the human reference sequence, with green, magenta, light-blue, magenta, and green hybridizations occurring in sequence. In contrast, we observed just one green and one magenta hybridization in HG00183, indicating deletion of one copy of the segmental duplication and the central unique region. The coordinate scale that is consistent across a – c does not apply to d , and, although the BAC clone<|im_end|> <|im_start|>assistant The largest ever study of global genetic variation in the human Y chromosome has uncovered the hidden history of men. Research published today (25 April) in Nature Genetics reveals explosions in male population numbers in five continents, occurring at times between 55 thousand and four thousand years ago. The study, led by Dr Chris Tyler-Smith of the Wellcome Trust Sanger Institute, analysed sequence differences between the Y chromosomes of more than 1200 men from 26 populations around the world using data generated by the 1000 Genomes Project. The work involved 42 scientists from four continents. Dr David Poznik, from Stanford University, California, first author on the paper, said: "We identified more than 60,000 positions where one DNA letter was replaced by another in a man with modern descendants, and we discovered thousands of more complex DNA variants. These data constitute a rich and publicly available resource for further genealogical, historical and forensic studies." Analysing the Y chromosomes of modern men can tell us about the lives of our ancestors. The Y chromosome is only passed from father to son and so is wholly linked to male characteristics and behaviours. The team used the data to build a tree of these 1200 Y chromosomes; it shows how they are all related to one another. As expected, they all descend from a single man who lived approximately 190,000 years ago. The most intriguing and novel finding was that some parts of the tree were more like a bush than a tree, with many branches originating at the same point. Dr Yali Xue, lead author from the Wellcome Trust Sanger Institute, explained: "This pattern tells us that there was an explosive increase in the number of men carrying a certain type of Y chromosome, within just a few generations. We only observed this phenomenon in males, and only in a few groups of men." The earliest explosive increases of male numbers occurred 50,000-55,000 years ago, across Asia and Europe, and 15,000 years ago in the Americas. There were also later expansions in sub-Saharan Africa, Western Europe, South Asia and East Asia, at times between 4,000 and 8,000 years ago. The team believes the earlier population increases resulted from the first peopling by modern humans of vast continents, where plenty of resources were available. The later expansions are more enigmatic. Dr Chris Tyler-Smith, from the Sanger Institute, added: "The best explanation is that they may have resulted from advances in technology that could be controlled by small groups of men. Wheeled transport, metal working and organised warfare are all candidate explanations that can now be investigated further." All of the samples and data from the 1000 Genomes Project are freely available for use by other scientists and interested investigators. <|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 Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phylogeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1- cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage. Introduction Bacteria across a wide range of phyla produce capsular polysaccharides that are associated with diverse experimentally validated functions and have been shown to improve bacterial persistence and adaptation to new environments 1 , 2 . Human bacterial pathogens use these capsules as major virulence determinants to promote colonization and persistence in the gastrointestinal, respiratory, and urogenital tracts, as well as other tissues 3 , 4 , 5 . Capsular polysaccharides are often identical or similar in structure and chemical composition to polysaccharides found in human tissues, thereby providing non-immunogenic coatings for bacteria to survive in human tissues and to cause disease 5 . In addition, capsules can reduce the efficiency of antimicrobial peptides and complement 6 , 7 , 8 , 9 , suppress phagocytosis by innate immune cells and promote intracellular survival 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , and contribute to defence against antimicrobial agents 8 , 18 . Although E. coli can produce around 80 distinct capsular chemotypes that are organised into four major groups 19 , only a subset of these chemically distinct capsular types are associated with the capacity to cause invasive extraintestinal diseases; such infections include bloodstream infections (BSI), pyelonephritis and meningitis 20 . In particular, the polysialic acid-containing K1 capsule 21 , 22 , chrondodontin-containing K4 capsule 23 and heparosan-containing K5 capsule 24 , 25 are associated with the extraintestinal pathogenic E. coli (ExPEC) clones linked to such invasive diseases 26 , 27 , likely through the propensity of these capsule type to mimic polysaccharides present on cells in the human tissues 5 . However, the epidemiology of the capsular types remains largely unexplored due to the absence of serological typing data or specific methods that can computationally predict E. coli capsular types based on whole-genome sequencing data. Our current understanding of the evolution and functional properties of the distinct capsular polysaccharides in the global E. coli population is therefore limited and mainly based on pre-genomic studies. The K1 capsule polysaccharide has repeatedly been linked to BSI, neonatal meningitis and pyelonephritis 5 , 28 , 29 , 30 , 31 . The K1 capsule is a homopolymer of α−2,8-linked N-acetylneuraminic acid (sialic acid; NeuNAc) termed polysialic acid (polySia) that mimics the polySia modification found on human neuronal and immune cells 32 , 33 , 34 , 35 and likely promotes the capacity of K1-expressing E. coli to hide and reside within the blood and neuronal compartments. Indeed, polySia prevents full activation of innate host defences and confers resistance to complement- and phagocyte-mediated killing 36 , 37 , 38 . In agreement with epidemiological links of K1 capsule to invasive human infections, experimental animal models using isogenic strains have revealed that K1 expression promotes stable gastrointestinal (GI) tract colonisation and promotes the development of invasive systemic infections by E. coli 39 , 40 , 41 , 42 . In contrast to the association of K1 with BSI and meningitis, other well-studied K antigens including types K2, K4 and K5 are mostly associated with UTIs 5 , 6 , 43 , 44 . Despite the association of K1 encapsulated E. coli with BSI and meningitis, and the fact that polySia can be utilized as a powerful tool for diagnosis and therapeutic targeting 45 , 46 , we lack basic knowledge on the prevalence, evolution and functional properties of the K1 capsule at the population level. This lack of knowledge limits our capacity to develop efficient strategies to combat E. coli infections. In this study, we elucidated the prevalence, distribution, and evolution of the K1 capsule in E. coli populations by considering a global dataset of 5065 clinical isolates. The position and synteny of the K1 capsule (K1- cps ) locus in the genomes were resolved by considering K1 complete genomes. Using a Bayesian inference approach, we estimated the introduction date of K1- cps in the most predominant extraintestinal lineages. To show that the K1 capsule was functional among the distinct lineages, we performed several phenotypic assays to show that the K1 capsule was expressed and conferred E. coli with immune resistance independent of its genetic background. Our results show that a quarter of BSIs are caused by E. coli carrying this the K1- cps locus, and this is driven by multiple introductions of K1- cps into the ExPEC pathotype. For the first time, we estimated the introduction times of the capsule among the main ExPEC lineages and dated that the K1- cps locus was acquired at least 500 years ago. In support of the role of K1 capsule in virulence, we show that the enzymatic removal of the K1 capsule renders E. coli susceptible to complement-replete human serum, suggesting that the therapeutic use of capsule depolymerases is likely to be a promising approach", "role": "user" }, { "content": "In a new study, published today in Nature Communications, a multi-center team led by the Wellcome Sanger Institute, the University of Oslo, Imperial College London and UCL, has mapped for the first time the evolutionary timeline and population distribution of Escherichia coli's protective outer capsule, which is responsible for the bacterium's virulence. The study also shows how targeting the bacterium's protective layer can help treat extraintestinal infections. This new work focused on a particular subset of E. coli with a specific capsule—the extracellular barrier that surrounds a bacterium—which scientists have called K1. E. coli with this type of capsule are known to cause invasive diseases such as bloodstream or kidney infections, and meningitis in newborns. This is because this particular cover allows them to mimic molecules already present in human tissues and enter the body unnoticed. The researchers present evidence that targeting the capsule can be used as the basis of treatment, paving the way to prevent serious E. coli infections. E. coli is a common cause of urinary tract and bloodstream infections and can cause meningitis in premature and term newborns, with a mortality rate as high as 40%. Furthermore, the rise in hypervirulent and multi-drug resistant E. coli during the last decade means that developing effective strategies to prevent and treat E. coli has now become urgent. Understanding the bacterium's anatomy and how this plays a role in causing disease is key for the prevention of serious infections. Scientists until now lacked basic knowledge of the prevalence, evolution and functional properties of the K1 capsule, limiting their capacity to combat E. coli infections. Researchers at the Wellcome Sanger Institute, the University of Oslo, Imperial College London and UCL have now mapped the evolution of this E. coli strain, its prevalence and distribution. Using high-resolution population genomics, whole genome sequencing and advanced computational tools, they analyzed 5,065 clinical samples from different countries and time periods. The data included large collections of samples from the UK and Norway, newly-generated adult and neonatal samples from six countries, such as Brazil, Mexico and Laos among others, and samples from the pre-antibiotic era—from 1932 onwards. They found that this specifically virulent capsule—K1—actually dates further back in time, approximately 500 years earlier than previously imagined. This highlights the importance of the capsule for the bacterium's survival and the role of the extracellular barrier in the success of E. coli as the main cause of extraintestinal infections. Dr. Sergio Arredondo-Alonso, lead author of the study from the University of Oslo and the Wellcome Sanger Institute, said, \"It was exciting to discover the possibility of reconstructing the evolutionary history of the K1 capsule over the last half millennium, and to see how the capsule genes have been acquired over and over again by many different lineages of this pathogen species over the centuries. As neither the prevalence nor the history of K1 was known, it felt like we entered truly unchartered territory and significantly advanced understanding of this major pathogen species.\" The study also shows that 25% of all current E. coli strains responsible for blood infections contain the genetic information needed to develop the K1 capsule. Obtaining a complete evolutionary history of this strain will now allow researchers to understand how bacteria obtain the genetic material responsible for severe virulence in the first place, and analyze ways to combat them. By using enzymes from bacteriophages, which are viruses that infect and kill bacteria, researchers were able to remove the bacterium's extracellular barrier and make it vulnerable to the human immune system. The researchers demonstrated in in vitro studies using human serum—a liquid part of the blood that is commonly used in laboratory studies—that targeting this capsule can be a way to broadly treat E. coli infection without the use of antibiotics, consistent with previous experimental infections in animals. Dr. Alex McCarthy, a senior author of the study from Imperial College London, said, \"We specifically demonstrated the advances made possible by combining experimental microbiology with population genomics and evolutionary modeling tools, to open a window into translating the findings into future clinical practice. We show that therapeutic targeting of the K1 capsule makes these pathogens more vulnerable to our immune system, and offers the possibility of preventing serious infections. For example, it could help treat newborn babies with meningitis caused by K1 E. coli, which is a rare but dangerous condition associated with high mortality and serious long-term adverse health effects.\" Professor Jukka Corander, a co-senior author of the study from the Wellcome Sanger Institute and the University of Oslo, said, \"Our research shows the importance of representative genomic surveys of pathogens over time and space. These studies will enable us to reconstruct the evolutionary history of successful bacterial lineages and pinpoint changes in their genetic make-up that can lead to their ability to spread and cause disease. Such knowledge is ultimately providing the basis for designing future interventions and therapies against these pathogens.\" ", "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 Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phylogeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1- cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage. Introduction Bacteria across a wide range of phyla produce capsular polysaccharides that are associated with diverse experimentally validated functions and have been shown to improve bacterial persistence and adaptation to new environments 1 , 2 . Human bacterial pathogens use these capsules as major virulence determinants to promote colonization and persistence in the gastrointestinal, respiratory, and urogenital tracts, as well as other tissues 3 , 4 , 5 . Capsular polysaccharides are often identical or similar in structure and chemical composition to polysaccharides found in human tissues, thereby providing non-immunogenic coatings for bacteria to survive in human tissues and to cause disease 5 . In addition, capsules can reduce the efficiency of antimicrobial peptides and complement 6 , 7 , 8 , 9 , suppress phagocytosis by innate immune cells and promote intracellular survival 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , and contribute to defence against antimicrobial agents 8 , 18 . Although E. coli can produce around 80 distinct capsular chemotypes that are organised into four major groups 19 , only a subset of these chemically distinct capsular types are associated with the capacity to cause invasive extraintestinal diseases; such infections include bloodstream infections (BSI), pyelonephritis and meningitis 20 . In particular, the polysialic acid-containing K1 capsule 21 , 22 , chrondodontin-containing K4 capsule 23 and heparosan-containing K5 capsule 24 , 25 are associated with the extraintestinal pathogenic E. coli (ExPEC) clones linked to such invasive diseases 26 , 27 , likely through the propensity of these capsule type to mimic polysaccharides present on cells in the human tissues 5 . However, the epidemiology of the capsular types remains largely unexplored due to the absence of serological typing data or specific methods that can computationally predict E. coli capsular types based on whole-genome sequencing data. Our current understanding of the evolution and functional properties of the distinct capsular polysaccharides in the global E. coli population is therefore limited and mainly based on pre-genomic studies. The K1 capsule polysaccharide has repeatedly been linked to BSI, neonatal meningitis and pyelonephritis 5 , 28 , 29 , 30 , 31 . The K1 capsule is a homopolymer of α−2,8-linked N-acetylneuraminic acid (sialic acid; NeuNAc) termed polysialic acid (polySia) that mimics the polySia modification found on human neuronal and immune cells 32 , 33 , 34 , 35 and likely promotes the capacity of K1-expressing E. coli to hide and reside within the blood and neuronal compartments. Indeed, polySia prevents full activation of innate host defences and confers resistance to complement- and phagocyte-mediated killing 36 , 37 , 38 . In agreement with epidemiological links of K1 capsule to invasive human infections, experimental animal models using isogenic strains have revealed that K1 expression promotes stable gastrointestinal (GI) tract colonisation and promotes the development of invasive systemic infections by E. coli 39 , 40 , 41 , 42 . In contrast to the association of K1 with BSI and meningitis, other well-studied K antigens including types K2, K4 and K5 are mostly associated with UTIs 5 , 6 , 43 , 44 . Despite the association of K1 encapsulated E. coli with BSI and meningitis, and the fact that polySia can be utilized as a powerful tool for diagnosis and therapeutic targeting 45 , 46 , we lack basic knowledge on the prevalence, evolution and functional properties of the K1 capsule at the population level. This lack of knowledge limits our capacity to develop efficient strategies to combat E. coli infections. In this study, we elucidated the prevalence, distribution, and evolution of the K1 capsule in E. coli populations by considering a global dataset of 5065 clinical isolates. The position and synteny of the K1 capsule (K1- cps ) locus in the genomes were resolved by considering K1 complete genomes. Using a Bayesian inference approach, we estimated the introduction date of K1- cps in the most predominant extraintestinal lineages. To show that the K1 capsule was functional among the distinct lineages, we performed several phenotypic assays to show that the K1 capsule was expressed and conferred E. coli with immune resistance independent of its genetic background. Our results show that a quarter of BSIs are caused by E. coli carrying this the K1- cps locus, and this is driven by multiple introductions of K1- cps into the ExPEC pathotype. For the first time, we estimated the introduction times of the capsule among the main ExPEC lineages and dated that the K1- cps locus was acquired at least 500 years ago. In support of the role of K1 capsule in virulence, we show that the enzymatic removal of the K1 capsule renders E. coli susceptible to complement-replete human serum, suggesting that the therapeutic use of capsule depolymerases is likely to be a promising approach<|im_end|> <|im_start|>assistant In a new study, published today in Nature Communications, a multi-center team led by the Wellcome Sanger Institute, the University of Oslo, Imperial College London and UCL, has mapped for the first time the evolutionary timeline and population distribution of Escherichia coli's protective outer capsule, which is responsible for the bacterium's virulence. The study also shows how targeting the bacterium's protective layer can help treat extraintestinal infections. This new work focused on a particular subset of E. coli with a specific capsule—the extracellular barrier that surrounds a bacterium—which scientists have called K1. E. coli with this type of capsule are known to cause invasive diseases such as bloodstream or kidney infections, and meningitis in newborns. This is because this particular cover allows them to mimic molecules already present in human tissues and enter the body unnoticed. The researchers present evidence that targeting the capsule can be used as the basis of treatment, paving the way to prevent serious E. coli infections. E. coli is a common cause of urinary tract and bloodstream infections and can cause meningitis in premature and term newborns, with a mortality rate as high as 40%. Furthermore, the rise in hypervirulent and multi-drug resistant E. coli during the last decade means that developing effective strategies to prevent and treat E. coli has now become urgent. Understanding the bacterium's anatomy and how this plays a role in causing disease is key for the prevention of serious infections. Scientists until now lacked basic knowledge of the prevalence, evolution and functional properties of the K1 capsule, limiting their capacity to combat E. coli infections. Researchers at the Wellcome Sanger Institute, the University of Oslo, Imperial College London and UCL have now mapped the evolution of this E. coli strain, its prevalence and distribution. Using high-resolution population genomics, whole genome sequencing and advanced computational tools, they analyzed 5,065 clinical samples from different countries and time periods. The data included large collections of samples from the UK and Norway, newly-generated adult and neonatal samples from six countries, such as Brazil, Mexico and Laos among others, and samples from the pre-antibiotic era—from 1932 onwards. They found that this specifically virulent capsule—K1—actually dates further back in time, approximately 500 years earlier than previously imagined. This highlights the importance of the capsule for the bacterium's survival and the role of the extracellular barrier in the success of E. coli as the main cause of extraintestinal infections. Dr. Sergio Arredondo-Alonso, lead author of the study from the University of Oslo and the Wellcome Sanger Institute, said, "It was exciting to discover the possibility of reconstructing the evolutionary history of the K1 capsule over the last half millennium, and to see how the capsule genes have been acquired over and over again by many different lineages of this pathogen species over the centuries. As neither the prevalence nor the history of K1 was known, it felt like we entered truly unchartered territory and significantly advanced understanding of this major pathogen species." The study also shows that 25% of all current E. coli strains responsible for blood infections contain the genetic information needed to develop the K1 capsule. Obtaining a complete evolutionary history of this strain will now allow researchers to understand how bacteria obtain the genetic material responsible for severe virulence in the first place, and analyze ways to combat them. By using enzymes from bacteriophages, which are viruses that infect and kill bacteria, researchers were able to remove the bacterium's extracellular barrier and make it vulnerable to the human immune system. The researchers demonstrated in in vitro studies using human serum—a liquid part of the blood that is commonly used in laboratory studies—that targeting this capsule can be a way to broadly treat E. coli infection without the use of antibiotics, consistent with previous experimental infections in animals. Dr. Alex McCarthy, a senior author of the study from Imperial College London, said, "We specifically demonstrated the advances made possible by combining experimental microbiology with population genomics and evolutionary modeling tools, to open a window into translating the findings into future clinical practice. We show that therapeutic targeting of the K1 capsule makes these pathogens more vulnerable to our immune system, and offers the possibility of preventing serious infections. For example, it could help treat newborn babies with meningitis caused by K1 E. coli, which is a rare but dangerous condition associated with high mortality and serious long-term adverse health effects." Professor Jukka Corander, a co-senior author of the study from the Wellcome Sanger Institute and the University of Oslo, said, "Our research shows the importance of representative genomic surveys of pathogens over time and space. These studies will enable us to reconstruct the evolutionary history of successful bacterial lineages and pinpoint changes in their genetic make-up that can lead to their ability to spread and cause disease. Such knowledge is ultimately providing the basis for designing future interventions and therapies against these pathogens." <|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 MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the ‘seed’ region of the miRNA and its counterpart mRNA 1 . Here we use R 1ρ relaxation-dispersion nuclear magnetic resonance 2 and molecular simulations 3 to reveal a dynamic switch—based on the rearrangement of a single base pair in the miRNA–mRNA duplex—that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago 4 , 5 . Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA–mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial ‘screening’ state to an ‘active’ state, and unveil the role of the RNA duplex beyond the seed in Ago2. Main MicroRNAs—non-coding RNA molecules—regulate gene expression by targeting mRNAs. Each mature miRNA of roughly 22 nucleotides is bound to one Argonaute protein (Ago1 to Ago4 in humans), forming an RNA-induced silencing complex (RISC). In the RISC, nucleotides 2–6 of the guide miRNA (g2–g6) are prearranged to recognize mRNA targets through Watson–Crick base pairing 6 , 7 , 8 in the seed (Fig. 1a, b ). This base-pair complementarity (involving up to g2–g8) largely determines RISC activity 9 , 10 : for example, complementarity involving just g2–g6 (a 5-mer) is rejected as unspecific. In human Ago2 (hereafter, Ago2 refers to human Ago2 unless specified otherwise), sites with prolonged base pairing, using at least g2–g7 base-pairing (a 6-mer or larger), can override the checkpoint imposed by Ago2’s flexible helix-7 (ref. 11 ) and induce a conformational transition in Ago2, allowing extended 3′-pairing of the RNA 12 . However, bioinformatics analysis of validated miRNA–mRNA pairs cannot discern sequence determinants in this region, beyond a preference for forming bulges 13 . Moreover, X-ray structures of ternary complexes are unable to resolve the central region of the duplex, supporting the idea of its flexibility 14 . In vitro biochemical studies 15 showed that mismatches in this region contribute little to target binding affinity but can impair catalytic cleavage of short interfering RNAs (siRNAs) in Drosophila Ago2. This implied that the dynamics of the central RNA bases are essential for the fate of target mRNAs; however, the precise nature of the guide–target interaction beyond the seed region remained unclear. Fig. 1: Conformational dynamics in the seed of miR-34a–Sirt1 mRNA. a , Secondary structure of the miR-34a–mSirt1 duplex determined by NMR. The seed (g2–g6 bound to t23–t27) comprises five base-pairs. The grey box indicates nucleotides selected to generate the reduced construct for R 1ρ relaxation-dispersion measurements. b , Sketch of human Ago2 accommodating the miR-34a–mSirt1 duplex. Helix-7 is part of Ago2 and is shown with yellow cylinders. c , 15 N and 1 H R 1ρ individual relaxation-dispersion profiles of gG8N1 and gG8H1, revealing the single-base-pair switching of gG8:C to gG8:U (circled in a ). R 1 and R 2 are the longitudinal and transverse relaxation rates, respectively; R ex is the exchange contribution to the relaxation rate; ω eff 2π –1 is the effective measured spinlock power; Ω 2π –1 is the offset; Δ ω ES is the chemical shift, a structural parameter of the ground-state-to-excited-state transition; ω SL 2π –1 is the measured spinlock power. Error bars represent one standard deviation (s.d.), derived from Monte Carlo simulations of experimental uncertainty (see Supplementary Methods ). d , Chemical-shift distribution for 1 H1– 15 N1 moieties of guanosines in G:C (yellow) or G:U (purple) base pairs from the BMRB 20 . Crosses indicate average chemical shifts for G:C and G:U; dashed ellipses show 1 s.d.; black dots indicate chemical shifts for gG8 in the ground state (GS) and relaxation-dispersion-derived excited state (ES). e , The G:C to G:U base-pair switch, highlighting the guanosine 1 H1– 15 N1 (imino-global fit, one-sided F -test, n = 1) groups in the ground state (yellow) and excited state (purple). Errors represent 1 s.d. derived from Monte Carlo simulations of experimental uncertainty (see Supplementary Methods ). Full size image Here we use nuclear magnetic resonance (NMR) to observe the dynamic process underlying miRNA–mRNA targeting. To elucidate the effects of the conformational transition on RISC function, we combine these measurements with molecular simulations and dual-luciferase reporter (DLR) assays in human cells. We study hsa-miR-34a-5p (‘miR-34a’), part of the evolutionarily conserved miR-34/449 family of miRNAs 16 , which targets the mRNA encoding silent information regulator 1 (Sirt1)—a p53-deacetylating enzyme—in a tumour-suppressive feedback loop. Using R 1ρ NMR relaxation dispersion, we show that the weak so-called 7-mer–A1 seed of the miR-34a–mSirt1 duplex (Fig. 1a, b ) is in equilibrium with a transient and low-populated excited state that results in an 8-mer seed with a G:U base-pair at its 3′-end. The extended seed alters the topology of the duplex by shifting the bending angle between the seed and the 3′-helix in the RISC, as shown by simulations. In a cell-based assay, a structural mimic of the extended seed produces a roughly two-fold increase in target downregulation. Our data suggest a model whereby RISC undergoes a structural transition mediated by RNA dynamics: the RISC first screens targets for correct seed pairing, than transitions into an active complex, releasing the miR-34a 3′-end which is allowed to fully bind the Sirt1 mRNA in the compensatory region. Seed dynamics of miR-34a–mSirt1 binding site Given that an RISC recognizes thousands of distinct binding sites in its target mRNA, with no apparent sequence preference beside the seed, we hypothesize that miRNA–mRNA pairs possess distinct conformational characteristics in the central bulge, facilitating their accommodation within Ago2. First, we solved the secondary structure of miR-34a bound to the validated target site in Sirt1 mRNA (miR-34a–mSirt1 duplex) 17 by NMR (Fig. 1a , Supplementary Fig. 2 and Supplementary Discussion", "role": "user" }, { "content": "Research from Karolinska Institutet published today in Nature shows that an RNA molecule involved in preventing tumour formation can change its structure and thereby control protein production in the cell. The finding can have important clinical implications as it opens for new strategies to treat different types of cancer. Short RNA molecules in our cells, called microRNAs, are important regulators of messenger RNAs (mRNA) - the molecule that codes for the building blocks of our body, the proteins. The exact mechanism of this regulation remains elusive, but it is known that microRNAs can silence mRNA molecules and thereby prevent protein production. Therefore, they have the potential to be used as tools or targets for drugs. \"It's important to increase our understanding of how microRNA regulates protein production because this process is disturbed in many different types of diseases, including cancer,\" says Katja Petzold, Associate Professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet in Sweden who led the study. \"We show for the first time that a microRNA-mRNA complex has a structure that changes and that this movement has an effect on the biological outcome, i.e. the amount of protein produced in the cell.\" The researchers studied a microRNA known as miR-34a, which plays an important role in cancer by indirectly regulating the activity of the p53 protein, known as the guardian of the genome for its ability to prevent cancer formation. Changes in the function of p53 are very common in human cancers. miR-34a downregulates the mRNA that codes for Sirt1, a protein that deactivates p53. Using Nuclear Magnetic Resonance (NMR) and other biophysical methods, the researchers solved the structure and dynamics of miR-34a binding the mRNA molecule. When they measured these dynamics, they found that the complex exists in two structurally different states, one moderately active with a population of 99 per cent and one with enhanced activity, a population of 1 per cent. These states can interconvert, as they are in equilibrium, and the population of each state can be modified by external factors. \"Once we find out how to turn the switch, we can use this in the clinic as a drug to control the production of specific proteins,\" explains Katja Petzold. The researchers were then able to show that miR-34a uses the same strategy to downregulate the production of other proteins, not just Sirt1. \"We reveal the first understanding of how regulation of protein output is steered by small microRNAs based on structure and dynamics,\" says Lorenzo Baronti, Ph.D. student in Katja Petzold's research group and first author of the study. \"This is important because it opens for the development of drugs with a completely new mechanism of action.\" ", "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 MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the ‘seed’ region of the miRNA and its counterpart mRNA 1 . Here we use R 1ρ relaxation-dispersion nuclear magnetic resonance 2 and molecular simulations 3 to reveal a dynamic switch—based on the rearrangement of a single base pair in the miRNA–mRNA duplex—that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago 4 , 5 . Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA–mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial ‘screening’ state to an ‘active’ state, and unveil the role of the RNA duplex beyond the seed in Ago2. Main MicroRNAs—non-coding RNA molecules—regulate gene expression by targeting mRNAs. Each mature miRNA of roughly 22 nucleotides is bound to one Argonaute protein (Ago1 to Ago4 in humans), forming an RNA-induced silencing complex (RISC). In the RISC, nucleotides 2–6 of the guide miRNA (g2–g6) are prearranged to recognize mRNA targets through Watson–Crick base pairing 6 , 7 , 8 in the seed (Fig. 1a, b ). This base-pair complementarity (involving up to g2–g8) largely determines RISC activity 9 , 10 : for example, complementarity involving just g2–g6 (a 5-mer) is rejected as unspecific. In human Ago2 (hereafter, Ago2 refers to human Ago2 unless specified otherwise), sites with prolonged base pairing, using at least g2–g7 base-pairing (a 6-mer or larger), can override the checkpoint imposed by Ago2’s flexible helix-7 (ref. 11 ) and induce a conformational transition in Ago2, allowing extended 3′-pairing of the RNA 12 . However, bioinformatics analysis of validated miRNA–mRNA pairs cannot discern sequence determinants in this region, beyond a preference for forming bulges 13 . Moreover, X-ray structures of ternary complexes are unable to resolve the central region of the duplex, supporting the idea of its flexibility 14 . In vitro biochemical studies 15 showed that mismatches in this region contribute little to target binding affinity but can impair catalytic cleavage of short interfering RNAs (siRNAs) in Drosophila Ago2. This implied that the dynamics of the central RNA bases are essential for the fate of target mRNAs; however, the precise nature of the guide–target interaction beyond the seed region remained unclear. Fig. 1: Conformational dynamics in the seed of miR-34a–Sirt1 mRNA. a , Secondary structure of the miR-34a–mSirt1 duplex determined by NMR. The seed (g2–g6 bound to t23–t27) comprises five base-pairs. The grey box indicates nucleotides selected to generate the reduced construct for R 1ρ relaxation-dispersion measurements. b , Sketch of human Ago2 accommodating the miR-34a–mSirt1 duplex. Helix-7 is part of Ago2 and is shown with yellow cylinders. c , 15 N and 1 H R 1ρ individual relaxation-dispersion profiles of gG8N1 and gG8H1, revealing the single-base-pair switching of gG8:C to gG8:U (circled in a ). R 1 and R 2 are the longitudinal and transverse relaxation rates, respectively; R ex is the exchange contribution to the relaxation rate; ω eff 2π –1 is the effective measured spinlock power; Ω 2π –1 is the offset; Δ ω ES is the chemical shift, a structural parameter of the ground-state-to-excited-state transition; ω SL 2π –1 is the measured spinlock power. Error bars represent one standard deviation (s.d.), derived from Monte Carlo simulations of experimental uncertainty (see Supplementary Methods ). d , Chemical-shift distribution for 1 H1– 15 N1 moieties of guanosines in G:C (yellow) or G:U (purple) base pairs from the BMRB 20 . Crosses indicate average chemical shifts for G:C and G:U; dashed ellipses show 1 s.d.; black dots indicate chemical shifts for gG8 in the ground state (GS) and relaxation-dispersion-derived excited state (ES). e , The G:C to G:U base-pair switch, highlighting the guanosine 1 H1– 15 N1 (imino-global fit, one-sided F -test, n = 1) groups in the ground state (yellow) and excited state (purple). Errors represent 1 s.d. derived from Monte Carlo simulations of experimental uncertainty (see Supplementary Methods ). Full size image Here we use nuclear magnetic resonance (NMR) to observe the dynamic process underlying miRNA–mRNA targeting. To elucidate the effects of the conformational transition on RISC function, we combine these measurements with molecular simulations and dual-luciferase reporter (DLR) assays in human cells. We study hsa-miR-34a-5p (‘miR-34a’), part of the evolutionarily conserved miR-34/449 family of miRNAs 16 , which targets the mRNA encoding silent information regulator 1 (Sirt1)—a p53-deacetylating enzyme—in a tumour-suppressive feedback loop. Using R 1ρ NMR relaxation dispersion, we show that the weak so-called 7-mer–A1 seed of the miR-34a–mSirt1 duplex (Fig. 1a, b ) is in equilibrium with a transient and low-populated excited state that results in an 8-mer seed with a G:U base-pair at its 3′-end. The extended seed alters the topology of the duplex by shifting the bending angle between the seed and the 3′-helix in the RISC, as shown by simulations. In a cell-based assay, a structural mimic of the extended seed produces a roughly two-fold increase in target downregulation. Our data suggest a model whereby RISC undergoes a structural transition mediated by RNA dynamics: the RISC first screens targets for correct seed pairing, than transitions into an active complex, releasing the miR-34a 3′-end which is allowed to fully bind the Sirt1 mRNA in the compensatory region. Seed dynamics of miR-34a–mSirt1 binding site Given that an RISC recognizes thousands of distinct binding sites in its target mRNA, with no apparent sequence preference beside the seed, we hypothesize that miRNA–mRNA pairs possess distinct conformational characteristics in the central bulge, facilitating their accommodation within Ago2. First, we solved the secondary structure of miR-34a bound to the validated target site in Sirt1 mRNA (miR-34a–mSirt1 duplex) 17 by NMR (Fig. 1a , Supplementary Fig. 2 and Supplementary Discussion<|im_end|> <|im_start|>assistant Research from Karolinska Institutet published today in Nature shows that an RNA molecule involved in preventing tumour formation can change its structure and thereby control protein production in the cell. The finding can have important clinical implications as it opens for new strategies to treat different types of cancer. Short RNA molecules in our cells, called microRNAs, are important regulators of messenger RNAs (mRNA) - the molecule that codes for the building blocks of our body, the proteins. The exact mechanism of this regulation remains elusive, but it is known that microRNAs can silence mRNA molecules and thereby prevent protein production. Therefore, they have the potential to be used as tools or targets for drugs. "It's important to increase our understanding of how microRNA regulates protein production because this process is disturbed in many different types of diseases, including cancer," says Katja Petzold, Associate Professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet in Sweden who led the study. "We show for the first time that a microRNA-mRNA complex has a structure that changes and that this movement has an effect on the biological outcome, i.e. the amount of protein produced in the cell." The researchers studied a microRNA known as miR-34a, which plays an important role in cancer by indirectly regulating the activity of the p53 protein, known as the guardian of the genome for its ability to prevent cancer formation. Changes in the function of p53 are very common in human cancers. miR-34a downregulates the mRNA that codes for Sirt1, a protein that deactivates p53. Using Nuclear Magnetic Resonance (NMR) and other biophysical methods, the researchers solved the structure and dynamics of miR-34a binding the mRNA molecule. When they measured these dynamics, they found that the complex exists in two structurally different states, one moderately active with a population of 99 per cent and one with enhanced activity, a population of 1 per cent. These states can interconvert, as they are in equilibrium, and the population of each state can be modified by external factors. "Once we find out how to turn the switch, we can use this in the clinic as a drug to control the production of specific proteins," explains Katja Petzold. The researchers were then able to show that miR-34a uses the same strategy to downregulate the production of other proteins, not just Sirt1. "We reveal the first understanding of how regulation of protein output is steered by small microRNAs based on structure and dynamics," says Lorenzo Baronti, Ph.D. student in Katja Petzold's research group and first author of the study. "This is important because it opens for the development of drugs with a completely new mechanism of action." <|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 Mixed-species groups are common and are thought to provide benefits to group members via enhanced food finding and antipredator abilities. These benefits could accrue due to larger group sizes in general but also to the diverse species composition in the groups. We tested these possibilities using a novel feeder test in a wild songbird community containing three species that varied in their dominant-subordinate status and in their nuclear-satellite roles: Carolina chickadees ( Poecile carolinensis ), tufted titmice ( Baeolophus bicolor ), and white-breasted nuthatches ( Sitta carolinensis ). We found that chickadees and titmice were more likely to obtain seed from the novel feeder with greater diversity of species composition in their mixed-species flocks. For successful chickadee flocks, furthermore, the latency to obtain seed from the novel feeder was shorter the more diverse their flocks were. These results in a natural setting indicate that diversity, per se, can benefit individuals in mixed-species groups in biologically meaningful contexts such as finding food in novel places. Introduction One of the key benefits of group living is enhanced ability to find and exploit food resources 1 . In many social species, larger groups comprise members with a diversity of personality/temperament types, and variation of types within groups may affect social organization and may improve ability to find and exploit food resources 2 . For example, a mix of reactive and proactive individuals in great tit ( Parus major ) flocks results in substantial movement of individuals while maintaining flock cohesion, facilitating effective exploration of foraging spaces 3 . Furthermore, social network analysis of mixed species flocks of great tits, marsh tits ( Poecile palustris ), and blue tits ( Cyanistes caeruleus ) revealed that individuals benefit not just from the exploration and behavior of conspecifics, but also of heterospecifics 4 , 5 . Diversity of types within social groups may provide group members with the ability to explore and exploit food resources in new and potentially risky environmental contexts. One way in which diversity within groups is thought to benefit group members is because it enhances problem-solving ability 6 . When groups comprise members who vary in phenotype or in social network connections with one another, the group as a whole has a more diverse set of skills. The broader set of skills in diverse groups allows for more effective exploration of the problem space and greater ability to gain a solution – in comparison to more homogeneous groups, diverse groups can possess swarm intelligence 7 , 8 and tend to be more robust (i.e., they maintain stability and functionality despite environmental changes) over time 9 . In Apis honeybees, for example, diverse hives containing workers from multiple sires were able to maintain consistent internal hive temperatures despite fluctuations in external environmental conditions, in comparison to hives containing workers from a single sire 10 . In experiments with human groups facing marketplace trading decisions, ethnically diverse groups were more accurate in their pricing estimates than ethnically homogeneous groups 11 . Whereas benefits of diversity have been documented in conspecific groups, it is not clear whether such benefits might extend to mixed-species groups, in which interests of members of different species are not aligned in many contexts 12 . Mixed-species groups may form as temporary assemblages of species or as more stable associations of different species in space and time 13 , 14 , 15 . Stable mixed-species groups may establish dominance hierarchies, typically based on body-size differences among the species 13 . In these cases, we would predict that the behavior of individuals of a more subordinate species should be sensitive to the presence and number of individuals of the more dominant species. For example, the tendency of cyprinid fish to occupy a specific height in a water column varied depending upon the presence or absence of other species in each of three sympatric cyprinid species 16 . Willow tits ( Poecile montanus ) shifted their primary foraging areas to less-preferred parts of the canopy when they were in the presence of crested tits ( Lophophanes cristatus ) in mixed-species flocks, compared to when they foraged alone 17 . Mixed-species groups of animals could therefore represent an instance of greater diversity of species having a detrimental effect on behavior, especially for subordinate species in those groups. Mixed-species groups are also often larger than conspecific groups. Increased group size – whether single-species groups or mixed-species groups – brings benefits to group members 18 . More individuals can provide greater ability to detect and exploit food (though they can also lead to greater competition over that food), and to detect and evade predators 19 . For example, downy woodpeckers ( Picoides pubescens ) spent less time being vigilant and more time foraging when in the presence of larger mixed-species groups, compared to when they were alone or with a conspecific flockmate 20 . Larger flocks of blue tits ( Cyanistes caeruleus ) and great tits ( Parus major ) were better able to solve a novel lever-pulling apparatus to obtain food, resulting in more food per individual, compared to smaller flocks 21 . Experimental manipulation of group size in captive flocks of house sparrows ( Passer domesticus ) likewise indicated that larger groups were better able to solve food-related problems, in terms of both latency to solve the problem and in the ability to exploit food sources, compared to smaller groups 22 . It is therefore possible that benefits of mixed-species groups accrue not because of increased diversity, but because of increased group size 23 . Benefits of increased group size could result from larger conspecific group sizes, but also from greater numbers of individuals of other species resulting in larger total group size. We tested two major predictions about flexible behavior in a feeding context in wild songbird groups. First, we assessed whether the number of individuals in a group was positively associated with ability to obtain food from a novel feeder. Second, we asked whether the diversity of mixed-species groups affects ability", "role": "user" }, { "content": "Humans seeking to improve their problem-solving and survival skills can learn a thing or two from an unlikely source—songbirds. A new study from the University of Tennessee, Knoxville, shows that diversity within a wild songbird community can enhance its members' access to food. The research was published recently in Scientific Reports, a division of the journal Nature. The study's lead author is Todd Freeberg, a UT professor of psychology and expert in birds' vocal communication. Collaborators include researchers from the University of Florida and Purdue University. Mixed-species groups among wild songbirds are common and are thought to benefit group members by allowing them to protect one another from predators, increasing their ability to find food sources in unsafe environments. The new study demonstrates that those benefits increase the larger the group size and the more diverse the species composition. The study also shows that diversity results in a broader set of effective problem-solving skills available to the group. \"We now have added what is, to our knowledge, the first evidence in a natural setting that diversity can benefit individuals in mixed-species groups in biologically meaningful contexts such as finding food in novel places,\" the study states. Research concerning humans has shown similar results, according to the songbird study authors. For example, ethnically diverse groups of people were more accurate in their pricing estimates than ethnically homogenous groups in marketplace trading decisions. \"There is a large and growing amount of scientific literature on the benefits of diversity in human groups for human problem solving,\" Freeberg said. \"When we are working in groups, we can solve problems more efficiently and effectively if the individual composition of our groups is diverse and if there is good communication among all group members.\" For their study, Freeberg and his collaborators used a novel feeder test in a wild songbird community, which included three species that varied in their roles as the dominant or subordinate ones in groups: Carolina chickadees (Poecile carolinensis), tufted titmice (Baeolophus bicolor) and white-breasted nuthatches (Sitta carolinensis). Although these birds are common to the Southeast and are found together in winter months, they occasionally stick to their specific groups—like cliques in a middle school cafeteria. The researchers built feeders different from the ones birds find in human backyards. They placed them in four locations—the UT Forest Resources Research and Education Center, Norris Dam State Park, Ijams Nature Center and a private residence. The sites represented an unpredictable food source for the birds in the study. The researchers wanted to see if the birds would overcome their fear of the unknown to get seeds, an important winter resource for them. They found that when just one species ate at the feeders, they didn't take as much seed. But when multiple species that included chickadees, titmice and nuthatches were present together, they were more likely to get seed from the novel feeder at a much faster rate because they figured out how to work together to get more out of the feeder. Freeberg, who has studied the calls of chickadees and titmice for 20 years, said a next step would be to assess the signaling and communication that occur in the bird groups to determine how they play into technical problem-solving tasks. He also would like to examine how the signals and cues of individuals in diverse mixed-species flocks differ from those of individuals in single-species flocks. ", "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 Mixed-species groups are common and are thought to provide benefits to group members via enhanced food finding and antipredator abilities. These benefits could accrue due to larger group sizes in general but also to the diverse species composition in the groups. We tested these possibilities using a novel feeder test in a wild songbird community containing three species that varied in their dominant-subordinate status and in their nuclear-satellite roles: Carolina chickadees ( Poecile carolinensis ), tufted titmice ( Baeolophus bicolor ), and white-breasted nuthatches ( Sitta carolinensis ). We found that chickadees and titmice were more likely to obtain seed from the novel feeder with greater diversity of species composition in their mixed-species flocks. For successful chickadee flocks, furthermore, the latency to obtain seed from the novel feeder was shorter the more diverse their flocks were. These results in a natural setting indicate that diversity, per se, can benefit individuals in mixed-species groups in biologically meaningful contexts such as finding food in novel places. Introduction One of the key benefits of group living is enhanced ability to find and exploit food resources 1 . In many social species, larger groups comprise members with a diversity of personality/temperament types, and variation of types within groups may affect social organization and may improve ability to find and exploit food resources 2 . For example, a mix of reactive and proactive individuals in great tit ( Parus major ) flocks results in substantial movement of individuals while maintaining flock cohesion, facilitating effective exploration of foraging spaces 3 . Furthermore, social network analysis of mixed species flocks of great tits, marsh tits ( Poecile palustris ), and blue tits ( Cyanistes caeruleus ) revealed that individuals benefit not just from the exploration and behavior of conspecifics, but also of heterospecifics 4 , 5 . Diversity of types within social groups may provide group members with the ability to explore and exploit food resources in new and potentially risky environmental contexts. One way in which diversity within groups is thought to benefit group members is because it enhances problem-solving ability 6 . When groups comprise members who vary in phenotype or in social network connections with one another, the group as a whole has a more diverse set of skills. The broader set of skills in diverse groups allows for more effective exploration of the problem space and greater ability to gain a solution – in comparison to more homogeneous groups, diverse groups can possess swarm intelligence 7 , 8 and tend to be more robust (i.e., they maintain stability and functionality despite environmental changes) over time 9 . In Apis honeybees, for example, diverse hives containing workers from multiple sires were able to maintain consistent internal hive temperatures despite fluctuations in external environmental conditions, in comparison to hives containing workers from a single sire 10 . In experiments with human groups facing marketplace trading decisions, ethnically diverse groups were more accurate in their pricing estimates than ethnically homogeneous groups 11 . Whereas benefits of diversity have been documented in conspecific groups, it is not clear whether such benefits might extend to mixed-species groups, in which interests of members of different species are not aligned in many contexts 12 . Mixed-species groups may form as temporary assemblages of species or as more stable associations of different species in space and time 13 , 14 , 15 . Stable mixed-species groups may establish dominance hierarchies, typically based on body-size differences among the species 13 . In these cases, we would predict that the behavior of individuals of a more subordinate species should be sensitive to the presence and number of individuals of the more dominant species. For example, the tendency of cyprinid fish to occupy a specific height in a water column varied depending upon the presence or absence of other species in each of three sympatric cyprinid species 16 . Willow tits ( Poecile montanus ) shifted their primary foraging areas to less-preferred parts of the canopy when they were in the presence of crested tits ( Lophophanes cristatus ) in mixed-species flocks, compared to when they foraged alone 17 . Mixed-species groups of animals could therefore represent an instance of greater diversity of species having a detrimental effect on behavior, especially for subordinate species in those groups. Mixed-species groups are also often larger than conspecific groups. Increased group size – whether single-species groups or mixed-species groups – brings benefits to group members 18 . More individuals can provide greater ability to detect and exploit food (though they can also lead to greater competition over that food), and to detect and evade predators 19 . For example, downy woodpeckers ( Picoides pubescens ) spent less time being vigilant and more time foraging when in the presence of larger mixed-species groups, compared to when they were alone or with a conspecific flockmate 20 . Larger flocks of blue tits ( Cyanistes caeruleus ) and great tits ( Parus major ) were better able to solve a novel lever-pulling apparatus to obtain food, resulting in more food per individual, compared to smaller flocks 21 . Experimental manipulation of group size in captive flocks of house sparrows ( Passer domesticus ) likewise indicated that larger groups were better able to solve food-related problems, in terms of both latency to solve the problem and in the ability to exploit food sources, compared to smaller groups 22 . It is therefore possible that benefits of mixed-species groups accrue not because of increased diversity, but because of increased group size 23 . Benefits of increased group size could result from larger conspecific group sizes, but also from greater numbers of individuals of other species resulting in larger total group size. We tested two major predictions about flexible behavior in a feeding context in wild songbird groups. First, we assessed whether the number of individuals in a group was positively associated with ability to obtain food from a novel feeder. Second, we asked whether the diversity of mixed-species groups affects ability<|im_end|> <|im_start|>assistant Humans seeking to improve their problem-solving and survival skills can learn a thing or two from an unlikely source—songbirds. A new study from the University of Tennessee, Knoxville, shows that diversity within a wild songbird community can enhance its members' access to food. The research was published recently in Scientific Reports, a division of the journal Nature. The study's lead author is Todd Freeberg, a UT professor of psychology and expert in birds' vocal communication. Collaborators include researchers from the University of Florida and Purdue University. Mixed-species groups among wild songbirds are common and are thought to benefit group members by allowing them to protect one another from predators, increasing their ability to find food sources in unsafe environments. The new study demonstrates that those benefits increase the larger the group size and the more diverse the species composition. The study also shows that diversity results in a broader set of effective problem-solving skills available to the group. "We now have added what is, to our knowledge, the first evidence in a natural setting that diversity can benefit individuals in mixed-species groups in biologically meaningful contexts such as finding food in novel places," the study states. Research concerning humans has shown similar results, according to the songbird study authors. For example, ethnically diverse groups of people were more accurate in their pricing estimates than ethnically homogenous groups in marketplace trading decisions. "There is a large and growing amount of scientific literature on the benefits of diversity in human groups for human problem solving," Freeberg said. "When we are working in groups, we can solve problems more efficiently and effectively if the individual composition of our groups is diverse and if there is good communication among all group members." For their study, Freeberg and his collaborators used a novel feeder test in a wild songbird community, which included three species that varied in their roles as the dominant or subordinate ones in groups: Carolina chickadees (Poecile carolinensis), tufted titmice (Baeolophus bicolor) and white-breasted nuthatches (Sitta carolinensis). Although these birds are common to the Southeast and are found together in winter months, they occasionally stick to their specific groups—like cliques in a middle school cafeteria. The researchers built feeders different from the ones birds find in human backyards. They placed them in four locations—the UT Forest Resources Research and Education Center, Norris Dam State Park, Ijams Nature Center and a private residence. The sites represented an unpredictable food source for the birds in the study. The researchers wanted to see if the birds would overcome their fear of the unknown to get seeds, an important winter resource for them. They found that when just one species ate at the feeders, they didn't take as much seed. But when multiple species that included chickadees, titmice and nuthatches were present together, they were more likely to get seed from the novel feeder at a much faster rate because they figured out how to work together to get more out of the feeder. Freeberg, who has studied the calls of chickadees and titmice for 20 years, said a next step would be to assess the signaling and communication that occur in the bird groups to determine how they play into technical problem-solving tasks. He also would like to examine how the signals and cues of individuals in diverse mixed-species flocks differ from those of individuals in single-species flocks. <|im_end|>

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1,966

[ { "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 Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency ( NOD2 ) or effect size ( TNFSF15 and ATG16L1 ) or a combination of these factors ( IL23R and IRGM ). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations. Main IBD is composed of chronic, relapsing intestinal inflammatory diseases affecting more than 2.5 million people in Europe, with increasing prevalence in Asia and developing countries 1 , 2 . IBD is thought to arise from inappropriate activation of the intestinal mucosal immune system in response to commensal bacteria in a genetically susceptible host. Thus far, 163 genetic loci have been associated with IBD via large-scale genome-wide association studies (GWAS) in cohorts of European descent. Smaller GWAS performed in populations from Japan, India and Korea have reported six new genome-wide significant associations outside of the human leukocyte antigen (HLA) region. Three of these loci (13q12, FCGR2A and SLC26A3 ) subsequently achieved genome-wide significant evidence of association in European cohorts. The remaining three loci demonstrated a consistent direction of effect and nominally significant evidence of association ( P < 1 × 10 −4 ) in previous European GWAS analyses 3 , 4 , 5 , 6 . A number of loci initially associated with IBD in European cohorts have now also been shown to underlie risk in non-Europeans, including JAK2 , IL23R and NKX2-3 . The evidence of shared IBD risk loci across diverse populations suggests that combining genotype data from cohorts of different ancestry will enable the detection of additional IBD-associated loci. Such trans-ancestry association studies have successfully identified susceptibility loci for other complex diseases, including type 2 diabetes and rheumatoid arthritis 7 , 8 . In this study, we aggregate genome-wide or Immunochip genotype data from 96,486 individuals. In comparison to our previously published GWAS meta-analysis, this study includes an additional 11,535 individuals of European ancestry and 9,846 individuals of non-European ancestry. Using these data, we aim to identify new IBD risk loci and compare the genetic architecture of IBD susceptibility across ancestrally divergent populations. Results Study design After quality control and 1000 Genomes Project imputation (Phase I–August 2012), we used 5,956 Crohn's disease cases, 6,968 ulcerative colitis cases and 21,770 population controls of European descent to perform GWAS of Crohn's disease, ulcerative colitis and IBD (Crohn's disease and ulcerative colitis together) (Online Methods ). Replication was undertaken using an additional 16,619 Crohn's disease cases, 13,449 ulcerative colitis cases and 31,766 population controls genotyped on the Immunochip. The replication cohort included 2,025 Crohn's disease cases, 2,770 ulcerative colitis cases and 5,051 population controls of non-European ancestry ( Table 1 and Supplementary Figs. 1 and 2 ), so principal-component analysis was used to assign individuals to 1 of 4 ancestral groups (European, Iranian, Indian or East Asian) ( Supplementary Fig. 3 ). Case-control association tests were performed within each ancestry group using a linear mixed model (MMM) 9 (Online Methods ). A fixed-effects meta-analysis was undertaken to combine the summary statistics from our European-only GWAS meta-analysis with those from the European replication cohort. We next performed a Bayesian trans-ancestry meta-analysis, as implemented in MANTRA, to enable heterogeneity in effect sizes to be correlated with the genetic distance between populations, as estimated by the mean fixation index ( F ST ) across all SNPs 10 (Online Methods ). For the trans-ancestry meta-analysis, the 6,392 cases and 7,262 population controls of European ancestry that were present in both the GWAS and replication cohorts were excluded from the Immunochip replication study ( Supplementary Fig. 2 ). To maximize power for our solely Immunochip-based comparisons across ancestral groups, the mixed-model association analysis was repeated after reinstating these individuals in the Immunochip cohort. Table 1 Cohort sample sizes for GWAS and Immunochip trans-ancestry meta-analysis Full size table Trans-ancestry meta-analysis identifies 38 new IBD loci In total, 38 new disease-associated loci were identified at genome-wide significance in either the association analysis of individual ancestry groups ( P < 5 × 10 −8 ) or the trans-ancestry meta-analysis that included all ancestries (log 10 (Bayes factor) > 6) for ulcerative colitis, Crohn's disease or IBD ( Table 2 , Supplementary Figs. 4–7 and Supplementary Tables 1 and 2 ). To reduce false positive associations, we required all loci only implicated in disease risk via the trans-ancestry meta-analysis (with log 10 (Bayes factor) > 6 but P > 5 × 10 −8 in each individual ancestry cohort) to show no significant evidence of heterogeneity across all four ancestry groups ( I 2 > 85.7%) (Online Methods and Supplementary Table 3 ). Table 2 Newly associated IBD risk loci Full size table Twenty-five of the 38 newly associated loci overlapped with loci previously reported for other traits, including immune-mediated diseases, whereas 13 had not previously been associated with any disease or trait (Online Methods and Supplementary Table 4 ). A likelihood-modeling approach showed that 27 of the 38 newly identified loci were associated with both Crohn's disease and ulcerative colitis (designated here as IBD-associated loci), with 7 of these loci demonstrating evidence of heterogeneity of effect between the 2 diseases. Of the remaining 11 loci, 7 were classified as specific to Crohn's disease and 4 were classified as specific to ulcerative colitis ( Table 2 and Supplementary Table 1 ). As a result of our updated sample quality control procedure, 17", "role": "user" }, { "content": "The first genetic study of inflammatory bowel disease (IBD) to include individuals from diverse populations has shown that the regions of the genome underlying the disease are consistent around the world. This study, conducted under the auspices of the International IBD Genetics Consortium, included nearly 10,000 DNA samples from people of East Asian, Indian or Iranian descent and an existing set of 86,640 samples drawn from across Europe, North America and Oceania. The observation that genetic effects on disease risk are consistent across diverse populations is an important one because it suggests that the biology underlying disease is also consistent. This could have profound consequences for the treatment of IBD because drugs developed based on insights from genetic studies in one population could be used worldwide. \"The prevalence of IBD has increased dramatically in Asia over the last 50 years, probably due to lifestyle changes brought about by economic growth\" says Dr Carl Anderson, a corresponding author from the Wellcome Trust Sanger Institute. \"We are now able to compare genetic risk profiles of IBD across diverse populations to find out how similar they are. Discovering differences can provide us with biological insights that would be missed if we were to focus our efforts on just a single population. In turn, this can lead to the identification of new drug targets.\" \"In our study we found little difference in the genetic risk of IBD across the populations we studied. This is a very important finding because it suggests that biological lessons learned by studying the genetics of IBD will be relevant globally.\" More than 163 variants in the human genome have already been associated with increased risk of IBD, the most common forms of which are Crohn's disease and ulcerative colitis, but this research has only been conducted at a large scale in Europeans. By including 10,000 non-European samples alongside the existing European samples, the team were able to detect 38 additional regions of the genome that influence susceptibility to IBD. Because the genetic effects were largely consistent across populations, the researchers hypothesized that the reason they were able to discover these new regions was the big increase in sample size, rather than because the additional samples were drawn from non-European individuals. \"We've already seen the benefit of using trans-ethnic approaches to understand complex diseases such as type-2 diabetes and rheumatoid arthritis,\" says Dr Jimmy Liu, a first author from the Sanger Institute. \"This study demonstrates the importance of collecting trans-ethnic data on IBD, firstly because any increase in the number of samples improves our ability identify regions of the genome influencing disease risk, and secondly because we can gain new insights into the biology underlying IBD by comparing results across the diverse populations.\" Despite the wide-spread similarities, the study did confirm previously identified differences between IBD risk in European and non-Europeans. There are genetic variants in a gene called NOD2 which increase risk of IBD in Europeans that are simply not present in Asian populations. It remains to be seen if there are IBD risk-increasing variants in NOD2 that are only present in Asia. At another gene, called TNFSF15, the IBD risk increasing variants are at a similar frequency in both Europeans and East Asians, but the variants seem to have a much stronger effect on disease risk in East Asia. The team have suggested this finding could be due to subtle differences in the environment or genome structure. \"This study is testimony to the need for large-scale international collaborations that enable us to answer questions that would not be possible using samples drawn from a single population,\" says Dr Rinse K Weersma, a corresponding author from University Medical Center Groningen. \"We thank every individual who donated a DNA sample to the study and the clinicians within the International IBD Genetics Consortium who collected these, particularly those outside of the US and Europe. \"The finding that the biology underlying IBD is consistent across populations is hugely important, it tells us that we can use insights from genetic studies of IBD to develop globally relevant drugs with the potential to improve disease management around the world.\" ", "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 Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency ( NOD2 ) or effect size ( TNFSF15 and ATG16L1 ) or a combination of these factors ( IL23R and IRGM ). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations. Main IBD is composed of chronic, relapsing intestinal inflammatory diseases affecting more than 2.5 million people in Europe, with increasing prevalence in Asia and developing countries 1 , 2 . IBD is thought to arise from inappropriate activation of the intestinal mucosal immune system in response to commensal bacteria in a genetically susceptible host. Thus far, 163 genetic loci have been associated with IBD via large-scale genome-wide association studies (GWAS) in cohorts of European descent. Smaller GWAS performed in populations from Japan, India and Korea have reported six new genome-wide significant associations outside of the human leukocyte antigen (HLA) region. Three of these loci (13q12, FCGR2A and SLC26A3 ) subsequently achieved genome-wide significant evidence of association in European cohorts. The remaining three loci demonstrated a consistent direction of effect and nominally significant evidence of association ( P < 1 × 10 −4 ) in previous European GWAS analyses 3 , 4 , 5 , 6 . A number of loci initially associated with IBD in European cohorts have now also been shown to underlie risk in non-Europeans, including JAK2 , IL23R and NKX2-3 . The evidence of shared IBD risk loci across diverse populations suggests that combining genotype data from cohorts of different ancestry will enable the detection of additional IBD-associated loci. Such trans-ancestry association studies have successfully identified susceptibility loci for other complex diseases, including type 2 diabetes and rheumatoid arthritis 7 , 8 . In this study, we aggregate genome-wide or Immunochip genotype data from 96,486 individuals. In comparison to our previously published GWAS meta-analysis, this study includes an additional 11,535 individuals of European ancestry and 9,846 individuals of non-European ancestry. Using these data, we aim to identify new IBD risk loci and compare the genetic architecture of IBD susceptibility across ancestrally divergent populations. Results Study design After quality control and 1000 Genomes Project imputation (Phase I–August 2012), we used 5,956 Crohn's disease cases, 6,968 ulcerative colitis cases and 21,770 population controls of European descent to perform GWAS of Crohn's disease, ulcerative colitis and IBD (Crohn's disease and ulcerative colitis together) (Online Methods ). Replication was undertaken using an additional 16,619 Crohn's disease cases, 13,449 ulcerative colitis cases and 31,766 population controls genotyped on the Immunochip. The replication cohort included 2,025 Crohn's disease cases, 2,770 ulcerative colitis cases and 5,051 population controls of non-European ancestry ( Table 1 and Supplementary Figs. 1 and 2 ), so principal-component analysis was used to assign individuals to 1 of 4 ancestral groups (European, Iranian, Indian or East Asian) ( Supplementary Fig. 3 ). Case-control association tests were performed within each ancestry group using a linear mixed model (MMM) 9 (Online Methods ). A fixed-effects meta-analysis was undertaken to combine the summary statistics from our European-only GWAS meta-analysis with those from the European replication cohort. We next performed a Bayesian trans-ancestry meta-analysis, as implemented in MANTRA, to enable heterogeneity in effect sizes to be correlated with the genetic distance between populations, as estimated by the mean fixation index ( F ST ) across all SNPs 10 (Online Methods ). For the trans-ancestry meta-analysis, the 6,392 cases and 7,262 population controls of European ancestry that were present in both the GWAS and replication cohorts were excluded from the Immunochip replication study ( Supplementary Fig. 2 ). To maximize power for our solely Immunochip-based comparisons across ancestral groups, the mixed-model association analysis was repeated after reinstating these individuals in the Immunochip cohort. Table 1 Cohort sample sizes for GWAS and Immunochip trans-ancestry meta-analysis Full size table Trans-ancestry meta-analysis identifies 38 new IBD loci In total, 38 new disease-associated loci were identified at genome-wide significance in either the association analysis of individual ancestry groups ( P < 5 × 10 −8 ) or the trans-ancestry meta-analysis that included all ancestries (log 10 (Bayes factor) > 6) for ulcerative colitis, Crohn's disease or IBD ( Table 2 , Supplementary Figs. 4–7 and Supplementary Tables 1 and 2 ). To reduce false positive associations, we required all loci only implicated in disease risk via the trans-ancestry meta-analysis (with log 10 (Bayes factor) > 6 but P > 5 × 10 −8 in each individual ancestry cohort) to show no significant evidence of heterogeneity across all four ancestry groups ( I 2 > 85.7%) (Online Methods and Supplementary Table 3 ). Table 2 Newly associated IBD risk loci Full size table Twenty-five of the 38 newly associated loci overlapped with loci previously reported for other traits, including immune-mediated diseases, whereas 13 had not previously been associated with any disease or trait (Online Methods and Supplementary Table 4 ). A likelihood-modeling approach showed that 27 of the 38 newly identified loci were associated with both Crohn's disease and ulcerative colitis (designated here as IBD-associated loci), with 7 of these loci demonstrating evidence of heterogeneity of effect between the 2 diseases. Of the remaining 11 loci, 7 were classified as specific to Crohn's disease and 4 were classified as specific to ulcerative colitis ( Table 2 and Supplementary Table 1 ). As a result of our updated sample quality control procedure, 17<|im_end|> <|im_start|>assistant The first genetic study of inflammatory bowel disease (IBD) to include individuals from diverse populations has shown that the regions of the genome underlying the disease are consistent around the world. This study, conducted under the auspices of the International IBD Genetics Consortium, included nearly 10,000 DNA samples from people of East Asian, Indian or Iranian descent and an existing set of 86,640 samples drawn from across Europe, North America and Oceania. The observation that genetic effects on disease risk are consistent across diverse populations is an important one because it suggests that the biology underlying disease is also consistent. This could have profound consequences for the treatment of IBD because drugs developed based on insights from genetic studies in one population could be used worldwide. "The prevalence of IBD has increased dramatically in Asia over the last 50 years, probably due to lifestyle changes brought about by economic growth" says Dr Carl Anderson, a corresponding author from the Wellcome Trust Sanger Institute. "We are now able to compare genetic risk profiles of IBD across diverse populations to find out how similar they are. Discovering differences can provide us with biological insights that would be missed if we were to focus our efforts on just a single population. In turn, this can lead to the identification of new drug targets." "In our study we found little difference in the genetic risk of IBD across the populations we studied. This is a very important finding because it suggests that biological lessons learned by studying the genetics of IBD will be relevant globally." More than 163 variants in the human genome have already been associated with increased risk of IBD, the most common forms of which are Crohn's disease and ulcerative colitis, but this research has only been conducted at a large scale in Europeans. By including 10,000 non-European samples alongside the existing European samples, the team were able to detect 38 additional regions of the genome that influence susceptibility to IBD. Because the genetic effects were largely consistent across populations, the researchers hypothesized that the reason they were able to discover these new regions was the big increase in sample size, rather than because the additional samples were drawn from non-European individuals. "We've already seen the benefit of using trans-ethnic approaches to understand complex diseases such as type-2 diabetes and rheumatoid arthritis," says Dr Jimmy Liu, a first author from the Sanger Institute. "This study demonstrates the importance of collecting trans-ethnic data on IBD, firstly because any increase in the number of samples improves our ability identify regions of the genome influencing disease risk, and secondly because we can gain new insights into the biology underlying IBD by comparing results across the diverse populations." Despite the wide-spread similarities, the study did confirm previously identified differences between IBD risk in European and non-Europeans. There are genetic variants in a gene called NOD2 which increase risk of IBD in Europeans that are simply not present in Asian populations. It remains to be seen if there are IBD risk-increasing variants in NOD2 that are only present in Asia. At another gene, called TNFSF15, the IBD risk increasing variants are at a similar frequency in both Europeans and East Asians, but the variants seem to have a much stronger effect on disease risk in East Asia. The team have suggested this finding could be due to subtle differences in the environment or genome structure. "This study is testimony to the need for large-scale international collaborations that enable us to answer questions that would not be possible using samples drawn from a single population," says Dr Rinse K Weersma, a corresponding author from University Medical Center Groningen. "We thank every individual who donated a DNA sample to the study and the clinicians within the International IBD Genetics Consortium who collected these, particularly those outside of the US and Europe. "The finding that the biology underlying IBD is consistent across populations is hugely important, it tells us that we can use insights from genetic studies of IBD to develop globally relevant drugs with the potential to improve disease management around the world." <|im_end|>

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2,288

[ { "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 Coordinated shifts of neuronal activity in the prefrontal cortex are associated with strategy adaptations in behavioural tasks, when animals switch from following one rule to another. However, network dynamics related to multiple-rule changes are scarcely known. We show how firing rates of individual neurons in the prelimbic and cingulate cortex correlate with the performance of rats trained to change their navigation multiple times according to allocentric and egocentric strategies. The concerted population activity exhibits a stable firing during the performance of one rule but shifted to another neuronal firing state when a new rule is learnt. Interestingly, when the same rule is presented a second time within the same session, neuronal firing does not revert back to the original neuronal firing state, but a new activity-state is formed. Our data indicate that neuronal firing of prefrontal cortical neurons represents changes in strategy and task-performance rather than specific strategies or rules. Introduction In ancient Greek, Heraclitus famously stated that “No man ever steps in the same river twice, for it’s not the same river and he’s not the same man”. He referred to the ambiguity that conscious actions and plans are never truly experienced the same way, however similar they may appear. Earlier research demonstrated how distinct behavioural rules and strategies are entailed in the activity of prefrontal neurons 1 , 2 , 3 . We aim to address the question how a certain behavioural strategy, applied on two different occasions within the same session, is represented in the neuronal firing rate of the prefrontal cortex. The prefrontal cortex is a central structure for executive control of flexible behaviour to assess new rules and strategies, not only in humans 4 , 5 but also in monkeys 6 , 7 and rodents 8 , 9 , 10 , and is highly interconnected with other brain regions 11 , 12 indicative of an integrative structure 13 and a multifunctional role during cognitive tasks 14 . The importance of the prefrontal cortex is highlighted by neuronal firing patterns contributing to error-related activity 15 , 16 , 17 , working memory 18 , 19 , 20 , 21 , 22 , 23 , decision making 24 , 25 , 26 , 27 , 28 , and reward encoding 29 , 30 , 31 , 32 , 33 . It has been shown that lesions of the medial prefrontal cortex lead to an impairment of the ability to follow changing spatial rules 34 . Prefrontal neurons also change their firing activity when animals are switching between different strategies 1 . This indicates the importance of the prefrontal cortex for rule-guided behaviour. In addition, behavioural rule changes can lead to abrupt neuronal population activity changes within a very short period of time 2 . Furthermore, abrupt and coordinated changes of neuronal firing have been reported when animal behaviour reflects uncertainty and evaluation of possible new strategies 3 . However, the following questions remain unclear: (1) how multiple and consecutive changes of strategy would be reflected in the firing of prefrontal neurons and (2) how the same repeated strategy would be represented on different occasions. To address neuronal computations in consecutive rule presentations, we used single-unit recordings in freely moving rats to assess neuronal activity during a prefrontal cortex-dependent rule-switching task 10 . In our task design, animals managed to perform under multiple rules during a single recording session, which allowed us to study the neuronal representations when animals changed new rules and acquired new strategies. Additionally, we examined how neuronal population states are changing during the presentation and repetition of multiple rules in the course of a single session. The results of this study show that the neuronal population forms a different and stable firing-state every time a new rule is learnt, even when the same rule is presented twice during the same session. This implies that the concerted neuronal population in the prelimbic cortex does not represent individual rules permanently, but it reflects a change of strategies. Results A strategy-switching task with multiple rule changes Rats ( n = 5) performed a strategy-switching task with multiple rule changes (from 1 up to 6 changes, median = 3) within each behavioural session (Fig. 1a ), while the activity of neurons in the prefrontal cortex was extracellularly recorded with 12 tetrodes (Fig. 1b ). Rats were seeking a food reward on a plus-maze using one out of four possible strategies based on two allocentric (landmark-referenced) and two egocentric (self-referenced) rules. The animals were placed at one of the two possible starting arms (North or South arm) and they had to decide to run towards one of the two goal arms (East or West arm), while the arm opposite of the starting position was blocked. After reaching the end of the goal arm, a reward was given for a correct choice according to the current rule. Then the animal was manually positioned into a bin at the centre of the maze to break stereotyped behaviour. After 3–7 s, the rat was placed again at one of the starting arms to begin the next trial. When an animal successfully succeeded in performing 13 out 15 consecutive trials, the rule was changed without notice and the animal had to switch strategy in order to maximise reward based on trial and error information. We analysed the performance of the animal using the behavioural choices (correct and incorrect) using a Markov-chain Monte–Carlo analysis 35 (Fig. 1c ), which defines the probability of the rat being correct during each trial together with the associated confidence intervals. Those intervals are used to determine learning periods (see Methods). Only one recording session was carried out on a single day. Fig. 1 Strategy-switching task and behavioural analysis. a Rats were placed randomly at one of the two possible start positions during consecutive trials. On the basis of landmark-referenced (allocentric strategy, rules: 1, 2) or self-referenced (egocentric strategy, rules: 3, 4) navigation, the animal has to travel on a plus-maze in order to receive reward (R). After", "role": "user" }, { "content": "Neuronal activity in the prefrontal cortex represents every experience as \"novel.\" The neurons adapt their activity accordingly, even if the new experience is very similar to a previous one. That is the main finding of a study conducted by researchers from MedUni Vienna's Division of Cognitive Neurobiology and recently published in the leading journal Nature Communications. \"As far as the brain is concerned, every experience is unique, no matter how similar it is to an earlier one. The neurons in the prefrontal cortex will be active each time – just as if the experience was entirely new,\" explains study author Hugo Malagon-Vina from the Division of Cognitive Neurobiology at MedUni Vienna's Center for Brain Research. Potential neuronal activity \"mismatching\" during this process might lead to the phenomenon of déjà vu, explains Malagon-Vina. This has now been demonstrated by the MedUni Vienna researchers for the first time, using an animal model. They recorded and analysed the activity of around 300 neurons. Nothing is ever perceived in the same way twice \"Of course, there is memory,\" says Malagon-Vina. \"But the brain needs flexibility, so that it can constantly adapt. This is achieved by each event being perceived as new.\" From a philosophical perspective, says the MedUni Vienna researcher, an analogous explanation is provided by a quote from the old Greek philosopher Heraclitus: \"No man ever steps in the same river twice, for it's not the same river and he's not the same man.\" Malagon-Vina explains that \"He (Heraclitus) was referring to the ambiguity that deliberate actions and plans are never perceived in the same way, no matter how similar they were to each other.\" At the same time, this flexibility, and the experience of uniqueness, allows people to experience feelings of joy or surprise, or the so-called \"wow\" effect, says Malagon-Vina. The results also show that the brain is able to perceive lifelong experiences as something new, so long as the neuronal activity is not impaired by a disease. According to the MedUni Vienna brain researcher, this is an argument in favour of staying mentally active into old age. Neurons are always ready to \"adapt\" in the face of new knowledge and to process new experiences as unique. ", "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 Coordinated shifts of neuronal activity in the prefrontal cortex are associated with strategy adaptations in behavioural tasks, when animals switch from following one rule to another. However, network dynamics related to multiple-rule changes are scarcely known. We show how firing rates of individual neurons in the prelimbic and cingulate cortex correlate with the performance of rats trained to change their navigation multiple times according to allocentric and egocentric strategies. The concerted population activity exhibits a stable firing during the performance of one rule but shifted to another neuronal firing state when a new rule is learnt. Interestingly, when the same rule is presented a second time within the same session, neuronal firing does not revert back to the original neuronal firing state, but a new activity-state is formed. Our data indicate that neuronal firing of prefrontal cortical neurons represents changes in strategy and task-performance rather than specific strategies or rules. Introduction In ancient Greek, Heraclitus famously stated that “No man ever steps in the same river twice, for it’s not the same river and he’s not the same man”. He referred to the ambiguity that conscious actions and plans are never truly experienced the same way, however similar they may appear. Earlier research demonstrated how distinct behavioural rules and strategies are entailed in the activity of prefrontal neurons 1 , 2 , 3 . We aim to address the question how a certain behavioural strategy, applied on two different occasions within the same session, is represented in the neuronal firing rate of the prefrontal cortex. The prefrontal cortex is a central structure for executive control of flexible behaviour to assess new rules and strategies, not only in humans 4 , 5 but also in monkeys 6 , 7 and rodents 8 , 9 , 10 , and is highly interconnected with other brain regions 11 , 12 indicative of an integrative structure 13 and a multifunctional role during cognitive tasks 14 . The importance of the prefrontal cortex is highlighted by neuronal firing patterns contributing to error-related activity 15 , 16 , 17 , working memory 18 , 19 , 20 , 21 , 22 , 23 , decision making 24 , 25 , 26 , 27 , 28 , and reward encoding 29 , 30 , 31 , 32 , 33 . It has been shown that lesions of the medial prefrontal cortex lead to an impairment of the ability to follow changing spatial rules 34 . Prefrontal neurons also change their firing activity when animals are switching between different strategies 1 . This indicates the importance of the prefrontal cortex for rule-guided behaviour. In addition, behavioural rule changes can lead to abrupt neuronal population activity changes within a very short period of time 2 . Furthermore, abrupt and coordinated changes of neuronal firing have been reported when animal behaviour reflects uncertainty and evaluation of possible new strategies 3 . However, the following questions remain unclear: (1) how multiple and consecutive changes of strategy would be reflected in the firing of prefrontal neurons and (2) how the same repeated strategy would be represented on different occasions. To address neuronal computations in consecutive rule presentations, we used single-unit recordings in freely moving rats to assess neuronal activity during a prefrontal cortex-dependent rule-switching task 10 . In our task design, animals managed to perform under multiple rules during a single recording session, which allowed us to study the neuronal representations when animals changed new rules and acquired new strategies. Additionally, we examined how neuronal population states are changing during the presentation and repetition of multiple rules in the course of a single session. The results of this study show that the neuronal population forms a different and stable firing-state every time a new rule is learnt, even when the same rule is presented twice during the same session. This implies that the concerted neuronal population in the prelimbic cortex does not represent individual rules permanently, but it reflects a change of strategies. Results A strategy-switching task with multiple rule changes Rats ( n = 5) performed a strategy-switching task with multiple rule changes (from 1 up to 6 changes, median = 3) within each behavioural session (Fig. 1a ), while the activity of neurons in the prefrontal cortex was extracellularly recorded with 12 tetrodes (Fig. 1b ). Rats were seeking a food reward on a plus-maze using one out of four possible strategies based on two allocentric (landmark-referenced) and two egocentric (self-referenced) rules. The animals were placed at one of the two possible starting arms (North or South arm) and they had to decide to run towards one of the two goal arms (East or West arm), while the arm opposite of the starting position was blocked. After reaching the end of the goal arm, a reward was given for a correct choice according to the current rule. Then the animal was manually positioned into a bin at the centre of the maze to break stereotyped behaviour. After 3–7 s, the rat was placed again at one of the starting arms to begin the next trial. When an animal successfully succeeded in performing 13 out 15 consecutive trials, the rule was changed without notice and the animal had to switch strategy in order to maximise reward based on trial and error information. We analysed the performance of the animal using the behavioural choices (correct and incorrect) using a Markov-chain Monte–Carlo analysis 35 (Fig. 1c ), which defines the probability of the rat being correct during each trial together with the associated confidence intervals. Those intervals are used to determine learning periods (see Methods). Only one recording session was carried out on a single day. Fig. 1 Strategy-switching task and behavioural analysis. a Rats were placed randomly at one of the two possible start positions during consecutive trials. On the basis of landmark-referenced (allocentric strategy, rules: 1, 2) or self-referenced (egocentric strategy, rules: 3, 4) navigation, the animal has to travel on a plus-maze in order to receive reward (R). After<|im_end|> <|im_start|>assistant Neuronal activity in the prefrontal cortex represents every experience as "novel." The neurons adapt their activity accordingly, even if the new experience is very similar to a previous one. That is the main finding of a study conducted by researchers from MedUni Vienna's Division of Cognitive Neurobiology and recently published in the leading journal Nature Communications. "As far as the brain is concerned, every experience is unique, no matter how similar it is to an earlier one. The neurons in the prefrontal cortex will be active each time – just as if the experience was entirely new," explains study author Hugo Malagon-Vina from the Division of Cognitive Neurobiology at MedUni Vienna's Center for Brain Research. Potential neuronal activity "mismatching" during this process might lead to the phenomenon of déjà vu, explains Malagon-Vina. This has now been demonstrated by the MedUni Vienna researchers for the first time, using an animal model. They recorded and analysed the activity of around 300 neurons. Nothing is ever perceived in the same way twice "Of course, there is memory," says Malagon-Vina. "But the brain needs flexibility, so that it can constantly adapt. This is achieved by each event being perceived as new." From a philosophical perspective, says the MedUni Vienna researcher, an analogous explanation is provided by a quote from the old Greek philosopher Heraclitus: "No man ever steps in the same river twice, for it's not the same river and he's not the same man." Malagon-Vina explains that "He (Heraclitus) was referring to the ambiguity that deliberate actions and plans are never perceived in the same way, no matter how similar they were to each other." At the same time, this flexibility, and the experience of uniqueness, allows people to experience feelings of joy or surprise, or the so-called "wow" effect, says Malagon-Vina. The results also show that the brain is able to perceive lifelong experiences as something new, so long as the neuronal activity is not impaired by a disease. According to the MedUni Vienna brain researcher, this is an argument in favour of staying mentally active into old age. Neurons are always ready to "adapt" in the face of new knowledge and to process new experiences as unique. <|im_end|>

