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 Quasi-2D perovskites have been demonstrated to be competitive materials in the photodetection fields due to the enhanced moisture stability by large organic cations. However, as the increasing demands of modern technology, it is still challenging to combine the flexibility with the capability of weak light detection in a low-cost way. Here, amides, carboxylic acids, and anhydrides groups-rich carbonized polymer dots (CPDs) were employed to fill in the perovskite grain boundaries, which can passivate the point defects of perovskite by coordinating with the unbonded Pb atoms, and reduce the leakage current. Weak light detection capability was demonstrated by directly resolving light with an intensity of 10.1 pW cm −2 . More importantly, the stretchable polymer chains on CPDs strongly interact with perovskite ions through multiple supramolecular interactions, and extend the stretchable properties to the perovskite/CPDs composites, which can maintain the integral structure stability during the deformation of perovskite crystals and restricted any crack by releasing the film strain. Our fabricated devices show extraordinary flexible stability in the bending-dependent response tests. The viscoelasticity of CPDs improves the bending stability of the flexible quasi-2D perovskite photodetectors, and device performance shows no degradation after bending 10000 times, comparable or even outperforming the dominating flexible photodetectors. Introduction High-performance photodetectors with great detection capability have been widely deployed in our daily life, such as driverless technology, intraoperative navigated surgery, face recognition, anti-counterfeiting, and so on. However, we still face challenges as new demands are required for additional functions like excellent flexibility with no sensitivity/stability loss. Therefore, novel photosensitive materials or multi-functional composites are needed to meet the fast technology development. Perovskites as excellent optoelectronic semiconductors have attracted great interest in interdisciplinary fields such as energy conversion 1 , 2 , 3 , light emitting diodes 4 , 5 , displays 6 , 7 , ionizing radiation detection, and UV-visible light detection 8 , 9 , 10 , 11 , 12 , and so on. The attractive properties such as low-cost solution processes 13 , 14 , 15 , low nucleation formation energy 16 , 17 , great defects tolerance feature 18 , 19 , 20 , 21 , and the extraordinary charge carrier kinetics 22 , 23 , 24 , 25 , 26 enable perovskites as ideal optoelectronic materials for photodetection applications. However, due to the low forming energy of the three-dimensional organic-inorganic hybrid perovskites such as methylammonium lead iodide (MAPbI 3 ), formamidine lead iodide (FAPbI 3 ), and methylamine tin iodide (MASnI 3 ), their moisture instability or thermal instability limit their further commercialization 27 , 28 , 29 . To solve these issues, low dimensional perovskites are a good choice by separating the inorganic framework with large organic cations. 2D/quasi-2D perovskites have been demonstrated to be good candidates with improved device stability 11 , 30 , 31 . Furthermore, to expand the function of perovskite materials, composite materials were designed by combining the advantages of perovskite with other materials like MXene, metal-organic framework, and so on 32 , 33 , 34 , 35 , 36 , 37 . The optoelectronic device’s performance and stability can be largely improved. However, the rigid nature of these materials limits the flexibility of the perovskite devices. Carbonized polymer dots (CPDs) are composed of carbonized crystalline carbon as a nucleus core in the center and capped by amorphous polymer chains as shells. The size of the carbon nucleus can be easily controlled by modulating the carbonized temperature and time, and the polymer chains possess abundant functional groups, which bring tunable surface chemical properties. Therefore, the unique core-shell structure of CPDs ensures excellent viscoelasticity and tunable optoelectronic properties of CPDs. In addition, the raw materials of CPDs are abundant in nature, and synthesis processes are also facile and low cost. Based on these considerations, we proposed that perovskite/CPDs composites may exhibit excellent photodetection performance and flexibility. In this manuscript, we developed three different 4-fluorophenethylamine based methylammonium lead iodide (FPEA 2 MA 3 Pb 4 I 13 , FMPI) perovskite/CPDs composites for flexible photodetectors application. The CPDs distribute at the grain boundaries of FMPI material, passivate the surface defects of the FMPI grain, and cross-link the grains with coordinative interactions between electrical negative functional groups and the unbonded Pb atoms. The passivation effect of CPDs reduces the device leakage current and improves the capability of weak light detection. Functional groups, including amides, carboxylic acids, and anhydrides, were gradiently distributed on the polymer chains by increasing the carbonation degree of CPDs. The viscoelasticity of the polymer chains facilitates maintaining the perovskite grains’ integrity and film uniformity during deformation and improves the bending stability of the flexible FMPI/CPDs composites. The flexible FMPI/CPDs photodetector shows no photocurrent signal loss after 10000 times bending, and simultaneously resolves weak light intensity of 10.1 pW cm −2 , comparable or even outperforming the state-of-the-art photodetectors. Results Coordinative groups design on polymer chains of CPDs The CPDs were fabricated according to our previous method 38 . To obtain functional CPDs with various coordinative behavior and carbon nuclear sizes, the carbonization temperatures were set as 120 °C, 150 °C, and 180 °C, respectively as illustrated in Fig. 1a . Insert is the corresponding photo of synthesized CPDs, highlighting the viscoelastic property brought by their surface polymer chains. We employed transmission electron microscope (TEM) measurements to quantify the carbon core size of the three CPDs (Fig. S1 ), and the results are summarized in Fig. 1b . The average core sizes of the CPDs are 6 nm, 23 nm, and 25 nm, respectively, as temperature increases, indicating enhanced carbonization degree. We also used dynamic light scattering (DLS) measurements to characterize the polymer chain lengths of the CPDs, as shown in Fig. 1c . It should be noted that the DLS results are the hydration size of CPDs, which is normally larger than the actual size of the CPDs. CPDs-120 °C are around 500 nm in diameter, larger than that CPDs-150 °C and CPDs-180 °C of 350 nm and 240 nm, respectively. To further confirm the polymer chains sizes,", "role": "user" }, { "content": "High-performance photodetectors with great detection capability have been widely deployed in our daily life, such as driverless technology, intraoperative navigated surgery, face recognition, anti-counterfeiting, and so on. However, we still face challenges as new demands are made for additional functions like excellent flexibility with no sensitivity/stability loss. Therefore, novel photosensitive materials or multi-functional composites are needed to meet the fast technology development. In a new paper published in Light: Science & Applications, a team of scientists, led by Professor Haotong Wei from State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, China have developed a method to introduce carbonized polymer dots (CPDs) to promote the performance of quasi-2D perovskite based flexible photodetectors. By controlling the morphology of the CPDs unique core/shell structure with viscoelasticity polymer chains, they greatly improved the flexible stability of perovskite photodetectors, showing no loss in photo-response after bending 10,000 times. Furthermore, the defects distributed in the grain boundary of perovskite were passivated through the coordination effect between the unbonded Pb atoms and the carbonyl groups in the CPDs' polymer chains. The devices exhibited a lower dark current and resolve a weak light with the detectable light intensity lowing to 1/50, compared to the initial performance. The reported method provides an economical and available path to boost the photodetection performance of flexible optoelectronic devices. The CPDs are composed of carbonized crystalline carbon as a nucleus core in the center and capped by amorphous polymer chains as shells. The size of the carbon nucleus can be easily controlled by modulating the carbonized temperature and time, and the polymer chains possess abundant functional groups, which brings tunable surface chemical properties. Therefore, the unique core-shell structure of CPDs ensures excellent viscoelasticity and tunable optoelectronic properties of CPDs. In addition, the raw materials of CPDs are abundant in nature, and synthesis processes are also facile and low cost. Based on these considerations, these scientists proposed that perovskite/CPDs composites may exhibit excellent photodetection performance and flexibility: \"We fabricated a series of CPDs with different morphology properties. By changing the temperature, the adjusted carbonization process leads to various lengths of polymer chains on the CPDs. And as we regulated the raw materials, these CPDs would carry abundant and controllable functional groups, which meet our demands,\" the researchers write. \"The different lengths of the CPDs provide a convenient way to control the flexibility of the devices. The stretchable polymer chains of the CPDs would work as an anchor at the grain boundaries, making the morphology of the perovskite more stable during the deformation process. Furthermore, the abundant available raw materials of the CPDs provide us with more choices to adjust the properties of the CPDs. The various functional groups the CPDs carried in the polymer chains coordinate with the Pb atoms to passivate the defects at the grain boundaries. Via control of the functional groups, the CPDs provide a path to regulate the optoelectronic performance of the devices,\" they added. \"Our method contributes a new path to adjust the properties of optoelectronic materials and devices. By introducing these easy-to-prepare CPDs, we combine the properties of CPDs and perovskite materials and achieve high-performance photodetectors with great flexibility and stability. Our work would inspire and promote flexible and foldable optoelectronic devices and promote their development and advancement.\" ", "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 Quasi-2D perovskites have been demonstrated to be competitive materials in the photodetection fields due to the enhanced moisture stability by large organic cations. However, as the increasing demands of modern technology, it is still challenging to combine the flexibility with the capability of weak light detection in a low-cost way. Here, amides, carboxylic acids, and anhydrides groups-rich carbonized polymer dots (CPDs) were employed to fill in the perovskite grain boundaries, which can passivate the point defects of perovskite by coordinating with the unbonded Pb atoms, and reduce the leakage current. Weak light detection capability was demonstrated by directly resolving light with an intensity of 10.1 pW cm −2 . More importantly, the stretchable polymer chains on CPDs strongly interact with perovskite ions through multiple supramolecular interactions, and extend the stretchable properties to the perovskite/CPDs composites, which can maintain the integral structure stability during the deformation of perovskite crystals and restricted any crack by releasing the film strain. Our fabricated devices show extraordinary flexible stability in the bending-dependent response tests. The viscoelasticity of CPDs improves the bending stability of the flexible quasi-2D perovskite photodetectors, and device performance shows no degradation after bending 10000 times, comparable or even outperforming the dominating flexible photodetectors. Introduction High-performance photodetectors with great detection capability have been widely deployed in our daily life, such as driverless technology, intraoperative navigated surgery, face recognition, anti-counterfeiting, and so on. However, we still face challenges as new demands are required for additional functions like excellent flexibility with no sensitivity/stability loss. Therefore, novel photosensitive materials or multi-functional composites are needed to meet the fast technology development. Perovskites as excellent optoelectronic semiconductors have attracted great interest in interdisciplinary fields such as energy conversion 1 , 2 , 3 , light emitting diodes 4 , 5 , displays 6 , 7 , ionizing radiation detection, and UV-visible light detection 8 , 9 , 10 , 11 , 12 , and so on. The attractive properties such as low-cost solution processes 13 , 14 , 15 , low nucleation formation energy 16 , 17 , great defects tolerance feature 18 , 19 , 20 , 21 , and the extraordinary charge carrier kinetics 22 , 23 , 24 , 25 , 26 enable perovskites as ideal optoelectronic materials for photodetection applications. However, due to the low forming energy of the three-dimensional organic-inorganic hybrid perovskites such as methylammonium lead iodide (MAPbI 3 ), formamidine lead iodide (FAPbI 3 ), and methylamine tin iodide (MASnI 3 ), their moisture instability or thermal instability limit their further commercialization 27 , 28 , 29 . To solve these issues, low dimensional perovskites are a good choice by separating the inorganic framework with large organic cations. 2D/quasi-2D perovskites have been demonstrated to be good candidates with improved device stability 11 , 30 , 31 . Furthermore, to expand the function of perovskite materials, composite materials were designed by combining the advantages of perovskite with other materials like MXene, metal-organic framework, and so on 32 , 33 , 34 , 35 , 36 , 37 . The optoelectronic device’s performance and stability can be largely improved. However, the rigid nature of these materials limits the flexibility of the perovskite devices. Carbonized polymer dots (CPDs) are composed of carbonized crystalline carbon as a nucleus core in the center and capped by amorphous polymer chains as shells. The size of the carbon nucleus can be easily controlled by modulating the carbonized temperature and time, and the polymer chains possess abundant functional groups, which bring tunable surface chemical properties. Therefore, the unique core-shell structure of CPDs ensures excellent viscoelasticity and tunable optoelectronic properties of CPDs. In addition, the raw materials of CPDs are abundant in nature, and synthesis processes are also facile and low cost. Based on these considerations, we proposed that perovskite/CPDs composites may exhibit excellent photodetection performance and flexibility. In this manuscript, we developed three different 4-fluorophenethylamine based methylammonium lead iodide (FPEA 2 MA 3 Pb 4 I 13 , FMPI) perovskite/CPDs composites for flexible photodetectors application. The CPDs distribute at the grain boundaries of FMPI material, passivate the surface defects of the FMPI grain, and cross-link the grains with coordinative interactions between electrical negative functional groups and the unbonded Pb atoms. The passivation effect of CPDs reduces the device leakage current and improves the capability of weak light detection. Functional groups, including amides, carboxylic acids, and anhydrides, were gradiently distributed on the polymer chains by increasing the carbonation degree of CPDs. The viscoelasticity of the polymer chains facilitates maintaining the perovskite grains’ integrity and film uniformity during deformation and improves the bending stability of the flexible FMPI/CPDs composites. The flexible FMPI/CPDs photodetector shows no photocurrent signal loss after 10000 times bending, and simultaneously resolves weak light intensity of 10.1 pW cm −2 , comparable or even outperforming the state-of-the-art photodetectors. Results Coordinative groups design on polymer chains of CPDs The CPDs were fabricated according to our previous method 38 . To obtain functional CPDs with various coordinative behavior and carbon nuclear sizes, the carbonization temperatures were set as 120 °C, 150 °C, and 180 °C, respectively as illustrated in Fig. 1a . Insert is the corresponding photo of synthesized CPDs, highlighting the viscoelastic property brought by their surface polymer chains. We employed transmission electron microscope (TEM) measurements to quantify the carbon core size of the three CPDs (Fig. S1 ), and the results are summarized in Fig. 1b . The average core sizes of the CPDs are 6 nm, 23 nm, and 25 nm, respectively, as temperature increases, indicating enhanced carbonization degree. We also used dynamic light scattering (DLS) measurements to characterize the polymer chain lengths of the CPDs, as shown in Fig. 1c . It should be noted that the DLS results are the hydration size of CPDs, which is normally larger than the actual size of the CPDs. CPDs-120 °C are around 500 nm in diameter, larger than that CPDs-150 °C and CPDs-180 °C of 350 nm and 240 nm, respectively. To further confirm the polymer chains sizes,<|im_end|> <|im_start|>assistant High-performance photodetectors with great detection capability have been widely deployed in our daily life, such as driverless technology, intraoperative navigated surgery, face recognition, anti-counterfeiting, and so on. However, we still face challenges as new demands are made for additional functions like excellent flexibility with no sensitivity/stability loss. Therefore, novel photosensitive materials or multi-functional composites are needed to meet the fast technology development. In a new paper published in Light: Science & Applications, a team of scientists, led by Professor Haotong Wei from State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, China have developed a method to introduce carbonized polymer dots (CPDs) to promote the performance of quasi-2D perovskite based flexible photodetectors. By controlling the morphology of the CPDs unique core/shell structure with viscoelasticity polymer chains, they greatly improved the flexible stability of perovskite photodetectors, showing no loss in photo-response after bending 10,000 times. Furthermore, the defects distributed in the grain boundary of perovskite were passivated through the coordination effect between the unbonded Pb atoms and the carbonyl groups in the CPDs' polymer chains. The devices exhibited a lower dark current and resolve a weak light with the detectable light intensity lowing to 1/50, compared to the initial performance. The reported method provides an economical and available path to boost the photodetection performance of flexible optoelectronic devices. The CPDs are composed of carbonized crystalline carbon as a nucleus core in the center and capped by amorphous polymer chains as shells. The size of the carbon nucleus can be easily controlled by modulating the carbonized temperature and time, and the polymer chains possess abundant functional groups, which brings tunable surface chemical properties. Therefore, the unique core-shell structure of CPDs ensures excellent viscoelasticity and tunable optoelectronic properties of CPDs. In addition, the raw materials of CPDs are abundant in nature, and synthesis processes are also facile and low cost. Based on these considerations, these scientists proposed that perovskite/CPDs composites may exhibit excellent photodetection performance and flexibility: "We fabricated a series of CPDs with different morphology properties. By changing the temperature, the adjusted carbonization process leads to various lengths of polymer chains on the CPDs. And as we regulated the raw materials, these CPDs would carry abundant and controllable functional groups, which meet our demands," the researchers write. "The different lengths of the CPDs provide a convenient way to control the flexibility of the devices. The stretchable polymer chains of the CPDs would work as an anchor at the grain boundaries, making the morphology of the perovskite more stable during the deformation process. Furthermore, the abundant available raw materials of the CPDs provide us with more choices to adjust the properties of the CPDs. The various functional groups the CPDs carried in the polymer chains coordinate with the Pb atoms to passivate the defects at the grain boundaries. Via control of the functional groups, the CPDs provide a path to regulate the optoelectronic performance of the devices," they added. "Our method contributes a new path to adjust the properties of optoelectronic materials and devices. By introducing these easy-to-prepare CPDs, we combine the properties of CPDs and perovskite materials and achieve high-performance photodetectors with great flexibility and stability. Our work would inspire and promote flexible and foldable optoelectronic devices and promote their development and advancement." <|im_end|>

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2,253

[ { "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 Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health. Introduction The 2016 Global Burden of Diseases, Injuries and Risk Factors Study 1 estimated that dental caries in permanent teeth and periodontitis were the leading and 11th most prevalent causes of disease worldwide in 2016. Characterising the aetiology of these diseases is a priority as they confer major health 2 and financial burden, with the global cost of dental diseases exceeding 540 billion US dollars in 2015 3 . Part of this story is the genetic contribution to oral health outcomes and the heritability of dental caries and periodontitis have been reported to be as high as 50% 4 , 5 . However, the nature of this contribution remains poorly characterised despite the promise that increased understanding of genetic factors can bring with respect to aetiology dissection and theoretically, clinical management Genome-wide association studies (GWAS) for dental caries have investigated measures, including overall caries experience 6 , 7 , specific presentations of disease and the presence or absence of disease in paediatric populations 8 , 9 . To date, few reliable genetic-association signals have been found, and this is likely to reflect different measurement approaches used, complex genetic architecture 10 of dental caries or limited statistical power to detect associations. GWAS for periodontitis have investigated measures, including the presence or absence of disease 11 , quantitative measures of periodontal status 12 , severe presentations of disease 13 , molecular and microbial intermediaries of disease 14 and composite phenotypes such as GWAS for principal components which aim to capture multiple facets of periodontal health 15 . These studies have not yielded consistent evidence of specific genetic contributions to periodontitis 9 . Currently, there is a trade-off between phenotypic refinement and obtaining valid phenotype data in sufficiently large cohorts to allow statistical power for genome-wide analyses. Given the logistical and economic challenges in obtaining detailed phenotypes in large populations, studies have focused on clinical outcomes indicating the presence or absence of manifest disease. Recent studies of other complex traits have taken a different approach and circumvented the limited availability of refined clinical phenotypes by taking advantage of extremely large, population-based, cohorts with both genetic data and less-refined proxy phenotypes. The UK Biobank (UKB), for example, includes information from approximately half a million participants 16 . The presence of less well defined but informative phenotypes has enabled successful association signal discoveries for several complex traits, yielding important biological insights 17 . In order to achieve further understanding of genetic contributions to caries and periodontitis, a shift in analysis scale—afforded by a similar approach to measurement—is required. Here, we synthesise evidence from two sources; the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium 18 , which is a unique collection of epidemiological cohorts with detailed information on clinical endpoints of dental diseases; and UKB, which contains less-refined self-reported oral health data at a larger scale. In isolation, the biological meaning and relevance of the approximate measures in UKB would not be clear, but anchored against and unified with the more detailed clinical information in GLIDE, this combination of complementary resources provides a unique opportunity for genetic association discovery and application. Using this combination of resources, we identify 47 novel risk loci for dental caries and show that the heritability of dental caries is partially shared with a range of complex traits. Applied analysis using Mendelian randomisation suggests that dental caries has undesirable downstream effects on health. Together, these findings improve our understanding of the potential causes and consequences of an important complex disease. Results Heritability and shared heritability of dental diseases Genome-wide association studies (GWAS) were undertaken within the GLIDE consortium, using clinical measures of dental diseases and imputed genotype data, accounting for age-specific, sex-specific and other study-specific covariates. The primary traits were measures of caries experience (the sum of Decayed, Missing and Filled tooth Surfaces (DMFS) and the sum of Decayed and Filled tooth Surfaces per available tooth Surface (DFSS)), number of teeth (Nteeth) and a dichotomous classification of periodontal health or disease (Table 1 ). All meta-analyses within GLIDE used a fixed effects inverse-variance-weighted strategy implemented in METAL 19 (Methods; Supplementary Data 1 , Supplementary Data 2 ). Table 1 Overview of dental disease phenotypes in GLIDE Full size table In parallel, genetic contributions to self-reported measures of oral health were characterised in UK Biobank (UKB). Participants were asked to report whether they had bleeding gums, painful gums, dentures, loose teeth, toothache or mouth ulcers as part of a baseline study questionnaire. GWAS for each trait was performed within individuals of European ancestry, accounting for age, sex and relatedness using a linear mixed model ( n = 461,031 for all traits; see the Methods section) For each dental disease trait, genome-wide single nucleotide polymorphism (SNP)-based heritability (h 2 LDSR ) was estimated using univariate linkage-disequilibrium score regression (LDSR) 20 (Methods). In GLIDE, the highest and lowest heritability estimates were reported for Nteeth (0.13, se = 0.02) and periodontitis (0.01, se = 0.01), respectively; while in UKB the highest and lowest heritability estimates were for dentures (0.09, se = 0.004) and toothache (0.04, se = 0.007), respectively (Fig. 1a ). Fig. 1 Estimated heritability of and genetic correlation between measures of dental disease. a estimated heritability (h 2 LDSR ) for each trait in GLIDE (plotted in circles) and UKB (plotted in", "role": "user" }, { "content": "Tooth decay and gum disease impact on illness and healthcare spending, yet the role of genetics in dental problems is largely unknown. New research led by an international team, including researchers at the University of Bristol, suggests hereditary traits and factors such as obesity, education and personality could play a role in tooth decay and gum disease. Tooth decay and periodontitis, also known as gum disease, are among the most common diseases around the world but unlike many other well-known diseases knowledge of how genes affect the risk of developing these dental diseases is still limited. Researchers know that two people who eat the same things and take care of their mouth the same way may end up with a different number of cavities but have not been able to explain why until now. Ingegerd Johansson, Senior Professor in the Institute of Odontology at Umeå University, Sweden, who led the research, said: \"The study makes it clear that teeth are part of the body. Among other things, we can see that there seems to be a causal link between risk factors for cardiovascular disease and tooth decay.\" Previous research has suggested several genes may be involved but none had been confirmed. This is partly because complex diseases, such as tooth decay and periodontitis, require large studies to draw firm conclusions. The meta-analysis study, published in Nature Communications, combined data from nine international clinical studies with 62,000 participants together with data on self-reported dental health from the UK Biobank including 461,000 participants, making it the largest study of its kind. The analysis involved scanning millions of strategic points in the genome to find genes with links to dental diseases. The researchers were able to identify 47 new genes with connections to tooth decay. The study also confirmed a previously known immune-related gene is linked to periodontitis. Among the genes that could be linked to tooth decay are those that help form teeth and the jawbone, those with protective functions in saliva and those which affect the bacteria found on the teeth. The study also looked at the genetic link to cardiovascular and metabolic health factors such as smoking, obesity, education and personality to try and understand connections with dental health. Using a technique called Mendelian randomisation, it appears there may be more than correlation but also a causal link between decay and some cardiovascular-metabolic risk factors. Simon Haworth, from the Bristol Dental School, Bristol Population Health Science Institute and corresponding author, said: \"In the future, studies like this may pave the way to identifying people who are at particular risk of dental problems. However, no matter what genes people carry, good oral hygiene and diet are the most important things people can do to reduce the risk of tooth decay and gum 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 Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health. Introduction The 2016 Global Burden of Diseases, Injuries and Risk Factors Study 1 estimated that dental caries in permanent teeth and periodontitis were the leading and 11th most prevalent causes of disease worldwide in 2016. Characterising the aetiology of these diseases is a priority as they confer major health 2 and financial burden, with the global cost of dental diseases exceeding 540 billion US dollars in 2015 3 . Part of this story is the genetic contribution to oral health outcomes and the heritability of dental caries and periodontitis have been reported to be as high as 50% 4 , 5 . However, the nature of this contribution remains poorly characterised despite the promise that increased understanding of genetic factors can bring with respect to aetiology dissection and theoretically, clinical management Genome-wide association studies (GWAS) for dental caries have investigated measures, including overall caries experience 6 , 7 , specific presentations of disease and the presence or absence of disease in paediatric populations 8 , 9 . To date, few reliable genetic-association signals have been found, and this is likely to reflect different measurement approaches used, complex genetic architecture 10 of dental caries or limited statistical power to detect associations. GWAS for periodontitis have investigated measures, including the presence or absence of disease 11 , quantitative measures of periodontal status 12 , severe presentations of disease 13 , molecular and microbial intermediaries of disease 14 and composite phenotypes such as GWAS for principal components which aim to capture multiple facets of periodontal health 15 . These studies have not yielded consistent evidence of specific genetic contributions to periodontitis 9 . Currently, there is a trade-off between phenotypic refinement and obtaining valid phenotype data in sufficiently large cohorts to allow statistical power for genome-wide analyses. Given the logistical and economic challenges in obtaining detailed phenotypes in large populations, studies have focused on clinical outcomes indicating the presence or absence of manifest disease. Recent studies of other complex traits have taken a different approach and circumvented the limited availability of refined clinical phenotypes by taking advantage of extremely large, population-based, cohorts with both genetic data and less-refined proxy phenotypes. The UK Biobank (UKB), for example, includes information from approximately half a million participants 16 . The presence of less well defined but informative phenotypes has enabled successful association signal discoveries for several complex traits, yielding important biological insights 17 . In order to achieve further understanding of genetic contributions to caries and periodontitis, a shift in analysis scale—afforded by a similar approach to measurement—is required. Here, we synthesise evidence from two sources; the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium 18 , which is a unique collection of epidemiological cohorts with detailed information on clinical endpoints of dental diseases; and UKB, which contains less-refined self-reported oral health data at a larger scale. In isolation, the biological meaning and relevance of the approximate measures in UKB would not be clear, but anchored against and unified with the more detailed clinical information in GLIDE, this combination of complementary resources provides a unique opportunity for genetic association discovery and application. Using this combination of resources, we identify 47 novel risk loci for dental caries and show that the heritability of dental caries is partially shared with a range of complex traits. Applied analysis using Mendelian randomisation suggests that dental caries has undesirable downstream effects on health. Together, these findings improve our understanding of the potential causes and consequences of an important complex disease. Results Heritability and shared heritability of dental diseases Genome-wide association studies (GWAS) were undertaken within the GLIDE consortium, using clinical measures of dental diseases and imputed genotype data, accounting for age-specific, sex-specific and other study-specific covariates. The primary traits were measures of caries experience (the sum of Decayed, Missing and Filled tooth Surfaces (DMFS) and the sum of Decayed and Filled tooth Surfaces per available tooth Surface (DFSS)), number of teeth (Nteeth) and a dichotomous classification of periodontal health or disease (Table 1 ). All meta-analyses within GLIDE used a fixed effects inverse-variance-weighted strategy implemented in METAL 19 (Methods; Supplementary Data 1 , Supplementary Data 2 ). Table 1 Overview of dental disease phenotypes in GLIDE Full size table In parallel, genetic contributions to self-reported measures of oral health were characterised in UK Biobank (UKB). Participants were asked to report whether they had bleeding gums, painful gums, dentures, loose teeth, toothache or mouth ulcers as part of a baseline study questionnaire. GWAS for each trait was performed within individuals of European ancestry, accounting for age, sex and relatedness using a linear mixed model ( n = 461,031 for all traits; see the Methods section) For each dental disease trait, genome-wide single nucleotide polymorphism (SNP)-based heritability (h 2 LDSR ) was estimated using univariate linkage-disequilibrium score regression (LDSR) 20 (Methods). In GLIDE, the highest and lowest heritability estimates were reported for Nteeth (0.13, se = 0.02) and periodontitis (0.01, se = 0.01), respectively; while in UKB the highest and lowest heritability estimates were for dentures (0.09, se = 0.004) and toothache (0.04, se = 0.007), respectively (Fig. 1a ). Fig. 1 Estimated heritability of and genetic correlation between measures of dental disease. a estimated heritability (h 2 LDSR ) for each trait in GLIDE (plotted in circles) and UKB (plotted in<|im_end|> <|im_start|>assistant Tooth decay and gum disease impact on illness and healthcare spending, yet the role of genetics in dental problems is largely unknown. New research led by an international team, including researchers at the University of Bristol, suggests hereditary traits and factors such as obesity, education and personality could play a role in tooth decay and gum disease. Tooth decay and periodontitis, also known as gum disease, are among the most common diseases around the world but unlike many other well-known diseases knowledge of how genes affect the risk of developing these dental diseases is still limited. Researchers know that two people who eat the same things and take care of their mouth the same way may end up with a different number of cavities but have not been able to explain why until now. Ingegerd Johansson, Senior Professor in the Institute of Odontology at Umeå University, Sweden, who led the research, said: "The study makes it clear that teeth are part of the body. Among other things, we can see that there seems to be a causal link between risk factors for cardiovascular disease and tooth decay." Previous research has suggested several genes may be involved but none had been confirmed. This is partly because complex diseases, such as tooth decay and periodontitis, require large studies to draw firm conclusions. The meta-analysis study, published in Nature Communications, combined data from nine international clinical studies with 62,000 participants together with data on self-reported dental health from the UK Biobank including 461,000 participants, making it the largest study of its kind. The analysis involved scanning millions of strategic points in the genome to find genes with links to dental diseases. The researchers were able to identify 47 new genes with connections to tooth decay. The study also confirmed a previously known immune-related gene is linked to periodontitis. Among the genes that could be linked to tooth decay are those that help form teeth and the jawbone, those with protective functions in saliva and those which affect the bacteria found on the teeth. The study also looked at the genetic link to cardiovascular and metabolic health factors such as smoking, obesity, education and personality to try and understand connections with dental health. Using a technique called Mendelian randomisation, it appears there may be more than correlation but also a causal link between decay and some cardiovascular-metabolic risk factors. Simon Haworth, from the Bristol Dental School, Bristol Population Health Science Institute and corresponding author, said: "In the future, studies like this may pave the way to identifying people who are at particular risk of dental problems. However, no matter what genes people carry, good oral hygiene and diet are the most important things people can do to reduce the risk of tooth decay and gum disease." <|im_end|>