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2955, 11, 10099, 9152, 311, 2804, 1234, 5361, 5718, 2391, 264, 3254, 14975, 3882, 11, 902, 5535, 603, 311, 4007, 279, 79402, 44713, 994, 10099, 5614, 502, 5718, 323, 19426, 502, 15174, 13, 23212, 11, 584, 25078, 1268, 79402, 7187, 5415, 527, 10223, 2391, 279, 15864, 323, 54515, 315, 5361, 5718, 304, 279, 3388, 315, 264, 3254, 3882, 13, 578, 3135, 315, 420, 4007, 1501, 430, 279, 79402, 7187, 7739, 264, 2204, 323, 15528, 23677, 21395, 1475, 892, 264, 502, 6037, 374, 50350, 11, 1524, 994, 279, 1890, 6037, 374, 10666, 11157, 2391, 279, 1890, 3882, 13, 1115, 24897, 430, 279, 97666, 79402, 7187, 304, 279, 30713, 94598, 49370, 1587, 539, 4097, 3927, 5718, 31859, 11, 719, 433, 27053, 264, 2349, 315, 15174, 13, 18591, 362, 8446, 48296, 287, 3465, 449, 5361, 6037, 4442, 432, 1900, 320, 308, 284, 220, 20, 8, 10887, 264, 8446, 48296, 287, 3465, 449, 5361, 6037, 4442, 320, 1527, 220, 16, 709, 311, 220, 21, 4442, 11, 23369, 284, 220, 18, 8, 2949, 1855, 88979, 3882, 320, 30035, 13, 220, 16, 64, 7026, 1418, 279, 5820, 315, 34313, 304, 279, 864, 7096, 278, 49370, 574, 11741, 65441, 398, 12715, 449, 220, 717, 259, 8980, 5919, 320, 30035, 13, 220, 16, 65, 7609, 432, 1900, 1051, 11125, 264, 3691, 11565, 389, 264, 5636, 1474, 10033, 1701, 832, 704, 315, 3116, 3284, 15174, 3196, 389, 1403, 5691, 40509, 320, 1974, 4075, 5621, 809, 5886, 8, 323, 1403, 8866, 511, 40509, 320, 726, 5621, 809, 5886, 8, 5718, 13, 578, 10099, 1051, 9277, 520, 832, 315, 279, 1403, 3284, 6041, 11977, 320, 26287, 477, 4987, 6916, 8, 323, 814, 1047, 311, 10491, 311, 1629, 7119, 832, 315, 279, 1403, 5915, 11977, 320, 37440, 477, 4410, 6916, 705, 1418, 279, 6916, 14329, 315, 279, 6041, 2361, 574, 19857, 13, 4740, 19261, 279, 842, 315, 279, 5915, 6916, 11, 264, 11565, 574, 2728, 369, 264, 4495, 5873, 4184, 311, 279, 1510, 6037, 13, 5112, 279, 10065, 574, 20684, 35328, 1139, 264, 9736, 520, 279, 12541, 315, 279, 36196, 311, 1464, 23473, 354, 33601, 17432, 13, 4740, 220, 18, 4235, 22, 274, 11, 279, 11494, 574, 9277, 1578, 520, 832, 315, 279, 6041, 11977, 311, 3240, 279, 1828, 9269, 13, 3277, 459, 10065, 7946, 26399, 304, 16785, 220, 1032, 704, 220, 868, 24871, 19622, 11, 279, 6037, 574, 5614, 2085, 5406, 323, 279, 10065, 1047, 311, 3480, 8446, 304, 2015, 311, 31127, 1082, 11565, 3196, 389, 9269, 323, 1493, 2038, 13, 1226, 67458, 279, 5178, 315, 279, 10065, 1701, 279, 88979, 11709, 320, 20523, 323, 15465, 8, 1701, 264, 4488, 869, 66286, 46867, 4235, 9028, 385, 6492, 220, 1758, 320, 30035, 13, 220, 16, 66, 7026, 902, 19170, 279, 19463, 315, 279, 11494, 1694, 4495, 2391, 1855, 9269, 3871, 449, 279, 5938, 12410, 28090, 13, 13266, 28090, 527, 1511, 311, 8417, 6975, 18852, 320, 4151, 19331, 570, 8442, 832, 14975, 3882, 574, 11953, 704, 389, 264, 3254, 1938, 13, 23966, 13, 220, 16, 28845, 48296, 287, 3465, 323, 88979, 6492, 13, 264, 432, 1900, 1051, 9277, 27716, 520, 832, 315, 279, 1403, 3284, 1212, 10093, 2391, 24871, 19622, 13, 1952, 279, 8197, 315, 38350, 5621, 809, 5886, 320, 4847, 40509, 8446, 11, 5718, 25, 220, 16, 11, 220, 17, 8, 477, 659, 5621, 809, 5886, 320, 797, 511, 40509, 8446, 11, 5718, 25, 220, 18, 11, 220, 19, 8, 10873, 11, 279, 10065, 706, 311, 5944, 389, 264, 5636, 1474, 10033, 304, 2015, 311, 5371, 11565, 320, 49, 570, 4740, 128257, 198, 128256, 78191, 198, 8989, 324, 25180, 5820, 304, 279, 864, 7096, 278, 49370, 11105, 1475, 3217, 439, 330, 39142, 301, 1210, 578, 34313, 10737, 872, 5820, 28178, 11, 1524, 422, 279, 502, 3217, 374, 1633, 4528, 311, 264, 3766, 832, 13, 3011, 374, 279, 1925, 9455, 315, 264, 4007, 13375, 555, 12074, 505, 3344, 92830, 47387, 596, 14829, 315, 73235, 32359, 81162, 323, 6051, 4756, 304, 279, 6522, 8486, 22037, 26545, 13, 330, 2170, 3117, 439, 279, 8271, 374, 11920, 11, 1475, 3217, 374, 5016, 11, 912, 5030, 1268, 4528, 433, 374, 311, 459, 6931, 832, 13, 578, 34313, 304, 279, 864, 7096, 278, 49370, 690, 387, 4642, 1855, 892, 1389, 1120, 439, 422, 279, 3217, 574, 11622, 502, 1359, 15100, 4007, 3229, 52194, 8560, 6241, 20198, 2259, 505, 279, 14829, 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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 Fibroblast reprogramming offers the potential for myocardial regeneration via in situ cell transdifferentiation. We explored a novel strategy leveraging endothelial cell plasticity to enhance reprogramming efficiency. Rat cardiac endothelial cells and fibroblasts were treated with Gata4, Mef2c, and Tbx5 (GMT) to assess the cardio-differentiation potential of these cells. The endothelial cell transdifferentiation factor ETV2 was transiently over-expressed in fibroblasts followed by GMT treatment to assess “trans-endothelial” cardio-differentiation. Endothelial cells treated with GMT generated more cTnT + cells than did cardiac fibroblasts (13% ± 2% vs 4% ± 0.5%, p < 0.01). Cardiac fibroblasts treated with ETV2 demonstrated increased endothelial cell markers, and when then treated with GMT yielded greater prevalence of cells expressing cardiomyocyte markers including cTnT than did fibroblasts treated with GMT or ETV2 (10.3% ± 0.2% vs 1.7% ± 0.06% and 0.6 ± 0.03, p < 0.01). Rat cardiac fibroblasts treated with GMT + ETV2 demonstrated calcium transients upon electrical stimulation and contractility synchronous with surrounding neonatal cardiomyocytes, whereas cells treated with GMT or ETV2 alone failed to contract in co-culture experiments. Human cardiac fibroblasts treated with ETV2 and then GMT likewise demonstrated greater prevalence of cTnT expression than did cells treated with GMT alone (2.8-fold increase, p < 0.05). Cardiac fibroblast transitioning through a trans-endothelial state appears to enhance cardio-differentiation by enhancing fibroblast plasticity. Since the first demonstration a decade ago of the possibility of cardiac cellular reprogramming, a wide variety of transcription factors, microRNAs and chemicals have been shown to induce the transdifferentiation of cardiac fibroblasts into “induced cardiomyocytes” (iCMs) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Despite encouraging observations that cardiac transdifferentiation improves post-infarct cardiac function in small animal models, limits on the efficiency of this process, especially in human cells, has catalyzed the search for more effective cardiac reprograming strategies 10 , 11 , 12 , 13 , 14 . Evidence that epigenetic repression of gene activation in higher order species may underlie cell resistance to reprogramming suggests that enhancing cell plasticity —the susceptibility of cells to transdifferentiation – may represent a promising strategy for enhancing cell reprogramming efficacy 6 , 14 , 15 . Endothelial cells possess the capacity to undergo a native cell transdifferentiation process termed endothelial mesenchymal transition (EndMT), which is characterized by enhanced cell plasticity 16 , 17 , 18 , 19 . During development, endothelial cells likewise share a common mesodermal progenitor with cardiomyocytes. We therefore hypothesized that endothelial cells may represent a “plastic” cell target more conducive to cardio-differentiation than are fibroblasts. Given however the relative scarcity of endothelial cells compared to fibroblast in the infarct milieu, we theorized that it would be desirable to transdifferentiate fibroblasts into endothelial cells as our primary reprogramming target, and then use these cells as a substrate for the application of our cardio-differentiating factors. In this report, we describe the efficacy of this strategy using the vascular endothelial cell master regulator ETS variant 2 (ETV2) to induce an endothelial cell “trans-state,” which in turn enhanced our ability to generate iCMs from cardiac fibroblasts 20 , 21 , 22 , 23 . Methods Cell and vectors All animal experiments were approved by Institutional Animal Care and Use Committee (IACUC) at Baylor College of Medicine and all methods were carried out in accordance with the NIH guidelines (Guide for the care and use of laboratory animals) and under protocol AN-6223, approved by the IACUC. These studies were conducted and are reported in compliance with relevant elements of ARRIVE guidelines. Commercially procured rat cardiac microvascular endothelial cells (AS One International Inc., SantaClara, CA) were cultured on fibronectin-coated dishes in EGM-2 medium supplemented with 10 ng/ml VEGF and bFGF (Lonza, cc-3156, cc-3162). Cardiac fibroblasts were isolated from adult rat cardiac tissues harvested from 6- to 8-week-old Sprague–Dawley rats (Envigo International Holding Inc., Hackensack, NJ) using standard cell explant protocols, and cultured in DMEM, 10% fetal bovine serum (FBS), and 1% penicillin/streptomycin. Human cardiac fibroblasts (PromoCell GmbH, Heidelberg, Germany) were cultured in Medium 106 (Gibco, ThermoFisher) supplemented with low serum growth supplement kit (S003K, Gibco, ThermoFisher). Lentivirus vectors encoding ETV2 tagged with yellow fluorescent protein (Venus), or encoding Gata4, Mef2c orTbx5 tagged with green fluorescent protein (GFP), or GFP alone were prepared from relevant plasmids by the Baylor College of Medicine Gene Vector Core, as previously described 4 , 5 , 10 . Plasmids for human ETV2 and reverse tetracycline-controlled transactivator (rtTA) were gifts from Dr. Rinpei Morita, Department of Microbiology and Immunology, Keio University, Tokyo, Japan. An adenovirus vector expressing VEGF (AdVEGF-All6A + ) based on an Ad5 serotype backbone with deletions in the E1 and E3 regions and containing an artificial splice sequence cassette was prepared by the Belfer Gene Therapy Core Facility at Weill Cornell Medical College, New York, NY. Cell reprogramming To assess cardio-differentiation efficiency, endothelial cells and cardiac fibroblasts cultured in EGM-2 medium supplemented with 10 ng/ml VEGF and bFGF were treated for 14 days with lentivirus encoding Gata4, Mef2c and Tbx5 (GMT) or GFP alone at a multiplicity of infection (MOI) of 20. To induce ETV2 expression, rat cardiac fibroblasts were treated with lentivirus encoding ETV2 and a second lentivirus encoding rtTA (MOI of 20 each) in EGM-2 medium supplemented with SingleQuots (cc-4176, Lonza). ETV2 was overexpressed in ETV2/rtTA-treated cells by doxycycline addition (100 ng/ml) into the cell culture media for a period of 10 days for rat cardiac fibroblasts, but for a period of only 3 days for human cardiac fibroblasts because of the rapid proliferation of these cells. As a control, naïve cells received only doxycycline. Three days after doxycycline removal, cells were treated with lentivirus encoding GMT (20 MOI) and maintained for 14 days in iCM medium (DMEM with 10% FBS and 20% M199). For cell contractility studies, neonatal rat cardiomyocytes isolated from 0 to 3 days old neonatal rat pups were cultured DMEM and M199 in a 4:1 ratio and supplement with 10% horse serum, 5% fetal bovine serum, as previously described 15 . Adult", "role": "user" }, { "content": "Not too long ago, the idea of taking—for instance—a skin cell and transforming it into a muscle cell was unthinkable. About 10 years ago, however, revolutionary research showed that it is indeed possible to reprogram differentiated adult cells into other types fully capable of conducting new functions. Cell reprogramming is a main interest of the lab of Dr. Todd Rosengart, chair and professor of the Michael E. DeBakey Department of Surgery at Baylor College of Medicine, whose research focuses on finding innovative therapeutic approaches for heart failure. \"Heart failure remains the leading cause of death from heart disease,\" said Rosengart, DeBakey-Bard Chair in Surgery and professor of molecular and cellular biology at Baylor. \"Nearly 5 million Americans can be expected to develop advanced congestive heart failure, and heart transplant or mechanical circulatory support implantation currently are the only options for patients with end-stage heart disease. However, these options are limited. We need to improve how to treat this devastating condition.\" After a heart attack, the parts of the heart muscle that die do not regenerate into new heart tissue; instead, they are replaced by a scar that does not help the heart to beat. \"The idea behind cell reprogramming is to coach the heart to heal itself by inducing the scar tissue, which is made mostly of fibroblasts, to change into functional heart muscle,\" said Rosengart, professor of heart and vascular disease at the Texas Heart Institute. Researchers have succeeded at reprogramming fibroblasts from small animals to become heart muscle, with dramatic improvements in heart function. The challenge has been to apply this technology to human cells—human fibroblasts are more resistant to reprogramming. In this study, Rosengart and his colleagues explored a novel strategy to enhance the reprogramming efficiency of human fibroblasts. \"While human fibroblasts resist being reprogramed, endothelial cells, those that line the blood vessels, are known to be more flexible—they have the capacity to naturally transdifferentiate or change into other cells,\" said co-first author Dr. Megumi Mathison, associate professor of surgery at Baylor. \"This gave us the idea of using this endothelial cell plasticity to improve the reprogramming efficiency.\" The researchers' idea was to first induce fibroblasts to transition into an endothelial cell-like state and then treat these cells with their reprogramming cocktail that directs them to change into cardiomyocytes. The expectation was that transitioning into endothelial cell-like cells, a cell type more open to reprogramming than fibroblasts, would facilitate the desired change into heart muscle. \"We were delighted to see that our approach significantly enhanced reprogramming efficiency both in human and rat fibroblasts,\" Mathison said. \"Previously, inducing cardiomyocytes from fibroblasts directly was only 3% efficient. With our new approach, the efficiency increased 5 times. It took about two to three weeks for the fibroblasts to transition into cardiomyocytes in the lab. It was exciting to see the reprogrammed cells contracting in synchrony with surrounding cardiomyocytes.\" The researchers' experimental results with the rat model show that their new strategy can revert large scar tissue into working muscle, supporting continuing their investigations to bring this procedure to the clinic. \"Although more research is needed, we anticipate that this novel approach can become part of the next generation of biological therapies,\" Rosengart said. \"In a future scenario, patients with congestive heart failure would come to the catheterization laboratory, commonly referred to as the cath lab, in a hospital. The cath lab has diagnostic imaging equipment that helps surgeons visualize the chambers of the heart and surrounding blood vessels as they conduct procedures. Assisted by this equipment, the surgeon would inject the factors that promote the transition from fibroblasts to endothelial cells and then to cardiomyocytes directly into the heart. Follow ups would monitor the progress of the procedure.\" This work strongly ties into the prominent role Baylor College of Medicine has played in the history of the artificial heart and heart transplants pioneered by Dr. Michael E. DeBakey and Dr. Denton A. Cooley in the 1950s and 60s. \"Years ago, Dr. Cooley said to me, regarding the next procedures needed to help people with heart failure, \"Todd, you got to do something that is dramatic.\" For me, cell reprogramming is a 21st-century answer to this request,\" Rosengart said. Find all the details of this work in the journal Scientific Reports. Other contributors to this work include Deepthi Sanagasetti, Vivek P. Singh, Aarthi Pugazenthi, Jaya Pratap Pinnamaneni, Christopher T. Ryan and Jianchang Yang, all at Baylor College of Medicine. ", "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 Fibroblast reprogramming offers the potential for myocardial regeneration via in situ cell transdifferentiation. We explored a novel strategy leveraging endothelial cell plasticity to enhance reprogramming efficiency. Rat cardiac endothelial cells and fibroblasts were treated with Gata4, Mef2c, and Tbx5 (GMT) to assess the cardio-differentiation potential of these cells. The endothelial cell transdifferentiation factor ETV2 was transiently over-expressed in fibroblasts followed by GMT treatment to assess “trans-endothelial” cardio-differentiation. Endothelial cells treated with GMT generated more cTnT + cells than did cardiac fibroblasts (13% ± 2% vs 4% ± 0.5%, p < 0.01). Cardiac fibroblasts treated with ETV2 demonstrated increased endothelial cell markers, and when then treated with GMT yielded greater prevalence of cells expressing cardiomyocyte markers including cTnT than did fibroblasts treated with GMT or ETV2 (10.3% ± 0.2% vs 1.7% ± 0.06% and 0.6 ± 0.03, p < 0.01). Rat cardiac fibroblasts treated with GMT + ETV2 demonstrated calcium transients upon electrical stimulation and contractility synchronous with surrounding neonatal cardiomyocytes, whereas cells treated with GMT or ETV2 alone failed to contract in co-culture experiments. Human cardiac fibroblasts treated with ETV2 and then GMT likewise demonstrated greater prevalence of cTnT expression than did cells treated with GMT alone (2.8-fold increase, p < 0.05). Cardiac fibroblast transitioning through a trans-endothelial state appears to enhance cardio-differentiation by enhancing fibroblast plasticity. Since the first demonstration a decade ago of the possibility of cardiac cellular reprogramming, a wide variety of transcription factors, microRNAs and chemicals have been shown to induce the transdifferentiation of cardiac fibroblasts into “induced cardiomyocytes” (iCMs) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Despite encouraging observations that cardiac transdifferentiation improves post-infarct cardiac function in small animal models, limits on the efficiency of this process, especially in human cells, has catalyzed the search for more effective cardiac reprograming strategies 10 , 11 , 12 , 13 , 14 . Evidence that epigenetic repression of gene activation in higher order species may underlie cell resistance to reprogramming suggests that enhancing cell plasticity —the susceptibility of cells to transdifferentiation – may represent a promising strategy for enhancing cell reprogramming efficacy 6 , 14 , 15 . Endothelial cells possess the capacity to undergo a native cell transdifferentiation process termed endothelial mesenchymal transition (EndMT), which is characterized by enhanced cell plasticity 16 , 17 , 18 , 19 . During development, endothelial cells likewise share a common mesodermal progenitor with cardiomyocytes. We therefore hypothesized that endothelial cells may represent a “plastic” cell target more conducive to cardio-differentiation than are fibroblasts. Given however the relative scarcity of endothelial cells compared to fibroblast in the infarct milieu, we theorized that it would be desirable to transdifferentiate fibroblasts into endothelial cells as our primary reprogramming target, and then use these cells as a substrate for the application of our cardio-differentiating factors. In this report, we describe the efficacy of this strategy using the vascular endothelial cell master regulator ETS variant 2 (ETV2) to induce an endothelial cell “trans-state,” which in turn enhanced our ability to generate iCMs from cardiac fibroblasts 20 , 21 , 22 , 23 . Methods Cell and vectors All animal experiments were approved by Institutional Animal Care and Use Committee (IACUC) at Baylor College of Medicine and all methods were carried out in accordance with the NIH guidelines (Guide for the care and use of laboratory animals) and under protocol AN-6223, approved by the IACUC. These studies were conducted and are reported in compliance with relevant elements of ARRIVE guidelines. Commercially procured rat cardiac microvascular endothelial cells (AS One International Inc., SantaClara, CA) were cultured on fibronectin-coated dishes in EGM-2 medium supplemented with 10 ng/ml VEGF and bFGF (Lonza, cc-3156, cc-3162). Cardiac fibroblasts were isolated from adult rat cardiac tissues harvested from 6- to 8-week-old Sprague–Dawley rats (Envigo International Holding Inc., Hackensack, NJ) using standard cell explant protocols, and cultured in DMEM, 10% fetal bovine serum (FBS), and 1% penicillin/streptomycin. Human cardiac fibroblasts (PromoCell GmbH, Heidelberg, Germany) were cultured in Medium 106 (Gibco, ThermoFisher) supplemented with low serum growth supplement kit (S003K, Gibco, ThermoFisher). Lentivirus vectors encoding ETV2 tagged with yellow fluorescent protein (Venus), or encoding Gata4, Mef2c orTbx5 tagged with green fluorescent protein (GFP), or GFP alone were prepared from relevant plasmids by the Baylor College of Medicine Gene Vector Core, as previously described 4 , 5 , 10 . Plasmids for human ETV2 and reverse tetracycline-controlled transactivator (rtTA) were gifts from Dr. Rinpei Morita, Department of Microbiology and Immunology, Keio University, Tokyo, Japan. An adenovirus vector expressing VEGF (AdVEGF-All6A + ) based on an Ad5 serotype backbone with deletions in the E1 and E3 regions and containing an artificial splice sequence cassette was prepared by the Belfer Gene Therapy Core Facility at Weill Cornell Medical College, New York, NY. Cell reprogramming To assess cardio-differentiation efficiency, endothelial cells and cardiac fibroblasts cultured in EGM-2 medium supplemented with 10 ng/ml VEGF and bFGF were treated for 14 days with lentivirus encoding Gata4, Mef2c and Tbx5 (GMT) or GFP alone at a multiplicity of infection (MOI) of 20. To induce ETV2 expression, rat cardiac fibroblasts were treated with lentivirus encoding ETV2 and a second lentivirus encoding rtTA (MOI of 20 each) in EGM-2 medium supplemented with SingleQuots (cc-4176, Lonza). ETV2 was overexpressed in ETV2/rtTA-treated cells by doxycycline addition (100 ng/ml) into the cell culture media for a period of 10 days for rat cardiac fibroblasts, but for a period of only 3 days for human cardiac fibroblasts because of the rapid proliferation of these cells. As a control, naïve cells received only doxycycline. Three days after doxycycline removal, cells were treated with lentivirus encoding GMT (20 MOI) and maintained for 14 days in iCM medium (DMEM with 10% FBS and 20% M199). For cell contractility studies, neonatal rat cardiomyocytes isolated from 0 to 3 days old neonatal rat pups were cultured DMEM and M199 in a 4:1 ratio and supplement with 10% horse serum, 5% fetal bovine serum, as previously described 15 . Adult<|im_end|> <|im_start|>assistant Not too long ago, the idea of taking—for instance—a skin cell and transforming it into a muscle cell was unthinkable. About 10 years ago, however, revolutionary research showed that it is indeed possible to reprogram differentiated adult cells into other types fully capable of conducting new functions. Cell reprogramming is a main interest of the lab of Dr. Todd Rosengart, chair and professor of the Michael E. DeBakey Department of Surgery at Baylor College of Medicine, whose research focuses on finding innovative therapeutic approaches for heart failure. "Heart failure remains the leading cause of death from heart disease," said Rosengart, DeBakey-Bard Chair in Surgery and professor of molecular and cellular biology at Baylor. "Nearly 5 million Americans can be expected to develop advanced congestive heart failure, and heart transplant or mechanical circulatory support implantation currently are the only options for patients with end-stage heart disease. However, these options are limited. We need to improve how to treat this devastating condition." After a heart attack, the parts of the heart muscle that die do not regenerate into new heart tissue; instead, they are replaced by a scar that does not help the heart to beat. "The idea behind cell reprogramming is to coach the heart to heal itself by inducing the scar tissue, which is made mostly of fibroblasts, to change into functional heart muscle," said Rosengart, professor of heart and vascular disease at the Texas Heart Institute. Researchers have succeeded at reprogramming fibroblasts from small animals to become heart muscle, with dramatic improvements in heart function. The challenge has been to apply this technology to human cells—human fibroblasts are more resistant to reprogramming. In this study, Rosengart and his colleagues explored a novel strategy to enhance the reprogramming efficiency of human fibroblasts. "While human fibroblasts resist being reprogramed, endothelial cells, those that line the blood vessels, are known to be more flexible—they have the capacity to naturally transdifferentiate or change into other cells," said co-first author Dr. Megumi Mathison, associate professor of surgery at Baylor. "This gave us the idea of using this endothelial cell plasticity to improve the reprogramming efficiency." The researchers' idea was to first induce fibroblasts to transition into an endothelial cell-like state and then treat these cells with their reprogramming cocktail that directs them to change into cardiomyocytes. The expectation was that transitioning into endothelial cell-like cells, a cell type more open to reprogramming than fibroblasts, would facilitate the desired change into heart muscle. "We were delighted to see that our approach significantly enhanced reprogramming efficiency both in human and rat fibroblasts," Mathison said. "Previously, inducing cardiomyocytes from fibroblasts directly was only 3% efficient. With our new approach, the efficiency increased 5 times. It took about two to three weeks for the fibroblasts to transition into cardiomyocytes in the lab. It was exciting to see the reprogrammed cells contracting in synchrony with surrounding cardiomyocytes." The researchers' experimental results with the rat model show that their new strategy can revert large scar tissue into working muscle, supporting continuing their investigations to bring this procedure to the clinic. "Although more research is needed, we anticipate that this novel approach can become part of the next generation of biological therapies," Rosengart said. "In a future scenario, patients with congestive heart failure would come to the catheterization laboratory, commonly referred to as the cath lab, in a hospital. The cath lab has diagnostic imaging equipment that helps surgeons visualize the chambers of the heart and surrounding blood vessels as they conduct procedures. Assisted by this equipment, the surgeon would inject the factors that promote the transition from fibroblasts to endothelial cells and then to cardiomyocytes directly into the heart. Follow ups would monitor the progress of the procedure." This work strongly ties into the prominent role Baylor College of Medicine has played in the history of the artificial heart and heart transplants pioneered by Dr. Michael E. DeBakey and Dr. Denton A. Cooley in the 1950s and 60s. "Years ago, Dr. Cooley said to me, regarding the next procedures needed to help people with heart failure, "Todd, you got to do something that is dramatic." For me, cell reprogramming is a 21st-century answer to this request," Rosengart said. Find all the details of this work in the journal Scientific Reports. Other contributors to this work include Deepthi Sanagasetti, Vivek P. Singh, Aarthi Pugazenthi, Jaya Pratap Pinnamaneni, Christopher T. Ryan and Jianchang Yang, all at Baylor College of Medicine. <|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 recent advent of hard x-ray free electron lasers (XFELs) opens new areas of science due to their exceptional brightness, coherence and time structure. In principle, such sources enable studies of dynamics of condensed matter systems over times ranging from femtoseconds to seconds. However, the studies of “slow” dynamics in polymeric materials still remain in question due to the characteristics of the XFEL beam and concerns about sample damage. Here we demonstrate the feasibility of measuring the relaxation dynamics of gold nanoparticles suspended in polymer melts using X-ray photon correlation spectroscopy (XPCS), while also monitoring eventual X-ray induced damage. In spite of inherently large pulse-to-pulse intensity and position variations of the XFEL beam, measurements can be realized at slow time scales. The X-ray induced damage and heating are less than initially expected for soft matter materials. Introduction Since the recent availability of X-ray free electron lasers (XFELs) in the hard x-ray regime, many new scientific areas have been explored due to their unprecedented flux, coherence and time structures 1 , 2 , 3 . Dynamics of complex materials are one of the important areas to investigate with XFELs 4 . The brilliance of these machines, a billion times higher than that of third generation synchrotrons, allows experiments in ranges where the scattering intensity was too low previously, but concomitantly raises the issue of beam damage and other beam induced effects such as sample heating. The fully transversely coherent beam constitutes an unexcelled asset compared to the third generation synchrotron sources, but the random nature of the SASE emission process 5 of XFEL radiation implies pulse-to-pulse variations of the longitudinal coherence length 6 and intensity. It therefore induces contrast variations and sets an upper limit on the accessible wave vector transfer range for experiments relying on the spatial coherence of the beam 7 . The coherence characteristics of the beam were verified from detailed photon statistics analysis 5 , 8 , 9 , 10 . There are three different possible experimental regimes of XFEL studies related to the photon density at the sample: (i) extremely high photon flux in a small beam size, i.e. in the regime of “diffract before destroy”, where the sample is irreversibly damaged after a single pulse and ultrafast X-ray induced electronic processes are investigated; (ii) medium photon fluxes and beam sizes, where the sample can endure a few pulses at least and damage is on a spatial scale that does not impede the intended experiments. In this case, double shot experiments allow us to study the basic mechanism of X-ray excited phonon states and heat transfer; (iii) low photon densities, where degradation effects of a single pulse can be neglected, sample heating is minimal and multi-pulse exposures are used for equilibrium studies. The boundaries between these regimes obviously depend on the photon flux and sample composition and need to be experimentally determined and verified. X-ray photon correlation spectroscopy (XPCS) is a powerful technique for probing various steady state [i.e. equilibrium] and non-equilibrium dynamics in condensed matter physics, e.g., the kinetics of de-mixing in crystalline metal alloys 11 , magnetic domain switching 12 and polymer relaxation dynamics 13 , 14 , 15 . XPCS typically measures the temporal correlations in the intensity of speckle patterns scattered by disordered systems when illuminated by coherent x-rays with sequential exposures. The feasibility of XPCS with the XFELs was suggested in terms of experimental setup and possible scientific applications involving different temporal regimes 4 , 16 . For example, a new technical approach with split-and-delay lines 8 , 17 , 18 was proposed for probing time scales from femtoseconds to nanoseconds by splitting the beam, delaying one and collinearly recombining the essentially identical beams with a tuned delay before impinging them on the sample. Other approaches in data analysis, e.g., speckle visibility analysis 19 , 20 , 21 are also being developed to get to time scales faster than those available from sequential XPCS. Prior to the current experiment, sequential XPCS had not yet been realized with the XFEL because of the complications of large pulse-to-pulse intensity variations and the potential X-ray induced sample damages. In terms of the damage issue, the thresholds for disturbing the atomic arrangements by a single XFEL pulse were for example studied recently in a Ni 2 Pd 2 P glass 10 . It is of primary importance, though, to take into account multiple pulses for low scattering systems. The sample damage from sequential XFEL pulses is a key to interpreting XPCS results, since XPCS requires the recording of hundreds of frames, with one or multiple pulses for each frame. In this study, we show that one can extract the dynamics of gold nanoparticles in entangled polymer melts using sequential XPCS over time scales for 10 to 10 3 seconds despite the large intrinsic fluctuations of the XFEL beam. We demonstrate that an experimental window exists for soft-matter materials to study steady state fluctuation dynamics before X-ray induced damage is of concern. A two-time correlation method was applied to analyze the results obtained by sequential XPCS. Adiabatic heating and steady-state heating on the sample were also estimated for quantifying beam induced effects. These XPCS experiments show that the amount of heat deposited is highly overestimated by the simple energy deposition formula and suggest that more complex heat diffusion processes are in play. Results The experiment was performed at the X-ray Correlation Spectroscopy (XCS) instrument 22 at the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory (Menlo Park, USA). The schematic of the XCS instrument is shown in Fig. 1(a) . Figure 1(b) shows a TEM image of the gold nanoparticles in the polymer matrix with the typical sizes and concentrations used in this study, confirming that the gold nanoparticles are not aggregated but well dispersed in the polymer matrix. Figure 1(c) presents a speckle pattern at a sample to detector distance (SDD) of 5037 mm from gold nanospheres of 5.5 nm diameter with polystyrene (M w = 30 kg/mol) attached to the", "role": "user" }, { "content": "Plastics are made of polymers, which are a challenge for scientists to study. Their chainlike strands of thousands of atoms are tangled up in a spaghetti-like jumble, their motion can be measured at many time scales and they are essentially invisible to some common X-ray study techniques. A better understanding of polymers at the molecular scale, particularly as they are cooled from a molten state to a more solid form, could lead to improved manufacturing techniques and the creation of new, customizable materials. In an experiment at the Department of Energy's SLAC National Accelerator Laboratory using SLAC's Linac Coherent Light Source (LCLS) X-ray laser, a DOE Office of Science User Facility, scientists unraveled the complex behavior of polystyrene, a popular polymer found in packing foams and plastic cups, with a sequence of ultrabright X-ray laser pulses. Their work is detailed in the Aug. 11 edition of Scientific Reports. They measured natural motion in polystyrene samples heated to a gel-like middle ground between their melting point and solid state. This was the first demonstration that LCLS could be used for studying polymers and a whole range of other complex materials using a technique called X-ray photon correlation spectroscopy (XPCS), Hyunjung Kim of Sogang University in Korea, who led this research, said, \"It was unknown whether the sample would survive the exposure to the ultrabright X-ray laser pulses. However, the X-ray damage effects on the sample were weaker than expected.\" SLAC staff scientist Aymeric Robert said, \"To see how you get from something that was completely moving to something completely static is very poorly understood. Observations of how polymers move in response to temperature changes and other effects can be compared with theoretical models to predict their behavior.\" Robert oversees the experimental station at LCLS that is specially designed for this X-ray technique. This photograph shows a polymer in a molten, gel-like state. Credit: iStockphoto/Steve Bjorklund \"LCLS should allow scientists to measure motion in these materials in even more detail than possible using conventional X-ray tools,\" he added. To study motion in the heated samples, researchers embedded a matrix of nanoscale gold spheres into the polymer. Then, they recorded sequences of up to about 150 X-ray images on different sections of the sample, with the delay between images ranging from as little as seven seconds to as much as 17 minutes. A view of the X-ray Correlation Spectroscopy experimental station at SLAC's Linac Coherent Light Source (LCLS) X-ray laser. This station is designed to explore polymers and other hard-to-study materials. Credit: SLAC National Accelerator Laboratory The XPCS technique measures successive \"speckle\" patterns that revealed subtle changes in the position of the gold spheres relative to one another – a measure of motion within the overall sample. While many experiments at LCLS capture X-ray data in the instant before samples are destroyed by the intense light, this technique allows some materials to survive the effects of many X-ray pulses, which is useful for studying longer-lived properties spanning from milliseconds to minutes. This image (a) shows the experimental setup for an X-ray photon correlation spectroscopy experiment using polymer samples at SLAC's Linac Coherent Light Source X-ray laser. (b) This transmission electron microscopy image shows nanoscale gold spheres that were embedded in a molten polymer to help study its motion. (c) This speckle pattern was produced as X-rays struck the polymer sample. A succession of these patterns show the changing positions of the gold spheres in the polymer sample, which provides a measure of the polymer's motion. (10.1038/srep06017) \"We showed that we could study the complex dynamics in the polymer sample even at slow time scales,\" Kim said. While this experiment proved that LCLS can be used to measure the long-duration motions across the entire sample, Kim said future experiments could vary the arrangement and size of the implanted gold spheres to better gauge motion at the scale of the molecular chains. Also, faster repetition of the X-ray laser pulses could help to study motion on a shorter time scale. ", "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 recent advent of hard x-ray free electron lasers (XFELs) opens new areas of science due to their exceptional brightness, coherence and time structure. In principle, such sources enable studies of dynamics of condensed matter systems over times ranging from femtoseconds to seconds. However, the studies of “slow” dynamics in polymeric materials still remain in question due to the characteristics of the XFEL beam and concerns about sample damage. Here we demonstrate the feasibility of measuring the relaxation dynamics of gold nanoparticles suspended in polymer melts using X-ray photon correlation spectroscopy (XPCS), while also monitoring eventual X-ray induced damage. In spite of inherently large pulse-to-pulse intensity and position variations of the XFEL beam, measurements can be realized at slow time scales. The X-ray induced damage and heating are less than initially expected for soft matter materials. Introduction Since the recent availability of X-ray free electron lasers (XFELs) in the hard x-ray regime, many new scientific areas have been explored due to their unprecedented flux, coherence and time structures 1 , 2 , 3 . Dynamics of complex materials are one of the important areas to investigate with XFELs 4 . The brilliance of these machines, a billion times higher than that of third generation synchrotrons, allows experiments in ranges where the scattering intensity was too low previously, but concomitantly raises the issue of beam damage and other beam induced effects such as sample heating. The fully transversely coherent beam constitutes an unexcelled asset compared to the third generation synchrotron sources, but the random nature of the SASE emission process 5 of XFEL radiation implies pulse-to-pulse variations of the longitudinal coherence length 6 and intensity. It therefore induces contrast variations and sets an upper limit on the accessible wave vector transfer range for experiments relying on the spatial coherence of the beam 7 . The coherence characteristics of the beam were verified from detailed photon statistics analysis 5 , 8 , 9 , 10 . There are three different possible experimental regimes of XFEL studies related to the photon density at the sample: (i) extremely high photon flux in a small beam size, i.e. in the regime of “diffract before destroy”, where the sample is irreversibly damaged after a single pulse and ultrafast X-ray induced electronic processes are investigated; (ii) medium photon fluxes and beam sizes, where the sample can endure a few pulses at least and damage is on a spatial scale that does not impede the intended experiments. In this case, double shot experiments allow us to study the basic mechanism of X-ray excited phonon states and heat transfer; (iii) low photon densities, where degradation effects of a single pulse can be neglected, sample heating is minimal and multi-pulse exposures are used for equilibrium studies. The boundaries between these regimes obviously depend on the photon flux and sample composition and need to be experimentally determined and verified. X-ray photon correlation spectroscopy (XPCS) is a powerful technique for probing various steady state [i.e. equilibrium] and non-equilibrium dynamics in condensed matter physics, e.g., the kinetics of de-mixing in crystalline metal alloys 11 , magnetic domain switching 12 and polymer relaxation dynamics 13 , 14 , 15 . XPCS typically measures the temporal correlations in the intensity of speckle patterns scattered by disordered systems when illuminated by coherent x-rays with sequential exposures. The feasibility of XPCS with the XFELs was suggested in terms of experimental setup and possible scientific applications involving different temporal regimes 4 , 16 . For example, a new technical approach with split-and-delay lines 8 , 17 , 18 was proposed for probing time scales from femtoseconds to nanoseconds by splitting the beam, delaying one and collinearly recombining the essentially identical beams with a tuned delay before impinging them on the sample. Other approaches in data analysis, e.g., speckle visibility analysis 19 , 20 , 21 are also being developed to get to time scales faster than those available from sequential XPCS. Prior to the current experiment, sequential XPCS had not yet been realized with the XFEL because of the complications of large pulse-to-pulse intensity variations and the potential X-ray induced sample damages. In terms of the damage issue, the thresholds for disturbing the atomic arrangements by a single XFEL pulse were for example studied recently in a Ni 2 Pd 2 P glass 10 . It is of primary importance, though, to take into account multiple pulses for low scattering systems. The sample damage from sequential XFEL pulses is a key to interpreting XPCS results, since XPCS requires the recording of hundreds of frames, with one or multiple pulses for each frame. In this study, we show that one can extract the dynamics of gold nanoparticles in entangled polymer melts using sequential XPCS over time scales for 10 to 10 3 seconds despite the large intrinsic fluctuations of the XFEL beam. We demonstrate that an experimental window exists for soft-matter materials to study steady state fluctuation dynamics before X-ray induced damage is of concern. A two-time correlation method was applied to analyze the results obtained by sequential XPCS. Adiabatic heating and steady-state heating on the sample were also estimated for quantifying beam induced effects. These XPCS experiments show that the amount of heat deposited is highly overestimated by the simple energy deposition formula and suggest that more complex heat diffusion processes are in play. Results The experiment was performed at the X-ray Correlation Spectroscopy (XCS) instrument 22 at the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory (Menlo Park, USA). The schematic of the XCS instrument is shown in Fig. 1(a) . Figure 1(b) shows a TEM image of the gold nanoparticles in the polymer matrix with the typical sizes and concentrations used in this study, confirming that the gold nanoparticles are not aggregated but well dispersed in the polymer matrix. Figure 1(c) presents a speckle pattern at a sample to detector distance (SDD) of 5037 mm from gold nanospheres of 5.5 nm diameter with polystyrene (M w = 30 kg/mol) attached to the<|im_end|> <|im_start|>assistant Plastics are made of polymers, which are a challenge for scientists to study. Their chainlike strands of thousands of atoms are tangled up in a spaghetti-like jumble, their motion can be measured at many time scales and they are essentially invisible to some common X-ray study techniques. A better understanding of polymers at the molecular scale, particularly as they are cooled from a molten state to a more solid form, could lead to improved manufacturing techniques and the creation of new, customizable materials. In an experiment at the Department of Energy's SLAC National Accelerator Laboratory using SLAC's Linac Coherent Light Source (LCLS) X-ray laser, a DOE Office of Science User Facility, scientists unraveled the complex behavior of polystyrene, a popular polymer found in packing foams and plastic cups, with a sequence of ultrabright X-ray laser pulses. Their work is detailed in the Aug. 11 edition of Scientific Reports. They measured natural motion in polystyrene samples heated to a gel-like middle ground between their melting point and solid state. This was the first demonstration that LCLS could be used for studying polymers and a whole range of other complex materials using a technique called X-ray photon correlation spectroscopy (XPCS), Hyunjung Kim of Sogang University in Korea, who led this research, said, "It was unknown whether the sample would survive the exposure to the ultrabright X-ray laser pulses. However, the X-ray damage effects on the sample were weaker than expected." SLAC staff scientist Aymeric Robert said, "To see how you get from something that was completely moving to something completely static is very poorly understood. Observations of how polymers move in response to temperature changes and other effects can be compared with theoretical models to predict their behavior." Robert oversees the experimental station at LCLS that is specially designed for this X-ray technique. This photograph shows a polymer in a molten, gel-like state. Credit: iStockphoto/Steve Bjorklund "LCLS should allow scientists to measure motion in these materials in even more detail than possible using conventional X-ray tools," he added. To study motion in the heated samples, researchers embedded a matrix of nanoscale gold spheres into the polymer. Then, they recorded sequences of up to about 150 X-ray images on different sections of the sample, with the delay between images ranging from as little as seven seconds to as much as 17 minutes. A view of the X-ray Correlation Spectroscopy experimental station at SLAC's Linac Coherent Light Source (LCLS) X-ray laser. This station is designed to explore polymers and other hard-to-study materials. Credit: SLAC National Accelerator Laboratory The XPCS technique measures successive "speckle" patterns that revealed subtle changes in the position of the gold spheres relative to one another – a measure of motion within the overall sample. While many experiments at LCLS capture X-ray data in the instant before samples are destroyed by the intense light, this technique allows some materials to survive the effects of many X-ray pulses, which is useful for studying longer-lived properties spanning from milliseconds to minutes. This image (a) shows the experimental setup for an X-ray photon correlation spectroscopy experiment using polymer samples at SLAC's Linac Coherent Light Source X-ray laser. (b) This transmission electron microscopy image shows nanoscale gold spheres that were embedded in a molten polymer to help study its motion. (c) This speckle pattern was produced as X-rays struck the polymer sample. A succession of these patterns show the changing positions of the gold spheres in the polymer sample, which provides a measure of the polymer's motion. (10.1038/srep06017) "We showed that we could study the complex dynamics in the polymer sample even at slow time scales," Kim said. While this experiment proved that LCLS can be used to measure the long-duration motions across the entire sample, Kim said future experiments could vary the arrangement and size of the implanted gold spheres to better gauge motion at the scale of the molecular chains. Also, faster repetition of the X-ray laser pulses could help to study motion on a shorter time scale. <|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 How do large-bodied frugivores contribute to seed dispersal of large-diaspore plants? This study examined seed dispersal effectiveness for two large-diaspore tree species, Astrotrichilia asterotricha ( AA ) and Abrahamia deflexa ( AD ), in a Madagascan forest. I evaluated fruit removal rates through focal tree observations and factors affecting seedling recruitment up to the 2-year-old seedling stage. I confirmed brown lemur ( Eulemur fulvus ) as the sole disperser, removing 58.8% and 26.0% of fruits produced by AA and AD . Brown lemurs frequently visited large-crowned AA trees with high density of fallen fruits and more adjacent fruiting trees during seasons with low fruit diversity. Most AA seedlings were removed by predators, although canopy openness slightly improved seedling establishment. Although AD seeds were severely attacked by predators under mother trees, the seedlings survived under dispersal conditions distant from the mother trees, and with low density of diaspores. AD had a higher cumulative probability from fruit removal to seedling recruitment (6.5%) than AA (1.5%) in the first rainy season. This study clarifies the significance of seed dispersal to tree recruitment strategies, which vary among different combinations of tree species and large frugivores, i.e. quantitative dispersal to reach suitable microhabitats, and qualitative dispersal to escape from dangerous zones near mother trees. Introduction Seed dispersal represents a plant strategy to enhance reproductive success, and recruitment patterns presumably influence population dynamics and biodiversity at the community level 1 , 2 . Seed dispersal by animals has been studied in detail in tropical forests, because 50–90% of plant species in these ecosystems are endozoochorous 1 , 3 . The roles of seed dispersal agents have been evaluated systematically in accordance with the concept of seed disperser effectiveness (SDE), expressed as the product of quantitative and qualitative components, i.e. the number of seeds dispersed from fruiting mother plants and the probability of seed/seedling survival and recruitment as new adults, respectively 4 . The SDE has mostly been evaluated separately for quantitative component in the dispersal phase from fruit production to seed dispersal and qualitative component in the post-dispersal phase from seed deposition to new recruitment as surviving seedlings 2 , 5 , 6 . However, the definition of SDE has been broadened to “seed dispersal effectiveness”, emphasizing the need to evaluate the overall effectiveness of the full process of plant regeneration from seed dispersal to seedling establishment and survival 7 . As such, recent studies have comprehensively evaluated SDE by incorporating both the quantitative and qualitative components 8 , 9 , 10 , 11 , 12 . During the dispersal phase, the quantitative component of SDE has mainly been evaluated by observing fruit removal from focal plants by animals 13 , 14 , 15 . To gain an understanding of the mechanisms of successful fruit removal, researchers have examined intrinsic (plant size, fruit density, pulp ratio per fruit, and so forth) and extrinsic factors (fruiting of neighbouring trees, fruit availability of the forest, and so forth) 16 . Examination of the feeding strategies of frugivores has indicated that some birds visit trees with high pulp ratio per fruit 14 , and that primates and birds remove more fruits from trees with larger crop sizes 14 , 17 , 18 , 19 . As the main component of quantitative effectiveness, the relative quantity of fruit removal has been mostly evaluated by comparisons among seed disperser assemblages 15 , 20 . However, to evaluate dispersal effectiveness rather than disperser effectiveness, it is necessary to evaluate the fruit removal rate of each targeted animal taxon in the amount of fruit production as an absolute quantitative assessment of SDE in the dispersal phase of focal plants 13 , 14 , 16 . During the post-dispersal phase, the probability of seedling recruitment, the primary qualitative component of SDE, has been evaluated by monitoring the fates of seeds or seedlings, which is influenced by predation, secondary dispersal, pathogen disease, and stress among other environmental factors 21 , 22 , 23 , 24 . Such monitoring has indicated high mortality rates of seeds/seedlings at sites with high seed densities and close to conspecific fruiting trees, known as the Janzen-Connell effect 23 , 25 , 26 , 27 , 28 . Monitoring studies have also reported high survival rates and/or high growth rates in open-canopy microhabitats 21 , 23 and high survival rates via secondary dispersal 24 , 29 , 30 . Some studies that have evaluated SDE by multiplying the quantitative and qualitative components report that the initial effects of fruit removal by frugivores during the dispersal phase are often hindered by high and heterogeneous mortality 13 , 31 , 32 , 33 , whereas others have detected effects of frugivores on seedling recruitment patterns 34 , 35 . Thus, further study is required for a more holistic understanding of SDE. In recent years, low densities of seedlings/saplings of large-seeded plants and aggregated distribution around mother trees were found in empty and half-empty forests following the disappearance or decrease in number of large frugivores 36 , 37 , 38 , 39 . These findings suggest that in species-depauperate networks formed by strong mutualism between large-seeded plants and large-bodied frugivores, a small number of key frugivores have a large SDE and provide robust connectivity between the dispersal and post-dispersal phases. This hypothesis was recently tested by evaluating the SDE of primates, bears, and elephants for large-seeded plants growing in a seasonal evergreen forest in Thailand 8 , 10 , 12 . However, such studies have only reported on a limited number of taxonomic groups and involved few study sites. Furthermore, since the concept of attracting and introducing frugivores as effective restoration agents for reforestation has been proposed 40 , 41 , 42 , to understand SDE of large frugivores is also an important issue in conservation biology. To examine the SDE of large frugivores for large-seeded plants, this study focused on seed dispersal systems in Madagascar, where the frugivorous guild is depauperate of large avian and mammalian seed dispersers 43 , 44 .", "role": "user" }, { "content": "Unchecked hunting and environmental degradation in tropical forests, which previous studies have correlated with the reduction of large animals in this biome, may impede the generational renewal of large fruit and seed-producing plant species. Such degradation takes place as scientists are still figuring out how large animals contribute to plant reproductive strategies. Now, a team of researchers at Kyoto University has found that the brown lemur is northwestern Madagascar's single largest fruit-eating animal, swallowing fruit and dispersing seeds. \"From our day and night observations of the Eulemur fulvus, the brown lemur fed on the fruit of two species of large trees in the tropical dry forests of Ankarafantsika National Park,\" explains Hiroki Sato of the Graduate School of Asian and African Area Studies. Due to Madagascar's isolation since the Cretaceous period, the island is devoid of the large fruit-eating birds and mammals that inhabit other landmasses, except for relatively smaller Lemuridae primates. Weighing two to three kilograms, the largest frugivorous lemurs in the study are credited with the renewal of large-fruit plants, whose seeds measure one centimeter or more in diameter. (a) The common brown lemur (Eulemur fulvus) feeding in a fruiting canopy of Astrotrichilia asterotricha (b) Fruits and seeds of Astrotrichilia asterotricha. (c) Seedling of Astrotrichilia asterotricha. (d) Fruits of Abrahamia deflexa. (e) Seedling of Abrahamia deflexa. Credit: KyotoU/Hiroki Sato These primates have been observed to swallow fruit whole, while repeatedly visiting the fruit-bearing Astrotrichilia asterotricha during the dry season when the diversity of fruiting species is low. Sato's team followed the process from seed germination to survival for two years to elucidate the plants' lemur-assisted reproductive strategies. Large trees with high fruit yields had higher fruit removal rates due to repeated lemur visits: as much as 59% in the case of A asteroticha. Through lemur seed dispersal, 1.5% of the seeds produced by A asterotricha and 6.5% by its endangered counterpart, Abrahamia deflexa, spouted seedlings during the first rainy season. Additionally, lemur-dispersed seeds may have a greater chance of survival when carried far from the mother tree to areas of abundant sunlight and fewer predators. In contrast, seeds that fall under the mother tree are most likely to be eaten by rodents and insects. Seedling of Astrotrichilia asterotricha. Credit: KyotoU/Hiroki Sato \"The combination of animal behavioral strategies and the functional traits of seeds and seedlings led us to a new understanding of seed dispersal and the diversity of forest regeneration,\" Sato says. \"By contributing to this regeneration of tropical forests, the endangered frugivore is also helping to maintainbiodiversity. Our study demonstrates the importance of intact plant-animal interaction in the context of maintaining healthy ecosystems.\" The study is published in the journal 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 How do large-bodied frugivores contribute to seed dispersal of large-diaspore plants? This study examined seed dispersal effectiveness for two large-diaspore tree species, Astrotrichilia asterotricha ( AA ) and Abrahamia deflexa ( AD ), in a Madagascan forest. I evaluated fruit removal rates through focal tree observations and factors affecting seedling recruitment up to the 2-year-old seedling stage. I confirmed brown lemur ( Eulemur fulvus ) as the sole disperser, removing 58.8% and 26.0% of fruits produced by AA and AD . Brown lemurs frequently visited large-crowned AA trees with high density of fallen fruits and more adjacent fruiting trees during seasons with low fruit diversity. Most AA seedlings were removed by predators, although canopy openness slightly improved seedling establishment. Although AD seeds were severely attacked by predators under mother trees, the seedlings survived under dispersal conditions distant from the mother trees, and with low density of diaspores. AD had a higher cumulative probability from fruit removal to seedling recruitment (6.5%) than AA (1.5%) in the first rainy season. This study clarifies the significance of seed dispersal to tree recruitment strategies, which vary among different combinations of tree species and large frugivores, i.e. quantitative dispersal to reach suitable microhabitats, and qualitative dispersal to escape from dangerous zones near mother trees. Introduction Seed dispersal represents a plant strategy to enhance reproductive success, and recruitment patterns presumably influence population dynamics and biodiversity at the community level 1 , 2 . Seed dispersal by animals has been studied in detail in tropical forests, because 50–90% of plant species in these ecosystems are endozoochorous 1 , 3 . The roles of seed dispersal agents have been evaluated systematically in accordance with the concept of seed disperser effectiveness (SDE), expressed as the product of quantitative and qualitative components, i.e. the number of seeds dispersed from fruiting mother plants and the probability of seed/seedling survival and recruitment as new adults, respectively 4 . The SDE has mostly been evaluated separately for quantitative component in the dispersal phase from fruit production to seed dispersal and qualitative component in the post-dispersal phase from seed deposition to new recruitment as surviving seedlings 2 , 5 , 6 . However, the definition of SDE has been broadened to “seed dispersal effectiveness”, emphasizing the need to evaluate the overall effectiveness of the full process of plant regeneration from seed dispersal to seedling establishment and survival 7 . As such, recent studies have comprehensively evaluated SDE by incorporating both the quantitative and qualitative components 8 , 9 , 10 , 11 , 12 . During the dispersal phase, the quantitative component of SDE has mainly been evaluated by observing fruit removal from focal plants by animals 13 , 14 , 15 . To gain an understanding of the mechanisms of successful fruit removal, researchers have examined intrinsic (plant size, fruit density, pulp ratio per fruit, and so forth) and extrinsic factors (fruiting of neighbouring trees, fruit availability of the forest, and so forth) 16 . Examination of the feeding strategies of frugivores has indicated that some birds visit trees with high pulp ratio per fruit 14 , and that primates and birds remove more fruits from trees with larger crop sizes 14 , 17 , 18 , 19 . As the main component of quantitative effectiveness, the relative quantity of fruit removal has been mostly evaluated by comparisons among seed disperser assemblages 15 , 20 . However, to evaluate dispersal effectiveness rather than disperser effectiveness, it is necessary to evaluate the fruit removal rate of each targeted animal taxon in the amount of fruit production as an absolute quantitative assessment of SDE in the dispersal phase of focal plants 13 , 14 , 16 . During the post-dispersal phase, the probability of seedling recruitment, the primary qualitative component of SDE, has been evaluated by monitoring the fates of seeds or seedlings, which is influenced by predation, secondary dispersal, pathogen disease, and stress among other environmental factors 21 , 22 , 23 , 24 . Such monitoring has indicated high mortality rates of seeds/seedlings at sites with high seed densities and close to conspecific fruiting trees, known as the Janzen-Connell effect 23 , 25 , 26 , 27 , 28 . Monitoring studies have also reported high survival rates and/or high growth rates in open-canopy microhabitats 21 , 23 and high survival rates via secondary dispersal 24 , 29 , 30 . Some studies that have evaluated SDE by multiplying the quantitative and qualitative components report that the initial effects of fruit removal by frugivores during the dispersal phase are often hindered by high and heterogeneous mortality 13 , 31 , 32 , 33 , whereas others have detected effects of frugivores on seedling recruitment patterns 34 , 35 . Thus, further study is required for a more holistic understanding of SDE. In recent years, low densities of seedlings/saplings of large-seeded plants and aggregated distribution around mother trees were found in empty and half-empty forests following the disappearance or decrease in number of large frugivores 36 , 37 , 38 , 39 . These findings suggest that in species-depauperate networks formed by strong mutualism between large-seeded plants and large-bodied frugivores, a small number of key frugivores have a large SDE and provide robust connectivity between the dispersal and post-dispersal phases. This hypothesis was recently tested by evaluating the SDE of primates, bears, and elephants for large-seeded plants growing in a seasonal evergreen forest in Thailand 8 , 10 , 12 . However, such studies have only reported on a limited number of taxonomic groups and involved few study sites. Furthermore, since the concept of attracting and introducing frugivores as effective restoration agents for reforestation has been proposed 40 , 41 , 42 , to understand SDE of large frugivores is also an important issue in conservation biology. To examine the SDE of large frugivores for large-seeded plants, this study focused on seed dispersal systems in Madagascar, where the frugivorous guild is depauperate of large avian and mammalian seed dispersers 43 , 44 .<|im_end|> <|im_start|>assistant Unchecked hunting and environmental degradation in tropical forests, which previous studies have correlated with the reduction of large animals in this biome, may impede the generational renewal of large fruit and seed-producing plant species. Such degradation takes place as scientists are still figuring out how large animals contribute to plant reproductive strategies. Now, a team of researchers at Kyoto University has found that the brown lemur is northwestern Madagascar's single largest fruit-eating animal, swallowing fruit and dispersing seeds. "From our day and night observations of the Eulemur fulvus, the brown lemur fed on the fruit of two species of large trees in the tropical dry forests of Ankarafantsika National Park," explains Hiroki Sato of the Graduate School of Asian and African Area Studies. Due to Madagascar's isolation since the Cretaceous period, the island is devoid of the large fruit-eating birds and mammals that inhabit other landmasses, except for relatively smaller Lemuridae primates. Weighing two to three kilograms, the largest frugivorous lemurs in the study are credited with the renewal of large-fruit plants, whose seeds measure one centimeter or more in diameter. (a) The common brown lemur (Eulemur fulvus) feeding in a fruiting canopy of Astrotrichilia asterotricha (b) Fruits and seeds of Astrotrichilia asterotricha. (c) Seedling of Astrotrichilia asterotricha. (d) Fruits of Abrahamia deflexa. (e) Seedling of Abrahamia deflexa. Credit: KyotoU/Hiroki Sato These primates have been observed to swallow fruit whole, while repeatedly visiting the fruit-bearing Astrotrichilia asterotricha during the dry season when the diversity of fruiting species is low. Sato's team followed the process from seed germination to survival for two years to elucidate the plants' lemur-assisted reproductive strategies. Large trees with high fruit yields had higher fruit removal rates due to repeated lemur visits: as much as 59% in the case of A asteroticha. Through lemur seed dispersal, 1.5% of the seeds produced by A asterotricha and 6.5% by its endangered counterpart, Abrahamia deflexa, spouted seedlings during the first rainy season. Additionally, lemur-dispersed seeds may have a greater chance of survival when carried far from the mother tree to areas of abundant sunlight and fewer predators. In contrast, seeds that fall under the mother tree are most likely to be eaten by rodents and insects. Seedling of Astrotrichilia asterotricha. Credit: KyotoU/Hiroki Sato "The combination of animal behavioral strategies and the functional traits of seeds and seedlings led us to a new understanding of seed dispersal and the diversity of forest regeneration," Sato says. "By contributing to this regeneration of tropical forests, the endangered frugivore is also helping to maintainbiodiversity. Our study demonstrates the importance of intact plant-animal interaction in the context of maintaining healthy ecosystems." The study is published in the journal Scientific Reports. <|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 Spin-orbit interactions (SOIs) endow light with intriguing properties and applications such as photonic spin-Hall effects and spin-dependent vortex generations. However, it is counterintuitive that SOIs can exist for sound, which is a longitudinal wave that carries no intrinsic spin. Here, we theoretically and experimentally demonstrate that airborne sound can possess artificial transversality in an acoustic micropolar metamaterial and thus carry both spin and orbital angular momentum. This enables the realization of acoustic SOIs with rich phenomena beyond those in conventional acoustic systems. We demonstrate that acoustic activity of the metamaterial can induce coupling between the spin and linear crystal momentum k , which leads to negative refraction of the transverse sound. In addition, we show that the scattering of the transverse sound by a dipole particle can generate spin-dependent acoustic vortices via the geometric phase effect. The acoustic SOIs can provide new perspectives and functionalities for sound manipulations beyond the conventional scalar degree of freedom and may open an avenue to the development of spin-orbit acoustics. Introduction Spin and orbital angular momentum (OAM) are intrinsic properties of classical waves. Spin is associated with circular polarization (vector degrees of freedom) of waves and is characterized by the local rotation of a vector field. OAM originates from the spatial phase gradient (scalar degree of freedom) of waves and manifests as a helical wave front 1 . The couplings between spin and OAM, referred to as spin–orbit interactions (SOIs), can give rise to intriguing phenomena and applications in optics 2 , 3 , 4 , 5 , 6 , 7 , 8 , such as photonic spin-Hall effect 9 , 10 , 11 and spin-dependent vortex generation 12 , 13 . SOIs are unique to transverse waves such as light and are absent for longitudinal waves. This is because although longitudinal waves such as airborne sound can carry OAM 14 , 15 , 16 , 17 , 18 , they are spin-0 in nature. Recent studies show that an engineered sound field can possess a locally rotational velocity field v that may be regarded as acoustic spin 19 , 20 , 21 , similar to electric spin deriving from the local rotation of electric field. Such an acoustic spin can emerge locally in nonuniform acoustic fields 20 , 21 and has recently been observed in experiments 19 , 22 . In a homogenous medium, however, the spatial integration of acoustic spin density for a localized wave must vanish, in agreement with its spin-0 nature 20 . Despite this discovery of acoustic spin, SOIs remain beyond reach in sound, a fact that mainly owes to the lack of degrees of freedom. In other words, sound is characterized by a scalar pressure field p and a vector velocity field v , whereas light is characterized by two vector fields E and H . In this work, we show that airborne sound can behave as a transverse wave with well-defined polarization in an acoustic metamaterial that goes beyond the Cauchy elasticity and follows a micropolar elasticity theory 23 . Unlike previous spin-sustaining acoustic fields 19 , 20 , 22 , the transverse sound is spin-1 in nature and carries the properties of elastic waves. It is characterized by two types of vector-field degrees of freedom, i.e., a velocity field and a microrotation field. The acoustic activity of the metamaterial can induce coupling between the velocity and microrotation fields, which can be considered an analog of chirality in electromagnetism (i.e., optical activity). Such a material property has recently been realized in elastic wave systems 24 , 25 , 26 , 27 but is so far missing in acoustic wave systems. We theoretically and experimentally demonstrate two types of acoustic SOIs in momentum space and in real space, respectively. In the momentum space, the acoustic activity induces the coupling between spin and linear crystal momentum k , and enables the chirality-induced negative refraction, which was previously possible only in optical metamaterials 28 , 29 . In the real space, scattering of the circularly polarized transverse sound by a dipole particle can generate a sound vortex with a topological charge determined by the acoustic spin. Results Transverse sound The longitudinal nature of airborne sound ( \${{{{{\\boldsymbol{\\nabla }}}}}}\\times {{{{{\\bf{v}}}}}}=0\$ ) dictates that the velocity field v aligns with the direction of wave vector k in general. However, this is not necessarily true when sound is confined in a closed space. Consider a one-dimensional (1D) lattice stacked along the z axis with a unit cell shown in Fig. 1a . The unit cell consists of a cylindrical resonator with eight internal blades segmenting the air to achieve subwavelength resonance, as indicated by the blue arrows. The resonators are sequentially connected by four tubes. All solid–air interfaces are regarded as sound-hard boundaries. The resonator supports two degenerate and orthogonal dipole resonances with pressure eigenfields shown in Fig. 1b . The positive and negative pressure (indicated by the red and blue colors, respectively) induces an in-plane velocity field that is perpendicular to the propagating direction of sound (i.e., z axis). This corresponds to the oscillating dipole moments \${{{{{{\\bf{p}}}}}}}_{x}\$ and \${{{{{{\\bf{p}}}}}}}_{y}\$ , where the positive (negative) charge corresponds to the positive (negative) pressure and the yellow arrow denotes the velocity field. Next, we break the spatial inversion symmetry by twisting the resonator geometry with respect to z axis, as shown in Fig. 1c . The degeneracy of \${{{{{{\\bf{p}}}}}}}_{x}\$ and \${{{{{{\\bf{p}}}}}}}_{y}\$ is removed, and the resonator supports two chiral eigenmodes \${{{{{{\\bf{p}}}}}}}_{x}-i{{{{{{\\bf{p}}}}}}}_{y}\$ and \${{{{{{\\bf{p}}}}}}}_{x}+i{{{{{{\\bf{p}}}}}}}_{y}\$ , corresponding to a left-handed circularly polarized (LCP) dipole and a right-handed circularly polarized (RCP) dipole, respectively, as shown in Fig. 1d . Thus, the collective excitations of the acoustic dipoles in Fig. 1b, d will give rise to linearly polarized and circularly polarized transverse sounds propagating in the z direction, respectively. Fig. 1: Eigenmodes of the 1D acoustic lattices. a The unit cell of the achiral lattice. The arrows show the flow of air inside the resonator. b The pressure eigenfields of the two transverse dipole modes. The velocity is", "role": "user" }, { "content": "Can you imagine sound traveling in the same way as light does? A research team at City University of Hong Kong (CityU) has discovered a new type of sound wave: The airborne sound wave vibrates transversely and carries both spin and orbital angular momentum like light does. The findings shattered scientists' previous beliefs about the sound wave, opening an avenue to the development of novel applications in acoustic communications, acoustic sensing and imaging. The research was initiated and co-led by Dr. Shubo Wang, Assistant Professor in the Department of Physics at CityU, and conducted in collaboration with scientists from Hong Kong Baptist University (HKBU) and the Hong Kong University of Science and Technology (HKUST). It was published in Nature Communications, titled \"Spin-orbit interactions of transverse sound.\" Beyond the conventional understanding of sound wave The physics textbooks tell us there are two kinds of waves. In transverse waves like light, the vibrations are perpendicular to the direction of wave propagation. In longitudinal waves like sound, the vibrations are parallel to the direction of wave propagation. But the latest discovery by scientists from CityU changes this understanding of sound waves. \"If you speak to a physicist about airborne transverse sound, s/he would think you are a layman without training in university physics because textbooks say that airborne sound (i.e., sound propagating in the air) is a longitudinal wave,\" said Dr. Wang. \"While the airborne sound is a longitudinal wave in usual cases, we demonstrated for the first time that it can be a transverse wave under certain conditions. And we investigated its spin-orbit interactions (an important property only exists in transverse waves), i.e. the coupling between two types of angular momentum. The finding provides new degrees of freedom for sound manipulations.\" The absence of shear force in the air, or fluids, is the reason why sound is a longitudinal wave, Dr. Wang explained. He had been exploring whether it is possible to realize transverse sound, which requires shear force. Then he conceived the idea that synthetic shear force may arise if the air is discretized into \"meta-atoms,\" i.e., volumetric air confined in small resonators with size much smaller than the wavelength. The collective motion of these air \"meta-atoms\" can give rise to a transverse sound on the macroscopic scale. Negative refraction induced by the spin-orbit interaction in momentum space. Credit: S. Wang et al. DOI: 10.1038/s41467-021-26375-9 Conception and realization of 'micropolar metamaterial' He ingeniously designed a type of artificial material called \"micropolar metamaterial\" to implement this idea, which appears like a complex network of resonators. Air is confined inside these mutually connected resonators, forming the \"meta-atoms.\" The metamaterial is hard enough so that only the air inside can vibrate and support sound propagation. The theoretical calculations showed that the collective motion of these air \"meta-atoms\" indeed produces the shear force, which gives rise to the transverse sound with spin-orbit interactions inside this metamaterial. This theory was verified by experiments conducted by Dr. Ma Guancong's group in HKBU. Moreover, the research team discovered that air behaves like an elastic material inside the micropolar metamaterial and thus supports transverse sound with both spin and orbital angular momentum. Using this metamaterial, they demonstrated two types of spin-orbit interactions of sound for the first time. One is the momentum-space spin-orbit interaction, which gives rise to negative refraction of the transverse sound, meaning that sound bends in the opposite directions when passing through an interface. Another one is the real-space spin-orbit interaction, which generates sound vortices under the excitation of the transverse sound. The findings demonstrated that airborne sound, or sound in fluids, can be a transverse wave and carry full vector properties such as spin angular momentum the same as light does. It provides new perspectives and functionalities for sound manipulations beyond the conventional scalar degree of freedom. \"This is just a precursor. We anticipate more explorations of the intriguing properties of the transverse sound,\" Dr. Wang said. \"In future, by manipulating these extra vector properties, scientists may be able to encode more data into the transverse sound to break the bottleneck of traditional acoustic communication by normal sound waves.\" Sound vortex generation enabled by the spin-orbit interaction in real space. Credit: S. Wang et al. DOI: 10.1038/s41467-021-26375-9 The interaction of spin with orbital angular momentum enables unprecedented sound manipulations via its angular momentum. \"The discovery may open an avenue to the development of novel applications in acoustic communications, acoustic sensing and imaging,\" he added. Dr. Wang is the first author and the corresponding author of the paper. Dr. Ma is another corresponding author. Collaborators include Professor Li Jensen from The Hong Kong University of Science and Technology, Ms. Tong Qing, a Ph.D. student from CityU, and other researchers from HKBU. ", "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 Spin-orbit interactions (SOIs) endow light with intriguing properties and applications such as photonic spin-Hall effects and spin-dependent vortex generations. However, it is counterintuitive that SOIs can exist for sound, which is a longitudinal wave that carries no intrinsic spin. Here, we theoretically and experimentally demonstrate that airborne sound can possess artificial transversality in an acoustic micropolar metamaterial and thus carry both spin and orbital angular momentum. This enables the realization of acoustic SOIs with rich phenomena beyond those in conventional acoustic systems. We demonstrate that acoustic activity of the metamaterial can induce coupling between the spin and linear crystal momentum k , which leads to negative refraction of the transverse sound. In addition, we show that the scattering of the transverse sound by a dipole particle can generate spin-dependent acoustic vortices via the geometric phase effect. The acoustic SOIs can provide new perspectives and functionalities for sound manipulations beyond the conventional scalar degree of freedom and may open an avenue to the development of spin-orbit acoustics. Introduction Spin and orbital angular momentum (OAM) are intrinsic properties of classical waves. Spin is associated with circular polarization (vector degrees of freedom) of waves and is characterized by the local rotation of a vector field. OAM originates from the spatial phase gradient (scalar degree of freedom) of waves and manifests as a helical wave front 1 . The couplings between spin and OAM, referred to as spin–orbit interactions (SOIs), can give rise to intriguing phenomena and applications in optics 2 , 3 , 4 , 5 , 6 , 7 , 8 , such as photonic spin-Hall effect 9 , 10 , 11 and spin-dependent vortex generation 12 , 13 . SOIs are unique to transverse waves such as light and are absent for longitudinal waves. This is because although longitudinal waves such as airborne sound can carry OAM 14 , 15 , 16 , 17 , 18 , they are spin-0 in nature. Recent studies show that an engineered sound field can possess a locally rotational velocity field v that may be regarded as acoustic spin 19 , 20 , 21 , similar to electric spin deriving from the local rotation of electric field. Such an acoustic spin can emerge locally in nonuniform acoustic fields 20 , 21 and has recently been observed in experiments 19 , 22 . In a homogenous medium, however, the spatial integration of acoustic spin density for a localized wave must vanish, in agreement with its spin-0 nature 20 . Despite this discovery of acoustic spin, SOIs remain beyond reach in sound, a fact that mainly owes to the lack of degrees of freedom. In other words, sound is characterized by a scalar pressure field p and a vector velocity field v , whereas light is characterized by two vector fields E and H . In this work, we show that airborne sound can behave as a transverse wave with well-defined polarization in an acoustic metamaterial that goes beyond the Cauchy elasticity and follows a micropolar elasticity theory 23 . Unlike previous spin-sustaining acoustic fields 19 , 20 , 22 , the transverse sound is spin-1 in nature and carries the properties of elastic waves. It is characterized by two types of vector-field degrees of freedom, i.e., a velocity field and a microrotation field. The acoustic activity of the metamaterial can induce coupling between the velocity and microrotation fields, which can be considered an analog of chirality in electromagnetism (i.e., optical activity). Such a material property has recently been realized in elastic wave systems 24 , 25 , 26 , 27 but is so far missing in acoustic wave systems. We theoretically and experimentally demonstrate two types of acoustic SOIs in momentum space and in real space, respectively. In the momentum space, the acoustic activity induces the coupling between spin and linear crystal momentum k , and enables the chirality-induced negative refraction, which was previously possible only in optical metamaterials 28 , 29 . In the real space, scattering of the circularly polarized transverse sound by a dipole particle can generate a sound vortex with a topological charge determined by the acoustic spin. Results Transverse sound The longitudinal nature of airborne sound ( ${{{{{\boldsymbol{\nabla }}}}}}\times {{{{{\bf{v}}}}}}=0$ ) dictates that the velocity field v aligns with the direction of wave vector k in general. However, this is not necessarily true when sound is confined in a closed space. Consider a one-dimensional (1D) lattice stacked along the z axis with a unit cell shown in Fig. 1a . The unit cell consists of a cylindrical resonator with eight internal blades segmenting the air to achieve subwavelength resonance, as indicated by the blue arrows. The resonators are sequentially connected by four tubes. All solid–air interfaces are regarded as sound-hard boundaries. The resonator supports two degenerate and orthogonal dipole resonances with pressure eigenfields shown in Fig. 1b . The positive and negative pressure (indicated by the red and blue colors, respectively) induces an in-plane velocity field that is perpendicular to the propagating direction of sound (i.e., z axis). This corresponds to the oscillating dipole moments ${{{{{{\bf{p}}}}}}}_{x}$ and ${{{{{{\bf{p}}}}}}}_{y}$ , where the positive (negative) charge corresponds to the positive (negative) pressure and the yellow arrow denotes the velocity field. Next, we break the spatial inversion symmetry by twisting the resonator geometry with respect to z axis, as shown in Fig. 1c . The degeneracy of ${{{{{{\bf{p}}}}}}}_{x}$ and ${{{{{{\bf{p}}}}}}}_{y}$ is removed, and the resonator supports two chiral eigenmodes ${{{{{{\bf{p}}}}}}}_{x}-i{{{{{{\bf{p}}}}}}}_{y}$ and ${{{{{{\bf{p}}}}}}}_{x}+i{{{{{{\bf{p}}}}}}}_{y}$ , corresponding to a left-handed circularly polarized (LCP) dipole and a right-handed circularly polarized (RCP) dipole, respectively, as shown in Fig. 1d . Thus, the collective excitations of the acoustic dipoles in Fig. 1b, d will give rise to linearly polarized and circularly polarized transverse sounds propagating in the z direction, respectively. Fig. 1: Eigenmodes of the 1D acoustic lattices. a The unit cell of the achiral lattice. The arrows show the flow of air inside the resonator. b The pressure eigenfields of the two transverse dipole modes. The velocity is<|im_end|> <|im_start|>assistant Can you imagine sound traveling in the same way as light does? A research team at City University of Hong Kong (CityU) has discovered a new type of sound wave: The airborne sound wave vibrates transversely and carries both spin and orbital angular momentum like light does. The findings shattered scientists' previous beliefs about the sound wave, opening an avenue to the development of novel applications in acoustic communications, acoustic sensing and imaging. The research was initiated and co-led by Dr. Shubo Wang, Assistant Professor in the Department of Physics at CityU, and conducted in collaboration with scientists from Hong Kong Baptist University (HKBU) and the Hong Kong University of Science and Technology (HKUST). It was published in Nature Communications, titled "Spin-orbit interactions of transverse sound." Beyond the conventional understanding of sound wave The physics textbooks tell us there are two kinds of waves. In transverse waves like light, the vibrations are perpendicular to the direction of wave propagation. In longitudinal waves like sound, the vibrations are parallel to the direction of wave propagation. But the latest discovery by scientists from CityU changes this understanding of sound waves. "If you speak to a physicist about airborne transverse sound, s/he would think you are a layman without training in university physics because textbooks say that airborne sound (i.e., sound propagating in the air) is a longitudinal wave," said Dr. Wang. "While the airborne sound is a longitudinal wave in usual cases, we demonstrated for the first time that it can be a transverse wave under certain conditions. And we investigated its spin-orbit interactions (an important property only exists in transverse waves), i.e. the coupling between two types of angular momentum. The finding provides new degrees of freedom for sound manipulations." The absence of shear force in the air, or fluids, is the reason why sound is a longitudinal wave, Dr. Wang explained. He had been exploring whether it is possible to realize transverse sound, which requires shear force. Then he conceived the idea that synthetic shear force may arise if the air is discretized into "meta-atoms," i.e., volumetric air confined in small resonators with size much smaller than the wavelength. The collective motion of these air "meta-atoms" can give rise to a transverse sound on the macroscopic scale. Negative refraction induced by the spin-orbit interaction in momentum space. Credit: S. Wang et al. DOI: 10.1038/s41467-021-26375-9 Conception and realization of 'micropolar metamaterial' He ingeniously designed a type of artificial material called "micropolar metamaterial" to implement this idea, which appears like a complex network of resonators. Air is confined inside these mutually connected resonators, forming the "meta-atoms." The metamaterial is hard enough so that only the air inside can vibrate and support sound propagation. The theoretical calculations showed that the collective motion of these air "meta-atoms" indeed produces the shear force, which gives rise to the transverse sound with spin-orbit interactions inside this metamaterial. This theory was verified by experiments conducted by Dr. Ma Guancong's group in HKBU. Moreover, the research team discovered that air behaves like an elastic material inside the micropolar metamaterial and thus supports transverse sound with both spin and orbital angular momentum. Using this metamaterial, they demonstrated two types of spin-orbit interactions of sound for the first time. One is the momentum-space spin-orbit interaction, which gives rise to negative refraction of the transverse sound, meaning that sound bends in the opposite directions when passing through an interface. Another one is the real-space spin-orbit interaction, which generates sound vortices under the excitation of the transverse sound. The findings demonstrated that airborne sound, or sound in fluids, can be a transverse wave and carry full vector properties such as spin angular momentum the same as light does. It provides new perspectives and functionalities for sound manipulations beyond the conventional scalar degree of freedom. "This is just a precursor. We anticipate more explorations of the intriguing properties of the transverse sound," Dr. Wang said. "In future, by manipulating these extra vector properties, scientists may be able to encode more data into the transverse sound to break the bottleneck of traditional acoustic communication by normal sound waves." Sound vortex generation enabled by the spin-orbit interaction in real space. Credit: S. Wang et al. DOI: 10.1038/s41467-021-26375-9 The interaction of spin with orbital angular momentum enables unprecedented sound manipulations via its angular momentum. "The discovery may open an avenue to the development of novel applications in acoustic communications, acoustic sensing and imaging," he added. Dr. Wang is the first author and the corresponding author of the paper. Dr. Ma is another corresponding author. Collaborators include Professor Li Jensen from The Hong Kong University of Science and Technology, Ms. Tong Qing, a Ph.D. student from CityU, and other researchers from HKBU. <|im_end|>