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1,953

[ { "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 perovskite light-emitting diodes (PeLEDs) have recently experienced significant progress, there are only scattered reports of PeLEDs with both high efficiency and long operational stability, calling for additional strategies to address this challenge. Here, we develop perovskite-molecule composite thin films for efficient and stable PeLEDs. The perovskite-molecule composite thin films consist of in-situ formed high-quality perovskite nanocrystals embedded in the electron-transport molecular matrix, which controls nucleation process of perovskites, leading to PeLEDs with a peak external quantum efficiency of 17.3% and half-lifetime of approximately 100 h. In addition, we find that the device degradation mechanism at high driving voltages is different from that at low driving voltages. This work provides an effective strategy and deep understanding for achieving efficient and stable PeLEDs from both material and device perspectives. Introduction Metal halide perovskites have attracted significant attention for light-emitting applications, because of their excellent properties such as high photoluminescence quantum efficiency (PLQE), narrow emission bandwidth, readily tunable emission spectra ranging from ultraviolet to near-infrared, and solution processability 1 , 2 , 3 , 4 . Recently, rapid progress has been made in perovskite light-emitting diodes (PeLEDs), with external quantum efficiencies (EQEs) reaching more than 20% through suppression of non-radiative recombination and improvement of light out-coupling efficiency 5 , 6 , 7 , 8 , 9 . In addition to high efficiency, it is also important to achieve PeLEDs with long operational stability, a key factor towards practical applications. However, improving operational stability of PeLEDs is still a major challenge, and obtaining PeLEDs with both high efficiency and long operational stability remains elusive. From the materials point of view, a highly luminescent and stable perovskite film is essential to achieve PeLEDs with both high efficiency and long operational stability. Several approaches have been attempted towards this direction, including mixed A-site cations 10 , 11 , 12 , 13 , 14 , all-inorganic perovskites 15 , perovskite–polymer bulk heterostructures 7 , quasi-core/shell structure 6 , etc. Unfortunately, most of these approaches lead to either low efficiency or poor device stability. Not until very recently did rational additive engineering enable PeLEDs with both high efficiency and long operational stability in a few reports 5 , 8 . Herein, we develop an effective approach, i.e., perovskite-molecule composite (PMC) thin films, for efficient and stable PeLEDs. Our PMC films consist of formamidinium lead iodide (FAPbI 3 ) perovskite nanocrystal islands embedded in an electron-transport molecular matrix of 4,4′-diaminodiphenyl sulfone (DDS). We find that DDS controls nucleation process of the perovskite nanocrystals, leading to the formation of PMC thin films with enhanced PLQEs and prolonged PL lifetime. Moreover, this PMC structure shows impressive structural stability of α-phase FAPbI 3 for over half a year in ambient air with relative humidity of 20–80%. By employing the PMC thin films as emissive layers, we achieve LEDs with a peak EQE of 17.3% and half-lifetime ( T 50 , the time it takes until the light output reaches 50% of the maximum output) of 100 h at a constant current density of 20 mA cm –2 (initial radiance of 15 W m −2 sr −1 ). Considering the huge library of molecular semiconductors developed in organic LEDs 16 , 17 , more efficient and stable PMC thin films can be expected for achieving high-performance PeLEDs. In addition, from the device point of view, we find that the degradation mechanism of PeLEDs at high driving voltages is different from that at low driving voltages. Our findings in both materials and devices will spur further developments of PeLEDs with high efficiency and long operational stability for practical applications in lighting and display. Results PMC thin films The PMC thin films are prepared by facile one-step spin-coating from precursor solutions of formamidinium iodide (FAI), lead iodide (PbI 2 ), and DDS dissolved in N,N-dimethylformamide (DMF) ( x DDS films, where x = 0.5, 1.0 and 2.0, denote the films prepared with a DDS:Pb 2+ molar ratio of x :1.0; see the “Methods” section for details). Diphenyl sulfone is widely used as an electron-transport building block in molecular semiconductors 18 , and its derivatives such as di(4-(4-diphenylaminophenyl) phenyl) sulfone have been reported as efficient blue emissive molecules 17 . In this study, a diphenyl sulfone derivative, DDS (the chemical structure shown in Fig. 1a ), is chosen as the target molecular semiconductor due to its high singlet and triplet energies of 3.59 and 2.95 eV 19 , respectively, avoiding energy transfer from the perovskite nanocrystals to the molecule. In addition, DDS retains the electron-transport property of diphenyl sulfone (Supplementary Fig. 1 and Supplementary Note 1 ), while its amino group can help to control the growth of perovskite nanocrystals through chemical bonding with the perovskite, as will be discussed later. Fig. 1: Morphology of PMC thin films. a Molecular structure of DDS. b Top-view SEM images of perovskite films. The scale bars are 500 nm. c Cross-sectional bright-field TEM image, and d cross-sectional HAADF-STEM image and associated EDS maps of the 1.0 DDS film-based LED. The scale bars are 200 nm. Full size image The morphology of the PMC thin films is investigated with scanning electron microscope (SEM). As shown in Fig. 1b , the control film (FAPbI 3 ) without DDS is a reticular film composed of irregularly shaped particles. The bright areas in this SEM image are attributed to the parts of the polyethylenimine ethoxylated-modified zinc oxide nanoparticles (PEIE-ZnO) layer which are not covered by FAPbI 3 . With addition of DDS, the perovskite particles adopt a cuboid shape. In contrast to the control film, the perovskite grains in the PMC thin films are unambiguously bright while the uncovered areas become dark with the addition of DDS. In addition, increasing amount of DDS leads to decreasing areal density of the perovskite grains. In order to understand the composition of the areas which are not covered by the perovskite grains in the PMC thin films, we perform cross-sectional transmission electron microscopy (TEM) characterizations. We take the 1.0 DDS film as an example,", "role": "user" }, { "content": "Researchers at Linköping University, working with colleagues in Great Britain, China and the Czech Republic, have developed a perovskite light-emitting diode (LED) with both high efficiency and long operational stability. The result has been published in Nature Communications. \"Light-emitting diodes based on perovskites are still not sufficiently stable for practical use, but we have brought them one step closer,\" says Professor Feng Gao, and head of research at the Division of Biomolecular and Organic Electronics, Linköping University. Perovskites are a large family of semiconducting materials that have aroused the interest of scientists around the world. Their special crystal structure means that they have excellent optical and electronic properties, while they are both easy and cheap to manufacture. Most progress has been made in research into the use of perovskites in solar cells, but they are also well-suited for the manufacture of LEDs. The efficiency of the LEDs, which measures the fraction of charge carriers input to the material that are subsequently emitted as light, has increased considerably in recent years, and will soon reach that of competing technology. They are, however, not particularly stable, which means that so far they cannot be used in practice. \"Much remains to be done. Until now, most of the perovskite LEDs have either low efficiency or poor device stability,\" says Xiao-Ke LiU, research fellow in the Division of Biomolecular and Organic Electronics. He and Feng Gao are the principal authors of the article. Many research groups have worked on this dilemma, without particular success. Now, researchers at LiU, working with colleagues in Great Britain, China and the Czech Republic, have found a way forward. They have used a perovskite that consists of lead, iodine and an organic substance, formamidinium. They have then embedded the perovskite into an organic molecule matrix to form a composite thin film. \"This molecule with two amino groups at its ends helps the other substances to form a high quality crystal structure that is characteristic for perovskites, and makes the crystal stable,\" says Heyong Wang, doctoral student in the Division of Biomolecular and Organic Electronics. The new composite thin film has enabled the research group to develop LEDs with an efficiency of 17.3% with a long half-lifetime, approximately 100 hours. Perovskites that contain lead and a halogen, in this case iodine, have the best light-emitting properties. \"We would very much like to get rid of the lead. So far we haven't found a good way to do this, but we are working hard on it, says Feng Gao. The next steps are to test new combinations of different perovskites and organic molecules and to understand in detail how the nucleation and crystallisation processes occur. Different perovskites give light at different wavelengths, which is a requirement for the long-term goal of obtaining white light LEDs. ", "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 perovskite light-emitting diodes (PeLEDs) have recently experienced significant progress, there are only scattered reports of PeLEDs with both high efficiency and long operational stability, calling for additional strategies to address this challenge. Here, we develop perovskite-molecule composite thin films for efficient and stable PeLEDs. The perovskite-molecule composite thin films consist of in-situ formed high-quality perovskite nanocrystals embedded in the electron-transport molecular matrix, which controls nucleation process of perovskites, leading to PeLEDs with a peak external quantum efficiency of 17.3% and half-lifetime of approximately 100 h. In addition, we find that the device degradation mechanism at high driving voltages is different from that at low driving voltages. This work provides an effective strategy and deep understanding for achieving efficient and stable PeLEDs from both material and device perspectives. Introduction Metal halide perovskites have attracted significant attention for light-emitting applications, because of their excellent properties such as high photoluminescence quantum efficiency (PLQE), narrow emission bandwidth, readily tunable emission spectra ranging from ultraviolet to near-infrared, and solution processability 1 , 2 , 3 , 4 . Recently, rapid progress has been made in perovskite light-emitting diodes (PeLEDs), with external quantum efficiencies (EQEs) reaching more than 20% through suppression of non-radiative recombination and improvement of light out-coupling efficiency 5 , 6 , 7 , 8 , 9 . In addition to high efficiency, it is also important to achieve PeLEDs with long operational stability, a key factor towards practical applications. However, improving operational stability of PeLEDs is still a major challenge, and obtaining PeLEDs with both high efficiency and long operational stability remains elusive. From the materials point of view, a highly luminescent and stable perovskite film is essential to achieve PeLEDs with both high efficiency and long operational stability. Several approaches have been attempted towards this direction, including mixed A-site cations 10 , 11 , 12 , 13 , 14 , all-inorganic perovskites 15 , perovskite–polymer bulk heterostructures 7 , quasi-core/shell structure 6 , etc. Unfortunately, most of these approaches lead to either low efficiency or poor device stability. Not until very recently did rational additive engineering enable PeLEDs with both high efficiency and long operational stability in a few reports 5 , 8 . Herein, we develop an effective approach, i.e., perovskite-molecule composite (PMC) thin films, for efficient and stable PeLEDs. Our PMC films consist of formamidinium lead iodide (FAPbI 3 ) perovskite nanocrystal islands embedded in an electron-transport molecular matrix of 4,4′-diaminodiphenyl sulfone (DDS). We find that DDS controls nucleation process of the perovskite nanocrystals, leading to the formation of PMC thin films with enhanced PLQEs and prolonged PL lifetime. Moreover, this PMC structure shows impressive structural stability of α-phase FAPbI 3 for over half a year in ambient air with relative humidity of 20–80%. By employing the PMC thin films as emissive layers, we achieve LEDs with a peak EQE of 17.3% and half-lifetime ( T 50 , the time it takes until the light output reaches 50% of the maximum output) of 100 h at a constant current density of 20 mA cm –2 (initial radiance of 15 W m −2 sr −1 ). Considering the huge library of molecular semiconductors developed in organic LEDs 16 , 17 , more efficient and stable PMC thin films can be expected for achieving high-performance PeLEDs. In addition, from the device point of view, we find that the degradation mechanism of PeLEDs at high driving voltages is different from that at low driving voltages. Our findings in both materials and devices will spur further developments of PeLEDs with high efficiency and long operational stability for practical applications in lighting and display. Results PMC thin films The PMC thin films are prepared by facile one-step spin-coating from precursor solutions of formamidinium iodide (FAI), lead iodide (PbI 2 ), and DDS dissolved in N,N-dimethylformamide (DMF) ( x DDS films, where x = 0.5, 1.0 and 2.0, denote the films prepared with a DDS:Pb 2+ molar ratio of x :1.0; see the “Methods” section for details). Diphenyl sulfone is widely used as an electron-transport building block in molecular semiconductors 18 , and its derivatives such as di(4-(4-diphenylaminophenyl) phenyl) sulfone have been reported as efficient blue emissive molecules 17 . In this study, a diphenyl sulfone derivative, DDS (the chemical structure shown in Fig. 1a ), is chosen as the target molecular semiconductor due to its high singlet and triplet energies of 3.59 and 2.95 eV 19 , respectively, avoiding energy transfer from the perovskite nanocrystals to the molecule. In addition, DDS retains the electron-transport property of diphenyl sulfone (Supplementary Fig. 1 and Supplementary Note 1 ), while its amino group can help to control the growth of perovskite nanocrystals through chemical bonding with the perovskite, as will be discussed later. Fig. 1: Morphology of PMC thin films. a Molecular structure of DDS. b Top-view SEM images of perovskite films. The scale bars are 500 nm. c Cross-sectional bright-field TEM image, and d cross-sectional HAADF-STEM image and associated EDS maps of the 1.0 DDS film-based LED. The scale bars are 200 nm. Full size image The morphology of the PMC thin films is investigated with scanning electron microscope (SEM). As shown in Fig. 1b , the control film (FAPbI 3 ) without DDS is a reticular film composed of irregularly shaped particles. The bright areas in this SEM image are attributed to the parts of the polyethylenimine ethoxylated-modified zinc oxide nanoparticles (PEIE-ZnO) layer which are not covered by FAPbI 3 . With addition of DDS, the perovskite particles adopt a cuboid shape. In contrast to the control film, the perovskite grains in the PMC thin films are unambiguously bright while the uncovered areas become dark with the addition of DDS. In addition, increasing amount of DDS leads to decreasing areal density of the perovskite grains. In order to understand the composition of the areas which are not covered by the perovskite grains in the PMC thin films, we perform cross-sectional transmission electron microscopy (TEM) characterizations. We take the 1.0 DDS film as an example,<|im_end|> <|im_start|>assistant Researchers at Linköping University, working with colleagues in Great Britain, China and the Czech Republic, have developed a perovskite light-emitting diode (LED) with both high efficiency and long operational stability. The result has been published in Nature Communications. "Light-emitting diodes based on perovskites are still not sufficiently stable for practical use, but we have brought them one step closer," says Professor Feng Gao, and head of research at the Division of Biomolecular and Organic Electronics, Linköping University. Perovskites are a large family of semiconducting materials that have aroused the interest of scientists around the world. Their special crystal structure means that they have excellent optical and electronic properties, while they are both easy and cheap to manufacture. Most progress has been made in research into the use of perovskites in solar cells, but they are also well-suited for the manufacture of LEDs. The efficiency of the LEDs, which measures the fraction of charge carriers input to the material that are subsequently emitted as light, has increased considerably in recent years, and will soon reach that of competing technology. They are, however, not particularly stable, which means that so far they cannot be used in practice. "Much remains to be done. Until now, most of the perovskite LEDs have either low efficiency or poor device stability," says Xiao-Ke LiU, research fellow in the Division of Biomolecular and Organic Electronics. He and Feng Gao are the principal authors of the article. Many research groups have worked on this dilemma, without particular success. Now, researchers at LiU, working with colleagues in Great Britain, China and the Czech Republic, have found a way forward. They have used a perovskite that consists of lead, iodine and an organic substance, formamidinium. They have then embedded the perovskite into an organic molecule matrix to form a composite thin film. "This molecule with two amino groups at its ends helps the other substances to form a high quality crystal structure that is characteristic for perovskites, and makes the crystal stable," says Heyong Wang, doctoral student in the Division of Biomolecular and Organic Electronics. The new composite thin film has enabled the research group to develop LEDs with an efficiency of 17.3% with a long half-lifetime, approximately 100 hours. Perovskites that contain lead and a halogen, in this case iodine, have the best light-emitting properties. "We would very much like to get rid of the lead. So far we haven't found a good way to do this, but we are working hard on it, says Feng Gao. The next steps are to test new combinations of different perovskites and organic molecules and to understand in detail how the nucleation and crystallisation processes occur. Different perovskites give light at different wavelengths, which is a requirement for the long-term goal of obtaining white light LEDs. <|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 Electric eels ( Electrophorus electricus ) are legendary for their ability to incapacitate fish, humans, and horses with hundreds of volts of electricity. The function of this output as a weapon has been obvious for centuries but its potential role for electroreception has been overlooked. Here it is shown that electric eels use high-voltage simultaneously as a weapon and for precise and rapid electrolocation of fast-moving prey and conductors. Their speed, accuracy, and high-frequency pulse rate are reminiscent of bats using a ‘terminal feeding buzz’ to track insects. Eel’s exhibit ‘sensory conflict’ when mechanosensory and electrosensory cues are separated, striking first toward mechanosensory cues and later toward conductors. Strikes initiated in the absence of conductors are aborted. In addition to providing new insights into the evolution of strongly electric fish and showing electric eels to be far more sophisticated than previously described, these findings reveal a trait with markedly dichotomous functions. Introduction Few species have garnered more historical interest and investigation than electric eels. First used as a prized source of electricity in experiments by Walsh 1 , Humboldt 2 and Faraday 3 they later played a pivotal role in the isolation of the acetylcholine receptor 4 and determining the structure of voltage-gated sodium channels 5 . For centuries it was obvious that eels used their high voltage as a weapon, but how it evolved remained a mystery to Darwin 6 who considered electric organs under ‘Special Difficulties of the Theory of Natural Selection’. The difficulty in the case of strongly electric fish was that no function had been ascribed to the smaller electric organs that were present in many extant species and that must have been present in eel ancestors. The discovery in the 1950s that weakly electric fish generate minute electric fields as part of an elaborate sensory system 7 solved this longstanding mystery. Weakly electric fish, including close relatives of the electric eel, are able to discriminate objects with electricity by monitoring distortions in a self-generated electric field surrounding their body 8 , 9 , 10 , 11 . Electric eels retain this low-voltage sensory system 12 , 13 including a weak electrical discharge and corresponding electroreceptors ( Fig. 1 ). But the possibility that the eel’s high-voltage discharge plays a sensory role has been overlooked. Figure 1: Electric eel senses and discharge. ( a ) Eel colourized to show electroreceptors (magenta) and mechanoreceptors-neuromast canals (blue). ( b ) The weak, low-voltage output used for electrolocation and the high-voltage, high-frequency output used as a weapon. ( c ) Schematic illustration of electrolocation based on the convergence of electric field lines on the eel’s skin (arrow). Full size image The experiments described below address this question by taking advantage of the binary nature of the eel’s hunting behaviour. Eels emit the low-voltage weak output while searching and the high-voltage output when striking. Strikes begin with high-voltage volley onset (≈400 Hz, Fig. 1 ) followed milliseconds later by rapid head translation, and culminate in suction-feeding when the target is reached. Here experiments show that eels can find and track conductors using these high-voltage volleys without the aid of vision, mechanosensation, chemoreception or biogenic electric fields. Results Experiments using stationary conductors In the first set of experiments eel attacks were elicited by twitch artificially generated from a prey fish. Electric eels use hunting ‘doublets’ (two closely spaced high-voltage discharges 14 , 15 ) to induce involuntary twitch in nearby hidden prey, which generates a mechanosensory cue detectable by the eel 15 . For these experiments prey fish were anaesthetized, pithed to destroy the brain and electrically insulated in a plastic bag. Twitch in the pithed-fish preparation was generated through a Grass stimulator that could be triggered by the investigator or by a PowerLab unit in response to an eel hunting doublet. The pithed-fish preparation was covered with a thin electrically permeable agar barrier 16 , 17 that did not mask mechanosensory cues 6 . For one eel (eel A), preliminary data were collected for attacks either in the presence of only the insulated fish preparation, or alternatively in the presence of the fish preparation and a conductive carbon rod. When only the insulated fish preparation was present, the eel responded to fish twitch with a high-voltage volley and rapid strike often towards and over the fish, but the strike never culminated in a suction-feeding attempt ( Supplementary Movie 1 ) characteristic of final prey capture (six trials). When a conductive carbon rod was added to the preparation, fish twitch elicited high-voltage volleys, rapid head translation and a violent suction-feeding attempt ( Supplementary Movie 1 ) at the carbon rod (six trials). These observations were followed by more detailed investigation in two additional eels ( Fig. 2 ). In this second paradigm, the insulated fish preparation was placed next to a series of six equally spaced plastic rods and a single, conductive carbon rod (relocated between trials), all covered with a thin electrically permeable agar barrier ( Fig. 2a ). Figure 2: Paradigm showing that electric eels find and attack conductors. ( a ) Recording and stimulator configuration that triggered pithed-fish twitch and eel attack in the presence of six plastic rods and one conductor (arrow). ( b ) Plates from high-speed movie (top) and real-time (bottom) of same trial illustrating circuitous path to conductor. ( c ) Eel low- and high-voltage discharge marked with short, and tall ticks, respectively, illustrating the exclusive use of high-voltage during strike movement. ( d ) Eel path to conductor. Full size image Fish twitch again elicited eel high-voltage attack volleys and rapid strikes. The eel strikes took variable and often indirect paths, but always culminated with an aggressive suction-feeding attempt directed at the conductor ( Fig. 2 , Supplementary Fig. 1 , Supplementary Movie 2A and 2B ). The attacks were significantly concentrated on the conductor when considered as a two-choice test between any plastic rod or the single conductive carbon rod (eel B, n =6 trials, P =0.016; eel C, n =12", "role": "user" }, { "content": "(Phys.org)—Kenneth Catania, a biological scientist with Vanderbilt University, has found evidence that suggests that electric eels use their electrical powers to both stun prey and to find them. In his paper published in the journal Nature Communications, he describes the study he undertook of the eels in his lab and how he showed that they use electrolocation to find the prey they have stunned. Contrary to popular belief, the jolt of electricity administered by an electric eel (which the eel stores in cells known as electrocytes—similar to a battery) is not meant to kill prey, but instead is meant to stun it into submission by causing its muscles to spasm uncontrollably (like a taser) leaving it unable to swim away. But, logic suggests that would not be enough, after all the eel lives in the murky depths of the Amazon River where it is difficult to see very far. A fish that was stunned while moving fast would keep on moving for a little while due to simple momentum—so, how does the eel find the fish it just stunned? Catania suggests by using a skill very similar to bats—by sensing where they are using the very same electricity they used to stun it. Catania came to this conclusion by running two sorts of tests in his lab—the first involved putting a fish (prey) that had been made brain dead and insulated to prevent them from being shocked into a tank with various eels and then causing the fish to flinch with an electrode. The eels behaved as if confused—instead of consuming the fish, they wandered aimlessly, suggesting they could not find them. When he added charged metal and uncharged plastic rods to the tank, the eels tended to move towards the metal rod after trying to shock the fish, instead of the fish, but never towards the plastic rod. In the second set of tests, Catania attached various objects to a spinning wheel, only one of which was electrically conductive, and then incited the eels to strike under different conditions—the eels regularly went for the conductive object, and ignored the others indicating very strongly that they were using their own electrical charge as a means for finding prey after stunning it. Electric eel. Credit: Kenneth Catania Taken together the experiments show that electric eels do indeed use electrolocation to find prey after stunning it. Preliminary trials showing electric eel attacks induced by pitched fish twitch in the absence and presence of conductor. Credit: Kenneth Catania Electric eel attacks induced by pitched fish twitch in the absence of conductor. Credit: Kenneth Catania Eel strike at moving conductor under full spectrum lighting, first in real time, then in slow motion. Credit: Kenneth Catania ", "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 Electric eels ( Electrophorus electricus ) are legendary for their ability to incapacitate fish, humans, and horses with hundreds of volts of electricity. The function of this output as a weapon has been obvious for centuries but its potential role for electroreception has been overlooked. Here it is shown that electric eels use high-voltage simultaneously as a weapon and for precise and rapid electrolocation of fast-moving prey and conductors. Their speed, accuracy, and high-frequency pulse rate are reminiscent of bats using a ‘terminal feeding buzz’ to track insects. Eel’s exhibit ‘sensory conflict’ when mechanosensory and electrosensory cues are separated, striking first toward mechanosensory cues and later toward conductors. Strikes initiated in the absence of conductors are aborted. In addition to providing new insights into the evolution of strongly electric fish and showing electric eels to be far more sophisticated than previously described, these findings reveal a trait with markedly dichotomous functions. Introduction Few species have garnered more historical interest and investigation than electric eels. First used as a prized source of electricity in experiments by Walsh 1 , Humboldt 2 and Faraday 3 they later played a pivotal role in the isolation of the acetylcholine receptor 4 and determining the structure of voltage-gated sodium channels 5 . For centuries it was obvious that eels used their high voltage as a weapon, but how it evolved remained a mystery to Darwin 6 who considered electric organs under ‘Special Difficulties of the Theory of Natural Selection’. The difficulty in the case of strongly electric fish was that no function had been ascribed to the smaller electric organs that were present in many extant species and that must have been present in eel ancestors. The discovery in the 1950s that weakly electric fish generate minute electric fields as part of an elaborate sensory system 7 solved this longstanding mystery. Weakly electric fish, including close relatives of the electric eel, are able to discriminate objects with electricity by monitoring distortions in a self-generated electric field surrounding their body 8 , 9 , 10 , 11 . Electric eels retain this low-voltage sensory system 12 , 13 including a weak electrical discharge and corresponding electroreceptors ( Fig. 1 ). But the possibility that the eel’s high-voltage discharge plays a sensory role has been overlooked. Figure 1: Electric eel senses and discharge. ( a ) Eel colourized to show electroreceptors (magenta) and mechanoreceptors-neuromast canals (blue). ( b ) The weak, low-voltage output used for electrolocation and the high-voltage, high-frequency output used as a weapon. ( c ) Schematic illustration of electrolocation based on the convergence of electric field lines on the eel’s skin (arrow). Full size image The experiments described below address this question by taking advantage of the binary nature of the eel’s hunting behaviour. Eels emit the low-voltage weak output while searching and the high-voltage output when striking. Strikes begin with high-voltage volley onset (≈400 Hz, Fig. 1 ) followed milliseconds later by rapid head translation, and culminate in suction-feeding when the target is reached. Here experiments show that eels can find and track conductors using these high-voltage volleys without the aid of vision, mechanosensation, chemoreception or biogenic electric fields. Results Experiments using stationary conductors In the first set of experiments eel attacks were elicited by twitch artificially generated from a prey fish. Electric eels use hunting ‘doublets’ (two closely spaced high-voltage discharges 14 , 15 ) to induce involuntary twitch in nearby hidden prey, which generates a mechanosensory cue detectable by the eel 15 . For these experiments prey fish were anaesthetized, pithed to destroy the brain and electrically insulated in a plastic bag. Twitch in the pithed-fish preparation was generated through a Grass stimulator that could be triggered by the investigator or by a PowerLab unit in response to an eel hunting doublet. The pithed-fish preparation was covered with a thin electrically permeable agar barrier 16 , 17 that did not mask mechanosensory cues 6 . For one eel (eel A), preliminary data were collected for attacks either in the presence of only the insulated fish preparation, or alternatively in the presence of the fish preparation and a conductive carbon rod. When only the insulated fish preparation was present, the eel responded to fish twitch with a high-voltage volley and rapid strike often towards and over the fish, but the strike never culminated in a suction-feeding attempt ( Supplementary Movie 1 ) characteristic of final prey capture (six trials). When a conductive carbon rod was added to the preparation, fish twitch elicited high-voltage volleys, rapid head translation and a violent suction-feeding attempt ( Supplementary Movie 1 ) at the carbon rod (six trials). These observations were followed by more detailed investigation in two additional eels ( Fig. 2 ). In this second paradigm, the insulated fish preparation was placed next to a series of six equally spaced plastic rods and a single, conductive carbon rod (relocated between trials), all covered with a thin electrically permeable agar barrier ( Fig. 2a ). Figure 2: Paradigm showing that electric eels find and attack conductors. ( a ) Recording and stimulator configuration that triggered pithed-fish twitch and eel attack in the presence of six plastic rods and one conductor (arrow). ( b ) Plates from high-speed movie (top) and real-time (bottom) of same trial illustrating circuitous path to conductor. ( c ) Eel low- and high-voltage discharge marked with short, and tall ticks, respectively, illustrating the exclusive use of high-voltage during strike movement. ( d ) Eel path to conductor. Full size image Fish twitch again elicited eel high-voltage attack volleys and rapid strikes. The eel strikes took variable and often indirect paths, but always culminated with an aggressive suction-feeding attempt directed at the conductor ( Fig. 2 , Supplementary Fig. 1 , Supplementary Movie 2A and 2B ). The attacks were significantly concentrated on the conductor when considered as a two-choice test between any plastic rod or the single conductive carbon rod (eel B, n =6 trials, P =0.016; eel C, n =12<|im_end|> <|im_start|>assistant (Phys.org)—Kenneth Catania, a biological scientist with Vanderbilt University, has found evidence that suggests that electric eels use their electrical powers to both stun prey and to find them. In his paper published in the journal Nature Communications, he describes the study he undertook of the eels in his lab and how he showed that they use electrolocation to find the prey they have stunned. Contrary to popular belief, the jolt of electricity administered by an electric eel (which the eel stores in cells known as electrocytes—similar to a battery) is not meant to kill prey, but instead is meant to stun it into submission by causing its muscles to spasm uncontrollably (like a taser) leaving it unable to swim away. But, logic suggests that would not be enough, after all the eel lives in the murky depths of the Amazon River where it is difficult to see very far. A fish that was stunned while moving fast would keep on moving for a little while due to simple momentum—so, how does the eel find the fish it just stunned? Catania suggests by using a skill very similar to bats—by sensing where they are using the very same electricity they used to stun it. Catania came to this conclusion by running two sorts of tests in his lab—the first involved putting a fish (prey) that had been made brain dead and insulated to prevent them from being shocked into a tank with various eels and then causing the fish to flinch with an electrode. The eels behaved as if confused—instead of consuming the fish, they wandered aimlessly, suggesting they could not find them. When he added charged metal and uncharged plastic rods to the tank, the eels tended to move towards the metal rod after trying to shock the fish, instead of the fish, but never towards the plastic rod. In the second set of tests, Catania attached various objects to a spinning wheel, only one of which was electrically conductive, and then incited the eels to strike under different conditions—the eels regularly went for the conductive object, and ignored the others indicating very strongly that they were using their own electrical charge as a means for finding prey after stunning it. Electric eel. Credit: Kenneth Catania Taken together the experiments show that electric eels do indeed use electrolocation to find prey after stunning it. Preliminary trials showing electric eel attacks induced by pitched fish twitch in the absence and presence of conductor. Credit: Kenneth Catania Electric eel attacks induced by pitched fish twitch in the absence of conductor. Credit: Kenneth Catania Eel strike at moving conductor under full spectrum lighting, first in real time, then in slow motion. Credit: Kenneth Catania <|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 Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs 1 , 2 , 3 . Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier 4 , 5 , 6 , 7 , 8 , 9 . Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration 7 , 8 , 9 . However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies. Main Apoptosis and necroptosis are major forms of regulated cell death 10 . Necroptosis involves in part molecules also found to regulate apoptosis but depends on the formation of the necrosome, consisting of RIPK1 and RIPK3, which activates the pseudokinase mixed lineage kinase domain-like (MLKL) by phosphorylation, leading to the execution of the necroptotic program 11 , 12 , 13 . Critical for the formation of the necrosome is a compromised caspase-8 activity, which functions as a mediator of apoptosis 14 , 15 . While studying the interaction of tumour cells (TCs) and endothelial cells (ECs), we found an increased number of dead ECs when co-cultured with TCs ( Fig. 1a ). Dying ECs lacked typical apoptotic features such as nuclear condensation and/or fragmentation 16 as well as annexin-V-positivity that were found in apoptotic ECs after treatment with TRAIL, staurosporine or tumour-necrosis factor-α (TNF-α) ( Fig. 1a and Extended Data Fig. 1a–c ). Instead, similar to nuclei of cells that underwent H 2 O 2 - or hypoxia-induced accidental necrosis, nuclei of ECs exposed to TCs showed minor changes in morphology but were positive for ethidium-homodimer-III (EthD-III), which, like propidium iodide, indicates necrotic cells with compromised membrane integrity 16 ( Fig. 1a , Extended Data Fig. 1a, d and Supplementary Videos 1 , 2 , 3 and 4 ). TC-induced necrotic EC death was not affected by addition of peripheral blood mononuclear cells and platelets ( Extended Data Fig. 1e ) and was seen during co-culture of different primary human and murine ECs with a variety of TC lines in a concentration-dependent manner ( Fig. 1b and Extended Data Fig. 1f–h ). Figure 1: TC-induced endothelial necroptosis promotes TC transendothelial migration. a , Fluorescent images of human umbilical vein ECs (HUVECs) cultured in the presence of TCs (green) and stained as indicated. Arrowheads, EthD-III-positive ECs; scale bar, 10 μm. b , EC necrosis upon exposure to different TCs. c – f , EC necrosis in the presence of MDA-MB-231 TCs ( c , d ) and MDA-MB-231 TC transmigration over an endothelial layer ( e , f ) after siRNA-mediated knockdown in ECs as indicated ( c , e ) or after treatment with Nec-1 (30 μM) or z-VAD-fmk (zVAD, 100 μM) ( d , f ). Shown are representative data of two ( b ) or three ( c – f ) independent experiments with mean values ± s.e.m. ( b – d ) or ± s.d. ( e , f ) from biological triplicates ( n = 3) ( b ) or sextuplicates ( n = 6) ( c – f ). * P < 0.05; ** P < 0.01; *** P < 0.001. One-way analysis of variance (ANOVA) and Bonferroni’s post hoc test. PowerPoint slide Full size image EthD-III-positive ECs also co-stained for phospho-MLKL ( Extended Data Fig. 1i ), and knockdown of RIPK3 or MLKL in ECs as well as treatment of cells with the RIPK1 kinase inhibitor necrostatin-1 (Nec-1) blocked TC-induced endothelial necrotic cell death ( Fig. 1c, d and Extended Data Fig. 1j, k ). In contrast, knockdown of caspase-8, a major negative regulator of necroptosis 14 , 15 , or inhibition of caspases by treatment of cells with z-VAD-fmk (zVAD) increased the number of necrotic ECs ( Fig. 1c, d and Extended Data Fig. 1j ). These data identify the mode of TC-induced EC death as necroptosis. Interestingly, inhibition of TC-induced necroptosis reduced TC migration over an EC layer whereas enhanced necroptosis promoted transmigration ( Fig. 1e, f ). Within a few hours after intravenous (i.v.) injection of syngeneic B16F10 (B16) melanoma or LLC1 (Lewis lung carcinoma line 1) cells into C57BL/6 wild-type (WT) mice, the lungs of these animals showed EthD-III-positive cells ( Fig. 2a and Extended Data Fig. 2a ), which co-stained for the EC markers ERG and CD31 ( Fig. 2b and Extended Data Fig. 2b ) but did not show any overlap with fluorescently labelled TCs or CD45-positive leukocytes ( Extended Data Fig. 2c ). EthD-III-positive ECs showed no signs of chromatin condensation or fragmentation ( Fig. 2a ) and were negative for cleaved caspase-3, TdT-mediated dUTP nick end labelling (TUNEL) or annexin-V ( Fig. 2a and Extended Data Fig. 2d ). TC-induced EC necrosis was not a result of physical blood vessel occlusion, as it was not reproduced by i.v. injection of equal amounts of 15 μm microspheres ( Extended Data Fig. 2e ). In mice with tamoxifen-induced endothelium-specific RIPK3-deficiency (Tie2-CreER T2 ;RIPK3 loxP/loxP (RIPK3 ECKO ); Extended Data", "role": "user" }, { "content": "Many cancers only become a mortal danger if they form metastases elsewhere in the body. Such secondary tumours are formed when individual cells break away from the main tumour and travel through the bloodstream to distant areas of the body. To do so, they have to pass through the walls of small blood vessels. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Goethe University Frankfurt have now shown that tumour cells kill specific cells in the vascular wall. This enables them to leave the vessels and establish metastases, a process facilitated by a molecule called DR6. The most common cause of cancer deaths is not the primary tumour itself but metastases that subsequently form. Most tumour cells spread via the bloodstream. To do so, individual tumour cells have to enter blood vessels and leave the bloodstream again at remote locations. Together with scientists at the universities of Cologne and Heidelberg, the Research Group led by Stefan Offermanns, Director of the Department of Pharmacology at the Max Planck Institute for Heart and Lung Research and professor at Goethe University Frankfurt, has now succeeded in clarifying the underlying mechanism. The researchers, working with cell cultures, first observed how individual tumour cells kill specific cells in the vascular wall, called endothelial cells. This process, known as necroptosis, enabled cancer cells to overcome an endothelial cell layer in the laboratory. \"We were then able to show in studies on mice that the same process occurs in living organisms,\" says Boris Strilic, first author of the study. The scientists also found that endothelial cells themselves give the signal for their own death: To do this, the vascular wall cells have a receptor molecule called Death Receptor 6 (DR6) on their surface. \"When a cancer cell comes into contact with it, a protein on the cell's surface, known as APP, activates DR6. This marks the start of the cancer cells' attack on the vascular wall, which culminates in the necroptosis of wall cells,\" Strilic explains. Death Receptor in the cell membrane The Max Planck researchers then showed that less necroptosis of endothelial cells and less metastasis occur in genetically modified animals in which Death Receptor 6 is disabled. \"This effect was also found after a blockade of DR6 or the cancer-cell protein APP, thus confirming our previous observations,\" Strilic says. It is still not entirely clear whether the cancer cells migrate directly through the resulting gap in the vascular wall or whether there is an indirect effect: \"We have evidence that many more molecules are released when the vascular wall cell dies and that they render the surrounding area more permeable to cancer cells,\" says Offermanns. \"This mechanism could be a promising starting point for treatments to prevent the formation of metastases,\" says Offermanns. First, however, it must be determined whether a blockade of DR6 triggers unwanted side effects. It must also be determined to what extent the observations can be transferred to 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 Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs 1 , 2 , 3 . Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier 4 , 5 , 6 , 7 , 8 , 9 . Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration 7 , 8 , 9 . However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies. Main Apoptosis and necroptosis are major forms of regulated cell death 10 . Necroptosis involves in part molecules also found to regulate apoptosis but depends on the formation of the necrosome, consisting of RIPK1 and RIPK3, which activates the pseudokinase mixed lineage kinase domain-like (MLKL) by phosphorylation, leading to the execution of the necroptotic program 11 , 12 , 13 . Critical for the formation of the necrosome is a compromised caspase-8 activity, which functions as a mediator of apoptosis 14 , 15 . While studying the interaction of tumour cells (TCs) and endothelial cells (ECs), we found an increased number of dead ECs when co-cultured with TCs ( Fig. 1a ). Dying ECs lacked typical apoptotic features such as nuclear condensation and/or fragmentation 16 as well as annexin-V-positivity that were found in apoptotic ECs after treatment with TRAIL, staurosporine or tumour-necrosis factor-α (TNF-α) ( Fig. 1a and Extended Data Fig. 1a–c ). Instead, similar to nuclei of cells that underwent H 2 O 2 - or hypoxia-induced accidental necrosis, nuclei of ECs exposed to TCs showed minor changes in morphology but were positive for ethidium-homodimer-III (EthD-III), which, like propidium iodide, indicates necrotic cells with compromised membrane integrity 16 ( Fig. 1a , Extended Data Fig. 1a, d and Supplementary Videos 1 , 2 , 3 and 4 ). TC-induced necrotic EC death was not affected by addition of peripheral blood mononuclear cells and platelets ( Extended Data Fig. 1e ) and was seen during co-culture of different primary human and murine ECs with a variety of TC lines in a concentration-dependent manner ( Fig. 1b and Extended Data Fig. 1f–h ). Figure 1: TC-induced endothelial necroptosis promotes TC transendothelial migration. a , Fluorescent images of human umbilical vein ECs (HUVECs) cultured in the presence of TCs (green) and stained as indicated. Arrowheads, EthD-III-positive ECs; scale bar, 10 μm. b , EC necrosis upon exposure to different TCs. c – f , EC necrosis in the presence of MDA-MB-231 TCs ( c , d ) and MDA-MB-231 TC transmigration over an endothelial layer ( e , f ) after siRNA-mediated knockdown in ECs as indicated ( c , e ) or after treatment with Nec-1 (30 μM) or z-VAD-fmk (zVAD, 100 μM) ( d , f ). Shown are representative data of two ( b ) or three ( c – f ) independent experiments with mean values ± s.e.m. ( b – d ) or ± s.d. ( e , f ) from biological triplicates ( n = 3) ( b ) or sextuplicates ( n = 6) ( c – f ). * P < 0.05; ** P < 0.01; *** P < 0.001. One-way analysis of variance (ANOVA) and Bonferroni’s post hoc test. PowerPoint slide Full size image EthD-III-positive ECs also co-stained for phospho-MLKL ( Extended Data Fig. 1i ), and knockdown of RIPK3 or MLKL in ECs as well as treatment of cells with the RIPK1 kinase inhibitor necrostatin-1 (Nec-1) blocked TC-induced endothelial necrotic cell death ( Fig. 1c, d and Extended Data Fig. 1j, k ). In contrast, knockdown of caspase-8, a major negative regulator of necroptosis 14 , 15 , or inhibition of caspases by treatment of cells with z-VAD-fmk (zVAD) increased the number of necrotic ECs ( Fig. 1c, d and Extended Data Fig. 1j ). These data identify the mode of TC-induced EC death as necroptosis. Interestingly, inhibition of TC-induced necroptosis reduced TC migration over an EC layer whereas enhanced necroptosis promoted transmigration ( Fig. 1e, f ). Within a few hours after intravenous (i.v.) injection of syngeneic B16F10 (B16) melanoma or LLC1 (Lewis lung carcinoma line 1) cells into C57BL/6 wild-type (WT) mice, the lungs of these animals showed EthD-III-positive cells ( Fig. 2a and Extended Data Fig. 2a ), which co-stained for the EC markers ERG and CD31 ( Fig. 2b and Extended Data Fig. 2b ) but did not show any overlap with fluorescently labelled TCs or CD45-positive leukocytes ( Extended Data Fig. 2c ). EthD-III-positive ECs showed no signs of chromatin condensation or fragmentation ( Fig. 2a ) and were negative for cleaved caspase-3, TdT-mediated dUTP nick end labelling (TUNEL) or annexin-V ( Fig. 2a and Extended Data Fig. 2d ). TC-induced EC necrosis was not a result of physical blood vessel occlusion, as it was not reproduced by i.v. injection of equal amounts of 15 μm microspheres ( Extended Data Fig. 2e ). In mice with tamoxifen-induced endothelium-specific RIPK3-deficiency (Tie2-CreER T2 ;RIPK3 loxP/loxP (RIPK3 ECKO ); Extended Data<|im_end|> <|im_start|>assistant Many cancers only become a mortal danger if they form metastases elsewhere in the body. Such secondary tumours are formed when individual cells break away from the main tumour and travel through the bloodstream to distant areas of the body. To do so, they have to pass through the walls of small blood vessels. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Goethe University Frankfurt have now shown that tumour cells kill specific cells in the vascular wall. This enables them to leave the vessels and establish metastases, a process facilitated by a molecule called DR6. The most common cause of cancer deaths is not the primary tumour itself but metastases that subsequently form. Most tumour cells spread via the bloodstream. To do so, individual tumour cells have to enter blood vessels and leave the bloodstream again at remote locations. Together with scientists at the universities of Cologne and Heidelberg, the Research Group led by Stefan Offermanns, Director of the Department of Pharmacology at the Max Planck Institute for Heart and Lung Research and professor at Goethe University Frankfurt, has now succeeded in clarifying the underlying mechanism. The researchers, working with cell cultures, first observed how individual tumour cells kill specific cells in the vascular wall, called endothelial cells. This process, known as necroptosis, enabled cancer cells to overcome an endothelial cell layer in the laboratory. "We were then able to show in studies on mice that the same process occurs in living organisms," says Boris Strilic, first author of the study. The scientists also found that endothelial cells themselves give the signal for their own death: To do this, the vascular wall cells have a receptor molecule called Death Receptor 6 (DR6) on their surface. "When a cancer cell comes into contact with it, a protein on the cell's surface, known as APP, activates DR6. This marks the start of the cancer cells' attack on the vascular wall, which culminates in the necroptosis of wall cells," Strilic explains. Death Receptor in the cell membrane The Max Planck researchers then showed that less necroptosis of endothelial cells and less metastasis occur in genetically modified animals in which Death Receptor 6 is disabled. "This effect was also found after a blockade of DR6 or the cancer-cell protein APP, thus confirming our previous observations," Strilic says. It is still not entirely clear whether the cancer cells migrate directly through the resulting gap in the vascular wall or whether there is an indirect effect: "We have evidence that many more molecules are released when the vascular wall cell dies and that they render the surrounding area more permeable to cancer cells," says Offermanns. "This mechanism could be a promising starting point for treatments to prevent the formation of metastases," says Offermanns. First, however, it must be determined whether a blockade of DR6 triggers unwanted side effects. It must also be determined to what extent the observations can be transferred to humans. <|im_end|>

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13, 320, 293, 1389, 294, 883, 477, 20903, 274, 962, 13, 320, 384, 1174, 282, 883, 505, 24156, 8577, 416, 988, 320, 308, 284, 220, 18, 8, 320, 293, 883, 477, 38103, 41714, 320, 308, 284, 220, 21, 8, 320, 272, 1389, 282, 7609, 353, 393, 366, 220, 15, 13, 2304, 26, 3146, 393, 366, 220, 15, 13, 1721, 26, 17601, 393, 366, 220, 15, 13, 4119, 13, 3861, 27896, 6492, 315, 33373, 320, 55994, 13114, 8, 323, 13789, 69, 618, 21446, 753, 1772, 67490, 1296, 13, 54600, 15332, 8797, 1404, 2217, 14693, 35, 12, 23440, 69788, 21283, 82, 1101, 1080, 5594, 2692, 369, 33088, 78, 12, 2735, 54083, 320, 41665, 2956, 23966, 13, 220, 16, 72, 7026, 323, 14459, 2996, 315, 91964, 42, 18, 477, 20187, 54083, 304, 21283, 82, 439, 1664, 439, 6514, 315, 7917, 449, 279, 91964, 42, 16, 82160, 70785, 19591, 299, 10079, 258, 12, 16, 320, 45, 762, 12, 16, 8, 19857, 25610, 38973, 93329, 59544, 19591, 4744, 292, 2849, 4648, 320, 23966, 13, 220, 16, 66, 11, 294, 323, 41665, 2956, 23966, 13, 220, 16, 73, 11, 597, 7609, 763, 13168, 11, 14459, 2996, 315, 4865, 79, 521, 12, 23, 11, 264, 3682, 8389, 40704, 315, 19591, 299, 418, 10934, 220, 975, 1174, 220, 868, 1174, 477, 61478, 315, 4865, 79, 2315, 555, 6514, 315, 7917, 449, 1167, 20198, 1846, 2269, 25457, 320, 89, 53, 1846, 8, 7319, 279, 1396, 315, 19591, 4744, 292, 21283, 82, 320, 23966, 13, 220, 16, 66, 11, 294, 323, 41665, 2956, 23966, 13, 220, 16, 73, 7609, 4314, 828, 10765, 279, 3941, 315, 25610, 38973, 21283, 4648, 439, 19591, 299, 418, 10934, 13, 58603, 11, 61478, 315, 25610, 38973, 19591, 299, 418, 10934, 11293, 25610, 12172, 927, 459, 21283, 6324, 20444, 24872, 19591, 299, 418, 10934, 30026, 1380, 81327, 320, 23966, 13, 220, 16, 68, 11, 282, 7609, 25218, 264, 2478, 4207, 1306, 10805, 81443, 320, 72, 3211, 6266, 26127, 315, 6705, 983, 1994, 292, 426, 845, 37, 605, 320, 33, 845, 8, 68012, 7942, 477, 15620, 16, 320, 100172, 21271, 89468, 1584, 220, 16, 8, 7917, 1139, 356, 3226, 9574, 14, 21, 8545, 10827, 320, 18961, 8, 24548, 11, 279, 45274, 315, 1521, 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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 mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia (72 miRNAs, B-H FDR 5%). Integrative miRNA-mRNA analysis implicates several infection-responsive miRNAs (e.g., miR-16-5p, miR-15a-5p and miR-181c-5p) promoting lymphocyte cell death. miRNA cis -eQTL analysis using whole-genome sequencing data identified 1,376 genetic variants associated with the expression of 34 miRNAs (B-H FDR 5%). We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression. These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria. Introduction Malaria is a major cause of morbidity and mortality with nearly half of the world’s population at risk of infection and 435,000 deaths annually 1 . The largest burden of the disease occurs in Sub-Saharan Africa with significant negative socio-economic consequences on the continent where Plasmodium falciparum accounts for >99% of estimated cases 1 . The search for effective and sustainable therapeutic strategies for malaria is hampered by limited understanding of the sources of variation in host immune response to natural P. falciparum infection. Several factors such as host and parasite genetics, state of immunity, and environment contribute to the observed variation. This in turn leads to variability in the symptomology and clinical manifestations of the disease, ranging from asymptomatic and symptomatic parasitemia to complicated and cerebral malaria 2 , 3 . Our understanding of the biological mechanisms underlying variation in host immune response to P. falciparum infection and in particular immune evasion is poorly understood 4 . Genome-wide association studies (GWAS) have only mapped a few loci contributing to host resistance to malaria 5 , 6 , 7 , 8 , 9 . The complexity of genotype–phenotype relationships in malaria and the limited power of GWAS in African populations warranted the use of alternative approaches that capture both genetic and environmental effects in vivo. Gene expression profiling has emerged as a powerful approach to study these mechanisms and overcome these limitations 10 , 11 , 12 , 13 . A central mechanism in immune response to infection is post-transcriptional regulation 14 and miRNAs in particular have emerged as key regulators of this response 15 , 16 , 17 . In malaria, a few studies have investigated the expression profiles of host miRNAs using either animal models or in vitro settings 18 , 19 , 20 , 21 . Using targeted miRNA profiling of adults experimentally infected with Plasmodium , Burel et al. 22 reported evidence of a potential role for miRNAs in inter-individual variability in immune response to P. falciparum infection. This study also demonstrated that individuals with higher expression of miR-15a-5p, miR-30c-5p, and miR-30e-5p had an increased frequency of activated and proliferating T cells and could better control P. falciparum growth during infection. Importantly, given the specificity of host immune processes and the fact that they vary based on host genotype and the environment 11 , 23 , it follows that studying these effects in vivo in African children before and after natural Plasmodium infection would be informative. To address this, we recruited and sampled a longitudinal pediatric cohort in Burkina Faso and completed global miRNASeq, total RNASeq profiling experiments and whole genome sequencing (WGS) at 30× coverage. The cohort was comprehensively assessed for various clinical, molecular, and cellular phenotypes before infection, during asymptomatic parasitemia and symptomatic parasitemia, and after treatment (68 samples in the discovery phase). Our hypothesis is that a robust matched design where children are monitored closely and sampled over time will reveal key differentially expressed miRNAs and early transcriptional response associated with biological pathways and functions implicated in in vivo host response to P. falciparum infection. The identified signature of miRNAs expression is striking with over one-third of the expressed miRNAs being significantly differentially expressed (127 miRNAs at Benjamini–Hochberg FDR (B–H FDR) 5%) following P. falciparum infection of noninfected children. To follow-up on this finding, in the following year we profiled a replication cohort of 53 infected children and captured a host-specific miRNA signature (72 miRNAs, B–H FDR 5%) of a primary blood-stage malaria clinical trait (parasitemia). In total, 36 miRNAs were associated with both infection (noninfected relative to infected individuals) and parasitemia (within the infected group) in the discovery and replication sets. Using joint analysis of miRNA and mRNA profiles generated separately but from the same blood samples collected from the same individuals, we identified key core adaptive immune pathways and cellular processes dysregulated during infection. In particular, we highlight infection-responsive miR-16-5p, miR-15a-5p, and miR-181c-5p that target the anti-apoptotic gene BCL2, induce apoptosis of immune cells and restrict the development of T cells 24 , 25 , 26 . Finally, genetic mapping of miRNAs using WGS data identified 1,376 genetic variants associated with the expression levels of 34 miRNAs (B–H FDR 5%). Together, these findings suggest that the mechanisms involved in controlling P. falciparum infection are under host genetic control at both the transcriptional and post-transcriptional levels. Results Study population (discovery and replication sets) A longitudinal pediatric cohort of 150 healthy children was recruited in Banfora, Burkina Faso. Enrollment took place at the end of the dry season and none of the children were P. falciparum -infected at the time of the first sample collection. The children were of age 2–10 years, had no disease symptoms or chronic disease history (including sickle cell disease) based on medical records and thorough physical assessment. In this study, a subset of 72 children 88% of whom have hemoglobin genotype AA were included, all of whom were not P. falciparum -infected when initially sampled and were subsequently followed on a weekly basis for up to 6 months. For the discovery set, clinical", "role": "user" }, { "content": "The plasmodium parasite, which transmits malaria to humans through infected mosquitos, triggers changes in human genes that alter the body's adaptive immune response to malarial infections, according to a team of researchers at NYU Abu Dhabi (NYUAD). The findings could bring hope for novel therapeutic strategies and a vaccine to regions where hundreds of thousands of people die annually from malaria, a preventable and curable disease, and where another 3 billion people are at risk of infection. The NYUAD researchers, in collaboration with the Center National de Recherche et de Formation sur le Paludisme in Burkina Faso, NYUAD Assistant Professor of Biology Youssef Idaghdour, Associate Scientist Mame Massar Dieng, and Aïssatou Diawara, studied the blood of children in rural Burkina Faso, West Africa, and have discovered a new immune evasion strategy used by the Plasmodium parasite. In the paper titled \"Integrative genomic analysis reveals mechanisms of immune evasion in P. falciparum malaria,\" published in the journal Nature Communications, the team of scientists studied the immune responses and genomes of the children before, during and after infection. They found that a class of genes, microRNAs (small molecules that play an integral role in regulation of genes involved in immune response) cause cell death of adaptive immune cells when in the presence of the Plasmodium parasite. Once the parasite avoids the immune response in the blood, it is then able to proliferate and invade other blood cells. It was also discovered that some microRNAs are under genetic control, which may explain why individuals and populations vary in their ability to cope with infection. Collecting a saliva sample from a child taking part in the study. Credit: Aissatou Diawara The largest burden of the disease occurs in sub-Saharan Africa, where the negative socioeconomic consequences are significant. The search for effective and sustainable therapeutic strategies for malaria has been stalled by a limited understanding of the sources of variation in host immune response to the parasitic infection. \"Our results shed new light on a mechanism for the weakening of adaptive immunity by invasive parasites,\" said Diawara. \"This could explain why it takes years for children to develop immunity and why vaccines do not provide long-term protection,\" added Dieng. \"The next step for the team will be to perform more functional tests and to gain a better understanding of why certain groups of people in Africa are more immune to the disease than others,\" said Idaghdour. \"Due to the impact of COVID-19 on healthcare systems, and screening and prevention programs, the burden of malaria could be worse in the coming years and it is our hope that this research can contribute to reaching the long-term goal of malaria elimination.\" ", "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 behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia (72 miRNAs, B-H FDR 5%). Integrative miRNA-mRNA analysis implicates several infection-responsive miRNAs (e.g., miR-16-5p, miR-15a-5p and miR-181c-5p) promoting lymphocyte cell death. miRNA cis -eQTL analysis using whole-genome sequencing data identified 1,376 genetic variants associated with the expression of 34 miRNAs (B-H FDR 5%). We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression. These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria. Introduction Malaria is a major cause of morbidity and mortality with nearly half of the world’s population at risk of infection and 435,000 deaths annually 1 . The largest burden of the disease occurs in Sub-Saharan Africa with significant negative socio-economic consequences on the continent where Plasmodium falciparum accounts for >99% of estimated cases 1 . The search for effective and sustainable therapeutic strategies for malaria is hampered by limited understanding of the sources of variation in host immune response to natural P. falciparum infection. Several factors such as host and parasite genetics, state of immunity, and environment contribute to the observed variation. This in turn leads to variability in the symptomology and clinical manifestations of the disease, ranging from asymptomatic and symptomatic parasitemia to complicated and cerebral malaria 2 , 3 . Our understanding of the biological mechanisms underlying variation in host immune response to P. falciparum infection and in particular immune evasion is poorly understood 4 . Genome-wide association studies (GWAS) have only mapped a few loci contributing to host resistance to malaria 5 , 6 , 7 , 8 , 9 . The complexity of genotype–phenotype relationships in malaria and the limited power of GWAS in African populations warranted the use of alternative approaches that capture both genetic and environmental effects in vivo. Gene expression profiling has emerged as a powerful approach to study these mechanisms and overcome these limitations 10 , 11 , 12 , 13 . A central mechanism in immune response to infection is post-transcriptional regulation 14 and miRNAs in particular have emerged as key regulators of this response 15 , 16 , 17 . In malaria, a few studies have investigated the expression profiles of host miRNAs using either animal models or in vitro settings 18 , 19 , 20 , 21 . Using targeted miRNA profiling of adults experimentally infected with Plasmodium , Burel et al. 22 reported evidence of a potential role for miRNAs in inter-individual variability in immune response to P. falciparum infection. This study also demonstrated that individuals with higher expression of miR-15a-5p, miR-30c-5p, and miR-30e-5p had an increased frequency of activated and proliferating T cells and could better control P. falciparum growth during infection. Importantly, given the specificity of host immune processes and the fact that they vary based on host genotype and the environment 11 , 23 , it follows that studying these effects in vivo in African children before and after natural Plasmodium infection would be informative. To address this, we recruited and sampled a longitudinal pediatric cohort in Burkina Faso and completed global miRNASeq, total RNASeq profiling experiments and whole genome sequencing (WGS) at 30× coverage. The cohort was comprehensively assessed for various clinical, molecular, and cellular phenotypes before infection, during asymptomatic parasitemia and symptomatic parasitemia, and after treatment (68 samples in the discovery phase). Our hypothesis is that a robust matched design where children are monitored closely and sampled over time will reveal key differentially expressed miRNAs and early transcriptional response associated with biological pathways and functions implicated in in vivo host response to P. falciparum infection. The identified signature of miRNAs expression is striking with over one-third of the expressed miRNAs being significantly differentially expressed (127 miRNAs at Benjamini–Hochberg FDR (B–H FDR) 5%) following P. falciparum infection of noninfected children. To follow-up on this finding, in the following year we profiled a replication cohort of 53 infected children and captured a host-specific miRNA signature (72 miRNAs, B–H FDR 5%) of a primary blood-stage malaria clinical trait (parasitemia). In total, 36 miRNAs were associated with both infection (noninfected relative to infected individuals) and parasitemia (within the infected group) in the discovery and replication sets. Using joint analysis of miRNA and mRNA profiles generated separately but from the same blood samples collected from the same individuals, we identified key core adaptive immune pathways and cellular processes dysregulated during infection. In particular, we highlight infection-responsive miR-16-5p, miR-15a-5p, and miR-181c-5p that target the anti-apoptotic gene BCL2, induce apoptosis of immune cells and restrict the development of T cells 24 , 25 , 26 . Finally, genetic mapping of miRNAs using WGS data identified 1,376 genetic variants associated with the expression levels of 34 miRNAs (B–H FDR 5%). Together, these findings suggest that the mechanisms involved in controlling P. falciparum infection are under host genetic control at both the transcriptional and post-transcriptional levels. Results Study population (discovery and replication sets) A longitudinal pediatric cohort of 150 healthy children was recruited in Banfora, Burkina Faso. Enrollment took place at the end of the dry season and none of the children were P. falciparum -infected at the time of the first sample collection. The children were of age 2–10 years, had no disease symptoms or chronic disease history (including sickle cell disease) based on medical records and thorough physical assessment. In this study, a subset of 72 children 88% of whom have hemoglobin genotype AA were included, all of whom were not P. falciparum -infected when initially sampled and were subsequently followed on a weekly basis for up to 6 months. For the discovery set, clinical<|im_end|> <|im_start|>assistant The plasmodium parasite, which transmits malaria to humans through infected mosquitos, triggers changes in human genes that alter the body's adaptive immune response to malarial infections, according to a team of researchers at NYU Abu Dhabi (NYUAD). The findings could bring hope for novel therapeutic strategies and a vaccine to regions where hundreds of thousands of people die annually from malaria, a preventable and curable disease, and where another 3 billion people are at risk of infection. The NYUAD researchers, in collaboration with the Center National de Recherche et de Formation sur le Paludisme in Burkina Faso, NYUAD Assistant Professor of Biology Youssef Idaghdour, Associate Scientist Mame Massar Dieng, and Aïssatou Diawara, studied the blood of children in rural Burkina Faso, West Africa, and have discovered a new immune evasion strategy used by the Plasmodium parasite. In the paper titled "Integrative genomic analysis reveals mechanisms of immune evasion in P. falciparum malaria," published in the journal Nature Communications, the team of scientists studied the immune responses and genomes of the children before, during and after infection. They found that a class of genes, microRNAs (small molecules that play an integral role in regulation of genes involved in immune response) cause cell death of adaptive immune cells when in the presence of the Plasmodium parasite. Once the parasite avoids the immune response in the blood, it is then able to proliferate and invade other blood cells. It was also discovered that some microRNAs are under genetic control, which may explain why individuals and populations vary in their ability to cope with infection. Collecting a saliva sample from a child taking part in the study. Credit: Aissatou Diawara The largest burden of the disease occurs in sub-Saharan Africa, where the negative socioeconomic consequences are significant. The search for effective and sustainable therapeutic strategies for malaria has been stalled by a limited understanding of the sources of variation in host immune response to the parasitic infection. "Our results shed new light on a mechanism for the weakening of adaptive immunity by invasive parasites," said Diawara. "This could explain why it takes years for children to develop immunity and why vaccines do not provide long-term protection," added Dieng. "The next step for the team will be to perform more functional tests and to gain a better understanding of why certain groups of people in Africa are more immune to the disease than others," said Idaghdour. "Due to the impact of COVID-19 on healthcare systems, and screening and prevention programs, the burden of malaria could be worse in the coming years and it is our hope that this research can contribute to reaching the long-term goal of malaria elimination." <|im_end|>