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13, 29346, 13, 330, 8142, 279, 70863, 5222, 374, 264, 68102, 12330, 304, 13783, 5157, 11, 584, 21091, 369, 279, 1176, 892, 430, 433, 649, 387, 264, 1380, 4550, 12330, 1234, 3738, 4787, 13, 1628, 584, 27313, 1202, 12903, 27609, 4590, 22639, 320, 276, 3062, 3424, 1193, 6866, 304, 1380, 4550, 17301, 705, 602, 1770, 13, 279, 59086, 1990, 1403, 4595, 315, 20932, 24151, 13, 578, 9455, 5825, 502, 12628, 315, 11542, 369, 5222, 14951, 7607, 1210, 578, 19821, 315, 65344, 5457, 304, 279, 3805, 11, 477, 56406, 11, 374, 279, 2944, 3249, 5222, 374, 264, 68102, 12330, 11, 2999, 13, 29346, 11497, 13, 1283, 1047, 1027, 24919, 3508, 433, 374, 3284, 311, 13383, 1380, 4550, 5222, 11, 902, 7612, 65344, 5457, 13, 5112, 568, 50178, 279, 4623, 430, 28367, 65344, 5457, 1253, 31889, 422, 279, 3805, 374, 28558, 1534, 1139, 330, 5607, 29883, 7085, 1359, 602, 1770, 2637, 63920, 16743, 3805, 45408, 304, 2678, 29280, 3046, 449, 1404, 1790, 9333, 1109, 279, 46406, 13, 578, 22498, 11633, 315, 1521, 3805, 330, 5607, 29883, 7085, 1, 649, 3041, 10205, 311, 264, 1380, 4550, 5222, 389, 279, 18563, 58510, 5569, 13, 51957, 2098, 16597, 36572, 555, 279, 12903, 27609, 4590, 16628, 304, 24151, 3634, 13, 16666, 25, 328, 13, 29346, 1880, 453, 13, 59670, 25, 220, 605, 13, 6889, 23, 2754, 17448, 3080, 12, 11592, 12, 15666, 2075, 12, 24, 1221, 1010, 323, 49803, 315, 364, 21914, 897, 7569, 88848, 2229, 6, 1283, 46492, 13610, 6319, 264, 955, 315, 21075, 3769, 2663, 330, 21914, 897, 7569, 88848, 2229, 1, 311, 4305, 420, 4623, 11, 902, 8111, 1093, 264, 6485, 4009, 315, 29280, 3046, 13, 6690, 374, 45408, 4871, 1521, 53579, 8599, 29280, 3046, 11, 30164, 279, 330, 5607, 29883, 7085, 1210, 578, 88848, 2229, 374, 2653, 3403, 779, 430, 1193, 279, 3805, 4871, 649, 348, 44192, 323, 1862, 5222, 54743, 13, 578, 32887, 29217, 8710, 430, 279, 22498, 11633, 315, 1521, 3805, 330, 5607, 29883, 7085, 1, 13118, 19159, 279, 65344, 5457, 11, 902, 6835, 10205, 311, 279, 1380, 4550, 5222, 449, 12903, 27609, 4590, 22639, 4871, 420, 88848, 2229, 13, 1115, 10334, 574, 24884, 555, 21896, 13375, 555, 2999, 13, 11583, 4673, 276, 444, 70, 596, 1912, 304, 43317, 15275, 13, 23674, 11, 279, 3495, 2128, 11352, 430, 3805, 74157, 1093, 459, 36573, 3769, 4871, 279, 19748, 897, 7569, 88848, 2229, 323, 8617, 11815, 1380, 4550, 5222, 449, 2225, 12903, 323, 65691, 20932, 24151, 13, 12362, 420, 88848, 2229, 11, 814, 21091, 1403, 4595, 315, 12903, 27609, 4590, 22639, 315, 5222, 369, 279, 1176, 892, 13, 3861, 374, 279, 24151, 29047, 12903, 27609, 4590, 16628, 11, 902, 6835, 10205, 311, 8389, 2098, 16597, 315, 279, 1380, 4550, 5222, 11, 7438, 430, 5222, 93897, 304, 279, 14329, 18445, 994, 12579, 1555, 459, 3834, 13, 13596, 832, 374, 279, 1972, 29047, 12903, 27609, 4590, 16628, 11, 902, 27983, 5222, 348, 371, 1238, 1234, 279, 3521, 7709, 315, 279, 1380, 4550, 5222, 13, 578, 14955, 21091, 430, 70863, 5222, 11, 477, 5222, 304, 56406, 11, 649, 387, 264, 1380, 4550, 12330, 323, 6920, 2539, 4724, 6012, 1778, 439, 12903, 20932, 24151, 279, 1890, 439, 3177, 1587, 13, 1102, 5825, 502, 39555, 323, 93180, 369, 5222, 14951, 7607, 7953, 279, 21349, 17722, 8547, 315, 11542, 13, 330, 2028, 374, 1120, 264, 71261, 13, 1226, 48248, 810, 48539, 811, 315, 279, 41765, 6012, 315, 279, 1380, 4550, 5222, 1359, 2999, 13, 29346, 1071, 13, 330, 644, 3938, 11, 555, 63614, 1521, 5066, 4724, 6012, 11, 14248, 1253, 387, 3025, 311, 16559, 810, 828, 1139, 279, 1380, 4550, 5222, 311, 1464, 279, 88938, 315, 8776, 45166, 10758, 555, 4725, 5222, 17301, 1210, 14936, 87627, 9659, 9147, 555, 279, 12903, 27609, 4590, 16628, 304, 1972, 3634, 13, 16666, 25, 328, 13, 29346, 1880, 453, 13, 59670, 25, 220, 605, 13, 6889, 23, 2754, 17448, 3080, 12, 11592, 12, 15666, 2075, 12, 24, 578, 16628, 315, 12903, 449, 65691, 20932, 24151, 20682, 31069, 5222, 14951, 7607, 4669, 1202, 20932, 24151, 13, 330, 791, 18841, 1253, 1825, 459, 62803, 311, 279, 4500, 315, 11775, 8522, 304, 45166, 17320, 11, 45166, 60199, 323, 32758, 1359, 568, 3779, 13, 2999, 13, 29346, 374, 279, 1176, 3229, 323, 279, 12435, 3229, 315, 279, 5684, 13, 2999, 13, 11583, 374, 2500, 12435, 3229, 13, 49681, 3046, 2997, 17054, 14851, 65109, 505, 578, 19730, 18711, 3907, 315, 10170, 323, 12053, 11, 16450, 13, 51491, 63012, 11, 264, 2405, 920, 13, 5575, 505, 4409, 52, 11, 323, 1023, 12074, 505, 43317, 15275, 13, 220, 128257, 198 ]

2,493

[ { "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 Shape-morphing systems can be found in many areas, including smart textiles 1 , autonomous robotics 2 , biomedical devices 3 , drug delivery 4 and tissue engineering 5 . The natural analogues of such systems are exemplified by nastic plant motions, where a variety of organs such as tendrils, bracts, leaves and flowers respond to environmental stimuli (such as humidity, light or touch) by varying internal turgor, which leads to dynamic conformations governed by the tissue composition and microstructural anisotropy of cell walls 6 , 7 , 8 , 9 , 10 . Inspired by these botanical systems, we printed composite hydrogel architectures that are encoded with localized, anisotropic swelling behaviour controlled by the alignment of cellulose fibrils along prescribed four-dimensional printing pathways. When combined with a minimal theoretical framework that allows us to solve the inverse problem of designing the alignment patterns for prescribed target shapes, we can programmably fabricate plant-inspired architectures that change shape on immersion in water, yielding complex three-dimensional morphologies. Main Plants exhibit hydration-trigged changes in their morphology due to differences in local swelling behaviour that arise from the directional orientation of stiff cellulose fibrils within plant cell walls 6 , 7 , 8 , 9 , 10 . Emerging pathways for mimicking these dynamic architectures incorporate materials that can respond to external stimuli, such as shape memory alloys 11 , 12 and swellable hydrogel composites 13 , 14 , and are assembled by methods such as four-dimensional (4D) printing 11 , 15 and self-folding origami 16 , 17 , 18 . For example, recent efforts to create plant-inspired, shape-changing structures 10 have employed differential swelling in isotropic or composite bilayers and hinges 8 , 13 , 14 , 16 . However, none of these approaches enable shape change using a single material patterned in a one-step process, nor do they utilize a predictive model capable of tackling both the forward and inverse design problems ( Supplementary Text and Supplementary Figs 1 and 2 ). Here, we develop a biomimetic hydrogel composite that can be 4D printed into programmable bilayer architectures patterned in space and time, which are encoded with localized swelling anisotropy that induces complex shape changes on immersion in water. Our hydrogel composite ink is composed of stiff cellulose fibrils embedded in a soft acrylamide matrix, which mimics the composition of plant cell walls. The composite architectures are printed using a viscoelastic ink that contains an aqueous solution of N , N -dimethylacrylamide (or N -isopropylacrylamide for reversible systems), photoinitiator, nanoclay, glucose oxidase, glucose, and nanofibrillated cellulose (NFC). The constituents serve different purposes: the clay particles are a rheological aid, inducing the desired viscoelastic behaviour required for direct ink writing 19 ( Supplementary Fig. 3 ); glucose oxidase and glucose minimize oxygen inhibition during the ultraviolet curing process by scavenging ambient oxygen 20 , thereby improving polymerization in the printed filamentary features ( ∼ 100 μm to 1 mm in diameter) to yield mechanically robust structures; the wood-derived cellulose fibrils, which bundle into microfibrils with high aspect ratio ( ∼ 100), serve as stiff fillers ( E > 100 GPa; ref. 21 ). After printing under ambient conditions, the acrylamide monomer is photopolymerized and physically crosslinked by the nanoclay particles, producing a biocompatible hydrogel matrix that swells readily in water 22 . (See Methods for further details.) The efficacy of our biomimetic 4D printing (bio-4DP) method relies on the ability to deterministically define the elastic and swelling anisotropies by local control of the orientation of cellulose fibrils within the hydrogel composite. During printing, these fibrils undergo shear-induced alignment 23 as the ink flows through the deposition nozzle 24 , which leads to printed filaments with anisotropic stiffness, and, hence, swelling behaviour in the longitudinal direction (along the filament length, as defined by the printing path) compared to the transverse direction ( Fig. 1a ). Significant cellulose fibril alignment is directly observed in the printed samples compared to isotropic cast sheets of the same material ( Fig. 1b–d ). Fourier analysis quantifies the relative alignment between cast and printed specimens, which indicates a clear directionality peak in the latter case ( Fig. 1e and Supplementary Fig. 4 ). Thus, the printed architectures exhibit a fourfold difference in longitudinal and transverse swelling strains of α ∥ ∼ 10% and α ⊥ ∼ 40%, respectively ( Fig. 1f, g ). Likewise, this signature of anisotropy is present in the elastic moduli, with longitudinal and transverse values of E ∥ ∼ 40 kPa and E ⊥ ∼ 20 kPa, respectively ( Supplementary Figs 5 and 6 ). The extent of shear-induced alignment, and, hence, the magnitude of the anisotropic swelling, depends on the nozzle diameter and printing speed. For a fixed printing speed, the shear forces that align the cellulose fibrils scale inversely with nozzle size, as reflected in the observed longitudinal and transverse swelling strains ( Fig. 1f ). Figure 1: Programming localized anisotropy via biomimetic 4D printing. One-step alignment of cellulose fibrils during hydrogel composite ink printing. a , Schematic of the shear-induced alignment of cellulose fibrils during direct ink writing and subsequent effects on anisotropic stiffness E and swelling strain α . b – d , Direct imaging of cellulose fibrils (stained blue) in isotropic (cast) ( b ), unidirectional (printed) ( c ) and patterned (printed) ( d ) samples (scale bar, 200 μm). e , Applying Fourier analysis to NFC-stained images allows quantification of directionality: printed unidirectional samples exhibit a clear peak at 0°, corresponding to the print direction, whereas isotropic samples show no clear directional peaks. f , Effect of nozzle diameter on transverse and longitudinal swelling behaviour of printed hydrogel composites. g , Swelling strain of cast and printed samples (nozzle diameter = 510 μm). All error bars represent the standard deviation ( n = 6). Full size image Harnessing anisotropic swelling allows precise control over the curvature in bilayer structures 9 , 25 . Quantifying this requires a mathematical model for the mechanics of anisotropic plates and shells, which", "role": "user" }, { "content": "A team of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Harvard John A. Paulson School of Engineering and Applied Sciences has evolved their microscale 3D printing technology to the fourth dimension, time. Inspired by natural structures like plants, which respond and change their form over time according to environmental stimuli, the team has unveiled 4D-printed hydrogel composite structures that change shape upon immersion in water. \"This work represents an elegant advance in programmable materials assembly, made possible by a multidisciplinary approach,\" said Jennifer Lewis, Sc.D., senior author on the new study. \"We have now gone beyond integrating form and function to create transformable architectures.\" Lewis is a Core Faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Hansjörg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Science (SEAS). L. Mahadevan, Ph.D., a Wyss Core Faculty member as well as the Lola England de Valpine Professor of Applied Mathematics, Professor of Organismic and Evolutionary Biology, and Professor of Physics at Harvard University and Harvard SEAS, is a co-author on the study. Their team also includes co-author, Ralph Nuzzo, Ph.D., the G.L. Clark Professor of Chemistry at the University of Illinois at Urbana-Champaign. In nature, flowers and plants have tissue composition and microstructures that result in dynamic morphologies that change according to their environments. Mimicking the variety of shape changes undergone by plant organs such as tendrils, leaves, and flowers in response to environmental stimuli like humidity and/or temperature, the 4D-printed hydrogel composites developed by Lewis and her team are programmed to contain precise, localized swelling behaviors. Importantly, the hydrogel composites contain cellulose fibrils that are derived from wood and are similar to the microstructures that enable shape changes in plants. Reported on January 25 in a new study in Nature Materials, the 4D printing advance combined materials science and mathematics through the involvement of the study's co-lead authors A. Sydney Gladman, who is a graduate research assistant advised by Lewis and specializing in the printing of polymers and composites at the Wyss Institute and SEAS, and Elisabetta Matsumoto, Ph.D., who is a postdoctoral fellow at the Wyss and SEAS advised by Mahadevan and specializing in condensed matter and material physics. By aligning cellulose fibrils during printing, the hydrogel composite ink is encoded with anisotropic swelling and stiffness, which can be patterned to produce intricate shape changes. The anisotropic nature of the cellulose fibrils gives rise to varied directional properties that can be predicted and controlled. Just like wood, which can be split easier along the grain rather than across it. Likewise, when immersed in water, the hydrogel-cellulose fibril ink undergoes differential swelling behavior along and orthogonal to the printing path. Combined with a proprietary mathematical model developed by the team that predicts how a 4D object must be printed to achieve prescribed transformable shapes, the new method opens up many new and exciting potential applications for 4D printing technology including smart textiles, soft electronics, biomedical devices, and tissue engineering. \"Using one composite ink printed in a single step, we can achieve shape-changing hydrogel geometries containing more complexity than any other technique, and we can do so simply by modifying the print path,\" said Gladman. \"What's more, we can interchange different materials to tune for properties such as conductivity or biocompatibility.\" The composite ink that the team uses flows like liquid through the printhead, yet rapidly solidifies once printed. A variety of hydrogel materials can be used interchangeably resulting in different stimuli-responsive behavior, while the cellulose fibrils can be replaced with other anisotropic fillers of choice, including conductive fillers. \"Our mathematical model prescribes the printing pathways required to achieve the desired shape-transforming response,\" said Matsumoto. \"We can control the curvature both discretely and continuously using our entirely tunable and programmable method.\" Specifically, the mathematical modeling solves the \"inverse problem\", which is the challenge of being able to predict what the printing toolpath must be in order to encode swelling behaviors toward achieving a specific desired target shape. \"It is wonderful to be able to design and realize, in an engineered structure, some of nature's solutions,\" said Mahadevan, who has studied phenomena such as how botanical tendrils coil, how flowers bloom, and how pine cones open and close. \"By solving the inverse problem, we are now able to reverse-engineer the problem and determine how to vary local inhomogeneity, i.e. the spacing between the printed ink filaments, and the anisotropy, i.e. the direction of these filaments, to control the spatiotemporal response of these shapeshifting sheets. \" \"What's remarkable about this 4D printing advance made by Jennifer and her team is that it enables the design of almost any arbitrary, transformable shape from a wide range of available materials with different properties and potential applications, truly establishing a new platform for printing self-assembling, dynamic microscale structures that could be applied to a broad range of industrial and medical applications,\" said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children's Hospital and Professor of Bioengineering at Harvard SEAS. ", "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 Shape-morphing systems can be found in many areas, including smart textiles 1 , autonomous robotics 2 , biomedical devices 3 , drug delivery 4 and tissue engineering 5 . The natural analogues of such systems are exemplified by nastic plant motions, where a variety of organs such as tendrils, bracts, leaves and flowers respond to environmental stimuli (such as humidity, light or touch) by varying internal turgor, which leads to dynamic conformations governed by the tissue composition and microstructural anisotropy of cell walls 6 , 7 , 8 , 9 , 10 . Inspired by these botanical systems, we printed composite hydrogel architectures that are encoded with localized, anisotropic swelling behaviour controlled by the alignment of cellulose fibrils along prescribed four-dimensional printing pathways. When combined with a minimal theoretical framework that allows us to solve the inverse problem of designing the alignment patterns for prescribed target shapes, we can programmably fabricate plant-inspired architectures that change shape on immersion in water, yielding complex three-dimensional morphologies. Main Plants exhibit hydration-trigged changes in their morphology due to differences in local swelling behaviour that arise from the directional orientation of stiff cellulose fibrils within plant cell walls 6 , 7 , 8 , 9 , 10 . Emerging pathways for mimicking these dynamic architectures incorporate materials that can respond to external stimuli, such as shape memory alloys 11 , 12 and swellable hydrogel composites 13 , 14 , and are assembled by methods such as four-dimensional (4D) printing 11 , 15 and self-folding origami 16 , 17 , 18 . For example, recent efforts to create plant-inspired, shape-changing structures 10 have employed differential swelling in isotropic or composite bilayers and hinges 8 , 13 , 14 , 16 . However, none of these approaches enable shape change using a single material patterned in a one-step process, nor do they utilize a predictive model capable of tackling both the forward and inverse design problems ( Supplementary Text and Supplementary Figs 1 and 2 ). Here, we develop a biomimetic hydrogel composite that can be 4D printed into programmable bilayer architectures patterned in space and time, which are encoded with localized swelling anisotropy that induces complex shape changes on immersion in water. Our hydrogel composite ink is composed of stiff cellulose fibrils embedded in a soft acrylamide matrix, which mimics the composition of plant cell walls. The composite architectures are printed using a viscoelastic ink that contains an aqueous solution of N , N -dimethylacrylamide (or N -isopropylacrylamide for reversible systems), photoinitiator, nanoclay, glucose oxidase, glucose, and nanofibrillated cellulose (NFC). The constituents serve different purposes: the clay particles are a rheological aid, inducing the desired viscoelastic behaviour required for direct ink writing 19 ( Supplementary Fig. 3 ); glucose oxidase and glucose minimize oxygen inhibition during the ultraviolet curing process by scavenging ambient oxygen 20 , thereby improving polymerization in the printed filamentary features ( ∼ 100 μm to 1 mm in diameter) to yield mechanically robust structures; the wood-derived cellulose fibrils, which bundle into microfibrils with high aspect ratio ( ∼ 100), serve as stiff fillers ( E > 100 GPa; ref. 21 ). After printing under ambient conditions, the acrylamide monomer is photopolymerized and physically crosslinked by the nanoclay particles, producing a biocompatible hydrogel matrix that swells readily in water 22 . (See Methods for further details.) The efficacy of our biomimetic 4D printing (bio-4DP) method relies on the ability to deterministically define the elastic and swelling anisotropies by local control of the orientation of cellulose fibrils within the hydrogel composite. During printing, these fibrils undergo shear-induced alignment 23 as the ink flows through the deposition nozzle 24 , which leads to printed filaments with anisotropic stiffness, and, hence, swelling behaviour in the longitudinal direction (along the filament length, as defined by the printing path) compared to the transverse direction ( Fig. 1a ). Significant cellulose fibril alignment is directly observed in the printed samples compared to isotropic cast sheets of the same material ( Fig. 1b–d ). Fourier analysis quantifies the relative alignment between cast and printed specimens, which indicates a clear directionality peak in the latter case ( Fig. 1e and Supplementary Fig. 4 ). Thus, the printed architectures exhibit a fourfold difference in longitudinal and transverse swelling strains of α ∥ ∼ 10% and α ⊥ ∼ 40%, respectively ( Fig. 1f, g ). Likewise, this signature of anisotropy is present in the elastic moduli, with longitudinal and transverse values of E ∥ ∼ 40 kPa and E ⊥ ∼ 20 kPa, respectively ( Supplementary Figs 5 and 6 ). The extent of shear-induced alignment, and, hence, the magnitude of the anisotropic swelling, depends on the nozzle diameter and printing speed. For a fixed printing speed, the shear forces that align the cellulose fibrils scale inversely with nozzle size, as reflected in the observed longitudinal and transverse swelling strains ( Fig. 1f ). Figure 1: Programming localized anisotropy via biomimetic 4D printing. One-step alignment of cellulose fibrils during hydrogel composite ink printing. a , Schematic of the shear-induced alignment of cellulose fibrils during direct ink writing and subsequent effects on anisotropic stiffness E and swelling strain α . b – d , Direct imaging of cellulose fibrils (stained blue) in isotropic (cast) ( b ), unidirectional (printed) ( c ) and patterned (printed) ( d ) samples (scale bar, 200 μm). e , Applying Fourier analysis to NFC-stained images allows quantification of directionality: printed unidirectional samples exhibit a clear peak at 0°, corresponding to the print direction, whereas isotropic samples show no clear directional peaks. f , Effect of nozzle diameter on transverse and longitudinal swelling behaviour of printed hydrogel composites. g , Swelling strain of cast and printed samples (nozzle diameter = 510 μm). All error bars represent the standard deviation ( n = 6). Full size image Harnessing anisotropic swelling allows precise control over the curvature in bilayer structures 9 , 25 . Quantifying this requires a mathematical model for the mechanics of anisotropic plates and shells, which<|im_end|> <|im_start|>assistant A team of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Harvard John A. Paulson School of Engineering and Applied Sciences has evolved their microscale 3D printing technology to the fourth dimension, time. Inspired by natural structures like plants, which respond and change their form over time according to environmental stimuli, the team has unveiled 4D-printed hydrogel composite structures that change shape upon immersion in water. "This work represents an elegant advance in programmable materials assembly, made possible by a multidisciplinary approach," said Jennifer Lewis, Sc.D., senior author on the new study. "We have now gone beyond integrating form and function to create transformable architectures." Lewis is a Core Faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Hansjörg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Science (SEAS). L. Mahadevan, Ph.D., a Wyss Core Faculty member as well as the Lola England de Valpine Professor of Applied Mathematics, Professor of Organismic and Evolutionary Biology, and Professor of Physics at Harvard University and Harvard SEAS, is a co-author on the study. Their team also includes co-author, Ralph Nuzzo, Ph.D., the G.L. Clark Professor of Chemistry at the University of Illinois at Urbana-Champaign. In nature, flowers and plants have tissue composition and microstructures that result in dynamic morphologies that change according to their environments. Mimicking the variety of shape changes undergone by plant organs such as tendrils, leaves, and flowers in response to environmental stimuli like humidity and/or temperature, the 4D-printed hydrogel composites developed by Lewis and her team are programmed to contain precise, localized swelling behaviors. Importantly, the hydrogel composites contain cellulose fibrils that are derived from wood and are similar to the microstructures that enable shape changes in plants. Reported on January 25 in a new study in Nature Materials, the 4D printing advance combined materials science and mathematics through the involvement of the study's co-lead authors A. Sydney Gladman, who is a graduate research assistant advised by Lewis and specializing in the printing of polymers and composites at the Wyss Institute and SEAS, and Elisabetta Matsumoto, Ph.D., who is a postdoctoral fellow at the Wyss and SEAS advised by Mahadevan and specializing in condensed matter and material physics. By aligning cellulose fibrils during printing, the hydrogel composite ink is encoded with anisotropic swelling and stiffness, which can be patterned to produce intricate shape changes. The anisotropic nature of the cellulose fibrils gives rise to varied directional properties that can be predicted and controlled. Just like wood, which can be split easier along the grain rather than across it. Likewise, when immersed in water, the hydrogel-cellulose fibril ink undergoes differential swelling behavior along and orthogonal to the printing path. Combined with a proprietary mathematical model developed by the team that predicts how a 4D object must be printed to achieve prescribed transformable shapes, the new method opens up many new and exciting potential applications for 4D printing technology including smart textiles, soft electronics, biomedical devices, and tissue engineering. "Using one composite ink printed in a single step, we can achieve shape-changing hydrogel geometries containing more complexity than any other technique, and we can do so simply by modifying the print path," said Gladman. "What's more, we can interchange different materials to tune for properties such as conductivity or biocompatibility." The composite ink that the team uses flows like liquid through the printhead, yet rapidly solidifies once printed. A variety of hydrogel materials can be used interchangeably resulting in different stimuli-responsive behavior, while the cellulose fibrils can be replaced with other anisotropic fillers of choice, including conductive fillers. "Our mathematical model prescribes the printing pathways required to achieve the desired shape-transforming response," said Matsumoto. "We can control the curvature both discretely and continuously using our entirely tunable and programmable method." Specifically, the mathematical modeling solves the "inverse problem", which is the challenge of being able to predict what the printing toolpath must be in order to encode swelling behaviors toward achieving a specific desired target shape. "It is wonderful to be able to design and realize, in an engineered structure, some of nature's solutions," said Mahadevan, who has studied phenomena such as how botanical tendrils coil, how flowers bloom, and how pine cones open and close. "By solving the inverse problem, we are now able to reverse-engineer the problem and determine how to vary local inhomogeneity, i.e. the spacing between the printed ink filaments, and the anisotropy, i.e. the direction of these filaments, to control the spatiotemporal response of these shapeshifting sheets. " "What's remarkable about this 4D printing advance made by Jennifer and her team is that it enables the design of almost any arbitrary, transformable shape from a wide range of available materials with different properties and potential applications, truly establishing a new platform for printing self-assembling, dynamic microscale structures that could be applied to a broad range of industrial and medical applications," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children's Hospital and Professor of Bioengineering at Harvard SEAS. <|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 Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases—representing breast, lung and prostate cancers, as well as multiple myeloma—exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca 2+ ) release channel (RyR1). The oxidized RyR1 channels leaked Ca 2+ , resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer–associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca 2+ -induced muscle force production. Main Skeletal muscle weakness is a debilitating consequence of advanced malignancies, which are often associated with bone metastases. Research and therapy have focused on increasing muscle mass in humans with cancer-associated skeletal muscle weakness 1 , but it is unclear whether a gain of mass alone will improve muscle function 2 , 3 . Moreover, little is known about whether tumors and their associated metastases cause muscle dysfunction resulting in weakness, or whether cancer-associated weakness is due solely to loss of muscle mass. Therefore, using mouse models of human cancers with bone metastases, we investigated whether there is a cause of muscle weakness that is independent of muscle mass loss. Individuals with advanced cancer (including those of the breast, prostate and lung), often have bone metastases and muscle weakness. In the tumor-bone microenvironment, cancer cells (including those in individuals with multiple myeloma) secrete factors that stimulate osteoclastic bone resorption, resulting in skeletal complications of bone pain, fractures, hypercalcemia, nerve compression syndromes and muscle weakness 4 . Osteoclastic bone resorption releases growth factors stored in the bone matrix, principally TGF-β, that further promote cancer cell invasion, growth and osteolytic factor production to fuel a feed-forward cycle that induces more bone destruction and tumor growth 4 , 5 , 6 , 7 . Bone resorption and formation is dynamically coupled by TGF-β (ref. 8 ), and pathologically increased TGF-β release from bone, due to tumor-induced osteolysis, could be contributing to muscle weakness. Here we found that mouse models of human breast, lung and prostate cancers, as well as a mouse model of multiple myeloma, in which all mice develop osteolytic bone metastases and exhibit profound skeletal muscle weakness. We report that pathologically increased TGF-β release from bone causes muscle weakness by inducing intracellular Ca 2+ leakage via Nox4-mediated oxidation of RyR1 on the sarcoplasmic reticulum (SR). In normal muscle, activation of RyR1 results in the release of SR Ca 2+ that is the required signal to trigger skeletal muscle contraction 9 . Pathological oxidation of RyR1 results in leaky channels that contribute to muscle weakness 10 . Here we show that targeting intracellular Ca 2+ leakage, bone resorption, TGF-β activity and Nox4 activity can all prevent muscle weakness in mice with breast cancer–derived bone metastases. Furthermore, increased Nox4 binding to RyR1, oxidation of RyR1 and muscle weakness were observed in a mouse model of Camurati-Engelmann disease (CED), a nonmalignant metabolic bone disorder associated with increased TGF-β activity and bone destruction. These findings raise the possibility that increased bone destruction and associated elevations in TGF-β activity can induce skeletal muscle weakness by the oxidation of RyR1 and the resultant Ca 2+ leakage. Thus, targeting any portion of this pathway might help to ameliorate muscle weakness in cancer patients with bone metastases. Results Weakness and RyR1 oxidation in mice with bone metastases To explore the basis for cancer-associated muscle weakness, we used a mouse model of human breast cancer (MDA-MB-231) that causes osteolytic bone metastases and muscle weakness ( Supplementary Fig. 1a ) 11 . We inoculated 5-week-old female nude mice with 100,000 MDA-MB-231 human breast cancer cells via the left cardiac ventricle and found that these mice had bone metastases, lower skeletal muscle mass and reduced body weight, fat and lean content ( Supplementary Fig. 1b ) 4 weeks post-tumor inoculation as compared to tumor-free (non-tumor) control mice ( Supplementary Fig. 1c,d ). As compared to the non-tumor control mice, the tumor-bearing mice developed muscle weakness (reduction in forelimb grip strength) ( Fig. 1a ), and the extensor digitorum longus (EDL) muscle showed lower ex vivo muscle-specific force (which represents the muscle force corrected for changes in muscle size) ( Fig. 1b ). Peak tetanic Ca 2+ determines muscle force, and we found that this was also lower in the MDA-MB-231–inoculated mice than in the non–tumor-bearing control mice ( Fig. 1c ) Thus, in addition to loss of muscle mass, mice with breast cancer bone metastases had loss of muscle function. Figure 1: Skeletal muscle weakness is due to breast cancer bone metastases. ( a , b ) In vivo forelimb grip strength ( n = 10) ( a ) and ex vivo specific force of the extensor digitorum longus (EDL) muscle ( n = 10) ( b ) in mice with MDA-MB-231 breast cancer bone metastases. ( c ) Tetanic Ca 2+ peak (measured by using the Ca 2+ -sensitive fluorescent dye Fluo-4 (Δ F , change in fluorescence; Δ F/F 0 , resting signal)) in isolated flexor digitorum brevis (FDB) muscle fibers. Representative single traces (left) and quantification from n = 25 fibers (right). ( d ) Immunoblot (left) and quantification (right) of RyR1 oxidation (DNP) and nitrosylation (Cys NO) and of RyR1-calstabin1 binding, as measured by coimmunoprecipitation, from EDL", "role": "user" }, { "content": "Cancer researchers at Indiana University and their colleagues have discovered how cancer-induced bone destruction causes skeletal muscle weakness. Led by Theresa Guise, M.D., the Jerry and Peggy Throgmartin Professor of Oncology at the IU School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, the investigators have identified the molecular pathways that lead to cancer-associated muscle weakness. They found that inhibiting TGF-β, a growth factor released from bone during cancer-induced bone destruction, improved muscle function in mouse models of human cancers. \"Advanced cancer often spreads to the bone and patients can have muscle weakness because of that. This weakness can severely reduce the quality of life in patients and increase the risk to fracture bone. We previously showed that when cancer spreads and causes bone destruction it releases growth factors into the circulation. In the present study, we found that these factors can cause muscle weakness,\" Dr. Guise explained. She added: \"In mice with cancer in bone, muscle weakness could be prevented by drugs that inhibit bone destruction or block the growth factor activity or stabilize calcium in the muscle. These drugs have the potential to prevent muscle weakness in patients with cancer in the bone.\" Their research was published online today in Nature Medicine. For the study, Dr. Guise, who is also a Komen Scholar, pointed out that the same mechanisms cause muscle weakness in many different tumor types in which cancer grows in bone. Dr. Guise and her colleagues studied breast cancer, prostate cancer, lung cancer, and multiple myeloma—all cancers that typically spread to bone. Four different molecular checkpoints were identified and were successfully targeted by four different drugs, improving muscle function. In addition, the findings were confirmed in human muscle samples from patients with cancer in bone. Once cancer spreads to bone, patients often experience bone pain, fractures, nerve compression and muscle weakness. Currently, there are no effective treatments for cancer-associated muscle weakness. \"These findings should lead to new therapies to treat cancer-associated muscle weakness that could be studied in the clinic over the next few years,\" Dr. Guise said. A nationally acclaimed endocrinologist, Dr. Guise's research focuses on understanding why some cancers spread to bone and how they affect bone, as well as the long-term effects of cancer therapies on bone. As such, she leads a team of researchers at IU School of Medicine who are investigating ways to improve treatments for bone metastases and muscle weakness. ", "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 Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases—representing breast, lung and prostate cancers, as well as multiple myeloma—exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca 2+ ) release channel (RyR1). The oxidized RyR1 channels leaked Ca 2+ , resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer–associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca 2+ -induced muscle force production. Main Skeletal muscle weakness is a debilitating consequence of advanced malignancies, which are often associated with bone metastases. Research and therapy have focused on increasing muscle mass in humans with cancer-associated skeletal muscle weakness 1 , but it is unclear whether a gain of mass alone will improve muscle function 2 , 3 . Moreover, little is known about whether tumors and their associated metastases cause muscle dysfunction resulting in weakness, or whether cancer-associated weakness is due solely to loss of muscle mass. Therefore, using mouse models of human cancers with bone metastases, we investigated whether there is a cause of muscle weakness that is independent of muscle mass loss. Individuals with advanced cancer (including those of the breast, prostate and lung), often have bone metastases and muscle weakness. In the tumor-bone microenvironment, cancer cells (including those in individuals with multiple myeloma) secrete factors that stimulate osteoclastic bone resorption, resulting in skeletal complications of bone pain, fractures, hypercalcemia, nerve compression syndromes and muscle weakness 4 . Osteoclastic bone resorption releases growth factors stored in the bone matrix, principally TGF-β, that further promote cancer cell invasion, growth and osteolytic factor production to fuel a feed-forward cycle that induces more bone destruction and tumor growth 4 , 5 , 6 , 7 . Bone resorption and formation is dynamically coupled by TGF-β (ref. 8 ), and pathologically increased TGF-β release from bone, due to tumor-induced osteolysis, could be contributing to muscle weakness. Here we found that mouse models of human breast, lung and prostate cancers, as well as a mouse model of multiple myeloma, in which all mice develop osteolytic bone metastases and exhibit profound skeletal muscle weakness. We report that pathologically increased TGF-β release from bone causes muscle weakness by inducing intracellular Ca 2+ leakage via Nox4-mediated oxidation of RyR1 on the sarcoplasmic reticulum (SR). In normal muscle, activation of RyR1 results in the release of SR Ca 2+ that is the required signal to trigger skeletal muscle contraction 9 . Pathological oxidation of RyR1 results in leaky channels that contribute to muscle weakness 10 . Here we show that targeting intracellular Ca 2+ leakage, bone resorption, TGF-β activity and Nox4 activity can all prevent muscle weakness in mice with breast cancer–derived bone metastases. Furthermore, increased Nox4 binding to RyR1, oxidation of RyR1 and muscle weakness were observed in a mouse model of Camurati-Engelmann disease (CED), a nonmalignant metabolic bone disorder associated with increased TGF-β activity and bone destruction. These findings raise the possibility that increased bone destruction and associated elevations in TGF-β activity can induce skeletal muscle weakness by the oxidation of RyR1 and the resultant Ca 2+ leakage. Thus, targeting any portion of this pathway might help to ameliorate muscle weakness in cancer patients with bone metastases. Results Weakness and RyR1 oxidation in mice with bone metastases To explore the basis for cancer-associated muscle weakness, we used a mouse model of human breast cancer (MDA-MB-231) that causes osteolytic bone metastases and muscle weakness ( Supplementary Fig. 1a ) 11 . We inoculated 5-week-old female nude mice with 100,000 MDA-MB-231 human breast cancer cells via the left cardiac ventricle and found that these mice had bone metastases, lower skeletal muscle mass and reduced body weight, fat and lean content ( Supplementary Fig. 1b ) 4 weeks post-tumor inoculation as compared to tumor-free (non-tumor) control mice ( Supplementary Fig. 1c,d ). As compared to the non-tumor control mice, the tumor-bearing mice developed muscle weakness (reduction in forelimb grip strength) ( Fig. 1a ), and the extensor digitorum longus (EDL) muscle showed lower ex vivo muscle-specific force (which represents the muscle force corrected for changes in muscle size) ( Fig. 1b ). Peak tetanic Ca 2+ determines muscle force, and we found that this was also lower in the MDA-MB-231–inoculated mice than in the non–tumor-bearing control mice ( Fig. 1c ) Thus, in addition to loss of muscle mass, mice with breast cancer bone metastases had loss of muscle function. Figure 1: Skeletal muscle weakness is due to breast cancer bone metastases. ( a , b ) In vivo forelimb grip strength ( n = 10) ( a ) and ex vivo specific force of the extensor digitorum longus (EDL) muscle ( n = 10) ( b ) in mice with MDA-MB-231 breast cancer bone metastases. ( c ) Tetanic Ca 2+ peak (measured by using the Ca 2+ -sensitive fluorescent dye Fluo-4 (Δ F , change in fluorescence; Δ F/F 0 , resting signal)) in isolated flexor digitorum brevis (FDB) muscle fibers. Representative single traces (left) and quantification from n = 25 fibers (right). ( d ) Immunoblot (left) and quantification (right) of RyR1 oxidation (DNP) and nitrosylation (Cys NO) and of RyR1-calstabin1 binding, as measured by coimmunoprecipitation, from EDL<|im_end|> <|im_start|>assistant Cancer researchers at Indiana University and their colleagues have discovered how cancer-induced bone destruction causes skeletal muscle weakness. Led by Theresa Guise, M.D., the Jerry and Peggy Throgmartin Professor of Oncology at the IU School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, the investigators have identified the molecular pathways that lead to cancer-associated muscle weakness. They found that inhibiting TGF-β, a growth factor released from bone during cancer-induced bone destruction, improved muscle function in mouse models of human cancers. "Advanced cancer often spreads to the bone and patients can have muscle weakness because of that. This weakness can severely reduce the quality of life in patients and increase the risk to fracture bone. We previously showed that when cancer spreads and causes bone destruction it releases growth factors into the circulation. In the present study, we found that these factors can cause muscle weakness," Dr. Guise explained. She added: "In mice with cancer in bone, muscle weakness could be prevented by drugs that inhibit bone destruction or block the growth factor activity or stabilize calcium in the muscle. These drugs have the potential to prevent muscle weakness in patients with cancer in the bone." Their research was published online today in Nature Medicine. For the study, Dr. Guise, who is also a Komen Scholar, pointed out that the same mechanisms cause muscle weakness in many different tumor types in which cancer grows in bone. Dr. Guise and her colleagues studied breast cancer, prostate cancer, lung cancer, and multiple myeloma—all cancers that typically spread to bone. Four different molecular checkpoints were identified and were successfully targeted by four different drugs, improving muscle function. In addition, the findings were confirmed in human muscle samples from patients with cancer in bone. Once cancer spreads to bone, patients often experience bone pain, fractures, nerve compression and muscle weakness. Currently, there are no effective treatments for cancer-associated muscle weakness. "These findings should lead to new therapies to treat cancer-associated muscle weakness that could be studied in the clinic over the next few years," Dr. Guise said. A nationally acclaimed endocrinologist, Dr. Guise's research focuses on understanding why some cancers spread to bone and how they affect bone, as well as the long-term effects of cancer therapies on bone. As such, she leads a team of researchers at IU School of Medicine who are investigating ways to improve treatments for bone metastases and muscle weakness. <|im_end|>

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617, 279, 4754, 311, 5471, 16124, 23948, 304, 6978, 449, 9572, 304, 279, 17685, 1210, 11205, 3495, 574, 4756, 2930, 3432, 304, 22037, 19152, 13, 1789, 279, 4007, 11, 2999, 13, 4673, 1082, 11, 889, 374, 1101, 264, 735, 6431, 25542, 11, 14618, 704, 430, 279, 1890, 24717, 5353, 16124, 23948, 304, 1690, 2204, 36254, 4595, 304, 902, 9572, 28815, 304, 17685, 13, 2999, 13, 4673, 1082, 323, 1077, 18105, 20041, 17659, 9572, 11, 47447, 9572, 11, 21271, 9572, 11, 323, 5361, 856, 301, 7942, 87247, 51423, 430, 11383, 9041, 311, 17685, 13, 13625, 2204, 31206, 68309, 1051, 11054, 323, 1051, 7946, 17550, 555, 3116, 2204, 11217, 11, 18899, 16124, 734, 13, 763, 5369, 11, 279, 14955, 1051, 11007, 304, 3823, 16124, 10688, 505, 6978, 449, 9572, 304, 17685, 13, 9843, 9572, 43653, 311, 17685, 11, 6978, 3629, 3217, 17685, 6784, 11, 78332, 11, 32015, 26168, 323, 16124, 23948, 13, 25122, 11, 1070, 527, 912, 7524, 22972, 369, 9572, 75968, 16124, 23948, 13, 330, 9673, 14955, 1288, 3063, 311, 502, 52312, 311, 4322, 9572, 75968, 16124, 23948, 430, 1436, 387, 20041, 304, 279, 28913, 927, 279, 1828, 2478, 1667, 1359, 2999, 13, 4673, 1082, 1071, 13, 362, 40343, 50082, 842, 91153, 16549, 11, 2999, 13, 4673, 1082, 596, 3495, 24400, 389, 8830, 3249, 1063, 51423, 9041, 311, 17685, 323, 1268, 814, 7958, 17685, 11, 439, 1664, 439, 279, 1317, 9860, 6372, 315, 9572, 52312, 389, 17685, 13, 1666, 1778, 11, 1364, 11767, 264, 2128, 315, 12074, 520, 81725, 6150, 315, 19152, 889, 527, 24834, 5627, 311, 7417, 22972, 369, 17685, 68370, 2315, 323, 16124, 23948, 13, 220, 128257, 198 ]

2,010

[ { "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: Resumo: Text Introduction Material and Methods Results and Discussion Conclusions Publication Dates History Abstract: A list of plant species, in alphabetical order by their scientific name, and the viruses found naturally infecting them in Brazilian territory, with some comments, was prepared . The production of such a list was based on a yearly catalog of publications on plant viruses collected by the author, from 1926 to 2018. Listed species of viruses were those recognized by the International Committee on Taxonomy of Viruses (ICTV), but also those characterized and still waiting official recognition, were included. Several cases of putative viral diseases were listed for historical reasons expecting to raise interest for their clarification. This list includes 345 plants species belonging to 74 families naturally infected by plant viruses in Brazil. Fabaceae and Asteraceae had most virus-infected species, respectively 49 and 36. Until 2018, a total of 213 plant virus and 6 viroid species belonging to 57 genera and 22 families and 6 orders, officially recognized by ICTV, were found naturally infecting these plants. Begomovirus and Potyvirus genera have most representatives, with 45 and 42 species, respectively. There are 59 characterized plant viruses, up to species level, described in Brazil waiting for the inclusion in the ICTV Master Species List. One hundred and thirteen viruses were identified up to genus level but still uncharacterized, while four putative isometric viruses and eleven presumptive viral diseases (“unidentified”) are included in the list. A reverse catalog, listing viruses and the plant species in which they were found is also included. Keywords: ICTV; plant species; virus species Resumo: Esta publicação consiste em uma listagem de espécies de plantas, em ordem alfabética de seus nomes científicos, e dos vírus que foram encontrados naturalmente infetando-as em território brasileiro, com alguns comentários. O preparo de tal lista foi basedo nas publicações sobre vírus de plantas e as doenças que eles causam, colecionadas pelo autor de 1926 a 2018. Os vírus listados incluem aqueles já oficialmente reconhecidos pelo International Committee on Taxonomy of Viruses (ICTV), constantes do “Master Species List 2018”. Também estão incluídos vírus já caracterizados, aguardando oficialização pelo ICTV, e outros casos de possíveis viroses, cujo agente causal ainda não se acha adequadamente caracterizado. A listagem inclui 345 espécies de plantas, pertencentes a 74 famílias, que foram encontradas naturalmente infetadas por diferentes vírus. Fabáceas e Asteráceas foram as famílias que tiveram mais espécies infetadas por vírus, respectivamente 49 e 36. Até 2018, 213 espécies de vírus e 6 de viróides, pertencentes a 57 gêneros e 22 famílias e 6 ordens, oficialmente reconhecidas pelo ICTV, acham-se descritas no Brasil. Os gêneros Begomovirus e Potyvirus têm mais espécies representadas, com 45 e 42 respectivamente. Além das espécies identificadas e aceitas pelo ICTV, foram incluídas na lista 59 possíveis espécies que ainda aguardam oficialização, 113 vírus identificados a nível de gênero, quatro possíveis vírus isométricos e onze presumíveis viroses, de agentes etiológicos não confirmados. Foi incluída também uma lista reversa, com catalogação dos vírus e viróides descritos no Brasdil e suas respectivas plantas hospedeiras. Palavras-chave: ICTV; espécies de plantas; espécies de vírus Introduction The concept that viruses are part of the bioma is still a controversial subject. Their chemical composition is akin of the cellular organisms. They have DNA or RNA as their genome, proteins (protective, enzymes) and lipid and glycid (in membrane bounded viruses). Being unable to replicate by themselves, viruses rely entirely on a cellular host to do so, as a molecular parasite. As far as we know, most of cellular organisms, from pro- to eucaryotes, have been found infected by one or more viruses, some of them already integrated into their genomes ( Shors, 2008 SHORS, T. 2008.Understanding viruses. Jones & Bartlett Publ., Sudbury. ; Hull, 2014 HULL, R. Plant Virology, 5th ed. 2014. Elsevier, Amsterdam. ). Recent works, using next generation sequencing (NGS) or high-throughput sequencing (HTS) technologies ( Reuter et al., 2015 REUTER, J.A., SPACEK, D & SNYDER, M.P. 2015. High-throughput sequencing Technologies. Mol.Cell 58(4): 586-597. ), discovered a huge number of virus-like sequences in several environments ( Walker et al., 2019 WALKER, P.J., SIDDELL, S.G., LEFKOWITZ, E.J. MUSHEGIAN, A.R., DEMPSEY, D.M., DUTILH, B.E, HARRACH, B., HARRISON, L., HENDRICKSON, R.C., JUNGLEN, S., KNOWLES, N.J., KROPINSKI, A.M., KRUPOVIC, M., KUHN, J.H., NIBERT, M., RUBINO, L., SABANADZOVIC, S., SIMMONDS, P., VARSANI, A., ZERBINI, F.M., DAVISON, A.J. Changes to virus taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses. 2019. Arch.Virology 164: 2417-2429. ). Their proposition to incorporate them in the present official taxonomic system seems unreal as discussed by van Regenmortel (2016) VAN REGENMORTEL, M.H.V. 2016. Only viruses, but not their genome sequences, can be classified into hierarchical species and genus classes. Current Topics in Virology 13: 59-68. , who mentions that “the phenotypic and biological properties of members of new species taxa proposed on the basis of metagenomic data must be known before it becomes feasible to try to incorporate such hypothetical species in the current official system of virus classification”. Because the intimate relationship of viruses in the biology and evolution of cellular organisms, common sense and the ever-increasing evidences strongly suggest that viruses must be part of the living world. Theories about the origin of viruses are speculative but we can roughly list three main lines ( Forterre, 2006 FORTERRE, P. 2006. The origins of viruses and their possible roles in major evolutionary transitions. Virus Res. 1177: 5-16. ; Garcia-Arenal et al., 2003 GARCIA-ARENAL, F., FRAILE, A. & MALPICA, J.M. 2003. Variation and evolution of plant virus populations. Int.Microb. 6:225-232. ; Koonin & Dolja, 2006 KOONIN, E.V. & DOLJA, V. 2006. Evolution of complexity in the viral world: the dawn of a new vision.Virus Res. 117: 1-4. doi:10.1016/j.virusRes.2006.01.018 ; Lefeuvre et al., 2019 LEFEUVRE, P., MARTIN, D.P., ELENA, S.F., SHEPHERD, D.N., ROUMAGNAC, P. & VARSANI, A. 2019.Evolution and ecology of plant viruses. Nature Reviews/Microbiology. ; Krupovic et al., 2019 KRUPOVIC, M., DOLJA, V.V. & KOONIN, E.V. 2019. Origin of viruses: primordial replicators recruiting capsids", "role": "user" }, { "content": "A Brazilian scientist has produced an inventory of 219 pathogens that infect plants in Brazil, including many agriculturally important species. The annotated list, published in Biota Neotropica, is the largest compilation of information on plant viruses ever produced in Brazil. It presents descriptions of the microorganisms, data on the diseases they cause, and information on their occurrence in native, cultivated and ornamental plants as well as weeds. \"Since the start of my career, I've been in the habit of collecting publications on plant viruses in Brazil. I've been doing it for decades and have recorded some 8,000 references to date,\" said the author, Elliot Watanabe Kitajima, a researcher in the Phytopathology and Nematology Department of the University of São Paulo's Luiz de Queiroz College of Agriculture (ESALQ-USP). \"I eventually realized that if I were asked how many viruses have been recorded in Brazil, I wouldn't know the answer, so I drew up an alphabetic list of plant species and of the viruses that naturally infect them. I also produced a reverse list in which the viruses and viroids are followed by the plants infected by each one.\" Viroids are the smallest infectious pathogens known to science, consisting of a short strand of RNA with no protein coating. All known viroids are inhabitants of higher plants, and most cause diseases. Dr. Kitajima graduated in agronomy from ESALQ-USP in 1958 and earned his PhD in 1967 at the same institution. His résumé includes positions as a researcher at the Agronomic Institute (IAC), an agency of the São Paulo State Government, as a professor at the University of Brasília (UnB) and as a visiting professor at his alma mater, where he retired in 2006 and works as a research collaborator. The inventory is the outcome of projects conducted under the aegis of the FAPESP Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA-FAPESP). \"This review of the viruses documented between 1926 and 2018 basically sums up everything known about plant viruses in Brazil that infect both spontaneous and cultivated vegetation. The author has produced a most important database that will be both useful to researchers and a relevant pest prevention policy input,\" said Carlos Joly, a professor at UNICAMP and a member of BIOTA-FAPESP's steering committee. Joly also stressed the importance of the inventory to economic activity. \"The list includes 346 plant species belonging to 74 different families and the viruses that naturally infect them. Several viruses are listed for such important crops as the citrus group, for example. Many are well known, but others aren't. In any event, the occurrence of these pathogens affects fruit production and quality. The ability to recognize them quickly can prevent harm and avoid losses,\" Joly said. Most of the viruses and viroids in the inventory are recognized by the International Committee on Taxonomy of Viruses (ICTV), which authorizes and organizes taxonomic classification and nomenclature. Some of the microorganisms listed have yet to be officially recognized. The list maps the history of pathogenic occurrences in Brazilian agriculture and the evolution of plant virology in Brazil as well as the main centers of research in the field. For example, citrus tristeza virus (CTV) is one of the top 20 viruses in molecular plant pathology. It causes citrus plants to decline quickly and is the most economically important citrus disease worldwide, being responsible for enormous losses, including the destruction of some 10 million orange trees in the 1940s. This problem was solved on the basis of scientific research, and the state of São Paulo became the world's largest producer and exporter of industrialized orange juice. Another important crop pest is bean golden mosaic virus, which emerged in the 1970s, when Brazil was one of the world's leading producers of beans but had to import the commodity from Mexico owing to the severe losses caused by the disease. Additionally, mosaic is caused in papaya by papaya ringspot virus (PRSV). This disease has wiped out entire plantations in Brazil. Control by roguing (systematic removal of diseased plants) has been sufficiently effective to enable the state of Espírito Santo, which pioneered the technique, to become a major exporter of papaya. \"No viruses can be considered more important than others,\" Kitajima said. \"Several factors, such as geography, climate, plant species or variety, vectors, and crop practices, will determine how hazardous they are. In monocultures with genetic uniformity, viral diseases can spread very quickly if epidemiological conditions are favorable, causing significant losses. This is a hazard growers must always deal with, and we researchers must also be prepared to offer solutions. To this end, we need appropriate information.\" ", "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: Resumo: Text Introduction Material and Methods Results and Discussion Conclusions Publication Dates History Abstract: A list of plant species, in alphabetical order by their scientific name, and the viruses found naturally infecting them in Brazilian territory, with some comments, was prepared . The production of such a list was based on a yearly catalog of publications on plant viruses collected by the author, from 1926 to 2018. Listed species of viruses were those recognized by the International Committee on Taxonomy of Viruses (ICTV), but also those characterized and still waiting official recognition, were included. Several cases of putative viral diseases were listed for historical reasons expecting to raise interest for their clarification. This list includes 345 plants species belonging to 74 families naturally infected by plant viruses in Brazil. Fabaceae and Asteraceae had most virus-infected species, respectively 49 and 36. Until 2018, a total of 213 plant virus and 6 viroid species belonging to 57 genera and 22 families and 6 orders, officially recognized by ICTV, were found naturally infecting these plants. Begomovirus and Potyvirus genera have most representatives, with 45 and 42 species, respectively. There are 59 characterized plant viruses, up to species level, described in Brazil waiting for the inclusion in the ICTV Master Species List. One hundred and thirteen viruses were identified up to genus level but still uncharacterized, while four putative isometric viruses and eleven presumptive viral diseases (“unidentified”) are included in the list. A reverse catalog, listing viruses and the plant species in which they were found is also included. Keywords: ICTV; plant species; virus species Resumo: Esta publicação consiste em uma listagem de espécies de plantas, em ordem alfabética de seus nomes científicos, e dos vírus que foram encontrados naturalmente infetando-as em território brasileiro, com alguns comentários. O preparo de tal lista foi basedo nas publicações sobre vírus de plantas e as doenças que eles causam, colecionadas pelo autor de 1926 a 2018. Os vírus listados incluem aqueles já oficialmente reconhecidos pelo International Committee on Taxonomy of Viruses (ICTV), constantes do “Master Species List 2018”. Também estão incluídos vírus já caracterizados, aguardando oficialização pelo ICTV, e outros casos de possíveis viroses, cujo agente causal ainda não se acha adequadamente caracterizado. A listagem inclui 345 espécies de plantas, pertencentes a 74 famílias, que foram encontradas naturalmente infetadas por diferentes vírus. Fabáceas e Asteráceas foram as famílias que tiveram mais espécies infetadas por vírus, respectivamente 49 e 36. Até 2018, 213 espécies de vírus e 6 de viróides, pertencentes a 57 gêneros e 22 famílias e 6 ordens, oficialmente reconhecidas pelo ICTV, acham-se descritas no Brasil. Os gêneros Begomovirus e Potyvirus têm mais espécies representadas, com 45 e 42 respectivamente. Além das espécies identificadas e aceitas pelo ICTV, foram incluídas na lista 59 possíveis espécies que ainda aguardam oficialização, 113 vírus identificados a nível de gênero, quatro possíveis vírus isométricos e onze presumíveis viroses, de agentes etiológicos não confirmados. Foi incluída também uma lista reversa, com catalogação dos vírus e viróides descritos no Brasdil e suas respectivas plantas hospedeiras. Palavras-chave: ICTV; espécies de plantas; espécies de vírus Introduction The concept that viruses are part of the bioma is still a controversial subject. Their chemical composition is akin of the cellular organisms. They have DNA or RNA as their genome, proteins (protective, enzymes) and lipid and glycid (in membrane bounded viruses). Being unable to replicate by themselves, viruses rely entirely on a cellular host to do so, as a molecular parasite. As far as we know, most of cellular organisms, from pro- to eucaryotes, have been found infected by one or more viruses, some of them already integrated into their genomes ( Shors, 2008 SHORS, T. 2008.Understanding viruses. Jones & Bartlett Publ., Sudbury. ; Hull, 2014 HULL, R. Plant Virology, 5th ed. 2014. Elsevier, Amsterdam. ). Recent works, using next generation sequencing (NGS) or high-throughput sequencing (HTS) technologies ( Reuter et al., 2015 REUTER, J.A., SPACEK, D & SNYDER, M.P. 2015. High-throughput sequencing Technologies. Mol.Cell 58(4): 586-597. ), discovered a huge number of virus-like sequences in several environments ( Walker et al., 2019 WALKER, P.J., SIDDELL, S.G., LEFKOWITZ, E.J. MUSHEGIAN, A.R., DEMPSEY, D.M., DUTILH, B.E, HARRACH, B., HARRISON, L., HENDRICKSON, R.C., JUNGLEN, S., KNOWLES, N.J., KROPINSKI, A.M., KRUPOVIC, M., KUHN, J.H., NIBERT, M., RUBINO, L., SABANADZOVIC, S., SIMMONDS, P., VARSANI, A., ZERBINI, F.M., DAVISON, A.J. Changes to virus taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses. 2019. Arch.Virology 164: 2417-2429. ). Their proposition to incorporate them in the present official taxonomic system seems unreal as discussed by van Regenmortel (2016) VAN REGENMORTEL, M.H.V. 2016. Only viruses, but not their genome sequences, can be classified into hierarchical species and genus classes. Current Topics in Virology 13: 59-68. , who mentions that “the phenotypic and biological properties of members of new species taxa proposed on the basis of metagenomic data must be known before it becomes feasible to try to incorporate such hypothetical species in the current official system of virus classification”. Because the intimate relationship of viruses in the biology and evolution of cellular organisms, common sense and the ever-increasing evidences strongly suggest that viruses must be part of the living world. Theories about the origin of viruses are speculative but we can roughly list three main lines ( Forterre, 2006 FORTERRE, P. 2006. The origins of viruses and their possible roles in major evolutionary transitions. Virus Res. 1177: 5-16. ; Garcia-Arenal et al., 2003 GARCIA-ARENAL, F., FRAILE, A. & MALPICA, J.M. 2003. Variation and evolution of plant virus populations. Int.Microb. 6:225-232. ; Koonin & Dolja, 2006 KOONIN, E.V. & DOLJA, V. 2006. Evolution of complexity in the viral world: the dawn of a new vision.Virus Res. 117: 1-4. doi:10.1016/j.virusRes.2006.01.018 ; Lefeuvre et al., 2019 LEFEUVRE, P., MARTIN, D.P., ELENA, S.F., SHEPHERD, D.N., ROUMAGNAC, P. & VARSANI, A. 2019.Evolution and ecology of plant viruses. Nature Reviews/Microbiology. ; Krupovic et al., 2019 KRUPOVIC, M., DOLJA, V.V. & KOONIN, E.V. 2019. Origin of viruses: primordial replicators recruiting capsids<|im_end|> <|im_start|>assistant A Brazilian scientist has produced an inventory of 219 pathogens that infect plants in Brazil, including many agriculturally important species. The annotated list, published in Biota Neotropica, is the largest compilation of information on plant viruses ever produced in Brazil. It presents descriptions of the microorganisms, data on the diseases they cause, and information on their occurrence in native, cultivated and ornamental plants as well as weeds. "Since the start of my career, I've been in the habit of collecting publications on plant viruses in Brazil. I've been doing it for decades and have recorded some 8,000 references to date," said the author, Elliot Watanabe Kitajima, a researcher in the Phytopathology and Nematology Department of the University of São Paulo's Luiz de Queiroz College of Agriculture (ESALQ-USP). "I eventually realized that if I were asked how many viruses have been recorded in Brazil, I wouldn't know the answer, so I drew up an alphabetic list of plant species and of the viruses that naturally infect them. I also produced a reverse list in which the viruses and viroids are followed by the plants infected by each one." Viroids are the smallest infectious pathogens known to science, consisting of a short strand of RNA with no protein coating. All known viroids are inhabitants of higher plants, and most cause diseases. Dr. Kitajima graduated in agronomy from ESALQ-USP in 1958 and earned his PhD in 1967 at the same institution. His résumé includes positions as a researcher at the Agronomic Institute (IAC), an agency of the São Paulo State Government, as a professor at the University of Brasília (UnB) and as a visiting professor at his alma mater, where he retired in 2006 and works as a research collaborator. The inventory is the outcome of projects conducted under the aegis of the FAPESP Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA-FAPESP). "This review of the viruses documented between 1926 and 2018 basically sums up everything known about plant viruses in Brazil that infect both spontaneous and cultivated vegetation. The author has produced a most important database that will be both useful to researchers and a relevant pest prevention policy input," said Carlos Joly, a professor at UNICAMP and a member of BIOTA-FAPESP's steering committee. Joly also stressed the importance of the inventory to economic activity. "The list includes 346 plant species belonging to 74 different families and the viruses that naturally infect them. Several viruses are listed for such important crops as the citrus group, for example. Many are well known, but others aren't. In any event, the occurrence of these pathogens affects fruit production and quality. The ability to recognize them quickly can prevent harm and avoid losses," Joly said. Most of the viruses and viroids in the inventory are recognized by the International Committee on Taxonomy of Viruses (ICTV), which authorizes and organizes taxonomic classification and nomenclature. Some of the microorganisms listed have yet to be officially recognized. The list maps the history of pathogenic occurrences in Brazilian agriculture and the evolution of plant virology in Brazil as well as the main centers of research in the field. For example, citrus tristeza virus (CTV) is one of the top 20 viruses in molecular plant pathology. It causes citrus plants to decline quickly and is the most economically important citrus disease worldwide, being responsible for enormous losses, including the destruction of some 10 million orange trees in the 1940s. This problem was solved on the basis of scientific research, and the state of São Paulo became the world's largest producer and exporter of industrialized orange juice. Another important crop pest is bean golden mosaic virus, which emerged in the 1970s, when Brazil was one of the world's leading producers of beans but had to import the commodity from Mexico owing to the severe losses caused by the disease. Additionally, mosaic is caused in papaya by papaya ringspot virus (PRSV). This disease has wiped out entire plantations in Brazil. Control by roguing (systematic removal of diseased plants) has been sufficiently effective to enable the state of Espírito Santo, which pioneered the technique, to become a major exporter of papaya. "No viruses can be considered more important than others," Kitajima said. "Several factors, such as geography, climate, plant species or variety, vectors, and crop practices, will determine how hazardous they are. In monocultures with genetic uniformity, viral diseases can spread very quickly if epidemiological conditions are favorable, causing significant losses. This is a hazard growers must always deal with, and we researchers must also be prepared to offer solutions. To this end, we need appropriate information." <|im_end|>