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2,049

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chromatin organization and enhancer-promoter contacts establish unique spatiotemporal gene expression patterns in distinct cell types. Non-coding genetic variants can influence cellular phenotypes by modifying higher-order transcriptional hubs and consequently gene expression. To elucidate genomic regulation in human retina, we mapped chromatin contacts at high resolution and integrated with super-enhancers (SEs), histone marks, binding of CTCF and select transcription factors. We show that topologically associated domains (TADs) with central SEs exhibit stronger insulation and augmented contact with retinal genes relative to TADs with edge SEs. Merging genome-wide expression quantitative trait loci (eQTLs) with topology map reveals physical links between 100 eQTLs and corresponding eGenes associated with retinal neurodegeneration. Additionally, we uncover candidate genes for susceptibility variants linked to age-related macular degeneration and glaucoma. Our study of high-resolution genomic architecture of human retina provides insights into genetic control of tissue-specific functions, suggests paradigms for missing heritability, and enables the dissection of common blinding disease phenotypes. Introduction The three-dimensional (3D) architecture of the human genome is regulated across multiple levels of organization, yielding precise spatiotemporal patterns of gene expression for morphogenesis and functional specification 1 , 2 . Gene regulation occurs within transcriptional units through productive enhancer-promoter contacts and/or by inclusion within transcriptionally active membraneless structures, called phase-separated condensates 3 , 4 , 5 , 6 . The transcriptional units are contained within megabase-sized self-interacting chromatin structures known as topologically associated domains (TADs). The boundaries of TADs are enriched for binding of structural proteins including CTCF and cohesin 7 , 8 , 9 . Genome organization also exhibits A (active) and B (inactive) chromatin compartments, which display distinct patterns of DNA replication and transcription along with differences in regulatory marks 10 , 11 , 12 , 13 . Across the 3D hierarchy, genome topology undergoes dynamic and contextual physical alterations in distinct tissues and cell types 14 , 15 . These adaptations correlate with activation of specific cis -regulatory elements (CREs) that contribute to the establishment of unique gene expression patterns 14 , 16 , 17 . Cell-type specific gene expression is further orchestrated by super-enhancers (SEs), regulatory regions spanning over tens of kilobases that are highly enriched for master transcription factor (TF) binding and co-localized with the active histone mark H3K27Ac 18 , 19 , 20 . Over the past decade, millions of human genetic variations have been cataloged 21 , 22 , permitting exploration of evolutionary divergence as well as healthy and disease phenotypes. Genome-wide association studies (GWAS) of common multifactorial retinal diseases afflicting adult human populations, such as age-related macular degeneration (AMD) and glaucoma, have predominantly identified common variants in non-coding regions of the genome 23 , 24 . However, the biological relevance of association signals has been difficult to assess because of the local linkage disequilibrium (LD) in the region of lead variants, hindering identification of specific causal genes and variants 25 . Even in Mendelian retinal diseases with over 200 associated genes identified (RetNet; ), causal mutations can only be identified in about half of the patients (primarily in European population) 26 and genotype-phenotype correlations have been difficult to decipher. Non-coding variants in cis -regulatory regions may lead to variable penetrance of pathogenic coding mutations in their target genes 27 , genetic epistasis 28 , or account for missing heritability 29 . Widespread variability in gene expression observed in humans can be assigned to cis - or trans -acting variants (expression quantitative trait loci, eQTLs) and epistasis 30 . Elucidating how trait-associated genetic variations impact the regulatory landscape and consequently phenotypes requires understanding the 3D genome topology in relevant tissues and cell types. Here, we report a high-resolution chromatin contact map of the adult human retina by performing Hi-C 1 . Further integration of chromatin contacts with histone marks, chromatin accessibility, selected TF binding, and gene expression datasets reveals targets of CREs and uncovers properties of 3D chromatin organization of SEs in human retina. Finally, we combine the resulting retinal genomic regulation network with eQTLs and genetic variants identified through GWAS of AMD and glaucoma. Thus, our analysis of regulatory 3D genome architecture contributes to better understanding of genetic control of human retinal phenotypes. Results Deep Hi-C sequencing identifies chromatin structures in human retina at 5 kb resolution Figure 1A illustrates the design of our study to elucidate regulatory networks controlling gene expression in the human retina and their potential disruption by genetic variants associated with clinical phenotypes. Briefly, we have generated a high-resolution chromatin contact map of the human retina using Hi-C and integrated this data with histone marks, chromatin accessibility, CTCF, and binding of selected TFs. We then explored the genome topology of eQTLs and variants associated with AMD and glaucoma (Fig. 1A ). Fig. 1: High-resolution Hi-C identifies human retinal chromatin structures. A Schematic of project workflow. Input data on blue backgrounds were generated in this manuscript; input data on yellow backgrounds were downloaded from public databases. Hi-C contact maps of observed contacts across ( B ) all chromosomes, ( C ) the q arm of chromosome 14, and ( D ) the NRL and VSX2 / ESRRB loci. Scale represents the number of raw contacts. Loops at the NRL and VSX2 / ESRRB loci are plotted on the top; contact maps are below with TADs plotted as black triangles. E Distribution of chromatin loop sizes within and across A/B compartments ( n = 15,441 loops within A compartment, n = 4318 loops within B compartments, n = 2697 loops in A-B compartments). Boxplots represent the median and interquartile range (IQR); whiskers mark 1.5x the IQR; data beyond 1.5x the IQR are plotted as individual points. The three groups differ significantly (one-way ANOVA, F 2,22453 = 2232, p < 0.001). Abbreviations: ROSE Rank Ordering of Super-Enhancers, AMD Age-related macular degeneration, GWAS Genome-wide association study. Full size image To decipher the 3D organization of chromatin, we performed Hi-C analysis of four independent postmortem human retina samples. The Hi-C data exhibited high similarity among samples with a stratified correlation coefficient (SCC) of >0.97 for all autosomes.", "role": "user" }, { "content": "National Eye Institute researchers mapped the organization of human retinal cell chromatin, the fibers that package 3 billion nucleotide-long DNA molecules into compact structures that fit into chromosomes within each cell's nucleus. The resulting comprehensive gene regulatory network provides insights into regulation of gene expression in general, and in retinal function, in both rare and common eye diseases. The study is published in Nature Communications. \"This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,\" said the study's lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health. Adult human retinal cells are highly specialized sensory neurons that do not divide, and are therefore relatively stable for exploring how the chromatin's three-dimensional structure contributes to the expression of genetic information. Chromatin fibers package long strands of DNA, which are spooled around histone proteins and then repeatedly looped to form highly compact structures. All those loops create multiple contact points where genetic sequences that code for proteins interact with gene regulatory sequences, such as super enhancers, promoters, and transcription factors. Such non-coding sequences were long considered \"junk DNA.\" But more advanced studies demonstrate ways these sequences control which genes get transcribed and when, shedding light on the specific mechanisms by which non-coding regulatory elements exert control even when their location on a DNA strand is remote from the genes they regulate. Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Maps were constructed using post-mortem retinal samples from four human donors. The researchers then integrated that chromatin topology map with datasets on retinal genes and regulatory elements. What emerged was a dynamic picture of interactions within chromatin over time, including gene activity hot spots and areas with varying degrees of insulation from other regions of DNA. They found distinct patterns of interaction at retinal genes suggesting how chromatin's 3D organization plays an important role in tissue-specific gene regulation. \"Having such a high-resolution picture of genomic architecture will continue to provide insights into the genetic control of tissue-specific functions,\" Swaroop said. Furthermore, similarities between mice and human chromatin organization suggest conservation across species, underscoring the relevance of chromatin organizational patterns for retinal gene regulation. More than a third (35.7%) of gene pairs interacting through a chromatin loop in mice also did so in human retina. The researchers integrated the chromatin topology map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, two leading causes of vision loss and blindness. The findings point to specific candidate causal genes involved in those diseases. The integrated genome regulatory map will also assist in evaluating genes associated with other common retina-associated diseases such as diabetic retinopathy, determining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chromatin organization and enhancer-promoter contacts establish unique spatiotemporal gene expression patterns in distinct cell types. Non-coding genetic variants can influence cellular phenotypes by modifying higher-order transcriptional hubs and consequently gene expression. To elucidate genomic regulation in human retina, we mapped chromatin contacts at high resolution and integrated with super-enhancers (SEs), histone marks, binding of CTCF and select transcription factors. We show that topologically associated domains (TADs) with central SEs exhibit stronger insulation and augmented contact with retinal genes relative to TADs with edge SEs. Merging genome-wide expression quantitative trait loci (eQTLs) with topology map reveals physical links between 100 eQTLs and corresponding eGenes associated with retinal neurodegeneration. Additionally, we uncover candidate genes for susceptibility variants linked to age-related macular degeneration and glaucoma. Our study of high-resolution genomic architecture of human retina provides insights into genetic control of tissue-specific functions, suggests paradigms for missing heritability, and enables the dissection of common blinding disease phenotypes. Introduction The three-dimensional (3D) architecture of the human genome is regulated across multiple levels of organization, yielding precise spatiotemporal patterns of gene expression for morphogenesis and functional specification 1 , 2 . Gene regulation occurs within transcriptional units through productive enhancer-promoter contacts and/or by inclusion within transcriptionally active membraneless structures, called phase-separated condensates 3 , 4 , 5 , 6 . The transcriptional units are contained within megabase-sized self-interacting chromatin structures known as topologically associated domains (TADs). The boundaries of TADs are enriched for binding of structural proteins including CTCF and cohesin 7 , 8 , 9 . Genome organization also exhibits A (active) and B (inactive) chromatin compartments, which display distinct patterns of DNA replication and transcription along with differences in regulatory marks 10 , 11 , 12 , 13 . Across the 3D hierarchy, genome topology undergoes dynamic and contextual physical alterations in distinct tissues and cell types 14 , 15 . These adaptations correlate with activation of specific cis -regulatory elements (CREs) that contribute to the establishment of unique gene expression patterns 14 , 16 , 17 . Cell-type specific gene expression is further orchestrated by super-enhancers (SEs), regulatory regions spanning over tens of kilobases that are highly enriched for master transcription factor (TF) binding and co-localized with the active histone mark H3K27Ac 18 , 19 , 20 . Over the past decade, millions of human genetic variations have been cataloged 21 , 22 , permitting exploration of evolutionary divergence as well as healthy and disease phenotypes. Genome-wide association studies (GWAS) of common multifactorial retinal diseases afflicting adult human populations, such as age-related macular degeneration (AMD) and glaucoma, have predominantly identified common variants in non-coding regions of the genome 23 , 24 . However, the biological relevance of association signals has been difficult to assess because of the local linkage disequilibrium (LD) in the region of lead variants, hindering identification of specific causal genes and variants 25 . Even in Mendelian retinal diseases with over 200 associated genes identified (RetNet; ), causal mutations can only be identified in about half of the patients (primarily in European population) 26 and genotype-phenotype correlations have been difficult to decipher. Non-coding variants in cis -regulatory regions may lead to variable penetrance of pathogenic coding mutations in their target genes 27 , genetic epistasis 28 , or account for missing heritability 29 . Widespread variability in gene expression observed in humans can be assigned to cis - or trans -acting variants (expression quantitative trait loci, eQTLs) and epistasis 30 . Elucidating how trait-associated genetic variations impact the regulatory landscape and consequently phenotypes requires understanding the 3D genome topology in relevant tissues and cell types. Here, we report a high-resolution chromatin contact map of the adult human retina by performing Hi-C 1 . Further integration of chromatin contacts with histone marks, chromatin accessibility, selected TF binding, and gene expression datasets reveals targets of CREs and uncovers properties of 3D chromatin organization of SEs in human retina. Finally, we combine the resulting retinal genomic regulation network with eQTLs and genetic variants identified through GWAS of AMD and glaucoma. Thus, our analysis of regulatory 3D genome architecture contributes to better understanding of genetic control of human retinal phenotypes. Results Deep Hi-C sequencing identifies chromatin structures in human retina at 5 kb resolution Figure 1A illustrates the design of our study to elucidate regulatory networks controlling gene expression in the human retina and their potential disruption by genetic variants associated with clinical phenotypes. Briefly, we have generated a high-resolution chromatin contact map of the human retina using Hi-C and integrated this data with histone marks, chromatin accessibility, CTCF, and binding of selected TFs. We then explored the genome topology of eQTLs and variants associated with AMD and glaucoma (Fig. 1A ). Fig. 1: High-resolution Hi-C identifies human retinal chromatin structures. A Schematic of project workflow. Input data on blue backgrounds were generated in this manuscript; input data on yellow backgrounds were downloaded from public databases. Hi-C contact maps of observed contacts across ( B ) all chromosomes, ( C ) the q arm of chromosome 14, and ( D ) the NRL and VSX2 / ESRRB loci. Scale represents the number of raw contacts. Loops at the NRL and VSX2 / ESRRB loci are plotted on the top; contact maps are below with TADs plotted as black triangles. E Distribution of chromatin loop sizes within and across A/B compartments ( n = 15,441 loops within A compartment, n = 4318 loops within B compartments, n = 2697 loops in A-B compartments). Boxplots represent the median and interquartile range (IQR); whiskers mark 1.5x the IQR; data beyond 1.5x the IQR are plotted as individual points. The three groups differ significantly (one-way ANOVA, F 2,22453 = 2232, p < 0.001). Abbreviations: ROSE Rank Ordering of Super-Enhancers, AMD Age-related macular degeneration, GWAS Genome-wide association study. Full size image To decipher the 3D organization of chromatin, we performed Hi-C analysis of four independent postmortem human retina samples. The Hi-C data exhibited high similarity among samples with a stratified correlation coefficient (SCC) of >0.97 for all autosomes.<|im_end|> <|im_start|>assistant National Eye Institute researchers mapped the organization of human retinal cell chromatin, the fibers that package 3 billion nucleotide-long DNA molecules into compact structures that fit into chromosomes within each cell's nucleus. The resulting comprehensive gene regulatory network provides insights into regulation of gene expression in general, and in retinal function, in both rare and common eye diseases. The study is published in Nature Communications. "This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness," said the study's lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health. Adult human retinal cells are highly specialized sensory neurons that do not divide, and are therefore relatively stable for exploring how the chromatin's three-dimensional structure contributes to the expression of genetic information. Chromatin fibers package long strands of DNA, which are spooled around histone proteins and then repeatedly looped to form highly compact structures. All those loops create multiple contact points where genetic sequences that code for proteins interact with gene regulatory sequences, such as super enhancers, promoters, and transcription factors. Such non-coding sequences were long considered "junk DNA." But more advanced studies demonstrate ways these sequences control which genes get transcribed and when, shedding light on the specific mechanisms by which non-coding regulatory elements exert control even when their location on a DNA strand is remote from the genes they regulate. Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Maps were constructed using post-mortem retinal samples from four human donors. The researchers then integrated that chromatin topology map with datasets on retinal genes and regulatory elements. What emerged was a dynamic picture of interactions within chromatin over time, including gene activity hot spots and areas with varying degrees of insulation from other regions of DNA. They found distinct patterns of interaction at retinal genes suggesting how chromatin's 3D organization plays an important role in tissue-specific gene regulation. "Having such a high-resolution picture of genomic architecture will continue to provide insights into the genetic control of tissue-specific functions," Swaroop said. Furthermore, similarities between mice and human chromatin organization suggest conservation across species, underscoring the relevance of chromatin organizational patterns for retinal gene regulation. More than a third (35.7%) of gene pairs interacting through a chromatin loop in mice also did so in human retina. The researchers integrated the chromatin topology map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, two leading causes of vision loss and blindness. The findings point to specific candidate causal genes involved in those diseases. The integrated genome regulatory map will also assist in evaluating genes associated with other common retina-associated diseases such as diabetic retinopathy, determining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases. <|im_end|>