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2,797

[ { "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 Characterizing the genome of mature virions is pivotal to understanding the highly dynamic processes of virus assembly and infection. Owing to the different cellular fates of DNA and RNA, the life cycles of double-stranded (ds)DNA and dsRNA viruses are dissimilar. In terms of nucleic acid packing, dsDNA viruses, which lack genome segmentation and intra-capsid transcriptional machinery, predominantly display single-spooled genome organizations 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Because the release of dsRNA into the cytoplasm triggers host defence mechanisms 9 , dsRNA viruses retain their genomes within a core particle that contains the enzymes required for RNA replication and transcription 10 , 11 , 12 . The genomes of dsRNA viruses vary greatly in the degree of segmentation. In members of the Reoviridae family, genomes consist of 10–12 segments and exhibit a non-spooled arrangement mediated by RNA-dependent RNA polymerases 11 , 12 , 13 , 14 . However, whether this arrangement is a general feature of dsRNA viruses remains unknown. Here, using cryo-electron microscopy to resolve the dsRNA genome structure of the tri-segmented bacteriophage ɸ6 of the Cystoviridae family, we show that dsRNA viruses can adopt a dsDNA-like single-spooled genome organization. We find that in this group of viruses, RNA-dependent RNA polymerases do not direct genome ordering, and the dsRNA can adopt multiple conformations. We build a model that encompasses 90% of the genome, and use this to quantify variation in the packing density and to characterize the different liquid crystalline geometries that are exhibited by the tightly compacted nucleic acid. Our results demonstrate that the canonical model for the packing of dsDNA can be extended to dsRNA viruses. Main Bacteriophage ɸ6 is a model for the study of genome packaging, replication and transcription in dsRNA viruses. The ɸ6 nucleocapsid contains approximately 8–12 copies of P2 (the ɸ6 RNA-dependent RNA polymerase (RdRP)) and a tri-segmented genome 15 , 16 , 17 , 18 . To elucidate the organization of the dsRNA genome in ɸ6, we first determined the structure of the icosahedral double-shelled capsid to a resolution of 3.5 Å using cryo-electron microscopy (cryo-EM) (Fig. 1a , Extended Data Fig. 1 , Extended Data Tables 1 , 2 ). Consistent with our previous findings 18 , the capsid is composed of 240 trimers of the outer-shell protein P8, together with 60 asymmetric P1 A –P1 B dimers that form the inner shell. We resolved dsRNA density using a multimodal priors maximum likelihood refinement and volume classification without any symmetry constraints (see Methods ) (Fig. 1b , Extended Data Fig. 1 , Extended Data Table 2 ). In some regions, the major and minor grooves of the A-form double helix are discernible (Fig. 1b , inset). Most of the dsRNA follows an approximate D 3 symmetry (Fig. 1c ), with five layers of supercoiled dsRNA spooled around an axis of icosahedral three-fold symmetry (Fig. 1d , Extended Data Fig. 2 ). In each layer, the central equatorial parts of the spool are considerably better resolved than the top and bottom regions. In most areas, however, individual strands of dsRNA are resolved (Extended Data Fig. 2 ). Fig. 1: Structure of the ɸ6 nucleocapsid and dsRNA genome. a , Structure of the ɸ6 nucleocapsid seen along an axis of icosahedral two-fold symmetry (ellipse). A three-fold axis (black line) is denoted with a triangle. The positions of four P4 packaging NTPases are indicated. Different subunits of P8 that build the outer shell are coloured in yellow, green, gold and brown. Different subunits of P1 that build the inner protein shell are coloured in blue and red. b , A cut-open view of the structure in the same orientation as a , showing the dsRNA density (purple) proximal to the P1 shell, which is reconstructed here without symmetry. Areas where the RNA transitions from the first layer to the second are indicated with triangles. The left inset shows a model of dsRNA (purple) built into the density (transparent surface) showing the major (filled triangles) and minor (open triangles) grooves. Scale bars, 200 Å ( a , b ). c , The same dsRNA density as in b is shown in four different views (indicated by a rotation of the given angle (120° or 90°)) around an axis. A cage with D 3 symmetry (grey) is shown as a reference. d , Histogram showing the number of base pairs at different distances from the centre of the virion. The RNA is organized in five layers (1–5), numbered consecutively from outside to inside. e , A slab cutting through the full genome model (ribbons) showing parts for all the five layers (coloured as in d ). f , Complete models are shown as ribbons for the five layers (coloured as in d and e ). Mean values for α (arc), which is the angle between a segment of RNA (double dashed line) and the spool long axis (arrow), are given. Source data Full size image The first (outer) layer displayed several slightly different pseudo- D 3 geometries ( pD 3, pD 3′, pD 3′-1, pD 3′-2, pD 3′-3; Extended Data Fig. 1 ), and was particularly well resolved in pD 3′-1. This map, together with the pD 3 map in which the resolved parts of the dsRNA strands in layers 2–5 were unambiguous, was used to build a model that covers around 90% of the dsRNA genome (total length 13,385 bp; Fig. 1e, f , Extended Data Fig. 2 ). Layers 1, 2, 3 and 4 are centred at radii of 201, 170, 141 and 107 Å, respectively, and the fifth layer is centred at a radius between 65 and 100 Å (Fig. 1d ). The mean interstrand distance is 26 Å between strands in the same layer, and 29 Å between strands in different layers. The first four layers (1–4) are organized as nearly coaxial right-handed spools in which the inclination of the double helix axes to the spool axis is 82°, 77°, 77°", "role": "user" }, { "content": "Scientists at the University of Helsinki working in collaboration with the University of Oxford have deciphered for the first time how a virus genome is condensed inside the capsid of a virus. \"The motivation of the study was to increase our basic understanding of viral replication, but in the long term this may contribute to tackling viral disease,\" says the director of the of the project, Associate Professor Juha Huiskonen from the Helsinki Institute of Life Science, HiLIFE. The breakthrough results were achieved using cryogenic electron microscopy, a method that has in recent years revolutionised structural biology—a field of biology that aims to understand how molecules of life work at the atomic level. Using powerful electron microscopes, the team took tens of thousands of images of highly purified viruses. The images were then combined into three-dimensional models, allowing the scientists to not only see the proteins that make up the shell of the virus, but also, for the first time, to trace the nucleic acid genome inside the protein shell. The genome was seen to form a liquid crystal, a highly condensed and ordered state of matter that is still fluid. \"The degree of condensation is remarkable. To illustrate, if the virus was the size of an exercise ball and the viral genome was thick manila rope, there would be almost 70 metres of such rope stuffed inside the ball,\" Huiskonen says. The fluidity of the genome may be required to allow expression of the viral genes in the confines of the viral capsid, but it is still an open question how the virus genome doesn't get entangled in the process. In a follow-up study the team aims to address this very question. \"The virus particles are molecular machines that can be switched on by giving them the right chemical compounds,\" explains Minna Poranen, university lecturer from the Faculty of Biological and Environmental Sciences of the University of Helsinki. \"When the viruses are carrying out their work, they can be observed at different states. This way we can gain an even better understanding of how these fascinating nanomachines function,\" adds Huiskonen. The study is published in journal 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 Characterizing the genome of mature virions is pivotal to understanding the highly dynamic processes of virus assembly and infection. Owing to the different cellular fates of DNA and RNA, the life cycles of double-stranded (ds)DNA and dsRNA viruses are dissimilar. In terms of nucleic acid packing, dsDNA viruses, which lack genome segmentation and intra-capsid transcriptional machinery, predominantly display single-spooled genome organizations 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Because the release of dsRNA into the cytoplasm triggers host defence mechanisms 9 , dsRNA viruses retain their genomes within a core particle that contains the enzymes required for RNA replication and transcription 10 , 11 , 12 . The genomes of dsRNA viruses vary greatly in the degree of segmentation. In members of the Reoviridae family, genomes consist of 10–12 segments and exhibit a non-spooled arrangement mediated by RNA-dependent RNA polymerases 11 , 12 , 13 , 14 . However, whether this arrangement is a general feature of dsRNA viruses remains unknown. Here, using cryo-electron microscopy to resolve the dsRNA genome structure of the tri-segmented bacteriophage ɸ6 of the Cystoviridae family, we show that dsRNA viruses can adopt a dsDNA-like single-spooled genome organization. We find that in this group of viruses, RNA-dependent RNA polymerases do not direct genome ordering, and the dsRNA can adopt multiple conformations. We build a model that encompasses 90% of the genome, and use this to quantify variation in the packing density and to characterize the different liquid crystalline geometries that are exhibited by the tightly compacted nucleic acid. Our results demonstrate that the canonical model for the packing of dsDNA can be extended to dsRNA viruses. Main Bacteriophage ɸ6 is a model for the study of genome packaging, replication and transcription in dsRNA viruses. The ɸ6 nucleocapsid contains approximately 8–12 copies of P2 (the ɸ6 RNA-dependent RNA polymerase (RdRP)) and a tri-segmented genome 15 , 16 , 17 , 18 . To elucidate the organization of the dsRNA genome in ɸ6, we first determined the structure of the icosahedral double-shelled capsid to a resolution of 3.5 Å using cryo-electron microscopy (cryo-EM) (Fig. 1a , Extended Data Fig. 1 , Extended Data Tables 1 , 2 ). Consistent with our previous findings 18 , the capsid is composed of 240 trimers of the outer-shell protein P8, together with 60 asymmetric P1 A –P1 B dimers that form the inner shell. We resolved dsRNA density using a multimodal priors maximum likelihood refinement and volume classification without any symmetry constraints (see Methods ) (Fig. 1b , Extended Data Fig. 1 , Extended Data Table 2 ). In some regions, the major and minor grooves of the A-form double helix are discernible (Fig. 1b , inset). Most of the dsRNA follows an approximate D 3 symmetry (Fig. 1c ), with five layers of supercoiled dsRNA spooled around an axis of icosahedral three-fold symmetry (Fig. 1d , Extended Data Fig. 2 ). In each layer, the central equatorial parts of the spool are considerably better resolved than the top and bottom regions. In most areas, however, individual strands of dsRNA are resolved (Extended Data Fig. 2 ). Fig. 1: Structure of the ɸ6 nucleocapsid and dsRNA genome. a , Structure of the ɸ6 nucleocapsid seen along an axis of icosahedral two-fold symmetry (ellipse). A three-fold axis (black line) is denoted with a triangle. The positions of four P4 packaging NTPases are indicated. Different subunits of P8 that build the outer shell are coloured in yellow, green, gold and brown. Different subunits of P1 that build the inner protein shell are coloured in blue and red. b , A cut-open view of the structure in the same orientation as a , showing the dsRNA density (purple) proximal to the P1 shell, which is reconstructed here without symmetry. Areas where the RNA transitions from the first layer to the second are indicated with triangles. The left inset shows a model of dsRNA (purple) built into the density (transparent surface) showing the major (filled triangles) and minor (open triangles) grooves. Scale bars, 200 Å ( a , b ). c , The same dsRNA density as in b is shown in four different views (indicated by a rotation of the given angle (120° or 90°)) around an axis. A cage with D 3 symmetry (grey) is shown as a reference. d , Histogram showing the number of base pairs at different distances from the centre of the virion. The RNA is organized in five layers (1–5), numbered consecutively from outside to inside. e , A slab cutting through the full genome model (ribbons) showing parts for all the five layers (coloured as in d ). f , Complete models are shown as ribbons for the five layers (coloured as in d and e ). Mean values for α (arc), which is the angle between a segment of RNA (double dashed line) and the spool long axis (arrow), are given. Source data Full size image The first (outer) layer displayed several slightly different pseudo- D 3 geometries ( pD 3, pD 3′, pD 3′-1, pD 3′-2, pD 3′-3; Extended Data Fig. 1 ), and was particularly well resolved in pD 3′-1. This map, together with the pD 3 map in which the resolved parts of the dsRNA strands in layers 2–5 were unambiguous, was used to build a model that covers around 90% of the dsRNA genome (total length 13,385 bp; Fig. 1e, f , Extended Data Fig. 2 ). Layers 1, 2, 3 and 4 are centred at radii of 201, 170, 141 and 107 Å, respectively, and the fifth layer is centred at a radius between 65 and 100 Å (Fig. 1d ). The mean interstrand distance is 26 Å between strands in the same layer, and 29 Å between strands in different layers. The first four layers (1–4) are organized as nearly coaxial right-handed spools in which the inclination of the double helix axes to the spool axis is 82°, 77°, 77°<|im_end|> <|im_start|>assistant Scientists at the University of Helsinki working in collaboration with the University of Oxford have deciphered for the first time how a virus genome is condensed inside the capsid of a virus. "The motivation of the study was to increase our basic understanding of viral replication, but in the long term this may contribute to tackling viral disease," says the director of the of the project, Associate Professor Juha Huiskonen from the Helsinki Institute of Life Science, HiLIFE. The breakthrough results were achieved using cryogenic electron microscopy, a method that has in recent years revolutionised structural biology—a field of biology that aims to understand how molecules of life work at the atomic level. Using powerful electron microscopes, the team took tens of thousands of images of highly purified viruses. The images were then combined into three-dimensional models, allowing the scientists to not only see the proteins that make up the shell of the virus, but also, for the first time, to trace the nucleic acid genome inside the protein shell. The genome was seen to form a liquid crystal, a highly condensed and ordered state of matter that is still fluid. "The degree of condensation is remarkable. To illustrate, if the virus was the size of an exercise ball and the viral genome was thick manila rope, there would be almost 70 metres of such rope stuffed inside the ball," Huiskonen says. The fluidity of the genome may be required to allow expression of the viral genes in the confines of the viral capsid, but it is still an open question how the virus genome doesn't get entangled in the process. In a follow-up study the team aims to address this very question. "The virus particles are molecular machines that can be switched on by giving them the right chemical compounds," explains Minna Poranen, university lecturer from the Faculty of Biological and Environmental Sciences of the University of Helsinki. "When the viruses are carrying out their work, they can be observed at different states. This way we can gain an even better understanding of how these fascinating nanomachines function," adds Huiskonen. The study is published in journal Nature. <|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 Chemical signals play a crucial role in reproduction as a means for locating mates and/or gaining information about their quality, ultimately affecting mating system dynamics and mate choice. In spiders, one of the potential sources of chemical signalling is silk. However, while female silk is known to attract mates and/or elicit courtship, due to sex-specific roles in mate searching, male silk-related signals are often neglected. In the hunting spider Pisaura mirabilis (Pisauridae), both sexes leave silk draglines during movements while males additionally use silk to wrap nuptial gifts (food donations to females at mating). We explored the potential for both silk types (draglines and gift silk) to release signals and tested the hypothesis that chemical compounds bound to gifts’ silk serve to elicit female attraction. We conducted behavioural choice assays for dragline and gift silk, and their putative transmission mode (airborne or contact) by testing (i) male and female attraction towards draglines of the opposite sex and (ii) female attraction towards gift silk. Whereas males were attracted to female draglines (contact cues), females did not respond to male silk of any type. We suggest that females use draglines for advertisement to secure copulation and foraging of nuptial gifts. If these signals ease male mate searching, attractive male draglines are unnecessary. Overall, males may not invest in chemical stimulation but rather exploit female foraging interests through gift giving. Alternatively, they may release signals that prime other female sexual behaviours or towards which females may have evolved resistance. Significance statement Animals commonly use chemical signals to communicate during reproduction, and spiders have the potential to release such signals from their silk. We investigated whether two silk types, draglines released during movements and silk covering male nuptial gifts (prey offered to females at mating) are attractive to the opposite sex in a hunting spider. While males were attracted to female draglines, females did not respond to male silk of any type. Females may be using silk to advertise themselves to secure matings and food through reception of nuptial gifts. If males can successfully locate females, attracting females through draglines may be unnecessary. The finding that males do not release attractant signals in the silk cover of their nuptial gifts further suggests that rather than attempting to increase their attractiveness by using chemical stimulation, males may be uniquely exploiting females’ interest in food through gift giving behaviour. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Chemical signalling is considered to be one of the most ancient and widespread forms of communication (Bradbury and Vehrencamp 2011 ; Wyatt 2003 ), and its central role in sexual reproduction has been acknowledged for over a century (Darwin 1871 ). Studies across taxa show that animals use pheromone signals for mate location, sex recognition and mate choice (Johansson and Jones 2007 ; Wyatt 2009 ). Sex pheromones are sex-specific semiochemicals, known to attract mating partners (Eisner and Meinwald 1995 ) but also convey information on potential mates, such as body condition (Rantala et al. 2003 ), age (Nieberding et al. 2012 ), dominance (Moore et al. 1997 ) or mating status (Thomas 2011 ). Since males generally perform mate searching (Kasumovic et al. 2006 ; Fromhage et al. 2016 ), selection may favour advertisement in females and fine-scale sensory detection mechanisms in males, leading to sex-specific pheromone emitter and detector roles. Nevertheless, male pheromones are also described, and can be considered elaborate sexual traits shaped by selection through female choice (Rantala et al. 2002 ; Howard et al. 2003 ; Thomas and Simmons 2009 ), or by sexual conflict, where by soliciting an acceptance response in the receiver, they may be used to manipulate the opposite sex into mating beyond its optimum (Arnqvist and Rowe 2013 ). Spiders represent a particularly well-suited taxonomical group for studying the evolutionary function of pheromone communication due to the large amount of behavioural studies providing evidence for their role in mating (Huber 2005 ; Gaskett 2007 ). Spider pheromones, which can be emitted not only from the animals’ body but also from its silk, can enable the exchange of information between emitter and receiver at long distances through airborne chemicals, or through direct interaction with short-range contact chemicals (Schulz 2004 ; Gaskett 2007 ). Most of our knowledge of sex pheromone use in spiders comes from studies investigating female chemical signals bound to silk. Stationary females of web-building species primarily rely on airborne emission to be located by males (Cory and Schneider 2016 ) through which they provide detailed information about their quality, e.g. sexual maturity (van Helsdingen 1965 ) and mating status (Tuni and Berger-Tal 2012 ). In webless wandering species, silk draglines may instead have a higher relevance for both mate searching and mate attraction (Baruffaldi et al. 2010 ), inducing male courtship (Rypstra et al. 2003 , 2009 ; Roberts and Uetz 2005 ) and providing information about female quality, e.g. mating status (Stoltz et al. 2007 ) and body condition (Havrilak et al. 2014 ). Despite their potential role in shaping mating dynamics, fewer studies have instead investigated male pheromones, which have been found to trigger courtship behaviour in females in species with sex role reversal (Aisenberg et al. 2010 ), or mutual mate assessment (Cross and Jackson 2009 ). These studies specifically focus on volatile body compounds, leaving male silk pheromones poorly understood. Nuptial gift-giving spiders provide an interesting system to investigate chemical signalling through silk. The mating of these webless hunting species is characterised by the presence of nuptial gifts consisting of prey wrapped in dense silk layers offered by males and eaten by females during copulation. Therefore, while both sexes leave silk draglines during movements, males additionally use silk for mating, providing two distinct media (draglines and gift silk) through which spiders can potentially release chemical compounds and use signals in different modalities. Nuptial gifts in spiders are rare, with only two well-studied species, the Palearctic Pisaura mirabilis (Pisauridae) and the Neotropical Paratrechalea ornata (Trechaleidae) (Albo", "role": "user" }, { "content": "One of the central features of courtship behavior in the nursery-web spider (Pisaura mirabilis) is that the male must have a gift on hand in order to make a good impression on the females. So before setting out to look for a mate, the male spider traps a prey insect and wraps it festively in silk threads ready for presentation. If accepted, the food parcel is consumed by the female during mating. A new study carried out by LMU biologist Cristina Tuni reveals that successful mating depends solely on the quality of the gift, as the female does not react to any sex chemicals (pheromones) present in the male's silk. – This is rather surprising, in light of the fact that chemical communication via volatile or tactile pheromones is such a widespread feature of mating and reproductive behavior in the animal world. The new study appears in the journal Behavioral Ecology and Sociobiology. Because pheromones can potentially be incorporated into spider silk, Tuni and her colleagues at LMU's Behavioral Ecology Group wanted to define the role played by chemical signals in mating and reproduction in P. mirabilis, which belongs to the family of the wandering hunter spiders. To test whether the silk in which the males wrap their nuptial gifts might serve as a source of pheromones to attract mates, the researchers performed a series of experiments on a total of 100 nursery web spiders. The tests revealed, however, that male and female nursery web spiders react differently to the silk that their potential partners secrete. Threads spun by the females indeed appear to contain pheromones that attract males. However, females themselves show no interest whatsoever in the threads made by the male. They show no reaction either to the threads in which the nuptial gift is wrapped or to the 'draglines' secreted by the males during their visits to females. These findings imply either that male nursery spiders do not emit any volatile pheromones and must therefore rely on the effect of the gift itself, or that the females have learned to disregard any male pheromones into order to focus on the quality of the gift. ", "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 Chemical signals play a crucial role in reproduction as a means for locating mates and/or gaining information about their quality, ultimately affecting mating system dynamics and mate choice. In spiders, one of the potential sources of chemical signalling is silk. However, while female silk is known to attract mates and/or elicit courtship, due to sex-specific roles in mate searching, male silk-related signals are often neglected. In the hunting spider Pisaura mirabilis (Pisauridae), both sexes leave silk draglines during movements while males additionally use silk to wrap nuptial gifts (food donations to females at mating). We explored the potential for both silk types (draglines and gift silk) to release signals and tested the hypothesis that chemical compounds bound to gifts’ silk serve to elicit female attraction. We conducted behavioural choice assays for dragline and gift silk, and their putative transmission mode (airborne or contact) by testing (i) male and female attraction towards draglines of the opposite sex and (ii) female attraction towards gift silk. Whereas males were attracted to female draglines (contact cues), females did not respond to male silk of any type. We suggest that females use draglines for advertisement to secure copulation and foraging of nuptial gifts. If these signals ease male mate searching, attractive male draglines are unnecessary. Overall, males may not invest in chemical stimulation but rather exploit female foraging interests through gift giving. Alternatively, they may release signals that prime other female sexual behaviours or towards which females may have evolved resistance. Significance statement Animals commonly use chemical signals to communicate during reproduction, and spiders have the potential to release such signals from their silk. We investigated whether two silk types, draglines released during movements and silk covering male nuptial gifts (prey offered to females at mating) are attractive to the opposite sex in a hunting spider. While males were attracted to female draglines, females did not respond to male silk of any type. Females may be using silk to advertise themselves to secure matings and food through reception of nuptial gifts. If males can successfully locate females, attracting females through draglines may be unnecessary. The finding that males do not release attractant signals in the silk cover of their nuptial gifts further suggests that rather than attempting to increase their attractiveness by using chemical stimulation, males may be uniquely exploiting females’ interest in food through gift giving behaviour. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Chemical signalling is considered to be one of the most ancient and widespread forms of communication (Bradbury and Vehrencamp 2011 ; Wyatt 2003 ), and its central role in sexual reproduction has been acknowledged for over a century (Darwin 1871 ). Studies across taxa show that animals use pheromone signals for mate location, sex recognition and mate choice (Johansson and Jones 2007 ; Wyatt 2009 ). Sex pheromones are sex-specific semiochemicals, known to attract mating partners (Eisner and Meinwald 1995 ) but also convey information on potential mates, such as body condition (Rantala et al. 2003 ), age (Nieberding et al. 2012 ), dominance (Moore et al. 1997 ) or mating status (Thomas 2011 ). Since males generally perform mate searching (Kasumovic et al. 2006 ; Fromhage et al. 2016 ), selection may favour advertisement in females and fine-scale sensory detection mechanisms in males, leading to sex-specific pheromone emitter and detector roles. Nevertheless, male pheromones are also described, and can be considered elaborate sexual traits shaped by selection through female choice (Rantala et al. 2002 ; Howard et al. 2003 ; Thomas and Simmons 2009 ), or by sexual conflict, where by soliciting an acceptance response in the receiver, they may be used to manipulate the opposite sex into mating beyond its optimum (Arnqvist and Rowe 2013 ). Spiders represent a particularly well-suited taxonomical group for studying the evolutionary function of pheromone communication due to the large amount of behavioural studies providing evidence for their role in mating (Huber 2005 ; Gaskett 2007 ). Spider pheromones, which can be emitted not only from the animals’ body but also from its silk, can enable the exchange of information between emitter and receiver at long distances through airborne chemicals, or through direct interaction with short-range contact chemicals (Schulz 2004 ; Gaskett 2007 ). Most of our knowledge of sex pheromone use in spiders comes from studies investigating female chemical signals bound to silk. Stationary females of web-building species primarily rely on airborne emission to be located by males (Cory and Schneider 2016 ) through which they provide detailed information about their quality, e.g. sexual maturity (van Helsdingen 1965 ) and mating status (Tuni and Berger-Tal 2012 ). In webless wandering species, silk draglines may instead have a higher relevance for both mate searching and mate attraction (Baruffaldi et al. 2010 ), inducing male courtship (Rypstra et al. 2003 , 2009 ; Roberts and Uetz 2005 ) and providing information about female quality, e.g. mating status (Stoltz et al. 2007 ) and body condition (Havrilak et al. 2014 ). Despite their potential role in shaping mating dynamics, fewer studies have instead investigated male pheromones, which have been found to trigger courtship behaviour in females in species with sex role reversal (Aisenberg et al. 2010 ), or mutual mate assessment (Cross and Jackson 2009 ). These studies specifically focus on volatile body compounds, leaving male silk pheromones poorly understood. Nuptial gift-giving spiders provide an interesting system to investigate chemical signalling through silk. The mating of these webless hunting species is characterised by the presence of nuptial gifts consisting of prey wrapped in dense silk layers offered by males and eaten by females during copulation. Therefore, while both sexes leave silk draglines during movements, males additionally use silk for mating, providing two distinct media (draglines and gift silk) through which spiders can potentially release chemical compounds and use signals in different modalities. Nuptial gifts in spiders are rare, with only two well-studied species, the Palearctic Pisaura mirabilis (Pisauridae) and the Neotropical Paratrechalea ornata (Trechaleidae) (Albo<|im_end|> <|im_start|>assistant One of the central features of courtship behavior in the nursery-web spider (Pisaura mirabilis) is that the male must have a gift on hand in order to make a good impression on the females. So before setting out to look for a mate, the male spider traps a prey insect and wraps it festively in silk threads ready for presentation. If accepted, the food parcel is consumed by the female during mating. A new study carried out by LMU biologist Cristina Tuni reveals that successful mating depends solely on the quality of the gift, as the female does not react to any sex chemicals (pheromones) present in the male's silk. – This is rather surprising, in light of the fact that chemical communication via volatile or tactile pheromones is such a widespread feature of mating and reproductive behavior in the animal world. The new study appears in the journal Behavioral Ecology and Sociobiology. Because pheromones can potentially be incorporated into spider silk, Tuni and her colleagues at LMU's Behavioral Ecology Group wanted to define the role played by chemical signals in mating and reproduction in P. mirabilis, which belongs to the family of the wandering hunter spiders. To test whether the silk in which the males wrap their nuptial gifts might serve as a source of pheromones to attract mates, the researchers performed a series of experiments on a total of 100 nursery web spiders. The tests revealed, however, that male and female nursery web spiders react differently to the silk that their potential partners secrete. Threads spun by the females indeed appear to contain pheromones that attract males. However, females themselves show no interest whatsoever in the threads made by the male. They show no reaction either to the threads in which the nuptial gift is wrapped or to the 'draglines' secreted by the males during their visits to females. These findings imply either that male nursery spiders do not emit any volatile pheromones and must therefore rely on the effect of the gift itself, or that the females have learned to disregard any male pheromones into order to focus on the quality of the gift. <|im_end|>

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1,837

[ { "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 Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1 S340A/S340A mice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC. Introduction The mechanisms driving the progression of chronic inflammatory liver diseases such as alcoholic steatohepatitis and non-alcoholic steatohepatitis (ASH and NASH) to hepatocellular carcinoma (HCC) are poorly understood. The majority of HCC develops on the background of cirrhosis 1 , which is the end-stage result of fibrogenesis, a process of excessive wound repair. This has led to the concept that the fibrotic extracellular matrix and/or pro-fibrogenic myofibroblasts may be stimulators of HCC 2 . However, the increasing awareness that non-cirrhotic HCC represents a high proportion of liver cancers argues for additional mechanisms inherent in the inflammatory process. Inflammation underpins roughly 20% of all solid tumours and experimental studies have provided mechanistic links between inflammatory mediators such as interleukin (IL)-6 and carcinogenesis 3 . The histopathological changes associated with chronic ASH and NASH include persistent tissue infiltration by neutrophils and lymphocytes 4 . Appearance of neutrophils in the hepatic parenchyma is normally a transient process triggered by damage-induced expression of soluble and insoluble neutrophil guidance cues and is subsequently terminated by neutrophil death and/or clearance by Kupffer cells 5 , 6 . This transitory response is important for resolution of inflammation and for protecting epithelial cells from bystander damage resulting from exposure to neutrophil-derived reactive oxygen species (ROS) and proteases. Persistence of neutrophils in chronic liver disease (CLD) is therefore a pathological feature; however, it remains unclear as to how neutrophils contribute to disease progression. Experimental work in rodent models argues against a role for neutrophils in wound repair or fibrogenesis 7 , 8 . As neutrophils are present in human HCC and its surrounding tissue ( Supplementary Fig. 1a ), we were interested to determine whether they functionally contribute to tumour development. Here we demonstrate a requirement of hepatic neutrophils for the development of carcinogen-induced HCC and define a pro-tumour mechanism in which neutrophils cause telomere DNA damage in bystander hepatocytes. We additionally define a tumour suppressor role for the nfkb1 gene, which through the expression of anti-inflammatory p50:p50 nuclear factor-κB (NF-κB) dimers is able to transcriptionally repress a neutrophil chemokine network. Results Neutrophils are required for experimentally induced HCC Diethylnitrosamine (DEN) acts as a complete liver carcinogen when administered to mice 15 days after birth 9 . However, a role for inflammatory mechanisms in this model is demonstrated by the requirement for NF-κB activation in myeloid cells and for the production of IL-6 by Kupffer cells, for injury to progress to HCC 10 , 11 . To begin to investigate a role for neutrophils in this process, we examined hepatic neutrophils across a 5- to 40-week time course of DEN-induced disease in male C57BL/6 mice ( Fig. 1a ). Elevated numbers of hepatic neutrophils were evident throughout the disease process and underwent a steady increase until 40 weeks where they were accompanied by enlarged livers, substantial tumour frequency ( Fig. 1b ), large tumours ( Supplementary Fig. 1b ) and high numbers of PCNA+ proliferating hepatocytes (PCNA+) ( Fig. 1c ). To determine whether neutrophils contribute to DEN-induced HCC, mice were treated between weeks 32 and 40 with an antibody specific for the mouse neutrophil antigen Ly6G, known to effectively suppress neutrophil recruitment to tissues 12 . We confirmed that anti-Ly6G suppressed DEN-induced hepatic neutrophil accumulation with little effect on F4/80+ macrophages or CD3+ lymphocytes ( Supplementary Fig. 1c ). Selective depletion of neutrophils was associated with a 3.5-fold reduction in tumour burden at 40 weeks and a slight reduction in liver/body weight ratio ( Fig. 1d ). Mice lacking nfkb1 (encoding the NF-κB p50 subunit) display exaggerated neutrophil inflammatory responses to injury in multiple organs, including the liver 13 , 14 , 15 . Early (5 weeks) and persistent elevation of hepatic neutrophils was observed in DEN-injured nfkb1 −/− mice ( Fig. 1a ). Furthermore, these animals exhibited rapid progression to aggressive HCC ( Fig. 1b ). Of note, Cyp2E1 expression ( Supplementary Fig. 1d ) and levels of liver injury and apoptosis ( Supplementary Table 1 and Supplementary Fig. 1e ) were similar between the two genotypes, ruling out the possibility that differences in DEN-induced liver injury caused the increased tumour burden. Dysplastic cells and small tumours were evident at 20 weeks ( Supplementary Fig. 2a ) in nfkb1 −/− mice, and by 30 weeks there was an average of 32 visible surface liver tumour foci compared with just 3 for wild type (WT; Fig. 1b ). By week 40, an average of 73 and 12 surface growths were recorded for nfkb1 −/− and WT, respectively. Accelerated disease in nfkb1 −/− liver was confirmed by increased cell proliferation ( Fig. 1c ), elevated hepatic expression of cyclin D1 ( Supplementary Fig. 2b ) and loss of phospho-p38α ( Supplementary Fig. 2c ), the latter being a feature of advanced human HCCs 16 . C57BL/6 mice have a characteristically low rate (<4%) for the development of spontaneous liver cancer. We were therefore surprised to observe spontaneous CLD, a nodular appearance of the liver surface, emergence of dysplastic nodules, an increase in liver/body weight ratio and tumour frequency at 20 months in nfkb1 −/− males ( Fig.", "role": "user" }, { "content": "A team of Newcastle University scientists have found that specialised immune cells in our bodies that normally act to protect us from infections can have a dark side in the development of liver cancer. In a paper published in the journal Nature Communications, the team describes how cells called neutrophils can promote cancer-inducing effects in liver cells that are already damaged due to chronic disease. It is already known that chronic liver inflammation or hepatitis are risk factors for developing a particular type of liver cancer known as hepatocellular carcinoma (HCC). However, inflammation is a complicated process involving many different types of cells from our immune system working together. This has made it difficult to determine the molecular links between inflammation and HCC. This latest research identified neutrophils as a key inflammatory cell type that drives the progression of liver damage to cancer in mice. The team at Newcastle University's Institute of Cellular Medicine - Derek Mann, Professor of Hepatology, Dr Fiona Oakley and Dr Caroline Wilson - showed that among the effects that neutrophils produce, is an increase in Reactive Oxygen Species (ROS), part of normal cell metabolism which at low levels helps the body's immune system but which can cause damage to cellular components, including damage to DNA, if they reach high levels. Professor Mann explains: \"Neutrophils normally help our bodies to fight infections by producing powerful substances that kill germs. They are also sent to our liver when it is damaged by substances like alcohol, only in this scenario, when the liver is being subjected to sustained damage on an ongoing basis, there is a continuous flow of neutrophils to the damaged site. This overwhelming response, and the flood of germ-killing molecules the neutrophils release, can actually harm the genetic material in liver cells and stimulate cancer growth.\" The research, which was jointly funded by the European Commission, Medical Research Council and the Wellcome Trust, also suggested a possible way towards stopping the cancer-promoting actions of neutrophils. Dr Oakley added: \"We found that neutrophils cause an increase in ROS in liver cells and this damages their DNA which can be a trigger for cancer growth. Remarkably, anti-oxidants were able to almost completely stop HCC in our experiments\" Dr Mann commented: \"Now we know that neutrophils are the culprits we can move forward with new studies aimed at stopping their cancer-promoting activities in high risk patients suffering from severe liver disease. We need to develop our understanding of how we might be able to prevent ongoing neutrophil traffic to the liver, or block the release of ROS. We also need to carry out more work to understand how we might be able to use anti-oxidants, naturally found in fruits and vegetables.\" Liver cancer is a devastating disease with a poor prognosis and limited therapeutic options. The World Health Organisation estimate that liver cancer was the second leading cause of cancer deaths in 2012, accounting for almost 750,000 deaths worldwide. ", "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 Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1 S340A/S340A mice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC. Introduction The mechanisms driving the progression of chronic inflammatory liver diseases such as alcoholic steatohepatitis and non-alcoholic steatohepatitis (ASH and NASH) to hepatocellular carcinoma (HCC) are poorly understood. The majority of HCC develops on the background of cirrhosis 1 , which is the end-stage result of fibrogenesis, a process of excessive wound repair. This has led to the concept that the fibrotic extracellular matrix and/or pro-fibrogenic myofibroblasts may be stimulators of HCC 2 . However, the increasing awareness that non-cirrhotic HCC represents a high proportion of liver cancers argues for additional mechanisms inherent in the inflammatory process. Inflammation underpins roughly 20% of all solid tumours and experimental studies have provided mechanistic links between inflammatory mediators such as interleukin (IL)-6 and carcinogenesis 3 . The histopathological changes associated with chronic ASH and NASH include persistent tissue infiltration by neutrophils and lymphocytes 4 . Appearance of neutrophils in the hepatic parenchyma is normally a transient process triggered by damage-induced expression of soluble and insoluble neutrophil guidance cues and is subsequently terminated by neutrophil death and/or clearance by Kupffer cells 5 , 6 . This transitory response is important for resolution of inflammation and for protecting epithelial cells from bystander damage resulting from exposure to neutrophil-derived reactive oxygen species (ROS) and proteases. Persistence of neutrophils in chronic liver disease (CLD) is therefore a pathological feature; however, it remains unclear as to how neutrophils contribute to disease progression. Experimental work in rodent models argues against a role for neutrophils in wound repair or fibrogenesis 7 , 8 . As neutrophils are present in human HCC and its surrounding tissue ( Supplementary Fig. 1a ), we were interested to determine whether they functionally contribute to tumour development. Here we demonstrate a requirement of hepatic neutrophils for the development of carcinogen-induced HCC and define a pro-tumour mechanism in which neutrophils cause telomere DNA damage in bystander hepatocytes. We additionally define a tumour suppressor role for the nfkb1 gene, which through the expression of anti-inflammatory p50:p50 nuclear factor-κB (NF-κB) dimers is able to transcriptionally repress a neutrophil chemokine network. Results Neutrophils are required for experimentally induced HCC Diethylnitrosamine (DEN) acts as a complete liver carcinogen when administered to mice 15 days after birth 9 . However, a role for inflammatory mechanisms in this model is demonstrated by the requirement for NF-κB activation in myeloid cells and for the production of IL-6 by Kupffer cells, for injury to progress to HCC 10 , 11 . To begin to investigate a role for neutrophils in this process, we examined hepatic neutrophils across a 5- to 40-week time course of DEN-induced disease in male C57BL/6 mice ( Fig. 1a ). Elevated numbers of hepatic neutrophils were evident throughout the disease process and underwent a steady increase until 40 weeks where they were accompanied by enlarged livers, substantial tumour frequency ( Fig. 1b ), large tumours ( Supplementary Fig. 1b ) and high numbers of PCNA+ proliferating hepatocytes (PCNA+) ( Fig. 1c ). To determine whether neutrophils contribute to DEN-induced HCC, mice were treated between weeks 32 and 40 with an antibody specific for the mouse neutrophil antigen Ly6G, known to effectively suppress neutrophil recruitment to tissues 12 . We confirmed that anti-Ly6G suppressed DEN-induced hepatic neutrophil accumulation with little effect on F4/80+ macrophages or CD3+ lymphocytes ( Supplementary Fig. 1c ). Selective depletion of neutrophils was associated with a 3.5-fold reduction in tumour burden at 40 weeks and a slight reduction in liver/body weight ratio ( Fig. 1d ). Mice lacking nfkb1 (encoding the NF-κB p50 subunit) display exaggerated neutrophil inflammatory responses to injury in multiple organs, including the liver 13 , 14 , 15 . Early (5 weeks) and persistent elevation of hepatic neutrophils was observed in DEN-injured nfkb1 −/− mice ( Fig. 1a ). Furthermore, these animals exhibited rapid progression to aggressive HCC ( Fig. 1b ). Of note, Cyp2E1 expression ( Supplementary Fig. 1d ) and levels of liver injury and apoptosis ( Supplementary Table 1 and Supplementary Fig. 1e ) were similar between the two genotypes, ruling out the possibility that differences in DEN-induced liver injury caused the increased tumour burden. Dysplastic cells and small tumours were evident at 20 weeks ( Supplementary Fig. 2a ) in nfkb1 −/− mice, and by 30 weeks there was an average of 32 visible surface liver tumour foci compared with just 3 for wild type (WT; Fig. 1b ). By week 40, an average of 73 and 12 surface growths were recorded for nfkb1 −/− and WT, respectively. Accelerated disease in nfkb1 −/− liver was confirmed by increased cell proliferation ( Fig. 1c ), elevated hepatic expression of cyclin D1 ( Supplementary Fig. 2b ) and loss of phospho-p38α ( Supplementary Fig. 2c ), the latter being a feature of advanced human HCCs 16 . C57BL/6 mice have a characteristically low rate (<4%) for the development of spontaneous liver cancer. We were therefore surprised to observe spontaneous CLD, a nodular appearance of the liver surface, emergence of dysplastic nodules, an increase in liver/body weight ratio and tumour frequency at 20 months in nfkb1 −/− males ( Fig.<|im_end|> <|im_start|>assistant A team of Newcastle University scientists have found that specialised immune cells in our bodies that normally act to protect us from infections can have a dark side in the development of liver cancer. In a paper published in the journal Nature Communications, the team describes how cells called neutrophils can promote cancer-inducing effects in liver cells that are already damaged due to chronic disease. It is already known that chronic liver inflammation or hepatitis are risk factors for developing a particular type of liver cancer known as hepatocellular carcinoma (HCC). However, inflammation is a complicated process involving many different types of cells from our immune system working together. This has made it difficult to determine the molecular links between inflammation and HCC. This latest research identified neutrophils as a key inflammatory cell type that drives the progression of liver damage to cancer in mice. The team at Newcastle University's Institute of Cellular Medicine - Derek Mann, Professor of Hepatology, Dr Fiona Oakley and Dr Caroline Wilson - showed that among the effects that neutrophils produce, is an increase in Reactive Oxygen Species (ROS), part of normal cell metabolism which at low levels helps the body's immune system but which can cause damage to cellular components, including damage to DNA, if they reach high levels. Professor Mann explains: "Neutrophils normally help our bodies to fight infections by producing powerful substances that kill germs. They are also sent to our liver when it is damaged by substances like alcohol, only in this scenario, when the liver is being subjected to sustained damage on an ongoing basis, there is a continuous flow of neutrophils to the damaged site. This overwhelming response, and the flood of germ-killing molecules the neutrophils release, can actually harm the genetic material in liver cells and stimulate cancer growth." The research, which was jointly funded by the European Commission, Medical Research Council and the Wellcome Trust, also suggested a possible way towards stopping the cancer-promoting actions of neutrophils. Dr Oakley added: "We found that neutrophils cause an increase in ROS in liver cells and this damages their DNA which can be a trigger for cancer growth. Remarkably, anti-oxidants were able to almost completely stop HCC in our experiments" Dr Mann commented: "Now we know that neutrophils are the culprits we can move forward with new studies aimed at stopping their cancer-promoting activities in high risk patients suffering from severe liver disease. We need to develop our understanding of how we might be able to prevent ongoing neutrophil traffic to the liver, or block the release of ROS. We also need to carry out more work to understand how we might be able to use anti-oxidants, naturally found in fruits and vegetables." Liver cancer is a devastating disease with a poor prognosis and limited therapeutic options. The World Health Organisation estimate that liver cancer was the second leading cause of cancer deaths in 2012, accounting for almost 750,000 deaths worldwide. <|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 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death and contributes to tumor rejection by cytotoxic lymphocytes in cancer immunosurveillance and immunotherapy. TRAIL and TRAIL receptor agonists have garnered wide popularity as promising agents for cancer therapy. We previously demonstrated that the loss of fucosylation in cancer cells impairs TRAIL sensitivity; however, the precise structures of the fucosylated glycans that regulate TRAIL sensitivity and their carrier molecules remain elusive. Herein, we observed that Lewis glycans among various fucosylated glycans positively regulate TRAIL-induced cell death. Specifically, Lewis glycans on lacto/neolacto glycosphingolipids, but not glycoproteins including TRAIL receptors, enhanced TRAIL-induced formation of the cytosolic caspase 8 complex, without affecting the formation of the membranous receptor complex. Furthermore, type I Lewis glycan expression in colon cancer cell lines and patient-derived cancer organoids was positively correlated with TRAIL sensitivity. These findings provide novel insights into the regulatory mechanism of TRAIL-induced cell death and facilitate the identification of novel predictive biomarkers for TRAIL-related cancer therapies in future. Introduction Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the death ligand family, which can induce cell death by binding to cognate death receptors (DRs). TRAIL contributes to tumor rejection by cytotoxic lymphocytes in cancer immunosurveillance and thereby plays a pivotal role in cancer immunotherapy [ 1 ]. In addition, the treatment of tumor-bearing mice with recombinant TRAIL or agonistic antibodies targeting TRAIL receptors, DR4 or DR5, successfully eliminates tumor cells by inducing cell death without significant toxicity toward normal tissues. Consequently, TRAIL has attracted considerable attention as a promising target for cancer therapy [ 2 ]. However, certain cancer cells are resistant to TRAIL-induced cell death [ 3 ]. Therefore, understanding the precise underlying molecular mechanism of TRAIL-induced cell death and identifying predictive biomarkers to determine the TRAIL sensitivity of cancer cells are critical for designing effective cancer therapies. Upon ligand binding, DR4 and DR5 form higher-order receptor clusters and recruit Fas-associated death domain (FADD) owing to their interaction via homotypic death domain (DD). Thereafter, FADD recruits caspase 8 and nucleates its oligomerization [ 4 , 5 ]. This membrane-bound receptor complex is known as the death-inducing signaling complex (DISC). Caspase 8 is activated by proximity-induced auto-cleavage within DISC and it triggers apoptosis by cleaving caspase 3, either directly or via the mitochondrial pathway. After this early event on cell membranes, FADD and caspase 8 dissociate from the receptor complex and maintain their interaction in the cytosol. This secondary cytosolic complex, termed Complex II, magnifies the apoptotic signal by further activating caspase 8 and also imparts gene-activating signaling [ 6 , 7 , 8 , 9 , 10 ]. Cytosolic signaling proteins in DISC and their post-translational modifications, such as K63- and M1-linked ubiquitination, regulate the formation of Complex II [ 11 ]. However, the detailed mechanism underlying the transition from membrane-bound DISC to cytosolic Complex II remains unexplored. Fucosylation, which is a type of glycosylation, occurs in the Golgi apparatus, in which fucosyltransferases transfer fucose from the donor substrate, GDP-fucose, to oligosaccharides on proteins and lipids via α1-2, α1-3, α1-4, and α1-6 linkages [ 12 ]. An additional type of fucosylation is O -linked fucosylation, which is rare and found only in certain proteins, such as Notch and thrombospondin [ 13 ]. GDP-fucose is synthesized via sequential reactions by multiple enzymes in the cytosol, and is transported to the Golgi apparatus by the GDP-fucose transporter. The expression of fucosylated glycans depends on the activities of fucosyltransferases, and the availability of acceptor substrates and GDP-fucose. Among the various types of fucosylated glycans, α1-3 and α1-4, termed as type II and type I Lewis glycans, respectively, are well-known cancer-related antigens [ 14 ]. In particular, sialylated Lewis glycans, such as sialyl Lewis A (sLe a , CA19-9) and sialyl Lewis X (sLe x ), are established tumor markers that are used for the diagnosis and prediction of various types of cancer. In our previous study, we demonstrated that the loss of fucosylation in cancer cells due to the deficiency of GDP-mannose-4,6-dehydratase (GMDS), an essential enzyme for the synthesis of GDP-fucose, reduces sensitivity to TRAIL-induced apoptosis, thereby conferring the cancer cells resistance to natural killer cell-mediated cytotoxicity [ 15 , 16 ]. Other studies have also revealed that the fucosyltransferases, FUT3 and FUT6, positively affect TRAIL-induced apoptosis [ 17 , 18 ]. However, the fucosylated glycan structures and the associated carrier molecules that modulate TRAIL sensitivity are yet to be identified. Herein, we observed that Lewis glycans facilitate TRAIL-induced cell death. Interestingly, Lewis glycans specifically promoted caspase 8 oligomerization and activation in Complex II without affecting the oligomerization of DR4, DR5, and caspase 8 in DISC. We also found that Lewis glycans were not detected on DR4 and DR5, and that Lewis glycans on lacto/neolacto-glycolipids, but not glycoproteins, play a critical role in the regulation of TRAIL-induced cell death. Furthermore, using various human colon cancer cell lines and colon cancer patient-derived cancer organoids, we found that cancer cells with high expression of type I Lewis glycans were highly sensitive to TRAIL-induced cell death. These findings elucidate a novel regulatory mechanism of TRAIL-induced cell death and provide an avenue for the identification of biomarkers that can be used to effectively predict the TRAIL sensitivity of cancer cells. Results Lewis glycans promote TRAIL-induced apoptosis We previously reported that the colon cancer cell line, HCT116, lacks GDP-fucose owing to mutation in the GMDS gene and is thus deficient in all types of fucosylated glycans [ 15 ]. HCT116 cells rescued by the ectopic expression of wild-type GMDS (HCT GMDS cells) exhibit improved caspase 8 activation and apoptosis in response to the stimulation by TRAIL, in comparison to HCT mock cells. HCT GMDS cells expressed various types of fucosylated glycans, except for type II Lewis glycans, such as Le x and sLe x (Fig. 1A ). To determine which types of fucosylated glycans promote TRAIL-induced apoptosis, we independently deleted individual fucosyltransferases responsible for the generation of each type of fucosylated glycans in HCT GMDS cells (Fig. 1A ). The", "role": "user" }, { "content": "A cytokine named TRAIL binds to TRAIL receptors and kills cancer cells, but not normal cells. Various anticancer drugs targeting TRAIL receptors have been developed and gained great attention as a promising cancer therapeutics, but a certain population of cancer patients does not respond to the therapy. Therefore, many researchers have tried to identify a key molecule that determines the sensitivity of cancer cells to the TRAIL therapy. The surface of every cell in our body is decorated with sugar chains called glycans, which determine the character of cells and enable cells to talk to each other. Glycan structures on the cell surface dramatically change when cells become cancerous. In this multi-institutional study published in Oncogene and led by Associate Professor Moriwaki in Toho University and Professor Miyoshi in Osaka University, researchers identified the glycan structure that makes cancer cells vulnerable to the death-inducing cytokine known as TRAIL, and paved a new way to develop a predictive biomarker for the TRAIL therapy. Previously, Drs. Moriwaki and Miyoshi had found that fucose, which is one of building blocks of glycans, is an important sugar affecting the sensitivity of cancer cells to TRAIL. This time, they closely looked at the structures of glycans carrying fucose and discovered that cancer cells highly expressing the specific glycan structure named Lewis glycans on the surface were more vulnerable to TRAIL-induced cell death. They also found that although Lewis glycans are attached to proteins and lipids on the surface, Lewis glycans on lipids, but not on proteins, enhance TRAIL sensitivity. Furthermore, they could predict the sensitivity of colon cancer patient-derived cancer cells to TRAIL-induced cell death by testing the expression level of Lewis glycans. Therefore, this specific glycan structure is expected to be a valuable biomarker to predict the effectiveness of the TRAIL therapy. Dr. Tomoya Fukuoka, a lead author of the study, said, \"These findings shed light on the regulatory mechanism of TRAIL-induced cell death and encourage the development of a novel therapeutic strategy targeting the TRAIL signaling. Furthermore, TRAIL resistance is a vital intrinsic mechanism that renders cancer cells insensitive to certain kind of cancer immunotherapy, so these findings also have a great impact on the development of a predictive biomarker for cancer immunotherapy.\" This research was conducted in collaboration with Drs. Keiichi Ozono at Osaka University, Masahiro Inoue at Kyoto University, Yasuhide Miyamoto at Osaka International Cancer Institute, and Hiroyuki Kaji at National Institute of Advanced Industrial Science and Technology. ", "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 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death and contributes to tumor rejection by cytotoxic lymphocytes in cancer immunosurveillance and immunotherapy. TRAIL and TRAIL receptor agonists have garnered wide popularity as promising agents for cancer therapy. We previously demonstrated that the loss of fucosylation in cancer cells impairs TRAIL sensitivity; however, the precise structures of the fucosylated glycans that regulate TRAIL sensitivity and their carrier molecules remain elusive. Herein, we observed that Lewis glycans among various fucosylated glycans positively regulate TRAIL-induced cell death. Specifically, Lewis glycans on lacto/neolacto glycosphingolipids, but not glycoproteins including TRAIL receptors, enhanced TRAIL-induced formation of the cytosolic caspase 8 complex, without affecting the formation of the membranous receptor complex. Furthermore, type I Lewis glycan expression in colon cancer cell lines and patient-derived cancer organoids was positively correlated with TRAIL sensitivity. These findings provide novel insights into the regulatory mechanism of TRAIL-induced cell death and facilitate the identification of novel predictive biomarkers for TRAIL-related cancer therapies in future. Introduction Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the death ligand family, which can induce cell death by binding to cognate death receptors (DRs). TRAIL contributes to tumor rejection by cytotoxic lymphocytes in cancer immunosurveillance and thereby plays a pivotal role in cancer immunotherapy [ 1 ]. In addition, the treatment of tumor-bearing mice with recombinant TRAIL or agonistic antibodies targeting TRAIL receptors, DR4 or DR5, successfully eliminates tumor cells by inducing cell death without significant toxicity toward normal tissues. Consequently, TRAIL has attracted considerable attention as a promising target for cancer therapy [ 2 ]. However, certain cancer cells are resistant to TRAIL-induced cell death [ 3 ]. Therefore, understanding the precise underlying molecular mechanism of TRAIL-induced cell death and identifying predictive biomarkers to determine the TRAIL sensitivity of cancer cells are critical for designing effective cancer therapies. Upon ligand binding, DR4 and DR5 form higher-order receptor clusters and recruit Fas-associated death domain (FADD) owing to their interaction via homotypic death domain (DD). Thereafter, FADD recruits caspase 8 and nucleates its oligomerization [ 4 , 5 ]. This membrane-bound receptor complex is known as the death-inducing signaling complex (DISC). Caspase 8 is activated by proximity-induced auto-cleavage within DISC and it triggers apoptosis by cleaving caspase 3, either directly or via the mitochondrial pathway. After this early event on cell membranes, FADD and caspase 8 dissociate from the receptor complex and maintain their interaction in the cytosol. This secondary cytosolic complex, termed Complex II, magnifies the apoptotic signal by further activating caspase 8 and also imparts gene-activating signaling [ 6 , 7 , 8 , 9 , 10 ]. Cytosolic signaling proteins in DISC and their post-translational modifications, such as K63- and M1-linked ubiquitination, regulate the formation of Complex II [ 11 ]. However, the detailed mechanism underlying the transition from membrane-bound DISC to cytosolic Complex II remains unexplored. Fucosylation, which is a type of glycosylation, occurs in the Golgi apparatus, in which fucosyltransferases transfer fucose from the donor substrate, GDP-fucose, to oligosaccharides on proteins and lipids via α1-2, α1-3, α1-4, and α1-6 linkages [ 12 ]. An additional type of fucosylation is O -linked fucosylation, which is rare and found only in certain proteins, such as Notch and thrombospondin [ 13 ]. GDP-fucose is synthesized via sequential reactions by multiple enzymes in the cytosol, and is transported to the Golgi apparatus by the GDP-fucose transporter. The expression of fucosylated glycans depends on the activities of fucosyltransferases, and the availability of acceptor substrates and GDP-fucose. Among the various types of fucosylated glycans, α1-3 and α1-4, termed as type II and type I Lewis glycans, respectively, are well-known cancer-related antigens [ 14 ]. In particular, sialylated Lewis glycans, such as sialyl Lewis A (sLe a , CA19-9) and sialyl Lewis X (sLe x ), are established tumor markers that are used for the diagnosis and prediction of various types of cancer. In our previous study, we demonstrated that the loss of fucosylation in cancer cells due to the deficiency of GDP-mannose-4,6-dehydratase (GMDS), an essential enzyme for the synthesis of GDP-fucose, reduces sensitivity to TRAIL-induced apoptosis, thereby conferring the cancer cells resistance to natural killer cell-mediated cytotoxicity [ 15 , 16 ]. Other studies have also revealed that the fucosyltransferases, FUT3 and FUT6, positively affect TRAIL-induced apoptosis [ 17 , 18 ]. However, the fucosylated glycan structures and the associated carrier molecules that modulate TRAIL sensitivity are yet to be identified. Herein, we observed that Lewis glycans facilitate TRAIL-induced cell death. Interestingly, Lewis glycans specifically promoted caspase 8 oligomerization and activation in Complex II without affecting the oligomerization of DR4, DR5, and caspase 8 in DISC. We also found that Lewis glycans were not detected on DR4 and DR5, and that Lewis glycans on lacto/neolacto-glycolipids, but not glycoproteins, play a critical role in the regulation of TRAIL-induced cell death. Furthermore, using various human colon cancer cell lines and colon cancer patient-derived cancer organoids, we found that cancer cells with high expression of type I Lewis glycans were highly sensitive to TRAIL-induced cell death. These findings elucidate a novel regulatory mechanism of TRAIL-induced cell death and provide an avenue for the identification of biomarkers that can be used to effectively predict the TRAIL sensitivity of cancer cells. Results Lewis glycans promote TRAIL-induced apoptosis We previously reported that the colon cancer cell line, HCT116, lacks GDP-fucose owing to mutation in the GMDS gene and is thus deficient in all types of fucosylated glycans [ 15 ]. HCT116 cells rescued by the ectopic expression of wild-type GMDS (HCT GMDS cells) exhibit improved caspase 8 activation and apoptosis in response to the stimulation by TRAIL, in comparison to HCT mock cells. HCT GMDS cells expressed various types of fucosylated glycans, except for type II Lewis glycans, such as Le x and sLe x (Fig. 1A ). To determine which types of fucosylated glycans promote TRAIL-induced apoptosis, we independently deleted individual fucosyltransferases responsible for the generation of each type of fucosylated glycans in HCT GMDS cells (Fig. 1A ). The<|im_end|> <|im_start|>assistant A cytokine named TRAIL binds to TRAIL receptors and kills cancer cells, but not normal cells. Various anticancer drugs targeting TRAIL receptors have been developed and gained great attention as a promising cancer therapeutics, but a certain population of cancer patients does not respond to the therapy. Therefore, many researchers have tried to identify a key molecule that determines the sensitivity of cancer cells to the TRAIL therapy. The surface of every cell in our body is decorated with sugar chains called glycans, which determine the character of cells and enable cells to talk to each other. Glycan structures on the cell surface dramatically change when cells become cancerous. In this multi-institutional study published in Oncogene and led by Associate Professor Moriwaki in Toho University and Professor Miyoshi in Osaka University, researchers identified the glycan structure that makes cancer cells vulnerable to the death-inducing cytokine known as TRAIL, and paved a new way to develop a predictive biomarker for the TRAIL therapy. Previously, Drs. Moriwaki and Miyoshi had found that fucose, which is one of building blocks of glycans, is an important sugar affecting the sensitivity of cancer cells to TRAIL. This time, they closely looked at the structures of glycans carrying fucose and discovered that cancer cells highly expressing the specific glycan structure named Lewis glycans on the surface were more vulnerable to TRAIL-induced cell death. They also found that although Lewis glycans are attached to proteins and lipids on the surface, Lewis glycans on lipids, but not on proteins, enhance TRAIL sensitivity. Furthermore, they could predict the sensitivity of colon cancer patient-derived cancer cells to TRAIL-induced cell death by testing the expression level of Lewis glycans. Therefore, this specific glycan structure is expected to be a valuable biomarker to predict the effectiveness of the TRAIL therapy. Dr. Tomoya Fukuoka, a lead author of the study, said, "These findings shed light on the regulatory mechanism of TRAIL-induced cell death and encourage the development of a novel therapeutic strategy targeting the TRAIL signaling. Furthermore, TRAIL resistance is a vital intrinsic mechanism that renders cancer cells insensitive to certain kind of cancer immunotherapy, so these findings also have a great impact on the development of a predictive biomarker for cancer immunotherapy." This research was conducted in collaboration with Drs. Keiichi Ozono at Osaka University, Masahiro Inoue at Kyoto University, Yasuhide Miyamoto at Osaka International Cancer Institute, and Hiroyuki Kaji at National Institute of Advanced Industrial Science and Technology. <|im_end|>

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2,099

[ { "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 genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A’s association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency <1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD. Introduction Bipolar disorder (BPD) affects ∼ 2.5% of the United States population aged 18 and older based on data from the population-based National Comorbidity Survey Replication. 1 The risk of BPD for a first-degree relative of an affected individual is 9%, and the concordance rate for monozygotic twins is 40–45%. 2 Relatives of BPD probands are also at an increased risk of other related psychiatric disorders, such as psychotic, anxiety, substance abuse and impulse control disorders. 1 , 2 , 3 , 4 With an overall heritability estimated at 80–90%, 2 these and other findings make clear that susceptibility to BPD has a very strong genetic basis that overlaps with the genetic susceptibility for other neuropsychiatric disorders. The two most common subtypes of BPD are bipolar disorder I (BPD I) and bipolar disorder II (BPD II). The lifetime risks in the US population is 1% for BPD I and 1.1% for BPD II. 1 The clinical course of BPD I and BPD II differ in that BPD I patients exhibit one or more manic episodes while BPD II patients are characterized by recurrent depressive episodes. 2 , 3 Recurrence of manic/depressive episodes and associated disabilities is common 5 , 6 , 7 and there exists no curative treatment. Although BPD I and BPD II have been shown to co-segregate within families, 2 , 8 the diverse clinical symptoms indicate that subtypes of the BPD phenotype exist and/or that phenotypic modifiers are involved. 9 The identification of BPD I and BPD II susceptibility genes may lead to more effective targets for therapy. Several recent genome-wide genetic association studies and meta-analyses 2 , 10 have jointly analyzed BPD I and BPD II subjects, 10 , 11 , 12 , 13 , 14 , 15 , 16 or have focused only on BPD I subjects. 17 , 18 , 19 One motivation for grouping the subtypes is that it remains possible that BPD II is a milder form of BPD I as opposed to being a distinct disorder. However, genetic heterogeneity can reduce the power to detect susceptibility variants when samples of BPD I and BPD II are combined for analysis. For this study, we analyzed BPD I and BPD II separately to increase the likelihood of genetic homogeneity among cases. A substantial body of evidence indicates a relationship between BPD and cyclic adenosine monophosphate (cAMP) signaling although the specific nature of the relationship remains obscure (reviewed in Gould and Manji 20 and Dwivedi and Pandy 21 ). Several studies on peripheral cells or post-mortem brain have reported that basal and receptor-activated adenylyl cyclase (AC) activities are increased in BPD patients. 22 , 23 Other studies have reported that the mood stabilizers lithium and carbamazepine interact directly or indirectly to attenuate the receptor-activation of ACs, 24 , 25 , 26 , 27 , 28 , 29 consistent with the possibility that an increased AC activity or activation is a biochemical phenotype associated with BPD. Several studies have shown that mRNA levels for Gαs, the stimulatory G-protein that couples with AC, are increased in peripheral cells of BPD patients. 30 , 31 , 32 , 33 , 34 Post-mortem analyses on brain have demonstrated an increased abundance of the Gαs protein, but not Gαi or Gαo, 32 , 30 and lithium has been found to decrease the abundance of mRNAs for several G-proteins. 35 , 36 Lithium may also decrease the coupling of receptors to G-proteins. 22 , 26 , 37 , 38 , 39 Post-mortem analyses have demonstrated a decreased level of the regulatory subunits for protein kinase A (PKA) in BPD, 40 with increased PKA activity observed in lymphocytes and platelets from BPD subjects. 41 , 42 Some substrates of PKA have been found to be hyperphosphorylated and increased PKA activity and immunoreactivity have been observed in post-mortem brain 43 , 44 and in peripheral cells 41 , 45 , 46 , 47 of BPD patients. Finally, the antidepressant rolipram inhibits cAMP phosphodiesterases (PDE) of the dunce class of PDEs (PDE4), 48 implicating this class of enzymes in the general state of depression. PDE4 expression is also altered in both BPD and schizophrenia. 49 Overall, the evidence strongly suggests that aberrant cAMP signaling is part of the spectrum of biochemical phenotypes associated with BPD. Because of the well-established roles of cAMP in regulating behavioral processes, we hypothesize that genetic variation in the cAMP pathway genes is associated BPD etiology. To test this hypothesis, and to identify", "role": "user" }, { "content": "(Medical Xpress)—Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small variations in a number of genes that are closely linked to an increased risk of bipolar disorder, a mental illness that affects nearly six million Americans, according to the National Institute of Mental Health. \"Using samples from some 3,400 individuals, we identified several new variants in genes closely associated with bipolar disorder,\" said Scripps Florida Professor Ron Davis, who led the new study, which was published recently by the journal Translational Psychiatry. A strong tendency towards bipolar disorder runs in families; children with a parent or sibling who has bipolar disorder are four to six times more likely to develop the illness, according to the National Institute of Mental Health. While the genetic basis for bipolar disorder is complex and involves multiple genes, it appears to be associated with a biochemical pathway known as cyclic adenosine monophosphate (cAMP) signaling system. The Davis laboratory and others have previously shown that the cAMP signaling plays a critical role in learning and memory processes. The new study focused on this signaling pathway. \"As far as I know, this has not been done before—to query a single signaling pathway,\" said Davis. \"This is a new approach. The idea is if there are variants in one gene in the pathway that are associated with bipolar disorder, it makes sense there would be variants in other genes of the same signaling pathway also associated with the disorder.\" The new study examined variations in 29 genes found in the two common types of bipolar disorder—bipolar disorder I (the most common form and the most severe) and bipolar disorder II. Genes from a total of 1,172 individuals with bipolar disorder I; 516 individuals with bipolar disorder II; and 1,728 controls were analyzed. Several statistically significant associations were noted between bipolar disorder I and variants in the PDE10A gene. Associations were also found between bipolar disorder II and variants in the DISC1 and GNAS genes. Davis noted that the location of PDE10A gene expression in the striatum, the part of the brain associated with learning and memory, decision making and motivation, makes it especially interesting as a therapeutic target. ", "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 genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A’s association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency <1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD. Introduction Bipolar disorder (BPD) affects ∼ 2.5% of the United States population aged 18 and older based on data from the population-based National Comorbidity Survey Replication. 1 The risk of BPD for a first-degree relative of an affected individual is 9%, and the concordance rate for monozygotic twins is 40–45%. 2 Relatives of BPD probands are also at an increased risk of other related psychiatric disorders, such as psychotic, anxiety, substance abuse and impulse control disorders. 1 , 2 , 3 , 4 With an overall heritability estimated at 80–90%, 2 these and other findings make clear that susceptibility to BPD has a very strong genetic basis that overlaps with the genetic susceptibility for other neuropsychiatric disorders. The two most common subtypes of BPD are bipolar disorder I (BPD I) and bipolar disorder II (BPD II). The lifetime risks in the US population is 1% for BPD I and 1.1% for BPD II. 1 The clinical course of BPD I and BPD II differ in that BPD I patients exhibit one or more manic episodes while BPD II patients are characterized by recurrent depressive episodes. 2 , 3 Recurrence of manic/depressive episodes and associated disabilities is common 5 , 6 , 7 and there exists no curative treatment. Although BPD I and BPD II have been shown to co-segregate within families, 2 , 8 the diverse clinical symptoms indicate that subtypes of the BPD phenotype exist and/or that phenotypic modifiers are involved. 9 The identification of BPD I and BPD II susceptibility genes may lead to more effective targets for therapy. Several recent genome-wide genetic association studies and meta-analyses 2 , 10 have jointly analyzed BPD I and BPD II subjects, 10 , 11 , 12 , 13 , 14 , 15 , 16 or have focused only on BPD I subjects. 17 , 18 , 19 One motivation for grouping the subtypes is that it remains possible that BPD II is a milder form of BPD I as opposed to being a distinct disorder. However, genetic heterogeneity can reduce the power to detect susceptibility variants when samples of BPD I and BPD II are combined for analysis. For this study, we analyzed BPD I and BPD II separately to increase the likelihood of genetic homogeneity among cases. A substantial body of evidence indicates a relationship between BPD and cyclic adenosine monophosphate (cAMP) signaling although the specific nature of the relationship remains obscure (reviewed in Gould and Manji 20 and Dwivedi and Pandy 21 ). Several studies on peripheral cells or post-mortem brain have reported that basal and receptor-activated adenylyl cyclase (AC) activities are increased in BPD patients. 22 , 23 Other studies have reported that the mood stabilizers lithium and carbamazepine interact directly or indirectly to attenuate the receptor-activation of ACs, 24 , 25 , 26 , 27 , 28 , 29 consistent with the possibility that an increased AC activity or activation is a biochemical phenotype associated with BPD. Several studies have shown that mRNA levels for Gαs, the stimulatory G-protein that couples with AC, are increased in peripheral cells of BPD patients. 30 , 31 , 32 , 33 , 34 Post-mortem analyses on brain have demonstrated an increased abundance of the Gαs protein, but not Gαi or Gαo, 32 , 30 and lithium has been found to decrease the abundance of mRNAs for several G-proteins. 35 , 36 Lithium may also decrease the coupling of receptors to G-proteins. 22 , 26 , 37 , 38 , 39 Post-mortem analyses have demonstrated a decreased level of the regulatory subunits for protein kinase A (PKA) in BPD, 40 with increased PKA activity observed in lymphocytes and platelets from BPD subjects. 41 , 42 Some substrates of PKA have been found to be hyperphosphorylated and increased PKA activity and immunoreactivity have been observed in post-mortem brain 43 , 44 and in peripheral cells 41 , 45 , 46 , 47 of BPD patients. Finally, the antidepressant rolipram inhibits cAMP phosphodiesterases (PDE) of the dunce class of PDEs (PDE4), 48 implicating this class of enzymes in the general state of depression. PDE4 expression is also altered in both BPD and schizophrenia. 49 Overall, the evidence strongly suggests that aberrant cAMP signaling is part of the spectrum of biochemical phenotypes associated with BPD. Because of the well-established roles of cAMP in regulating behavioral processes, we hypothesize that genetic variation in the cAMP pathway genes is associated BPD etiology. To test this hypothesis, and to identify<|im_end|> <|im_start|>assistant (Medical Xpress)—Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small variations in a number of genes that are closely linked to an increased risk of bipolar disorder, a mental illness that affects nearly six million Americans, according to the National Institute of Mental Health. "Using samples from some 3,400 individuals, we identified several new variants in genes closely associated with bipolar disorder," said Scripps Florida Professor Ron Davis, who led the new study, which was published recently by the journal Translational Psychiatry. A strong tendency towards bipolar disorder runs in families; children with a parent or sibling who has bipolar disorder are four to six times more likely to develop the illness, according to the National Institute of Mental Health. While the genetic basis for bipolar disorder is complex and involves multiple genes, it appears to be associated with a biochemical pathway known as cyclic adenosine monophosphate (cAMP) signaling system. The Davis laboratory and others have previously shown that the cAMP signaling plays a critical role in learning and memory processes. The new study focused on this signaling pathway. "As far as I know, this has not been done before—to query a single signaling pathway," said Davis. "This is a new approach. The idea is if there are variants in one gene in the pathway that are associated with bipolar disorder, it makes sense there would be variants in other genes of the same signaling pathway also associated with the disorder." The new study examined variations in 29 genes found in the two common types of bipolar disorder—bipolar disorder I (the most common form and the most severe) and bipolar disorder II. Genes from a total of 1,172 individuals with bipolar disorder I; 516 individuals with bipolar disorder II; and 1,728 controls were analyzed. Several statistically significant associations were noted between bipolar disorder I and variants in the PDE10A gene. Associations were also found between bipolar disorder II and variants in the DISC1 and GNAS genes. Davis noted that the location of PDE10A gene expression in the striatum, the part of the brain associated with learning and memory, decision making and motivation, makes it especially interesting as a therapeutic target. <|im_end|>