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2,107

[ { "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 Ultra-compact, densely integrated optical components manufactured on a CMOS-foundry platform are highly desirable for optical information processing and electronic-photonic co-integration. However, the large spatial extent of evanescent waves arising from nanoscale confinement, ubiquitous in silicon photonic devices, causes significant cross-talk and scattering loss. Here, we demonstrate that anisotropic all-dielectric metamaterials open a new degree of freedom in total internal reflection to shorten the decay length of evanescent waves. We experimentally show the reduction of cross-talk by greater than 30 times and the bending loss by greater than 3 times in densely integrated, ultra-compact photonic circuit blocks. Our prototype all-dielectric metamaterial-waveguide achieves a low propagation loss of approximately 3.7±1.0 dB/cm, comparable to those of silicon strip waveguides. Our approach marks a departure from interference-based confinement as in photonic crystals or slot waveguides, which utilize nanoscale field enhancement. Its ability to suppress evanescent waves without substantially increasing the propagation loss shall pave the way for all-dielectric metamaterial-based dense integration. Introduction One of the long-standing goals of nanophotonics is the integration of electronic and photonic circuitry on a single CMOS chip for applications ranging from information processing and data centers to massively parallel sensing 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . This necessarily requires miniaturization with low power consumption in optical interconnects, active as well as passive photonic devices. There are two major figures of merit in designing photonic devices for a densely integrated circuit. One is the cross-talk, which occurs due to the field overlap of two adjacent photonic waveguides, and the second is the radiation loss at sharp bends which limits the integration density 6 . Plasmonic waveguides can strongly reduce cross-talk and bending loss owing to the sub-diffraction nature of light coupling to the free electrons of metals 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . However, the large ohmic loss of metals restricts the application of plasmonic structures for photonic integration 20 , 21 . Over the last decade, many efforts have been made to miniaturize photonic components using all-dielectric structures 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . Figure 1 illustrates a few classes of dielectric waveguides for light confinement in photonic chips. Strip waveguides, the most common type of waveguides for routing light in a silicon chip, are composed of a silicon channel surrounded by silicon oxide 6 (Fig. 1a ). Owing to the high contrast between the refractive index of the core and the cladding, light is confined inside the core as a result of total internal reflection (TIR). However, the mode size is seen to increase as we reduce the core size which hampers the use of strip waveguides to further miniaturize photonic circuits 37 . Photonic crystal waveguides can confine light inside a line defect due to Bragg reflection 40 (Fig. 1b ). These waveguides perform efficiently at very sharp bends 41 , however, the integration density is limited as the periodicity of Bragg reflectors is on the order of the wavelength and it cannot be perturbed by another waveguide nearby 42 . Additionally, slot waveguides have been proposed to confine light inside a sub-wavelength low-index gap surrounded by high-index dielectric rods 43 (Fig. 1c ). To satisfy the continuity of the normal component of the displacement current at the high-contrast interface, the electric field peaks inside the gap, leading to light confinement but at the cost of skin-depth expansion in the cladding. This causes cross-talk between adjacent waveguides and radiation loss at sharp bends in dense photonic-integrated circuits. Fig. 1 Fundamental differences between dielectric waveguides on an SOI platform. a Strip waveguide; b photonic crystal waveguide; c slot waveguide; d e-skid waveguide. The skin-depth in the cladding of e-skid waveguide is shorter compared to the other structures due to the strong effective anisotropy of the multilayer cladding. This counterintuitive approach can have a cladding with a higher average index than the core and marks a departure from interference-based confinement as in photonic crystal waveguides or slot waveguides which utilize nanoscale field enhancement Full size image Several alternative approaches inspired from atomic physics 44 , 45 , transformation optics 46 , and inverse design algorithms 47 , 48 have also been proposed to minimize the cross-talk and the bending loss. However, these techniques add design complexity and often require modification of the core as well as cladding 46 . They are not implementable on a large-scale and cause propagation loss fundamentally limiting device performance. Thus, a new low-loss and scalable platform is needed for CMOS-foundry compatible dense photonic integration with low cross-talk and reduced bending loss. In this paper, we demonstrate a platform that is fundamentally different from the existing approaches for designing CMOS compatible, ultra-compact, and low-loss waveguides using all-dielectric anisotropic metamaterials. Our approach works based on photonic skin-depth engineering of evanescent waves in the cladding using a recently proposed degree of freedom in TIR 37 , 49 . To describe the light confinement mechanism in our waveguides, first, we experimentally demonstrate the phenomenon of relaxed TIR in anisotropic metamaterials. These relaxed conditions allow the control of evanescent wave decay, which is the fundamental origin of cross-talk and bending loss in silicon photonic devices. As illustrated in Fig. 1d , we use these anisotropic metamaterials as a cladding for on-chip dielectric waveguides fabricated on a monolithic silicon-on-insulator (SOI) platform. As a result, cross-talk is reduced down to −30 dB in the photonic circuit. Furthermore, we use a transformation optics approach to show that the radiation loss at sharp bends is strongly influenced by the skin-depth in the cladding. We experimentally show that the anisotropic metamaterial cladding can simultaneously reduce the bending loss at sharp bends up to three times compared with conventional silicon strip waveguides. We clarify the counterintuitive nature of light confinement in our approach compared", "role": "user" }, { "content": "Replacing traditional computer chip components with light-based counterparts will eventually make electronic devices faster due to the wide bandwidth of light. A new protective metamaterial \"cladding\" prevents light from leaking out of the very curvy pathways it would travel in a computer chip. Because processing information with light can be more efficient than with electrons used in current devices, there is good reason to confine light onto a chip. But light and the bits of information it carries tend to leak and scatter out of the tiny components that must fit on a chip. A Purdue University-led effort has built a novel cladding along the highways for light travel, called waveguides, to prevent information leaks—particularly around sharp bends where light bounces off track and scatters. Information then gets lost or jumbled rather than communicated throughout a device. Preventing this could facilitate the integration of photonic with electric circuitry, increasing communication speed and reducing power consumption. \"We want the bits of information that we are sending in the waveguide to travel along tight bends and simultaneously not be lost as heat. This is a challenge,\" said Zubin Jacob, Purdue assistant professor of electrical and computer engineering. What makes the waveguide cladding so unique is anisotropy, meaning that the cladding design enables light to travel at different velocities in different directions. By controlling the anisotropy of the cladding, the researchers prevented light from leaking off track into other waveguides where \"crosstalk,\" or mixing, of information would occur. Instead, bits of information carried by light bounce off by \"total internal reflection\" and stay strongly confined within a waveguide. \"The waveguide we made is an extreme skin-depth structure, which means that any leakage that does happen will be really small,\" said Saman Jahani, Purdue graduate research assistant in electrical and computer engineering. \"This approach can pave the way for dense photonic integration on a computer chip without worrying about light leakage.\" ", "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 Ultra-compact, densely integrated optical components manufactured on a CMOS-foundry platform are highly desirable for optical information processing and electronic-photonic co-integration. However, the large spatial extent of evanescent waves arising from nanoscale confinement, ubiquitous in silicon photonic devices, causes significant cross-talk and scattering loss. Here, we demonstrate that anisotropic all-dielectric metamaterials open a new degree of freedom in total internal reflection to shorten the decay length of evanescent waves. We experimentally show the reduction of cross-talk by greater than 30 times and the bending loss by greater than 3 times in densely integrated, ultra-compact photonic circuit blocks. Our prototype all-dielectric metamaterial-waveguide achieves a low propagation loss of approximately 3.7±1.0 dB/cm, comparable to those of silicon strip waveguides. Our approach marks a departure from interference-based confinement as in photonic crystals or slot waveguides, which utilize nanoscale field enhancement. Its ability to suppress evanescent waves without substantially increasing the propagation loss shall pave the way for all-dielectric metamaterial-based dense integration. Introduction One of the long-standing goals of nanophotonics is the integration of electronic and photonic circuitry on a single CMOS chip for applications ranging from information processing and data centers to massively parallel sensing 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . This necessarily requires miniaturization with low power consumption in optical interconnects, active as well as passive photonic devices. There are two major figures of merit in designing photonic devices for a densely integrated circuit. One is the cross-talk, which occurs due to the field overlap of two adjacent photonic waveguides, and the second is the radiation loss at sharp bends which limits the integration density 6 . Plasmonic waveguides can strongly reduce cross-talk and bending loss owing to the sub-diffraction nature of light coupling to the free electrons of metals 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . However, the large ohmic loss of metals restricts the application of plasmonic structures for photonic integration 20 , 21 . Over the last decade, many efforts have been made to miniaturize photonic components using all-dielectric structures 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . Figure 1 illustrates a few classes of dielectric waveguides for light confinement in photonic chips. Strip waveguides, the most common type of waveguides for routing light in a silicon chip, are composed of a silicon channel surrounded by silicon oxide 6 (Fig. 1a ). Owing to the high contrast between the refractive index of the core and the cladding, light is confined inside the core as a result of total internal reflection (TIR). However, the mode size is seen to increase as we reduce the core size which hampers the use of strip waveguides to further miniaturize photonic circuits 37 . Photonic crystal waveguides can confine light inside a line defect due to Bragg reflection 40 (Fig. 1b ). These waveguides perform efficiently at very sharp bends 41 , however, the integration density is limited as the periodicity of Bragg reflectors is on the order of the wavelength and it cannot be perturbed by another waveguide nearby 42 . Additionally, slot waveguides have been proposed to confine light inside a sub-wavelength low-index gap surrounded by high-index dielectric rods 43 (Fig. 1c ). To satisfy the continuity of the normal component of the displacement current at the high-contrast interface, the electric field peaks inside the gap, leading to light confinement but at the cost of skin-depth expansion in the cladding. This causes cross-talk between adjacent waveguides and radiation loss at sharp bends in dense photonic-integrated circuits. Fig. 1 Fundamental differences between dielectric waveguides on an SOI platform. a Strip waveguide; b photonic crystal waveguide; c slot waveguide; d e-skid waveguide. The skin-depth in the cladding of e-skid waveguide is shorter compared to the other structures due to the strong effective anisotropy of the multilayer cladding. This counterintuitive approach can have a cladding with a higher average index than the core and marks a departure from interference-based confinement as in photonic crystal waveguides or slot waveguides which utilize nanoscale field enhancement Full size image Several alternative approaches inspired from atomic physics 44 , 45 , transformation optics 46 , and inverse design algorithms 47 , 48 have also been proposed to minimize the cross-talk and the bending loss. However, these techniques add design complexity and often require modification of the core as well as cladding 46 . They are not implementable on a large-scale and cause propagation loss fundamentally limiting device performance. Thus, a new low-loss and scalable platform is needed for CMOS-foundry compatible dense photonic integration with low cross-talk and reduced bending loss. In this paper, we demonstrate a platform that is fundamentally different from the existing approaches for designing CMOS compatible, ultra-compact, and low-loss waveguides using all-dielectric anisotropic metamaterials. Our approach works based on photonic skin-depth engineering of evanescent waves in the cladding using a recently proposed degree of freedom in TIR 37 , 49 . To describe the light confinement mechanism in our waveguides, first, we experimentally demonstrate the phenomenon of relaxed TIR in anisotropic metamaterials. These relaxed conditions allow the control of evanescent wave decay, which is the fundamental origin of cross-talk and bending loss in silicon photonic devices. As illustrated in Fig. 1d , we use these anisotropic metamaterials as a cladding for on-chip dielectric waveguides fabricated on a monolithic silicon-on-insulator (SOI) platform. As a result, cross-talk is reduced down to −30 dB in the photonic circuit. Furthermore, we use a transformation optics approach to show that the radiation loss at sharp bends is strongly influenced by the skin-depth in the cladding. We experimentally show that the anisotropic metamaterial cladding can simultaneously reduce the bending loss at sharp bends up to three times compared with conventional silicon strip waveguides. We clarify the counterintuitive nature of light confinement in our approach compared<|im_end|> <|im_start|>assistant Replacing traditional computer chip components with light-based counterparts will eventually make electronic devices faster due to the wide bandwidth of light. A new protective metamaterial "cladding" prevents light from leaking out of the very curvy pathways it would travel in a computer chip. Because processing information with light can be more efficient than with electrons used in current devices, there is good reason to confine light onto a chip. But light and the bits of information it carries tend to leak and scatter out of the tiny components that must fit on a chip. A Purdue University-led effort has built a novel cladding along the highways for light travel, called waveguides, to prevent information leaks—particularly around sharp bends where light bounces off track and scatters. Information then gets lost or jumbled rather than communicated throughout a device. Preventing this could facilitate the integration of photonic with electric circuitry, increasing communication speed and reducing power consumption. "We want the bits of information that we are sending in the waveguide to travel along tight bends and simultaneously not be lost as heat. This is a challenge," said Zubin Jacob, Purdue assistant professor of electrical and computer engineering. What makes the waveguide cladding so unique is anisotropy, meaning that the cladding design enables light to travel at different velocities in different directions. By controlling the anisotropy of the cladding, the researchers prevented light from leaking off track into other waveguides where "crosstalk," or mixing, of information would occur. Instead, bits of information carried by light bounce off by "total internal reflection" and stay strongly confined within a waveguide. "The waveguide we made is an extreme skin-depth structure, which means that any leakage that does happen will be really small," said Saman Jahani, Purdue graduate research assistant in electrical and computer engineering. "This approach can pave the way for dense photonic integration on a computer chip without worrying about light leakage." <|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 Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues 1 . Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists 2 . For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob / ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes. Main Obesity is characterized by dysfunctional adipose tissues in which failure to store excess energy appropriately leads to ectopic lipid deposition, progressive insulin resistance and heightened risk for type 2 diabetes. Disordered secretion of certain fat-derived hormones, called adipokines, also contributes to the metabolic dysfunction in obesity and diabetes. Adipose-tissue-directed insulin-sensitizing drugs, including the thiazolidinediones, potently improve whole-body sensitivity to insulin 3 . The thiazolidinedione drugs have two distinct functions as ligands for PPARγ: they promote the differentiation of preadipocytes 4 , 5 and they block the phosphorylation of PPARγ at S273 (ref. 1 ). We recently demonstrated that non-agonist PPARγ ligands capable of blocking the phosphorylation of PPARγ at S273 retain potent anti-diabetic effects despite the inability to promote adipogenesis 2 . These findings strongly suggested that obesity-mediated phosphorylation of PPARγ S273 may not only correlate positively with the development of insulin resistance but may also be causal to this state. A variety of protein kinases participate in insulin action and insulin resistance. Insulin signalling activates the Akt/phosphoinositide 3-kinase (PI(3)K) and Grb2/Ras/MEK/ERK kinase cascades 6 , 7 . Although much is known about the role of the former in promoting the canonical anabolic actions of insulin, studies in vitro had suggested that the latter cascade downstream of insulin signalling could contribute to insulin resistance 8 , 9 , although there is controversy on this point 10 . Obese rodents were shown to have elevated ERK activity, whereas mice lacking ERK1 were shown to be more sensitive to the effects of insulin 9 , 11 , 12 . Cdk5 function is both necessary and sufficient in cultured adipocytes to phosphorylate PPARγ at S273 (ref. 1 ). Mice with global or brain-restricted deletion of Cdk5 show increased perinatal mortality due to a defect in neurogenesis. We therefore set out to test whether modulation of PPARγ phosphorylation at S273 in adipose tissues would lead to altered insulin sensitivity in vivo by creating adipose-selective Cdk5-deficient mice (Cdk5-KO) 13 , 14 . In contrast to global knockouts 15 , 16 , Cdk5-KO mice are grossly normal in appearance, with no apparent differences in body weight or fasting glucose levels when maintained on a standard diet ( Extended Data Fig. 1 ). Deletion of Cdk5 in whole white adipose tissue was confirmed by both western blot analysis ( Fig. 1a ) and quantitative real-time PCR ( Fig. 1b ). To determine whether the residual Cdk5 expression in the knockout (KO) mice was emanating from non-adipocytes or from incomplete recombination, tissue fractionation was performed; no detectable Cdk5 protein was observed in the floating adipocyte fraction, whereas residual signal was observed in the stromal vascular fraction ( Fig. 1c ). On a standard chow diet, KO mice were normal, healthy and indistinguishable from Cdk5 Flox/Flox controls ( Extended Data Fig. 1 ). Figure 1: Insulin resistance after Cdk5 deletion in adipocytes. a , b , Deletion of Cdk5 in epididymal white adipose tissue from control (Cdk5 Flox/Flox ) or adipocyte-specific knockout, KO (Cdk5 Flox/Flox ::adiponectin-Cre) was confirmed by western blotting ( a ; n = 4) or quantitative real-time PCR ( b ; n = 5). Ctl, control. c , Fractionated adipose tissue confirmed deletion was confined to the adipocyte fraction of adipose tissue. d , Body weight of control or KO mice when maintained on a high-fat diet. n = 20 Ctl, 25 KO. e , f , Fasting glucose ( e ) and fasting insulin ( f ) in mice maintained on a high-fat diet. n = 10 (control) and 12 (KO). g , h , Insulin tolerance test ( g ) and glucose tolerance tests ( h ) are consistent with impaired insulin sensitivity. n = 15 (control) and 17 (KO). Histograms show the areas under the curves. i , Western blots of white adipose tissue for pS273 PPARγ in control and KO mice. j , Quantification of i . * P < 0.05; ** P < 0.01; *** P < 0.001; n.s., not significant. Error bars indicate s.e.m. PowerPoint slide Full size image Both PPARγ S273 phosphorylation and insulin resistance are strongly promoted by obesity and inflammatory cytokines 1 . When maintained on a high-fat diet to induce obesity, no differences were observed between wild-type (WT) and KO groups in food intake, energy expenditure or body weight ( Fig. 1d and Extended Data Fig. 2 ). Paradoxically, metabolic analyses of these Cdk5-KO mice demonstrated that their glucose homeostasis was impaired in comparison with control animals. Cdk5-KO mice had elevated fasting insulin levels, as well as impairment in insulin tolerance, with a trend towards impaired glucose tolerance ( Fig.1e–h ). We also observed a paradoxical increase in S273 PPARγ phosphorylation in obese Cdk5-KO mice, strongly suggesting compensation from an alternative", "role": "user" }, { "content": "A research team led by Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute (DFCI) has uncovered surprising new findings that underscore the role of an important signaling pathway, already known to be critical in cancer, in the development of type 2 diabetes. Their results, published in the November 17, 2014 advance online issue of the journal Nature, shed additional light on how a longstanding class of diabetes drugs, known as thiazolidinediones (TZDs), work to improve glucose metabolism and suggest that inhibitors of the signaling pathway—known as the MEK/ERK pathway—may also hold promise in the treatment of type 2 diabetes. \"It's been recognized that thiazolidinediones have tremendous benefits in the treatment of type 2 diabetes, but they also have significant risks,\" said Alexander S. Banks, PhD, lead author and a researcher in the Division of Endocrinology, Diabetes and Hypertension at BWH. \"The question is, can we minimize these adverse effects by modifying the drugs slightly or by approaching the pathway from a different direction?\" This hypothesis led Banks and DFCI's Bruce Spiegelman, PhD, a researcher in the department of Cancer Biology at Dana-Farber, to focus on a critical molecular player known as CDK5. A type of enzyme known as a kinase, CDK modifies a key site on the molecule targeted by TZDs (known as PPARγ). To further understand CDK5's role, Banks and his colleagues created a special strain of mice lacking CDK5 in adipose tissues —where PPARγ is most highly active and TZDs are thought to act. Instead of confirming their initial suspicions about CDK5, the team's results pointed them in a very different direction: their findings suggested that another key kinase was involved. In collaboration with researchers at Harvard Medical School, Banks, Spiegelman and their colleagues conducted a wide, unbiased search to determine its identity. That search ultimately led them to the kinase known as ERK. After a detailed biochemical study of ERK function, the team set out to test its role in glucose metabolism, and found that MEK inhibitors, which block ERK function, significantly improve insulin resistance in mouse models of diabetes. \"A new class of drugs, aimed primarily at cancer, has been developed that inhibits ERK's action. These drugs, known as MEK inhibitors, help to extend the lives of patients with advanced cases of melanoma,\" said Banks. \"One of the most exciting aspects of this paper is the concept that you could inhibit the abnormal activation of ERK seen in diabetes using these MEK inhibitors designed for treating cancer, but at lower, safer doses.\" \"All attempts to develop new therapeutics will carry risks, but the opportunities here certainly seem worth exploring in the clinic,\" said Spiegelman. While much more work must be done to determine if MEK inhibitors will be a safe and effective treatment for type 2 diabetes, the Nature study offers an important window on the molecular underpinnings of TZD action. In addition, it suggests that MEK/ERK inhibition may offer a viable route toward minimizing the drugs' undesired effects. ", "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 Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues 1 . Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists 2 . For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob / ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes. Main Obesity is characterized by dysfunctional adipose tissues in which failure to store excess energy appropriately leads to ectopic lipid deposition, progressive insulin resistance and heightened risk for type 2 diabetes. Disordered secretion of certain fat-derived hormones, called adipokines, also contributes to the metabolic dysfunction in obesity and diabetes. Adipose-tissue-directed insulin-sensitizing drugs, including the thiazolidinediones, potently improve whole-body sensitivity to insulin 3 . The thiazolidinedione drugs have two distinct functions as ligands for PPARγ: they promote the differentiation of preadipocytes 4 , 5 and they block the phosphorylation of PPARγ at S273 (ref. 1 ). We recently demonstrated that non-agonist PPARγ ligands capable of blocking the phosphorylation of PPARγ at S273 retain potent anti-diabetic effects despite the inability to promote adipogenesis 2 . These findings strongly suggested that obesity-mediated phosphorylation of PPARγ S273 may not only correlate positively with the development of insulin resistance but may also be causal to this state. A variety of protein kinases participate in insulin action and insulin resistance. Insulin signalling activates the Akt/phosphoinositide 3-kinase (PI(3)K) and Grb2/Ras/MEK/ERK kinase cascades 6 , 7 . Although much is known about the role of the former in promoting the canonical anabolic actions of insulin, studies in vitro had suggested that the latter cascade downstream of insulin signalling could contribute to insulin resistance 8 , 9 , although there is controversy on this point 10 . Obese rodents were shown to have elevated ERK activity, whereas mice lacking ERK1 were shown to be more sensitive to the effects of insulin 9 , 11 , 12 . Cdk5 function is both necessary and sufficient in cultured adipocytes to phosphorylate PPARγ at S273 (ref. 1 ). Mice with global or brain-restricted deletion of Cdk5 show increased perinatal mortality due to a defect in neurogenesis. We therefore set out to test whether modulation of PPARγ phosphorylation at S273 in adipose tissues would lead to altered insulin sensitivity in vivo by creating adipose-selective Cdk5-deficient mice (Cdk5-KO) 13 , 14 . In contrast to global knockouts 15 , 16 , Cdk5-KO mice are grossly normal in appearance, with no apparent differences in body weight or fasting glucose levels when maintained on a standard diet ( Extended Data Fig. 1 ). Deletion of Cdk5 in whole white adipose tissue was confirmed by both western blot analysis ( Fig. 1a ) and quantitative real-time PCR ( Fig. 1b ). To determine whether the residual Cdk5 expression in the knockout (KO) mice was emanating from non-adipocytes or from incomplete recombination, tissue fractionation was performed; no detectable Cdk5 protein was observed in the floating adipocyte fraction, whereas residual signal was observed in the stromal vascular fraction ( Fig. 1c ). On a standard chow diet, KO mice were normal, healthy and indistinguishable from Cdk5 Flox/Flox controls ( Extended Data Fig. 1 ). Figure 1: Insulin resistance after Cdk5 deletion in adipocytes. a , b , Deletion of Cdk5 in epididymal white adipose tissue from control (Cdk5 Flox/Flox ) or adipocyte-specific knockout, KO (Cdk5 Flox/Flox ::adiponectin-Cre) was confirmed by western blotting ( a ; n = 4) or quantitative real-time PCR ( b ; n = 5). Ctl, control. c , Fractionated adipose tissue confirmed deletion was confined to the adipocyte fraction of adipose tissue. d , Body weight of control or KO mice when maintained on a high-fat diet. n = 20 Ctl, 25 KO. e , f , Fasting glucose ( e ) and fasting insulin ( f ) in mice maintained on a high-fat diet. n = 10 (control) and 12 (KO). g , h , Insulin tolerance test ( g ) and glucose tolerance tests ( h ) are consistent with impaired insulin sensitivity. n = 15 (control) and 17 (KO). Histograms show the areas under the curves. i , Western blots of white adipose tissue for pS273 PPARγ in control and KO mice. j , Quantification of i . * P < 0.05; ** P < 0.01; *** P < 0.001; n.s., not significant. Error bars indicate s.e.m. PowerPoint slide Full size image Both PPARγ S273 phosphorylation and insulin resistance are strongly promoted by obesity and inflammatory cytokines 1 . When maintained on a high-fat diet to induce obesity, no differences were observed between wild-type (WT) and KO groups in food intake, energy expenditure or body weight ( Fig. 1d and Extended Data Fig. 2 ). Paradoxically, metabolic analyses of these Cdk5-KO mice demonstrated that their glucose homeostasis was impaired in comparison with control animals. Cdk5-KO mice had elevated fasting insulin levels, as well as impairment in insulin tolerance, with a trend towards impaired glucose tolerance ( Fig.1e–h ). We also observed a paradoxical increase in S273 PPARγ phosphorylation in obese Cdk5-KO mice, strongly suggesting compensation from an alternative<|im_end|> <|im_start|>assistant A research team led by Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute (DFCI) has uncovered surprising new findings that underscore the role of an important signaling pathway, already known to be critical in cancer, in the development of type 2 diabetes. Their results, published in the November 17, 2014 advance online issue of the journal Nature, shed additional light on how a longstanding class of diabetes drugs, known as thiazolidinediones (TZDs), work to improve glucose metabolism and suggest that inhibitors of the signaling pathway—known as the MEK/ERK pathway—may also hold promise in the treatment of type 2 diabetes. "It's been recognized that thiazolidinediones have tremendous benefits in the treatment of type 2 diabetes, but they also have significant risks," said Alexander S. Banks, PhD, lead author and a researcher in the Division of Endocrinology, Diabetes and Hypertension at BWH. "The question is, can we minimize these adverse effects by modifying the drugs slightly or by approaching the pathway from a different direction?" This hypothesis led Banks and DFCI's Bruce Spiegelman, PhD, a researcher in the department of Cancer Biology at Dana-Farber, to focus on a critical molecular player known as CDK5. A type of enzyme known as a kinase, CDK modifies a key site on the molecule targeted by TZDs (known as PPARγ). To further understand CDK5's role, Banks and his colleagues created a special strain of mice lacking CDK5 in adipose tissues —where PPARγ is most highly active and TZDs are thought to act. Instead of confirming their initial suspicions about CDK5, the team's results pointed them in a very different direction: their findings suggested that another key kinase was involved. In collaboration with researchers at Harvard Medical School, Banks, Spiegelman and their colleagues conducted a wide, unbiased search to determine its identity. That search ultimately led them to the kinase known as ERK. After a detailed biochemical study of ERK function, the team set out to test its role in glucose metabolism, and found that MEK inhibitors, which block ERK function, significantly improve insulin resistance in mouse models of diabetes. "A new class of drugs, aimed primarily at cancer, has been developed that inhibits ERK's action. These drugs, known as MEK inhibitors, help to extend the lives of patients with advanced cases of melanoma," said Banks. "One of the most exciting aspects of this paper is the concept that you could inhibit the abnormal activation of ERK seen in diabetes using these MEK inhibitors designed for treating cancer, but at lower, safer doses." "All attempts to develop new therapeutics will carry risks, but the opportunities here certainly seem worth exploring in the clinic," said Spiegelman. While much more work must be done to determine if MEK inhibitors will be a safe and effective treatment for type 2 diabetes, the Nature study offers an important window on the molecular underpinnings of TZD action. In addition, it suggests that MEK/ERK inhibition may offer a viable route toward minimizing the drugs' undesired effects. <|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 Microbes that protect their hosts from pathogens are widespread in nature and are attractive disease control agents. Given that pathogen adaptation to barriers against infection can drive changes in pathogen virulence, ‘defensive microbes’ may shape disease severity. Here we show that co-evolving a microbe with host-protective properties ( Enterococcus faecalis ) and a pathogen ( Staphylococcus aureus ) within Caenorhabditis elegans hosts drives the evolution of reduced pathogen virulence as a by-product of adaptation to the defensive microbe. Using both genomic and phenotypic analyses, we discover that the production of fewer iron-scavenging siderophores by the pathogen reduces the fitness of the defensive microbe and underpins the decline in pathogen virulence. These data show that defensive microbes can shape the evolution of pathogen virulence and that the mechanism of pathogen resistance can determine the direction of virulence evolution. Introduction Microbes can defend their hosts against pathogenic infection 1 . This phenomenon has been widely observed in nature across plant and animal species, including humans, to provide a strong line of defence beyond the host response 2 . As a result, microbes with protective traits are considered promising disease control agents and alternatives to antibiotics to combat devastating human and crop pathogens 3 , 4 , 5 , 6 . Importantly, pathogen adaptation to barriers against infection can drive the evolution of virulence 7 , as observed against immune-priming vaccines 8 and competing, co-infecting pathogens 9 . Given that defensive microbes likely impose strong selection on pathogens too 2 , they may also play a pivotal role in determining why some infections are more harmful than others. Thus, understanding the effect of defensive microbes on pathogen evolution could ultimately enable us to explain variation in disease severity in nature and to use defensive microbes for optimal disease control. In this study, we use the term pathogen ‘resistance’ to describe the pathogen’s ability to resist the defensive microbe. We propose that defensive microbes will drive the evolution of pathogen virulence when the mechanism of pathogen resistance to microbe-mediated defence is associated with harm to the host 2 , 10 . The direction of virulence evolution will depend on the shape of the relationship between resistance and virulence 2 , 10 . Specifically, we predict that defensive microbes will result in the evolution of increased pathogen virulence if pathogen resistance and virulence are positively associated ( Fig. 1a ), for example, pathogens could increase in competitive ability against the defensive microbe via a faster growth rate or inducing inflammation, both of which are also detrimental to the host 10 , 11 , 12 , 13 . Alternatively, if a trade-off exists between pathogen resistance and virulence traits, for example, resistance is costly and slows pathogen growth rate 14 , 15 , 16 , then defensive microbes will drive lower levels of virulence ( Fig. 1b ). Although the evolution of pathogen resistance to defensive microbes has been theoretically illustrated 10 , 17 and empirically evidenced 18 , studies are few. Our data will thus provide valuable information on the evolution of pathogen resistance in addition to virulence. Figure 1: Proposed associations between mechanisms of pathogen virulence and resistance to microbe-mediated defence. ( a ) Pathogen virulence is hypothesized to increase when it correlates positively with the pathogen’s ability to resist microbe-mediated defence. ( b ) Pathogen virulence is hypothesized to decrease when traded off against the pathogen’s ability to resist microbe-mediated defence. Full size image Here, we have studied the interactions between Staphylococcus aureus and Enterococcus faecalis within Caenorhabditis elegans hosts which emulate the interactions between a pathogen and a defensive microbe, respectively 19 . Both E. faecalis and S. aureus co-occur in animal microbiomes and can colonize the gut of C. elegans 20 . This nematode species is a model animal system for investigating microbial pathogenesis as well as natural and lab-based host–microbiota associations 21 , 22 , 23 , 24 , 25 . We used S. aureus strain MSSA 476 and E. faecalis strain OG1RF, both of which were isolated from humans. Their interaction within a nematode host is therefore novel, allowing us to explore the evolutionary consequences of defensive symbioses early in their formation. We have previously illustrated that S. aureus acts as a virulent pathogen within the nematode host 19 . Furthermore, we have shown that although E. faecalis imposes a small cost to host longevity while colonizing alone (un-colonized hosts experience no mortality under otherwise the same conditions 19 ), this bacterium provides a net benefit to hosts during S. aureus infection 19 . By having context-dependent fitness effects on its host, E. faecalis reflects symbionts found in nature. In particular, many defensive microbes have been found to impose costs on their hosts in the absence of the enemy 26 , 27 , 28 , 29 , 30 , 31 . Moreover, we know that E. faecalis significantly reduces the virulence of S. aureus by producing superoxide anions that decrease pathogen fitness 19 . This mechanism of defence is a form of interference competition, whereby defensive microbes produce toxic compounds that may either kill the pathogen or slow its growth rate 2 . Interference competition is currently the most commonly detected mechanism of microbe-mediated defence in nature 2 . To test the hypothesis that defensive microbes can affect pathogen virulence evolution, we co-passaged S. aureus and E. faecalis (co-evolution treatment) and independently passaged S. aureus (single evolution treatment) within non-evolving, genetically homogeneous C. elegans populations for 10 passages. Given that defensive microbes and pathogens likely evolve on similar timescales in nature, co-passaging allowed for the realistic possibility of co-evolutionary interactions to shape pathogen evolution. Throughout our experiments, we assay host mortality after 24 h of exposure to ancestral and evolved pathogen populations as a measure of virulence 32 . We use this measure of virulence for several reasons. Host mortality is a widespread measure in theoretical and experimental investigations on the evolution of virulence across a diversity of host–pathogen systems 9 , 32 , 33 , 34 ,", "role": "user" }, { "content": "In a new paper published in the journal Nature Communications, Oxford DPhil student Suzanne Ford from the Department of Zoology shows how the use of 'good bacteria' – or defensive microbes – could help fight diseases. Using a microscopic worm infected both with a host-protective microbe and a harmful pathogen, the study demonstrates that the presence of a defensive microbe can force a pathogen to become less virulent. Defensive microbes can also 'steal' vital proteins from pathogens to make themselves stronger, causing the pathogens to evolve to produce fewer such proteins. This, in turn, makes the defensive microbes weaker – but enough damage has already been done to the pathogen to stifle its future growth and virulence. In a video produced by fellow Oxford DPhil student Sally Le Page for her 'Shed Science' YouTube series, Suzanne explains how, in the era of antibiotic resistance, alternative strategies for disease control are of the utmost importance. Credit: Oxford Science Blog ", "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 Microbes that protect their hosts from pathogens are widespread in nature and are attractive disease control agents. Given that pathogen adaptation to barriers against infection can drive changes in pathogen virulence, ‘defensive microbes’ may shape disease severity. Here we show that co-evolving a microbe with host-protective properties ( Enterococcus faecalis ) and a pathogen ( Staphylococcus aureus ) within Caenorhabditis elegans hosts drives the evolution of reduced pathogen virulence as a by-product of adaptation to the defensive microbe. Using both genomic and phenotypic analyses, we discover that the production of fewer iron-scavenging siderophores by the pathogen reduces the fitness of the defensive microbe and underpins the decline in pathogen virulence. These data show that defensive microbes can shape the evolution of pathogen virulence and that the mechanism of pathogen resistance can determine the direction of virulence evolution. Introduction Microbes can defend their hosts against pathogenic infection 1 . This phenomenon has been widely observed in nature across plant and animal species, including humans, to provide a strong line of defence beyond the host response 2 . As a result, microbes with protective traits are considered promising disease control agents and alternatives to antibiotics to combat devastating human and crop pathogens 3 , 4 , 5 , 6 . Importantly, pathogen adaptation to barriers against infection can drive the evolution of virulence 7 , as observed against immune-priming vaccines 8 and competing, co-infecting pathogens 9 . Given that defensive microbes likely impose strong selection on pathogens too 2 , they may also play a pivotal role in determining why some infections are more harmful than others. Thus, understanding the effect of defensive microbes on pathogen evolution could ultimately enable us to explain variation in disease severity in nature and to use defensive microbes for optimal disease control. In this study, we use the term pathogen ‘resistance’ to describe the pathogen’s ability to resist the defensive microbe. We propose that defensive microbes will drive the evolution of pathogen virulence when the mechanism of pathogen resistance to microbe-mediated defence is associated with harm to the host 2 , 10 . The direction of virulence evolution will depend on the shape of the relationship between resistance and virulence 2 , 10 . Specifically, we predict that defensive microbes will result in the evolution of increased pathogen virulence if pathogen resistance and virulence are positively associated ( Fig. 1a ), for example, pathogens could increase in competitive ability against the defensive microbe via a faster growth rate or inducing inflammation, both of which are also detrimental to the host 10 , 11 , 12 , 13 . Alternatively, if a trade-off exists between pathogen resistance and virulence traits, for example, resistance is costly and slows pathogen growth rate 14 , 15 , 16 , then defensive microbes will drive lower levels of virulence ( Fig. 1b ). Although the evolution of pathogen resistance to defensive microbes has been theoretically illustrated 10 , 17 and empirically evidenced 18 , studies are few. Our data will thus provide valuable information on the evolution of pathogen resistance in addition to virulence. Figure 1: Proposed associations between mechanisms of pathogen virulence and resistance to microbe-mediated defence. ( a ) Pathogen virulence is hypothesized to increase when it correlates positively with the pathogen’s ability to resist microbe-mediated defence. ( b ) Pathogen virulence is hypothesized to decrease when traded off against the pathogen’s ability to resist microbe-mediated defence. Full size image Here, we have studied the interactions between Staphylococcus aureus and Enterococcus faecalis within Caenorhabditis elegans hosts which emulate the interactions between a pathogen and a defensive microbe, respectively 19 . Both E. faecalis and S. aureus co-occur in animal microbiomes and can colonize the gut of C. elegans 20 . This nematode species is a model animal system for investigating microbial pathogenesis as well as natural and lab-based host–microbiota associations 21 , 22 , 23 , 24 , 25 . We used S. aureus strain MSSA 476 and E. faecalis strain OG1RF, both of which were isolated from humans. Their interaction within a nematode host is therefore novel, allowing us to explore the evolutionary consequences of defensive symbioses early in their formation. We have previously illustrated that S. aureus acts as a virulent pathogen within the nematode host 19 . Furthermore, we have shown that although E. faecalis imposes a small cost to host longevity while colonizing alone (un-colonized hosts experience no mortality under otherwise the same conditions 19 ), this bacterium provides a net benefit to hosts during S. aureus infection 19 . By having context-dependent fitness effects on its host, E. faecalis reflects symbionts found in nature. In particular, many defensive microbes have been found to impose costs on their hosts in the absence of the enemy 26 , 27 , 28 , 29 , 30 , 31 . Moreover, we know that E. faecalis significantly reduces the virulence of S. aureus by producing superoxide anions that decrease pathogen fitness 19 . This mechanism of defence is a form of interference competition, whereby defensive microbes produce toxic compounds that may either kill the pathogen or slow its growth rate 2 . Interference competition is currently the most commonly detected mechanism of microbe-mediated defence in nature 2 . To test the hypothesis that defensive microbes can affect pathogen virulence evolution, we co-passaged S. aureus and E. faecalis (co-evolution treatment) and independently passaged S. aureus (single evolution treatment) within non-evolving, genetically homogeneous C. elegans populations for 10 passages. Given that defensive microbes and pathogens likely evolve on similar timescales in nature, co-passaging allowed for the realistic possibility of co-evolutionary interactions to shape pathogen evolution. Throughout our experiments, we assay host mortality after 24 h of exposure to ancestral and evolved pathogen populations as a measure of virulence 32 . We use this measure of virulence for several reasons. Host mortality is a widespread measure in theoretical and experimental investigations on the evolution of virulence across a diversity of host–pathogen systems 9 , 32 , 33 , 34 ,<|im_end|> <|im_start|>assistant In a new paper published in the journal Nature Communications, Oxford DPhil student Suzanne Ford from the Department of Zoology shows how the use of 'good bacteria' – or defensive microbes – could help fight diseases. Using a microscopic worm infected both with a host-protective microbe and a harmful pathogen, the study demonstrates that the presence of a defensive microbe can force a pathogen to become less virulent. Defensive microbes can also 'steal' vital proteins from pathogens to make themselves stronger, causing the pathogens to evolve to produce fewer such proteins. This, in turn, makes the defensive microbes weaker – but enough damage has already been done to the pathogen to stifle its future growth and virulence. In a video produced by fellow Oxford DPhil student Sally Le Page for her 'Shed Science' YouTube series, Suzanne explains how, in the era of antibiotic resistance, alternative strategies for disease control are of the utmost importance. Credit: Oxford Science Blog <|im_end|>

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1,568

[ { "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 Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used ‘omics’ survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research. Introduction Engineering the gut microbiome to treat disease is an exciting new direction in medical science 1 , 2 , 3 . Fecal microbiota transplant (FMT) from a healthy donor into patients with recurrent Clostridium difficile infections is the first widely adopted microbiome-related therapy and has a ~90% success rate 4 , 5 . Investigational trials are underway in new disease areas, such as inflammatory bowel disease, liver disease, Parkinson’s disease, severe acute malnutrition and infection by antibiotic-resistant pathogens 6 , 7 , 8 , 9 (see ongoing clinical trials at ). OpenBiome is a stool bank that has provided material for over 48,000 fecal transplants. Stool banks like OpenBiome represent an attractive opportunity for building a well-characterized culture collection because living biomass is preserved, allowing cultivation of isolated strains, and because dense longitudinal sampling (that is, several samples being collected per week) enables analysis of within-host dynamics. In addition, a resource of isolate genomes together with longitudinal dynamics can be useful in designing and analyzing future clinical trials. Finally, a comprehensive culture collection from successful donors could ultimately be used to replace FMT, which is a blunt tool for engineering the gut microbiome and may have long-term consequences due to the introduction of a wide variety of exogenous strains with unknown function 10 , 11 , 12 . While comprehensive strain collections are essential for mechanistic studies, culturing a diverse representation of gut bacteria has been challenging. Seminal work by several groups 13 , 14 , 15 , 16 , 17 has addressed many of the technological challenges of growing wide arrays of gut bacterial lineages, and two recent studies reported isolate and genome collections with broad phylogenetic representation 18 , 19 . However, existing isolate and genome collections are still limited, especially in strain-level diversity, for most of the bacterial species in the human gut. In addition, current collections are limited in examples of coexisting strain-level diversity from the same human host because the majority of strains were cultured from a large number of individuals or were targeted for maximizing phylogenetic diversity. Recent work has shown that this within-host strain diversity is extensive in the human population 20 and within individual people 21 , 22 , 23 . New studies increasingly point to functional differences between strains of the same species that can impact human health 21 , 24 , 25 . For instance, strain-level differences can influence the metabolism of dietary compounds, such as galacto-oligosaccharides 26 or nondigestible fibers 27 , 28 . Bacteria-mediated metabolism of drugs can also differ across strains, influencing drug efficacy and toxicity 29 , 30 . In addition, genomic variation in virulence genes can alter pathogenicity among strains 31 , 32 , 33 . Finally, distinct strains can elicit different immune responses, such as cytokine production 25 . For these reasons, a large collection of isolates of multiple strains from many gut bacterial species, sampled both within and across people, is needed to better understand host–microbe interactions and to efficiently screen for candidate features that could ultimately be leveraged in rationally designed microbiome-based therapeutics. Here, we introduce a comprehensive biobank of human gut bacteria: a library of 7,758 bacterial isolates obtained from healthy FMT donors recruited in the Boston area. This library covers most of the phylogenetic diversity found in the human gut, contains extensive strain diversity and is available to the research community. We report whole-genome sequences (WGSs) for 3,632 of these isolates that span a wide range of phyla and genera, to enable researchers to test and predict phenotypes in vitro and in vivo, such as metabolic capability or resistance to antibiotics. We also provide longitudinal 16S, metagenomic and metabolomic data for more than 80 FMT donors. Finally, we highlight examples that illustrate how these data can be used to better understand the eco-evolutionary dynamics of the gut microbiome within and between people. Results Isolation of an extensive collection of gut bacterial isolates for in vitro and in vivo testing of mechanistic hypotheses Many strict anaerobes in the human gut were considered unculturable until recently 14 , 15 , 16 , 17 , 18 , 19 , 34 , 35 . As a result, densely sampled sets of strains from many anaerobic species are still not readily available. Here, we leverage recent advances in culturing techniques to isolate a large phylogenetic diversity of gut bacterial strains from healthy FMT donors. Building a library of isolates that cover the diversity of gut bacteria from OpenBiome donors We have designed and implemented protocols to culture, isolate and store a large diversity of anaerobic gut bacterial strains in pure culture. We used filtered stool extracts from 11 donors within our cohort, and we used 12 different media, combined with antibiotic, acid and ethanol treatments, resulting in 19 different culturing conditions (see Supplementary Methods ). We used general media to obtain a wide phylogenetic diversity of bacterial species and selective media to grow specific clades of interest. This strategy allowed us to build a large and comprehensive open-access collection of human gut bacteria in pure culture (Fig. 1a and Extended", "role": "user" }, { "content": "The human digestive tract is home to thousands of different strains of bacteria. Many of these are beneficial, while others contribute to health problems such as inflammatory bowel disease. Researchers from MIT and the Broad Institute have now isolated and preserved samples of nearly 8,000 of these strains, while also clarifying their genetic and metabolic context. This data set (BIO-ML), which is available to other researchers who want to use it, should help to shed light on the dynamics of microbial populations in the human gut and may help scientists develop new treatments for a variety of diseases, says Eric Alm, director of MIT's Center for Microbiome Informatics and Therapeutics and a professor of biological engineering and of civil and environmental engineering at MIT. \"There's a lot of excitement in the microbiome field because there are associations between these bacteria and health and disease. But we're lacking in being able to understand why that is, what's the mechanism, and what are the functions of those bacteria that are causing them to associate with disease,\" says Alm, who is the senior author of the study. The researchers collected stool samples from about 90 people, for up to two years, allowing them to gain insight into how microbial populations change over time within individuals. This study focused on people living in the Boston area, but the research team is now gathering a larger diversity of samples from around the globe, in hopes of preserving microbial strains not found in people living in industrialized societies. \"More than ever before, modern techniques allow us to isolate previously uncultured human gut bacteria. Exploring this genetic and functional diversity is fascinating—everywhere we look, we discover new things. I'm convinced that enriching biobanks with a large diversity of strains from individuals living diverse lifestyles is essential for future advancements in human microbiome research,\" says Mathilde Poyet, a senior postdoc at MIT and one of the lead authors of the study. MIT research associate Mathieu Groussin and former postdoc Sean Gibbons are also lead authors of the study, which appears in the Sept. 2 issue of Nature Medicine. Ramnik Xavier, a professor of medicine at Harvard Medical School and member of the Broad Institute, is a senior author of the study along with Alm. Microbiome dynamics Humans have trillions of bacterial cells in their digestive tracts, and while scientists believe that these populations change and evolve over time, there has been little opportunity to observe this. Through the OpenBiome organization, which collects stool samples for research and therapeutic purposes, Alm and his colleagues at MIT and the Broad Institute had access to fecal samples from about 90 people. For most of their analysis, the researchers focused on microbes found in about a dozen individuals who had provided samples over an extended period, up to two years. \"That was a unique opportunity, and we thought that would be a great set of individuals to really try to dig down and characterize the microbial populations more thoroughly,\" Alm says. \"To date there hadn't been a ton of longitudinal studies, and we wanted to make that a key focus of our study, so we could understand what the variation is day-to-day.\" The researchers were able to isolate a total of 7,758 strains from the six major phyla of bacteria that dominate the human GI tract. For 3,632 of these strains, the researchers sequenced their full genomes, and they also sequenced partial genomes of the remaining strains. Analyzing how microbial populations changed over time within single hosts allowed the researchers to discover some novel interactions between strains. In one case, the researchers found three related strains of Bacteroides vulgatus coexisting within a host, all of which appeared to have diverged from one ancestor strain within the host. In another case, one strain of Turicibacter sanguinis completely replaced a related strain of the same species nearly overnight. \"This is the first time we're getting a glimpse of these really different dynamics,\" Alm says. Population variation The researchers also measured the quantities of many metabolites found in the stool samples. This analysis revealed that variations in amino acid levels were closely linked with changes in microbial populations over time within a single person. However, differences between the composition of microbial populations in different people were more closely associated with varying levels of bile acids, which help with digestion. The researchers don't know exactly what produces these differences in amino acid and bile acid levels, but say they could be influenced by diet—a connection that they hope to investigate in future studies. They have also made all of their data available online and are offering samples of the strains of bacteria they isolated, allowing other scientists to study the functions of these strains and their potential roles in human health. \"Comprehensive and high-resolution collections of bacterial isolates open the possibility to mechanistically investigate how our lifestyle shapes our gut microbiome, metabolism, and inflammation. We aim to provide such a resource to the research community worldwide, including to lower-income research institutions,\" Groussin says. The researchers have also begun a larger-scale project to collect microbiome samples from a greater diversity of populations around the world. They are especially focusing on underrepresented populations who live in nonindustrialized societies, as their diet and microbiomes are expected to be very different from those of people living in industrialized societies. \"It may be that as populations that have been living traditional lifestyles start to switch to a more industrialized lifestyle, they may lose a lot of that biodiversity. So one of the main things we want to do is conserve it, and then later we can go back and characterize it as well,\" Alm 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 Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used ‘omics’ survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research. Introduction Engineering the gut microbiome to treat disease is an exciting new direction in medical science 1 , 2 , 3 . Fecal microbiota transplant (FMT) from a healthy donor into patients with recurrent Clostridium difficile infections is the first widely adopted microbiome-related therapy and has a ~90% success rate 4 , 5 . Investigational trials are underway in new disease areas, such as inflammatory bowel disease, liver disease, Parkinson’s disease, severe acute malnutrition and infection by antibiotic-resistant pathogens 6 , 7 , 8 , 9 (see ongoing clinical trials at ). OpenBiome is a stool bank that has provided material for over 48,000 fecal transplants. Stool banks like OpenBiome represent an attractive opportunity for building a well-characterized culture collection because living biomass is preserved, allowing cultivation of isolated strains, and because dense longitudinal sampling (that is, several samples being collected per week) enables analysis of within-host dynamics. In addition, a resource of isolate genomes together with longitudinal dynamics can be useful in designing and analyzing future clinical trials. Finally, a comprehensive culture collection from successful donors could ultimately be used to replace FMT, which is a blunt tool for engineering the gut microbiome and may have long-term consequences due to the introduction of a wide variety of exogenous strains with unknown function 10 , 11 , 12 . While comprehensive strain collections are essential for mechanistic studies, culturing a diverse representation of gut bacteria has been challenging. Seminal work by several groups 13 , 14 , 15 , 16 , 17 has addressed many of the technological challenges of growing wide arrays of gut bacterial lineages, and two recent studies reported isolate and genome collections with broad phylogenetic representation 18 , 19 . However, existing isolate and genome collections are still limited, especially in strain-level diversity, for most of the bacterial species in the human gut. In addition, current collections are limited in examples of coexisting strain-level diversity from the same human host because the majority of strains were cultured from a large number of individuals or were targeted for maximizing phylogenetic diversity. Recent work has shown that this within-host strain diversity is extensive in the human population 20 and within individual people 21 , 22 , 23 . New studies increasingly point to functional differences between strains of the same species that can impact human health 21 , 24 , 25 . For instance, strain-level differences can influence the metabolism of dietary compounds, such as galacto-oligosaccharides 26 or nondigestible fibers 27 , 28 . Bacteria-mediated metabolism of drugs can also differ across strains, influencing drug efficacy and toxicity 29 , 30 . In addition, genomic variation in virulence genes can alter pathogenicity among strains 31 , 32 , 33 . Finally, distinct strains can elicit different immune responses, such as cytokine production 25 . For these reasons, a large collection of isolates of multiple strains from many gut bacterial species, sampled both within and across people, is needed to better understand host–microbe interactions and to efficiently screen for candidate features that could ultimately be leveraged in rationally designed microbiome-based therapeutics. Here, we introduce a comprehensive biobank of human gut bacteria: a library of 7,758 bacterial isolates obtained from healthy FMT donors recruited in the Boston area. This library covers most of the phylogenetic diversity found in the human gut, contains extensive strain diversity and is available to the research community. We report whole-genome sequences (WGSs) for 3,632 of these isolates that span a wide range of phyla and genera, to enable researchers to test and predict phenotypes in vitro and in vivo, such as metabolic capability or resistance to antibiotics. We also provide longitudinal 16S, metagenomic and metabolomic data for more than 80 FMT donors. Finally, we highlight examples that illustrate how these data can be used to better understand the eco-evolutionary dynamics of the gut microbiome within and between people. Results Isolation of an extensive collection of gut bacterial isolates for in vitro and in vivo testing of mechanistic hypotheses Many strict anaerobes in the human gut were considered unculturable until recently 14 , 15 , 16 , 17 , 18 , 19 , 34 , 35 . As a result, densely sampled sets of strains from many anaerobic species are still not readily available. Here, we leverage recent advances in culturing techniques to isolate a large phylogenetic diversity of gut bacterial strains from healthy FMT donors. Building a library of isolates that cover the diversity of gut bacteria from OpenBiome donors We have designed and implemented protocols to culture, isolate and store a large diversity of anaerobic gut bacterial strains in pure culture. We used filtered stool extracts from 11 donors within our cohort, and we used 12 different media, combined with antibiotic, acid and ethanol treatments, resulting in 19 different culturing conditions (see Supplementary Methods ). We used general media to obtain a wide phylogenetic diversity of bacterial species and selective media to grow specific clades of interest. This strategy allowed us to build a large and comprehensive open-access collection of human gut bacteria in pure culture (Fig. 1a and Extended<|im_end|> <|im_start|>assistant The human digestive tract is home to thousands of different strains of bacteria. Many of these are beneficial, while others contribute to health problems such as inflammatory bowel disease. Researchers from MIT and the Broad Institute have now isolated and preserved samples of nearly 8,000 of these strains, while also clarifying their genetic and metabolic context. This data set (BIO-ML), which is available to other researchers who want to use it, should help to shed light on the dynamics of microbial populations in the human gut and may help scientists develop new treatments for a variety of diseases, says Eric Alm, director of MIT's Center for Microbiome Informatics and Therapeutics and a professor of biological engineering and of civil and environmental engineering at MIT. "There's a lot of excitement in the microbiome field because there are associations between these bacteria and health and disease. But we're lacking in being able to understand why that is, what's the mechanism, and what are the functions of those bacteria that are causing them to associate with disease," says Alm, who is the senior author of the study. The researchers collected stool samples from about 90 people, for up to two years, allowing them to gain insight into how microbial populations change over time within individuals. This study focused on people living in the Boston area, but the research team is now gathering a larger diversity of samples from around the globe, in hopes of preserving microbial strains not found in people living in industrialized societies. "More than ever before, modern techniques allow us to isolate previously uncultured human gut bacteria. Exploring this genetic and functional diversity is fascinating—everywhere we look, we discover new things. I'm convinced that enriching biobanks with a large diversity of strains from individuals living diverse lifestyles is essential for future advancements in human microbiome research," says Mathilde Poyet, a senior postdoc at MIT and one of the lead authors of the study. MIT research associate Mathieu Groussin and former postdoc Sean Gibbons are also lead authors of the study, which appears in the Sept. 2 issue of Nature Medicine. Ramnik Xavier, a professor of medicine at Harvard Medical School and member of the Broad Institute, is a senior author of the study along with Alm. Microbiome dynamics Humans have trillions of bacterial cells in their digestive tracts, and while scientists believe that these populations change and evolve over time, there has been little opportunity to observe this. Through the OpenBiome organization, which collects stool samples for research and therapeutic purposes, Alm and his colleagues at MIT and the Broad Institute had access to fecal samples from about 90 people. For most of their analysis, the researchers focused on microbes found in about a dozen individuals who had provided samples over an extended period, up to two years. "That was a unique opportunity, and we thought that would be a great set of individuals to really try to dig down and characterize the microbial populations more thoroughly," Alm says. "To date there hadn't been a ton of longitudinal studies, and we wanted to make that a key focus of our study, so we could understand what the variation is day-to-day." The researchers were able to isolate a total of 7,758 strains from the six major phyla of bacteria that dominate the human GI tract. For 3,632 of these strains, the researchers sequenced their full genomes, and they also sequenced partial genomes of the remaining strains. Analyzing how microbial populations changed over time within single hosts allowed the researchers to discover some novel interactions between strains. In one case, the researchers found three related strains of Bacteroides vulgatus coexisting within a host, all of which appeared to have diverged from one ancestor strain within the host. In another case, one strain of Turicibacter sanguinis completely replaced a related strain of the same species nearly overnight. "This is the first time we're getting a glimpse of these really different dynamics," Alm says. Population variation The researchers also measured the quantities of many metabolites found in the stool samples. This analysis revealed that variations in amino acid levels were closely linked with changes in microbial populations over time within a single person. However, differences between the composition of microbial populations in different people were more closely associated with varying levels of bile acids, which help with digestion. The researchers don't know exactly what produces these differences in amino acid and bile acid levels, but say they could be influenced by diet—a connection that they hope to investigate in future studies. They have also made all of their data available online and are offering samples of the strains of bacteria they isolated, allowing other scientists to study the functions of these strains and their potential roles in human health. "Comprehensive and high-resolution collections of bacterial isolates open the possibility to mechanistically investigate how our lifestyle shapes our gut microbiome, metabolism, and inflammation. We aim to provide such a resource to the research community worldwide, including to lower-income research institutions," Groussin says. The researchers have also begun a larger-scale project to collect microbiome samples from a greater diversity of populations around the world. They are especially focusing on underrepresented populations who live in nonindustrialized societies, as their diet and microbiomes are expected to be very different from those of people living in industrialized societies. "It may be that as populations that have been living traditional lifestyles start to switch to a more industrialized lifestyle, they may lose a lot of that biodiversity. So one of the main things we want to do is conserve it, and then later we can go back and characterize it as well," Alm says. <|im_end|>

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2,463

[ { "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 Viruses can impose energetic demands on organisms they infect, in part by hosts mounting resistance. Recognizing that oxygen uptake reliably indicates steady-state energy consumption in all vertebrates, we comprehensively evaluated oxygen uptake and select transcriptomic messaging in sockeye salmon challenged with either a virulent rhabdovirus (IHNV) or a low-virulent reovirus (PRV). We tested three hypotheses relating to the energetic costs of viral resistance and tolerance in this vertebrate system: (1) mounting resistance incurs a metabolic cost or limitation, (2) induction of the innate antiviral interferon system compromises homeostasis, and (3) antiviral defenses are weakened by acute stress. Results IHNV infections either produced mortality within 1–4 weeks or the survivors cleared infections within 1–9 weeks. Transcription of three interferon-stimulated genes (ISGs) was strongly correlated with IHNV load but not respiratory performance. Instead, early IHNV resistance was associated with a mean 19% (95% CI = 7–31%; p = 0.003) reduction in standard metabolic rate. The stress of exhaustive exercise did not increase IHNV transcript loads, but elevated host inflammatory transcriptional signaling up to sevenfold. For PRV, sockeye tolerated high-load systemic PRV blood infections. ISG transcription was transiently induced at peak PRV loads without associated morbidity, microscopic lesions, or major changes in aerobic or anaerobic respiratory performance, but some individuals with high-load blood infections experienced a transient, minor reduction in hemoglobin concentration and increased duration of excess post-exercise oxygen consumption. Conclusions Contrary to our first hypothesis, effective resistance against life-threatening rhabdovirus infections or tolerance to high-load reovirus infections incurred minimal metabolic costs to salmon. Even robust systemic activation of the interferon system did not levy an allostatic load sufficient to compromise host homeostasis or respiratory performance, rejecting our second hypothesis that this ancient innate vertebrate antiviral defense is itself energetically expensive. Lastly, an acute stress experienced during testing did not weaken host antiviral defenses sufficiently to promote viral replication; however, a possibility for disease intensification contingent upon underlying inflammation was indicated. These data cumulatively demonstrate that fundamental innate vertebrate defense strategies against potentially life-threatening viral exposure impose limited putative costs on concurrent aerobic or energetic demands of the organism. Background The evolution and maintenance of immune systems for the purpose of parasite resistance is critical for animal survival; yet, immunological competence necessitates an internal resource allocation that could otherwise be used toward growth, reproduction, or other activities. Thus, parasite resistance incurs a putative energetic cost against all fitness-enhancing processes. This concept of “trading-off” energetic demands between life-history traits in the face of dynamic ecological challenges is the foundation of life-history theory [ 1 ]. Considerable debate has surrounded exactly what the overall energetic cost of parasite resistance might entail. Some immune functions appear energetically expensive [ 2 , 3 , 4 ]. For example, humans mounting a fever response following typhoid vaccination transiently increase metabolic rate by 16% [ 5 ], while calorie-restricted lizards experience a near 50% reduction in ovarian follicle mass development when tasked with wound healing compared to unwounded individuals [ 6 ]. In contrast, other immune responses seem to have little to no energetic cost [ 7 , 8 , 9 , 10 ], e.g., increased allelic polymorphism of erythrocyte Plasmodium -target antigens that enhance malaria resistance [ 8 , 11 ]. These varied responses have hindered our ability to accurately predict the likelihood for important tradeoffs and suggest that energetic costs of parasite resistance may be pathway- or even parasite-specific. Defense against viruses in eukaryotic vertebrates involves the coordination of both an innate and adaptive immune system, primarily under the regulation of interferon-sensitive pathways. Specifically, viral recognition by innate pattern recognition receptors triggers local transcriptional activation of interferons. Interferon in turn facilitates transcription of interferon-stimulated genes (ISGs) that enable local cells to mount antiviral molecular defenses, recruit immune cells to the site of infection, and restrain pro-inflammatory responses [ 12 , 13 ]. Interferons also play a critical role in activating the adaptive responses of T- and B-cells to target the invading virus in order to curtail persistent infections and defend against re-exposure [ 13 ]. Despite extensive mapping of the interferon molecular cascade in vertebrate systems, the metabolic costs associated with these responses are largely unclear. Data do suggest that, at a cellular level, activation of interferon promotes glycolysis (an anaerobic pathway) and in some cases increases mitochondrial respiration (an aerobic pathway) [ 14 ]. However, in most instances, it is questionable as to whether these costs exceed the allostatic capacities of an organism to absorb minor perturbations that would either affect homeostasis [ 15 ] or impact long-term growth and reproduction of the organism [ 9 , 10 , 16 ]. Dynamic environmental conditions further complicate assessments of viral-associated fitness costs, especially in ectotherms where environmental conditions directly influence metabolism. Specifically, studies identifying physiologically relevant costs for parasite resistance in vertebrate systems have mostly been conducted under resource-limiting conditions untenable to maintain metabolic homeostasis independent of immunological functioning [ 9 , 17 ]. Thus, although these studies provide evidence for prioritizing pathways during extensive resource limitation, there is currently little data to indicate the quantity of energetic resources required to fully engage an antiviral immune response (i.e., the energy required for uncompromised resistance). In this study, we set out to test three hypotheses relating to the metabolic and fitness costs of innate antiviral resistance and tolerance in a vertebrate model, the sockeye salmon ( Oncorhynchus nerka ), a teleost fish. First, we hypothesized that under stable environmental conditions conducive for maintaining metabolic homeostasis, virus resistance (defined here as actions specifically taken to curb virus colonization and replication) incurs a higher energetic cost relative to virus tolerance (allowing virus colonization and replication to progress relatively unimpeded) or non-exposure. This follows the logic that tolerance would not occur if energetic costs for active resistance were lower than the costs attributed to viral parasitism, which has been recently estimated to be minimal—approximately 1% of a eukaryotic cell’s energy budget [ 18 ]. Second, we hypothesized that at least part of the energetic costs for viral resistance would", "role": "user" }, { "content": "The respiratory performance of wild Pacific sockeye salmon functions normally even when infected with piscine orthoreovirus (PRV), according to a new study released today. The findings by researchers at UBC, Fisheries and Oceans Canada (DFO) and the Ministry of Agriculture, Food and Fisheries are published in BMC Biology. \"We saw little to no effect on sockeye salmon's respiratory fitness after PRV-infection and minimal impacts on their ability to sustain the vigorous activity needed to migrate, catch prey and avoid predators,\" said Dr. Yangfan Zhang, a post-doctoral researcher in UBC's faculty of land and food systems and the department of zoology, and the joint lead author of the study. The nine-week study found no physiological differences between PRV-infected fish and a control group, injected with a salt solution. \"This means PRV poses a very low risk to British Columbia's population of wild Pacific salmon,\" Dr. Zhang says. \"The findings highlight that not all animal viruses cause notable harm during infection,\" says joint lead author, Dr. Mark Polinski, a DFO researcher. PRV infects most farmed Atlantic salmon and just a small proportion of wild Pacific salmon. The study used sockeye salmon to test the respiratory impacts of wild salmon because they migrate near salmon farms. \"This is the first study to show that sockeye salmon can be a carrier of PRV without untoward physiological effects to their respiratory system,\" says Dr. Tony Farrell, a professor and Canada Research Chair with UBC's faculty of land and food systems and the department of zoology, and one of the principal investigators on the study. The research team ran their experiment on a total of 400 sockeye salmon at the DFO Pacific Biological Station in Nanaimo, BC. One group of sockeye salmon was injected with a dose of purified PRV to induce a high-dose infection scenario, another with a saline solution, and a third group was injected with the more virulent infectious hematopoietic necrosis virus (IHNV) in a separate positive-control study. None of the salmon died while carrying the PRV infection. But researchers noted IHNV triggered 30 percent mortality and a temporarily reduced maintenance metabolism, although survivors were able to resolve the infection within weeks. Researchers also measured the ability of red blood cells infected with PRV to bind oxygen, as well as the metabolic rate—or oxygen uptake—of infected salmon, to evaluate their ability to maximally use oxygen, recover from exhaustion, and function when oxygen is low. \"The experimental PRV infection of sockeye salmon shows that the virus had no substantial impact on their oxygen use during maximum exercise, or when oxygen is low,\" Dr. Farrell says. \"Pacific and Atlantic salmon can resist a PRV infection without a major metabolic cost,\" he says, addressing those concerned about the untested impacts of PRV on wild sockeye salmon. The authors previously performed similar investigations with PRV-infected farmed Atlantic salmon with similar results, published in 2019. The UBC researchers worked with scientists from the BC Ministry of Agriculture, Food and Fisheries, and Fisheries and Oceans Canada—which funded the study—with collaborative support from the BC Salmon Farmers Association (BCSFA) who did not participate in the study design, data collection, and analysis, preparation of the manuscript, or decision to publish. ", "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 Viruses can impose energetic demands on organisms they infect, in part by hosts mounting resistance. Recognizing that oxygen uptake reliably indicates steady-state energy consumption in all vertebrates, we comprehensively evaluated oxygen uptake and select transcriptomic messaging in sockeye salmon challenged with either a virulent rhabdovirus (IHNV) or a low-virulent reovirus (PRV). We tested three hypotheses relating to the energetic costs of viral resistance and tolerance in this vertebrate system: (1) mounting resistance incurs a metabolic cost or limitation, (2) induction of the innate antiviral interferon system compromises homeostasis, and (3) antiviral defenses are weakened by acute stress. Results IHNV infections either produced mortality within 1–4 weeks or the survivors cleared infections within 1–9 weeks. Transcription of three interferon-stimulated genes (ISGs) was strongly correlated with IHNV load but not respiratory performance. Instead, early IHNV resistance was associated with a mean 19% (95% CI = 7–31%; p = 0.003) reduction in standard metabolic rate. The stress of exhaustive exercise did not increase IHNV transcript loads, but elevated host inflammatory transcriptional signaling up to sevenfold. For PRV, sockeye tolerated high-load systemic PRV blood infections. ISG transcription was transiently induced at peak PRV loads without associated morbidity, microscopic lesions, or major changes in aerobic or anaerobic respiratory performance, but some individuals with high-load blood infections experienced a transient, minor reduction in hemoglobin concentration and increased duration of excess post-exercise oxygen consumption. Conclusions Contrary to our first hypothesis, effective resistance against life-threatening rhabdovirus infections or tolerance to high-load reovirus infections incurred minimal metabolic costs to salmon. Even robust systemic activation of the interferon system did not levy an allostatic load sufficient to compromise host homeostasis or respiratory performance, rejecting our second hypothesis that this ancient innate vertebrate antiviral defense is itself energetically expensive. Lastly, an acute stress experienced during testing did not weaken host antiviral defenses sufficiently to promote viral replication; however, a possibility for disease intensification contingent upon underlying inflammation was indicated. These data cumulatively demonstrate that fundamental innate vertebrate defense strategies against potentially life-threatening viral exposure impose limited putative costs on concurrent aerobic or energetic demands of the organism. Background The evolution and maintenance of immune systems for the purpose of parasite resistance is critical for animal survival; yet, immunological competence necessitates an internal resource allocation that could otherwise be used toward growth, reproduction, or other activities. Thus, parasite resistance incurs a putative energetic cost against all fitness-enhancing processes. This concept of “trading-off” energetic demands between life-history traits in the face of dynamic ecological challenges is the foundation of life-history theory [ 1 ]. Considerable debate has surrounded exactly what the overall energetic cost of parasite resistance might entail. Some immune functions appear energetically expensive [ 2 , 3 , 4 ]. For example, humans mounting a fever response following typhoid vaccination transiently increase metabolic rate by 16% [ 5 ], while calorie-restricted lizards experience a near 50% reduction in ovarian follicle mass development when tasked with wound healing compared to unwounded individuals [ 6 ]. In contrast, other immune responses seem to have little to no energetic cost [ 7 , 8 , 9 , 10 ], e.g., increased allelic polymorphism of erythrocyte Plasmodium -target antigens that enhance malaria resistance [ 8 , 11 ]. These varied responses have hindered our ability to accurately predict the likelihood for important tradeoffs and suggest that energetic costs of parasite resistance may be pathway- or even parasite-specific. Defense against viruses in eukaryotic vertebrates involves the coordination of both an innate and adaptive immune system, primarily under the regulation of interferon-sensitive pathways. Specifically, viral recognition by innate pattern recognition receptors triggers local transcriptional activation of interferons. Interferon in turn facilitates transcription of interferon-stimulated genes (ISGs) that enable local cells to mount antiviral molecular defenses, recruit immune cells to the site of infection, and restrain pro-inflammatory responses [ 12 , 13 ]. Interferons also play a critical role in activating the adaptive responses of T- and B-cells to target the invading virus in order to curtail persistent infections and defend against re-exposure [ 13 ]. Despite extensive mapping of the interferon molecular cascade in vertebrate systems, the metabolic costs associated with these responses are largely unclear. Data do suggest that, at a cellular level, activation of interferon promotes glycolysis (an anaerobic pathway) and in some cases increases mitochondrial respiration (an aerobic pathway) [ 14 ]. However, in most instances, it is questionable as to whether these costs exceed the allostatic capacities of an organism to absorb minor perturbations that would either affect homeostasis [ 15 ] or impact long-term growth and reproduction of the organism [ 9 , 10 , 16 ]. Dynamic environmental conditions further complicate assessments of viral-associated fitness costs, especially in ectotherms where environmental conditions directly influence metabolism. Specifically, studies identifying physiologically relevant costs for parasite resistance in vertebrate systems have mostly been conducted under resource-limiting conditions untenable to maintain metabolic homeostasis independent of immunological functioning [ 9 , 17 ]. Thus, although these studies provide evidence for prioritizing pathways during extensive resource limitation, there is currently little data to indicate the quantity of energetic resources required to fully engage an antiviral immune response (i.e., the energy required for uncompromised resistance). In this study, we set out to test three hypotheses relating to the metabolic and fitness costs of innate antiviral resistance and tolerance in a vertebrate model, the sockeye salmon ( Oncorhynchus nerka ), a teleost fish. First, we hypothesized that under stable environmental conditions conducive for maintaining metabolic homeostasis, virus resistance (defined here as actions specifically taken to curb virus colonization and replication) incurs a higher energetic cost relative to virus tolerance (allowing virus colonization and replication to progress relatively unimpeded) or non-exposure. This follows the logic that tolerance would not occur if energetic costs for active resistance were lower than the costs attributed to viral parasitism, which has been recently estimated to be minimal—approximately 1% of a eukaryotic cell’s energy budget [ 18 ]. Second, we hypothesized that at least part of the energetic costs for viral resistance would<|im_end|> <|im_start|>assistant The respiratory performance of wild Pacific sockeye salmon functions normally even when infected with piscine orthoreovirus (PRV), according to a new study released today. The findings by researchers at UBC, Fisheries and Oceans Canada (DFO) and the Ministry of Agriculture, Food and Fisheries are published in BMC Biology. "We saw little to no effect on sockeye salmon's respiratory fitness after PRV-infection and minimal impacts on their ability to sustain the vigorous activity needed to migrate, catch prey and avoid predators," said Dr. Yangfan Zhang, a post-doctoral researcher in UBC's faculty of land and food systems and the department of zoology, and the joint lead author of the study. The nine-week study found no physiological differences between PRV-infected fish and a control group, injected with a salt solution. "This means PRV poses a very low risk to British Columbia's population of wild Pacific salmon," Dr. Zhang says. "The findings highlight that not all animal viruses cause notable harm during infection," says joint lead author, Dr. Mark Polinski, a DFO researcher. PRV infects most farmed Atlantic salmon and just a small proportion of wild Pacific salmon. The study used sockeye salmon to test the respiratory impacts of wild salmon because they migrate near salmon farms. "This is the first study to show that sockeye salmon can be a carrier of PRV without untoward physiological effects to their respiratory system," says Dr. Tony Farrell, a professor and Canada Research Chair with UBC's faculty of land and food systems and the department of zoology, and one of the principal investigators on the study. The research team ran their experiment on a total of 400 sockeye salmon at the DFO Pacific Biological Station in Nanaimo, BC. One group of sockeye salmon was injected with a dose of purified PRV to induce a high-dose infection scenario, another with a saline solution, and a third group was injected with the more virulent infectious hematopoietic necrosis virus (IHNV) in a separate positive-control study. None of the salmon died while carrying the PRV infection. But researchers noted IHNV triggered 30 percent mortality and a temporarily reduced maintenance metabolism, although survivors were able to resolve the infection within weeks. Researchers also measured the ability of red blood cells infected with PRV to bind oxygen, as well as the metabolic rate—or oxygen uptake—of infected salmon, to evaluate their ability to maximally use oxygen, recover from exhaustion, and function when oxygen is low. "The experimental PRV infection of sockeye salmon shows that the virus had no substantial impact on their oxygen use during maximum exercise, or when oxygen is low," Dr. Farrell says. "Pacific and Atlantic salmon can resist a PRV infection without a major metabolic cost," he says, addressing those concerned about the untested impacts of PRV on wild sockeye salmon. The authors previously performed similar investigations with PRV-infected farmed Atlantic salmon with similar results, published in 2019. The UBC researchers worked with scientists from the BC Ministry of Agriculture, Food and Fisheries, and Fisheries and Oceans Canada—which funded the study—with collaborative support from the BC Salmon Farmers Association (BCSFA) who did not participate in the study design, data collection, and analysis, preparation of the manuscript, or decision to publish. <|im_end|>