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1,887

[ { "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 Knowledge of mechanical and physical property evolution due to irradiation damage is essential for the development of future fission and fusion reactors. Ion-irradiation provides an excellent proxy for studying irradiation damage, allowing high damage doses without sample activation. Limited ion-penetration-depth means that only few-micron-thick damaged layers are produced. Substantial effort has been devoted to probing the mechanical properties of these thin implanted layers. Yet, whilst key to reactor design, their thermal transport properties remain largely unexplored due to a lack of suitable measurement techniques. Here we demonstrate non-contact thermal diffusivity measurements in ion-implanted tungsten for nuclear fusion armour. Alloying with transmutation elements and the interaction of retained gas with implantation-induced defects both lead to dramatic reductions in thermal diffusivity. These changes are well captured by our modelling approaches. Our observations have important implications for the design of future fusion power plants. Introduction Nuclear fusion is an ideal sustainable energy source. A major hurdle to its commercial development is the availability of sufficiently resilient materials. Tungsten-based alloys are the main candidates for plasma-facing components in future magnetic confinement fusion reactors 1 . In a demonstration (DEMO) reactor they will be exposed to high temperatures (~1500 K), irradiation with 14.1 MeV fusion neutrons and a large flux of energetic ions (up to 15 MWm −2 ) 2 , 3 . High thermal conductivity is one of the main material selection criteria 4 . A significant degradation of thermal conductivity could result in excessive temperatures with potentially disastrous consequences for fusion armour integrity 5 . Exposure of fusion armour to 14.1 MeV neutrons leads to cascade damage and transmutation alloying. Calculations indicate that after 5 years of operation, initially pure tungsten (W) in a DEMO divertor would contain up to 4 atomic % rhenium (Re) 6 . A W-5%Re alloy has less than half the room temperature thermal diffusivity of pure tungsten 7 , 8 . Quantifying the effects of fusion neutron cascade damage on thermal conductivity is more difficult. As a proxy, thermal transport in fission neutron irradiated tungsten has been considered 9 , 10 . A damage level of 0.6 displacements per atom (dpa), which would be reached in 3 months in DEMO 6 , caused a reduction of room temperature thermal conductivity by 25% 10 . An interesting role is played by helium, which is formed by transmutation 6 and is also implanted from the plasma into the tungsten matrix. At elevated temperatures helium migrates from surfaces into the bulk and strongly interacts with irradiation induced defects 11 , binding to vacancies 12 , 13 and supressing their recombination with self-interstitial atoms (SIAs) 14 . Helium-ion implantation is an efficient tool to study this interaction 15 and great effort has been invested into the development of micro-mechanics approaches able to quantify the mechanical properties of micron-thin ion-implanted layers 16 , 17 , 18 . The thermal transport properties of ion-damaged layers, however, are as yet largely unexplored due to a lack of suitable experimental techniques. The references cited above used either a laser flash technique 8 , 9 , 10 or electrical resistivity measurements 7 . Both are only suited to bulk samples. Recently two new approaches, the 3-omega technique 19 and thermal reflectance measurements 20 , 21 , have been proposed to quantify thermal transport in thin, ion-irradiated surface layers. The former required deposition of complex surface features on the sample and showed significant experimental uncertainties. The latter required samples to be coated and the probed depth depended on the, a priori unknown, thermal diffusivity. Here we present a new, entirely different approach to measuring the thermal transport properties of ion-implanted materials. Using the non-contact laser-induced transient grating (TG) technique 22 we quantify thermal diffusivity in few-micron-thick layers of helium-implanted tungsten. The effect of transmutation alloying is mimicked by considering tungsten-rhenium alloys. In both types of samples we find substantial changes in thermal diffusivity. They are analysed using a kinetic theory model, providing insight into the underlying defect distribution. Our results are discussed in the light of current design practise for future fusion reactors. Results TG measurements use two short excitation laser pulses that are overlapped on the sample with a well-defined crossing angle ( Fig. 1(a) ). Interference of the pulses produces a spatially sinusoidal intensity grating with a fringe spacing λ 23 . Absorption of the light leads to a temperature grating with period λ. Rapid thermal expansion also launches two counter-propagating surface acoustic waves (SAWs) 24 . Both the thermal grating and the SAWs cause displacements of the sample surface. These are detected by diffraction of a quasi-continuous probe beam, heterodyned with a reflected reference beam ( Fig. 1(b) ). Fig. 1(c) presents the signal measured from a pure tungsten sample showing a number of oscillations, due to the propagating SAWs, superimposed on a background due to the decaying temperature grating. Figure 1 Transient grating thermal transport measurements. ( a ) Schematic of the measurement setup, showing the excitation beams (at time t = 0) that form the periodic transient grating light pattern (shown schematically in green) on the sample. ( b ) At time t > 0 the temperature grating and counter-propagating surface acoustic waves at the sample surface (both shown schematically in light grey) are probed. For heterodyne detection the scattered probe beam is combined with a reflected reference beam. ( c ) Experimentally recorded time trace of scattered probe intensity for the pure tungsten sample at 296 K. Also shown is a fit to the experimental data. Inset are time traces recorded for pure tungsten and tungsten implanted with 3100 appm of helium, both at 296 K. Thermal grating decay in the implanted sample is visibly slower. Full size image On the surface of bulk samples thermal transport occurs both in-plane, from peaks to troughs of the thermal grating and into the depth of the sample. The surface profile due to the thermal grating follows a non-exponential decay 23 : Here , t is time and α is the isotropic thermal diffusivity,", "role": "user" }, { "content": "Oxford University researchers have developed a new method that makes it possible to study whether the deterioration of nuclear fusion reactor materials in the face of extreme radiation may cause catastrophic thermal failure. Nuclear fusion is an attractive option for creating sustainable energy, in principle using the same reactions found at the centre of stars to generate large quantities of power without carbon emissions. But creating those conditions on Earth is difficult, and part of the problem is finding the correct materials to contain the fierce reactions. The most common approach is to magnetically contain the high-energy particles, known as a plasma, in a tight circle running through the centre of a giant metal torus. This set-up is employed at the JET facility in Culham, just outside Oxford, as well as in the forthcoming ITER experiment in the south of France. But even constrained by large magnetic fields, the plasma still subjects the walls of the vessel, likely to be made of tungsten, to extreme conditions. 'It really is pretty horrendous in there', admits Professor Felix Hofmann of Oxford University's Department of Engineering, the lead author of the research. 'The fusion reaction creates intense neutron radiation and extreme temperatures that can easily damage the wall of the torus. 'With the fundamental physics of fusion at least close to being solved, we're now at a stage where technical implantations, like material choices for future commercial systems, are the main challenge.' Previous experiments have shown that the variations in temperature at the torus wall can produce cracks and even catastrophic failure. But Professor Hofmann suspected that the radiation in the reactor might also affect the properties of the material used in the walls, reducing its thermal conductivity—a measure of how well it conducts heat—and in turn increasing the risk of such failure. So, along with researchers from the Massachusetts Institute of Technology and the Culham Centre for Fusion Energy, his team from the Department of Engineering Science has been carrying out experiments to investigate these effects. It's not possible for researchers to recreate the conditions of a fusion reactor in the lab—it would be prohibitively expensive as well as dangerous. Instead, Professor Hofmann and his team use samples of tungsten that have been bombarded with high-energy ions as part of the Materials for Fission and Fusion Power project at the Department of Materials Science. Helium ion bombardment is a good approximation of the conditions that the torus is exposed to, but only creates a very thin layer of irradiated material, making it difficult to use conventional means to measure properties like thermal conductivity. As a result the team has adapted a technique, previously used to measure the thermal conductivity in silicon semiconductors, known as laser-induced transient grating spectroscopy. This approach uses two short laser pulses that overlap as they hit the sample. The team then used sophisticated models, developed at the Culham Centre for Fusion Energy, to predict the theoretical changes in thermal conductivity that their experimental studies should generate. 'We were amazed by just how closely the two match up,' explains Professor Hofmann. The team's results show that even a small amount of irradiation damage can have a dramatic effect on thermal conductivity, reducing it by as much as 50 percent. 'That's bad news for fusion reactors as it means that their lifetime could be significantly shortened by this effect,' explains Professor Hofmann. 'But the good news is that, with this new approach to measuring thermal conductivity, we at least now have a tool to understand the detrimental effects of the radiation in much more detail.' The team is hopeful that the technique will allow engineers to choose the most appropriate materials for use in the fusion reactors of the future. 'Fusion power looks set to be one of the main sustainable energy sources in the long term. We need to ensure we can make it a reality, quickly, safely and reliably,' explains Professor Hofmann. 'This finding will allow us to understand the physics and material science required to choose the most appropriate materials for the job.' ", "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 Knowledge of mechanical and physical property evolution due to irradiation damage is essential for the development of future fission and fusion reactors. Ion-irradiation provides an excellent proxy for studying irradiation damage, allowing high damage doses without sample activation. Limited ion-penetration-depth means that only few-micron-thick damaged layers are produced. Substantial effort has been devoted to probing the mechanical properties of these thin implanted layers. Yet, whilst key to reactor design, their thermal transport properties remain largely unexplored due to a lack of suitable measurement techniques. Here we demonstrate non-contact thermal diffusivity measurements in ion-implanted tungsten for nuclear fusion armour. Alloying with transmutation elements and the interaction of retained gas with implantation-induced defects both lead to dramatic reductions in thermal diffusivity. These changes are well captured by our modelling approaches. Our observations have important implications for the design of future fusion power plants. Introduction Nuclear fusion is an ideal sustainable energy source. A major hurdle to its commercial development is the availability of sufficiently resilient materials. Tungsten-based alloys are the main candidates for plasma-facing components in future magnetic confinement fusion reactors 1 . In a demonstration (DEMO) reactor they will be exposed to high temperatures (~1500 K), irradiation with 14.1 MeV fusion neutrons and a large flux of energetic ions (up to 15 MWm −2 ) 2 , 3 . High thermal conductivity is one of the main material selection criteria 4 . A significant degradation of thermal conductivity could result in excessive temperatures with potentially disastrous consequences for fusion armour integrity 5 . Exposure of fusion armour to 14.1 MeV neutrons leads to cascade damage and transmutation alloying. Calculations indicate that after 5 years of operation, initially pure tungsten (W) in a DEMO divertor would contain up to 4 atomic % rhenium (Re) 6 . A W-5%Re alloy has less than half the room temperature thermal diffusivity of pure tungsten 7 , 8 . Quantifying the effects of fusion neutron cascade damage on thermal conductivity is more difficult. As a proxy, thermal transport in fission neutron irradiated tungsten has been considered 9 , 10 . A damage level of 0.6 displacements per atom (dpa), which would be reached in 3 months in DEMO 6 , caused a reduction of room temperature thermal conductivity by 25% 10 . An interesting role is played by helium, which is formed by transmutation 6 and is also implanted from the plasma into the tungsten matrix. At elevated temperatures helium migrates from surfaces into the bulk and strongly interacts with irradiation induced defects 11 , binding to vacancies 12 , 13 and supressing their recombination with self-interstitial atoms (SIAs) 14 . Helium-ion implantation is an efficient tool to study this interaction 15 and great effort has been invested into the development of micro-mechanics approaches able to quantify the mechanical properties of micron-thin ion-implanted layers 16 , 17 , 18 . The thermal transport properties of ion-damaged layers, however, are as yet largely unexplored due to a lack of suitable experimental techniques. The references cited above used either a laser flash technique 8 , 9 , 10 or electrical resistivity measurements 7 . Both are only suited to bulk samples. Recently two new approaches, the 3-omega technique 19 and thermal reflectance measurements 20 , 21 , have been proposed to quantify thermal transport in thin, ion-irradiated surface layers. The former required deposition of complex surface features on the sample and showed significant experimental uncertainties. The latter required samples to be coated and the probed depth depended on the, a priori unknown, thermal diffusivity. Here we present a new, entirely different approach to measuring the thermal transport properties of ion-implanted materials. Using the non-contact laser-induced transient grating (TG) technique 22 we quantify thermal diffusivity in few-micron-thick layers of helium-implanted tungsten. The effect of transmutation alloying is mimicked by considering tungsten-rhenium alloys. In both types of samples we find substantial changes in thermal diffusivity. They are analysed using a kinetic theory model, providing insight into the underlying defect distribution. Our results are discussed in the light of current design practise for future fusion reactors. Results TG measurements use two short excitation laser pulses that are overlapped on the sample with a well-defined crossing angle ( Fig. 1(a) ). Interference of the pulses produces a spatially sinusoidal intensity grating with a fringe spacing λ 23 . Absorption of the light leads to a temperature grating with period λ. Rapid thermal expansion also launches two counter-propagating surface acoustic waves (SAWs) 24 . Both the thermal grating and the SAWs cause displacements of the sample surface. These are detected by diffraction of a quasi-continuous probe beam, heterodyned with a reflected reference beam ( Fig. 1(b) ). Fig. 1(c) presents the signal measured from a pure tungsten sample showing a number of oscillations, due to the propagating SAWs, superimposed on a background due to the decaying temperature grating. Figure 1 Transient grating thermal transport measurements. ( a ) Schematic of the measurement setup, showing the excitation beams (at time t = 0) that form the periodic transient grating light pattern (shown schematically in green) on the sample. ( b ) At time t > 0 the temperature grating and counter-propagating surface acoustic waves at the sample surface (both shown schematically in light grey) are probed. For heterodyne detection the scattered probe beam is combined with a reflected reference beam. ( c ) Experimentally recorded time trace of scattered probe intensity for the pure tungsten sample at 296 K. Also shown is a fit to the experimental data. Inset are time traces recorded for pure tungsten and tungsten implanted with 3100 appm of helium, both at 296 K. Thermal grating decay in the implanted sample is visibly slower. Full size image On the surface of bulk samples thermal transport occurs both in-plane, from peaks to troughs of the thermal grating and into the depth of the sample. The surface profile due to the thermal grating follows a non-exponential decay 23 : Here , t is time and α is the isotropic thermal diffusivity,<|im_end|> <|im_start|>assistant Oxford University researchers have developed a new method that makes it possible to study whether the deterioration of nuclear fusion reactor materials in the face of extreme radiation may cause catastrophic thermal failure. Nuclear fusion is an attractive option for creating sustainable energy, in principle using the same reactions found at the centre of stars to generate large quantities of power without carbon emissions. But creating those conditions on Earth is difficult, and part of the problem is finding the correct materials to contain the fierce reactions. The most common approach is to magnetically contain the high-energy particles, known as a plasma, in a tight circle running through the centre of a giant metal torus. This set-up is employed at the JET facility in Culham, just outside Oxford, as well as in the forthcoming ITER experiment in the south of France. But even constrained by large magnetic fields, the plasma still subjects the walls of the vessel, likely to be made of tungsten, to extreme conditions. 'It really is pretty horrendous in there', admits Professor Felix Hofmann of Oxford University's Department of Engineering, the lead author of the research. 'The fusion reaction creates intense neutron radiation and extreme temperatures that can easily damage the wall of the torus. 'With the fundamental physics of fusion at least close to being solved, we're now at a stage where technical implantations, like material choices for future commercial systems, are the main challenge.' Previous experiments have shown that the variations in temperature at the torus wall can produce cracks and even catastrophic failure. But Professor Hofmann suspected that the radiation in the reactor might also affect the properties of the material used in the walls, reducing its thermal conductivity—a measure of how well it conducts heat—and in turn increasing the risk of such failure. So, along with researchers from the Massachusetts Institute of Technology and the Culham Centre for Fusion Energy, his team from the Department of Engineering Science has been carrying out experiments to investigate these effects. It's not possible for researchers to recreate the conditions of a fusion reactor in the lab—it would be prohibitively expensive as well as dangerous. Instead, Professor Hofmann and his team use samples of tungsten that have been bombarded with high-energy ions as part of the Materials for Fission and Fusion Power project at the Department of Materials Science. Helium ion bombardment is a good approximation of the conditions that the torus is exposed to, but only creates a very thin layer of irradiated material, making it difficult to use conventional means to measure properties like thermal conductivity. As a result the team has adapted a technique, previously used to measure the thermal conductivity in silicon semiconductors, known as laser-induced transient grating spectroscopy. This approach uses two short laser pulses that overlap as they hit the sample. The team then used sophisticated models, developed at the Culham Centre for Fusion Energy, to predict the theoretical changes in thermal conductivity that their experimental studies should generate. 'We were amazed by just how closely the two match up,' explains Professor Hofmann. The team's results show that even a small amount of irradiation damage can have a dramatic effect on thermal conductivity, reducing it by as much as 50 percent. 'That's bad news for fusion reactors as it means that their lifetime could be significantly shortened by this effect,' explains Professor Hofmann. 'But the good news is that, with this new approach to measuring thermal conductivity, we at least now have a tool to understand the detrimental effects of the radiation in much more detail.' The team is hopeful that the technique will allow engineers to choose the most appropriate materials for use in the fusion reactors of the future. 'Fusion power looks set to be one of the main sustainable energy sources in the long term. We need to ensure we can make it a reality, quickly, safely and reliably,' explains Professor Hofmann. 'This finding will allow us to understand the physics and material science required to choose the most appropriate materials for the job.' <|im_end|>

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2,167

[ { "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 establishment of covalent junctions between carbon nanotubes (CNTs) and the modification of their straight tubular morphology are two strategies needed to successfully synthesize nanotube-based three-dimensional (3D) frameworks exhibiting superior material properties. Engineering such 3D structures in scalable synthetic processes still remains a challenge. This work pioneers the bulk synthesis of 3D macroscale nanotube elastic solids directly via a boron-doping strategy during chemical vapour deposition, which influences the formation of atomic-scale “elbow” junctions and nanotube covalent interconnections. Detailed elemental analysis revealed that the “elbow” junctions are preferred sites for excess boron atoms, indicating the role of boron and curvature in the junction formation mechanism, in agreement with our first principle theoretical calculations. Exploiting this material’s ultra-light weight, super-hydrophobicity, high porosity, thermal stability and mechanical flexibility, the strongly oleophilic sponge-like solids are demonstrated as unique reusable sorbent scaffolds able to efficiently remove oil from contaminated seawater even after repeated use. Introduction Since the advent of carbon nanotubes (CNTs) 1 , 2 , engineering and controlled synthesis of these had been thoroughly investigated. Doping multi-walled (MW) and single-walled (SW) CNTs with elements such as nitrogen and boron had been used for altering their electronic properties for specific applications 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . It was later found that dopant atoms such as nitrogen or sulfur can also induce dramatic tubule morphology changes in CNTs, including covalent multi-junctions 12 , 13 , 14 , 15 , however never were these morphologies exploited to create 3D macroscale architectures. Theoretical studies had predicted that significant structural reorganization generates stable bends in CNTs due to the presence of pentagon-heptagon defects 16 that could accommodate foreign atoms besides carbon within the sp 2 hybridized carbon lattice 15 . In addition, it was found that boron doping acts as a “surfactant” during growth to significantly increase the aspect ratio of nanotubes by preventing tube closure – allowing longer tube lengths to be synthesized (~ 5–100 µm) and favoring the zigzag (or near zigzag) chirality 17 . Boron-doped MWCNTs (CB X MWNTs) could be synthesized by chemical vapour deposition (CVD) using various hydrocarbons and boron sources 18 , 19 , 20 , 21 , but none of these works yielded 3D solid structures, or were able to confirm the distinct tubular morphologies induced by boron found in this article. Theoretical and experimental research had demonstrated that boron interstitial atoms located between double-walled CNTs act as atomic “fusers” or “welders” under high temperature annealing (1400 – 1600°C) 22 , thus establishing covalent tube interconnections, but neither did this work produce macroscale solids. 3D solids of straight entangled non-doped CNTs were recently reported by others to create compressible sponges 23 and temperature-invariant viscoelastic solids 24 . However neither of these works show promise towards any degree of covalent bonding established between CNTs; nor do they possess dramatic defect sites within the CNT network. An abundance of localized and topological defects, including extreme tubular morphologies, are impactful features for many applications requiring further CNT functionalization chemistry, or anchor-sites for molecular/atomic/nanoparticle adsorption (decoration) within the 3D porous solid. Furthermore, substitutionally doped CNTs provide enhanced chemical reactivity. To the best of our knowledge, this material is the first demonstration to exploit the uniqueness of heteroatom substitutional dopant effects on CNT morphology to create elastic 3D macrostructures. The combination of boron’s interstitial “welding” and “surfactant” effects, makes the doping route a major step in the direction to realizing true (covalent) 3D hypothetical “superstructures” such as CNT monoliths, or interlocked nanotube ring structures recently proposed by Gogotsi 25 . These architectures had been studied theoretically as fascinating future materials with superior mechanical and electrical properties 26 . In this article, we describe the importance of substitutional doping effects of boron, experimentally and theoretically, so as to create a networked CB X MWNT solid. We further demonstrate that these materials possess intriguing dynamic mechanical properties and can be used as a reusable oil sorbent scaffold material in seawater. Results The CB X MWNT solids were grown directly onto the walls of a quartz tube furnace via an aerosol-assisted catalytic chemical vapour deposition (AACVD) method using triethylborane (TEB) (Aldrich >95%) as the boron source. High mass quantities (2–3 g) of CB X MWNT material was produced in just 30 minutes of growth (60–100 mg/min.), in the form of macroscopic elastic solids (see Supplementary Fig. S1 online), exhibiting fascinating physico-chemical properties including oleophilicity. The sample can be bent to a dramatic degree without breaking and will return to original position after released (see Fig. 1 a, b ). Supplementary Movie S1 demonstrates the robust mechanical durability and flexibility in response to ‘flicking’ a sample by hand in a cantilever loading fashion. Remarkably, the bulk densities of the porous solids were measured to be in the range of 10 to 29 mg/cm 3 (compared to low density carbon aerogel of 60 mg/cm 3 ). The nanotube diameters ranged from 40 to 150 nm, as measured from electron microscopy images ( Fig. 1 ). The synthesized 3D architectures are entirely made up of randomly orientated and entangled CNTs with little to no amorphous carbon as depicted from SEM ( Fig. 1c ). The X-ray powder diffraction pattern shows that as-produced CB X MWNT sponges are indeed crystalline and showed sharp (002) diffraction peaks, but no evidence of B 4 C phases were found (see Supplementary Fig. S2 online). Raman spectra of the sponges are compared to those of pristine MWCNTs (see Supplementary Fig. S3 online). In this context, we noted an intense D-band, which is expected considering the contribution of boron atoms embedded in the hexagonal sp 2 hybridized network of CNT sponges. Boron induces atomic-scale “elbow” junctions, as depicted in Fig. 1d and Supplementary Fig. S4 online. Many other fascinating nanotube morphologies, including covalent multi-junctions such as Y-junctions (see Supplementary Fig. S5 online) and four-way junctions ( Fig. 1 e and f ), were found within the entangled network structure. The most abundant of the morphologies", "role": "user" }, { "content": "(Phys.org) -- Researchers at Rice University and Penn State University have discovered that adding a dash of boron to carbon while creating nanotubes turns them into solid, spongy, reusable blocks that have an astounding ability to absorb oil spilled in water. That’s one of a range of potential innovations for the material created in a single step. The team found for the first time that boron puts kinks and elbows into the nanotubes as they grow and promotes the formation of covalent bonds, which give the sponges their robust qualities. The researchers, who collaborated with peers in labs around the nation and in Spain, Belgium and Japan, revealed their discovery in Nature’s online open-access journal Scientific Reports. Lead author Daniel Hashim, a graduate student in the Rice lab of materials scientist Pulickel Ajayan, said the blocks are both superhydrophobic (they hate water, so they float really well) and oleophilic (they love oil). The nanosponges, which are more than 99 percent air, also conduct electricity and can easily be manipulated with magnets. To demonstrate, Hashim dropped the sponge into a dish of water with used motor oil floating on top. The sponge soaked it up. He then put a match to the material, burned off the oil and returned the sponge to the water to absorb more. The robust sponge can be used repeatedly and stands up to abuse; he said a sample remained elastic after about 10,000 compressions in the lab. The sponge can also store the oil for later retrieval, he said. “These samples can be made pretty large and can be easily scaled up,” said Hashim, holding a half-inch square block of billions of nanotubes. “They’re super-low density, so the available volume is large. That’s why the uptake of oil can be so high.” He said the sponges described in the paper can absorb more than a hundred times their weight in oil. Ajayan, Rice’s Benjamin M. and Mary Greenwood Anderson Professor in Mechanical Engineering and Materials Science and of chemistry, said multiwalled carbon nanotubes grown on a substrate via chemical vapor deposition usually stand up straight without any real connections to their neighbors. But the boron-introduced defects induced the nanotubes to bond at the atomic level, which tangled them into a complex network. Nanotube sponges with oil-absorbing potential have been made before, but this is the first time the covalent junctions between nanotubes in such solids have been convincingly demonstrated, he said. “The interactions happen as they grow, and the material comes out of the furnace as a solid,” Ajayan said. “People have made nanotube solids via post-growth processing but without proper covalent connections. The advantage here is that the material is directly created during growth and comes out as a cross-linked porous network. “It’s easy for us to make nano building blocks, but getting to the macroscale has been tough,” he said. “The nanotubes have to connect either through some clever way of creating topological defects, or they have to be welded together.” When he was an undergraduate student of Ajayan’s at Rensselaer Polytechnic Institute, Hashim and his classmates discovered hints of a topological solution to the problem while participating in a National Science Foundation exchange program at the Institute of Scientific Research and Technology (IPICYT) in San Luis Potosí, Mexico. The paper’s co-author, Mauricio Terrones, a professor of physics, materials science and engineering at Penn State University with an appointment at Shinshu University, Japan, led a nanotechnology lab there. “Our goal was to find a way to make three-dimensional networks of these carbon nanotubes that would form a macroscale fabric — a spongy block of nanotubes that would be big and thick enough to be used to clean up oil spills and to perform other tasks,” Terrones said. “We realized that the trick was adding boron — a chemical element next to carbon on the periodic table — because boron helps to trigger the interconnections of the material. To add the boron, we used very high temperatures and we then ‘knitted’ the substance into the nanotube fabric.” The researchers have high hopes for the material’s environmental applications. “For oil spills, you would have to make large sheets of these or find a way to weld sheets together (a process Hashim continues to work on),” Ajayan said. “Oil-spill remediation and environmental cleanup are just the beginning of how useful these new nanotube materials could be,” Terrones added. “For example, we could use these materials to make more efficient and lighter batteries. We could use them as scaffolds for bone-tissue regeneration. We even could impregnate the nanotube sponge with polymers to fabricate robust and light composites for the automobile and plane industries.” Hashim suggested his nanosponges may also work as membranes for filtration. “I don’t think anybody has created anything like this before,” Ajayan said. “It’s a spectacular nanostructured sponge.” ", "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 establishment of covalent junctions between carbon nanotubes (CNTs) and the modification of their straight tubular morphology are two strategies needed to successfully synthesize nanotube-based three-dimensional (3D) frameworks exhibiting superior material properties. Engineering such 3D structures in scalable synthetic processes still remains a challenge. This work pioneers the bulk synthesis of 3D macroscale nanotube elastic solids directly via a boron-doping strategy during chemical vapour deposition, which influences the formation of atomic-scale “elbow” junctions and nanotube covalent interconnections. Detailed elemental analysis revealed that the “elbow” junctions are preferred sites for excess boron atoms, indicating the role of boron and curvature in the junction formation mechanism, in agreement with our first principle theoretical calculations. Exploiting this material’s ultra-light weight, super-hydrophobicity, high porosity, thermal stability and mechanical flexibility, the strongly oleophilic sponge-like solids are demonstrated as unique reusable sorbent scaffolds able to efficiently remove oil from contaminated seawater even after repeated use. Introduction Since the advent of carbon nanotubes (CNTs) 1 , 2 , engineering and controlled synthesis of these had been thoroughly investigated. Doping multi-walled (MW) and single-walled (SW) CNTs with elements such as nitrogen and boron had been used for altering their electronic properties for specific applications 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . It was later found that dopant atoms such as nitrogen or sulfur can also induce dramatic tubule morphology changes in CNTs, including covalent multi-junctions 12 , 13 , 14 , 15 , however never were these morphologies exploited to create 3D macroscale architectures. Theoretical studies had predicted that significant structural reorganization generates stable bends in CNTs due to the presence of pentagon-heptagon defects 16 that could accommodate foreign atoms besides carbon within the sp 2 hybridized carbon lattice 15 . In addition, it was found that boron doping acts as a “surfactant” during growth to significantly increase the aspect ratio of nanotubes by preventing tube closure – allowing longer tube lengths to be synthesized (~ 5–100 µm) and favoring the zigzag (or near zigzag) chirality 17 . Boron-doped MWCNTs (CB X MWNTs) could be synthesized by chemical vapour deposition (CVD) using various hydrocarbons and boron sources 18 , 19 , 20 , 21 , but none of these works yielded 3D solid structures, or were able to confirm the distinct tubular morphologies induced by boron found in this article. Theoretical and experimental research had demonstrated that boron interstitial atoms located between double-walled CNTs act as atomic “fusers” or “welders” under high temperature annealing (1400 – 1600°C) 22 , thus establishing covalent tube interconnections, but neither did this work produce macroscale solids. 3D solids of straight entangled non-doped CNTs were recently reported by others to create compressible sponges 23 and temperature-invariant viscoelastic solids 24 . However neither of these works show promise towards any degree of covalent bonding established between CNTs; nor do they possess dramatic defect sites within the CNT network. An abundance of localized and topological defects, including extreme tubular morphologies, are impactful features for many applications requiring further CNT functionalization chemistry, or anchor-sites for molecular/atomic/nanoparticle adsorption (decoration) within the 3D porous solid. Furthermore, substitutionally doped CNTs provide enhanced chemical reactivity. To the best of our knowledge, this material is the first demonstration to exploit the uniqueness of heteroatom substitutional dopant effects on CNT morphology to create elastic 3D macrostructures. The combination of boron’s interstitial “welding” and “surfactant” effects, makes the doping route a major step in the direction to realizing true (covalent) 3D hypothetical “superstructures” such as CNT monoliths, or interlocked nanotube ring structures recently proposed by Gogotsi 25 . These architectures had been studied theoretically as fascinating future materials with superior mechanical and electrical properties 26 . In this article, we describe the importance of substitutional doping effects of boron, experimentally and theoretically, so as to create a networked CB X MWNT solid. We further demonstrate that these materials possess intriguing dynamic mechanical properties and can be used as a reusable oil sorbent scaffold material in seawater. Results The CB X MWNT solids were grown directly onto the walls of a quartz tube furnace via an aerosol-assisted catalytic chemical vapour deposition (AACVD) method using triethylborane (TEB) (Aldrich >95%) as the boron source. High mass quantities (2–3 g) of CB X MWNT material was produced in just 30 minutes of growth (60–100 mg/min.), in the form of macroscopic elastic solids (see Supplementary Fig. S1 online), exhibiting fascinating physico-chemical properties including oleophilicity. The sample can be bent to a dramatic degree without breaking and will return to original position after released (see Fig. 1 a, b ). Supplementary Movie S1 demonstrates the robust mechanical durability and flexibility in response to ‘flicking’ a sample by hand in a cantilever loading fashion. Remarkably, the bulk densities of the porous solids were measured to be in the range of 10 to 29 mg/cm 3 (compared to low density carbon aerogel of 60 mg/cm 3 ). The nanotube diameters ranged from 40 to 150 nm, as measured from electron microscopy images ( Fig. 1 ). The synthesized 3D architectures are entirely made up of randomly orientated and entangled CNTs with little to no amorphous carbon as depicted from SEM ( Fig. 1c ). The X-ray powder diffraction pattern shows that as-produced CB X MWNT sponges are indeed crystalline and showed sharp (002) diffraction peaks, but no evidence of B 4 C phases were found (see Supplementary Fig. S2 online). Raman spectra of the sponges are compared to those of pristine MWCNTs (see Supplementary Fig. S3 online). In this context, we noted an intense D-band, which is expected considering the contribution of boron atoms embedded in the hexagonal sp 2 hybridized network of CNT sponges. Boron induces atomic-scale “elbow” junctions, as depicted in Fig. 1d and Supplementary Fig. S4 online. Many other fascinating nanotube morphologies, including covalent multi-junctions such as Y-junctions (see Supplementary Fig. S5 online) and four-way junctions ( Fig. 1 e and f ), were found within the entangled network structure. The most abundant of the morphologies<|im_end|> <|im_start|>assistant (Phys.org) -- Researchers at Rice University and Penn State University have discovered that adding a dash of boron to carbon while creating nanotubes turns them into solid, spongy, reusable blocks that have an astounding ability to absorb oil spilled in water. That’s one of a range of potential innovations for the material created in a single step. The team found for the first time that boron puts kinks and elbows into the nanotubes as they grow and promotes the formation of covalent bonds, which give the sponges their robust qualities. The researchers, who collaborated with peers in labs around the nation and in Spain, Belgium and Japan, revealed their discovery in Nature’s online open-access journal Scientific Reports. Lead author Daniel Hashim, a graduate student in the Rice lab of materials scientist Pulickel Ajayan, said the blocks are both superhydrophobic (they hate water, so they float really well) and oleophilic (they love oil). The nanosponges, which are more than 99 percent air, also conduct electricity and can easily be manipulated with magnets. To demonstrate, Hashim dropped the sponge into a dish of water with used motor oil floating on top. The sponge soaked it up. He then put a match to the material, burned off the oil and returned the sponge to the water to absorb more. The robust sponge can be used repeatedly and stands up to abuse; he said a sample remained elastic after about 10,000 compressions in the lab. The sponge can also store the oil for later retrieval, he said. “These samples can be made pretty large and can be easily scaled up,” said Hashim, holding a half-inch square block of billions of nanotubes. “They’re super-low density, so the available volume is large. That’s why the uptake of oil can be so high.” He said the sponges described in the paper can absorb more than a hundred times their weight in oil. Ajayan, Rice’s Benjamin M. and Mary Greenwood Anderson Professor in Mechanical Engineering and Materials Science and of chemistry, said multiwalled carbon nanotubes grown on a substrate via chemical vapor deposition usually stand up straight without any real connections to their neighbors. But the boron-introduced defects induced the nanotubes to bond at the atomic level, which tangled them into a complex network. Nanotube sponges with oil-absorbing potential have been made before, but this is the first time the covalent junctions between nanotubes in such solids have been convincingly demonstrated, he said. “The interactions happen as they grow, and the material comes out of the furnace as a solid,” Ajayan said. “People have made nanotube solids via post-growth processing but without proper covalent connections. The advantage here is that the material is directly created during growth and comes out as a cross-linked porous network. “It’s easy for us to make nano building blocks, but getting to the macroscale has been tough,” he said. “The nanotubes have to connect either through some clever way of creating topological defects, or they have to be welded together.” When he was an undergraduate student of Ajayan’s at Rensselaer Polytechnic Institute, Hashim and his classmates discovered hints of a topological solution to the problem while participating in a National Science Foundation exchange program at the Institute of Scientific Research and Technology (IPICYT) in San Luis Potosí, Mexico. The paper’s co-author, Mauricio Terrones, a professor of physics, materials science and engineering at Penn State University with an appointment at Shinshu University, Japan, led a nanotechnology lab there. “Our goal was to find a way to make three-dimensional networks of these carbon nanotubes that would form a macroscale fabric — a spongy block of nanotubes that would be big and thick enough to be used to clean up oil spills and to perform other tasks,” Terrones said. “We realized that the trick was adding boron — a chemical element next to carbon on the periodic table — because boron helps to trigger the interconnections of the material. To add the boron, we used very high temperatures and we then ‘knitted’ the substance into the nanotube fabric.” The researchers have high hopes for the material’s environmental applications. “For oil spills, you would have to make large sheets of these or find a way to weld sheets together (a process Hashim continues to work on),” Ajayan said. “Oil-spill remediation and environmental cleanup are just the beginning of how useful these new nanotube materials could be,” Terrones added. “For example, we could use these materials to make more efficient and lighter batteries. We could use them as scaffolds for bone-tissue regeneration. We even could impregnate the nanotube sponge with polymers to fabricate robust and light composites for the automobile and plane industries.” Hashim suggested his nanosponges may also work as membranes for filtration. “I don’t think anybody has created anything like this before,” Ajayan said. “It’s a spectacular nanostructured sponge.” <|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 Growing evidence demonstrates that climatic conditions can have a profound impact on the functioning of modern human societies 1 , 2 , but effects on economic activity appear inconsistent. Fundamental productive elements of modern economies, such as workers and crops, exhibit highly non-linear responses to local temperature even in wealthy countries 3 , 4 . In contrast, aggregate macroeconomic productivity of entire wealthy countries is reported not to respond to temperature 5 , while poor countries respond only linearly 5 , 6 . Resolving this conflict between micro and macro observations is critical to understanding the role of wealth in coupled human–natural systems 7 , 8 and to anticipating the global impact of climate change 9 , 10 . Here we unify these seemingly contradictory results by accounting for non-linearity at the macro scale. We show that overall economic productivity is non-linear in temperature for all countries, with productivity peaking at an annual average temperature of 13 °C and declining strongly at higher temperatures. The relationship is globally generalizable, unchanged since 1960, and apparent for agricultural and non-agricultural activity in both rich and poor countries. These results provide the first evidence that economic activity in all regions is coupled to the global climate and establish a new empirical foundation for modelling economic loss in response to climate change 11 , 12 , with important implications. If future adaptation mimics past adaptation, unmitigated warming is expected to reshape the global economy by reducing average global incomes roughly 23% by 2100 and widening global income inequality, relative to scenarios without climate change. In contrast to prior estimates, expected global losses are approximately linear in global mean temperature, with median losses many times larger than leading models indicate. Main Economic productivity—the efficiency with which societies transform labour, capital, energy, and other natural resources into new goods or services—is a key outcome in any society because it has a direct impact on individual wellbeing. While it is well known that temperature affects the dynamics of virtually all chemical, biological and ecological processes, how temperature effects recombine and aggregate within complex human societies to affect overall economic productivity remains poorly understood. Characterizing this influence remains a fundamental problem both in the emerging field of coupled human–natural systems and in economics more broadly, as it has implications for our understanding of historical patterns of human development and for how the future economy might respond to a changing climate. Prior analyses have identified how specific components of economic production, such as crop yields, respond to temperature using high-frequency micro-level data 3 , 4 . Meanwhile, macro-level analyses have documented strong correlations between total economic output and temperature over time 5 , 6 and across space 13 , 14 , but it is unknown whether these results are connected, and if so, how. In particular, strong responses of output to temperature observed in micro data from wealthy countries are not apparent in existing macro studies 5 . If wealthy populations actually are unaffected by temperature, this could indicate that wealth and human-made capital are substitutes for natural capital (for example, the composition of the atmosphere) in economic activity 5 , 7 . Resolving this apparent discrepancy thus has central implications for understanding the nature of sustainable development 7 . Numerous basic productive components of an economy display a highly non-linear relationship with daily or hourly temperature 1 . For example, labour supply 4 , labour productivity 6 , and crop yields 3 all decline abruptly beyond temperature thresholds located between 20 °C and 30 °C ( Fig. 1a–c ). However, it is unclear how these abrupt declines at the micro level are reflected in coarser macro-level data. When production is integrated over large regions (for example, countries) or long units of time (for example, years), there is a broad distribution of momentary temperatures to which individual components of the economy (for example, crops or workers) are exposed. If only the hottest locations or moments cause abrupt declines in output, then when combined with many cooler and highly productive moments they would sum to an aggregate level of output that only declines modestly when aggregate average temperature increases. Figure 1: Highly non-linear micro responses generate smooth and shifted macro response. a–c , Highly non-linear micro-level responses of labour supply 4 ( a ), labour performance 6 ( b ) and crop yield 3 ( c ) to daily temperature exposure exhibit similar ‘kinked’ structures between 20 and 30°C. d , e , These micro-level responses ( f i ( T ) in equation (1); d ) map onto country-level distributions of temperatures across different locations and times within that country ( in equation (1); e ). Shifts in country-level distributions correspond to changes in average annual temperature, altering the fraction of unit-hours ( m i 1 and m i 2 ) exposed to different regions of the micro-level response in d . f , Aggregating daily impacts according to equation (1) maps annual average temperature to annual output as a non-linear and concave function that is smoother than the micro response with a lower optimum ( in equation (1)). PowerPoint slide Full size image To fix ideas, let function f i ( T ) describe the productive contribution of an individual productive unit in industry i (for example, a firm) relative to instantaneous (for example, daily) temperature T ( Fig. 1d ). For a given country, period, and industry, denote the fraction of unit-hours spent below the critical temperature threshold as m i 1 and the fraction above as m i 2 ( Fig. 1e ). The full distribution of unit-hours across all temperatures is , centred at average temperature . Assume g i (.) is mean zero. If productivity loss within a single productive unit-hour has limited impact on other units, as suggested by earlier findings 8 , 15 , then aggregate production Y is the sum of output across industries, each integrated over all productive unit-hours in the country and period: As rises and a country", "role": "user" }, { "content": "With each upward degree, global warming will singe the economies of three-quarters of the world's nations and widen the north-south gap between rich and poor countries, according to a new economic and science study. Compared to what it would be without more global warming, the average global income will shrivel 23 percent at the end of the century if heat-trapping carbon dioxide pollution continues to grow at its current trajectory, according to a study published Wednesday in the scientific journal Nature. Some countries, like Russia, Mongolia and Canada, would see large economic benefits from global warming, the study projects. Most of Europe would do slightly better, the United States and China slightly worse. Essentially all of Africa, Asia, South America and the Middle East would be hurt dramatically, the economists found. \"What climate change is doing is basically devaluing all the real estate south of the United States and making the whole planet less productive,\" said study co-author Solomon Hsiang, an economist and public policy professor at the University of California Berkeley. \"Climate change is essentially a massive transfer of value from the hot parts of the world to the cooler parts of the world.\" \"This is like taking from the poor and giving to the rich,\" Hsiang said. Lead author Marshall Burke of Stanford and Hsiang examined 50 years of economic data in 160 countries and even county-by-county data in the United States and found what Burke called \"the goldilocks zone in global temperature at which humans are good at producing stuff\"—an annual temperature of around 13 degrees Celsius or 55.4 degrees Fahrenheit, give or take a degree. For countries colder than that economic sweet spot, every degree of warming heats up the economy and benefits. For the United States and other countries already at or above that temperature, every degree slows productivity, Burke and Hsiang said. The 20th-century global average annual temperature is 57 degrees, or 13.9 degrees Celsius, according to the National Oceanic and Atmospheric Administration. Last year—the hottest on record—was 58.24 degrees and this year is almost certain to break that record, according to NOAA. Burke and Hsiang use different population-weighted temperature figures than NOAA calculates. But the U.S. economy is humming despite the heat. When asked how that can be so, Burke said there were many factors important for growth beyond just temperature. He said one year's temperature and economic growth in one nation isn't telling. Instead, he and Hsiang looked at more than 6,000 \"country-years\" to get a bigger picture. Burke compared the effect of global warming on economies to a head wind on a cross-country airplane flight. The effects at any given moment are small and seemingly unnoticeable but they add up and slow you down. While it is fairly obvious that unusual high temperatures hurt agriculture, past studies show hot days even reduce car production at U.S. factories, Burke said. \"The U.S. is really close to the global optimum,\" Burke said, adding that as it warms, the U.S. will fall off that peak. The authors calculate a warmer U.S. in 2100 will have a gross domestic product per person that's 36 percent lower than it would be if warming stopped about now. But because the U.S. is now at that ultimate peak, there's greater uncertainty in the study's calculations than in places like India, Pakistan, Vietnam, Nigeria and Venezuela where it's already hot and there's more certainty about dramatic economic harm, Hsiang said. The authors' main figures are based on the premise that carbon dioxide emissions will continue to rise at the current trajectory. But countries across the world are pledging to control if not cut carbon pollution as international leaders prepare for a summit on climate change in Paris later this year. If the current pledges are kept, the warming cost in 2100 will drop from 23 percent to 15 percent, Burke said. Gary Yohe, an environmental economist at Wesleyan University in Connecticut, praised the study as significant and thorough, saying Burke and Hsiang \"use the most modern socio-economic scenarios.\" But Richard Tol, an economist at the University of Sussex in England, dismissed the study as unworthy to be published in an economics journal, saying \"the hypothesized relationship is without foundation.\" Other experts found good and bad points, with MIT's John Reilly saying it will spark quite a debate among economists. ", "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 Growing evidence demonstrates that climatic conditions can have a profound impact on the functioning of modern human societies 1 , 2 , but effects on economic activity appear inconsistent. Fundamental productive elements of modern economies, such as workers and crops, exhibit highly non-linear responses to local temperature even in wealthy countries 3 , 4 . In contrast, aggregate macroeconomic productivity of entire wealthy countries is reported not to respond to temperature 5 , while poor countries respond only linearly 5 , 6 . Resolving this conflict between micro and macro observations is critical to understanding the role of wealth in coupled human–natural systems 7 , 8 and to anticipating the global impact of climate change 9 , 10 . Here we unify these seemingly contradictory results by accounting for non-linearity at the macro scale. We show that overall economic productivity is non-linear in temperature for all countries, with productivity peaking at an annual average temperature of 13 °C and declining strongly at higher temperatures. The relationship is globally generalizable, unchanged since 1960, and apparent for agricultural and non-agricultural activity in both rich and poor countries. These results provide the first evidence that economic activity in all regions is coupled to the global climate and establish a new empirical foundation for modelling economic loss in response to climate change 11 , 12 , with important implications. If future adaptation mimics past adaptation, unmitigated warming is expected to reshape the global economy by reducing average global incomes roughly 23% by 2100 and widening global income inequality, relative to scenarios without climate change. In contrast to prior estimates, expected global losses are approximately linear in global mean temperature, with median losses many times larger than leading models indicate. Main Economic productivity—the efficiency with which societies transform labour, capital, energy, and other natural resources into new goods or services—is a key outcome in any society because it has a direct impact on individual wellbeing. While it is well known that temperature affects the dynamics of virtually all chemical, biological and ecological processes, how temperature effects recombine and aggregate within complex human societies to affect overall economic productivity remains poorly understood. Characterizing this influence remains a fundamental problem both in the emerging field of coupled human–natural systems and in economics more broadly, as it has implications for our understanding of historical patterns of human development and for how the future economy might respond to a changing climate. Prior analyses have identified how specific components of economic production, such as crop yields, respond to temperature using high-frequency micro-level data 3 , 4 . Meanwhile, macro-level analyses have documented strong correlations between total economic output and temperature over time 5 , 6 and across space 13 , 14 , but it is unknown whether these results are connected, and if so, how. In particular, strong responses of output to temperature observed in micro data from wealthy countries are not apparent in existing macro studies 5 . If wealthy populations actually are unaffected by temperature, this could indicate that wealth and human-made capital are substitutes for natural capital (for example, the composition of the atmosphere) in economic activity 5 , 7 . Resolving this apparent discrepancy thus has central implications for understanding the nature of sustainable development 7 . Numerous basic productive components of an economy display a highly non-linear relationship with daily or hourly temperature 1 . For example, labour supply 4 , labour productivity 6 , and crop yields 3 all decline abruptly beyond temperature thresholds located between 20 °C and 30 °C ( Fig. 1a–c ). However, it is unclear how these abrupt declines at the micro level are reflected in coarser macro-level data. When production is integrated over large regions (for example, countries) or long units of time (for example, years), there is a broad distribution of momentary temperatures to which individual components of the economy (for example, crops or workers) are exposed. If only the hottest locations or moments cause abrupt declines in output, then when combined with many cooler and highly productive moments they would sum to an aggregate level of output that only declines modestly when aggregate average temperature increases. Figure 1: Highly non-linear micro responses generate smooth and shifted macro response. a–c , Highly non-linear micro-level responses of labour supply 4 ( a ), labour performance 6 ( b ) and crop yield 3 ( c ) to daily temperature exposure exhibit similar ‘kinked’ structures between 20 and 30°C. d , e , These micro-level responses ( f i ( T ) in equation (1); d ) map onto country-level distributions of temperatures across different locations and times within that country ( in equation (1); e ). Shifts in country-level distributions correspond to changes in average annual temperature, altering the fraction of unit-hours ( m i 1 and m i 2 ) exposed to different regions of the micro-level response in d . f , Aggregating daily impacts according to equation (1) maps annual average temperature to annual output as a non-linear and concave function that is smoother than the micro response with a lower optimum ( in equation (1)). PowerPoint slide Full size image To fix ideas, let function f i ( T ) describe the productive contribution of an individual productive unit in industry i (for example, a firm) relative to instantaneous (for example, daily) temperature T ( Fig. 1d ). For a given country, period, and industry, denote the fraction of unit-hours spent below the critical temperature threshold as m i 1 and the fraction above as m i 2 ( Fig. 1e ). The full distribution of unit-hours across all temperatures is , centred at average temperature . Assume g i (.) is mean zero. If productivity loss within a single productive unit-hour has limited impact on other units, as suggested by earlier findings 8 , 15 , then aggregate production Y is the sum of output across industries, each integrated over all productive unit-hours in the country and period: As rises and a country<|im_end|> <|im_start|>assistant With each upward degree, global warming will singe the economies of three-quarters of the world's nations and widen the north-south gap between rich and poor countries, according to a new economic and science study. Compared to what it would be without more global warming, the average global income will shrivel 23 percent at the end of the century if heat-trapping carbon dioxide pollution continues to grow at its current trajectory, according to a study published Wednesday in the scientific journal Nature. Some countries, like Russia, Mongolia and Canada, would see large economic benefits from global warming, the study projects. Most of Europe would do slightly better, the United States and China slightly worse. Essentially all of Africa, Asia, South America and the Middle East would be hurt dramatically, the economists found. "What climate change is doing is basically devaluing all the real estate south of the United States and making the whole planet less productive," said study co-author Solomon Hsiang, an economist and public policy professor at the University of California Berkeley. "Climate change is essentially a massive transfer of value from the hot parts of the world to the cooler parts of the world." "This is like taking from the poor and giving to the rich," Hsiang said. Lead author Marshall Burke of Stanford and Hsiang examined 50 years of economic data in 160 countries and even county-by-county data in the United States and found what Burke called "the goldilocks zone in global temperature at which humans are good at producing stuff"—an annual temperature of around 13 degrees Celsius or 55.4 degrees Fahrenheit, give or take a degree. For countries colder than that economic sweet spot, every degree of warming heats up the economy and benefits. For the United States and other countries already at or above that temperature, every degree slows productivity, Burke and Hsiang said. The 20th-century global average annual temperature is 57 degrees, or 13.9 degrees Celsius, according to the National Oceanic and Atmospheric Administration. Last year—the hottest on record—was 58.24 degrees and this year is almost certain to break that record, according to NOAA. Burke and Hsiang use different population-weighted temperature figures than NOAA calculates. But the U.S. economy is humming despite the heat. When asked how that can be so, Burke said there were many factors important for growth beyond just temperature. He said one year's temperature and economic growth in one nation isn't telling. Instead, he and Hsiang looked at more than 6,000 "country-years" to get a bigger picture. Burke compared the effect of global warming on economies to a head wind on a cross-country airplane flight. The effects at any given moment are small and seemingly unnoticeable but they add up and slow you down. While it is fairly obvious that unusual high temperatures hurt agriculture, past studies show hot days even reduce car production at U.S. factories, Burke said. "The U.S. is really close to the global optimum," Burke said, adding that as it warms, the U.S. will fall off that peak. The authors calculate a warmer U.S. in 2100 will have a gross domestic product per person that's 36 percent lower than it would be if warming stopped about now. But because the U.S. is now at that ultimate peak, there's greater uncertainty in the study's calculations than in places like India, Pakistan, Vietnam, Nigeria and Venezuela where it's already hot and there's more certainty about dramatic economic harm, Hsiang said. The authors' main figures are based on the premise that carbon dioxide emissions will continue to rise at the current trajectory. But countries across the world are pledging to control if not cut carbon pollution as international leaders prepare for a summit on climate change in Paris later this year. If the current pledges are kept, the warming cost in 2100 will drop from 23 percent to 15 percent, Burke said. Gary Yohe, an environmental economist at Wesleyan University in Connecticut, praised the study as significant and thorough, saying Burke and Hsiang "use the most modern socio-economic scenarios." But Richard Tol, an economist at the University of Sussex in England, dismissed the study as unworthy to be published in an economics journal, saying "the hypothesized relationship is without foundation." Other experts found good and bad points, with MIT's John Reilly saying it will spark quite a debate among economists. <|im_end|>

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2,143

[ { "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 Neutrophils are the most abundant human white blood cell and constitute a first line of defense in the innate immune response. Neutrophils are short-lived cells and thus the impact of organismal aging on neutrophil biology, especially as a function of biological sex, remains poorly understood. Here, we describe a multi-omic resource of mouse primary bone-marrow neutrophils from young and old female and male mice, at the transcriptomic, metabolomic and lipidomic levels. We identify widespread regulation of neutrophil ‘omics’ landscapes with organismal aging and biological sex. In addition, we leverage our resource to predict functional differences, including changes in neutrophil responses to activation signals. This dataset represents a large multi-omics resource for neutrophils across sex and ages and identifies neutrophil characteristics that could be targeted to improve immune responses as a function of sex and/or age. Main Neutrophils are the most abundant cells in human blood, representing 50–70% of leukocytes 1 . These cells are continually produced in the bone marrow and released into circulation 2 , 3 . Neutrophils are short-lived, with estimated cellular lifespans of ~10–18 h once released in the bloodstream 4 , 5 , although they can survive longer 4 , 6 . Throughout their cellular lifespan, neutrophils undergo ‘neutrophil aging’, a process distinct from organismal aging 3 , 7 . Neutrophils perform many key functions, including production of antimicrobial granules and of ‘neutrophil extracellular traps’ (NETs) 3 , 8 . Although neutrophils are essential against infections as the ‘first line of defense’, their aberrant activation can also aggravate inflammatory disease 2 , 3 . Indeed, emerging evidence suggests that neutrophils play important roles in chronic inflammation 9 . Organismal aging in mammals is characterized by systematic immune dysfunction and chronic inflammation, a phenomenon dubbed ‘inflamm-aging’ 10 , which may be partially mediated by dysfunction of innate immune cells 11 . Indeed, emerging evidence suggests that neutrophils from aged organisms are dysfunctional 12 , 13 , 14 , 15 , 16 . Observed age-related dysfunctions in neutrophils include decreased NETosis in tumor necrosis factor (TNF)-α-primed conditions 13 , 14 , reduced chemotaxis to sites of inflammation 15 and secretion of intracellular granule proteases 15 , 17 . Although gene expression changes throughout the lifespan have been reported across many cell types 18 , 19 , how organismal aging (rather than ‘daily’ cell aging) affects neutrophil landscapes remains largely unknown. Females and males present with many biological differences, which may underlie lifelong health disparities between sexes 20 and could result from differential ‘omic’ regulation 21 , 22 . Although transcriptional differences between young female and male murine neutrophils have been profiled by ImmGen 22 , how these differences interplay with organismal aging and whether they are accompanied by other phenotypical differences remains largely unknown. Accumulated studies suggest that aspects of neutrophil biology are sex dimorphic, such as inflammatory mediator production 9 or functional modulation by testosterone 23 . However, the pathways underlying sex dimorphism in neutrophils, as well as the extent of sex dimorphism, are still unclear. To gain insights into how neutrophils are regulated as a function of age and sex, we generated a multi-omic resource covering transcriptome, metabolome and lipidome profiling of primary bone-marrow mouse neutrophils. We identified widespread age-related and sex-dimorphic ‘omic’ regulation, including transcriptional regulation of chromatin-related pathways. Using the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we showed that remodeling of chromatin-related pathways was associated with overall differences in the chromatin architecture of neutrophils from young versus old and female versus male mice. Consistently, we observed age- and sex-linked differences in NETosis inducibility. Machine learning showed that specific factors could predict age-related and sex-dimorphic gene regulation in neutrophils. Finally, we leveraged our resource and predicted sex differences in serum levels of neutrophil elastase in control and sepsis-like conditions. Results Multi-omics of bone-marrow neutrophils with age and sex To understand how neutrophils are regulated as a function of age and sex, we obtained primary bone-marrow neutrophils from young (4–5-month-old) and old (20–21-month-old) C57BL/6Nia female and male mice (Fig. 1a ). Primary neutrophils were isolated from bone marrow using magnetic-activated cell sorting (MACS) and profiling was then performed on purified neutrophils: (1) transcriptome profiling by RNA-sequencing (RNA-seq), (2) metabolomic profiling by untargeted liquid chromatography coupled with mass spectrometry (LC–MS) and (3) lipidomic profiling by targeted MS (Fig. 1a ). Fig. 1: A multi-omic analysis of primary mouse bone marrow neutrophils during aging and with respect to sex. a , Experimental setup scheme. b – d , MDS analysis results of RNA expression by RNA-seq ( b ), untargeted metabolomics ( c ) or targeted lipidomics ( d ). e – g , Heat map of significant (FDR < 5%) sex-dimorphic genes ( e ), metabolic features ( f ) or lipid species ( g ). Significance of gene regulation by RNA-seq was calculated by DESeq2 and significance of metabolic features or lipid species regulation were calculated by limma. Full size image As a first-level analysis to evaluate the similarity of our datasets, we utilized multidimensional scaling (MDS). MDS analysis for RNA-seq, metabolomics and lipidomics datasets showed clear separation of samples by animal sex, regardless of age (Fig. 1b–d ). In contrast, although young and old samples separated within each sex, global separation by age regardless of sex was not clearly observed for each omics (Fig. 1b–d ). To better understand the nature of differences between neutrophils from young versus old (with sex as a covariate) and female versus male animals (with age as a covariate), we identified transcriptional, metabolic and lipidomic features with significant age- or sex-related regulation at a false discovery rate (FDR) < 5% using multivariate linear modeling (Fig. 1e–g , Extended Data Fig. 1a–f and Supplementary Table 1a–f ). We quality-checked our dataset for appropriate expression of sex-specific genes (Extended Data Fig. 1b,c ). Finally, we confirmed differential gene expression trends between groups using a small replicate RNA-seq cohort (Extended Data Fig. 2a,b ) and comparing our data with published datasets from female versus male mouse spleen neutrophils 22 and human", "role": "user" }, { "content": "A new USC study of a common, yet poorly understood type of white blood cell reveals the immune cell's response to pathogens differs greatly by sex and by age. In this mouse study, males proved much more susceptible to a condition called sepsis than females. However, the scientists also found that the female disease-defense system is hardly perfect; their system changes with age to become nearly as harmful as the males'. Those are the key findings in a study that appears today in Nature Aging. The study has important implications for studying disease and cures, especially for sepsis, a condition in which the body's defense system turns harmful to itself. It also suggests that the quest for precision medicine may be overlooking more obvious disease determinants: age and sex. \"A big take-home message is that with the push for personalized medicine, people focus on minute genetic differences, but we find that biological sex—the biggest genetic difference of all—is actually a great predictor for immune response seldom taken into account,\" said Bérénice Benayoun, assistant professor at the USC Leonard Davis School of Gerontology and principal investigator of the study. Benayoun and her team focused on cells called \"neutrophils,\" which make up about 50% to 70% of our white blood cells and are critical to fighting off infections. Understanding sex- and age-based differences in how neutrophils function could help us understand similar disparities in human illnesses, such as why older people—and men in particular— are more likely to get severe symptoms with COVID-19 or why women are more likely to have autoimmune disorders, she added. Different defensive tactics Neutrophils respond to infections in a few different ways, such as by engulfing and digesting an invading pathogen—or by degranulation in which they secrete proteins that destroy the invader. Another method discovered in 2004 is \"NETosis,\" in which neutrophils expel strands of their own coagulated DNA, called chromatin, which act as a trap outside of the cell. These neutrophil extracellular traps, or so-called \"NETs,\" ensnare and destroy pathogens. Benayoun and colleagues discovered differences in neutrophil activity between young and old mice, as well as between male and female mice. Males appeared to have more degranulation activity, as evidenced by higher levels of a protein, neutrophil elastase. Meanwhile females exhibited more NETosis on average. High degranulation activity can cause damage to surrounding tissues, and these findings could illustrate why sepsis affects men more than women, Benayoun said. \"With sepsis, what kills you is not actually the bacteria; it's your response to the bacteria,\" she noted. \"And we know that males in general have much worse odds during sepsis than females, and neutrophil elastase, which is one of the main components of degranulation, is one of the big things that can be produced at very high level during sepsis.\" On the other hand, higher NETosis activity could contribute to the body's immune system attacking healthy cells, Benayoun added. Antibodies targeting the body's own DNA have been found in many autoimmune disorders, which could have been developed after neutrophils produced too many NETs. Thus, higher NET activity in females could be related to higher rates of autoimmune disorders in women. \"If you make NETs for no good reason, it can promote autoimmunity,\" Benayoun said. \"It's a known fact that women are more prone to autoimmune disease, like a 9:1 ratio compared to men.\" With age, female neutrophils became more reactive, in contrast to male neutrophils. \"In general, genetic programs seem to 'age' at a faster rate in male neutrophils,\" she said. \"These findings suggest that sex differences can become amplified with aging, at least for neutrophils.\" A new resource for immune system study Neutrophils have historically been difficult to study because they are so short-lived, lasting less than a day. The cells' short lifespans are spent as the immune system's first responders, working quickly to trap and destroy pathogens at the first sign of an infection and sacrificing themselves in the process. Applying machine learning techniques to the data, the team has begun to identify genetic pathways involved in the regulation of immune response that could explain why there are such dramatic differences between the sexes, also called sex dimorphism, in immune system activity. Sex dimorphism in immunity has played out in the current pandemic: Most of the severe COVID-19 cases and deaths were men, Benayoun noted. With other literature indicating a possible role of sex hormones in immunity, studying these interactions could lead scientists to discover new techniques to fight severe illness. \"If these differences are driven by the hormonal effects on immune cells, then in theory, you could try to intervene in early sepsis, maybe with anti-androgens in the short term, to bring down the response,\" Benayoun mused. \"You could tailor medicine just by using the fact that this patient has more androgens or this person has more estrogen.\" ", "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 Neutrophils are the most abundant human white blood cell and constitute a first line of defense in the innate immune response. Neutrophils are short-lived cells and thus the impact of organismal aging on neutrophil biology, especially as a function of biological sex, remains poorly understood. Here, we describe a multi-omic resource of mouse primary bone-marrow neutrophils from young and old female and male mice, at the transcriptomic, metabolomic and lipidomic levels. We identify widespread regulation of neutrophil ‘omics’ landscapes with organismal aging and biological sex. In addition, we leverage our resource to predict functional differences, including changes in neutrophil responses to activation signals. This dataset represents a large multi-omics resource for neutrophils across sex and ages and identifies neutrophil characteristics that could be targeted to improve immune responses as a function of sex and/or age. Main Neutrophils are the most abundant cells in human blood, representing 50–70% of leukocytes 1 . These cells are continually produced in the bone marrow and released into circulation 2 , 3 . Neutrophils are short-lived, with estimated cellular lifespans of ~10–18 h once released in the bloodstream 4 , 5 , although they can survive longer 4 , 6 . Throughout their cellular lifespan, neutrophils undergo ‘neutrophil aging’, a process distinct from organismal aging 3 , 7 . Neutrophils perform many key functions, including production of antimicrobial granules and of ‘neutrophil extracellular traps’ (NETs) 3 , 8 . Although neutrophils are essential against infections as the ‘first line of defense’, their aberrant activation can also aggravate inflammatory disease 2 , 3 . Indeed, emerging evidence suggests that neutrophils play important roles in chronic inflammation 9 . Organismal aging in mammals is characterized by systematic immune dysfunction and chronic inflammation, a phenomenon dubbed ‘inflamm-aging’ 10 , which may be partially mediated by dysfunction of innate immune cells 11 . Indeed, emerging evidence suggests that neutrophils from aged organisms are dysfunctional 12 , 13 , 14 , 15 , 16 . Observed age-related dysfunctions in neutrophils include decreased NETosis in tumor necrosis factor (TNF)-α-primed conditions 13 , 14 , reduced chemotaxis to sites of inflammation 15 and secretion of intracellular granule proteases 15 , 17 . Although gene expression changes throughout the lifespan have been reported across many cell types 18 , 19 , how organismal aging (rather than ‘daily’ cell aging) affects neutrophil landscapes remains largely unknown. Females and males present with many biological differences, which may underlie lifelong health disparities between sexes 20 and could result from differential ‘omic’ regulation 21 , 22 . Although transcriptional differences between young female and male murine neutrophils have been profiled by ImmGen 22 , how these differences interplay with organismal aging and whether they are accompanied by other phenotypical differences remains largely unknown. Accumulated studies suggest that aspects of neutrophil biology are sex dimorphic, such as inflammatory mediator production 9 or functional modulation by testosterone 23 . However, the pathways underlying sex dimorphism in neutrophils, as well as the extent of sex dimorphism, are still unclear. To gain insights into how neutrophils are regulated as a function of age and sex, we generated a multi-omic resource covering transcriptome, metabolome and lipidome profiling of primary bone-marrow mouse neutrophils. We identified widespread age-related and sex-dimorphic ‘omic’ regulation, including transcriptional regulation of chromatin-related pathways. Using the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we showed that remodeling of chromatin-related pathways was associated with overall differences in the chromatin architecture of neutrophils from young versus old and female versus male mice. Consistently, we observed age- and sex-linked differences in NETosis inducibility. Machine learning showed that specific factors could predict age-related and sex-dimorphic gene regulation in neutrophils. Finally, we leveraged our resource and predicted sex differences in serum levels of neutrophil elastase in control and sepsis-like conditions. Results Multi-omics of bone-marrow neutrophils with age and sex To understand how neutrophils are regulated as a function of age and sex, we obtained primary bone-marrow neutrophils from young (4–5-month-old) and old (20–21-month-old) C57BL/6Nia female and male mice (Fig. 1a ). Primary neutrophils were isolated from bone marrow using magnetic-activated cell sorting (MACS) and profiling was then performed on purified neutrophils: (1) transcriptome profiling by RNA-sequencing (RNA-seq), (2) metabolomic profiling by untargeted liquid chromatography coupled with mass spectrometry (LC–MS) and (3) lipidomic profiling by targeted MS (Fig. 1a ). Fig. 1: A multi-omic analysis of primary mouse bone marrow neutrophils during aging and with respect to sex. a , Experimental setup scheme. b – d , MDS analysis results of RNA expression by RNA-seq ( b ), untargeted metabolomics ( c ) or targeted lipidomics ( d ). e – g , Heat map of significant (FDR < 5%) sex-dimorphic genes ( e ), metabolic features ( f ) or lipid species ( g ). Significance of gene regulation by RNA-seq was calculated by DESeq2 and significance of metabolic features or lipid species regulation were calculated by limma. Full size image As a first-level analysis to evaluate the similarity of our datasets, we utilized multidimensional scaling (MDS). MDS analysis for RNA-seq, metabolomics and lipidomics datasets showed clear separation of samples by animal sex, regardless of age (Fig. 1b–d ). In contrast, although young and old samples separated within each sex, global separation by age regardless of sex was not clearly observed for each omics (Fig. 1b–d ). To better understand the nature of differences between neutrophils from young versus old (with sex as a covariate) and female versus male animals (with age as a covariate), we identified transcriptional, metabolic and lipidomic features with significant age- or sex-related regulation at a false discovery rate (FDR) < 5% using multivariate linear modeling (Fig. 1e–g , Extended Data Fig. 1a–f and Supplementary Table 1a–f ). We quality-checked our dataset for appropriate expression of sex-specific genes (Extended Data Fig. 1b,c ). Finally, we confirmed differential gene expression trends between groups using a small replicate RNA-seq cohort (Extended Data Fig. 2a,b ) and comparing our data with published datasets from female versus male mouse spleen neutrophils 22 and human<|im_end|> <|im_start|>assistant A new USC study of a common, yet poorly understood type of white blood cell reveals the immune cell's response to pathogens differs greatly by sex and by age. In this mouse study, males proved much more susceptible to a condition called sepsis than females. However, the scientists also found that the female disease-defense system is hardly perfect; their system changes with age to become nearly as harmful as the males'. Those are the key findings in a study that appears today in Nature Aging. The study has important implications for studying disease and cures, especially for sepsis, a condition in which the body's defense system turns harmful to itself. It also suggests that the quest for precision medicine may be overlooking more obvious disease determinants: age and sex. "A big take-home message is that with the push for personalized medicine, people focus on minute genetic differences, but we find that biological sex—the biggest genetic difference of all—is actually a great predictor for immune response seldom taken into account," said Bérénice Benayoun, assistant professor at the USC Leonard Davis School of Gerontology and principal investigator of the study. Benayoun and her team focused on cells called "neutrophils," which make up about 50% to 70% of our white blood cells and are critical to fighting off infections. Understanding sex- and age-based differences in how neutrophils function could help us understand similar disparities in human illnesses, such as why older people—and men in particular— are more likely to get severe symptoms with COVID-19 or why women are more likely to have autoimmune disorders, she added. Different defensive tactics Neutrophils respond to infections in a few different ways, such as by engulfing and digesting an invading pathogen—or by degranulation in which they secrete proteins that destroy the invader. Another method discovered in 2004 is "NETosis," in which neutrophils expel strands of their own coagulated DNA, called chromatin, which act as a trap outside of the cell. These neutrophil extracellular traps, or so-called "NETs," ensnare and destroy pathogens. Benayoun and colleagues discovered differences in neutrophil activity between young and old mice, as well as between male and female mice. Males appeared to have more degranulation activity, as evidenced by higher levels of a protein, neutrophil elastase. Meanwhile females exhibited more NETosis on average. High degranulation activity can cause damage to surrounding tissues, and these findings could illustrate why sepsis affects men more than women, Benayoun said. "With sepsis, what kills you is not actually the bacteria; it's your response to the bacteria," she noted. "And we know that males in general have much worse odds during sepsis than females, and neutrophil elastase, which is one of the main components of degranulation, is one of the big things that can be produced at very high level during sepsis." On the other hand, higher NETosis activity could contribute to the body's immune system attacking healthy cells, Benayoun added. Antibodies targeting the body's own DNA have been found in many autoimmune disorders, which could have been developed after neutrophils produced too many NETs. Thus, higher NET activity in females could be related to higher rates of autoimmune disorders in women. "If you make NETs for no good reason, it can promote autoimmunity," Benayoun said. "It's a known fact that women are more prone to autoimmune disease, like a 9:1 ratio compared to men." With age, female neutrophils became more reactive, in contrast to male neutrophils. "In general, genetic programs seem to 'age' at a faster rate in male neutrophils," she said. "These findings suggest that sex differences can become amplified with aging, at least for neutrophils." A new resource for immune system study Neutrophils have historically been difficult to study because they are so short-lived, lasting less than a day. The cells' short lifespans are spent as the immune system's first responders, working quickly to trap and destroy pathogens at the first sign of an infection and sacrificing themselves in the process. Applying machine learning techniques to the data, the team has begun to identify genetic pathways involved in the regulation of immune response that could explain why there are such dramatic differences between the sexes, also called sex dimorphism, in immune system activity. Sex dimorphism in immunity has played out in the current pandemic: Most of the severe COVID-19 cases and deaths were men, Benayoun noted. With other literature indicating a possible role of sex hormones in immunity, studying these interactions could lead scientists to discover new techniques to fight severe illness. "If these differences are driven by the hormonal effects on immune cells, then in theory, you could try to intervene in early sepsis, maybe with anti-androgens in the short term, to bring down the response," Benayoun mused. "You could tailor medicine just by using the fact that this patient has more androgens or this person has more estrogen." <|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 Individual cells and multicellular systems respond to cell-scale curvatures in their environments, guiding migration, orientation, and tissue formation. However, it remains largely unclear how cells collectively explore and pattern complex landscapes with curvature gradients across the Euclidean and non-Euclidean spectra. Here, we show that mathematically designed substrates with controlled curvature variations induce multicellular spatiotemporal organization of preosteoblasts. We quantify curvature-induced patterning and find that cells generally prefer regions with at least one negative principal curvature. However, we also show that the developing tissue can eventually cover unfavorably curved territories, can bridge large portions of the substrates, and is often characterized by collectively aligned stress fibers. We demonstrate that this is partly regulated by cellular contractility and extracellular matrix development, underscoring the mechanical nature of curvature guidance. Our findings offer a geometric perspective on cell-environment interactions that could be harnessed in tissue engineering and regenerative medicine applications. Introduction The dynamic, bidirectional interactions between cells and their intricate environment orchestrate tissue morphogenesis, homeostasis, and repair, and are implicated in numerous diseases 1 , 2 , 3 . The complexity of the extracellular environment is not only due to its diverse and heterogeneous composition but is also caused by its hierarchical spatial structure that imposes geometrical constraints on the force-generating cells 4 , 5 . Cells have long been known to sense such geometrical cues at subcellular scales 6 , 7 , yet recent evidence shows that geometrical features at much larger scales also affect cell migration, differentiation, and fate, as well as tissue shape and growth kinetics 8 . Unravelling this interplay between cells and the shape of their surroundings is key to advance the design of artificial scaffolds and biomaterials, where geometry can be harnessed as a micro-engineered cell cue 9 , 10 , 11 . From a mathematical viewpoint, the local geometry of the extracellular environment can be fundamentally characterized using the concept of surface curvature 12 . In recent years, numerous studies have begun to address the role of cell-scale curvature on the dynamics and organization of cells and tissues. Indeed, curvature guidance has been observed in the directional migration and preferential orientation of a variety of individual cells and multicellular monolayers 13 , 14 , 15 , 16 , 17 , 18 . Moreover, various cell types have expressed an overall preference for local concavities as opposed to convexities 19 , 20 . Biophysical models have suggested key roles for cytoskeletal contractility and nuclear deformation in this large-scale curvature sensation, generally implying that cells with pronounced stress fibers avoid bending and search for relaxed configurations 21 , 22 , 23 , 24 . Despite the availability of such pioneering findings, it remains elusive how cells behave in more complex curvature landscapes. Early studies typically resorted to substrates with limited architectural complexity, involving cylindrical wires 13 , 25 , 26 or isolated hemispherical substrates 27 , 28 , precluding many physiologically relevant geometries, including saddle shapes or sharp curvature transitions. Moreover, the mathematical descriptions of surface curvature have not received much attention, hampering the development of a unified, unambiguous theory of cell-scale curvature guidance. Indeed, many studies have considered only a single class of curved substrates 25 , 26 , or have relied exclusively on the concepts of convexity and concavity instead of the fundamental definitions of curvature as described by differential geometry 20 , 27 . Here, we adopt a geometry-centered perspective and demonstrate multicellular spatiotemporal organization in precise environments with varying curvature distributions. To this end, we designed several substrates, derived from mathematically defined surface families, covering a wide range of cell-scale types of curvature variation. Using high-resolution multiphoton lithography ( i.e ., a 3D printing technique with submicron resolution) and replica molding, we fabricated chips on which we cultured murine preosteoblasts for several days. Our focus on bone-like cells was motivated by the ongoing quest for geometrically optimized biomaterials that enhance bone tissue regeneration, and by the fact that these cells have been used before within the context of geometry-driven tissue growth, due to their ability to exert considerable forces on their environments (as do fibroblasts, for example) and their ability to synthesize a profound extracellular matrix at long enough time scales. While previous studies have either focused on individual cell behavior at short time scales 14 , 20 or on tissue-level performance in larger-scale environments 29 , 30 , 31 , we studied curvature guidance at the intermediate time points where cells collectively pattern their environment and establish a template for bone-like tissue formation. By mapping 3D confocal microscopy data to the underlying curvature distributions, we explored the rules for emergent cell patterning. Specifically, we found that regions with at least one concave direction are highly attractive to cell collectives. This includes the transitions between the curved structures and their planar surroundings, which are typically ignored in other studies but explicitly considered and quantified in our work. We also found that cell collectives spontaneously detach from certain curved regions, thereby altering the extracellular geometry sensed by new cells. Moreover, we studied curvature-guided stress fiber orientation and investigated the important role of contractility in collective curvature guidance. Our results provide deeper geometric perspectives on substrate-driven multicellular organization, paving the way towards the geometric optimization of micro-engineered environments. Results Development of cell substrates with controlled curvatures We first set out to design substrates that would expose cells to a broad, yet controlled spectrum of curvatures. A complete description of surface curvature requires two independent curvature measures. The most common choices are either the two principal curvatures (i.e., the maximum and minimum curvatures, \${\\kappa }_{1}\$ and \${\\kappa }_{2}\$ , respectively), or the pair of the mean ( \$H\$ ) and Gaussian ( \$K\$ ) curvatures (Fig. 1a ). $$H=\\frac{1}{2}\\left({\\kappa }_{1}+{\\kappa }_{2}\\right)$$ (1) $$K={\\kappa }_{1}{\\kappa }_{2}$$ (2) Fig. 1: Design and microfabrication of curved cell substrates. a Local surface geometry defined in terms of the principal curvatures, \${\\kappa }_{1}\$ and \${\\kappa }_{2}\$ , and the Gaussian curvature, \$K\$ . b The surface profiles (top view) used to design", "role": "user" }, { "content": "Living cells can perceive and respond to the geometry of their environment. \"Cells sense and respond to the geometry of the surfaces they are exposed to. Depending on their curvature, surfaces can either encourage cells to create new tissue or prevent them from doing so,\" says Amir Zadpoor, professor of Biomaterials and Tissue Biomechanics, supervisor of a study showing that the curvature of biomaterials inhibits or stimulates bone cells to make new tissue. \"Stimulating curvatures made by a 3D printer are an easy and safe way to promote tissue growth. As compared to drugs, they are also much cheaper.\" In petri dishes, the researchers grew bone cells surrounded by small molds made from biomaterials with which the researchers have experience. Depending on the curvatures in the molds, the cells tended to grow, divide, and form tissue to different extents. Although curved shapes seem to exist in endless variations, they always fall roughly into one of these three categories: a ball that has a convex curvature, a saddle that has a concave curvature, and a plate that is flat. One of the authors, assistant professor of Biomaterials Lidy Fratila-Apachitei, said, \"Cells prefer a saddle shape. If they perceive a saddle shape nearby, growth is stimulated. The study also shows that cells prefer valleys over hills.\" First author Sebastien Callens did the experiments and analysis in the study. \"Cells also have a skeleton, which consists of fibers that are under tension to different degrees. How tension builds up in those fibers strongly influences the behavior of cells. Our study shows that cells collectively align their stress fibers with the curvatures they experience to minimize their need to bend. I could see that cells prefer to align than to bend.\" Credit: Delft University of Technology You can't have only saddle curves around cells. Just as the three angles of a triangle always add up to 180 degrees, the sum of all curvatures must also equal some fundamental numbers. \"You always have a limited budget of saddle shapes,\" says Zadpoor. \"If you use too much negative curvature somewhere, you must use positive curvatures somewhere else to keep the sum constant. You need to use your budget wisely to encourage maximum tissue regeneration.\" The study provides guidance on the optimal geometry of biomaterials and implants to maximize tissue regeneration. The complex geometric designs required are made using high-precision 3D printing techniques to make the shapes so small that they are perceptible to cells. Callens stated, \"We have now discovered new playing rules by which biomaterials can stimulate tissue growth. In follow-up research, we will try to apply those rules optimally.\" ", "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 Individual cells and multicellular systems respond to cell-scale curvatures in their environments, guiding migration, orientation, and tissue formation. However, it remains largely unclear how cells collectively explore and pattern complex landscapes with curvature gradients across the Euclidean and non-Euclidean spectra. Here, we show that mathematically designed substrates with controlled curvature variations induce multicellular spatiotemporal organization of preosteoblasts. We quantify curvature-induced patterning and find that cells generally prefer regions with at least one negative principal curvature. However, we also show that the developing tissue can eventually cover unfavorably curved territories, can bridge large portions of the substrates, and is often characterized by collectively aligned stress fibers. We demonstrate that this is partly regulated by cellular contractility and extracellular matrix development, underscoring the mechanical nature of curvature guidance. Our findings offer a geometric perspective on cell-environment interactions that could be harnessed in tissue engineering and regenerative medicine applications. Introduction The dynamic, bidirectional interactions between cells and their intricate environment orchestrate tissue morphogenesis, homeostasis, and repair, and are implicated in numerous diseases 1 , 2 , 3 . The complexity of the extracellular environment is not only due to its diverse and heterogeneous composition but is also caused by its hierarchical spatial structure that imposes geometrical constraints on the force-generating cells 4 , 5 . Cells have long been known to sense such geometrical cues at subcellular scales 6 , 7 , yet recent evidence shows that geometrical features at much larger scales also affect cell migration, differentiation, and fate, as well as tissue shape and growth kinetics 8 . Unravelling this interplay between cells and the shape of their surroundings is key to advance the design of artificial scaffolds and biomaterials, where geometry can be harnessed as a micro-engineered cell cue 9 , 10 , 11 . From a mathematical viewpoint, the local geometry of the extracellular environment can be fundamentally characterized using the concept of surface curvature 12 . In recent years, numerous studies have begun to address the role of cell-scale curvature on the dynamics and organization of cells and tissues. Indeed, curvature guidance has been observed in the directional migration and preferential orientation of a variety of individual cells and multicellular monolayers 13 , 14 , 15 , 16 , 17 , 18 . Moreover, various cell types have expressed an overall preference for local concavities as opposed to convexities 19 , 20 . Biophysical models have suggested key roles for cytoskeletal contractility and nuclear deformation in this large-scale curvature sensation, generally implying that cells with pronounced stress fibers avoid bending and search for relaxed configurations 21 , 22 , 23 , 24 . Despite the availability of such pioneering findings, it remains elusive how cells behave in more complex curvature landscapes. Early studies typically resorted to substrates with limited architectural complexity, involving cylindrical wires 13 , 25 , 26 or isolated hemispherical substrates 27 , 28 , precluding many physiologically relevant geometries, including saddle shapes or sharp curvature transitions. Moreover, the mathematical descriptions of surface curvature have not received much attention, hampering the development of a unified, unambiguous theory of cell-scale curvature guidance. Indeed, many studies have considered only a single class of curved substrates 25 , 26 , or have relied exclusively on the concepts of convexity and concavity instead of the fundamental definitions of curvature as described by differential geometry 20 , 27 . Here, we adopt a geometry-centered perspective and demonstrate multicellular spatiotemporal organization in precise environments with varying curvature distributions. To this end, we designed several substrates, derived from mathematically defined surface families, covering a wide range of cell-scale types of curvature variation. Using high-resolution multiphoton lithography ( i.e ., a 3D printing technique with submicron resolution) and replica molding, we fabricated chips on which we cultured murine preosteoblasts for several days. Our focus on bone-like cells was motivated by the ongoing quest for geometrically optimized biomaterials that enhance bone tissue regeneration, and by the fact that these cells have been used before within the context of geometry-driven tissue growth, due to their ability to exert considerable forces on their environments (as do fibroblasts, for example) and their ability to synthesize a profound extracellular matrix at long enough time scales. While previous studies have either focused on individual cell behavior at short time scales 14 , 20 or on tissue-level performance in larger-scale environments 29 , 30 , 31 , we studied curvature guidance at the intermediate time points where cells collectively pattern their environment and establish a template for bone-like tissue formation. By mapping 3D confocal microscopy data to the underlying curvature distributions, we explored the rules for emergent cell patterning. Specifically, we found that regions with at least one concave direction are highly attractive to cell collectives. This includes the transitions between the curved structures and their planar surroundings, which are typically ignored in other studies but explicitly considered and quantified in our work. We also found that cell collectives spontaneously detach from certain curved regions, thereby altering the extracellular geometry sensed by new cells. Moreover, we studied curvature-guided stress fiber orientation and investigated the important role of contractility in collective curvature guidance. Our results provide deeper geometric perspectives on substrate-driven multicellular organization, paving the way towards the geometric optimization of micro-engineered environments. Results Development of cell substrates with controlled curvatures We first set out to design substrates that would expose cells to a broad, yet controlled spectrum of curvatures. A complete description of surface curvature requires two independent curvature measures. The most common choices are either the two principal curvatures (i.e., the maximum and minimum curvatures, ${\kappa }_{1}$ and ${\kappa }_{2}$ , respectively), or the pair of the mean ( $H$ ) and Gaussian ( $K$ ) curvatures (Fig. 1a ). $$H=\frac{1}{2}\left({\kappa }_{1}+{\kappa }_{2}\right)$$ (1) $$K={\kappa }_{1}{\kappa }_{2}$$ (2) Fig. 1: Design and microfabrication of curved cell substrates. a Local surface geometry defined in terms of the principal curvatures, ${\kappa }_{1}$ and ${\kappa }_{2}$ , and the Gaussian curvature, $K$ . b The surface profiles (top view) used to design<|im_end|> <|im_start|>assistant Living cells can perceive and respond to the geometry of their environment. "Cells sense and respond to the geometry of the surfaces they are exposed to. Depending on their curvature, surfaces can either encourage cells to create new tissue or prevent them from doing so," says Amir Zadpoor, professor of Biomaterials and Tissue Biomechanics, supervisor of a study showing that the curvature of biomaterials inhibits or stimulates bone cells to make new tissue. "Stimulating curvatures made by a 3D printer are an easy and safe way to promote tissue growth. As compared to drugs, they are also much cheaper." In petri dishes, the researchers grew bone cells surrounded by small molds made from biomaterials with which the researchers have experience. Depending on the curvatures in the molds, the cells tended to grow, divide, and form tissue to different extents. Although curved shapes seem to exist in endless variations, they always fall roughly into one of these three categories: a ball that has a convex curvature, a saddle that has a concave curvature, and a plate that is flat. One of the authors, assistant professor of Biomaterials Lidy Fratila-Apachitei, said, "Cells prefer a saddle shape. If they perceive a saddle shape nearby, growth is stimulated. The study also shows that cells prefer valleys over hills." First author Sebastien Callens did the experiments and analysis in the study. "Cells also have a skeleton, which consists of fibers that are under tension to different degrees. How tension builds up in those fibers strongly influences the behavior of cells. Our study shows that cells collectively align their stress fibers with the curvatures they experience to minimize their need to bend. I could see that cells prefer to align than to bend." Credit: Delft University of Technology You can't have only saddle curves around cells. Just as the three angles of a triangle always add up to 180 degrees, the sum of all curvatures must also equal some fundamental numbers. "You always have a limited budget of saddle shapes," says Zadpoor. "If you use too much negative curvature somewhere, you must use positive curvatures somewhere else to keep the sum constant. You need to use your budget wisely to encourage maximum tissue regeneration." The study provides guidance on the optimal geometry of biomaterials and implants to maximize tissue regeneration. The complex geometric designs required are made using high-precision 3D printing techniques to make the shapes so small that they are perceptible to cells. Callens stated, "We have now discovered new playing rules by which biomaterials can stimulate tissue growth. In follow-up research, we will try to apply those rules optimally." <|im_end|>

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1,959

[ { "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 Thermodynamic arguments imply that global mean rainfall increases in a warmer atmosphere; however, dynamical effects may result in more significant diversity of regional precipitation change. Here we investigate rainfall changes in the mid-Pliocene Warm Period (~ 3 Ma), a time when temperatures were 2–3ºC warmer than the pre-industrial era, using output from the Pliocene Model Intercomparison Projects phases 1 and 2 and sensitivity climate model experiments. In the Mid-Pliocene simulations, the higher rates of warming in the northern hemisphere create an interhemispheric temperature gradient that enhances the southward cross-equatorial energy flux by up to 48%. This intensified energy flux reorganizes the atmospheric circulation leading to a northward shift of the Inter-Tropical Convergence Zone and a weakened and poleward displaced Southern Hemisphere Subtropical Convergences Zones. These changes result in drier-than-normal Southern Hemisphere tropics and subtropics. The evaluation of the mid-Pliocene adds a constraint to possible future warmer scenarios associated with differing rates of warming between hemispheres. Introduction The Earth has experienced many periods in which climate was warmer than present. Understanding atmospheric circulation and precipitation during past warm climates is useful to produce constraints on possible future changes. Here we analyse the Southern Hemisphere large-scale rainfall response in the mid-Pliocene Warm Period (~ 3 Ma mPWP; hereafter referred as mid-Pliocene). During this period high-latitude Sea Surface Temperatures (SST) were as high as + 9 °C and + 4 °C in the Northern and Southern Hemisphere, respectively 1 , compared to pre-industrial times (~ 1850 Common Era [C.E.]; Fig. 1 ). In addition, the Greenland ice sheet had 50–70% 2 , 3 , 4 less mass and the western Antarctica was ice-free 5 , 6 . Atmospheric CO 2 concentrations were similar to today 7 (~ 400 ppm). Although the extent of the ice sheets for the end of the twenty-first century is still a topic of debate, especially due to model’s limitations in simulating land-ice processes 8 , 9 , the mid-Pliocene is considered a useful analogue for the end-of-century climate 10 . Figure 1 Data-model comparison of Sea Surface Temperatures anomalies during the mid-Pliocene and PlioMIP precipitation. ( a) Multi-model mean SST anomaly in the PlioMIP2 (mid-Pliocene minus pre-industrial). Circles indicate location of sites and SST anomalies compiled by PRISM 11 . Size of the circles indicate confidence level. Small: low confidence. Medium: medium confidence. Large: High confidence. ( b) zonal mean SST anomaly from PRISM (dashed black) and multi-model medians PlioMIP1 (magenta) and PlioMIP2 (red). ( c) as per ‘b’ but for precipitation. Banding indicates interquartile range. d) as per ‘a’ but including contours (black) of precipitation changes in mm.day −1 . Full size image Rainfall proxy archives do not exist for the tropics and Southern Hemisphere subtropics in the mid-Pliocene. However, paleo reconstructions of ice sheets, SSTs, vegetation distribution, soils and lakes performed by the Pliocene Research, Interpretation and Synoptic Mapping (PRISM) project 1 are available to force climate models 4 , 12 in order to estimate how rainfall may have looked in the mid-Pliocene. In this way, due to similarities between the mid-Pliocene and scenarios of future projected warming the Pliocene Model Intercomparison Project (PlioMIP) initiative was developed towards a better understanding of its climate scenario. To date, there has been no detailed investigation of Southern Hemisphere rainfall changes in the mid-Pliocene. Most studies have focused on the Northern Hemisphere monsoon systems 13 , 14 , 15 or global land monsoons 16 . These studies reported intensified western African, Asian and Australian monsoons and a weakened South American monsoon. SST changes indicated by both PlioMIP ensembles and proxy-data from the mid-Pliocene (Fig. 1 a) suggest possible changes in the atmospheric circulation through changes in the meridional heat transport. These data clearly indicate a Northern Hemisphere warmer than Southern Hemisphere during the mid-Pliocene (Fig. 1 a,b). Theoretical and observational studies indicate that in response to changes in the interhemispheric SST gradient, there is strengthening of the cooler hemisphere Hadley cell and displacement of the Inter-Tropical Convergence Zone (ITCZ) towards the warmer hemisphere 17 , 18 . In addition, changes in the intensity and position of the Hadley Cells and low-level winds can have a substantial impact on rainfall at subtropical latitudes. Indeed, Southern Hemisphere tropics and subtropics are the only regions that are simulated to be drier in the wetter atmosphere of the mid-Pliocene (Fig. 1 c). A closer examination in the tropical and subtropical Southern Hemisphere (Fig. 1 d) indicates that reduced rainfall in the subtropical Southern Hemisphere is also related to a minimum SST increase. In the subtropical South Pacific, there is a strengthening of rainfall in the west and a weakening in the central-east coincident with SST changes. A warmer tropical Northern Hemisphere across all basins is also consistent with its increased rainfall due to the thermodynamical effect 19 , 20 (‘wet-wetter’ theory). Furthermore, the non-uniform tropical warming results in increased tropical inter-hemispheric SST gradient, indicating that dynamical changes could also have contributed to changes in rainfall. As such, local changes in SST may also play a role in drying the subtropical Southern Hemisphere climate and amplifying the large-scale inter-hemispheric contrast. The largest changes in rainfall in the Southern Hemisphere are likely associated with changes in the Inter-Tropical Convergence Zone (ITCZ) and Subtropical Convergences Zones (STCZs; Fig. 1 d). In modern Southern Hemisphere climatology more than 50% of the annual rainfall occurs during the extended austral summer period (November to March) in most regions 21 , 22 . The ITCZ and SPCZs largely contribute to this. Firstly, the ITCZ that moves south during austral summer and increases rainfall in the Southern Hemisphere Tropical regions 21 . In addition, the STCZs are a summertime feature of the subtropics that can have rainfall rates comparable to the ITCZ 23 (up to ~ 400 mm month −1 ). The STCZs are bands of intense cloudiness and convection that set up transversally from tropical latitudes to the subtropics, commonly visible via satellite images. They develop when troughs of the subtropical jet penetrate the subtropics and poleward low-level winds", "role": "user" }, { "content": "Projections based on climate models for the mid-Pliocene Warm Period (about 3 million years ago) suggest that countries in the tropical and subtropical southern hemisphere, including Brazil, may face longer droughts in the future. Annual rainfall may decrease as much as 30% compared with current levels. One of the main variables considered in this scenario is a rise of 3 °C in the global average temperature, which may happen between 2050 and the end of the century unless the effects of climate change are mitigated. The mid-Pliocene, before the emergence of Homo sapiens, shares characteristics with modern warming because temperatures were then between 2 °C and 3 °C higher than in the pre-industrial age (around the 1850s). High-latitude sea surface temperatures rose as much as 9 °C in the northern hemisphere and 4 °C in the southern hemisphere. Atmospheric CO2 levels were similar to today's at about 400 parts per million (ppm). These considerations are in the article \"Drier tropical and subtropical Southern Hemisphere in the mid-Pliocene Warm Period,\" published in Scientific Reports. The lead author is Gabriel Marques Pontes, a Ph.D. candidate at the University of São Paulo's Oceanographic Institute (IO-USP) in Brazil with a scholarship from São Paulo Research Foundation—FAPESP . The second author is Ilana Wainer, a professor in IO-USP and Pontes's thesis adviser. Other co-authors include Andréa Taschetto of the University of New South Wales (UNSW) in Australia, a former awardee of a scholarship from FAPESP. According to the authors, their simulations showed that one of the most notable changes in southern hemisphere summer rainfall in the mid-Pliocene compared to pre-industrial conditions occurs in subtropical regions along the subtropical convergence zones (STCZs). Another change, they add, is associated with a northward shift of the inter-tropical convergence zone (ITCZ) due to consistent increased rainfall in the northern hemisphere tropics. The total November-to-March mean rainfall along the STCZs decreases in both models. \"These changes result in drier-than-normal southern hemisphere tropics and subtropics. The evaluation of the mid-Pliocene adds a constraint to possible future warmer scenarios associated with differing rates of warming between hemispheres,\" the article states. In an interview, Wainer explained that the mid-Pliocene is the most recent period in Earth's history when global warming was similar to that projected for the rest of this century. \"It's possible to put the expected natural variability in this context and distinguish it from the change caused by human activity,\" she said. \"Studying past climate extremes helps elucidate future scenarios and address the associated uncertainties.\" For Pontes, this is the first detailed investigation of southern hemisphere rainfall changes in the mid-Pliocene. \"Understanding atmospheric circulation and precipitation during past warm climates is useful to add constraints to future change scenarios,\" he said. Current impacts According to a report issued in July by the World Meteorological Organization (WMO), the global average temperature could rise more than 1.5 °C above pre-industrial levels by 2024, much sooner than scientists previously thought. The report warns of a high risk of extreme rainfall variability across the various regions in the next five years, with some facing drought and others flooding. In March the WMO confirmed that 2019 was the second warmest year on record, with a global average temperature that was 1.1 °C above pre-industrial levels. The warmest ever was 2016, partly owing to a strong El Niño, characterized by unusually warm sea surface temperatures in the Equatorial Pacific. Since the 1980s each decade has been warmer than the previous one, the WMO noted, adding that retreating ice, record sea levels, increasing ocean heat and acidification and extreme weather combine to have major impacts on the health and well-being of both humans and the environment. The problem affects world socio-economic development, causing migration and food insecurity in terrestrial and marine ecosystems. In 2015, 195 countries signed up to greenhouse gas emission reduction targets in the Paris Agreement and promised to limit global warming to between 1.5 °C and 2 °C. These promises have not been kept. \"The United Nations has promoted measures to try to limit warming, but 1.5 °C is already having a significant impact,\" Pontes said. \"The projections point to 3 °C by the end of the century when the consequences could look like the mid-Pliocene simulations performed in the study.\" There was practically no external impact on vegetation in the mid-Pliocene, when the Amazon rainforest was much larger, generating more moisture and helping to offset the drier climate in the region, he added. Future droughts will be worse if deforestation and burning continue at the present rate. Data published by the National Institute for Space Research (INPE) in Brazil shows a 34% increase in deforestation in the Amazon between August 2019 and July 2020 compared with a year earlier. Over 9,200 square kilometers of forest were destroyed in 12 months. Since 2013 deforestation in the Amazon has rebounded to reach high levels in consecutive years, after trending down for a period compared with the 1990s. Data from INPE also shows a 28% increase in forest fires in the Amazon in July 2020 compared with a year earlier, itself considered the worst since 2010. For Pontes, drier weather and higher temperatures in South America could decrease annual rainfall by as much as 30%, leading to water shortages across the continent. \"The more we can mitigate warming and deforestation, the more we can help reduce the impact of climate change on the population of South America,\" he said. The article recommends further research taking changes in plant cover into consideration by analyzing the effects of deforestation and warming together to estimate the possible decrease in rainfall in South America. ", "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 Thermodynamic arguments imply that global mean rainfall increases in a warmer atmosphere; however, dynamical effects may result in more significant diversity of regional precipitation change. Here we investigate rainfall changes in the mid-Pliocene Warm Period (~ 3 Ma), a time when temperatures were 2–3ºC warmer than the pre-industrial era, using output from the Pliocene Model Intercomparison Projects phases 1 and 2 and sensitivity climate model experiments. In the Mid-Pliocene simulations, the higher rates of warming in the northern hemisphere create an interhemispheric temperature gradient that enhances the southward cross-equatorial energy flux by up to 48%. This intensified energy flux reorganizes the atmospheric circulation leading to a northward shift of the Inter-Tropical Convergence Zone and a weakened and poleward displaced Southern Hemisphere Subtropical Convergences Zones. These changes result in drier-than-normal Southern Hemisphere tropics and subtropics. The evaluation of the mid-Pliocene adds a constraint to possible future warmer scenarios associated with differing rates of warming between hemispheres. Introduction The Earth has experienced many periods in which climate was warmer than present. Understanding atmospheric circulation and precipitation during past warm climates is useful to produce constraints on possible future changes. Here we analyse the Southern Hemisphere large-scale rainfall response in the mid-Pliocene Warm Period (~ 3 Ma mPWP; hereafter referred as mid-Pliocene). During this period high-latitude Sea Surface Temperatures (SST) were as high as + 9 °C and + 4 °C in the Northern and Southern Hemisphere, respectively 1 , compared to pre-industrial times (~ 1850 Common Era [C.E.]; Fig. 1 ). In addition, the Greenland ice sheet had 50–70% 2 , 3 , 4 less mass and the western Antarctica was ice-free 5 , 6 . Atmospheric CO 2 concentrations were similar to today 7 (~ 400 ppm). Although the extent of the ice sheets for the end of the twenty-first century is still a topic of debate, especially due to model’s limitations in simulating land-ice processes 8 , 9 , the mid-Pliocene is considered a useful analogue for the end-of-century climate 10 . Figure 1 Data-model comparison of Sea Surface Temperatures anomalies during the mid-Pliocene and PlioMIP precipitation. ( a) Multi-model mean SST anomaly in the PlioMIP2 (mid-Pliocene minus pre-industrial). Circles indicate location of sites and SST anomalies compiled by PRISM 11 . Size of the circles indicate confidence level. Small: low confidence. Medium: medium confidence. Large: High confidence. ( b) zonal mean SST anomaly from PRISM (dashed black) and multi-model medians PlioMIP1 (magenta) and PlioMIP2 (red). ( c) as per ‘b’ but for precipitation. Banding indicates interquartile range. d) as per ‘a’ but including contours (black) of precipitation changes in mm.day −1 . Full size image Rainfall proxy archives do not exist for the tropics and Southern Hemisphere subtropics in the mid-Pliocene. However, paleo reconstructions of ice sheets, SSTs, vegetation distribution, soils and lakes performed by the Pliocene Research, Interpretation and Synoptic Mapping (PRISM) project 1 are available to force climate models 4 , 12 in order to estimate how rainfall may have looked in the mid-Pliocene. In this way, due to similarities between the mid-Pliocene and scenarios of future projected warming the Pliocene Model Intercomparison Project (PlioMIP) initiative was developed towards a better understanding of its climate scenario. To date, there has been no detailed investigation of Southern Hemisphere rainfall changes in the mid-Pliocene. Most studies have focused on the Northern Hemisphere monsoon systems 13 , 14 , 15 or global land monsoons 16 . These studies reported intensified western African, Asian and Australian monsoons and a weakened South American monsoon. SST changes indicated by both PlioMIP ensembles and proxy-data from the mid-Pliocene (Fig. 1 a) suggest possible changes in the atmospheric circulation through changes in the meridional heat transport. These data clearly indicate a Northern Hemisphere warmer than Southern Hemisphere during the mid-Pliocene (Fig. 1 a,b). Theoretical and observational studies indicate that in response to changes in the interhemispheric SST gradient, there is strengthening of the cooler hemisphere Hadley cell and displacement of the Inter-Tropical Convergence Zone (ITCZ) towards the warmer hemisphere 17 , 18 . In addition, changes in the intensity and position of the Hadley Cells and low-level winds can have a substantial impact on rainfall at subtropical latitudes. Indeed, Southern Hemisphere tropics and subtropics are the only regions that are simulated to be drier in the wetter atmosphere of the mid-Pliocene (Fig. 1 c). A closer examination in the tropical and subtropical Southern Hemisphere (Fig. 1 d) indicates that reduced rainfall in the subtropical Southern Hemisphere is also related to a minimum SST increase. In the subtropical South Pacific, there is a strengthening of rainfall in the west and a weakening in the central-east coincident with SST changes. A warmer tropical Northern Hemisphere across all basins is also consistent with its increased rainfall due to the thermodynamical effect 19 , 20 (‘wet-wetter’ theory). Furthermore, the non-uniform tropical warming results in increased tropical inter-hemispheric SST gradient, indicating that dynamical changes could also have contributed to changes in rainfall. As such, local changes in SST may also play a role in drying the subtropical Southern Hemisphere climate and amplifying the large-scale inter-hemispheric contrast. The largest changes in rainfall in the Southern Hemisphere are likely associated with changes in the Inter-Tropical Convergence Zone (ITCZ) and Subtropical Convergences Zones (STCZs; Fig. 1 d). In modern Southern Hemisphere climatology more than 50% of the annual rainfall occurs during the extended austral summer period (November to March) in most regions 21 , 22 . The ITCZ and SPCZs largely contribute to this. Firstly, the ITCZ that moves south during austral summer and increases rainfall in the Southern Hemisphere Tropical regions 21 . In addition, the STCZs are a summertime feature of the subtropics that can have rainfall rates comparable to the ITCZ 23 (up to ~ 400 mm month −1 ). The STCZs are bands of intense cloudiness and convection that set up transversally from tropical latitudes to the subtropics, commonly visible via satellite images. They develop when troughs of the subtropical jet penetrate the subtropics and poleward low-level winds<|im_end|> <|im_start|>assistant Projections based on climate models for the mid-Pliocene Warm Period (about 3 million years ago) suggest that countries in the tropical and subtropical southern hemisphere, including Brazil, may face longer droughts in the future. Annual rainfall may decrease as much as 30% compared with current levels. One of the main variables considered in this scenario is a rise of 3 °C in the global average temperature, which may happen between 2050 and the end of the century unless the effects of climate change are mitigated. The mid-Pliocene, before the emergence of Homo sapiens, shares characteristics with modern warming because temperatures were then between 2 °C and 3 °C higher than in the pre-industrial age (around the 1850s). High-latitude sea surface temperatures rose as much as 9 °C in the northern hemisphere and 4 °C in the southern hemisphere. Atmospheric CO2 levels were similar to today's at about 400 parts per million (ppm). These considerations are in the article "Drier tropical and subtropical Southern Hemisphere in the mid-Pliocene Warm Period," published in Scientific Reports. The lead author is Gabriel Marques Pontes, a Ph.D. candidate at the University of São Paulo's Oceanographic Institute (IO-USP) in Brazil with a scholarship from São Paulo Research Foundation—FAPESP . The second author is Ilana Wainer, a professor in IO-USP and Pontes's thesis adviser. Other co-authors include Andréa Taschetto of the University of New South Wales (UNSW) in Australia, a former awardee of a scholarship from FAPESP. According to the authors, their simulations showed that one of the most notable changes in southern hemisphere summer rainfall in the mid-Pliocene compared to pre-industrial conditions occurs in subtropical regions along the subtropical convergence zones (STCZs). Another change, they add, is associated with a northward shift of the inter-tropical convergence zone (ITCZ) due to consistent increased rainfall in the northern hemisphere tropics. The total November-to-March mean rainfall along the STCZs decreases in both models. "These changes result in drier-than-normal southern hemisphere tropics and subtropics. The evaluation of the mid-Pliocene adds a constraint to possible future warmer scenarios associated with differing rates of warming between hemispheres," the article states. In an interview, Wainer explained that the mid-Pliocene is the most recent period in Earth's history when global warming was similar to that projected for the rest of this century. "It's possible to put the expected natural variability in this context and distinguish it from the change caused by human activity," she said. "Studying past climate extremes helps elucidate future scenarios and address the associated uncertainties." For Pontes, this is the first detailed investigation of southern hemisphere rainfall changes in the mid-Pliocene. "Understanding atmospheric circulation and precipitation during past warm climates is useful to add constraints to future change scenarios," he said. Current impacts According to a report issued in July by the World Meteorological Organization (WMO), the global average temperature could rise more than 1.5 °C above pre-industrial levels by 2024, much sooner than scientists previously thought. The report warns of a high risk of extreme rainfall variability across the various regions in the next five years, with some facing drought and others flooding. In March the WMO confirmed that 2019 was the second warmest year on record, with a global average temperature that was 1.1 °C above pre-industrial levels. The warmest ever was 2016, partly owing to a strong El Niño, characterized by unusually warm sea surface temperatures in the Equatorial Pacific. Since the 1980s each decade has been warmer than the previous one, the WMO noted, adding that retreating ice, record sea levels, increasing ocean heat and acidification and extreme weather combine to have major impacts on the health and well-being of both humans and the environment. The problem affects world socio-economic development, causing migration and food insecurity in terrestrial and marine ecosystems. In 2015, 195 countries signed up to greenhouse gas emission reduction targets in the Paris Agreement and promised to limit global warming to between 1.5 °C and 2 °C. These promises have not been kept. "The United Nations has promoted measures to try to limit warming, but 1.5 °C is already having a significant impact," Pontes said. "The projections point to 3 °C by the end of the century when the consequences could look like the mid-Pliocene simulations performed in the study." There was practically no external impact on vegetation in the mid-Pliocene, when the Amazon rainforest was much larger, generating more moisture and helping to offset the drier climate in the region, he added. Future droughts will be worse if deforestation and burning continue at the present rate. Data published by the National Institute for Space Research (INPE) in Brazil shows a 34% increase in deforestation in the Amazon between August 2019 and July 2020 compared with a year earlier. Over 9,200 square kilometers of forest were destroyed in 12 months. Since 2013 deforestation in the Amazon has rebounded to reach high levels in consecutive years, after trending down for a period compared with the 1990s. Data from INPE also shows a 28% increase in forest fires in the Amazon in July 2020 compared with a year earlier, itself considered the worst since 2010. For Pontes, drier weather and higher temperatures in South America could decrease annual rainfall by as much as 30%, leading to water shortages across the continent. "The more we can mitigate warming and deforestation, the more we can help reduce the impact of climate change on the population of South America," he said. The article recommends further research taking changes in plant cover into consideration by analyzing the effects of deforestation and warming together to estimate the possible decrease in rainfall in South America. <|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 Electrical communication between an enzyme and an electrode is one of the most important factors in determining the performance of biofuel cells. Here, we introduce a glucose oxidase-coated metallic cotton fiber-based hybrid biofuel cell with efficient electrical communication between the anodic enzyme and the conductive support. Gold nanoparticles are layer-by-layer assembled with small organic linkers onto cotton fibers to form metallic cotton fibers with extremely high conductivity (>2.1×10 4 S cm −1 ), and are used as an enzyme-free cathode as well as a conductive support for the enzymatic anode. For preparation of the anode, the glucose oxidase is sequentially layer-by-layer-assembled with the same linkers onto the metallic cotton fibers. The resulting biofuel cells exhibit a remarkable power density of 3.7 mW cm −2 , significantly outperforming conventional biofuel cells. Our strategy to promote charge transfer through electrodes can provide an important tool to improve the performance of biofuel cells. Introduction Biofuel cells (BFCs) 1 are thought to be one of the most attractive power sources for implantable and microscale biomedical devices because of their biocompatibility and operation at mild temperatures and near-neutral pH 2 , 3 , 4 . Despite these advantages, the relatively low power output of BFCs compared to other power sources, resulting from slow electron transfer, poor utilization efficiency of the enzyme, and limited mass transport, has restricted their practical applications. In particular, poor electrical communication between the enzyme and the conductive support has a critical effect on the power output of BFCs 5 , 6 . To overcome this problem, redox mediators between the enzyme and the conductive support have been introduced to improve the electrical communication between the two, thereby enhancing the power performance of the cell. To the best of our knowledge, the best power performance reported to date for these mediated electron-transfer-based BFCs (MET-BFCs) is 2.18 mW cm −2 7 . However, the incorporation of a redox mediator in BFCs can lead to several issues, such as toxicity, instability, the complex synthesis of redox mediators, and a reduced open-circuit voltage. Thus, recent research efforts have focused on the development of direct electron transfer-based BFCs (DET-BFCs) with improved performance 8 . A variety of conductive carbon materials (e.g., carbon nanotubes (CNTs) 9 , 10 , 11 , graphene 12 , and porous carbon 13 ) with large surface areas, 3D porous structures for facile mass transport, and high electrical conductivities (<300 S cm −1 ) have been proposed as supports having favorable electrical communication with the enzyme layer. For example, Zebda et al. demonstrate that DET-BFCs based on CNT supports exhibited a significantly higher power output of 1.25 mW cm −2 compared to previously reported DET-BFCs fabricated by solution drop casting and high mechanical compression 5 . Despite all the merits of the carbon substrates for the BFCs, their biosafety for long-term operation in the in vivo systems is still controversial due to the cellular toxicity nature 14 , 15 . Furthermore, in most cases, the enzymes have been directly deposited onto these carbon supports through conventional physical adsorption, which has limitations in terms of the precise control of the interfacial distance, conformation, and stability between the enzyme and the conductive support, resulting in poor utilization of the enzymes for catalyzing electrochemical reactions. With the advances of the anode for the glucose oxidation reaction through glucose oxidase (GOx), the proper design of the cathode to improve the oxygen reduction reaction (ORR) activity is also crucial to obtain the high-power density and efficiency. In this regard, the cathodic enzyme, such as laccase or bilirubin oxidase, have been intensively studied due to their excellent ORR activity 5 , 16 . However, the catalytic activity and stability are strongly dependent on the physiological conditions of the mammal’s body fluid such as pH, temperature, and chlorine concentration 17 , 18 , 19 , 20 . As an alternative, catalytic metal nanoparticles (NPs) such as Pt, Pd, and Au with high ORR activity have been considered as the competent candidates to the abiotic ORR catalysts 21 , 22 . Despite the improved performance, conventional methods of depositing NPs onto the substrates, such as the mixing of NPs with carbon-substrates 23 or chemical reduction of the metal precursor, etc. 22 , 24 have poor controls over the structures of NPs on the substrates. In addition, chemical reduction methods often cause particle agglomeration between adjacent NPs with the reduced electrochemical surface area, which hinders high mass loading of NPs on the substrates 25 . Therefore, it is ideal to incorporate the catalytic NPs onto the substrates in a controlled, 3D spatial arrangement without agglomeration, which can facilitate electron and ion transport for the efficient electrocatalytic reaction. Layer-by-layer (LbL) assembly methods offer effective opportunities to prepare enzymatic or conductive multilayer films with tailored thickness, functionalities, and composition on substrates of various sizes and shapes utilizing complementary interactions 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 . However, as bulky insulating polyelectrolytes are generally LbL-assembled with the desired functional components (e.g., metal NPs, enzymes, functional polymers 39 ) to build up multilayers, the mutual electron transfer is significantly suppressed due to the increased contact resistance 40 . Therefore, the ideal LbL assembly for BFC applications should replace bulky polymer electrolytes with small-molecule linkers that can facilitate the electrical communication between the active materials as well as enable the efficient assembly of the catalysts with a controlled structure and loading amount. Here, we introduce a highly porous metallic cotton fiber-based BFC (MCF-BFC) fabricated using small-molecule linker-induced LbL assembly of the active catalysts, which significantly boosts the DET rate between the enzymes and the conductive supports (Fig. 1 ). In particular, the Au NPs are selected to fabricate the MCF because of their several benefits in electrochemical biomedical fields 41 , such as the superior biocompatibility 42 , more facile surface modification 43 , and higher electrical conductivity. In this case, the MCFs act as not", "role": "user" }, { "content": "A glucose-powered biofuel cell that uses electrodes made from cotton fiber could someday help power implantable medical devices such as pacemakers and sensors. The new fuel cell, which provides twice as much power as conventional biofuel cells, could be paired with batteries or supercapacitors to provide a hybrid power source for the medical devices. Researchers at the Georgia Institute of Technology and Korea University used gold nanoparticles assembled on the cotton to create high-conductivity electrodes that helped improve the fuel cell's efficiency. That allowed them to address one of the major challenges limiting the performance of biofuel cells—connecting the enzyme used to oxidize glucose with an electrode. A layer-by-layer assembly technique used to fabricate the gold electrodes—which provide both the electrocatalytic cathode and the conductive substrate for the anode—helped boost the power capacity to as much as 3.7 milliwatts per square centimeter. Results of the research were reported October 26 in the journal Nature Communications. \"We could use this device as a continuous power source for converting chemical energy from glucose in the body to electrical energy,\" said Seung Woo Lee, an assistant professor in Georgia Tech's Woodruff School of Mechanical Engineering. \"The layer-by-layer deposition technique precisely controls deposition of both the gold nanoparticle and enzyme, dramatically increasing the power density of this fuel cell.\" Fabrication of the electrodes begins with porous cotton fiber composed of multiple hydrophilic microfibrils—cellulose fibers containing hydroxyl groups. Gold nanoparticles about eight nanometers in diameter are then assembled onto the fibers using organic linker materials. To create the anode for oxidizing the glucose, the researchers apply glucose oxidase enzyme in layers alternating with an amine-functionalized small molecule known as TREN. The cathode, where the oxygen reduction reaction takes place, used the gold-covered electrodes, which have electrocatalytic capabilities. Scanning electron microscope images show details of the cotton-based electrodes used in a new biofuel cell. Credit: Georgia Tech/Korea University \"We precisely control the loading of the enzyme,\" Lee said. \"We produce a very thin layer so that the charge transport between the conductive substrate and the enzyme is improved. We have made a very close connection between the materials so the transport of electrons is easier.\" The porosity of the cotton allowed an increase in the number of gold layers compared to a nylon fiber. \"Cotton has many pores that can support activity in electrochemical devices,\" explained Yongmin Ko, a visiting faculty member and one of the paper's co-authors. \"The cotton fiber is hydrophilic, meaning the electrolyte easily wets the surface.\" Beyond improving the conductivity of the electrodes, the cotton fiber could improve the biocompatibility of the device, which is designed to operate at low temperature to allow use inside the body. Implantable biofuel cells suffer from degradation over time, and the new cell developed by the U.S. and Korean team offers improved long-term stability. \"We have a record high power performance, and the lifetime should be improved for biomedical applications such as pacemakers,\" Lee said. Pacemakers and other implantable devices are now powered by batteries that last years, but may still require replacement in a procedure that requires surgery. The biofuel cell could provide a continuous charge for those batteries, potentially extending the time that devices may operate without battery replacement, Lee added. In addition, the biofuel cell could be used to power devices intended for temporary use. Such devices might be implanted to provide timed release of a drug, but would biodegrade over time without requiring surgical removal. For these applications, no battery would be included, and the limited power required could be provided by the biofuel cell. Future goals of the research include demonstrating operation of the biofuel cell with an energy storage device, and development of a functional implantable power source. \"We want to develop other biological applications for this,\" said Lee. \"We'd like to go farther with other applications including batteries and high-performance 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 Electrical communication between an enzyme and an electrode is one of the most important factors in determining the performance of biofuel cells. Here, we introduce a glucose oxidase-coated metallic cotton fiber-based hybrid biofuel cell with efficient electrical communication between the anodic enzyme and the conductive support. Gold nanoparticles are layer-by-layer assembled with small organic linkers onto cotton fibers to form metallic cotton fibers with extremely high conductivity (>2.1×10 4 S cm −1 ), and are used as an enzyme-free cathode as well as a conductive support for the enzymatic anode. For preparation of the anode, the glucose oxidase is sequentially layer-by-layer-assembled with the same linkers onto the metallic cotton fibers. The resulting biofuel cells exhibit a remarkable power density of 3.7 mW cm −2 , significantly outperforming conventional biofuel cells. Our strategy to promote charge transfer through electrodes can provide an important tool to improve the performance of biofuel cells. Introduction Biofuel cells (BFCs) 1 are thought to be one of the most attractive power sources for implantable and microscale biomedical devices because of their biocompatibility and operation at mild temperatures and near-neutral pH 2 , 3 , 4 . Despite these advantages, the relatively low power output of BFCs compared to other power sources, resulting from slow electron transfer, poor utilization efficiency of the enzyme, and limited mass transport, has restricted their practical applications. In particular, poor electrical communication between the enzyme and the conductive support has a critical effect on the power output of BFCs 5 , 6 . To overcome this problem, redox mediators between the enzyme and the conductive support have been introduced to improve the electrical communication between the two, thereby enhancing the power performance of the cell. To the best of our knowledge, the best power performance reported to date for these mediated electron-transfer-based BFCs (MET-BFCs) is 2.18 mW cm −2 7 . However, the incorporation of a redox mediator in BFCs can lead to several issues, such as toxicity, instability, the complex synthesis of redox mediators, and a reduced open-circuit voltage. Thus, recent research efforts have focused on the development of direct electron transfer-based BFCs (DET-BFCs) with improved performance 8 . A variety of conductive carbon materials (e.g., carbon nanotubes (CNTs) 9 , 10 , 11 , graphene 12 , and porous carbon 13 ) with large surface areas, 3D porous structures for facile mass transport, and high electrical conductivities (<300 S cm −1 ) have been proposed as supports having favorable electrical communication with the enzyme layer. For example, Zebda et al. demonstrate that DET-BFCs based on CNT supports exhibited a significantly higher power output of 1.25 mW cm −2 compared to previously reported DET-BFCs fabricated by solution drop casting and high mechanical compression 5 . Despite all the merits of the carbon substrates for the BFCs, their biosafety for long-term operation in the in vivo systems is still controversial due to the cellular toxicity nature 14 , 15 . Furthermore, in most cases, the enzymes have been directly deposited onto these carbon supports through conventional physical adsorption, which has limitations in terms of the precise control of the interfacial distance, conformation, and stability between the enzyme and the conductive support, resulting in poor utilization of the enzymes for catalyzing electrochemical reactions. With the advances of the anode for the glucose oxidation reaction through glucose oxidase (GOx), the proper design of the cathode to improve the oxygen reduction reaction (ORR) activity is also crucial to obtain the high-power density and efficiency. In this regard, the cathodic enzyme, such as laccase or bilirubin oxidase, have been intensively studied due to their excellent ORR activity 5 , 16 . However, the catalytic activity and stability are strongly dependent on the physiological conditions of the mammal’s body fluid such as pH, temperature, and chlorine concentration 17 , 18 , 19 , 20 . As an alternative, catalytic metal nanoparticles (NPs) such as Pt, Pd, and Au with high ORR activity have been considered as the competent candidates to the abiotic ORR catalysts 21 , 22 . Despite the improved performance, conventional methods of depositing NPs onto the substrates, such as the mixing of NPs with carbon-substrates 23 or chemical reduction of the metal precursor, etc. 22 , 24 have poor controls over the structures of NPs on the substrates. In addition, chemical reduction methods often cause particle agglomeration between adjacent NPs with the reduced electrochemical surface area, which hinders high mass loading of NPs on the substrates 25 . Therefore, it is ideal to incorporate the catalytic NPs onto the substrates in a controlled, 3D spatial arrangement without agglomeration, which can facilitate electron and ion transport for the efficient electrocatalytic reaction. Layer-by-layer (LbL) assembly methods offer effective opportunities to prepare enzymatic or conductive multilayer films with tailored thickness, functionalities, and composition on substrates of various sizes and shapes utilizing complementary interactions 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 . However, as bulky insulating polyelectrolytes are generally LbL-assembled with the desired functional components (e.g., metal NPs, enzymes, functional polymers 39 ) to build up multilayers, the mutual electron transfer is significantly suppressed due to the increased contact resistance 40 . Therefore, the ideal LbL assembly for BFC applications should replace bulky polymer electrolytes with small-molecule linkers that can facilitate the electrical communication between the active materials as well as enable the efficient assembly of the catalysts with a controlled structure and loading amount. Here, we introduce a highly porous metallic cotton fiber-based BFC (MCF-BFC) fabricated using small-molecule linker-induced LbL assembly of the active catalysts, which significantly boosts the DET rate between the enzymes and the conductive supports (Fig. 1 ). In particular, the Au NPs are selected to fabricate the MCF because of their several benefits in electrochemical biomedical fields 41 , such as the superior biocompatibility 42 , more facile surface modification 43 , and higher electrical conductivity. In this case, the MCFs act as not<|im_end|> <|im_start|>assistant A glucose-powered biofuel cell that uses electrodes made from cotton fiber could someday help power implantable medical devices such as pacemakers and sensors. The new fuel cell, which provides twice as much power as conventional biofuel cells, could be paired with batteries or supercapacitors to provide a hybrid power source for the medical devices. Researchers at the Georgia Institute of Technology and Korea University used gold nanoparticles assembled on the cotton to create high-conductivity electrodes that helped improve the fuel cell's efficiency. That allowed them to address one of the major challenges limiting the performance of biofuel cells—connecting the enzyme used to oxidize glucose with an electrode. A layer-by-layer assembly technique used to fabricate the gold electrodes—which provide both the electrocatalytic cathode and the conductive substrate for the anode—helped boost the power capacity to as much as 3.7 milliwatts per square centimeter. Results of the research were reported October 26 in the journal Nature Communications. "We could use this device as a continuous power source for converting chemical energy from glucose in the body to electrical energy," said Seung Woo Lee, an assistant professor in Georgia Tech's Woodruff School of Mechanical Engineering. "The layer-by-layer deposition technique precisely controls deposition of both the gold nanoparticle and enzyme, dramatically increasing the power density of this fuel cell." Fabrication of the electrodes begins with porous cotton fiber composed of multiple hydrophilic microfibrils—cellulose fibers containing hydroxyl groups. Gold nanoparticles about eight nanometers in diameter are then assembled onto the fibers using organic linker materials. To create the anode for oxidizing the glucose, the researchers apply glucose oxidase enzyme in layers alternating with an amine-functionalized small molecule known as TREN. The cathode, where the oxygen reduction reaction takes place, used the gold-covered electrodes, which have electrocatalytic capabilities. Scanning electron microscope images show details of the cotton-based electrodes used in a new biofuel cell. Credit: Georgia Tech/Korea University "We precisely control the loading of the enzyme," Lee said. "We produce a very thin layer so that the charge transport between the conductive substrate and the enzyme is improved. We have made a very close connection between the materials so the transport of electrons is easier." The porosity of the cotton allowed an increase in the number of gold layers compared to a nylon fiber. "Cotton has many pores that can support activity in electrochemical devices," explained Yongmin Ko, a visiting faculty member and one of the paper's co-authors. "The cotton fiber is hydrophilic, meaning the electrolyte easily wets the surface." Beyond improving the conductivity of the electrodes, the cotton fiber could improve the biocompatibility of the device, which is designed to operate at low temperature to allow use inside the body. Implantable biofuel cells suffer from degradation over time, and the new cell developed by the U.S. and Korean team offers improved long-term stability. "We have a record high power performance, and the lifetime should be improved for biomedical applications such as pacemakers," Lee said. Pacemakers and other implantable devices are now powered by batteries that last years, but may still require replacement in a procedure that requires surgery. The biofuel cell could provide a continuous charge for those batteries, potentially extending the time that devices may operate without battery replacement, Lee added. In addition, the biofuel cell could be used to power devices intended for temporary use. Such devices might be implanted to provide timed release of a drug, but would biodegrade over time without requiring surgical removal. For these applications, no battery would be included, and the limited power required could be provided by the biofuel cell. Future goals of the research include demonstrating operation of the biofuel cell with an energy storage device, and development of a functional implantable power source. "We want to develop other biological applications for this," said Lee. "We'd like to go farther with other applications including batteries and high-performance storage." <|im_end|>

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2,224

[ { "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 toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H 2 two-electron wave function in which electron–electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources. Introduction Imaging the wave function of electrons yields detailed information on the properties of matter, accordingly, experiments have pursued this goal since decades. For example, in solid state physics photoionization is routinely used as a powerful tool 1 for single-electron density imaging. Photon-based techniques have the particular strength that they can be in principle implemented in pump-probe experiments opening additionally the perspective to go from still images to movies. For atoms and molecules photoionization has also been proposed as a promising technique to image orbitals 2 , but no positive outcomes were reported so far. The reverse process of photoionization, namely high harmonic generation, has succeeded in accomplishing this goal of orbital imaging 3 . Further techniques for imaging molecular orbitals are electron momentum spectroscopy 4 or strong field tunnel ionization 5 . While the toolbox to image single electrons is well equipped, endeavors to directly examine an entangled two-electron wave function have, so far, not been successful and corresponding techniques are lacking. This is particularly unfortunate, as electron correlation which shapes two-electron wavefunctions is of major importance across physics and chemistry. It is electron correlation which is at the heart of fascinating quantum effects such as superconductivity 6 or giant magnetoresistance 7 . Even in single atoms or molecules, electron correlation plays a vital role and continues to challenge theory. For example, the single-photon double ionization, i.e., the simultaneous emission of two electrons after photoabsorption, is only possible due to electron–electron correlation effects, as the photon cannot interact with two electrons simultaneously. Instead, the second electron is emitted either after an interaction with the first electron (which is typically described as a “knock-off process”) or because of the initial entanglement of the two electrons due to electron correlation prior to the absorption of the photon (in a process termed “shake off”) 8 . Although the importance of electron correlation is intuitively understandable in processes which obviously involve two electrons, it turns out, that even for bound stationary states of atoms and molecules, electron correlation contributions are crucial: within the commonly used Hartree–Fock approximation, the calculated values of binding energies are often in no satisfying accordance to those actually occurring in nature. Here the basic cause is that the Hartree–Fock approximation is a mean-field theory, which considers only an overall mean potential generated by the ensemble of electrons, and as such neglects electron–electron correlation by definition. In this manuscript, we show that the correlated molecular wave function can be visualized by the simultaneous use of two well-established and well-understood methods: photoelectron emission on the one hand and coincident detection of reaction fragments on the other hand. Our novel experimental approach allows us to visualize the square of the H 2 correlated two-electron wave function. In the ionization step, one of the electrons is mapped onto a detector and simultaneously the quantum state of the second electron is determined by coincident detection of the fragments. Results Concept of correlation imaging The properties of a photoionization event, given by the ionization amplitude D , are determined (within the commonly used dipole approximation) by only three ingredients: the initial state of the system ϕ 0 , which we want to image, the properties of the dipole operator \$\\hat \\mu \$ (responsible for the photoionization) and the final state representing the remaining cation and a photoelectron with momentum k , χ k : $$D = {\\int} \\phi _0({\\mathbf{r}})\\hat \\mu ({\\mathbf{r}})\\chi _{\\mathbf{k}}({\\mathbf{r}}){\\mathrm d}{\\mathbf{r}},$$ (1) where r represents the coordinates of target electrons. The initial wave function is directly accessible provided that the other two constituents do not introduce significant distortions. This is the case when utilizing circularly polarized light and examining high energy electrons (Born limit) within the polarization plane. As an illustration, let us consider the one-electron \${\\mathrm{H}}_2^ + \$ molecular ion. At a high enough energy, the continuum electron can be described by a plane wave. In this case, the photoionization differential cross section in the electron emission direction (θ , φ ) (the so-called molecular frame photoelectron angular distribution, MFPAD) is simply proportional to the square of the Fourier transform (FT) of the initial state, ϕ 0 ( k ) (see methods section): $$\\frac{{{\\mathrm d}P}}{{{\\mathrm d}({\\mathrm{cos}}\\,\\theta ){\\mathrm d}k}} = k^2(2\\pi )^{3/2}\\left| {\\frac{1}{{2\\pi ^{3/2}}}{\\int} \\phi _0({\\mathbf{r}})e^{i{\\mathbf{kr}}}{\\mathrm d}{\\mathbf{r}}} \\right|^2$$ (2) $$ = k^2(2\\pi )^{3/2}\\left| {\\phi _0({\\mathbf{k}})} \\right|^2.$$ (3) Here θ denotes the polar angle with respect to the molecular axis and φ the corresponding azimuthal angle. Thus, by choosing high-photon energies and restricting the measurement of the MFPAD to the polarization plane ( φ = 90° and 270°) of the circularly polarized light, the initial electronic wave function is directly mapped onto the emitted photoelectron. Figure 1 illustrates this mapping procedure for the ground state of \${\\mathrm{H}}_2^ + \$ (Fig. 1 a: electronic wave function in coordinate space; Fig. 1 b the square of the Fourier transform of Fig. 1 a; Fig. 1 c the same in logarithmic color scale). As can be seen from Fig. 1 d, the MFPAD for an electron of 380 eV is very similar to \$\\left| {\\phi _0({\\mathbf{k}})} \\right|^2\$ for the chosen momentum k (the square of", "role": "user" }, { "content": "For the first time, physicists have developed a method to visually image the entanglement between electrons. As these correlations play a prominent role in determining a molecule's wave function—which describes the molecule's quantum state—the researchers then used the new method to produce the first images of the square of the two-electron wave function of a hydrogen (H2) molecule. Although numerous techniques already exist for imaging the individual electrons of atoms and molecules, this is the first method that can directly image the correlations between electrons and allow researchers to explore how the properties of electrons depend on one another. The researchers, M. Waitz et al., from various institutes in Germany, Spain, the US, Russia, and Australia, have published a paper on the new imaging method in a recent issue of Nature Communications. \"There are other methods that allow one to reconstruct correlations from different observations; however, to my knowledge, this is the first time that one gets a direct image of correlations by just looking at a spectrum,\" coauthor Fernando Martín at the Universidad Autónoma de Madrid told Phys.org. \"The recorded spectra are identical to the Fourier transforms of the different pieces of the square of the wave function (or equivalently, to the representation of the different pieces of the wave function in momentum space). No reconstruction or filtering or transformation is needed: the spectrum directly reflects pieces of the wave function in momentum space.\" The new method involves combining two imaging methods that are already widely used: photoelectron imaging and the coincident detection of reaction fragments. The researchers simultaneously employed both methods by using the first method on one electron to project that electron onto a detector, and using the second method on the other electron to determine how its properties change in response. The simultaneous use of both methods reveals how the two electrons are correlated and produces an image of the square of the H2 correlated two-electron wave function. The physicists emphasize one important point: that these are images of the square of the wave function, and not the wave function itself. \"The wave function is not an observable in quantum physics, so it cannot be observed,\" Martín said. \"Only the square of the wave function is an observable (if you have the tools to do it). This is one of the basic principles of quantum physics. Those who claim that they are able to observe the wave function are not using the proper language because this is not possible: what they do is to reconstruct it from some measured spectra by making some approximations. It can never be a direct observation.\" The researchers expect that the new approach can be used to image molecules with more than two electrons as well, by detecting the reaction fragments of multiple electrons. The method could also lead to the ability to image correlations between the wave functions of multiple molecules. \"Obviously, the natural step to follow is to try a similar method in more complicated molecules,\" Martín said. \"Most likely, the method will work for small molecules, but it is not clear if it will work in very complex molecules. Not because of limitations in the basic idea, but mainly because of experimental limitations, since coincidence experiments in complex molecules are much more difficult to analyze due to the many nuclear degrees of freedom.\" The ability to visualize electron-electron correlations and the corresponding molecular wave functions has far-reaching implications for understanding the basic properties of matter. For instance, one of the most commonly used methods for approximating a wave function, called the Hartree-Fock method, does not account for electron-electron correlations and, as a result, often disagrees with observations. In addition, electron-electron correlations lie at the heart of fascinating quantum effects, such as superconductivity (when electrical resistance drops to zero at very cold temperatures) and giant magnetoresistance (when electrical resistance greatly decreases due to the parallel alignment of the magnetization of nearby magnetic layers). Electron correlations also play a role in the simultaneous emission of two electrons from a molecule that has absorbed a single photon, a phenomenon called \"single-photon double ionization.\" And finally, the results may also lead to practical applications, such as the ability to realize correlation imaging with field-electron lasers and with laser-based X-ray sources. ", "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 toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H 2 two-electron wave function in which electron–electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources. Introduction Imaging the wave function of electrons yields detailed information on the properties of matter, accordingly, experiments have pursued this goal since decades. For example, in solid state physics photoionization is routinely used as a powerful tool 1 for single-electron density imaging. Photon-based techniques have the particular strength that they can be in principle implemented in pump-probe experiments opening additionally the perspective to go from still images to movies. For atoms and molecules photoionization has also been proposed as a promising technique to image orbitals 2 , but no positive outcomes were reported so far. The reverse process of photoionization, namely high harmonic generation, has succeeded in accomplishing this goal of orbital imaging 3 . Further techniques for imaging molecular orbitals are electron momentum spectroscopy 4 or strong field tunnel ionization 5 . While the toolbox to image single electrons is well equipped, endeavors to directly examine an entangled two-electron wave function have, so far, not been successful and corresponding techniques are lacking. This is particularly unfortunate, as electron correlation which shapes two-electron wavefunctions is of major importance across physics and chemistry. It is electron correlation which is at the heart of fascinating quantum effects such as superconductivity 6 or giant magnetoresistance 7 . Even in single atoms or molecules, electron correlation plays a vital role and continues to challenge theory. For example, the single-photon double ionization, i.e., the simultaneous emission of two electrons after photoabsorption, is only possible due to electron–electron correlation effects, as the photon cannot interact with two electrons simultaneously. Instead, the second electron is emitted either after an interaction with the first electron (which is typically described as a “knock-off process”) or because of the initial entanglement of the two electrons due to electron correlation prior to the absorption of the photon (in a process termed “shake off”) 8 . Although the importance of electron correlation is intuitively understandable in processes which obviously involve two electrons, it turns out, that even for bound stationary states of atoms and molecules, electron correlation contributions are crucial: within the commonly used Hartree–Fock approximation, the calculated values of binding energies are often in no satisfying accordance to those actually occurring in nature. Here the basic cause is that the Hartree–Fock approximation is a mean-field theory, which considers only an overall mean potential generated by the ensemble of electrons, and as such neglects electron–electron correlation by definition. In this manuscript, we show that the correlated molecular wave function can be visualized by the simultaneous use of two well-established and well-understood methods: photoelectron emission on the one hand and coincident detection of reaction fragments on the other hand. Our novel experimental approach allows us to visualize the square of the H 2 correlated two-electron wave function. In the ionization step, one of the electrons is mapped onto a detector and simultaneously the quantum state of the second electron is determined by coincident detection of the fragments. Results Concept of correlation imaging The properties of a photoionization event, given by the ionization amplitude D , are determined (within the commonly used dipole approximation) by only three ingredients: the initial state of the system ϕ 0 , which we want to image, the properties of the dipole operator $\hat \mu $ (responsible for the photoionization) and the final state representing the remaining cation and a photoelectron with momentum k , χ k : $$D = {\int} \phi _0({\mathbf{r}})\hat \mu ({\mathbf{r}})\chi _{\mathbf{k}}({\mathbf{r}}){\mathrm d}{\mathbf{r}},$$ (1) where r represents the coordinates of target electrons. The initial wave function is directly accessible provided that the other two constituents do not introduce significant distortions. This is the case when utilizing circularly polarized light and examining high energy electrons (Born limit) within the polarization plane. As an illustration, let us consider the one-electron ${\mathrm{H}}_2^ + $ molecular ion. At a high enough energy, the continuum electron can be described by a plane wave. In this case, the photoionization differential cross section in the electron emission direction (θ , φ ) (the so-called molecular frame photoelectron angular distribution, MFPAD) is simply proportional to the square of the Fourier transform (FT) of the initial state, ϕ 0 ( k ) (see methods section): $$\frac{{{\mathrm d}P}}{{{\mathrm d}({\mathrm{cos}}\,\theta ){\mathrm d}k}} = k^2(2\pi )^{3/2}\left| {\frac{1}{{2\pi ^{3/2}}}{\int} \phi _0({\mathbf{r}})e^{i{\mathbf{kr}}}{\mathrm d}{\mathbf{r}}} \right|^2$$ (2) $$ = k^2(2\pi )^{3/2}\left| {\phi _0({\mathbf{k}})} \right|^2.$$ (3) Here θ denotes the polar angle with respect to the molecular axis and φ the corresponding azimuthal angle. Thus, by choosing high-photon energies and restricting the measurement of the MFPAD to the polarization plane ( φ = 90° and 270°) of the circularly polarized light, the initial electronic wave function is directly mapped onto the emitted photoelectron. Figure 1 illustrates this mapping procedure for the ground state of ${\mathrm{H}}_2^ + $ (Fig. 1 a: electronic wave function in coordinate space; Fig. 1 b the square of the Fourier transform of Fig. 1 a; Fig. 1 c the same in logarithmic color scale). As can be seen from Fig. 1 d, the MFPAD for an electron of 380 eV is very similar to $\left| {\phi _0({\mathbf{k}})} \right|^2$ for the chosen momentum k (the square of<|im_end|> <|im_start|>assistant For the first time, physicists have developed a method to visually image the entanglement between electrons. As these correlations play a prominent role in determining a molecule's wave function—which describes the molecule's quantum state—the researchers then used the new method to produce the first images of the square of the two-electron wave function of a hydrogen (H2) molecule. Although numerous techniques already exist for imaging the individual electrons of atoms and molecules, this is the first method that can directly image the correlations between electrons and allow researchers to explore how the properties of electrons depend on one another. The researchers, M. Waitz et al., from various institutes in Germany, Spain, the US, Russia, and Australia, have published a paper on the new imaging method in a recent issue of Nature Communications. "There are other methods that allow one to reconstruct correlations from different observations; however, to my knowledge, this is the first time that one gets a direct image of correlations by just looking at a spectrum," coauthor Fernando Martín at the Universidad Autónoma de Madrid told Phys.org. "The recorded spectra are identical to the Fourier transforms of the different pieces of the square of the wave function (or equivalently, to the representation of the different pieces of the wave function in momentum space). No reconstruction or filtering or transformation is needed: the spectrum directly reflects pieces of the wave function in momentum space." The new method involves combining two imaging methods that are already widely used: photoelectron imaging and the coincident detection of reaction fragments. The researchers simultaneously employed both methods by using the first method on one electron to project that electron onto a detector, and using the second method on the other electron to determine how its properties change in response. The simultaneous use of both methods reveals how the two electrons are correlated and produces an image of the square of the H2 correlated two-electron wave function. The physicists emphasize one important point: that these are images of the square of the wave function, and not the wave function itself. "The wave function is not an observable in quantum physics, so it cannot be observed," Martín said. "Only the square of the wave function is an observable (if you have the tools to do it). This is one of the basic principles of quantum physics. Those who claim that they are able to observe the wave function are not using the proper language because this is not possible: what they do is to reconstruct it from some measured spectra by making some approximations. It can never be a direct observation." The researchers expect that the new approach can be used to image molecules with more than two electrons as well, by detecting the reaction fragments of multiple electrons. The method could also lead to the ability to image correlations between the wave functions of multiple molecules. "Obviously, the natural step to follow is to try a similar method in more complicated molecules," Martín said. "Most likely, the method will work for small molecules, but it is not clear if it will work in very complex molecules. Not because of limitations in the basic idea, but mainly because of experimental limitations, since coincidence experiments in complex molecules are much more difficult to analyze due to the many nuclear degrees of freedom." The ability to visualize electron-electron correlations and the corresponding molecular wave functions has far-reaching implications for understanding the basic properties of matter. For instance, one of the most commonly used methods for approximating a wave function, called the Hartree-Fock method, does not account for electron-electron correlations and, as a result, often disagrees with observations. In addition, electron-electron correlations lie at the heart of fascinating quantum effects, such as superconductivity (when electrical resistance drops to zero at very cold temperatures) and giant magnetoresistance (when electrical resistance greatly decreases due to the parallel alignment of the magnetization of nearby magnetic layers). Electron correlations also play a role in the simultaneous emission of two electrons from a molecule that has absorbed a single photon, a phenomenon called "single-photon double ionization." And finally, the results may also lead to practical applications, such as the ability to realize correlation imaging with field-electron lasers and with laser-based X-ray sources. <|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 genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10 −8 ), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2 , further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r 2 > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non–human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD ( r 2 > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up. Main Primary biliary cirrhosis is characterized by the immune-mediated destruction of intrahepatic bile ducts, resulting in chronic cholangitis, liver fibrosis and, ultimately, cirrhosis 1 . With a UK prevalence of 35:100,000, which rises to 94:100,000 in women over 40 years of age, it is the most common autoimmune liver disorder 1 , 2 . Family-based studies indicate a substantial genetic component to PBC susceptibility, with a sibling relative risk of ∼ 10.5 in the UK 3 . Genome-wide association studies (GWAS) have identified 22 PBC risk loci and have highlighted the role of nuclear factor (NF)-κB signaling, T-cell differentiation, and Toll-like receptor and tumor necrosis factor signaling in disease pathogenesis 4 , 5 , 6 . Sixteen of these loci are also associated with other immune-mediated diseases, such as multiple sclerosis, celiac disease and type 1 diabetes (T1D), shedding light on the involvement of common genes and pathways across these diseases 7 . Despite these advances, the specific causal variant at many of these loci remains unknown. To better define risk variants and identify additional susceptibility loci, we performed a fine-mapping and association study using a cohort of 2,861 cases from the UK PBC Consortium and 8,514 UK population controls from the 1958 British Birth Cohort and National Blood Service. All samples were genotyped on the Immunochip, an Illumina Infinium array containing 196,524 variants (718 small insertions and/or deletions and 195,806 SNPs) across 186 known autoimmunity risk loci. SNPs were derived from population-based sequencing projects such as the 1000 Genomes Project and autoimmune disease resequencing efforts 8 , 9 . Compared to GWAS arrays, the Immunochip has increased marker density within known autoimmunity-associated loci, increasing the power to detect PBC associations within these selected key candidate genes and providing a powerful means of fine mapping known PBC loci, as causal variants are more likely to be directly genotyped. After quality control (Online Methods), data at 143,020 polymorphic SNPs were available across 2,861 cases and 8,514 controls. ( Supplementary Figs. 1–6 and Supplementary Tables 1 and 2 ). An additional 94,559 SNPs in the Immunochip fine-mapping regions were imputed using genotypes from the 1000 Genomes Project June 2011 release (Online Methods). The inflation factor inferred from 2,258 SNPs not associated with autoimmune disease showed only modest inflation ( λ = 1.096; Online Methods) similar to that reported in our previous GWAS for PBC 6 . Of the 22 known PBC risk loci, 16 had associations that reached genome-wide significance ( P < 5 × 10 −8 ; Fig. 1 and Supplementary Fig. 7 ), and 4 showed nominal evidence of association (5 × 10 −8 < P < 5 × 10 −4 ; Supplementary Table 3 ). Two PBC-associated loci, 14q32 and 19q13, were not included on the Immunochip, as the array was designed before the publication of the most recent PBC GWAS 6 . At 12 of the loci that associated with genome-wide significance, the most associated SNP was different from the one previously reported at that locus ( Supplementary Table 3 ). There was little difference in the effect size estimates of the GWAS-identified tagging SNP and the most strongly associated Immunochip SNP ( Supplementary Fig. 8 ), although this may be due to a large proportion of overlapping samples between the two studies (Online Methods). Figure 1: Manhattan plot and list of PBC risk loci that reached genome-wide significance across the Immunochip. New risk loci are highlighted in blue. Loci with more than one independent signal are highlighted in red. The horizontal red line indicates the genome-wide significance threshold of P = 5 × 10 −8 . The peak on chromosome 6 is the HLA region. Full size image Stepwise conditional regression 10 revealed multiple independent signals at five loci, with 16p13 harboring three and 3q25 four such associations ( Table 1 ). At the 16p13 locus, the third independent signal, rs80073729, is a rare SNP (minor allele frequency (MAF) < 0.5%) that was recently associated with celiac disease 9 . In the same study 9 , multiple independent signals were also identified at 3q25, although rs80014155, a rare SNP that best tags the fourth most significant independent PBC association at this locus, was not among them. These results suggest that resequencing hundreds or thousands of cases across known GWAS loci will be a powerful means of identifying additional independent risk alleles. It is likely that these two rare SNP associations would have been missed using standard GWAS arrays, because of poor tagging, unless they were directly genotyped. As these are rare SNPs, further replication in large independent cohorts will be required to confirm their associations. Haplotype association analysis at loci with multiple independent signals identified similar effect size estimates, suggesting that the causal variant at each locus is among or is highly correlated with genotyped SNPs ( Supplementary Table 4 ). These additional independent association signals thus yield a more complete understanding of the genetic architecture of PBC and enable more informative genotype-based", "role": "user" }, { "content": "Researchers have newly identified three genetic regions associated with primary biliary cirrhosis (PBC), the most common autoimmune liver disease, increasing the number of known regions associated with the disorder to 25. The team used a DNA microchip, called Immunochip, to survey more thoroughly regions of the genome known to underlie other autoimmune diseases to discover if they play a role also in PBC susceptibility. By combining the results from this survey with details of gene activity from a database called ENCODE, they were able to identify which cells types are most likely to play a role in PBC. PBC affects approximately one in every three thousand people in the UK, and one in a thousand women over the age of 40. Inflammation in the bile ducts blocks the flow of bile, damaging the liver cells and causing further inflammation and scarring, and in severe cases will result in the need for a liver transplant. There is currently no cure for PBC, so treatment is focused on slowing down the progression of the disease and treating any symptoms or complications that may occur. The biological pathways underlying primary biliary cirrhosis are poorly understood, although autoimmunity, where the body attacks its own cells, is known to play a significant role. \"Previous genetic screens have identified 22 regions of the genome underlying PBC risk, and many of these are known to play a role in other autoimmune diseases, such as multiple sclerosis and type I diabetes,\" says Dr Carl Anderson, co-senior author from the Wellcome Trust Sanger Institute. \"Using the Immunochip we were able to perform a much more thorough screen of the genomic regions previously associated with other autoimmune diseases. This resulted in us identifying a further three regions involved in PBC risk and identifying additional independent signals within some of those we already knew about.\" The advantage of Immunochip over genome-wide technologies is that it focuses only on regions of the genome known to be associated with an autoimmune disease and thus captures more of the genetic variation within these regions. Immunochip can therefore be used to more thoroughly test these key candidate genes for association to a whole-host of immune-related traits, and identify low frequency and rare genetic variants associated with disease that would likely be missed by a microarray that covers a broader range of genetic regions. The researchers found five genomic regions with multiple independent signals associated with the disorder, with one small region on chromosome 3 harbouring four independent association signals. These findings suggest that densely genotyping or sequencing known disease regions will be a powerful approach for identifying additional genetic risk variants and for further elucidating the role of rare genetic variation in complex disease risk. \"This study has allowed us to better understand the genetic risk profile of PBC and, by comparing our results with similar studies of other autoimmune diseases, we hope to further characterise the genetic relationship between this group of clinically diverse but biologically related disorders\" says Dr Richard Sandford, co-senior author from the University of Cambridge \"Over the next few years we will be extending our studies to search for genetic variants that affect disease course and treatment response. We hope that our studies will have a clinical impact, either directly through a more personalized approach to treatment or indirectly by furthering our understanding of the biological pathways underlying PBC leading to new treatments.\" The most associated genetic variant within the newly implicated TYK2 gene was a low-frequency variant previously associated with multiple sclerosis (MS) that changes the coding sequence of the gene. Previous studies in MS have shown that individuals that carry a single copy of this variant have significantly reduced TYK2 activity, suggesting that modulation of TYK2 activity might represent a new therapeutic approach for the treatment of PBC. \"This study is an example of how people with rare conditions like primary biliary cirrhosis can work together with scientists and physicians to find a path towards drug targets and treatments for these diseases,\" says Collette Thain, MBE, Chief Executive of the PBC Foundation. \"Although this is just the beginning of a long road to finding the genetic basis of PBC, with each study we are moving closer and closer to finally understanding and tackling this 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 We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10 −8 ), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2 , further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r 2 > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non–human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD ( r 2 > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up. Main Primary biliary cirrhosis is characterized by the immune-mediated destruction of intrahepatic bile ducts, resulting in chronic cholangitis, liver fibrosis and, ultimately, cirrhosis 1 . With a UK prevalence of 35:100,000, which rises to 94:100,000 in women over 40 years of age, it is the most common autoimmune liver disorder 1 , 2 . Family-based studies indicate a substantial genetic component to PBC susceptibility, with a sibling relative risk of ∼ 10.5 in the UK 3 . Genome-wide association studies (GWAS) have identified 22 PBC risk loci and have highlighted the role of nuclear factor (NF)-κB signaling, T-cell differentiation, and Toll-like receptor and tumor necrosis factor signaling in disease pathogenesis 4 , 5 , 6 . Sixteen of these loci are also associated with other immune-mediated diseases, such as multiple sclerosis, celiac disease and type 1 diabetes (T1D), shedding light on the involvement of common genes and pathways across these diseases 7 . Despite these advances, the specific causal variant at many of these loci remains unknown. To better define risk variants and identify additional susceptibility loci, we performed a fine-mapping and association study using a cohort of 2,861 cases from the UK PBC Consortium and 8,514 UK population controls from the 1958 British Birth Cohort and National Blood Service. All samples were genotyped on the Immunochip, an Illumina Infinium array containing 196,524 variants (718 small insertions and/or deletions and 195,806 SNPs) across 186 known autoimmunity risk loci. SNPs were derived from population-based sequencing projects such as the 1000 Genomes Project and autoimmune disease resequencing efforts 8 , 9 . Compared to GWAS arrays, the Immunochip has increased marker density within known autoimmunity-associated loci, increasing the power to detect PBC associations within these selected key candidate genes and providing a powerful means of fine mapping known PBC loci, as causal variants are more likely to be directly genotyped. After quality control (Online Methods), data at 143,020 polymorphic SNPs were available across 2,861 cases and 8,514 controls. ( Supplementary Figs. 1–6 and Supplementary Tables 1 and 2 ). An additional 94,559 SNPs in the Immunochip fine-mapping regions were imputed using genotypes from the 1000 Genomes Project June 2011 release (Online Methods). The inflation factor inferred from 2,258 SNPs not associated with autoimmune disease showed only modest inflation ( λ = 1.096; Online Methods) similar to that reported in our previous GWAS for PBC 6 . Of the 22 known PBC risk loci, 16 had associations that reached genome-wide significance ( P < 5 × 10 −8 ; Fig. 1 and Supplementary Fig. 7 ), and 4 showed nominal evidence of association (5 × 10 −8 < P < 5 × 10 −4 ; Supplementary Table 3 ). Two PBC-associated loci, 14q32 and 19q13, were not included on the Immunochip, as the array was designed before the publication of the most recent PBC GWAS 6 . At 12 of the loci that associated with genome-wide significance, the most associated SNP was different from the one previously reported at that locus ( Supplementary Table 3 ). There was little difference in the effect size estimates of the GWAS-identified tagging SNP and the most strongly associated Immunochip SNP ( Supplementary Fig. 8 ), although this may be due to a large proportion of overlapping samples between the two studies (Online Methods). Figure 1: Manhattan plot and list of PBC risk loci that reached genome-wide significance across the Immunochip. New risk loci are highlighted in blue. Loci with more than one independent signal are highlighted in red. The horizontal red line indicates the genome-wide significance threshold of P = 5 × 10 −8 . The peak on chromosome 6 is the HLA region. Full size image Stepwise conditional regression 10 revealed multiple independent signals at five loci, with 16p13 harboring three and 3q25 four such associations ( Table 1 ). At the 16p13 locus, the third independent signal, rs80073729, is a rare SNP (minor allele frequency (MAF) < 0.5%) that was recently associated with celiac disease 9 . In the same study 9 , multiple independent signals were also identified at 3q25, although rs80014155, a rare SNP that best tags the fourth most significant independent PBC association at this locus, was not among them. These results suggest that resequencing hundreds or thousands of cases across known GWAS loci will be a powerful means of identifying additional independent risk alleles. It is likely that these two rare SNP associations would have been missed using standard GWAS arrays, because of poor tagging, unless they were directly genotyped. As these are rare SNPs, further replication in large independent cohorts will be required to confirm their associations. Haplotype association analysis at loci with multiple independent signals identified similar effect size estimates, suggesting that the causal variant at each locus is among or is highly correlated with genotyped SNPs ( Supplementary Table 4 ). These additional independent association signals thus yield a more complete understanding of the genetic architecture of PBC and enable more informative genotype-based<|im_end|> <|im_start|>assistant Researchers have newly identified three genetic regions associated with primary biliary cirrhosis (PBC), the most common autoimmune liver disease, increasing the number of known regions associated with the disorder to 25. The team used a DNA microchip, called Immunochip, to survey more thoroughly regions of the genome known to underlie other autoimmune diseases to discover if they play a role also in PBC susceptibility. By combining the results from this survey with details of gene activity from a database called ENCODE, they were able to identify which cells types are most likely to play a role in PBC. PBC affects approximately one in every three thousand people in the UK, and one in a thousand women over the age of 40. Inflammation in the bile ducts blocks the flow of bile, damaging the liver cells and causing further inflammation and scarring, and in severe cases will result in the need for a liver transplant. There is currently no cure for PBC, so treatment is focused on slowing down the progression of the disease and treating any symptoms or complications that may occur. The biological pathways underlying primary biliary cirrhosis are poorly understood, although autoimmunity, where the body attacks its own cells, is known to play a significant role. "Previous genetic screens have identified 22 regions of the genome underlying PBC risk, and many of these are known to play a role in other autoimmune diseases, such as multiple sclerosis and type I diabetes," says Dr Carl Anderson, co-senior author from the Wellcome Trust Sanger Institute. "Using the Immunochip we were able to perform a much more thorough screen of the genomic regions previously associated with other autoimmune diseases. This resulted in us identifying a further three regions involved in PBC risk and identifying additional independent signals within some of those we already knew about." The advantage of Immunochip over genome-wide technologies is that it focuses only on regions of the genome known to be associated with an autoimmune disease and thus captures more of the genetic variation within these regions. Immunochip can therefore be used to more thoroughly test these key candidate genes for association to a whole-host of immune-related traits, and identify low frequency and rare genetic variants associated with disease that would likely be missed by a microarray that covers a broader range of genetic regions. The researchers found five genomic regions with multiple independent signals associated with the disorder, with one small region on chromosome 3 harbouring four independent association signals. These findings suggest that densely genotyping or sequencing known disease regions will be a powerful approach for identifying additional genetic risk variants and for further elucidating the role of rare genetic variation in complex disease risk. "This study has allowed us to better understand the genetic risk profile of PBC and, by comparing our results with similar studies of other autoimmune diseases, we hope to further characterise the genetic relationship between this group of clinically diverse but biologically related disorders" says Dr Richard Sandford, co-senior author from the University of Cambridge "Over the next few years we will be extending our studies to search for genetic variants that affect disease course and treatment response. We hope that our studies will have a clinical impact, either directly through a more personalized approach to treatment or indirectly by furthering our understanding of the biological pathways underlying PBC leading to new treatments." The most associated genetic variant within the newly implicated TYK2 gene was a low-frequency variant previously associated with multiple sclerosis (MS) that changes the coding sequence of the gene. Previous studies in MS have shown that individuals that carry a single copy of this variant have significantly reduced TYK2 activity, suggesting that modulation of TYK2 activity might represent a new therapeutic approach for the treatment of PBC. "This study is an example of how people with rare conditions like primary biliary cirrhosis can work together with scientists and physicians to find a path towards drug targets and treatments for these diseases," says Collette Thain, MBE, Chief Executive of the PBC Foundation. "Although this is just the beginning of a long road to finding the genetic basis of PBC, with each study we are moving closer and closer to finally understanding and tackling this disease." <|im_end|>