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2,065

[ { "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 Humans perform object manipulation in order to execute a specific task. Seldom is such action started with no goal in mind. In contrast, traditional robotic grasping (first stage for object manipulation) seems to focus purely on getting hold of the object—neglecting the goal of the manipulation. Most metrics used in robotic grasping do not account for the final task in their judgement of quality and success. In this Perspective we suggest a change of view. Since the overall goal of a manipulation task shapes the actions of humans and their grasps, we advocate that the task itself should shape the metric of success. To this end, we propose a new metric centred on the task. Finally, we call for action to support the conversation and discussion on such an important topic for the community. Main Many manufacturing companies have modernized plants and factories, adopting high-tech solutions that involve robotic manipulators achieving high-throughput execution of repetitive jobs. Their presence in industrial settings is eased by the structured nature of such environments. However, fully useful robots are still a chimaera in more unstructured environments such as domestic settings. Industrial factories are laid out so that objects are placed in positions that are known a priori, and robots perform actions that can be defined with utmost certainty. In contrast, homes are an example of unstructured environments, as they are usually dynamic and unpredictable. Two solutions have been recently introduced to account for uncertainty in object position and to improve adaptability of robotic hands with respect to the environment 1 : compliance in the robotic structure (for example, variable stiffness actuators) and soft grippers. However, object manipulation involves a high degree of unpredictability, both when creating products in industry and, increasingly, when helping and assisting humans. In this view, there is a push in industry (for example, the current trend of automation named industry 4.0 (ref. 2 ) to allow robots and humans to collaborate in smart factories. In these shared environments, robots are expected to seamlessly interact with their surroundings and other concurrent agents—humans and potentially other robots—for successful cooperation and collaboration. To this end, robots need to be able to effectively manipulate objects not only in structured environments, but also in unstructured environments. Dexterous object manipulation is the basis of human interaction with the environment. We interact with objects to accomplish a task we have in mind 3 . We know our goal, we perceive the environment and we devise an action plan that we can modify on the go while acting. In this frame of mind, the first action we commit to is to grasp the object we want to use. Therefore, grasping and manipulation are conceived by humans as task-oriented or purposive actions. These actions are performed to accomplish a task and they are heavily defined and parameterized by it. At the level of human motor control, similarities in the main building blocks exist across different tasks, such as element of geometrical basis, or synergies. However, a task specialization needs the enrolment of additional elements of such a geometrical basis for action execution 4 , 5 . Grasp choice, hand shaping and hand position on the object are parameters heavily influenced by the task to perform 6 , 7 , 8 , 9 , 10 , 11 , 12 . Intuitively, we choose to place and shape our hands on the object to fulfil the requirements of the task. Different tasks might induce different hand shaping and hand placement even on the same object. When signing a document, we most probably grasp a pen leaving the tip free from obstruction while the pen itself is held stably, as in Fig. 1 . Such a grasp allows the pen to be moved and to leave the intended traces of ink on the paper 13 . Should we want to pass the pen to another person to sign the document, we would grasp the pen in a different way—most likely leaving the handle free for the second person to grasp the pen and write immediately after the handover 14 . Research in human cognitive and neurological models has long attributed the ‘how to grasp’ with the ‘why to grasp’, stemming from a separate process 15 . More recently, physiological data suggest that, instead of computing all decisions in an abstract form, decisions are made in the same regions of the brain that guide movement execution 16 , 17 . Neuroscientific data point to the sensorimotor regions of the frontal and parietal cerebral cortex as well as parts of the basal ganglia. Fig. 1: How a grasp changes because of a task. Left: grasping a pen for writing. Right: handing over the pen from a person in the right side to a person in the left side. Full size image Robotic manipulation—especially grasping—has advanced admirably in recent years, but the focus has mainly been on the success of a grasp that has no further goal than to grasp an object, correlating to what the sensorimotor control of the human grasping process would be. It is completely oblivious of the inherent purposive character of the object grasping and manipulation. Although some contributions have investigated robotic grasping and manipulation as being task-oriented, there seems to be a big divide between the analysis of the human action of object grasping and manipulation, and what we have reproduced on robotic platforms so far. In other words, higher-level decision making based on the task is not yet an input to the grasping process. In this Perspective, we argue that an approach more focused on the task might further the success of robotic grasping and manipulation. We also suggest that a metric used to judge the quality and success of a grasp should include the grasp and manipulation task alongside more common quality indexes such as mean picks per hour (MPPH) and stability. The need for object grasping and manipulation Manipulation is arguably one of the skills that have allowed humans to be successful 18 , 19 .", "role": "user" }, { "content": "Robots need to know the reason why they are doing a job if they are to effectively and safely work alongside people in the near future. In simple terms, this means machines need to understand motive the way humans do, and not just perform tasks blindly, without context. According to a new article by the National Centre for Nuclear Robotics, based at the University of Birmingham, this could herald a profound change for the world of robotics, but one that is necessary. Lead author Dr. Valerio Ortenzi, at the University of Birmingham, argues the shift in thinking will be necessary as economies embrace automation, connectivity and digitization (\"Industry 4.0') and levels of human—robot interaction, whether in factories or homes, increase dramatically. The paper, published in Nature Machine Intelligence, explores the issue of robots using objects. \"Grasping' is an action perfected long ago in nature but one which represents the cutting-edge of robotics research. Most factory-based machines are \"dumb,\" blindly picking up familiar objects that appear in pre-determined places at just the right moment. Getting a machine to pick up unfamiliar objects,randomly presented, requires the seamless interaction of multiple, complex technologies. These include vision systems and advanced AI so the machine can see the target and determine its properties (for example, is it rigid or flexible?); and potentially, sensors in the gripper are required so the robot does not inadvertently crush an object it has been told to pick up. Even when all this is accomplished, researchers in the National Centre for Nuclear Robotics highlighted a fundamental issue: what has traditionally counted as a 'successful' grasp for a robot might actually be a real-world failure, because the machine does not take into account what the goal is and whyit is picking an object up. The paper cites the example of a robot in a factory picking up an object for delivery to a customer. It successfully executes the task, holding the package securely without causing damage. Unfortunately, the robot's gripper obscures a crucial barcode, which means the object can't be tracked and the firm has no idea if the item has been picked up or not; the whole delivery system breaks down because the robot does not know the consequences of holding a box the wrong way. Dr. Ortenzi gives other examples, involving robots working alongside people. \"Imagine asking a robot to pass you a screwdriver in a workshop. Based on current conventions the best way for a robot to pick up the tool is by the handle,\" he said. \"Unfortunately, that could mean that a hugely powerful machine then thrusts a potentially lethal blade towards you, at speed. Instead, the robot needs to know what the end goal is, i.e.,to pass the screwdriver safely to its human colleague, in order to rethink its actions. \"Another scenario envisages a robot passing a glass of water to a resident in a care home. It must ensure that it doesn't drop the glass but also that water doesn't spill over the recipient during the act of passing, or that the glass is presented in such a way that the person can take hold of it. \"What is obvious to humans has to be programmed into a machine and this requires a profoundly different approach. The traditional metrics used by researchers, over the past twenty years, to assess robotic manipulation, are not sufficient. In the most practical sense, robots need a new philosophy to get a grip.\" Professor Rustam Stolkin, NCNR Director, said, \"National Centre for Nuclear Robotics is unique in working on practical problems with industry, while simultaneously generating the highest calibre of cutting-edge academic research—exemplified by this landmark paper.\" ", "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 Humans perform object manipulation in order to execute a specific task. Seldom is such action started with no goal in mind. In contrast, traditional robotic grasping (first stage for object manipulation) seems to focus purely on getting hold of the object—neglecting the goal of the manipulation. Most metrics used in robotic grasping do not account for the final task in their judgement of quality and success. In this Perspective we suggest a change of view. Since the overall goal of a manipulation task shapes the actions of humans and their grasps, we advocate that the task itself should shape the metric of success. To this end, we propose a new metric centred on the task. Finally, we call for action to support the conversation and discussion on such an important topic for the community. Main Many manufacturing companies have modernized plants and factories, adopting high-tech solutions that involve robotic manipulators achieving high-throughput execution of repetitive jobs. Their presence in industrial settings is eased by the structured nature of such environments. However, fully useful robots are still a chimaera in more unstructured environments such as domestic settings. Industrial factories are laid out so that objects are placed in positions that are known a priori, and robots perform actions that can be defined with utmost certainty. In contrast, homes are an example of unstructured environments, as they are usually dynamic and unpredictable. Two solutions have been recently introduced to account for uncertainty in object position and to improve adaptability of robotic hands with respect to the environment 1 : compliance in the robotic structure (for example, variable stiffness actuators) and soft grippers. However, object manipulation involves a high degree of unpredictability, both when creating products in industry and, increasingly, when helping and assisting humans. In this view, there is a push in industry (for example, the current trend of automation named industry 4.0 (ref. 2 ) to allow robots and humans to collaborate in smart factories. In these shared environments, robots are expected to seamlessly interact with their surroundings and other concurrent agents—humans and potentially other robots—for successful cooperation and collaboration. To this end, robots need to be able to effectively manipulate objects not only in structured environments, but also in unstructured environments. Dexterous object manipulation is the basis of human interaction with the environment. We interact with objects to accomplish a task we have in mind 3 . We know our goal, we perceive the environment and we devise an action plan that we can modify on the go while acting. In this frame of mind, the first action we commit to is to grasp the object we want to use. Therefore, grasping and manipulation are conceived by humans as task-oriented or purposive actions. These actions are performed to accomplish a task and they are heavily defined and parameterized by it. At the level of human motor control, similarities in the main building blocks exist across different tasks, such as element of geometrical basis, or synergies. However, a task specialization needs the enrolment of additional elements of such a geometrical basis for action execution 4 , 5 . Grasp choice, hand shaping and hand position on the object are parameters heavily influenced by the task to perform 6 , 7 , 8 , 9 , 10 , 11 , 12 . Intuitively, we choose to place and shape our hands on the object to fulfil the requirements of the task. Different tasks might induce different hand shaping and hand placement even on the same object. When signing a document, we most probably grasp a pen leaving the tip free from obstruction while the pen itself is held stably, as in Fig. 1 . Such a grasp allows the pen to be moved and to leave the intended traces of ink on the paper 13 . Should we want to pass the pen to another person to sign the document, we would grasp the pen in a different way—most likely leaving the handle free for the second person to grasp the pen and write immediately after the handover 14 . Research in human cognitive and neurological models has long attributed the ‘how to grasp’ with the ‘why to grasp’, stemming from a separate process 15 . More recently, physiological data suggest that, instead of computing all decisions in an abstract form, decisions are made in the same regions of the brain that guide movement execution 16 , 17 . Neuroscientific data point to the sensorimotor regions of the frontal and parietal cerebral cortex as well as parts of the basal ganglia. Fig. 1: How a grasp changes because of a task. Left: grasping a pen for writing. Right: handing over the pen from a person in the right side to a person in the left side. Full size image Robotic manipulation—especially grasping—has advanced admirably in recent years, but the focus has mainly been on the success of a grasp that has no further goal than to grasp an object, correlating to what the sensorimotor control of the human grasping process would be. It is completely oblivious of the inherent purposive character of the object grasping and manipulation. Although some contributions have investigated robotic grasping and manipulation as being task-oriented, there seems to be a big divide between the analysis of the human action of object grasping and manipulation, and what we have reproduced on robotic platforms so far. In other words, higher-level decision making based on the task is not yet an input to the grasping process. In this Perspective, we argue that an approach more focused on the task might further the success of robotic grasping and manipulation. We also suggest that a metric used to judge the quality and success of a grasp should include the grasp and manipulation task alongside more common quality indexes such as mean picks per hour (MPPH) and stability. The need for object grasping and manipulation Manipulation is arguably one of the skills that have allowed humans to be successful 18 , 19 .<|im_end|> <|im_start|>assistant Robots need to know the reason why they are doing a job if they are to effectively and safely work alongside people in the near future. In simple terms, this means machines need to understand motive the way humans do, and not just perform tasks blindly, without context. According to a new article by the National Centre for Nuclear Robotics, based at the University of Birmingham, this could herald a profound change for the world of robotics, but one that is necessary. Lead author Dr. Valerio Ortenzi, at the University of Birmingham, argues the shift in thinking will be necessary as economies embrace automation, connectivity and digitization ("Industry 4.0') and levels of human—robot interaction, whether in factories or homes, increase dramatically. The paper, published in Nature Machine Intelligence, explores the issue of robots using objects. "Grasping' is an action perfected long ago in nature but one which represents the cutting-edge of robotics research. Most factory-based machines are "dumb," blindly picking up familiar objects that appear in pre-determined places at just the right moment. Getting a machine to pick up unfamiliar objects,randomly presented, requires the seamless interaction of multiple, complex technologies. These include vision systems and advanced AI so the machine can see the target and determine its properties (for example, is it rigid or flexible?); and potentially, sensors in the gripper are required so the robot does not inadvertently crush an object it has been told to pick up. Even when all this is accomplished, researchers in the National Centre for Nuclear Robotics highlighted a fundamental issue: what has traditionally counted as a 'successful' grasp for a robot might actually be a real-world failure, because the machine does not take into account what the goal is and whyit is picking an object up. The paper cites the example of a robot in a factory picking up an object for delivery to a customer. It successfully executes the task, holding the package securely without causing damage. Unfortunately, the robot's gripper obscures a crucial barcode, which means the object can't be tracked and the firm has no idea if the item has been picked up or not; the whole delivery system breaks down because the robot does not know the consequences of holding a box the wrong way. Dr. Ortenzi gives other examples, involving robots working alongside people. "Imagine asking a robot to pass you a screwdriver in a workshop. Based on current conventions the best way for a robot to pick up the tool is by the handle," he said. "Unfortunately, that could mean that a hugely powerful machine then thrusts a potentially lethal blade towards you, at speed. Instead, the robot needs to know what the end goal is, i.e.,to pass the screwdriver safely to its human colleague, in order to rethink its actions. "Another scenario envisages a robot passing a glass of water to a resident in a care home. It must ensure that it doesn't drop the glass but also that water doesn't spill over the recipient during the act of passing, or that the glass is presented in such a way that the person can take hold of it. "What is obvious to humans has to be programmed into a machine and this requires a profoundly different approach. The traditional metrics used by researchers, over the past twenty years, to assess robotic manipulation, are not sufficient. In the most practical sense, robots need a new philosophy to get a grip." Professor Rustam Stolkin, NCNR Director, said, "National Centre for Nuclear Robotics is unique in working on practical problems with industry, while simultaneously generating the highest calibre of cutting-edge academic research—exemplified by this landmark paper." <|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 Phosphoinositides are a minor class of short-lived membrane phospholipids that serve crucial functions in cell physiology ranging from cell signalling and motility to their role as signposts of compartmental membrane identity 1 , 2 . Phosphoinositide 4-phosphates such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) are concentrated at the plasma membrane, on secretory organelles 3 , and on lysosomes 4 , whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P) 5 , are a hallmark of the endosomal system 1 , 2 . Directional membrane traffic between endosomal and secretory compartments, although inherently complex, therefore requires regulated phosphoinositide conversion. The molecular mechanism underlying this conversion of phosphoinositide identity during cargo exit from endosomes by exocytosis is unknown. Here we report that surface delivery of endosomal cargo requires hydrolysis of PI(3)P by the phosphatidylinositol 3-phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy (also called myotubular myopathy) in humans 6 . Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2α (PI4K2α)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Our data establish a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans. Main X-linked centronuclear myopathy (XLCNM) is a severe congenital myopathy caused by mutations in MTM1 (ref. 6 ). Patients with XLCNM suffer from defective muscle fibres due to disorganized membrane compartments and T-tubules 7 and are affected by severe hypotonia at birth, while the mildest surviving cases display muscle and non-muscle phenotypes 8 . MTM1 knockout mice are born below Mendelian ratios, and show progressive myopathy and growth impairment leading to early death 9 . Depletion of MTM1 in fruitflies causes endosomal accumulation of β1-integrin in developing muscles 10 , possibly because of defective phosphoinositide conversion at endosomes. Intracellular β1-integrin accumulations were indeed seen in endosomes of the MTM1-deficient XLCNM-patient fibroblast cell line H31 ( Fig. 1a ) and in MTM1-depleted HeLa cells ( Fig. 1b and Extended Data Fig. 1a ). Re-expression of active MTM1 rescued β1-integrin accumulation in H31 cells ( Fig. 1c ). Accumulations of β1-integrin in MTM1-depleted cells were immunopositive for recycling endosomal transferrin receptor (TfR) and late endosomal Rab7, but displayed limited overlap with early endosomal Rab5 and were negative for the trans-Golgi network marker Rab8 ( Extended Data Fig. 1a ). These data suggest that MTM1 loss-of-function causes β1-integrin accumulation in late endosomes, possibly to facilitate their degradation. We hypothesized that defective cargo exit from endosomes may underlie the endosomal sequestration of β1-integrin in XLCNM-patient cells. Therefore, we analysed the distribution of TfR, a receptor that, following internalization, is recycled by exocytosis from endosomes to the plasma membrane 11 . TfR surface levels, but not the total TfR levels, were decreased in H31 cells. This was rescued by re-expression of MTM1 ( Fig. 1d and Extended Data Fig. 1b ). Thus, MTM1 is required for efficient surface delivery of TfR, presumably by regulating exocytosis from endosomes. We directly monitored Tf exocytosis from endosomes by total internal reflection fluorescence (TIRF) microscopy. In fibroblasts from healthy controls, Tf-containing endosomal structures approached the plasma membrane before exocytic release of their Tf content. Exocytic fusion events were detected much less frequently in H31 cells ( Fig. 1e–g ), where Tf-loaded endosomes were largely immobile, a phenotype confirmed in cells from another patient with XLCNM ( Extended Data Fig. 1c ). Figure 1: Impaired exocytosis from endosomes in cells from patients with XLCNM. a , b , Confocal images of β1-integrin distribution in cells from patients with XLCNM (H31), healthy controls, or HeLa cells treated with scrambled (scr) short interfering RNA (siRNA) or siRNA against MTM1. Scale bar, 5 μm; magnified insets, 1 μm. c , Fraction of H31 cells displaying β1-integrin aggregates ( n = 3). d – g , Impaired Tf exocytosis from endosomes in XLCNM H31 cells. d , Ratio of surface/total TfR in XLCNM and control cells expressing eGFP or eGFP–MTM1 ( n = 3). e – g , TIRF microscopy analysis of Tf-exocytosis in XLCNM-patient and healthy control cells. e , Snapshot of a single exocytic event in healthy controls; scale bar, 400 nm. f , Kymographs of Tf fluorescence signal over 28 μm; arrowheads indicate time of fusion. g , Tf exocytic events per cell area ( n = 3). n , number of independent experiments with 15–30 images ( c , d ) or 5 videos ( g ) analysed per condition per experiment. Mean ± s.e.m.,* P < 0.05, ** P < 0.01, unpaired two-tailed t -test. a , b , e , f , Representative images from one of six ( a , b ) or three ( e , f ) independent experiments are shown. PowerPoint slide Full size image To dissect MTM1 function, we knocked down its expression in HeLa cells. MTM1 loss led to a partial depletion of TfR from the plasma membrane, resulting in reduced Tf internalization upon MTM1 knockdown (MTM1-KD) that was proportional to the diminished TfR surface levels ( Fig. 2a and Extended Data Fig. 2a, b ). Internalization kinetics and TfR expression were unaltered ( Extended Data Fig. 2c–f ). Thus, MTM1 is required for efficient surface delivery of cargo by mediating exocytosis from endosomes. Consistent with this hypothesis, exocytic fusion events were detected much less frequently in MTM1-depleted HeLa cells, where stalled endosomes that failed to fuse accumulated underneath the plasma membrane, a phenotype rescued by re-expression of active but not phosphatase-inactive (C375S) 12 MTM1 ( Fig. 2b and Extended Data Fig. 2g–j ). Stalled TfR-containing endosomes in MTM1-KD cells were accessible to internalized Tf ligand and distinct from surface TfR pools ( Fig. 2c and Extended Data Fig. 2i–j ). MTM1 depletion did not significantly affect degradative sorting of internalized epidermal growth factor (EGF), EGF receptor levels, secretion, or retrograde traffic of endocytosed cholera toxin B; nor did we", "role": "user" }, { "content": "Tiny deviations in the body's cells can sometimes have severe consequences. Researchers from Berlin have discovered why cells from patients suffering from the rare muscular disease myotubular myopathy cannot function properly. Through the paper published in Nature, it has become clear how a dynamic cellular process essential to muscle development and function is regulated by means of minute changes of certain membrane lipids. If a child is born with myotubular myopathy, the most severe form of centronuclear myopathies (also called XLCNM), it is barely able to breathe independently. The muscles are atrophied, the newborn lies limp in its mother's arms and is too weak to feed. Babies with this rare muscular disease might not survive the first few months of their lives. The group of Volker Haucke from the Leibniz Institute for Molecular Pharmacology (FMP) and Freie Universität (FUB) in Berlin, in collaboration with the laboratories of Jocelyn Laporte from the Institut Génétique Biologie Moléculaire Cellulaire (IGBMC) in Strasbourg and Carsten Schultz at the European Molecular Biology Laboratory (EMBL) in Heidelberg, has been researching what goes wrong in this disease at the molecular level - and has now come across a general organizational principle in cells. Up to now, it has been known that this hereditary disease involves a defect in the gene MTM1, as a result of which muscle fibers do not function normally. The gene codes for an enzyme that is specialized in cleaving phosphate groups from the heads of certain membrane lipids called phosphoinositide phosphates (PIPs) but how this leads to disease was unknown. PIPs are used by the cell to tag its compartments and to regulate the transport of substances. \"The cell is a very dynamic system, which one can imagine as a metropolis in which the people move back and forth,\" explains Volker Haucke. \"Depending on the occasion, the people change their clothes - if you put on a dress coat, to some extent you assume a different identity than if you come along in jeans and sweatshirt, and you won't be let in to the opera in pyjamas. In a similar manner, the compartments and transport vesicles within cells are constantly putting on different PIPs and thus change their identity.\" Each PIP consists of a fat-soluble tail that is anchored in the membranes of the cell compartments, and a water-soluble head that protrudes from the membrane. The head can be loaded with phosphates at different sites, the phosphate groups are detached by enzymes and attached at other sites. This is a minimal change that takes place in a flash, yet it is unmistakably read by the cell. Thus, for example, if a phosphate group tags a certain position, it is clear that a transport container is supposed to be transported into the interior of the cell; if the phosphate tag is different, it migrates to the outer cell membrane, docks there, and unloads its freight to the outside. This kind of transport comes to a halt in XLCNM patients, as could be shown by Katharina Ketel from the Haucke group with intricate experiments and high-resolution images from inside the cell. The cause of the disease is a defect in MTM1, an enzyme that removes phosphate groups from the PIPs and only works in co-operation with another enzyme that attaches a phosphate group to another site on the head. This clarifies how dynamic processes in cells are directed and illustrates how studying a rare genetic disease can discover an essential molecular mechanism for our cells to function properly. \"In healthy cells, phosphate groups are never randomly removed from PIPs, because a cell compartment would then suddenly be left completely without an identity - that would be equivalent to a loss of memory. The compartment would no longer know where it's from and where it's supposed to go,\" explains Volker Haucke. \"By adding synthetic PIPs with a certain code, we were able to alter the transport of containers, demonstrating that conversion of PIP identity really is the problem in XLCNM patient cells,\" adds Carsten Schultz. \"In XLCNM patients, some of the transport containers that were originally supposed to convey proteins to the cell surface get stranded inside the cell because a phosphate group cannot be removed from a certain PIP,\" says Jocelyn Laporte, an expert in XLCNM and contributor to the study. \"In muscles, this may mean that proteins necessary for their formation, integrity, and function do not get to the right place in the cell.\" In their experiments in cell culture, the FMP researchers were able to restart the transport with a certain active substance. This might be a starting point for the development of drugs for treating this severe and currently incurable hereditary 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 Phosphoinositides are a minor class of short-lived membrane phospholipids that serve crucial functions in cell physiology ranging from cell signalling and motility to their role as signposts of compartmental membrane identity 1 , 2 . Phosphoinositide 4-phosphates such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) are concentrated at the plasma membrane, on secretory organelles 3 , and on lysosomes 4 , whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P) 5 , are a hallmark of the endosomal system 1 , 2 . Directional membrane traffic between endosomal and secretory compartments, although inherently complex, therefore requires regulated phosphoinositide conversion. The molecular mechanism underlying this conversion of phosphoinositide identity during cargo exit from endosomes by exocytosis is unknown. Here we report that surface delivery of endosomal cargo requires hydrolysis of PI(3)P by the phosphatidylinositol 3-phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy (also called myotubular myopathy) in humans 6 . Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2α (PI4K2α)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Our data establish a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans. Main X-linked centronuclear myopathy (XLCNM) is a severe congenital myopathy caused by mutations in MTM1 (ref. 6 ). Patients with XLCNM suffer from defective muscle fibres due to disorganized membrane compartments and T-tubules 7 and are affected by severe hypotonia at birth, while the mildest surviving cases display muscle and non-muscle phenotypes 8 . MTM1 knockout mice are born below Mendelian ratios, and show progressive myopathy and growth impairment leading to early death 9 . Depletion of MTM1 in fruitflies causes endosomal accumulation of β1-integrin in developing muscles 10 , possibly because of defective phosphoinositide conversion at endosomes. Intracellular β1-integrin accumulations were indeed seen in endosomes of the MTM1-deficient XLCNM-patient fibroblast cell line H31 ( Fig. 1a ) and in MTM1-depleted HeLa cells ( Fig. 1b and Extended Data Fig. 1a ). Re-expression of active MTM1 rescued β1-integrin accumulation in H31 cells ( Fig. 1c ). Accumulations of β1-integrin in MTM1-depleted cells were immunopositive for recycling endosomal transferrin receptor (TfR) and late endosomal Rab7, but displayed limited overlap with early endosomal Rab5 and were negative for the trans-Golgi network marker Rab8 ( Extended Data Fig. 1a ). These data suggest that MTM1 loss-of-function causes β1-integrin accumulation in late endosomes, possibly to facilitate their degradation. We hypothesized that defective cargo exit from endosomes may underlie the endosomal sequestration of β1-integrin in XLCNM-patient cells. Therefore, we analysed the distribution of TfR, a receptor that, following internalization, is recycled by exocytosis from endosomes to the plasma membrane 11 . TfR surface levels, but not the total TfR levels, were decreased in H31 cells. This was rescued by re-expression of MTM1 ( Fig. 1d and Extended Data Fig. 1b ). Thus, MTM1 is required for efficient surface delivery of TfR, presumably by regulating exocytosis from endosomes. We directly monitored Tf exocytosis from endosomes by total internal reflection fluorescence (TIRF) microscopy. In fibroblasts from healthy controls, Tf-containing endosomal structures approached the plasma membrane before exocytic release of their Tf content. Exocytic fusion events were detected much less frequently in H31 cells ( Fig. 1e–g ), where Tf-loaded endosomes were largely immobile, a phenotype confirmed in cells from another patient with XLCNM ( Extended Data Fig. 1c ). Figure 1: Impaired exocytosis from endosomes in cells from patients with XLCNM. a , b , Confocal images of β1-integrin distribution in cells from patients with XLCNM (H31), healthy controls, or HeLa cells treated with scrambled (scr) short interfering RNA (siRNA) or siRNA against MTM1. Scale bar, 5 μm; magnified insets, 1 μm. c , Fraction of H31 cells displaying β1-integrin aggregates ( n = 3). d – g , Impaired Tf exocytosis from endosomes in XLCNM H31 cells. d , Ratio of surface/total TfR in XLCNM and control cells expressing eGFP or eGFP–MTM1 ( n = 3). e – g , TIRF microscopy analysis of Tf-exocytosis in XLCNM-patient and healthy control cells. e , Snapshot of a single exocytic event in healthy controls; scale bar, 400 nm. f , Kymographs of Tf fluorescence signal over 28 μm; arrowheads indicate time of fusion. g , Tf exocytic events per cell area ( n = 3). n , number of independent experiments with 15–30 images ( c , d ) or 5 videos ( g ) analysed per condition per experiment. Mean ± s.e.m.,* P < 0.05, ** P < 0.01, unpaired two-tailed t -test. a , b , e , f , Representative images from one of six ( a , b ) or three ( e , f ) independent experiments are shown. PowerPoint slide Full size image To dissect MTM1 function, we knocked down its expression in HeLa cells. MTM1 loss led to a partial depletion of TfR from the plasma membrane, resulting in reduced Tf internalization upon MTM1 knockdown (MTM1-KD) that was proportional to the diminished TfR surface levels ( Fig. 2a and Extended Data Fig. 2a, b ). Internalization kinetics and TfR expression were unaltered ( Extended Data Fig. 2c–f ). Thus, MTM1 is required for efficient surface delivery of cargo by mediating exocytosis from endosomes. Consistent with this hypothesis, exocytic fusion events were detected much less frequently in MTM1-depleted HeLa cells, where stalled endosomes that failed to fuse accumulated underneath the plasma membrane, a phenotype rescued by re-expression of active but not phosphatase-inactive (C375S) 12 MTM1 ( Fig. 2b and Extended Data Fig. 2g–j ). Stalled TfR-containing endosomes in MTM1-KD cells were accessible to internalized Tf ligand and distinct from surface TfR pools ( Fig. 2c and Extended Data Fig. 2i–j ). MTM1 depletion did not significantly affect degradative sorting of internalized epidermal growth factor (EGF), EGF receptor levels, secretion, or retrograde traffic of endocytosed cholera toxin B; nor did we<|im_end|> <|im_start|>assistant Tiny deviations in the body's cells can sometimes have severe consequences. Researchers from Berlin have discovered why cells from patients suffering from the rare muscular disease myotubular myopathy cannot function properly. Through the paper published in Nature, it has become clear how a dynamic cellular process essential to muscle development and function is regulated by means of minute changes of certain membrane lipids. If a child is born with myotubular myopathy, the most severe form of centronuclear myopathies (also called XLCNM), it is barely able to breathe independently. The muscles are atrophied, the newborn lies limp in its mother's arms and is too weak to feed. Babies with this rare muscular disease might not survive the first few months of their lives. The group of Volker Haucke from the Leibniz Institute for Molecular Pharmacology (FMP) and Freie Universität (FUB) in Berlin, in collaboration with the laboratories of Jocelyn Laporte from the Institut Génétique Biologie Moléculaire Cellulaire (IGBMC) in Strasbourg and Carsten Schultz at the European Molecular Biology Laboratory (EMBL) in Heidelberg, has been researching what goes wrong in this disease at the molecular level - and has now come across a general organizational principle in cells. Up to now, it has been known that this hereditary disease involves a defect in the gene MTM1, as a result of which muscle fibers do not function normally. The gene codes for an enzyme that is specialized in cleaving phosphate groups from the heads of certain membrane lipids called phosphoinositide phosphates (PIPs) but how this leads to disease was unknown. PIPs are used by the cell to tag its compartments and to regulate the transport of substances. "The cell is a very dynamic system, which one can imagine as a metropolis in which the people move back and forth," explains Volker Haucke. "Depending on the occasion, the people change their clothes - if you put on a dress coat, to some extent you assume a different identity than if you come along in jeans and sweatshirt, and you won't be let in to the opera in pyjamas. In a similar manner, the compartments and transport vesicles within cells are constantly putting on different PIPs and thus change their identity." Each PIP consists of a fat-soluble tail that is anchored in the membranes of the cell compartments, and a water-soluble head that protrudes from the membrane. The head can be loaded with phosphates at different sites, the phosphate groups are detached by enzymes and attached at other sites. This is a minimal change that takes place in a flash, yet it is unmistakably read by the cell. Thus, for example, if a phosphate group tags a certain position, it is clear that a transport container is supposed to be transported into the interior of the cell; if the phosphate tag is different, it migrates to the outer cell membrane, docks there, and unloads its freight to the outside. This kind of transport comes to a halt in XLCNM patients, as could be shown by Katharina Ketel from the Haucke group with intricate experiments and high-resolution images from inside the cell. The cause of the disease is a defect in MTM1, an enzyme that removes phosphate groups from the PIPs and only works in co-operation with another enzyme that attaches a phosphate group to another site on the head. This clarifies how dynamic processes in cells are directed and illustrates how studying a rare genetic disease can discover an essential molecular mechanism for our cells to function properly. "In healthy cells, phosphate groups are never randomly removed from PIPs, because a cell compartment would then suddenly be left completely without an identity - that would be equivalent to a loss of memory. The compartment would no longer know where it's from and where it's supposed to go," explains Volker Haucke. "By adding synthetic PIPs with a certain code, we were able to alter the transport of containers, demonstrating that conversion of PIP identity really is the problem in XLCNM patient cells," adds Carsten Schultz. "In XLCNM patients, some of the transport containers that were originally supposed to convey proteins to the cell surface get stranded inside the cell because a phosphate group cannot be removed from a certain PIP," says Jocelyn Laporte, an expert in XLCNM and contributor to the study. "In muscles, this may mean that proteins necessary for their formation, integrity, and function do not get to the right place in the cell." In their experiments in cell culture, the FMP researchers were able to restart the transport with a certain active substance. This might be a starting point for the development of drugs for treating this severe and currently incurable hereditary disease. <|im_end|>