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2,297

[ { "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 Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α v β 3 and α v β 5 engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture. Main Human pluripotent stem cells (both human embryonic stem (hES) and induced pluripotent stem (hiPS) cells) hold great promise for regenerative medicine 1 , 2 , 3 , 4 and human-disease modelling 5 . However, existing methods to grow human pluripotent stem cells are not well suited for genetic manipulation experiments and introduce animal components, increasing the risks of immune rejection. Present methods to grow hES and hiPS cells include growing them on a ‘feeder’ cell layer of mitotically inactivated mouse embryonic fibroblasts 1 , 2 , 3 , 6 (mEFs), and on ‘feeder free’ culture systems, composed of a variety of extracellular-matrix/serum proteins coated onto tissue-culture dishes 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 or synthetic materials 16 , 17 , 18 , 19 such as hyaluronic acid hydrogels. These have been reported to promote hES cell self-renewal when seeded at a suitably high cell density 9 , 16 , 17 (for example, ∼ 10 6 cells ml −1 for the hydrogel) and have not been demonstrated to efficiently promote clonal growth of single hES cells (efficiencies typically <10%). However, gene targeting in pluripotent stem cells necessitates clonal outgrowth of single cells to detect rare targeting events (1 in 10 5 –10 6 cells) and requires selective growth of a correctly gene-targeted cell within a population of >10 5 cells 20 , 21 , 22 . Further, current human culture methods use either animal products or undefined components, which make it problematic for the potential transplantation applications 4 . Here we employed a high-throughput approach to engineer new culture substrates that could be used to clonally expand human pluripotent stem cells in a chemically defined, xeno-free, feeder-free manner. To facilitate rapid synthesis and analysis of synthetic substrates, we manufactured cell-compatible, biomaterial microarrays 23 , 24 . Microarrays were prepared from 22 acrylate monomers with diversified hydrophobicity–hydrophilicity and crosslinking densities ( Fig. 1 a). The arrays were prepared by copolymerization between each of 16 ‘major’ monomers (numbered 1–16) and each of six ‘minor’ monomers (lettered A–F) at six different ratios (100:0, 90:10, 85:15, 80:20, 75:25, 70:30 (v/v)) ( Supplementary Fig. S1 ). In this way, arrays with 496 [16+(16×5×6)] different combinations were created, consisting of the major monomer (70–100%) and minor monomer (0–30%). These monomer mixtures were robotically deposited in triplicate on a non-cell adhesive layer of poly(2-hydroxyethyl methacrylate) covering conventional glass slides (75 mm×25 mm), and then polymerized with a long-wave ultraviolet source. Figure 1: High-throughput screening of biomaterials for clonal growth. a , Monomers used for array synthesis were classified into two categories: ‘major’ monomers that constitute >50% of the reactant mixture and ‘minor’ monomers that constitute <50% of the mixture. Sixteen major monomers were named numerically (blue), and six minor monomers were labelled alphabetically (orange). b , Schematic diagram of the screen. First, transgenic Oct4–GFP hES cells were maintained on mEFs. Then flow cytometry enabled the isolation of high-purity undifferentiated hES cells from the completely dissociated coculture of hES cells and mEFs. A flow-cytometry histogram during a representative cell sort is shown. GFP + cells (right of the black gate) were seeded onto the arrays, whereas the differentiated cells and mEFs (GFP − , left of the black gate) were not used. A photograph of the polymer microarray with 16 polymer spots is shown to illustrate dimensions and separation. Each polymer was also characterized using high-throughput methods to characterize its surface roughness, indentation elastic modulus, wettability (water contact angle, θ C ) and surface chemistry. Finally, the cellular response on the polymer array was quantified by using laser-scanning cytometry, and structure–function relationships were determined by numerical analysis of both the cellular response and materials characterization data. Full size image We next used fluorescence-activated cell sorting of transgenic hES cells to ensure that hES cells were both dissociated from one another and undifferentiated in our assays ( Fig. 1 b). A transgenic green-fluorescent protein (GFP) reporter for Oct4 expression, a marker of pluripotent cells ( Supplementary Fig. S2 ), was knocked in to the BG01 hES cell line and propagated under standard hES cell culture conditions using mEFs 25 . GFP + sorted hES single cells ( Fig. 1 b, Supplementary Fig. S3 ) were seeded onto the polymer arrays and cultured with mEF-conditioned medium, because soluble growth factors secreted by mEFs help maintain the undifferentiated hES cell state 7 , 17 ( Supplementary Fig. S2c ). Proteins can rapidly adsorb onto the surfaces of materials used for cell culture 26 , 27 , 28 . The surface properties of cell-culture substrates can modulate both the amount and the conformation of adsorbed proteins, and thereby interact with cell surface receptors (for example, integrins) to initiate signal transduction and alter cell behaviour 29 . To investigate the potential of different adsorbed proteins, fibronectin, laminin, bovine serum albumin, and fetal bovine serum (FBS) were separately adsorbed onto the microarrays from solution. In general, FBS was found to most effectively support the propagation of hES cells across the entire array, whereas fibronectin and laminin coatings led to more", "role": "user" }, { "content": "(PhysOrg.com) -- Large scale, cost-effective stem cell factories able to keep up with demand for new therapies to treat a range of human illnesses are a step closer to reality, thanks to a scientific breakthrough involving researchers at The University of Nottingham. Currently, stem cells are cultured using animal derived products that encourage the cells to reproduce without losing their pluripotency — their ability to be turned into any type of adult stem cell, whether it be a cardio myocyte to be used in treating heart attack victims or a bone cell for growing new bone to graft to a patient’s own. However, the potential for cross-species contamination and the difficulty in reproducing these cells in large numbers means that while they are useful as a research tool, a synthetic alternative would be essential for the treatment of patients. In a paper published in the September edition of Nature Materials, a team of Nottingham scientists led by Professor Morgan Alexander in the University’s School of Pharmacy, reveal they have discovered some man-made acrylate polymers which allow stem cells to reproduce while maintaining their pluripotency. Professor Alexander said: “This is an important breakthrough which could have significant implications for a wide range of stem cell therapies, including cancer, heart failure, muscle damage and a number of neurological disorders such as Parkinson’s and Huntington’s. “One of these new manmade materials may translate into an automated method of growing pluripotent stem cells which will be able to keep up with demand from emerging therapies that will require cells on an industrial scale, while being both cost-effective and safer for patients.” The research, a collaboration with colleagues Bob Langer, Dan Anderson, Rudolf Jaenisch and Krystyn Van Vliet at the Massachusetts Institute of Technology (MIT), involved using polymer microarrays — standard scientific glass slides with 1,700 polymer spots on the surface. Stem cells tagged with a fluorescent agent which allow them to be seen were placed onto the polymer spots. The scientists were then able to watch the stem cells and observe which polymers were most successful at promoting the most growth while also maintaining the pluripotency of the stem cells. Critically, in this paper the influence of the material properties was investigated though analysis of the polymer micro array spots. ", "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 Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α v β 3 and α v β 5 engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture. Main Human pluripotent stem cells (both human embryonic stem (hES) and induced pluripotent stem (hiPS) cells) hold great promise for regenerative medicine 1 , 2 , 3 , 4 and human-disease modelling 5 . However, existing methods to grow human pluripotent stem cells are not well suited for genetic manipulation experiments and introduce animal components, increasing the risks of immune rejection. Present methods to grow hES and hiPS cells include growing them on a ‘feeder’ cell layer of mitotically inactivated mouse embryonic fibroblasts 1 , 2 , 3 , 6 (mEFs), and on ‘feeder free’ culture systems, composed of a variety of extracellular-matrix/serum proteins coated onto tissue-culture dishes 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 or synthetic materials 16 , 17 , 18 , 19 such as hyaluronic acid hydrogels. These have been reported to promote hES cell self-renewal when seeded at a suitably high cell density 9 , 16 , 17 (for example, ∼ 10 6 cells ml −1 for the hydrogel) and have not been demonstrated to efficiently promote clonal growth of single hES cells (efficiencies typically <10%). However, gene targeting in pluripotent stem cells necessitates clonal outgrowth of single cells to detect rare targeting events (1 in 10 5 –10 6 cells) and requires selective growth of a correctly gene-targeted cell within a population of >10 5 cells 20 , 21 , 22 . Further, current human culture methods use either animal products or undefined components, which make it problematic for the potential transplantation applications 4 . Here we employed a high-throughput approach to engineer new culture substrates that could be used to clonally expand human pluripotent stem cells in a chemically defined, xeno-free, feeder-free manner. To facilitate rapid synthesis and analysis of synthetic substrates, we manufactured cell-compatible, biomaterial microarrays 23 , 24 . Microarrays were prepared from 22 acrylate monomers with diversified hydrophobicity–hydrophilicity and crosslinking densities ( Fig. 1 a). The arrays were prepared by copolymerization between each of 16 ‘major’ monomers (numbered 1–16) and each of six ‘minor’ monomers (lettered A–F) at six different ratios (100:0, 90:10, 85:15, 80:20, 75:25, 70:30 (v/v)) ( Supplementary Fig. S1 ). In this way, arrays with 496 [16+(16×5×6)] different combinations were created, consisting of the major monomer (70–100%) and minor monomer (0–30%). These monomer mixtures were robotically deposited in triplicate on a non-cell adhesive layer of poly(2-hydroxyethyl methacrylate) covering conventional glass slides (75 mm×25 mm), and then polymerized with a long-wave ultraviolet source. Figure 1: High-throughput screening of biomaterials for clonal growth. a , Monomers used for array synthesis were classified into two categories: ‘major’ monomers that constitute >50% of the reactant mixture and ‘minor’ monomers that constitute <50% of the mixture. Sixteen major monomers were named numerically (blue), and six minor monomers were labelled alphabetically (orange). b , Schematic diagram of the screen. First, transgenic Oct4–GFP hES cells were maintained on mEFs. Then flow cytometry enabled the isolation of high-purity undifferentiated hES cells from the completely dissociated coculture of hES cells and mEFs. A flow-cytometry histogram during a representative cell sort is shown. GFP + cells (right of the black gate) were seeded onto the arrays, whereas the differentiated cells and mEFs (GFP − , left of the black gate) were not used. A photograph of the polymer microarray with 16 polymer spots is shown to illustrate dimensions and separation. Each polymer was also characterized using high-throughput methods to characterize its surface roughness, indentation elastic modulus, wettability (water contact angle, θ C ) and surface chemistry. Finally, the cellular response on the polymer array was quantified by using laser-scanning cytometry, and structure–function relationships were determined by numerical analysis of both the cellular response and materials characterization data. Full size image We next used fluorescence-activated cell sorting of transgenic hES cells to ensure that hES cells were both dissociated from one another and undifferentiated in our assays ( Fig. 1 b). A transgenic green-fluorescent protein (GFP) reporter for Oct4 expression, a marker of pluripotent cells ( Supplementary Fig. S2 ), was knocked in to the BG01 hES cell line and propagated under standard hES cell culture conditions using mEFs 25 . GFP + sorted hES single cells ( Fig. 1 b, Supplementary Fig. S3 ) were seeded onto the polymer arrays and cultured with mEF-conditioned medium, because soluble growth factors secreted by mEFs help maintain the undifferentiated hES cell state 7 , 17 ( Supplementary Fig. S2c ). Proteins can rapidly adsorb onto the surfaces of materials used for cell culture 26 , 27 , 28 . The surface properties of cell-culture substrates can modulate both the amount and the conformation of adsorbed proteins, and thereby interact with cell surface receptors (for example, integrins) to initiate signal transduction and alter cell behaviour 29 . To investigate the potential of different adsorbed proteins, fibronectin, laminin, bovine serum albumin, and fetal bovine serum (FBS) were separately adsorbed onto the microarrays from solution. In general, FBS was found to most effectively support the propagation of hES cells across the entire array, whereas fibronectin and laminin coatings led to more<|im_end|> <|im_start|>assistant (PhysOrg.com) -- Large scale, cost-effective stem cell factories able to keep up with demand for new therapies to treat a range of human illnesses are a step closer to reality, thanks to a scientific breakthrough involving researchers at The University of Nottingham. Currently, stem cells are cultured using animal derived products that encourage the cells to reproduce without losing their pluripotency — their ability to be turned into any type of adult stem cell, whether it be a cardio myocyte to be used in treating heart attack victims or a bone cell for growing new bone to graft to a patient’s own. However, the potential for cross-species contamination and the difficulty in reproducing these cells in large numbers means that while they are useful as a research tool, a synthetic alternative would be essential for the treatment of patients. In a paper published in the September edition of Nature Materials, a team of Nottingham scientists led by Professor Morgan Alexander in the University’s School of Pharmacy, reveal they have discovered some man-made acrylate polymers which allow stem cells to reproduce while maintaining their pluripotency. Professor Alexander said: “This is an important breakthrough which could have significant implications for a wide range of stem cell therapies, including cancer, heart failure, muscle damage and a number of neurological disorders such as Parkinson’s and Huntington’s. “One of these new manmade materials may translate into an automated method of growing pluripotent stem cells which will be able to keep up with demand from emerging therapies that will require cells on an industrial scale, while being both cost-effective and safer for patients.” The research, a collaboration with colleagues Bob Langer, Dan Anderson, Rudolf Jaenisch and Krystyn Van Vliet at the Massachusetts Institute of Technology (MIT), involved using polymer microarrays — standard scientific glass slides with 1,700 polymer spots on the surface. Stem cells tagged with a fluorescent agent which allow them to be seen were placed onto the polymer spots. The scientists were then able to watch the stem cells and observe which polymers were most successful at promoting the most growth while also maintaining the pluripotency of the stem cells. Critically, in this paper the influence of the material properties was investigated though analysis of the polymer micro array spots. <|im_end|>

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1,995

[ { "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 Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A , as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At the molecular level we found that BCL11A is transcriptionally regulated by SOX2 and is required for its oncogenic functions. Furthermore, we show that BCL11A and SOX2 regulate the expression of several transcription factors, including SETD8 . We demonstrate that shRNA-mediated or pharmacological inhibition of SETD8 selectively inhibits LUSC growth. Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A–SOX2 transcriptional programme as a novel candidate for drug development. Introduction Lung cancer accounts for the highest rate of cancer-related diagnosis and mortality worldwide 1 . Broadly, there are two major types of lung cancers; small cell lung cancer (SCLC) accounting for 15% of cases and non-small cell lung cancer (NSCLC) accounting for 85% of cases 1 . NSCLC patients have a poor outcome in the clinic with only 15% of patients surviving 5 years or more 2 . At present NSCLC is defined histo-pathologically in the clinic into four broad categories: lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell carcinoma and undifferentiated NSCLC. LUAD and LUSC are the most common types of NSCLC (90% of cases). LUSC accounts for more than 400,000 deaths worldwide each year 3 and unlike LUAD there are limited targeted therapies available for LUSC. Platinum-based chemotherapy remains the first-line treatment for LUSC and although the recent FDA approval of Necitumumab in combination with platinum-based chemotherapy for metastatic LUSC has shown positive signs, a great deal of work still needs to be done in this field 4 . At the cellular level, LUAD tends to originate from the secretory epithelial cells in the lung while LUSC usually originates from basal cells (BCs) in the main and central airways 2 . At the molecular level LUAD is known to harbour mutations in epidermal growth factor receptor (EGFR), V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) and Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK), which are also well modelled and studied both in vitro and in vivo (for review see refs. 5 , 6 ). On the other hand, LUSC is less studied but it is known that amplifications of Sex Determining Region Y (SRY)-Box 2 (SOX2) tend to be present in 70–80% of patients 7 , 8 , 9 , 10 . We report here the identification and characterisation of the transcriptional regulator, BCL11A as a LUSC oncogene. We demonstrate that along with SOX2, it regulates key epigenetic factors, and that the disruption of one of these factors, SETD8 leads to selective affects in LUSC cells compared to LUAD cells. By disrupting the BCL11A-SOX2 transcriptional programme, our results provide a potential future framework for tackling the unmet clinical need for LUSC patients. Results BCL11A is a LUSC oncogene Recently, a detailed picture of the molecular differences between LUAD and LUSC has been made available through ‘The Cancer Genome Atlas’ (TCGA) 11 , 12 . To identify key drivers responsible for the differences between LUAD and LUSC we reanalysed the gene expression data from TCGA and focused on transcriptional regulators in the genome. As reported previously SOX2 was the most amplified gene in LUSC and its expression level was also significantly higher in LUSC vs. LUAD (Fig. 1a and Supplementary Fig. 1a ). The second most amplified locus in LUSC patients revealed by TCGA analysis contains the transcription factors BCL11A and REL 11 , 12 . BCL11A has been shown to be an oncogene in B-cell lymphoma and triple negative breast cancer 13 , 14 , 15 , 16 . Fig. 1 BCL11A is a lung squamous cell carcinoma (LUSC) oncogene. a Volcano plots of The Cancer Genome Atlas (TCGA) RNAseq data 11 , 12 indicating that BCL11A and SOX2 are highly expressed in LUSC compared to lung adenocarcinoma (LUAD). The plots show that REL is not differentially expressed in LUSC vs. LUAD patients. The x -axis represents log 2 expression fold-change (FC) in LUSC patients vs. LUAD patients and the y -axis represents –log 10 (pValue). The vertical dashed lines represent FC = 1.0 and the horizontal dashed line represents p -value = 0.01. b Volcano plots indicating that BCL11A and SOX2 are differentially expressed in LUSC patients vs. matched normal samples. The plot indicates that REL is not differentially expressed in LUSC vs. matched normal samples. c Volcano plots indicating that neither BCL11A, SOX2 nor REL are differentially expressed in LUAD patients vs. matched normal. d Images and scoring of BCL11A IHC staining on LUAD and LUSC tumours (see Methods for scoring). e , f Graphs depicting reduction in tumour size observed when shRNA1 or shRNA2 against BCL11A -transfected LK2 ( e ) and H520 ( f ) cells are injected subcutaneously into mice compared to control. Five mice per cell line were monitored for 25 days after which tumours were removed and measured. On the right are images showing actual tumours measured. The box plot extends from 25th to 75th percentile and the line represents the median. Data presented as mean ± s.d. One-way ANOVA with post Dunnett test performed, * p < 0.05, ** p < 0.005, and *** p < 0.001 Full size image We found that BCL11A expression levels were also significantly higher in LUSC vs. LUAD (Fig. 1a and Supplementary Fig. 1a ). Moreover, the expression of both BCL11A and SOX2 was significantly higher in LUSC but not in LUAD tumour samples compared to patient matched normal samples (Fig. 1b, c and Supplementary Fig. 1b–c ) supporting a driver role for these transcription factors in LUSC pathology. In contrast, REL expression was unchanged between LUSC and LUAD (Fig. 1a–c and Supplementary Fig. 1a–c ) suggesting", "role": "user" }, { "content": "Scientists have identified a key molecular player in a subtype of lung cancer which could lead to a new way to tackle the disease, according to research published in Nature Communications. Cancer Research UK-funded scientists based at the University of Cambridge found lung squamous cell carcinoma (LUSC) cells contained high amounts of a protein called BCL11A. The study showed that manipulating the gene responsible for the protein stopped the development of LUSC in a mouse model of the disease. The study also revealed a signaling pathway in which BCL11A was involved, and found a potential druggable target called SETD8. Targeting SETD8 genetically and with early forms of drugs selectively attacked LUSC cancer cells growing in the lab, and LUSC cells transplanted into mice. Dr. Kyren Lazarus, study author from the University of Cambridge, said, \"How LUSC develops is a bit of puzzle – until now, our molecular understanding of this process was limited. \"Our research has revealed a major piece of this puzzle, which we are now actively trying to make new drugs against.\" Over the last 40 years, lung cancer survival has remained stubbornly low, particularly when compared to overall cancer survival, which has more than doubled. One of the reasons for this is the lack of targeted treatments for lung cancer, and currently just five in 100 people survive their disease for 10 or more years. Dr. Walid Khaled, lead author from the University of Cambridge, said, \"Developing targeted treatments is a real opportunity for improving the outlook for patients. \"With this new drug discovery grant from Cancer Research UK, we are working to develop small molecules to specifically block BCL11A in LUSC cells. We are aiming to disrupt critical interactions that BCL11A has with other proteins and are working closely with our colleagues at the Department of Biochemistry in Cambridge and CRUK Beatson Institute Drug Discovery Unit to achieve this.\" Professor Karen Vousden, Cancer Research UK's chief scientist, said: \"Identifying potentially druggable targets is an early yet crucial stage in the journey toward precision medicine. \"While there is much to be done before this work could be translated into patient benefit, it's a fundamental step towards that goal and we look forward to seeing how this discovery progresses along the research pipeline.\" ", "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 Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A , as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At the molecular level we found that BCL11A is transcriptionally regulated by SOX2 and is required for its oncogenic functions. Furthermore, we show that BCL11A and SOX2 regulate the expression of several transcription factors, including SETD8 . We demonstrate that shRNA-mediated or pharmacological inhibition of SETD8 selectively inhibits LUSC growth. Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A–SOX2 transcriptional programme as a novel candidate for drug development. Introduction Lung cancer accounts for the highest rate of cancer-related diagnosis and mortality worldwide 1 . Broadly, there are two major types of lung cancers; small cell lung cancer (SCLC) accounting for 15% of cases and non-small cell lung cancer (NSCLC) accounting for 85% of cases 1 . NSCLC patients have a poor outcome in the clinic with only 15% of patients surviving 5 years or more 2 . At present NSCLC is defined histo-pathologically in the clinic into four broad categories: lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell carcinoma and undifferentiated NSCLC. LUAD and LUSC are the most common types of NSCLC (90% of cases). LUSC accounts for more than 400,000 deaths worldwide each year 3 and unlike LUAD there are limited targeted therapies available for LUSC. Platinum-based chemotherapy remains the first-line treatment for LUSC and although the recent FDA approval of Necitumumab in combination with platinum-based chemotherapy for metastatic LUSC has shown positive signs, a great deal of work still needs to be done in this field 4 . At the cellular level, LUAD tends to originate from the secretory epithelial cells in the lung while LUSC usually originates from basal cells (BCs) in the main and central airways 2 . At the molecular level LUAD is known to harbour mutations in epidermal growth factor receptor (EGFR), V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) and Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK), which are also well modelled and studied both in vitro and in vivo (for review see refs. 5 , 6 ). On the other hand, LUSC is less studied but it is known that amplifications of Sex Determining Region Y (SRY)-Box 2 (SOX2) tend to be present in 70–80% of patients 7 , 8 , 9 , 10 . We report here the identification and characterisation of the transcriptional regulator, BCL11A as a LUSC oncogene. We demonstrate that along with SOX2, it regulates key epigenetic factors, and that the disruption of one of these factors, SETD8 leads to selective affects in LUSC cells compared to LUAD cells. By disrupting the BCL11A-SOX2 transcriptional programme, our results provide a potential future framework for tackling the unmet clinical need for LUSC patients. Results BCL11A is a LUSC oncogene Recently, a detailed picture of the molecular differences between LUAD and LUSC has been made available through ‘The Cancer Genome Atlas’ (TCGA) 11 , 12 . To identify key drivers responsible for the differences between LUAD and LUSC we reanalysed the gene expression data from TCGA and focused on transcriptional regulators in the genome. As reported previously SOX2 was the most amplified gene in LUSC and its expression level was also significantly higher in LUSC vs. LUAD (Fig. 1a and Supplementary Fig. 1a ). The second most amplified locus in LUSC patients revealed by TCGA analysis contains the transcription factors BCL11A and REL 11 , 12 . BCL11A has been shown to be an oncogene in B-cell lymphoma and triple negative breast cancer 13 , 14 , 15 , 16 . Fig. 1 BCL11A is a lung squamous cell carcinoma (LUSC) oncogene. a Volcano plots of The Cancer Genome Atlas (TCGA) RNAseq data 11 , 12 indicating that BCL11A and SOX2 are highly expressed in LUSC compared to lung adenocarcinoma (LUAD). The plots show that REL is not differentially expressed in LUSC vs. LUAD patients. The x -axis represents log 2 expression fold-change (FC) in LUSC patients vs. LUAD patients and the y -axis represents –log 10 (pValue). The vertical dashed lines represent FC = 1.0 and the horizontal dashed line represents p -value = 0.01. b Volcano plots indicating that BCL11A and SOX2 are differentially expressed in LUSC patients vs. matched normal samples. The plot indicates that REL is not differentially expressed in LUSC vs. matched normal samples. c Volcano plots indicating that neither BCL11A, SOX2 nor REL are differentially expressed in LUAD patients vs. matched normal. d Images and scoring of BCL11A IHC staining on LUAD and LUSC tumours (see Methods for scoring). e , f Graphs depicting reduction in tumour size observed when shRNA1 or shRNA2 against BCL11A -transfected LK2 ( e ) and H520 ( f ) cells are injected subcutaneously into mice compared to control. Five mice per cell line were monitored for 25 days after which tumours were removed and measured. On the right are images showing actual tumours measured. The box plot extends from 25th to 75th percentile and the line represents the median. Data presented as mean ± s.d. One-way ANOVA with post Dunnett test performed, * p < 0.05, ** p < 0.005, and *** p < 0.001 Full size image We found that BCL11A expression levels were also significantly higher in LUSC vs. LUAD (Fig. 1a and Supplementary Fig. 1a ). Moreover, the expression of both BCL11A and SOX2 was significantly higher in LUSC but not in LUAD tumour samples compared to patient matched normal samples (Fig. 1b, c and Supplementary Fig. 1b–c ) supporting a driver role for these transcription factors in LUSC pathology. In contrast, REL expression was unchanged between LUSC and LUAD (Fig. 1a–c and Supplementary Fig. 1a–c ) suggesting<|im_end|> <|im_start|>assistant Scientists have identified a key molecular player in a subtype of lung cancer which could lead to a new way to tackle the disease, according to research published in Nature Communications. Cancer Research UK-funded scientists based at the University of Cambridge found lung squamous cell carcinoma (LUSC) cells contained high amounts of a protein called BCL11A. The study showed that manipulating the gene responsible for the protein stopped the development of LUSC in a mouse model of the disease. The study also revealed a signaling pathway in which BCL11A was involved, and found a potential druggable target called SETD8. Targeting SETD8 genetically and with early forms of drugs selectively attacked LUSC cancer cells growing in the lab, and LUSC cells transplanted into mice. Dr. Kyren Lazarus, study author from the University of Cambridge, said, "How LUSC develops is a bit of puzzle – until now, our molecular understanding of this process was limited. "Our research has revealed a major piece of this puzzle, which we are now actively trying to make new drugs against." Over the last 40 years, lung cancer survival has remained stubbornly low, particularly when compared to overall cancer survival, which has more than doubled. One of the reasons for this is the lack of targeted treatments for lung cancer, and currently just five in 100 people survive their disease for 10 or more years. Dr. Walid Khaled, lead author from the University of Cambridge, said, "Developing targeted treatments is a real opportunity for improving the outlook for patients. "With this new drug discovery grant from Cancer Research UK, we are working to develop small molecules to specifically block BCL11A in LUSC cells. We are aiming to disrupt critical interactions that BCL11A has with other proteins and are working closely with our colleagues at the Department of Biochemistry in Cambridge and CRUK Beatson Institute Drug Discovery Unit to achieve this." Professor Karen Vousden, Cancer Research UK's chief scientist, said: "Identifying potentially druggable targets is an early yet crucial stage in the journey toward precision medicine. "While there is much to be done before this work could be translated into patient benefit, it's a fundamental step towards that goal and we look forward to seeing how this discovery progresses along the research pipeline." <|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 healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity 1 . Reduction in synapse number is a consistent early feature of neurodegenerative diseases 2 , 3 , suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders 2 , 3 , how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity 4 , 5 . We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6 ). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice 7 , the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders. Main We used the phenomenon of physiological structural plasticity seen in hibernating mammals to determine the capacity for synapse regeneration in mouse models of neurodegenerative disease. When they enter torpor, the neurons of hibernators undergo morphological changes including changes in spine morphology 8 , 9 and/or changes in connectivity 4 , 5 . These are rapidly reversed on regaining normal body temperature 4 , 5 , 8 , 9 , 10 . We first established that the phenomenon of synapse dismantling and reassembly (structural plasticity) on artificial cooling and rewarming occurs in laboratory mice ( Fig. 1a and Extended Data Fig. 1a ). We then explored the capacity for structural plasticity after cooling in two mouse models of neurodegenerative disease: prion disease and the 5XFAD model of Alzheimer’s disease 7 . We used tg37 +/− mice 11 infected with Rocky Mountain Laboratory (RML) prions used in our previous studies 12 , 13 , 14 . These mice show substantial synapse loss from 7 weeks post-inoculation (w.p.i.) 13 ; 5XFAD mice have synapse loss from 4 months, after which time learning deficits emerge 7 . We tested the capacity for structural plasticity using cooling early in the course of disease, before the onset of established synapse loss in both models: from 4 w.p.i. in prion-infected animals and from 2 months of age in 5XFAD mice. Figure 1: The capacity for synaptic regeneration is lost early in neurodegenerative disease. a , Synapse numbers decline on cooling and recover on rewarming in wild-type mice, counted in both 3D and 2D. Representative electron micrographs (pseudo-coloured for ease of synapse identification: yellow, presynaptic; green, postsynaptic compartments) and bar charts showing quantification are shown for each experiment ( n = 4 animals at 18 °C and n = 2 at 37 °C; 192 images from 2 mice per condition for 3D analyses; 93 images from 3 animals per condition, for 2D analyses). A typical tripartite synapse is shown at higher magnification. b , c , The same response is seen in prion-diseased mice ( b ) at 4 and 5 w.p.i. but this fails at 6 w.p.i (arrow), and in 5XFAD ( c ) mice, where it fails at 3 months (arrow). P < 0.0001, P < 0.01; NS, not significant. Student’s t -test; two tailed. All data in bar charts are mean ± s.e.m. Scale bar, 1 μm. Source Data for all figures can be found in the Supplementary Tables . PowerPoint slide Source data Full size image All mice were cooled to 16–18 °C for 45 min, similar to core temperatures reached in small hibernators (deep hypothermia) using the biomolecule 5′-adenosine monophosphate (5′-AMP) 15 , after which they were allowed to slowly rewarm. Animals were euthanized at each stage of the cooling–rewarming process and synapses were counted in the CA1 region of hippocampus. Both synapse density and total synapse number significantly declined on cooling, but recovered on rewarming in wild-type mice, as measured using both three dimensional (3D) 16 and two dimensional (2D) analyses 13 ( Fig. 1a ). Neither brain volume nor synapse size changed on cooling and rewarming, excluding the possibility that changes in synapse density reflected changes in these parameters ( Extended Data Fig. 1a ). Thus, wild-type mice showed synaptic structural plasticity with reduction in synapse number on cooling and recovery on rewarming ( Fig. 1a ). This capacity for plasticity was also seen in both prion-infected and 5XFAD mice very early in the course of disease, at 4 and 5 w.p.i., and at 2 months of age, respectively ( Fig. 1b, c ). However, this capacity was lost by 6 w.p.i. in prion-diseased mice ( Fig. 1b and Extended Data Fig. 1b ) and at 3 months in 5XFAD mice ( Fig. 1c and Extended Data Fig. 1c ). Notably, impaired structural plasticity shortly preceded established decline in synapse number seen in prion-infected tg37 +/− mice at 7 w.p.i. (ref. 14 ), and in the 5XFAD mice from 4 months of age (see schematic, Extended Data Fig. 1d ). The lost ability to reassemble synapses was not due to loss of synaptic proteins at this stage ( Extended Data", "role": "user" }, { "content": "Researchers at the Medical Research Council Toxicology Unit at the University of Leicester have identified a molecular mechanism that helps protect brain cells against a fall in core body temperature, which also appears to protect against neurodegeneration in mice. Nerve cells communicate at junctions called synapses, which are fluid and can be formed and lost in response to triggers such as activity, damage or changes in the environment. They are also lost in neurodegenerative diseases such as Alzheimer's and prion diseases like CJD. Researchers have shown that when the body's core temperature drops, such as when mammals hibernate or during hypothermia, synapses break down and brain activity slows. Once the body returns to normal temperature again, synapses can regenerate to allow the brain to function at full capacity once more. The researchers studied some of the molecular events that control this process, including activation of a protein called RBM3. RBM3 protects nerve cells from damage at low temperatures but is also able to trigger the regeneration of synapses when the body recovers. The researchers wanted to investigate whether altering levels of RBM3 could protect nerve cells against neurodegeneration in the absence of a drop in body temperature. They first studied the brains of mice whose temperature was lowered to 16-18ºC for 45 min – mimicking the low temperatures experienced by other species of small mammals that hibernate. They found that the numbers of synapses fell on cooling, particularly in an area of the brain involved in memory, but these connections regenerated when the animals recovered. When they repeated this investigation with mice bred to show signs of neurodegeneration – re-creating damage seen in Alzheimer's and prion disease – the synapses were not able to regenerate again. In these animals, the team found that RBM3 did not respond to cooling and was not kick-starting the recovery process, suggesting the protein is key to protecting and regenerating synapses. The researchers then boosted levels of RBM3 in mice experiencing neurodegeneration, at normal temperature. They found that this was able to protect nerve cells against neurodegeneration and slow the memory problems usually developed by the mice. The researchers suggest that this mechanism could be targeted to develop new treatments to protect nerve cells against diseases like Alzheimer's. Dr Eric Karran, Director of Research at Alzheimer's Research UK, the UK's leading dementia research charity, said: \"This promising study highlights a natural process nerve cells use to protect themselves, which could be harnessed successfully in mice to resist damage associated with neurodegenerative diseases. It's still unclear exactly how and why nerve cells die in diseases like Alzheimer's, but a future treatment able to bolster nerve cells against damage could have wide-reaching benefits. \"This research is at an early stage and will need exploring further in humans before we know whether it could be developed into an effective treatment for diseases like Alzheimer's. There is currently a desperate lack of effective treatment options for people with dementia. Research to uncover the key biological mechanisms keeping brain cells healthy is important, as it provides more avenues for investigation in the search for treatments that could make a real difference to people's lives.\" ", "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 healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity 1 . Reduction in synapse number is a consistent early feature of neurodegenerative diseases 2 , 3 , suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders 2 , 3 , how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity 4 , 5 . We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6 ). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice 7 , the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders. Main We used the phenomenon of physiological structural plasticity seen in hibernating mammals to determine the capacity for synapse regeneration in mouse models of neurodegenerative disease. When they enter torpor, the neurons of hibernators undergo morphological changes including changes in spine morphology 8 , 9 and/or changes in connectivity 4 , 5 . These are rapidly reversed on regaining normal body temperature 4 , 5 , 8 , 9 , 10 . We first established that the phenomenon of synapse dismantling and reassembly (structural plasticity) on artificial cooling and rewarming occurs in laboratory mice ( Fig. 1a and Extended Data Fig. 1a ). We then explored the capacity for structural plasticity after cooling in two mouse models of neurodegenerative disease: prion disease and the 5XFAD model of Alzheimer’s disease 7 . We used tg37 +/− mice 11 infected with Rocky Mountain Laboratory (RML) prions used in our previous studies 12 , 13 , 14 . These mice show substantial synapse loss from 7 weeks post-inoculation (w.p.i.) 13 ; 5XFAD mice have synapse loss from 4 months, after which time learning deficits emerge 7 . We tested the capacity for structural plasticity using cooling early in the course of disease, before the onset of established synapse loss in both models: from 4 w.p.i. in prion-infected animals and from 2 months of age in 5XFAD mice. Figure 1: The capacity for synaptic regeneration is lost early in neurodegenerative disease. a , Synapse numbers decline on cooling and recover on rewarming in wild-type mice, counted in both 3D and 2D. Representative electron micrographs (pseudo-coloured for ease of synapse identification: yellow, presynaptic; green, postsynaptic compartments) and bar charts showing quantification are shown for each experiment ( n = 4 animals at 18 °C and n = 2 at 37 °C; 192 images from 2 mice per condition for 3D analyses; 93 images from 3 animals per condition, for 2D analyses). A typical tripartite synapse is shown at higher magnification. b , c , The same response is seen in prion-diseased mice ( b ) at 4 and 5 w.p.i. but this fails at 6 w.p.i (arrow), and in 5XFAD ( c ) mice, where it fails at 3 months (arrow). P < 0.0001, P < 0.01; NS, not significant. Student’s t -test; two tailed. All data in bar charts are mean ± s.e.m. Scale bar, 1 μm. Source Data for all figures can be found in the Supplementary Tables . PowerPoint slide Source data Full size image All mice were cooled to 16–18 °C for 45 min, similar to core temperatures reached in small hibernators (deep hypothermia) using the biomolecule 5′-adenosine monophosphate (5′-AMP) 15 , after which they were allowed to slowly rewarm. Animals were euthanized at each stage of the cooling–rewarming process and synapses were counted in the CA1 region of hippocampus. Both synapse density and total synapse number significantly declined on cooling, but recovered on rewarming in wild-type mice, as measured using both three dimensional (3D) 16 and two dimensional (2D) analyses 13 ( Fig. 1a ). Neither brain volume nor synapse size changed on cooling and rewarming, excluding the possibility that changes in synapse density reflected changes in these parameters ( Extended Data Fig. 1a ). Thus, wild-type mice showed synaptic structural plasticity with reduction in synapse number on cooling and recovery on rewarming ( Fig. 1a ). This capacity for plasticity was also seen in both prion-infected and 5XFAD mice very early in the course of disease, at 4 and 5 w.p.i., and at 2 months of age, respectively ( Fig. 1b, c ). However, this capacity was lost by 6 w.p.i. in prion-diseased mice ( Fig. 1b and Extended Data Fig. 1b ) and at 3 months in 5XFAD mice ( Fig. 1c and Extended Data Fig. 1c ). Notably, impaired structural plasticity shortly preceded established decline in synapse number seen in prion-infected tg37 +/− mice at 7 w.p.i. (ref. 14 ), and in the 5XFAD mice from 4 months of age (see schematic, Extended Data Fig. 1d ). The lost ability to reassemble synapses was not due to loss of synaptic proteins at this stage ( Extended Data<|im_end|> <|im_start|>assistant Researchers at the Medical Research Council Toxicology Unit at the University of Leicester have identified a molecular mechanism that helps protect brain cells against a fall in core body temperature, which also appears to protect against neurodegeneration in mice. Nerve cells communicate at junctions called synapses, which are fluid and can be formed and lost in response to triggers such as activity, damage or changes in the environment. They are also lost in neurodegenerative diseases such as Alzheimer's and prion diseases like CJD. Researchers have shown that when the body's core temperature drops, such as when mammals hibernate or during hypothermia, synapses break down and brain activity slows. Once the body returns to normal temperature again, synapses can regenerate to allow the brain to function at full capacity once more. The researchers studied some of the molecular events that control this process, including activation of a protein called RBM3. RBM3 protects nerve cells from damage at low temperatures but is also able to trigger the regeneration of synapses when the body recovers. The researchers wanted to investigate whether altering levels of RBM3 could protect nerve cells against neurodegeneration in the absence of a drop in body temperature. They first studied the brains of mice whose temperature was lowered to 16-18ºC for 45 min – mimicking the low temperatures experienced by other species of small mammals that hibernate. They found that the numbers of synapses fell on cooling, particularly in an area of the brain involved in memory, but these connections regenerated when the animals recovered. When they repeated this investigation with mice bred to show signs of neurodegeneration – re-creating damage seen in Alzheimer's and prion disease – the synapses were not able to regenerate again. In these animals, the team found that RBM3 did not respond to cooling and was not kick-starting the recovery process, suggesting the protein is key to protecting and regenerating synapses. The researchers then boosted levels of RBM3 in mice experiencing neurodegeneration, at normal temperature. They found that this was able to protect nerve cells against neurodegeneration and slow the memory problems usually developed by the mice. The researchers suggest that this mechanism could be targeted to develop new treatments to protect nerve cells against diseases like Alzheimer's. Dr Eric Karran, Director of Research at Alzheimer's Research UK, the UK's leading dementia research charity, said: "This promising study highlights a natural process nerve cells use to protect themselves, which could be harnessed successfully in mice to resist damage associated with neurodegenerative diseases. It's still unclear exactly how and why nerve cells die in diseases like Alzheimer's, but a future treatment able to bolster nerve cells against damage could have wide-reaching benefits. "This research is at an early stage and will need exploring further in humans before we know whether it could be developed into an effective treatment for diseases like Alzheimer's. There is currently a desperate lack of effective treatment options for people with dementia. Research to uncover the key biological mechanisms keeping brain cells healthy is important, as it provides more avenues for investigation in the search for treatments that could make a real difference to people's lives." <|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 axial resolution of three-dimensional structured illumination microscopy (3D SIM) is limited to ∼ 300 nm. Here we present two distinct, complementary methods to improve axial resolution in 3D SIM with minimal or no modification to the optical system. We show that placing a mirror directly opposite the sample enables four-beam interference with higher spatial frequency content than 3D SIM illumination, offering near-isotropic imaging with ∼ 120-nm lateral and 160-nm axial resolution. We also developed a deep learning method achieving ∼ 120-nm isotropic resolution. This method can be combined with denoising to facilitate volumetric imaging spanning dozens of timepoints. We demonstrate the potential of these advances by imaging a variety of cellular samples, delineating the nanoscale distribution of vimentin and microtubule filaments, observing the relative positions of caveolar coat proteins and lysosomal markers and visualizing cytoskeletal dynamics within T cells in the early stages of immune synapse formation. Main Three-dimensional structured illumination microscopy (3D SIM 1 ) excites the sample with non-uniform illumination, providing information outside the diffraction-limited passband that is encoded in the fluorescence captured by diffraction-limited images. Decoding this extra information mathematically yields a super-resolution reconstruction with doubled resolution compared to wide-field microscopy. Although a more modest gain than other methods 2 , in thin samples 3D SIM offers advantages including good optical sectioning, low illumination dose and high acquisition speed (enabling ‘4D’ volumetric time-lapse imaging in living cells 3 , 4 ) and compatibility with arbitrary fluorophores (facilitating multi-color super-resolution imaging 5 ). These attributes have provided a plethora of biological insights 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Although superior to wide-field microscopy, 3D SIM’s axial resolution is still limited to ∼ 300 nm, considerably worse than its ∼ 120-nm lateral resolution. Thus, 3D SIM reconstructions are anisotropic, distorting and obscuring fine features along the axial dimension. Relatively few solutions exist 20 , 21 for reducing this anisotropy, and none has been widely adopted. Here we demonstrate two complementary methods for improving axial resolution, with minimal or no modification to the 3D SIM optical path. First, we show that placing a mirror directly opposite the sample enables four-beam interference, producing higher axial spatial frequency components in the illumination pattern. This enables an axial resolution of ∼ 160 nm, producing nearly isotropic reconstructions. Second, we developed improved deep learning algorithms that operate on 3D SIM data (without the mirror), producing reconstructions with isotropic ∼ 120-nm spatial resolution. This computational method may be further combined with denoising, enabling high-quality, isotropic, 4D super-resolution imaging over dozens of volumes. We demonstrate these methods on a variety of fixed and live cellular samples. In vegetative and sporulating bacteria, we visualized membranes, cell division proteins and core components of the spore coat. In eukaryotic cells, we inspected membrane-encased actin filaments and pores that traversed thin membrane extensions; delineated the nanoscale positioning of vimentin and microtubules; observed the spatial distribution of caveolar coat proteins; and performed time-lapse volumetric imaging of mitochondrial, lysosomal and cytoskeletal dynamics. Results Four-beam interference for higher axial resolution Spatial resolution and optical sectioning in 3D SIM are determined by the convolution of the structured illumination pattern’s spatial frequency components with the wide-field detection optical transfer function (OTF; Extended Data Fig. 1a,b ) 1 . Anisotropic spatial resolution is a consequence of limited angular aperture: (1) the three wave vectors whose interference produces the illumination pattern lie on a spherical cap with limited angular extent; and (2) the limited angular range over which fluorescence is collected produces an OTF with greater lateral than axial extent. We, thus, considered strategies to increase angular aperture to improve axial resolution in 3D SIM. If the angle between illumination beams is increased beyond the limit imposed by the numerical aperture (NA) of the objective lens 22 , 23 , the resulting interference may contain higher axial frequency components up to 2n/λ, where n is the refractive index (RI) and λ is the wavelength of illumination. Such ‘standing-wave microscopes’ 23 —for very thin samples—indeed unveil axial detail obscured in 3D SIM. For thicker samples, however, gaps in the OTF support (Extended Data Fig. 1c ) preclude optical sectioning and generate severe axial ‘ringing’ in the resulting images. These problems are resolved in I 5 S (ref. 20 ), wherein two opposed objectives introduce six coherent illumination wave vectors, yielding more frequency components than in 3D SIM. The same objectives are used to collect fluorescence, which is also coherently interfered. The combination of coherent illumination and detection (Extended Data Fig. 1d ) produces ∼ 100-nm isotropic spatial resolution. However, I 5 S also presents severe practical challenges. (1) The illumination and fluorescence paths require more optics than 3D SIM, adding complexity and diminishing sensitivity. (2) Due to the short fluorescence coherence length, emission paths must be aligned to near-zero path length difference and maintained to much better than λ. In practice, this requires active feedback, further adding to instrument complexity. (3) Small RI mismatches introduce substantial aberrations. These reasons might explain why the only demonstration of I 5 S on biological samples 20 was limited to small imaging fields, fixed cells with special mounting protocols and single-color applications. An intriguing alternative to I 5 S was recently proposed 21 , whereby the 3D SIM central illumination beam is isolated, re-imaged to a mirror and reflected back toward the sample, yielding a four-beam interference pattern with finer axial structure than in 3D SIM (Extended Data Fig. 1e ). If a high NA objective lens is used to collect the fluorescence, the theoretically predicted axial resolution is worse than I 5 S but substantially better than 3D SIM. Although much simpler than I 5 S, notable challenges still exist. First, additional optics are still required, adding considerable complexity relative to the 3D SIM optical path. Second, the reflected beam must traverse these optics, air, sample and buffer, introducing RI mismatches that add undesirable wavefront distortion. Third,", "role": "user" }, { "content": "New methods to improve super-resolution imaging techniques are giving biologists a clearer and more complete view of the inner workings of living cells. A new paper in Nature Biotechnology from the Shroff Lab at Howard Hughes Medical Institute (HHMI)'s Janelia Research Campus details two practical ways to improve the axial (or z) resolution of 3D structured illumination microscopy, a technique to see inside living cells pioneered by former Janelia Group Leader Mats Gustafsson, who died in 2011. In 3D-SIM and other fluorescence microscopy techniques, the axial resolution of the image is often blurred. This means researchers can clearly see details in two dimensions, on the x and y planes, but details in the third dimension, on the z plane, are fuzzy. Previous attempts to resolve this issue were difficult to implement. A project led by Xuesong Li, a postdoc in the Shroff Lab, developed two ways to practically deal with the problem. In one method, a mirror is added to the microscope to create an additional beam of light, changing the interference pattern, and enabling finer, sharper resolution along the z axis. The second method, which uses deep learning, blurs the sharp x and y axes to look like the blurry z axis and then trains a neural network to reverse these blurry images. The network then uses that information to un-blur the z axis. A new paper in Nature Biotechnology from the Shroff Lab details two practical ways to improve the axial, or z, resolution of 3D structured illumination microscopy, a technique to see inside living cells. In one method, a mirror is added to the microscope to create an additional beam of light, changing the interference pattern, and enabling finer, sharper resolution along the z axis. (video 1). The second method, which uses deep learning, blurs the sharp x and y axes to look like the blurry z axis and then trains a neural network to reverse these blurry images. The network then uses that information to un-blur the z axis. (video 2). Credit: Li et al. Both methods provide a practical and effective way to improve axial resolution in 3D-SIM. This enables scientists to view the organelles inside cells sharply in all directions and potentially uncover new insights about the components inside cells. The new methods can be used to improve other microscopes, and the team is working to apply the methods to thicker samples. Some of the same concepts may also be useful in imaging techniques they are developing for use by biologists working in Janelia's new research area, 4D Cellular Physiology. ", "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 axial resolution of three-dimensional structured illumination microscopy (3D SIM) is limited to ∼ 300 nm. Here we present two distinct, complementary methods to improve axial resolution in 3D SIM with minimal or no modification to the optical system. We show that placing a mirror directly opposite the sample enables four-beam interference with higher spatial frequency content than 3D SIM illumination, offering near-isotropic imaging with ∼ 120-nm lateral and 160-nm axial resolution. We also developed a deep learning method achieving ∼ 120-nm isotropic resolution. This method can be combined with denoising to facilitate volumetric imaging spanning dozens of timepoints. We demonstrate the potential of these advances by imaging a variety of cellular samples, delineating the nanoscale distribution of vimentin and microtubule filaments, observing the relative positions of caveolar coat proteins and lysosomal markers and visualizing cytoskeletal dynamics within T cells in the early stages of immune synapse formation. Main Three-dimensional structured illumination microscopy (3D SIM 1 ) excites the sample with non-uniform illumination, providing information outside the diffraction-limited passband that is encoded in the fluorescence captured by diffraction-limited images. Decoding this extra information mathematically yields a super-resolution reconstruction with doubled resolution compared to wide-field microscopy. Although a more modest gain than other methods 2 , in thin samples 3D SIM offers advantages including good optical sectioning, low illumination dose and high acquisition speed (enabling ‘4D’ volumetric time-lapse imaging in living cells 3 , 4 ) and compatibility with arbitrary fluorophores (facilitating multi-color super-resolution imaging 5 ). These attributes have provided a plethora of biological insights 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Although superior to wide-field microscopy, 3D SIM’s axial resolution is still limited to ∼ 300 nm, considerably worse than its ∼ 120-nm lateral resolution. Thus, 3D SIM reconstructions are anisotropic, distorting and obscuring fine features along the axial dimension. Relatively few solutions exist 20 , 21 for reducing this anisotropy, and none has been widely adopted. Here we demonstrate two complementary methods for improving axial resolution, with minimal or no modification to the 3D SIM optical path. First, we show that placing a mirror directly opposite the sample enables four-beam interference, producing higher axial spatial frequency components in the illumination pattern. This enables an axial resolution of ∼ 160 nm, producing nearly isotropic reconstructions. Second, we developed improved deep learning algorithms that operate on 3D SIM data (without the mirror), producing reconstructions with isotropic ∼ 120-nm spatial resolution. This computational method may be further combined with denoising, enabling high-quality, isotropic, 4D super-resolution imaging over dozens of volumes. We demonstrate these methods on a variety of fixed and live cellular samples. In vegetative and sporulating bacteria, we visualized membranes, cell division proteins and core components of the spore coat. In eukaryotic cells, we inspected membrane-encased actin filaments and pores that traversed thin membrane extensions; delineated the nanoscale positioning of vimentin and microtubules; observed the spatial distribution of caveolar coat proteins; and performed time-lapse volumetric imaging of mitochondrial, lysosomal and cytoskeletal dynamics. Results Four-beam interference for higher axial resolution Spatial resolution and optical sectioning in 3D SIM are determined by the convolution of the structured illumination pattern’s spatial frequency components with the wide-field detection optical transfer function (OTF; Extended Data Fig. 1a,b ) 1 . Anisotropic spatial resolution is a consequence of limited angular aperture: (1) the three wave vectors whose interference produces the illumination pattern lie on a spherical cap with limited angular extent; and (2) the limited angular range over which fluorescence is collected produces an OTF with greater lateral than axial extent. We, thus, considered strategies to increase angular aperture to improve axial resolution in 3D SIM. If the angle between illumination beams is increased beyond the limit imposed by the numerical aperture (NA) of the objective lens 22 , 23 , the resulting interference may contain higher axial frequency components up to 2n/λ, where n is the refractive index (RI) and λ is the wavelength of illumination. Such ‘standing-wave microscopes’ 23 —for very thin samples—indeed unveil axial detail obscured in 3D SIM. For thicker samples, however, gaps in the OTF support (Extended Data Fig. 1c ) preclude optical sectioning and generate severe axial ‘ringing’ in the resulting images. These problems are resolved in I 5 S (ref. 20 ), wherein two opposed objectives introduce six coherent illumination wave vectors, yielding more frequency components than in 3D SIM. The same objectives are used to collect fluorescence, which is also coherently interfered. The combination of coherent illumination and detection (Extended Data Fig. 1d ) produces ∼ 100-nm isotropic spatial resolution. However, I 5 S also presents severe practical challenges. (1) The illumination and fluorescence paths require more optics than 3D SIM, adding complexity and diminishing sensitivity. (2) Due to the short fluorescence coherence length, emission paths must be aligned to near-zero path length difference and maintained to much better than λ. In practice, this requires active feedback, further adding to instrument complexity. (3) Small RI mismatches introduce substantial aberrations. These reasons might explain why the only demonstration of I 5 S on biological samples 20 was limited to small imaging fields, fixed cells with special mounting protocols and single-color applications. An intriguing alternative to I 5 S was recently proposed 21 , whereby the 3D SIM central illumination beam is isolated, re-imaged to a mirror and reflected back toward the sample, yielding a four-beam interference pattern with finer axial structure than in 3D SIM (Extended Data Fig. 1e ). If a high NA objective lens is used to collect the fluorescence, the theoretically predicted axial resolution is worse than I 5 S but substantially better than 3D SIM. Although much simpler than I 5 S, notable challenges still exist. First, additional optics are still required, adding considerable complexity relative to the 3D SIM optical path. Second, the reflected beam must traverse these optics, air, sample and buffer, introducing RI mismatches that add undesirable wavefront distortion. Third,<|im_end|> <|im_start|>assistant New methods to improve super-resolution imaging techniques are giving biologists a clearer and more complete view of the inner workings of living cells. A new paper in Nature Biotechnology from the Shroff Lab at Howard Hughes Medical Institute (HHMI)'s Janelia Research Campus details two practical ways to improve the axial (or z) resolution of 3D structured illumination microscopy, a technique to see inside living cells pioneered by former Janelia Group Leader Mats Gustafsson, who died in 2011. In 3D-SIM and other fluorescence microscopy techniques, the axial resolution of the image is often blurred. This means researchers can clearly see details in two dimensions, on the x and y planes, but details in the third dimension, on the z plane, are fuzzy. Previous attempts to resolve this issue were difficult to implement. A project led by Xuesong Li, a postdoc in the Shroff Lab, developed two ways to practically deal with the problem. In one method, a mirror is added to the microscope to create an additional beam of light, changing the interference pattern, and enabling finer, sharper resolution along the z axis. The second method, which uses deep learning, blurs the sharp x and y axes to look like the blurry z axis and then trains a neural network to reverse these blurry images. The network then uses that information to un-blur the z axis. A new paper in Nature Biotechnology from the Shroff Lab details two practical ways to improve the axial, or z, resolution of 3D structured illumination microscopy, a technique to see inside living cells. In one method, a mirror is added to the microscope to create an additional beam of light, changing the interference pattern, and enabling finer, sharper resolution along the z axis. (video 1). The second method, which uses deep learning, blurs the sharp x and y axes to look like the blurry z axis and then trains a neural network to reverse these blurry images. The network then uses that information to un-blur the z axis. (video 2). Credit: Li et al. Both methods provide a practical and effective way to improve axial resolution in 3D-SIM. This enables scientists to view the organelles inside cells sharply in all directions and potentially uncover new insights about the components inside cells. The new methods can be used to improve other microscopes, and the team is working to apply the methods to thicker samples. Some of the same concepts may also be useful in imaging techniques they are developing for use by biologists working in Janelia's new research area, 4D Cellular Physiology. <|im_end|>

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1,947

[ { "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 Resonant inelastic X-ray scattering and X-ray emission spectroscopy can be used to probe the energy and dispersion of the elementary low-energy excitations that govern functionality in matter: vibronic, charge, spin and orbital excitations 1 , 2 , 3 , 4 , 5 , 6 , 7 . A key drawback of resonant inelastic X-ray scattering has been the need for high photon densities to compensate for fluorescence yields of less than a per cent for soft X-rays 8 . Sample damage from the dominant non-radiative decays thus limits the materials to which such techniques can be applied and the spectral resolution that can be obtained. A means of improving the yield is therefore highly desirable. Here we demonstrate stimulated X-ray emission for crystalline silicon at photon densities that are easily achievable with free-electron lasers 9 . The stimulated radiative decay of core excited species at the expense of non-radiative processes reduces sample damage and permits narrow-bandwidth detection in the directed beam of stimulated radiation. We deduce how stimulated X-ray emission can be enhanced by several orders of magnitude to provide, with high yield and reduced sample damage, a superior probe for low-energy excitations and their dispersion in matter. This is the first step to bringing nonlinear X-ray physics in the condensed phase from theory 10 , 11 , 12 , 13 , 14 , 15 , 16 to application. Main In the soft X-ray region, the use of nonlinear techniques to enhance the signal levels has been prevented by the small cross-sections and the short lifetimes of core-excited states in the regime of a few femtoseconds. In the past few years, free-electron lasers have become available, producing ultrashort, intense soft X-ray pulses 9 , 17 , 18 , 19 , 20 . Recently, the stimulation of emission from a single fluorescence line in a rare gas 21 and hard X-ray/optical sum frequency generation 22 have been demonstrated. We present here stimulated X-ray emission from a solid-state sample recorded at the free-electron laser in Hamburg (FLASH) for non-resonant silicon L -edge excitation at a photon energy of 115 eV. With free-electron laser radiation we produce regions with high 2 p core excitation densities. The spontaneously emitted radiation from recombination of the 2 p core holes (photon energy of 85 eV to nearly 100 eV) seeds the stimulated emission of soft X-ray photons. The emitted spectrum is determined by the spontaneous emission as observed in a typical resonant inelastic X-ray scattering (RIXS) or X-ray emission spectroscopy (XES) experiment and thus conserves all the information and specificity of these methods. By carefully choosing the geometry, we can significantly enhance the weak fluorescence signal at the expense of Auger decays. Fewer electrons are emitted and electronic damage to the sample is minimized. By properly shaping the free-electron laser beam footprint on the sample the detected signal can be enhanced by orders of magnitude because the usually isotropic emission can be directed towards the detector. This opens up the possibility of nonlinear spectroscopy in the X-ray region by combining concepts from nonlinear optics with the high information depth of X-ray spectroscopy, which is intrinsically able to resolve femtosecond dynamics 10 , 11 , 12 , 13 , 14 , 15 , 16 , 23 , 24 , 25 . The absorption and stimulated emission probabilities P can be approximated for infinitesimally thin samples where the photons interact on a short length d x as: where ρ atom is the number density of absorbing atoms and ρ ch (for core hole) is the number density of excited atoms for stimulation. The X-ray absorption or stimulation cross-sections σ are determined by the dipole transition matrix elements between the core level and unoccupied (absorption) or occupied (stimulated emission) valence states and are assumed at this point to be approximately the same. The cross-section is connected with the absorption length λ = ( σ ρ atom ) –1 . The effect of stimulated emission is large, when the stimulation probability approaches unity , yielding: For effective stimulation, the absorption length relative to the interaction lengths of stimulating photons has to be similar to the fraction of core-excited atoms. For comparable interaction and absorption lengths, every atom needs to be core-excited; a population inversion is required. In the forward direction, stimulated X-ray emission has been demonstrated in the gas phase 21 . In this geometry, the maximum interaction length at which stimulating photons can interact with core holes is intrinsically given by the absorption length. The sample has to absorb one X-ray photon per atom. If applied to solids, this energy usually destroys the bonding network and is hence not suited for spectroscopic studies of the undisturbed system. The situation is very different for other geometries. Along the lateral dimension of the X-ray focus, the interaction length can be significantly larger. With soft X-rays on solids, the absorption length of the exciting radiation with a photon energy that is slightly above an absorption edge is typically tens or hundreds of nanometres, whereas the lateral dimensions of typical X-ray foci are a few to hundreds of micrometres. The interaction length is then limited by the absorption length of the RIXS and XES signals with a photon energy below the absorption edge, which are typically an order of magnitude larger than for the exciting radiation. Consequently, lower excitation densities are needed, when the observation direction is chosen to be along the lateral dimension of the projected focus instead. This situation is sketched in Fig. 1 , together with measured data of the total emission signal detected at several angles to the surface. We observe an emission maximum at around 9°, which is the result of the balance between the absorption length of the exciting radiation and the interaction length of the emitted radiation inside the excited volume. Figure 1: Geometry to observe spontaneously stimulated X-ray emission from solids. a , X-rays create core excitations in the solid (yellow). A cascade of stimulated emission builds up in a direction where the penetration", "role": "user" }, { "content": "Without the currently available plethora of X-ray methods, basic research in the physical sciences would be unthinkable. The methods are used in solid state physics, in the analysis of biological structures, and even art historians have X-rays to thank for many new insights. Now, scientists at the Helmholtz Center Berlin (HZB) have identified yet another area of application. The team around Dr. Martin Beye and Prof. Alexander Föhlisch was able to show that solids lend themselves to X-ray analysis based on nonlinear physical effects. Until now, this could only be done using laser analysis. The work is being published in the e-pub-ahead-of-print-issue of the journal Nature. Their results could potentially redefine what future lightsources ought to look like. Nonlinear effects form the basis of laser physics. Until now, they did not appear to be useful in X-ray analysis. The physics that underlie X-ray methods were based solely on linear effects, meaning whenever the radiation encounters the object that is being examined, each light particle – each photon – is working in isolation. With lasers, it's a different story. The energy and power density of incoming laser light can get so high that photons actually work together and nonlinear effects result from their interaction with matter. This results in materials greatly enhancing certain colors of light. In other words, if you irradiate a crystal with green light, the light that gets irradiated is actually red. This color can be precisely correlated with the structural properties of the material that is being analyzed. Now, Alexander Föhlisch from the HZB and his team were able to observe through a series of experiments at Hamburg's short-pulse X-ray laser FLASH that these types of effects can also be achieved using soft X-rays and that this method works on solids as well. \"Normally, inelastic scattering processes using soft X-rays are ineffective,\" explains Martin Beye, the study's primary author: \"Our experiment allowed us to document how inelastic X-ray scattering can be intelligently intensified. Just like a laser, the different photons are actually working together and amplifying each other and we end up with a very high measurement signal.\" Looking ahead, by setting up appropriate instruments, synchrotron sources might hold a strong appeal for research fields like superconductivity experiments, which previously relied almost exclusively on neutron scattering. Inelastic scattering processes are also in demand when we're talking about element specific investigations. Like, for instance, if the goal is to distinguish between ions of the same element according to their oxidation state, which, in turn, isn't possible using neutron scattering. Further examples are time-resolved processes, ultrafast processes like the breaking and formation of chemical bonds. \"Modern-day X-ray sources are not at all optimized for the application of inelastic scattering,\" says Alexander Föhlisch. \"With the current results, we know that we can use nonlinear effects even with soft X-ray radiation. What we need are photon sources capable of delivering short light pulses in rapid succession. This has to be taken into consideration during future photon source development.\" With its BESSY-VSR upgrade project, the HZB is creating just the right prerequisites. ", "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 Resonant inelastic X-ray scattering and X-ray emission spectroscopy can be used to probe the energy and dispersion of the elementary low-energy excitations that govern functionality in matter: vibronic, charge, spin and orbital excitations 1 , 2 , 3 , 4 , 5 , 6 , 7 . A key drawback of resonant inelastic X-ray scattering has been the need for high photon densities to compensate for fluorescence yields of less than a per cent for soft X-rays 8 . Sample damage from the dominant non-radiative decays thus limits the materials to which such techniques can be applied and the spectral resolution that can be obtained. A means of improving the yield is therefore highly desirable. Here we demonstrate stimulated X-ray emission for crystalline silicon at photon densities that are easily achievable with free-electron lasers 9 . The stimulated radiative decay of core excited species at the expense of non-radiative processes reduces sample damage and permits narrow-bandwidth detection in the directed beam of stimulated radiation. We deduce how stimulated X-ray emission can be enhanced by several orders of magnitude to provide, with high yield and reduced sample damage, a superior probe for low-energy excitations and their dispersion in matter. This is the first step to bringing nonlinear X-ray physics in the condensed phase from theory 10 , 11 , 12 , 13 , 14 , 15 , 16 to application. Main In the soft X-ray region, the use of nonlinear techniques to enhance the signal levels has been prevented by the small cross-sections and the short lifetimes of core-excited states in the regime of a few femtoseconds. In the past few years, free-electron lasers have become available, producing ultrashort, intense soft X-ray pulses 9 , 17 , 18 , 19 , 20 . Recently, the stimulation of emission from a single fluorescence line in a rare gas 21 and hard X-ray/optical sum frequency generation 22 have been demonstrated. We present here stimulated X-ray emission from a solid-state sample recorded at the free-electron laser in Hamburg (FLASH) for non-resonant silicon L -edge excitation at a photon energy of 115 eV. With free-electron laser radiation we produce regions with high 2 p core excitation densities. The spontaneously emitted radiation from recombination of the 2 p core holes (photon energy of 85 eV to nearly 100 eV) seeds the stimulated emission of soft X-ray photons. The emitted spectrum is determined by the spontaneous emission as observed in a typical resonant inelastic X-ray scattering (RIXS) or X-ray emission spectroscopy (XES) experiment and thus conserves all the information and specificity of these methods. By carefully choosing the geometry, we can significantly enhance the weak fluorescence signal at the expense of Auger decays. Fewer electrons are emitted and electronic damage to the sample is minimized. By properly shaping the free-electron laser beam footprint on the sample the detected signal can be enhanced by orders of magnitude because the usually isotropic emission can be directed towards the detector. This opens up the possibility of nonlinear spectroscopy in the X-ray region by combining concepts from nonlinear optics with the high information depth of X-ray spectroscopy, which is intrinsically able to resolve femtosecond dynamics 10 , 11 , 12 , 13 , 14 , 15 , 16 , 23 , 24 , 25 . The absorption and stimulated emission probabilities P can be approximated for infinitesimally thin samples where the photons interact on a short length d x as: where ρ atom is the number density of absorbing atoms and ρ ch (for core hole) is the number density of excited atoms for stimulation. The X-ray absorption or stimulation cross-sections σ are determined by the dipole transition matrix elements between the core level and unoccupied (absorption) or occupied (stimulated emission) valence states and are assumed at this point to be approximately the same. The cross-section is connected with the absorption length λ = ( σ ρ atom ) –1 . The effect of stimulated emission is large, when the stimulation probability approaches unity , yielding: For effective stimulation, the absorption length relative to the interaction lengths of stimulating photons has to be similar to the fraction of core-excited atoms. For comparable interaction and absorption lengths, every atom needs to be core-excited; a population inversion is required. In the forward direction, stimulated X-ray emission has been demonstrated in the gas phase 21 . In this geometry, the maximum interaction length at which stimulating photons can interact with core holes is intrinsically given by the absorption length. The sample has to absorb one X-ray photon per atom. If applied to solids, this energy usually destroys the bonding network and is hence not suited for spectroscopic studies of the undisturbed system. The situation is very different for other geometries. Along the lateral dimension of the X-ray focus, the interaction length can be significantly larger. With soft X-rays on solids, the absorption length of the exciting radiation with a photon energy that is slightly above an absorption edge is typically tens or hundreds of nanometres, whereas the lateral dimensions of typical X-ray foci are a few to hundreds of micrometres. The interaction length is then limited by the absorption length of the RIXS and XES signals with a photon energy below the absorption edge, which are typically an order of magnitude larger than for the exciting radiation. Consequently, lower excitation densities are needed, when the observation direction is chosen to be along the lateral dimension of the projected focus instead. This situation is sketched in Fig. 1 , together with measured data of the total emission signal detected at several angles to the surface. We observe an emission maximum at around 9°, which is the result of the balance between the absorption length of the exciting radiation and the interaction length of the emitted radiation inside the excited volume. Figure 1: Geometry to observe spontaneously stimulated X-ray emission from solids. a , X-rays create core excitations in the solid (yellow). A cascade of stimulated emission builds up in a direction where the penetration<|im_end|> <|im_start|>assistant Without the currently available plethora of X-ray methods, basic research in the physical sciences would be unthinkable. The methods are used in solid state physics, in the analysis of biological structures, and even art historians have X-rays to thank for many new insights. Now, scientists at the Helmholtz Center Berlin (HZB) have identified yet another area of application. The team around Dr. Martin Beye and Prof. Alexander Föhlisch was able to show that solids lend themselves to X-ray analysis based on nonlinear physical effects. Until now, this could only be done using laser analysis. The work is being published in the e-pub-ahead-of-print-issue of the journal Nature. Their results could potentially redefine what future lightsources ought to look like. Nonlinear effects form the basis of laser physics. Until now, they did not appear to be useful in X-ray analysis. The physics that underlie X-ray methods were based solely on linear effects, meaning whenever the radiation encounters the object that is being examined, each light particle – each photon – is working in isolation. With lasers, it's a different story. The energy and power density of incoming laser light can get so high that photons actually work together and nonlinear effects result from their interaction with matter. This results in materials greatly enhancing certain colors of light. In other words, if you irradiate a crystal with green light, the light that gets irradiated is actually red. This color can be precisely correlated with the structural properties of the material that is being analyzed. Now, Alexander Föhlisch from the HZB and his team were able to observe through a series of experiments at Hamburg's short-pulse X-ray laser FLASH that these types of effects can also be achieved using soft X-rays and that this method works on solids as well. "Normally, inelastic scattering processes using soft X-rays are ineffective," explains Martin Beye, the study's primary author: "Our experiment allowed us to document how inelastic X-ray scattering can be intelligently intensified. Just like a laser, the different photons are actually working together and amplifying each other and we end up with a very high measurement signal." Looking ahead, by setting up appropriate instruments, synchrotron sources might hold a strong appeal for research fields like superconductivity experiments, which previously relied almost exclusively on neutron scattering. Inelastic scattering processes are also in demand when we're talking about element specific investigations. Like, for instance, if the goal is to distinguish between ions of the same element according to their oxidation state, which, in turn, isn't possible using neutron scattering. Further examples are time-resolved processes, ultrafast processes like the breaking and formation of chemical bonds. "Modern-day X-ray sources are not at all optimized for the application of inelastic scattering," says Alexander Föhlisch. "With the current results, we know that we can use nonlinear effects even with soft X-ray radiation. What we need are photon sources capable of delivering short light pulses in rapid succession. This has to be taken into consideration during future photon source development." With its BESSY-VSR upgrade project, the HZB is creating just the right prerequisites. <|im_end|>

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315, 279, 1630, 30630, 5357, 11, 279, 16628, 3160, 649, 387, 12207, 8294, 13, 3161, 8579, 1630, 82817, 389, 82486, 11, 279, 44225, 3160, 315, 279, 13548, 25407, 449, 264, 69010, 4907, 430, 374, 10284, 3485, 459, 44225, 6964, 374, 11383, 22781, 477, 11758, 315, 20622, 4512, 417, 11, 20444, 279, 45569, 15696, 315, 14595, 1630, 30630, 282, 2168, 527, 264, 2478, 311, 11758, 315, 19748, 442, 295, 417, 13, 578, 16628, 3160, 374, 1243, 7347, 555, 279, 44225, 3160, 315, 279, 432, 5511, 50, 323, 1630, 1600, 17738, 449, 264, 69010, 4907, 3770, 279, 44225, 6964, 11, 902, 527, 11383, 459, 2015, 315, 26703, 8294, 1109, 369, 279, 13548, 25407, 13, 53123, 11, 4827, 3521, 7709, 90816, 527, 4460, 11, 994, 279, 22695, 5216, 374, 12146, 311, 387, 3235, 279, 45569, 13167, 315, 279, 28448, 5357, 4619, 13, 1115, 6671, 374, 1940, 37880, 304, 23966, 13, 220, 16, 1174, 3871, 449, 17303, 828, 315, 279, 2860, 41353, 8450, 16914, 520, 3892, 27030, 311, 279, 7479, 13, 1226, 23846, 459, 41353, 7340, 520, 2212, 220, 24, 11877, 11, 902, 374, 279, 1121, 315, 279, 8335, 1990, 279, 44225, 3160, 315, 279, 13548, 25407, 323, 279, 16628, 3160, 315, 279, 48042, 25407, 4871, 279, 12304, 8286, 13, 19575, 220, 16, 25, 40018, 311, 23846, 88558, 81471, 1630, 30630, 41353, 505, 82486, 13, 264, 1174, 1630, 82817, 1893, 6332, 25435, 811, 304, 279, 6573, 320, 28969, 570, 362, 43118, 315, 81471, 41353, 22890, 709, 304, 264, 5216, 1405, 279, 44596, 128257, 198, 128256, 78191, 198, 27131, 279, 5131, 2561, 68706, 315, 1630, 30630, 5528, 11, 6913, 3495, 304, 279, 7106, 36788, 1053, 387, 96603, 13, 578, 5528, 527, 1511, 304, 6573, 1614, 22027, 11, 304, 279, 6492, 315, 24156, 14726, 11, 323, 1524, 1989, 51801, 617, 1630, 82817, 311, 9901, 369, 1690, 502, 26793, 13, 4800, 11, 14248, 520, 279, 16183, 53016, 6312, 89, 5955, 20437, 320, 62859, 33, 8, 617, 11054, 3686, 2500, 3158, 315, 3851, 13, 578, 2128, 2212, 2999, 13, 11826, 426, 19494, 323, 8626, 13, 20643, 435, 3029, 18442, 16438, 574, 3025, 311, 1501, 430, 82486, 39580, 5694, 311, 1630, 30630, 6492, 3196, 389, 75098, 7106, 6372, 13, 30070, 1457, 11, 420, 1436, 1193, 387, 2884, 1701, 21120, 6492, 13, 578, 990, 374, 1694, 4756, 304, 279, 384, 2320, 392, 99588, 8838, 43245, 90465, 315, 279, 8486, 22037, 13, 11205, 3135, 1436, 13893, 84375, 1148, 3938, 13001, 2415, 22525, 311, 1427, 1093, 13, 11842, 23603, 6372, 1376, 279, 8197, 315, 21120, 22027, 13, 30070, 1457, 11, 814, 1550, 539, 5101, 311, 387, 5505, 304, 1630, 30630, 6492, 13, 578, 22027, 430, 1234, 11828, 1630, 30630, 5528, 1051, 3196, 21742, 389, 13790, 6372, 11, 7438, 15716, 279, 25407, 35006, 279, 1665, 430, 374, 1694, 25078, 11, 1855, 3177, 19320, 1389, 1855, 69010, 1389, 374, 3318, 304, 31398, 13, 3161, 72475, 11, 433, 596, 264, 2204, 3446, 13, 578, 4907, 323, 2410, 17915, 315, 19957, 21120, 3177, 649, 636, 779, 1579, 430, 89235, 3604, 990, 3871, 323, 75098, 6372, 1121, 505, 872, 16628, 449, 5030, 13, 1115, 3135, 304, 7384, 19407, 47594, 3738, 8146, 315, 3177, 13, 763, 1023, 4339, 11, 422, 499, 76327, 349, 264, 26110, 449, 6307, 3177, 11, 279, 3177, 430, 5334, 76327, 660, 374, 3604, 2579, 13, 1115, 1933, 649, 387, 24559, 49393, 449, 279, 24693, 6012, 315, 279, 3769, 430, 374, 1694, 30239, 13, 4800, 11, 20643, 435, 3029, 18442, 16438, 505, 279, 473, 57, 33, 323, 813, 2128, 1051, 3025, 311, 23846, 1555, 264, 4101, 315, 21896, 520, 51562, 596, 2875, 2320, 17660, 1630, 30630, 21120, 53426, 430, 1521, 4595, 315, 6372, 649, 1101, 387, 17427, 1701, 8579, 1630, 82817, 323, 430, 420, 1749, 4375, 389, 82486, 439, 1664, 13, 330, 95294, 11, 304, 63064, 72916, 11618, 1701, 8579, 1630, 82817, 527, 55288, 1359, 15100, 11826, 426, 19494, 11, 279, 4007, 596, 6156, 3229, 25, 330, 8140, 9526, 5535, 603, 311, 2246, 1268, 304, 63064, 1630, 30630, 72916, 649, 387, 60538, 4501, 79849, 13, 4702, 1093, 264, 21120, 11, 279, 2204, 89235, 527, 3604, 3318, 3871, 323, 23201, 7922, 1855, 1023, 323, 584, 842, 709, 449, 264, 1633, 1579, 19179, 8450, 1210, 21815, 8469, 11, 555, 6376, 709, 8475, 24198, 11, 6925, 331, 299, 35785, 8336, 2643, 3412, 264, 3831, 14638, 369, 3495, 5151, 1093, 2307, 77752, 1968, 21896, 11, 902, 8767, 41013, 4661, 24121, 389, 73404, 72916, 13, 763, 63064, 72916, 11618, 527, 1101, 304, 7631, 994, 584, 2351, 7556, 922, 2449, 3230, 26969, 13, 9086, 11, 369, 2937, 11, 422, 279, 5915, 374, 311, 33137, 1990, 65125, 315, 279, 1890, 2449, 4184, 311, 872, 71162, 1614, 11, 902, 11, 304, 2543, 11, 4536, 956, 3284, 1701, 73404, 72916, 13, 15903, 10507, 527, 892, 11849, 8905, 11618, 11, 24955, 9533, 11618, 1093, 279, 15061, 323, 18488, 315, 11742, 27460, 13, 330, 49552, 11477, 1630, 30630, 8336, 527, 539, 520, 682, 34440, 369, 279, 3851, 315, 304, 63064, 72916, 1359, 2795, 20643, 435, 3029, 18442, 16438, 13, 330, 2409, 279, 1510, 3135, 11, 584, 1440, 430, 584, 649, 1005, 75098, 6372, 1524, 449, 8579, 1630, 30630, 25407, 13, 3639, 584, 1205, 527, 69010, 8336, 13171, 315, 24944, 2875, 3177, 66557, 304, 11295, 50787, 13, 1115, 706, 311, 387, 4529, 1139, 18361, 2391, 3938, 69010, 2592, 4500, 1210, 3161, 1202, 7354, 1242, 56, 20198, 14899, 14234, 2447, 11, 279, 473, 57, 33, 374, 6968, 1120, 279, 1314, 86358, 13, 220, 128257, 198 ]

1,936

[ { "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 Each of us has a personal narrative: a story that defines us, and one that we tell about ourselves to our inner and outer worlds. A strong sense of identity is rooted in a personal narrative that has coherence and correspondence (Conway in J Mem Lang 53:594–628, 2005 ): coherence in the sense that the story we tell is consistent with and supportive of our current version of ‘self’; and correspondence in the sense that the story reflects the contents of autobiographical memory and the meaning of our experiences. These goals are achieved by a reciprocal interaction of autobiographical memory and the self, in which memories consistent with the self-image are reinforced, in turn strengthening the self-image they reflect. Thus, personal narratives depend crucially on the malleable nature of autobiographical memory: a strong sense of self requires that one remember what matters, and forget what does not. Today, anyone who is active online generates a highly detailed, ever—expanding, and permanent digital biographical ‘memory’—memory that identifies where we go, what we say, who we see, and what we do in increasing detail as our physical lives become more and more enmeshed with electronic devices capable of recording our communications, online activities, movements, and even bodily functions. This paper explores the consequences of this digital record for identity, arguing that it presents a challenge to our ability to construct our own personal narratives–narratives that are central to a sense of ‘self’. In the end, the ‘right to be forgotten’ may be, above all else, a psychological necessity that is core to identity—and therefore a value that we must ensure is protected. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes In 1994, Ulrich Neisser and Robyn Fivush edited a book entitled “The Remembering Self: Construction and Accuracy in the Self-Narrative”. In his chapter on the truth and falsehood of self-narratives (Neisser 1994 ), Neisser remarks: “the ordinary course of life rarely generates objective records” (p. 2). When that statement was made, it was undoubtedly accurate. Today, however, anyone who ventures onto the Internet leaves behind an almost incomprehensibly detailed biographical archive, consisting of personal information that individuals willingly and knowingly provide about themselves, information about them that others contribute, and digital traces of online actions that are created automatically, without direct involvement and sometimes without user knowledge, by the software and devices with which we interact. Thus rather than ‘rarely’ generating objective records, the ‘ordinary course of life’ today generates vast array of detailed, articulated, and deeply informative records: a ‘digital shadow’ that combines data created by users themselves (‘digital footprints’) with data created by others about them (‘data shadows’: Koops 2011 ). This paper explores the implications of digital shadows for identity, ultimately arguing is that our ability to construct and maintain our own identities is threatened by digital systems that ‘remember’ everything about us: thus, there is value in, and a need for, forgetting and being forgotten. Identity, narrative, and memory Personal narratives are important for, if not equivalent to, identity (McAdams 1992 , 1996 ). The narratives we tell to define ourselves draw selectively and strategically from our individual histories to constitute stories that demonstrate both coherence and correspondence (Conway 2005 ): coherence in the sense that the story is consistent with and supportive of the current version of ‘self’; and correspondence in the sense that the story reflects the content and meaning of autobiographical memory. These goals are achieved by a reciprocal interaction of autobiographical memory and the self, in which memories consistent with the self-image are reinforced, in turn strengthening the (typically favourable) self-image that those memories reflect (McAdams and McLean 2013 ). Lived experience reinforces the notion that memory is critical to identity: for example, conditions that lead to impairment in autobiographical memory (e.g., Alzeheimer’s disease) are said to lead to “loss of self” (Addis and Tippett 2004 ). Faced with the specter of a self that disappears as life memories erode, it is tempting to conclude that a flawless biographical memory is the optimal state. Research on hyperthymesia , or ‘unusual autobiographical memory’ (Parker et al. 2006 ), however, suggests otherwise, and those living with the condition describe their memories as ‘tyrannical’. By virtue of their inescapable accuracy and completeness, these memories compromise the ability to construct and recraft integrated personal narratives that tell us, and others, ‘who we are’ (McAdams 2003 ; Price and Davis 2008 ). It appears, then, that forgetting is as crucial to identity as is remembering. Indeed, Connerton ( 2008 ) identifies forgetting ‘ constitutive in the formation of a new identity’ as one of eight forms of forgetting, remarking that ‘what is allowed to be forgotten provides living space for present projects’ (p. 63). Connerton is explicit in his assertion that forgetting is critical to the ongoing project of the self—we cannot grow, or change, if we are too closely and unwaveringly held to the details of our pasts. To this end, we are aided by biological memories—mine of my own history, and yours of me—that are much less than perfect records of a lived life. Biological memories are selective—what is retained is only what is relevant at the time. They are also prone to disruption and decay—those memories that are rehearsed or revisited tend to persist, while others that are not recalled tend to fade over time. Biological memory is not an eidetic reflection of the past. Digital shadows and the problems of the ‘perfect’ record In comparison to biological memories, digital records are both complete and permanent, and the digital shadow therefore has these same characteristics. Some of the more evident contributors to the digital shadow are social network profiles, populated by users with personal details that include name, birth date, relationship status, preferences, activities, photographs, friends and acquaintances, etc. This self-initiated online archive is augmented by the information provided by others: photographs, posted by friends and tagged and indexed so that they are associated with a personal profile, widely", "role": "user" }, { "content": "We are built to forget – it is a psychological necessity. But in a social media world that captures – and, more importantly, remembers – everything we say and do, forgetting is becoming a thing of the past. If we lose the ability to forget our past, we lose the ability to construct our own stories – a part of what it means to be human, warned one Western researcher. \"We need to gloss, forget, emphasise. We need to be allowed to forget,\" said Jacquelyn Burkell, Assistant Dean and Research Associate Professor in the Faculty of Information and Media Studies. In \"Remembering Me: Big Data, Individual Identity, and the Psychological Necessity of Forgetting,\" an article she recently published in Ethics and Information Technology, Burkell argues our social media posts, photos, updates and 'check-ins' are creating a permanent digital biography. This biography doesn't allow us to forget and move on from our past, and subsequently, it interferes with our own concept of the self. \"Anyone who ventures onto the Internet leaves behind an almost incomprehensibly detailed biographical archive, consisting of personal information individuals willingly and knowingly provide about themselves,\" she said, adding information collected online without our consent and knowledge also adds to our digital biography. When we share our day-to-day events, musings, photos and the like, we allow our past to be permanently documented online. This abundance of shared memories that can never be lost may seem like the perfect archive, allowing us to remember everything. But for Burkell, a perfect memory has a downside. It gets in the way of us knowing who we are and shaping our own sense of self. Self and memory are undoubtedly linked, Burkell said. Consider Alzheimer's disease; those who suffer from it are said to lose themselves due to a loss of memory. On the flip side, individuals who have a perfect autobiographical memory, a condition called 'hyperthymesia,' also indicate there is a link between self and memory as they report not having a clear sense of self – particularly because they can't forget anything. Think of it this way: You're on Facebook. You log in and see an \"On This Day\" alert. It shows you what you were doing, on this day, only a few years ago. While the alert might serve as a welcome memento, it may also disrupt your current sense of self, leaving you thinking, 'I did that? That's not me. I'd never do that today.' For Burkell, that which is forgotten is as necessary as what is remembered when constructing the self. The key issue is what she calls the \"digital shadow\" or the \"perfect snapshot\" of our lives which we share through our online activities. In an age of social media, we are able to preserve our every memory in perfect detail through various multimedia. The web is even capable of unknowingly tracking and documenting our movements online, providing a detailed archive of things we've said, sites we've visited, links we click and what we \"like.\" \"The point is,\" Burkell said, \"forgetting some aspects of individual history is necessary to identity – and the continued existence of a perfect and complete history could pose a challenge to this psychologically necessary function, if every detail I forget is retained in a digital archive, ready to remind me again of that which is no longer relevant to my identity.\" Burkell is not arguing every instance of 'perfect' memory is a problem. She distinguishes between historical information and what she calls \"lifelogging,\" or the active recording of a personal digital record, which does come with a risk of identity theft. She suggests we find ways of regulating our own social media, monitoring our accounts in the style of \"reputation management.\" However, Burkell calls this the tip of the iceberg. She considers solutions such as an \"expiry date\" on information, and even algorithmic changes modeled after biological memory. In short, we must find ways to re-establish balance in what is remembered and what it forgotten, in order to allow for an integrated life story and a whole human identity. ", "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 Each of us has a personal narrative: a story that defines us, and one that we tell about ourselves to our inner and outer worlds. A strong sense of identity is rooted in a personal narrative that has coherence and correspondence (Conway in J Mem Lang 53:594–628, 2005 ): coherence in the sense that the story we tell is consistent with and supportive of our current version of ‘self’; and correspondence in the sense that the story reflects the contents of autobiographical memory and the meaning of our experiences. These goals are achieved by a reciprocal interaction of autobiographical memory and the self, in which memories consistent with the self-image are reinforced, in turn strengthening the self-image they reflect. Thus, personal narratives depend crucially on the malleable nature of autobiographical memory: a strong sense of self requires that one remember what matters, and forget what does not. Today, anyone who is active online generates a highly detailed, ever—expanding, and permanent digital biographical ‘memory’—memory that identifies where we go, what we say, who we see, and what we do in increasing detail as our physical lives become more and more enmeshed with electronic devices capable of recording our communications, online activities, movements, and even bodily functions. This paper explores the consequences of this digital record for identity, arguing that it presents a challenge to our ability to construct our own personal narratives–narratives that are central to a sense of ‘self’. In the end, the ‘right to be forgotten’ may be, above all else, a psychological necessity that is core to identity—and therefore a value that we must ensure is protected. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes In 1994, Ulrich Neisser and Robyn Fivush edited a book entitled “The Remembering Self: Construction and Accuracy in the Self-Narrative”. In his chapter on the truth and falsehood of self-narratives (Neisser 1994 ), Neisser remarks: “the ordinary course of life rarely generates objective records” (p. 2). When that statement was made, it was undoubtedly accurate. Today, however, anyone who ventures onto the Internet leaves behind an almost incomprehensibly detailed biographical archive, consisting of personal information that individuals willingly and knowingly provide about themselves, information about them that others contribute, and digital traces of online actions that are created automatically, without direct involvement and sometimes without user knowledge, by the software and devices with which we interact. Thus rather than ‘rarely’ generating objective records, the ‘ordinary course of life’ today generates vast array of detailed, articulated, and deeply informative records: a ‘digital shadow’ that combines data created by users themselves (‘digital footprints’) with data created by others about them (‘data shadows’: Koops 2011 ). This paper explores the implications of digital shadows for identity, ultimately arguing is that our ability to construct and maintain our own identities is threatened by digital systems that ‘remember’ everything about us: thus, there is value in, and a need for, forgetting and being forgotten. Identity, narrative, and memory Personal narratives are important for, if not equivalent to, identity (McAdams 1992 , 1996 ). The narratives we tell to define ourselves draw selectively and strategically from our individual histories to constitute stories that demonstrate both coherence and correspondence (Conway 2005 ): coherence in the sense that the story is consistent with and supportive of the current version of ‘self’; and correspondence in the sense that the story reflects the content and meaning of autobiographical memory. These goals are achieved by a reciprocal interaction of autobiographical memory and the self, in which memories consistent with the self-image are reinforced, in turn strengthening the (typically favourable) self-image that those memories reflect (McAdams and McLean 2013 ). Lived experience reinforces the notion that memory is critical to identity: for example, conditions that lead to impairment in autobiographical memory (e.g., Alzeheimer’s disease) are said to lead to “loss of self” (Addis and Tippett 2004 ). Faced with the specter of a self that disappears as life memories erode, it is tempting to conclude that a flawless biographical memory is the optimal state. Research on hyperthymesia , or ‘unusual autobiographical memory’ (Parker et al. 2006 ), however, suggests otherwise, and those living with the condition describe their memories as ‘tyrannical’. By virtue of their inescapable accuracy and completeness, these memories compromise the ability to construct and recraft integrated personal narratives that tell us, and others, ‘who we are’ (McAdams 2003 ; Price and Davis 2008 ). It appears, then, that forgetting is as crucial to identity as is remembering. Indeed, Connerton ( 2008 ) identifies forgetting ‘ constitutive in the formation of a new identity’ as one of eight forms of forgetting, remarking that ‘what is allowed to be forgotten provides living space for present projects’ (p. 63). Connerton is explicit in his assertion that forgetting is critical to the ongoing project of the self—we cannot grow, or change, if we are too closely and unwaveringly held to the details of our pasts. To this end, we are aided by biological memories—mine of my own history, and yours of me—that are much less than perfect records of a lived life. Biological memories are selective—what is retained is only what is relevant at the time. They are also prone to disruption and decay—those memories that are rehearsed or revisited tend to persist, while others that are not recalled tend to fade over time. Biological memory is not an eidetic reflection of the past. Digital shadows and the problems of the ‘perfect’ record In comparison to biological memories, digital records are both complete and permanent, and the digital shadow therefore has these same characteristics. Some of the more evident contributors to the digital shadow are social network profiles, populated by users with personal details that include name, birth date, relationship status, preferences, activities, photographs, friends and acquaintances, etc. This self-initiated online archive is augmented by the information provided by others: photographs, posted by friends and tagged and indexed so that they are associated with a personal profile, widely<|im_end|> <|im_start|>assistant We are built to forget – it is a psychological necessity. But in a social media world that captures – and, more importantly, remembers – everything we say and do, forgetting is becoming a thing of the past. If we lose the ability to forget our past, we lose the ability to construct our own stories – a part of what it means to be human, warned one Western researcher. "We need to gloss, forget, emphasise. We need to be allowed to forget," said Jacquelyn Burkell, Assistant Dean and Research Associate Professor in the Faculty of Information and Media Studies. In "Remembering Me: Big Data, Individual Identity, and the Psychological Necessity of Forgetting," an article she recently published in Ethics and Information Technology, Burkell argues our social media posts, photos, updates and 'check-ins' are creating a permanent digital biography. This biography doesn't allow us to forget and move on from our past, and subsequently, it interferes with our own concept of the self. "Anyone who ventures onto the Internet leaves behind an almost incomprehensibly detailed biographical archive, consisting of personal information individuals willingly and knowingly provide about themselves," she said, adding information collected online without our consent and knowledge also adds to our digital biography. When we share our day-to-day events, musings, photos and the like, we allow our past to be permanently documented online. This abundance of shared memories that can never be lost may seem like the perfect archive, allowing us to remember everything. But for Burkell, a perfect memory has a downside. It gets in the way of us knowing who we are and shaping our own sense of self. Self and memory are undoubtedly linked, Burkell said. Consider Alzheimer's disease; those who suffer from it are said to lose themselves due to a loss of memory. On the flip side, individuals who have a perfect autobiographical memory, a condition called 'hyperthymesia,' also indicate there is a link between self and memory as they report not having a clear sense of self – particularly because they can't forget anything. Think of it this way: You're on Facebook. You log in and see an "On This Day" alert. It shows you what you were doing, on this day, only a few years ago. While the alert might serve as a welcome memento, it may also disrupt your current sense of self, leaving you thinking, 'I did that? That's not me. I'd never do that today.' For Burkell, that which is forgotten is as necessary as what is remembered when constructing the self. The key issue is what she calls the "digital shadow" or the "perfect snapshot" of our lives which we share through our online activities. In an age of social media, we are able to preserve our every memory in perfect detail through various multimedia. The web is even capable of unknowingly tracking and documenting our movements online, providing a detailed archive of things we've said, sites we've visited, links we click and what we "like." "The point is," Burkell said, "forgetting some aspects of individual history is necessary to identity – and the continued existence of a perfect and complete history could pose a challenge to this psychologically necessary function, if every detail I forget is retained in a digital archive, ready to remind me again of that which is no longer relevant to my identity." Burkell is not arguing every instance of 'perfect' memory is a problem. She distinguishes between historical information and what she calls "lifelogging," or the active recording of a personal digital record, which does come with a risk of identity theft. She suggests we find ways of regulating our own social media, monitoring our accounts in the style of "reputation management." However, Burkell calls this the tip of the iceberg. She considers solutions such as an "expiry date" on information, and even algorithmic changes modeled after biological memory. In short, we must find ways to re-establish balance in what is remembered and what it forgotten, in order to allow for an integrated life story and a whole human identity. <|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 experimental violation of Bell inequalities using space-like separated measurements precludes the explanation of quantum correlations through causal influences propagating at subluminal speed 1 , 2 . Yet, any such experimental violation could always be explained in principle through models based on hidden influences propagating at a finite speed v > c , provided v is large enough 3 , 4 . Here, we show that for any finite speed v with , such models predict correlations that can be exploited for faster-than-light communication. This superluminal communication does not require access to any hidden physical quantities, but only the manipulation of measurement devices at the level of our present-day description of quantum experiments. Hence, assuming the impossibility of using non-local correlations for superluminal communication, we exclude any possible explanation of quantum correlations in terms of influences propagating at any finite speed. Our result uncovers a new aspect of the complex relationship between multipartite quantum non-locality and the impossibility of signalling. Main Correlations cry out for explanation 1 . Our intuitive understanding of correlations between events relies on the concept of causal influences, either relating directly the events, such as the position of the moon causing the tides, or involving a past common cause, such as seeing a flash and hearing the thunder when a lightning strikes. Importantly, we expect the chain of causal relations to satisfy a principle of continuity, that is, the idea that the physical carriers of causal influences propagate continuously through space at a finite speed. Given the theory of relativity, we expect moreover the speed of causal influences to be bounded by the speed of light. The correlations observed in certain quantum experiments call into question this viewpoint. When measurements are performed on two entangled quantum particles separated far apart from each other, such as in an Einstein–Podolsky–Rosen 5 type experiment, the measurement results of one particle are found to be correlated to that of the other particle. Bell showed that if these correlated values were due to past common causes, then they would necessarily satisfy a series of inequalities 1 . However, theory predicts and experiments confirm that these inequalities are violated 2 , thus excluding any past common cause type of explanation. Moreover, as the measurement events can be space-like separated 6 , 7 , 8 , any influence-type explanation must involve superluminal influences 9 , in contradiction with the intuitive notion of relativistic causality 10 . This non-local connection between distant particles represents a source of tension between quantum theory and relativity 10 , 11 ; however, it does not put the two theories in direct conflict owing to the no-signalling property of quantum correlations. This property guarantees that spatially separated observers in an Einstein, Podolsky and Rosen-type experiment cannot use their measurement choices and outcomes to communicate with one another. The complex relationship between quantum non-locality and relativity has been the subject of intense scrutiny 9 , 10 , 11 , 12 , but less attention has been paid to the fact that quantum non-locality seems to invalidate not only the intuitive notion of relativistic causality, but more fundamentally the idea that correlations can be explained by causal influences propagating continuously in space. Indeed, according to the standard textbook description, quantum correlations between distant particles, and hence the violation of Bell inequalities, can in principle be achieved instantaneously and independently of the spatial separation between the particles. Any explanation of quantum correlations using hypothetical influences would therefore require that they propagate at speed , that is jump instantaneously from one location to another as in real actions at a distance. Is such an infinite speed a necessary ingredient to account for the correlations observed in nature or could a finite speed v , recovering a principle of continuity, be sufficient? In particular, could an underlying theory with a limit v on the speed of causal influences reproduce correctly the quantum predictions, at least when distant quantum systems are within the range of finite-speed causal influences 13 ? Obviously, any such theory would cease to violate Bell inequalities beyond some range determined by the finite speed v . At first, this hypothesis seems untestable. Indeed, provided that v is large enough, any model based on finite-speed (hidden) influences can always be made compatible with all experimental results observed so far. It thus seems as if the best that one could hope for is to put lower bounds on v by testing the violation of Bell inequalities with systems that are further apart and better synchronized 3 , 4 . Here we show that there is a fundamental reason why influences propagating at a finite speed v may not account for the non-locality of quantum theory: all such models give, for any v > c , predictions that can be used for faster-than-light communication. Importantly, our argument does not require the observation of non-local correlations between simultaneous or arbitrarily distant events and is thus amenable to experimental tests. Our results answer a long-standing question on the plausibility of finite-speed models first raised in refs 14 , 15 . Progress on this problem was recently made in ref. 16 , where a conclusion with a similar flavour was obtained, but not for quantum theory. Technically, our approach is independent and different from the one in ref. 16 , which relies on transitivity of non-locality, a concept that has not yet found any application in quantum theory. We derive our results assuming that the speed of causal influences v is defined with respect to a privileged reference frame (or a particular foliation of spacetime into space-like hyperplanes). It should be stressed that although the assumption of a privileged frame is not in line with the spirit of relativity, there is also no empirical evidence implying its absence. In fact, even in a perfectly Lorentz-invariant theory, there can be natural preferred frames owing to the non-Lorentz-invariant distribution of matter—a well-known example of this is the reference frame in which the cosmic microwave background radiation seems to", "role": "user" }, { "content": "Physicists have proposed an experiment that could force us to make a choice between extremes to describe the behaviour of the Universe. The proposal comes from an international team of researchers from Switzerland, Belgium, Spain and Singapore, and is published today in Nature Physics. It is based on what the researchers call a 'hidden influence inequality'. This exposes how quantum predictions challenge our best understanding about the nature of space and time, Einstein's theory of relativity. \"We are interested in whether we can explain the funky phenomena we observe without sacrificing our sense of things happening smoothly in space and time,\" says Jean-Daniel Bancal, one of the researchers behind the new result, who carried out the research at the University of Geneva in Switzerland. He is now at the Centre for Quantum Technologies at the National University of Singapore. Excitingly, there is a real prospect of performing this test. The implications of quantum theory have been troubling physicists since the theory was invented in the early 20th Century. The problem is that quantum theory predicts bizarre behaviour for particles – such as two 'entangled' particles behaving as one even when far apart. This seems to violate our sense of cause and effect in space and time. Physicists call such behaviour 'nonlocal'. It was Einstein who first drew attention to the worrying implications of what he termed the \"spooky action at a distance\" predicted by quantum mechanics. Measure one in a pair of entangled atoms to have its magnetic 'spin' pointing up, for example, and quantum physics says the other can immediately be found pointing in the opposite direction, wherever it is and even when one could not predict beforehand which particle would do what. Common sense tells us that any such coordinated behaviour must result from one of two arrangements. First, it could be arranged in advance. The second option is that it could be synchronised by some signal sent between the particles. In the 1960s, John Bell came up with the first test to see whether entangled particles followed common sense. Specifically, a test of a 'Bell inequality' checks whether two particles' behaviour could have been based on prior arrangements. If measurements violate the inequality, pairs of particles are doing what quantum theory says: acting without any 'local hidden variables' directing their fate. Starting in the 1980s, experiments have found violations of Bell inequalities time and time again. Quantum theory was the winner, it seemed. However, conventional tests of Bell inequalities can never completely kill hope of a common sense story involving signals that don't flout the principles of relativity. That's why the researchers set out to devise a new inequality that would probe the role of signals directly. Experiments have already shown that if you want to invoke signals to explain things, the signals would have to be travelling faster than light – more than 10,000 times the speed of light, in fact. To those who know that Einstein's relativity sets the speed of light as a universal speed limit, the idea of signals travelling 10,000 times as fast as light already sets alarm bells ringing. However, physicists have a getout: such signals might stay as 'hidden influences' – useable for nothing, and thus not violating relativity. Only if the signals can be harnessed for faster-than-light communication do they openly contradict relativity. The new hidden influence inequality shows that the getout won't work when it comes to quantum predictions. To derive their inequality, which sets up a measurement of entanglement between four particles, the researchers considered what behaviours are possible for four particles that are connected by influences that stay hidden and that travel at some arbitrary finite speed. Mathematically (and mind-bogglingly), these constraints define an 80-dimensional object. The testable hidden influence inequality is the boundary of the shadow this 80-dimensional shape casts in 44 dimensions. The researchers showed that quantum predictions can lie outside this boundary, which means they are going against one of the assumptions. Outside the boundary, either the influences can't stay hidden, or they must have infinite speed. Experimental groups can already entangle four particles, so a test is feasible in the near future (though the precision of experiments will need to improve to make the difference measurable). Such a test will boil down to measuring a single number. In a Universe following the standard relativistic laws we are used to, 7 is the limit. If nature behaves as quantum physics predicts, the result can go up to 7.3. So if the result is greater than 7 – in other words, if the quantum nature of the world is confirmed – what will it mean? Here, there are two choices. On the one hand, there is the option to defy relativity and 'unhide' the influences, which means accepting faster-than-light communication. Relativity is a successful theory that researchers would not call into question lightly, so for many physicists this is seen as the most extreme possibility. The remaining option is to accept that influences must be infinitely fast – or that there exists some process that has an equivalent effect when viewed in our spacetime. The current test couldn't distinguish. Either way, it would mean that the Universe is fundamentally nonlocal, in the sense that every bit of the Universe can be connected to any other bit anywhere, instantly. That such connections are possible defies our everyday intuition and represents another extreme solution, but arguably preferable to faster-than-light communication. \"Our result gives weight to the idea that quantum correlations somehow arise from outside spacetime, in the sense that no story in space and time can describe them,\" says Nicolas Gisin, Professor at the University of Geneva, Switzerland, and member of the team. ", "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 experimental violation of Bell inequalities using space-like separated measurements precludes the explanation of quantum correlations through causal influences propagating at subluminal speed 1 , 2 . Yet, any such experimental violation could always be explained in principle through models based on hidden influences propagating at a finite speed v > c , provided v is large enough 3 , 4 . Here, we show that for any finite speed v with , such models predict correlations that can be exploited for faster-than-light communication. This superluminal communication does not require access to any hidden physical quantities, but only the manipulation of measurement devices at the level of our present-day description of quantum experiments. Hence, assuming the impossibility of using non-local correlations for superluminal communication, we exclude any possible explanation of quantum correlations in terms of influences propagating at any finite speed. Our result uncovers a new aspect of the complex relationship between multipartite quantum non-locality and the impossibility of signalling. Main Correlations cry out for explanation 1 . Our intuitive understanding of correlations between events relies on the concept of causal influences, either relating directly the events, such as the position of the moon causing the tides, or involving a past common cause, such as seeing a flash and hearing the thunder when a lightning strikes. Importantly, we expect the chain of causal relations to satisfy a principle of continuity, that is, the idea that the physical carriers of causal influences propagate continuously through space at a finite speed. Given the theory of relativity, we expect moreover the speed of causal influences to be bounded by the speed of light. The correlations observed in certain quantum experiments call into question this viewpoint. When measurements are performed on two entangled quantum particles separated far apart from each other, such as in an Einstein–Podolsky–Rosen 5 type experiment, the measurement results of one particle are found to be correlated to that of the other particle. Bell showed that if these correlated values were due to past common causes, then they would necessarily satisfy a series of inequalities 1 . However, theory predicts and experiments confirm that these inequalities are violated 2 , thus excluding any past common cause type of explanation. Moreover, as the measurement events can be space-like separated 6 , 7 , 8 , any influence-type explanation must involve superluminal influences 9 , in contradiction with the intuitive notion of relativistic causality 10 . This non-local connection between distant particles represents a source of tension between quantum theory and relativity 10 , 11 ; however, it does not put the two theories in direct conflict owing to the no-signalling property of quantum correlations. This property guarantees that spatially separated observers in an Einstein, Podolsky and Rosen-type experiment cannot use their measurement choices and outcomes to communicate with one another. The complex relationship between quantum non-locality and relativity has been the subject of intense scrutiny 9 , 10 , 11 , 12 , but less attention has been paid to the fact that quantum non-locality seems to invalidate not only the intuitive notion of relativistic causality, but more fundamentally the idea that correlations can be explained by causal influences propagating continuously in space. Indeed, according to the standard textbook description, quantum correlations between distant particles, and hence the violation of Bell inequalities, can in principle be achieved instantaneously and independently of the spatial separation between the particles. Any explanation of quantum correlations using hypothetical influences would therefore require that they propagate at speed , that is jump instantaneously from one location to another as in real actions at a distance. Is such an infinite speed a necessary ingredient to account for the correlations observed in nature or could a finite speed v , recovering a principle of continuity, be sufficient? In particular, could an underlying theory with a limit v on the speed of causal influences reproduce correctly the quantum predictions, at least when distant quantum systems are within the range of finite-speed causal influences 13 ? Obviously, any such theory would cease to violate Bell inequalities beyond some range determined by the finite speed v . At first, this hypothesis seems untestable. Indeed, provided that v is large enough, any model based on finite-speed (hidden) influences can always be made compatible with all experimental results observed so far. It thus seems as if the best that one could hope for is to put lower bounds on v by testing the violation of Bell inequalities with systems that are further apart and better synchronized 3 , 4 . Here we show that there is a fundamental reason why influences propagating at a finite speed v may not account for the non-locality of quantum theory: all such models give, for any v > c , predictions that can be used for faster-than-light communication. Importantly, our argument does not require the observation of non-local correlations between simultaneous or arbitrarily distant events and is thus amenable to experimental tests. Our results answer a long-standing question on the plausibility of finite-speed models first raised in refs 14 , 15 . Progress on this problem was recently made in ref. 16 , where a conclusion with a similar flavour was obtained, but not for quantum theory. Technically, our approach is independent and different from the one in ref. 16 , which relies on transitivity of non-locality, a concept that has not yet found any application in quantum theory. We derive our results assuming that the speed of causal influences v is defined with respect to a privileged reference frame (or a particular foliation of spacetime into space-like hyperplanes). It should be stressed that although the assumption of a privileged frame is not in line with the spirit of relativity, there is also no empirical evidence implying its absence. In fact, even in a perfectly Lorentz-invariant theory, there can be natural preferred frames owing to the non-Lorentz-invariant distribution of matter—a well-known example of this is the reference frame in which the cosmic microwave background radiation seems to<|im_end|> <|im_start|>assistant Physicists have proposed an experiment that could force us to make a choice between extremes to describe the behaviour of the Universe. The proposal comes from an international team of researchers from Switzerland, Belgium, Spain and Singapore, and is published today in Nature Physics. It is based on what the researchers call a 'hidden influence inequality'. This exposes how quantum predictions challenge our best understanding about the nature of space and time, Einstein's theory of relativity. "We are interested in whether we can explain the funky phenomena we observe without sacrificing our sense of things happening smoothly in space and time," says Jean-Daniel Bancal, one of the researchers behind the new result, who carried out the research at the University of Geneva in Switzerland. He is now at the Centre for Quantum Technologies at the National University of Singapore. Excitingly, there is a real prospect of performing this test. The implications of quantum theory have been troubling physicists since the theory was invented in the early 20th Century. The problem is that quantum theory predicts bizarre behaviour for particles – such as two 'entangled' particles behaving as one even when far apart. This seems to violate our sense of cause and effect in space and time. Physicists call such behaviour 'nonlocal'. It was Einstein who first drew attention to the worrying implications of what he termed the "spooky action at a distance" predicted by quantum mechanics. Measure one in a pair of entangled atoms to have its magnetic 'spin' pointing up, for example, and quantum physics says the other can immediately be found pointing in the opposite direction, wherever it is and even when one could not predict beforehand which particle would do what. Common sense tells us that any such coordinated behaviour must result from one of two arrangements. First, it could be arranged in advance. The second option is that it could be synchronised by some signal sent between the particles. In the 1960s, John Bell came up with the first test to see whether entangled particles followed common sense. Specifically, a test of a 'Bell inequality' checks whether two particles' behaviour could have been based on prior arrangements. If measurements violate the inequality, pairs of particles are doing what quantum theory says: acting without any 'local hidden variables' directing their fate. Starting in the 1980s, experiments have found violations of Bell inequalities time and time again. Quantum theory was the winner, it seemed. However, conventional tests of Bell inequalities can never completely kill hope of a common sense story involving signals that don't flout the principles of relativity. That's why the researchers set out to devise a new inequality that would probe the role of signals directly. Experiments have already shown that if you want to invoke signals to explain things, the signals would have to be travelling faster than light – more than 10,000 times the speed of light, in fact. To those who know that Einstein's relativity sets the speed of light as a universal speed limit, the idea of signals travelling 10,000 times as fast as light already sets alarm bells ringing. However, physicists have a getout: such signals might stay as 'hidden influences' – useable for nothing, and thus not violating relativity. Only if the signals can be harnessed for faster-than-light communication do they openly contradict relativity. The new hidden influence inequality shows that the getout won't work when it comes to quantum predictions. To derive their inequality, which sets up a measurement of entanglement between four particles, the researchers considered what behaviours are possible for four particles that are connected by influences that stay hidden and that travel at some arbitrary finite speed. Mathematically (and mind-bogglingly), these constraints define an 80-dimensional object. The testable hidden influence inequality is the boundary of the shadow this 80-dimensional shape casts in 44 dimensions. The researchers showed that quantum predictions can lie outside this boundary, which means they are going against one of the assumptions. Outside the boundary, either the influences can't stay hidden, or they must have infinite speed. Experimental groups can already entangle four particles, so a test is feasible in the near future (though the precision of experiments will need to improve to make the difference measurable). Such a test will boil down to measuring a single number. In a Universe following the standard relativistic laws we are used to, 7 is the limit. If nature behaves as quantum physics predicts, the result can go up to 7.3. So if the result is greater than 7 – in other words, if the quantum nature of the world is confirmed – what will it mean? Here, there are two choices. On the one hand, there is the option to defy relativity and 'unhide' the influences, which means accepting faster-than-light communication. Relativity is a successful theory that researchers would not call into question lightly, so for many physicists this is seen as the most extreme possibility. The remaining option is to accept that influences must be infinitely fast – or that there exists some process that has an equivalent effect when viewed in our spacetime. The current test couldn't distinguish. Either way, it would mean that the Universe is fundamentally nonlocal, in the sense that every bit of the Universe can be connected to any other bit anywhere, instantly. That such connections are possible defies our everyday intuition and represents another extreme solution, but arguably preferable to faster-than-light communication. "Our result gives weight to the idea that quantum correlations somehow arise from outside spacetime, in the sense that no story in space and time can describe them," says Nicolas Gisin, Professor at the University of Geneva, Switzerland, and member of the team. <|im_end|>

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2,375

[ { "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 Synaptic loss, plaques and neurofibrillary tangles are viewed as hallmarks of Alzheimer’s disease (AD). This study investigated synaptic markers in neocortical Brodmann area 9 (BA9) samples from 171 subjects with and without AD at different levels of cognitive impairment. The expression levels of vesicular glutamate transporters (VGLUT1&2), glutamate uptake site (EAAT2), post-synaptic density protein of 95 kD (PSD95), vesicular GABA/glycine transporter (VIAAT), somatostatin (som), synaptophysin and choline acetyl transferase (ChAT) were evaluated. VGLUT2 and EAAT2 were unaffected by dementia. The VGLUT1, PSD95, VIAAT, som, ChAT and synaptophysin expression levels significantly decreased as dementia progressed. The maximal decrease varied between 12% (synaptophysin) and 42% (som). VGLUT1 was more strongly correlated with dementia than all of the other markers (polyserial correlation = −0.41). Principal component analysis using these markers was unable to differentiate the CDR groups from one another. Therefore, the status of the major synaptic markers in BA9 does not seem to be linked to the cognitive status of AD patients. The findings of this study suggest that the loss of synaptic markers in BA9 is a late event that is only weakly related to AD dementia. Introduction Alzheimer’s disease (AD) is characterized by a progressive and severe loss of cognitive abilities. Accumulation of both amyloid beta-peptide (Aβ) deposits in the form of plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein are morphological hallmarks of AD. The pathogenic roles of Aβ and tau are not clearly understood and are still a matter of controversy 1 , 2 . In addition, heterogeneous and area-specific neuronal and synaptic loss is described in AD 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . A recent meta-analysis reported that the severity of cognitive impairment often correlates with the extent of the synaptic loss 12 . These observations suggest that synaptic loss is a common marker of multiple types of dementia across brain regions 13 , 14 . Accordingly, AD must have severe effects on the delicate neurochemical balance in brain areas such as the cerebral cortex. Identifying the vulnerability of various neurotransmitter systems in AD could lead to the identification of novel pharmacotherapeutic strategies that aim to alleviate dementia. Glutamate is the major excitatory neurotransmitter in the brain that is particularly relevant in the cerebral cortex. The fate of glutamatergic neurotransmission in AD has been the subject of numerous reports. In particular, excessive glutamatergic transmission and its accompanying excitotoxicity is often viewed as a key player in the neuronal loss associated with AD and other neurodegenerative pathologies 15 , 16 , 17 , 18 , 19 . If excitotoxicity is causal in AD, then glutamatergic transmission must increase at some point in AD. This has been reported in animal models following Aβ application 15 , 17 . Glutamatergic synaptic activity is tightly controlled by excitatory amino acid transporters (EAATs 18 , 20 ). Among the 5 high-affinity glutamate transporters, the major subtype, EAAT2, is mainly expressed in astrocytes 21 , 22 . EAAT2 is responsible for 90% of the clearance of glutamate from the extracellular space (for review see ref. 21 ). Consistent with the excitotoxicity hypothesis of AD, glutamate uptake and EAAT expression are reported to be significantly decreased in AD 23 , 24 , 25 . However, other studies have indicated a decreased density of cortical vesicular glutamate transporters (VGLUTs) in AD 26 and a mouse model of amyloidosis 27 , 28 . VGLUTs are pivotal pre-synaptic markers of glutamatergic neurotransmission. VGLUT1 and VGLUT2, the 2 major subtypes, are expressed in cortical and subcortical glutamatergic neurons 29 , and the expression levels of both have been found to decline in AD 23 , 26 , 28 , 30 . Furthermore, in neocortical Brodmann area 9 (BA9), the loss of VGLUT1 strongly correlates with cognitive decline 30 . These data suggest that the disease progression occurs in two stages. During the initial steps of the pathology, increased glutamatergic transmission leads to excitotoxicity and neuronal degeneration. This is followed by a decrease in glutamatergic transmission in AD patients 31 . However, this view is far from having been clearly established in human patients. Furthermore, it is not clear whether and to what extent the density of synaptic markers can be linked to synaptic loss of function 32 , 33 , 34 , 35 . For instance, it was recently reported that a massive loss of VGLUT3 (−80%) has only a limited impact on the function of VGLUT3-postive synapses 36 . The status of both synaptic and neurotransmission markers in AD, as well as in animal models, has been thoroughly investigated. Cholinergic 37 , as well as somatostatin-positive GABAergic interneurons 38 , 39 , have been reported to be centrally involved in AD and cognitive decline. The loss of cortical cholinergic innervation is considered one hallmark feature of AD 40 , 41 , 42 and was tentatively linked to attentional and cognitive decline that are associated with the pathology 43 , 44 . In animal models, the loss of cholinergic neurons in the basal forebrain was shown to be secondary to intraneuronal Aβ accumulation and glutamate excitotoxicity 15 , 17 , 45 , 46 . For decades, GABAergic transmission was considered to be preserved in AD compared to cholinergic and glutamatergic transmission. However, recent animal studies revealed the importance of the GABA/glutamate balance in the pathogenesis of AD 47 , 48 , 49 , 50 . These findings implied that to prevent or treat the dementia associated with AD, synaptic functions should be restored. Furthermore, these data suggest that synaptic proteins can be used as potential biomarkers of the progression of dementia. It is, therefore, of paramount importance to confirm or invalidate these findings. As highlighted by the meta-analysis of de Wilde and colleagues 12 , most studies supporting these conclusions were performed with relatively small sample sizes (on average, n = 10 controls and n = 10 AD patients). The present study sought to address this issue by conducting a thorough post-mortem assessment of", "role": "user" }, { "content": "Frequently encountered in the elderly, Alzheimer's is considered a neurodegenerative disease, which means that it is accompanied by a significant, progressive loss of neurons and their nerve endings, or synapses. A joint French and Canadian study published in Scientific Reports now challenges this view. Conducted among more than 170 subjects at various stages of Alzheimer's disease, the study by the team led by Salah El Mestikawy (Douglas Mental Health University Institute, Canada) and Stéphanie Daumas (Université Pierre et Marie Curie, France) has shown instead that the disease is accompanied by a minor decline in neuronal and synaptic markers. \"Much to our surprise, in studying the fate of eight neuronal and synaptic markers in our subjects' prefrontal cortices, we only observed very minor neuronal and synaptic losses. Our study therefore suggests that, contrary to what was believed, neuronal and synaptic loss is relatively limited in Alzheimer's disease. This is a radical change in thinking,\" explains El Mestikawy, an associate professor at McGill University. The scientists also attempted to correlate all these minor synaptic losses with the subjects' level of dementia. Their results show that the declines in synaptic biomarkers had little impact on the participants' cognitive skills. Towards other therapies The study implicitly suggests that dementia is associated with a synaptic dysfunction rather than the disappearance of synapses from the patient's cortex. Identifying this dysfunction could lead to the development of effective treatments for this disease. \"Until now, therapeutic interventions have been aimed at slowing synaptic destruction. Based on our study, we are going to have to change our therapeutic approach,\" says El Mestikawy. According to the Alzheimer Society of Canada, 564,000 Canadians currently have Alzheimer's disease or another form of dementia. The figure will be 937,000 within 15 years. Presently, there is no truly effective treatment for this 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 Synaptic loss, plaques and neurofibrillary tangles are viewed as hallmarks of Alzheimer’s disease (AD). This study investigated synaptic markers in neocortical Brodmann area 9 (BA9) samples from 171 subjects with and without AD at different levels of cognitive impairment. The expression levels of vesicular glutamate transporters (VGLUT1&2), glutamate uptake site (EAAT2), post-synaptic density protein of 95 kD (PSD95), vesicular GABA/glycine transporter (VIAAT), somatostatin (som), synaptophysin and choline acetyl transferase (ChAT) were evaluated. VGLUT2 and EAAT2 were unaffected by dementia. The VGLUT1, PSD95, VIAAT, som, ChAT and synaptophysin expression levels significantly decreased as dementia progressed. The maximal decrease varied between 12% (synaptophysin) and 42% (som). VGLUT1 was more strongly correlated with dementia than all of the other markers (polyserial correlation = −0.41). Principal component analysis using these markers was unable to differentiate the CDR groups from one another. Therefore, the status of the major synaptic markers in BA9 does not seem to be linked to the cognitive status of AD patients. The findings of this study suggest that the loss of synaptic markers in BA9 is a late event that is only weakly related to AD dementia. Introduction Alzheimer’s disease (AD) is characterized by a progressive and severe loss of cognitive abilities. Accumulation of both amyloid beta-peptide (Aβ) deposits in the form of plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein are morphological hallmarks of AD. The pathogenic roles of Aβ and tau are not clearly understood and are still a matter of controversy 1 , 2 . In addition, heterogeneous and area-specific neuronal and synaptic loss is described in AD 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . A recent meta-analysis reported that the severity of cognitive impairment often correlates with the extent of the synaptic loss 12 . These observations suggest that synaptic loss is a common marker of multiple types of dementia across brain regions 13 , 14 . Accordingly, AD must have severe effects on the delicate neurochemical balance in brain areas such as the cerebral cortex. Identifying the vulnerability of various neurotransmitter systems in AD could lead to the identification of novel pharmacotherapeutic strategies that aim to alleviate dementia. Glutamate is the major excitatory neurotransmitter in the brain that is particularly relevant in the cerebral cortex. The fate of glutamatergic neurotransmission in AD has been the subject of numerous reports. In particular, excessive glutamatergic transmission and its accompanying excitotoxicity is often viewed as a key player in the neuronal loss associated with AD and other neurodegenerative pathologies 15 , 16 , 17 , 18 , 19 . If excitotoxicity is causal in AD, then glutamatergic transmission must increase at some point in AD. This has been reported in animal models following Aβ application 15 , 17 . Glutamatergic synaptic activity is tightly controlled by excitatory amino acid transporters (EAATs 18 , 20 ). Among the 5 high-affinity glutamate transporters, the major subtype, EAAT2, is mainly expressed in astrocytes 21 , 22 . EAAT2 is responsible for 90% of the clearance of glutamate from the extracellular space (for review see ref. 21 ). Consistent with the excitotoxicity hypothesis of AD, glutamate uptake and EAAT expression are reported to be significantly decreased in AD 23 , 24 , 25 . However, other studies have indicated a decreased density of cortical vesicular glutamate transporters (VGLUTs) in AD 26 and a mouse model of amyloidosis 27 , 28 . VGLUTs are pivotal pre-synaptic markers of glutamatergic neurotransmission. VGLUT1 and VGLUT2, the 2 major subtypes, are expressed in cortical and subcortical glutamatergic neurons 29 , and the expression levels of both have been found to decline in AD 23 , 26 , 28 , 30 . Furthermore, in neocortical Brodmann area 9 (BA9), the loss of VGLUT1 strongly correlates with cognitive decline 30 . These data suggest that the disease progression occurs in two stages. During the initial steps of the pathology, increased glutamatergic transmission leads to excitotoxicity and neuronal degeneration. This is followed by a decrease in glutamatergic transmission in AD patients 31 . However, this view is far from having been clearly established in human patients. Furthermore, it is not clear whether and to what extent the density of synaptic markers can be linked to synaptic loss of function 32 , 33 , 34 , 35 . For instance, it was recently reported that a massive loss of VGLUT3 (−80%) has only a limited impact on the function of VGLUT3-postive synapses 36 . The status of both synaptic and neurotransmission markers in AD, as well as in animal models, has been thoroughly investigated. Cholinergic 37 , as well as somatostatin-positive GABAergic interneurons 38 , 39 , have been reported to be centrally involved in AD and cognitive decline. The loss of cortical cholinergic innervation is considered one hallmark feature of AD 40 , 41 , 42 and was tentatively linked to attentional and cognitive decline that are associated with the pathology 43 , 44 . In animal models, the loss of cholinergic neurons in the basal forebrain was shown to be secondary to intraneuronal Aβ accumulation and glutamate excitotoxicity 15 , 17 , 45 , 46 . For decades, GABAergic transmission was considered to be preserved in AD compared to cholinergic and glutamatergic transmission. However, recent animal studies revealed the importance of the GABA/glutamate balance in the pathogenesis of AD 47 , 48 , 49 , 50 . These findings implied that to prevent or treat the dementia associated with AD, synaptic functions should be restored. Furthermore, these data suggest that synaptic proteins can be used as potential biomarkers of the progression of dementia. It is, therefore, of paramount importance to confirm or invalidate these findings. As highlighted by the meta-analysis of de Wilde and colleagues 12 , most studies supporting these conclusions were performed with relatively small sample sizes (on average, n = 10 controls and n = 10 AD patients). The present study sought to address this issue by conducting a thorough post-mortem assessment of<|im_end|> <|im_start|>assistant Frequently encountered in the elderly, Alzheimer's is considered a neurodegenerative disease, which means that it is accompanied by a significant, progressive loss of neurons and their nerve endings, or synapses. A joint French and Canadian study published in Scientific Reports now challenges this view. Conducted among more than 170 subjects at various stages of Alzheimer's disease, the study by the team led by Salah El Mestikawy (Douglas Mental Health University Institute, Canada) and Stéphanie Daumas (Université Pierre et Marie Curie, France) has shown instead that the disease is accompanied by a minor decline in neuronal and synaptic markers. "Much to our surprise, in studying the fate of eight neuronal and synaptic markers in our subjects' prefrontal cortices, we only observed very minor neuronal and synaptic losses. Our study therefore suggests that, contrary to what was believed, neuronal and synaptic loss is relatively limited in Alzheimer's disease. This is a radical change in thinking," explains El Mestikawy, an associate professor at McGill University. The scientists also attempted to correlate all these minor synaptic losses with the subjects' level of dementia. Their results show that the declines in synaptic biomarkers had little impact on the participants' cognitive skills. Towards other therapies The study implicitly suggests that dementia is associated with a synaptic dysfunction rather than the disappearance of synapses from the patient's cortex. Identifying this dysfunction could lead to the development of effective treatments for this disease. "Until now, therapeutic interventions have been aimed at slowing synaptic destruction. Based on our study, we are going to have to change our therapeutic approach," says El Mestikawy. According to the Alzheimer Society of Canada, 564,000 Canadians currently have Alzheimer's disease or another form of dementia. The figure will be 937,000 within 15 years. Presently, there is no truly effective treatment for this disease. <|im_end|>

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1,853

[ { "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 Proton gradients are essential for biological systems. They not only drive the synthesis of ATP, but initiate molecule degradation and recycling inside lysosomes. However, the high mobility and permeability of protons through membranes make pH gradients very hard to sustain in vitro. Here we report that heat flow across a water-filled chamber forms and sustains stable pH gradients. Charged molecules accumulate by convection and thermophoresis better than uncharged species. In a dissociation reaction, this imbalances the reaction equilibrium and creates a difference in pH. In solutions of amino acids, phosphate, or nucleotides, we achieve pH differences of up to 2 pH units. The same mechanism cycles biomolecules by convection in the created proton gradient. This implements a feedback between biomolecules and a cyclic variation of the pH. The finding provides a mechanism to create a self-sustained proton gradient to drive biochemical reactions. Introduction The establishment of ion gradients holds an important place for the sustainment of all current life forms. Regions of different pH are essential for various cellular processes such as the synthesis of DNA, RNA, and proteins as well as their degradation and recycling 1 , 2 , 3 , 4 . These processes are accommodated in specialized compartments separated by biological membranes and important in lysosomes, mitochondria, and cell vacuoles. To form complex reaction networks, the variation of pH is essential to create different reaction conditions 5 , 6 . In the process of chemiosmosis, for example, the channeled movement of ions across a membrane drives the phosphorylation of ADP to ATP, life’s most commonly used energy currency 7 . Since ancient microbes, such as the last universal common ancestor (LUCA), are assumed to be chemiosmotic 8 , it has been argued toward the significance of proton gradients at the origin of life 9 , 10 , 11 . In addition, the synthesis of precursor molecules for early molecular evolution requires differing pH values for the synthesis of purine and pyrimidine ribonucleotides 12 , aminonitriles 13 , amino acids 14 , and phosphoenol pyruvate 15 . For living systems, the creation of pH differences is tedious and requires complex protein-mediated transport mechanisms. On prebiotic earth, natural pH gradients would form by laminar mixing of fluids with different pH values, e.g., at the interface between disequilibria at submarine hydrothermal vents and the Hadean ocean 16 , 17 , 18 . However, these systems rely on a continuous influx of mass and energy. Molecules would experience this gradient only for a short time and are washed out into a pH-equilibrated reservoir, keeping the mechanism transient. A repetitive pH oscillation inside a closed system would be desirable and keep molecules at one location without being lost by a flow or by diffusion. Here we found a mechanism to form stable pH gradients and continuous cycling of pH in a closed system. Thermal energy, the form of energy necessary for the mechanism, triggers an accumulation mechanism for individual ionic species. The heat flow forms a temperature gradient, spanning across sub-millimeter-sized water-filled compartments. This is likely a common setting on early earth, found for example in geothermally heated porous rocks such as hydrothermal vents or cooling volcanic sites 19 , 20 . This elementary setting has previously been shown to concentrate dilute nucleotides 21 , accumulate lipids to facilitate the formation of vesicles 22 , shift polymerization reactions toward longer DNA/RNA strands 23 , and selectively replicate longer polymers 24 . This study now extends these characteristics to include the formation of a stable pH gradient by thermally separating dissolved buffer molecules of different charge states. This locally shifts the buffer equilibrium, yielding pH differences of up to two units and provides another aspect for a promising long-term microhabitat for the onset of molecular evolution. In the following experiments, we demonstrate the formation of proton gradients in various buffer solutions. These include prebiotically plausible solutions of phosphate buffers, amino acids, and nucleotides 25 , 26 , 27 , 28 , 29 . In a temperature gradient, the thermophoretic movement of each ionic species is different. As a result, the concentration of ionic species is locally shifted, prompting the formation of proton gradients (Fig. 1 ). As indicated by the modeling, the formation of proton gradients is not affected by smaller concentrations of large biomolecules or vesicles. Such entities are shuttled inside the already established pH gradient by laminar convection, prompting them to move regularly between regions of varying pH. Thereby, each molecule undergoes individual pH oscillations with respect to their molecular properties, mostly their diffusion coefficient and Soret coefficient. The pH oscillations enable chemical reaction pathways that rely on pH fluctuations. The comparably fast shuttling of vesicles could trigger proton gradients across protocellular membranes without the need for active proton pumps. Fig. 1 Formation of pH gradients by chemical or thermal energy. a Modern cells run on an elaborate protein system to maintain proton gradients across a membrane. Chemical energy is used to pump protons against their concentration gradient which is then harnessed by chemiosmosis. b Heat fluxes across confined solutions, a common geological setting, induce a movement of ions that results in a stable pH gradient of up to 2 pH units. The charge selective thermophoretic accumulation of buffer molecules such as amino acids, phosphates, or nucleotides keeps the water self-ionization persistently out of equilibrium. The formation of a pH gradient is achieved in a closed system and biomolecules are repetitively exposed to differences in pH Full size image Results Thermally driven accumulation The formation of pH gradients is facilitated by a thermally driven accumulation mechanism inside a water-filled compartment. These flow chambers are subjected to a spatially confined horizontal temperature gradient. Based on the second law of thermodynamics, energy fluxes are necessary to maintain states of low entropies, in this case accumulated regions of molecules. The accumulation mechanism relies on the superposition of two effects: (i) thermal convection drives molecules up- and downwards in the flow chamber and (ii) thermophoresis—the movement of molecules in a temperature gradient (Fig. 2a", "role": "user" }, { "content": "Thermophoresis for the energy supply of early cells. NIM scientist Dr Christof Mast and his team suggest thermally driven formation of pH gradients and proton flux as source of chemical energy conversion in early stages of life. The transport of positively charged protons along a pH gradient serves to generate energy in cellular systems where membranes maintain the gradient. Without a membrane containing highly developed pump proteins, it will be difficult to prevent protons from rebalancing their concentration in the liquid immediately. A team led by the LMU biophysicist Christof Mast in Professor Dieter Braun's research group has discovered a process that can produce pH differences even without membranes only with the help of a heat flow through a water-filled pore. Thermal energy is converted into chemically usable energy. \"Living cells use pH differences as the universal driving force of their cell power plants,\" explains Mast. Approximately four billion years ago, before the evolution of proton pumps, other mechanisms were needed to generate pH gradients. \"On the early earth, thermally driven formation of pH gradients could have been achieved near heat sources in porous rock,\" adds Lorenz Keil, the first author of the publication in Nature Communications. Proton flux as source of energy Similar to the energy generation from water flowing along a height difference in hydro power stations, cells can produce chemical energy by the controlled equalization of protons along a pH difference through a membrane. Such pH differences also played an important role in the evolution of the most important molecular building blocks of life, such as ribonucleic acid (RNA) and various amino acids on the early earth. The heat flow, as it occurs for example in oceanic hydrothermal fields, creates a temperature difference between the opposite sides of the pore and causes two decisive effects: biomolecules migrate through the so-called thermophoresis along the temperature difference to the cold side. At the same time, a convective flow develops in the pore by the sinking of the slightly denser water on the cold side and the rise of the lighter water on the hot side. The interaction of both mechanisms concentrates higher charged molecules on the bottom of the pore. There, they can absorb free protons and thus establish a higher pH compared to the upper regions of the pore. Motor of the first cells on earth? Driven by thermal convection, the first cells could have cycled between regions with different pH-values. The comparatively fast transport of vesicles could cause a proton gradient across proto-cellular membranes, which is done by sophisticated proton pumps in their modern relatives. \"Applying this method would have enabled early cells to generate chemical energy without the need for actively driven proton pumps,\" said Mast summarizing their findings. A simple difference in temperature constituted not only a helpful tool for the formation and multiplication of the first biomolecules, but could also have driven the metabolism of the first cells. ", "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 Proton gradients are essential for biological systems. They not only drive the synthesis of ATP, but initiate molecule degradation and recycling inside lysosomes. However, the high mobility and permeability of protons through membranes make pH gradients very hard to sustain in vitro. Here we report that heat flow across a water-filled chamber forms and sustains stable pH gradients. Charged molecules accumulate by convection and thermophoresis better than uncharged species. In a dissociation reaction, this imbalances the reaction equilibrium and creates a difference in pH. In solutions of amino acids, phosphate, or nucleotides, we achieve pH differences of up to 2 pH units. The same mechanism cycles biomolecules by convection in the created proton gradient. This implements a feedback between biomolecules and a cyclic variation of the pH. The finding provides a mechanism to create a self-sustained proton gradient to drive biochemical reactions. Introduction The establishment of ion gradients holds an important place for the sustainment of all current life forms. Regions of different pH are essential for various cellular processes such as the synthesis of DNA, RNA, and proteins as well as their degradation and recycling 1 , 2 , 3 , 4 . These processes are accommodated in specialized compartments separated by biological membranes and important in lysosomes, mitochondria, and cell vacuoles. To form complex reaction networks, the variation of pH is essential to create different reaction conditions 5 , 6 . In the process of chemiosmosis, for example, the channeled movement of ions across a membrane drives the phosphorylation of ADP to ATP, life’s most commonly used energy currency 7 . Since ancient microbes, such as the last universal common ancestor (LUCA), are assumed to be chemiosmotic 8 , it has been argued toward the significance of proton gradients at the origin of life 9 , 10 , 11 . In addition, the synthesis of precursor molecules for early molecular evolution requires differing pH values for the synthesis of purine and pyrimidine ribonucleotides 12 , aminonitriles 13 , amino acids 14 , and phosphoenol pyruvate 15 . For living systems, the creation of pH differences is tedious and requires complex protein-mediated transport mechanisms. On prebiotic earth, natural pH gradients would form by laminar mixing of fluids with different pH values, e.g., at the interface between disequilibria at submarine hydrothermal vents and the Hadean ocean 16 , 17 , 18 . However, these systems rely on a continuous influx of mass and energy. Molecules would experience this gradient only for a short time and are washed out into a pH-equilibrated reservoir, keeping the mechanism transient. A repetitive pH oscillation inside a closed system would be desirable and keep molecules at one location without being lost by a flow or by diffusion. Here we found a mechanism to form stable pH gradients and continuous cycling of pH in a closed system. Thermal energy, the form of energy necessary for the mechanism, triggers an accumulation mechanism for individual ionic species. The heat flow forms a temperature gradient, spanning across sub-millimeter-sized water-filled compartments. This is likely a common setting on early earth, found for example in geothermally heated porous rocks such as hydrothermal vents or cooling volcanic sites 19 , 20 . This elementary setting has previously been shown to concentrate dilute nucleotides 21 , accumulate lipids to facilitate the formation of vesicles 22 , shift polymerization reactions toward longer DNA/RNA strands 23 , and selectively replicate longer polymers 24 . This study now extends these characteristics to include the formation of a stable pH gradient by thermally separating dissolved buffer molecules of different charge states. This locally shifts the buffer equilibrium, yielding pH differences of up to two units and provides another aspect for a promising long-term microhabitat for the onset of molecular evolution. In the following experiments, we demonstrate the formation of proton gradients in various buffer solutions. These include prebiotically plausible solutions of phosphate buffers, amino acids, and nucleotides 25 , 26 , 27 , 28 , 29 . In a temperature gradient, the thermophoretic movement of each ionic species is different. As a result, the concentration of ionic species is locally shifted, prompting the formation of proton gradients (Fig. 1 ). As indicated by the modeling, the formation of proton gradients is not affected by smaller concentrations of large biomolecules or vesicles. Such entities are shuttled inside the already established pH gradient by laminar convection, prompting them to move regularly between regions of varying pH. Thereby, each molecule undergoes individual pH oscillations with respect to their molecular properties, mostly their diffusion coefficient and Soret coefficient. The pH oscillations enable chemical reaction pathways that rely on pH fluctuations. The comparably fast shuttling of vesicles could trigger proton gradients across protocellular membranes without the need for active proton pumps. Fig. 1 Formation of pH gradients by chemical or thermal energy. a Modern cells run on an elaborate protein system to maintain proton gradients across a membrane. Chemical energy is used to pump protons against their concentration gradient which is then harnessed by chemiosmosis. b Heat fluxes across confined solutions, a common geological setting, induce a movement of ions that results in a stable pH gradient of up to 2 pH units. The charge selective thermophoretic accumulation of buffer molecules such as amino acids, phosphates, or nucleotides keeps the water self-ionization persistently out of equilibrium. The formation of a pH gradient is achieved in a closed system and biomolecules are repetitively exposed to differences in pH Full size image Results Thermally driven accumulation The formation of pH gradients is facilitated by a thermally driven accumulation mechanism inside a water-filled compartment. These flow chambers are subjected to a spatially confined horizontal temperature gradient. Based on the second law of thermodynamics, energy fluxes are necessary to maintain states of low entropies, in this case accumulated regions of molecules. The accumulation mechanism relies on the superposition of two effects: (i) thermal convection drives molecules up- and downwards in the flow chamber and (ii) thermophoresis—the movement of molecules in a temperature gradient (Fig. 2a<|im_end|> <|im_start|>assistant Thermophoresis for the energy supply of early cells. NIM scientist Dr Christof Mast and his team suggest thermally driven formation of pH gradients and proton flux as source of chemical energy conversion in early stages of life. The transport of positively charged protons along a pH gradient serves to generate energy in cellular systems where membranes maintain the gradient. Without a membrane containing highly developed pump proteins, it will be difficult to prevent protons from rebalancing their concentration in the liquid immediately. A team led by the LMU biophysicist Christof Mast in Professor Dieter Braun's research group has discovered a process that can produce pH differences even without membranes only with the help of a heat flow through a water-filled pore. Thermal energy is converted into chemically usable energy. "Living cells use pH differences as the universal driving force of their cell power plants," explains Mast. Approximately four billion years ago, before the evolution of proton pumps, other mechanisms were needed to generate pH gradients. "On the early earth, thermally driven formation of pH gradients could have been achieved near heat sources in porous rock," adds Lorenz Keil, the first author of the publication in Nature Communications. Proton flux as source of energy Similar to the energy generation from water flowing along a height difference in hydro power stations, cells can produce chemical energy by the controlled equalization of protons along a pH difference through a membrane. Such pH differences also played an important role in the evolution of the most important molecular building blocks of life, such as ribonucleic acid (RNA) and various amino acids on the early earth. The heat flow, as it occurs for example in oceanic hydrothermal fields, creates a temperature difference between the opposite sides of the pore and causes two decisive effects: biomolecules migrate through the so-called thermophoresis along the temperature difference to the cold side. At the same time, a convective flow develops in the pore by the sinking of the slightly denser water on the cold side and the rise of the lighter water on the hot side. The interaction of both mechanisms concentrates higher charged molecules on the bottom of the pore. There, they can absorb free protons and thus establish a higher pH compared to the upper regions of the pore. Motor of the first cells on earth? Driven by thermal convection, the first cells could have cycled between regions with different pH-values. The comparatively fast transport of vesicles could cause a proton gradient across proto-cellular membranes, which is done by sophisticated proton pumps in their modern relatives. "Applying this method would have enabled early cells to generate chemical energy without the need for actively driven proton pumps," said Mast summarizing their findings. A simple difference in temperature constituted not only a helpful tool for the formation and multiplication of the first biomolecules, but could also have driven the metabolism of the first cells. <|im_end|>

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