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2,678

[ { "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 HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4 + T memory stem cells (T SCM cells) harbor high per-cell levels of HIV-1 DNA and make increasing contributions to the total viral CD4 + T cell reservoir over time. Moreover, we conducted phylogenetic studies that suggested long-term persistence of viral quasispecies in CD4 + T SCM cells. Thus, HIV-1 may exploit the stem cell characteristics of cellular immune memory to promote long-term viral persistence. Main Antiretroviral combination therapy effectively suppresses HIV-1 replication, but replication-competent virus can persist in memory CD4 + T cells despite treatment 1 , 2 . The memory CD4 + T cell compartment includes long-lasting central memory (T CM ) cells, which undergo a sequential developmental program with progressive commitment to more differentiated, short-lived effector memory (T EM ) and terminally differentiated T cell types 3 , 4 . The presence of a more immature memory T cell population with stem cell–like properties has previously been hypothesized on the basis of animal studies 5 , 6 , 7 , 8 , 9 , and recently, small proportions of T cells with stem cell characteristics have been discovered in humans 10 , 11 , mice 12 and nonhuman primates 13 . These cells, termed T SCM cells, seem to represent the earliest and most long-lasting developmental stage of memory T cells, and can differentiate into large numbers of T CM , T EM and terminally differentiated T cells while maintaining their own pool size through homeostatic self-renewal. We hypothesized that HIV-1 can use CD4 + T SCM cells as a preferred niche for promoting long-term viral persistence. To test this concept, we initially investigated the susceptibility of CD4 + T SCM cells to HIV-1 infection. These experiments demonstrated that CD4 + T SCM cells, phenotypically defined as described in previous studies 10 , 14 and in Supplementary Figure 1 , were approximately as susceptible as CD4 + T CM cells to infection with an R5-tropic HIV-1 isolate ( Fig. 1a ), although their surface expression of CCR5 was slightly lower ( Supplementary Fig. 2a,b ). In addition, CD4 + T SCM cells were highly susceptible to infection with a vesicular stomatitis virus G protein (VSV-G)-pseudotyped HIV-1 viral particles ( Fig. 1a and Supplementary Fig. 3 ), despite their comparatively low expression of T cell activation makers ( Supplementary Fig. 4 ). We also observed that HIV-1 RNA was readily detectable in CD4 + T SCM cells from untreated HIV-1–infected patients ( Supplementary Fig. 2c ). CD4 + T SCM cells had low sensitivity to the cytopathic effects associated with HIV-1 infection ( Supplementary Fig. 2d ) and expressed reduced levels of the cell-intrinsic HIV-1 restriction factors TRIM5α, APOBEC3G and SAMHD1 ( Supplementary Fig. 2e ). Together, these data indicate that CD4 + T SCM cells are permissive to HIV-1 infection and can serve as physiologic target cells for HIV-1. Figure 1: CD4 + T SCM cells represent a long-term reservoir for HIV-1 in HAART-treated patients. ( a ) Proportion of HIV-1 infected cells after ex vivo infection with GFP-encoding R5-tropic or VSV-G–pseudotyped HIV-1 (R5: n = 17 subjects, VSV-G: n = 14 subjects). T NA , naive T cells; T TD , terminally differentiated T cells. Box and whisker plots indicate the median, interquartile range, and minimum and maximum values. ( b ) Cell-associated HIV-1 DNA in sorted CD4 + T cell populations (left) and corresponding contributions to the total HIV-1 reservoir in CD4 + T cells from HAART-treated individuals (right). Data from n = 20 subjects are shown; horizontal lines reflect the median. ( c ) Left, representative pie charts reflecting the contribution of CD4 + T SCM cells to the total viral CD4 + T cell reservoir in two persons with large and small HIV-1 reservoirs in total CD4 + T cells, respectively. Right, Spearman correlation between contributions of CD4 + T SCM cells to the total HIV-1 CD4 + T cell reservoir, and corresponding size of the HIV-1 reservoir in total CD4 + T cell from all patients shown in b . ( d ) Reactivation of replication-competent HIV-1 from memory CD4 + T cell subsets. Orange bars reflect proportions of wells with detectable replication-competent HIV-1; blue bars indicate proportions of wells without detectable replication-competent HIV-1. Numbers above columns reflect total numbers of wells analyzed for each CD4 + T cell population; numbers below columns reflect estimated frequencies of cells with replication-competent HIV-1 per million cells (IUPM) based on limiting-dilution analysis. CI, confidence interval. ( e ) Longitudinal evolution of HIV-1 DNA in CD4 + T cell subsets in n = 8 study persons who initiated antiretroviral therapy in primary infection. ( f ) Pair-wise fold differences in HIV-1 DNA levels measured after short-term and long-term antiretroviral therapy. Mean and s.e.m. from the eight study individuals from e are shown. ( g ) Corresponding contribution of individual CD4 + T cell subsets to the total CD4 + T cell pool and to the total HIV-1 CD4 + T cell HIV-1 reservoir after short-term and long-term antiretroviral therapy. Data are pooled from the eight study individuals from e . Statistical significance was tested with Wilcoxon's rank-sum test for panels a , b , e – g . * P < 0.05, ** P < 0.01, *** P < 0.001 after Bonferroni's correction for multiple comparisons in a and b . Full size image We next determined the levels of HIV-1 DNA in sorted CD4 + T SCM cells from HIV-1–infected patients who had been treated with suppressive highly active antiretroviral therapy (HAART) for a median of 7 years ( Supplementary Table 1 ). The proportions of CD4 + T SCM cells in these patients did not differ from those in an HIV-1–negative control cohort ( Supplementary Fig. 5 ). In these HAART-treated patients, per-cell levels of HIV-1 DNA were highest in CD4 + T SCM cells, but their average contribution to the total viral reservoir", "role": "user" }, { "content": "Although antiviral therapy against HIV suppresses viral replication and allows infected individuals to live relatively healthy lives for many years, the virus persists in the body, and replication resumes if treatment is interrupted. Now investigators from Massachusetts General Hospital (MGH) and the Ragon Institute of MGH, MIT and Harvard may have found where the virus hides - in a small group of recently identified T cells with stem-cell-like properties. \"Most human cells are short lived, so it has been unclear how HIV manages to stick around for decades in spite of very effective antiviral treatment,\" says Mathias Lichterfeld, MD, of the MGH Infectious Disease Division, corresponding author of the report receiving advance online publication in Nature Medicine. \"This question led to the hypothesis that HIV might infect stem cells - the most long-lasting cells in the body - but traditional organ-specific stem cells, even those that give rise to all immune and blood cells, are resistant to HIV infection. We have discovered that a new group of T cells, called T memory stem cells, are susceptible to HIV and likely represent the longest lasting cellular niche for the virus.\" HIV has such a devastating impact on the human immune system because it infects the CD4-positive T cells that normally direct and support the infection-fighting activities of other immune cells. Several subtypes of CD4 T cells have different functions; and all are capable of being infected by HIV, although antiviral treatment keeps the virus in those cells from replicating. Most of these CD4 T cells are short-lived and die relatively soon. What is distinct about CD4 T memory stem cells is their ability to live for decades, while giving rise to several subgroups of T cells. Therefore, HIV-infected T memory stem cells could continuously regenerate new HIV-infected cells, fueling the fire of HIV persistence in the human body. The MGH/Ragon team found that T memory stem cells express both CD4 and CCR5 - the receptor proteins used by HIV to enter cells - suggesting that these long-lived cells could be the long-sought HIV reservoir. They then found that these cells can be readily infected with HIV, which was unexpected since traditional stem cells resist HIV infection. Importantly, the investigators found that levels of HIV DNA in patients receiving long-term antiviral treatment were highest in T memory stem cells. Testing blood samples that had been taken from patients soon after initial infection and several years later revealed that the viral sequences found in T memory stem cells after 6 to 10 years of treatment were similar to those found in circulating T cells soon after infection, indicating that HIV had persisted relatively unchanged in T memory stem cells. In addition, the amount of HIV DNA in these cells remained relatively stable over time, even after long-term treatment caused viral levels to drop in other T cell subsets. \"Our findings suggest that novel, specific interventions will have to be designed to target HIV-infected T memory stem cells,\" says Lichterfeld, an assistant professor of Medicine at Harvard Medical School. \"Methods of inhibiting stem cell pathways are being studied to eliminate cancer stem cells - persistent cells that are responsible for tumor recurrence after conventional treatments kill proliferating tumor cells. We are now investigating whether any of the drugs that target cancer stem cells might be effective against HIV-infected T memory stem cells. \"Identifying the reservoirs for HIV persistence is a critical step toward developing interventions that could induce a long-term remission without the need for antiviral medication, or possibly eliminate the virus entirely,\" Lichterfeld adds. \"Although a real cure for HIV has been elusive, it is not impossible.\" ", "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 HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4 + T memory stem cells (T SCM cells) harbor high per-cell levels of HIV-1 DNA and make increasing contributions to the total viral CD4 + T cell reservoir over time. Moreover, we conducted phylogenetic studies that suggested long-term persistence of viral quasispecies in CD4 + T SCM cells. Thus, HIV-1 may exploit the stem cell characteristics of cellular immune memory to promote long-term viral persistence. Main Antiretroviral combination therapy effectively suppresses HIV-1 replication, but replication-competent virus can persist in memory CD4 + T cells despite treatment 1 , 2 . The memory CD4 + T cell compartment includes long-lasting central memory (T CM ) cells, which undergo a sequential developmental program with progressive commitment to more differentiated, short-lived effector memory (T EM ) and terminally differentiated T cell types 3 , 4 . The presence of a more immature memory T cell population with stem cell–like properties has previously been hypothesized on the basis of animal studies 5 , 6 , 7 , 8 , 9 , and recently, small proportions of T cells with stem cell characteristics have been discovered in humans 10 , 11 , mice 12 and nonhuman primates 13 . These cells, termed T SCM cells, seem to represent the earliest and most long-lasting developmental stage of memory T cells, and can differentiate into large numbers of T CM , T EM and terminally differentiated T cells while maintaining their own pool size through homeostatic self-renewal. We hypothesized that HIV-1 can use CD4 + T SCM cells as a preferred niche for promoting long-term viral persistence. To test this concept, we initially investigated the susceptibility of CD4 + T SCM cells to HIV-1 infection. These experiments demonstrated that CD4 + T SCM cells, phenotypically defined as described in previous studies 10 , 14 and in Supplementary Figure 1 , were approximately as susceptible as CD4 + T CM cells to infection with an R5-tropic HIV-1 isolate ( Fig. 1a ), although their surface expression of CCR5 was slightly lower ( Supplementary Fig. 2a,b ). In addition, CD4 + T SCM cells were highly susceptible to infection with a vesicular stomatitis virus G protein (VSV-G)-pseudotyped HIV-1 viral particles ( Fig. 1a and Supplementary Fig. 3 ), despite their comparatively low expression of T cell activation makers ( Supplementary Fig. 4 ). We also observed that HIV-1 RNA was readily detectable in CD4 + T SCM cells from untreated HIV-1–infected patients ( Supplementary Fig. 2c ). CD4 + T SCM cells had low sensitivity to the cytopathic effects associated with HIV-1 infection ( Supplementary Fig. 2d ) and expressed reduced levels of the cell-intrinsic HIV-1 restriction factors TRIM5α, APOBEC3G and SAMHD1 ( Supplementary Fig. 2e ). Together, these data indicate that CD4 + T SCM cells are permissive to HIV-1 infection and can serve as physiologic target cells for HIV-1. Figure 1: CD4 + T SCM cells represent a long-term reservoir for HIV-1 in HAART-treated patients. ( a ) Proportion of HIV-1 infected cells after ex vivo infection with GFP-encoding R5-tropic or VSV-G–pseudotyped HIV-1 (R5: n = 17 subjects, VSV-G: n = 14 subjects). T NA , naive T cells; T TD , terminally differentiated T cells. Box and whisker plots indicate the median, interquartile range, and minimum and maximum values. ( b ) Cell-associated HIV-1 DNA in sorted CD4 + T cell populations (left) and corresponding contributions to the total HIV-1 reservoir in CD4 + T cells from HAART-treated individuals (right). Data from n = 20 subjects are shown; horizontal lines reflect the median. ( c ) Left, representative pie charts reflecting the contribution of CD4 + T SCM cells to the total viral CD4 + T cell reservoir in two persons with large and small HIV-1 reservoirs in total CD4 + T cells, respectively. Right, Spearman correlation between contributions of CD4 + T SCM cells to the total HIV-1 CD4 + T cell reservoir, and corresponding size of the HIV-1 reservoir in total CD4 + T cell from all patients shown in b . ( d ) Reactivation of replication-competent HIV-1 from memory CD4 + T cell subsets. Orange bars reflect proportions of wells with detectable replication-competent HIV-1; blue bars indicate proportions of wells without detectable replication-competent HIV-1. Numbers above columns reflect total numbers of wells analyzed for each CD4 + T cell population; numbers below columns reflect estimated frequencies of cells with replication-competent HIV-1 per million cells (IUPM) based on limiting-dilution analysis. CI, confidence interval. ( e ) Longitudinal evolution of HIV-1 DNA in CD4 + T cell subsets in n = 8 study persons who initiated antiretroviral therapy in primary infection. ( f ) Pair-wise fold differences in HIV-1 DNA levels measured after short-term and long-term antiretroviral therapy. Mean and s.e.m. from the eight study individuals from e are shown. ( g ) Corresponding contribution of individual CD4 + T cell subsets to the total CD4 + T cell pool and to the total HIV-1 CD4 + T cell HIV-1 reservoir after short-term and long-term antiretroviral therapy. Data are pooled from the eight study individuals from e . Statistical significance was tested with Wilcoxon's rank-sum test for panels a , b , e – g . * P < 0.05, ** P < 0.01, *** P < 0.001 after Bonferroni's correction for multiple comparisons in a and b . Full size image We next determined the levels of HIV-1 DNA in sorted CD4 + T SCM cells from HIV-1–infected patients who had been treated with suppressive highly active antiretroviral therapy (HAART) for a median of 7 years ( Supplementary Table 1 ). The proportions of CD4 + T SCM cells in these patients did not differ from those in an HIV-1–negative control cohort ( Supplementary Fig. 5 ). In these HAART-treated patients, per-cell levels of HIV-1 DNA were highest in CD4 + T SCM cells, but their average contribution to the total viral reservoir<|im_end|> <|im_start|>assistant Although antiviral therapy against HIV suppresses viral replication and allows infected individuals to live relatively healthy lives for many years, the virus persists in the body, and replication resumes if treatment is interrupted. Now investigators from Massachusetts General Hospital (MGH) and the Ragon Institute of MGH, MIT and Harvard may have found where the virus hides - in a small group of recently identified T cells with stem-cell-like properties. "Most human cells are short lived, so it has been unclear how HIV manages to stick around for decades in spite of very effective antiviral treatment," says Mathias Lichterfeld, MD, of the MGH Infectious Disease Division, corresponding author of the report receiving advance online publication in Nature Medicine. "This question led to the hypothesis that HIV might infect stem cells - the most long-lasting cells in the body - but traditional organ-specific stem cells, even those that give rise to all immune and blood cells, are resistant to HIV infection. We have discovered that a new group of T cells, called T memory stem cells, are susceptible to HIV and likely represent the longest lasting cellular niche for the virus." HIV has such a devastating impact on the human immune system because it infects the CD4-positive T cells that normally direct and support the infection-fighting activities of other immune cells. Several subtypes of CD4 T cells have different functions; and all are capable of being infected by HIV, although antiviral treatment keeps the virus in those cells from replicating. Most of these CD4 T cells are short-lived and die relatively soon. What is distinct about CD4 T memory stem cells is their ability to live for decades, while giving rise to several subgroups of T cells. Therefore, HIV-infected T memory stem cells could continuously regenerate new HIV-infected cells, fueling the fire of HIV persistence in the human body. The MGH/Ragon team found that T memory stem cells express both CD4 and CCR5 - the receptor proteins used by HIV to enter cells - suggesting that these long-lived cells could be the long-sought HIV reservoir. They then found that these cells can be readily infected with HIV, which was unexpected since traditional stem cells resist HIV infection. Importantly, the investigators found that levels of HIV DNA in patients receiving long-term antiviral treatment were highest in T memory stem cells. Testing blood samples that had been taken from patients soon after initial infection and several years later revealed that the viral sequences found in T memory stem cells after 6 to 10 years of treatment were similar to those found in circulating T cells soon after infection, indicating that HIV had persisted relatively unchanged in T memory stem cells. In addition, the amount of HIV DNA in these cells remained relatively stable over time, even after long-term treatment caused viral levels to drop in other T cell subsets. "Our findings suggest that novel, specific interventions will have to be designed to target HIV-infected T memory stem cells," says Lichterfeld, an assistant professor of Medicine at Harvard Medical School. "Methods of inhibiting stem cell pathways are being studied to eliminate cancer stem cells - persistent cells that are responsible for tumor recurrence after conventional treatments kill proliferating tumor cells. We are now investigating whether any of the drugs that target cancer stem cells might be effective against HIV-infected T memory stem cells. "Identifying the reservoirs for HIV persistence is a critical step toward developing interventions that could induce a long-term remission without the need for antiviral medication, or possibly eliminate the virus entirely," Lichterfeld adds. "Although a real cure for HIV has been elusive, it is not impossible." <|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 newt, a urodele amphibian, is able to repeatedly regenerate its limbs throughout its lifespan, whereas other amphibians deteriorate or lose their ability to regenerate limbs after metamorphosis. It remains to be determined whether such an exceptional ability of the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis. Here we report that the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis. We demonstrate that larval newts use stem/progenitor cells such as satellite cells for new muscle in a regenerated limb, whereas metamorphosed newts recruit muscle fibre cells in the stump for the same purpose. We conclude that the newt has evolved novel strategies to secure its regenerative ability of the limbs after metamorphosis. Introduction In contrast to mammals, the newt, a urodele amphibian classified into the family of Salamandridae , has the ability to repeatedly regenerate its limbs independently of its age. When the limb is amputated, the newt generates at the stump a cell mass called the blastema, from which a new functional limb is eventually regenerated. On the other hand, other amphibians, which also have the ability to regenerate limbs in larval stage, deteriorate or lose such ability after metamorphosis. It remains to be determined whether such an exceptional ability of limb regeneration in the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis 1 . In urodeles, either skeletal muscle fibre cells (SMFCs) or muscle stem/progenitor cells (MPCs) such as satellite cells have been suggested to be contributing to new muscle in regenerated limbs. A recent study revealed that the adult newt uses SMFCs, whereas the axolotl (a neotenic species of the family Ambystomatidae ) uses satellite cells even after artificially metamorphosed by administration of thyroid hormone, raising the argument that such a difference in the origin of muscle is attributed to differences in species 2 . However, it is still not determined whether pre-metamorphosed newt limbs employ dedifferentiation of muscle fibres or not. Although the idea of species differences makes sense, it is imperative that other questions are asked. In this study, to address this issue, we created transgenic newts ( Cynops pyrrhogaster ) carrying a cassette, CreER T2 <CarA-CAGGs>[EGFP]mCherry, using the I-SceI protocol 3 . In these animals, SMFCs that differentiate in the larval stage (between St 34 and St 53) are labelled by mCherry after tamoxifen administration. Using this system, we tracked SMFCs during limb regeneration in both larval and metamorphosed newts. We found that larval newts did not require muscle fibre cells to regenerate their amputated limbs. New muscle in a regenerated limb seems to originate from stem/progenitor cells, because Pax7+ cells such as satellite cells, which are muscle progenitors, are recruited to the blastema. In contrast, after metamorphosis, the muscle fibre cells in the stump were mobilized to form the blastema, eventually giving rise to new muscle in the regenerated limb. To receive a whole picture of tissue fate during limb regeneration and to compare with similar studies in axolotl, we further followed regeneration of all other tissues in adult newt via grafting experiments. We found that the principal tissues of the adult limb such as the skin, bone, muscle and nerves strictly regenerate the same type of tissues. Our current results demonstrate that the newt developmentally switches cellular mechanism of limb regeneration, revealing novel strategies that have evolved in the newt to secure its regenerative ability of the limbs after metamorphosis. Results SMFC tracking in larval newt limb regeneration In larval newts at St 56–57 ( ∼ 3 months old; Fig. 1a ), whose forelimbs had grown with four digits, we found that SMFCs did not contribute to restoration of the missing part of the forelimb after amputation. When mCherry was monitored in living animals, it did not appear in the regenerating part of the limb (neither as cells from fragmented fibres nor as fibres) until ∼ 30 days when the amputated limb structure had almost been restored ( Fig. 1b,c and Supplementary Movie 1 ). We subsequently examined satellite cells. We carried out immunohistochemistry with Pax7 antibody (a marker of MPCs including satellite cells) 2 and found that Pax7-immunoreactive (Pax7+) mononucleated cells appeared in the blastema by day 12 post amputation ( Fig. 1d–f ; 3–17 cells per blastema, n =3) and increased in number in the next few days ( Fig. 1g ; 55–144 cells per blastema, n =3), suggesting that MPCs (potentially satellite cells) were recruited for new muscle during limb regeneration. Thus, these results suggest that SMFCs were not the primary source of new muscle in larval newts. Consequently, they also revealed close similarity between the larval newt and the axolotl, at least in terms of muscle regeneration ( Fig. 1h ). Figure 1: SMFC tracking in larval newt limb regeneration. ( a ) Larva (3 months old). It has four limbs, as well as the gills and tail fin. Scale bar, 4 mm. ( b ) Monitoring of SMFCs (mCherry+) during limb regeneration ( n =6). mCherry was not detected in the regenerating part of the limb until ∼ 30 days when the amputated limb had almost been recovered (see Supplementary Movie 1 ). Arrowheads: flexor muscle for digits (see Fig. 2 ). Scale bar, 1 mm. ( c ) Sections of regenerating limbs ( n =3 for each stage). SMFC-derived mCherry+ cells were not observed in the blastema. Lines: amputation site. m : muscle. Scale bar, 100 μm. ( d – f ) Pax7 immunolabelling of regenerating limbs on day 12 ( n =3) and ( g ) day 15 ( n =3) after amputation. ( d ) On day 12, a few Pax7+ nuclei (arrowheads) were detected in blastema cells and in satellite cells along the muscle fibres. Col IV, collagen type IV immunoreactivity. DAPI (4,6-diamidino-2-phenylindole), nuclei.", "role": "user" }, { "content": "Imagine losing an eye, an arm or even your spinal cord. When we are wounded, our bodies, and those of other mammals, generally respond by sealing the wound with scar tissue. The newt, however, has evolved unique strategies that allow it to repeatedly regenerate lost tissues, even as an adult. Newts are the masters of regeneration. No other animal can match their regenerative abilities in body parts including the limbs, the tail and spinal cord, parts of the eye (such as the retina and the lens), the brain, the heart and the jaws. What happens when a newt loses, for example, a leg? A mass of cells, called a blastema, is generated at the stump, from which a new, fully functional leg is eventually regenerated. The newt is unique in having this ability even as an adult. Other amphibians with regenerative potential, such as axolotls, lose this ability once they metamorphose from a larva to a juvenile. Research led by Chikafumi Chiba at the University of Tsukuba, Japan and Panagiotis Tsonis at the University of Dayton, Ohio, and published in the current volume of the prestigious journal Nature Communications, has shed some light on the newt's exceptional regenerative ability and may provide further insight into regeneration in other species, including mammals. The researchers made the exciting discovery that the mechanism for regeneration in the larval newt is different to the one used after metamorphosis. This discovery was made using transgenic newts, the use of which has only recently been made possible. One of the researchers on the team, Martin Casco-Robles, from the Faculty of Life and Environmental Sciences, University of Tsukuba, is a pioneer in developing techniques for the creation of transgenic newts. Using transgenic Japanese fire bellied newts, the team were able to track different types of muscle cells during limb regeneration in both larval and metamorphosed animals. It had been suggested previously that either skeletal muscle fiber cells (SMFCs) or muscle stem/progenitor cells (MPCs) contribute to new muscle in regenerated limbs of newts. SMFCs make up skeletal muscles, which are one of the three major types of muscles. MPCs are the dormant predecessors of muscle fiber cells and are located within muscle fibers. They can be triggered to proliferate for both self-renewal and specialization into muscle fiber cells. The researchers inserted a gene known to be active in SMFCs into single-celled newt embryos. The transgenic newt embryos were then reared until the swimming larval stage, at 3 months of age, or the metamorphosed juvenile stage, at 16 months. The gene was linked to a red fluorescent protein which could be switched on and off at precise times with the addition of a particular chemical to the rearing solution.Selected transgenic newts had a limb removed under anesthesia. The fluorescence of the tissues in the living newts was monitored under a microscope during development and limb regeneration. In addition, tissue samples were collected for further MPC cell-specific staining. Lead author, Hibiki Tanaka, of the Graduate School of Life and Environmental Sciences, University of Tsukuba, explains that \"we found that larval newts did not require muscle fiber cells to regenerate their amputated limbs.\" These experiments showed that the new muscle in larval newt regeneration tissue is primarily derived from muscle stem/progenitor cells, not skeletal muscle fiber cells. In contrast, after metamorphosis, the team found that the skeletal muscle fiber cells in the stump temporarily regress to a more primitive state, that is, they become dedifferentiated. The cells then re-enter the cell cycle and proliferate to produce more muscle cells. Hibiki Tanaka says \"larval newts use stem/progenitor cells for new muscle in a regenerated limb while metamorphosed newts recruit muscle fiber cells in the stump for the same purpose.\" Next the researchers looked at whether or not the tissues in the limb strictly regenerated the same tissue types using reporter-gene expressing tissue transplantation experiments. The principal tissues of the adult limb, skin, bone, muscle and nerve tissues, were obtained from transgenic newts and grafted onto or into the corresponding regions of normal newts. These newts were then used in regeneration experiments. The team discovered that skin, bone, muscle and nerve tissues faithfully regenerated themselves. Chikafumi Chiba explains these remarkable discoveries, saying \"the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis\". He says \"delineating the mechanisms of these strategies will undoubtedly provide clues for regeneration in other species including mammals\". Thus, while we may never have the incredible regenerative powers of the newt, it is likely that this little amphibian will continue to provide us with insights into mammalian tissue regeneration, wound healing and repair. ", "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 newt, a urodele amphibian, is able to repeatedly regenerate its limbs throughout its lifespan, whereas other amphibians deteriorate or lose their ability to regenerate limbs after metamorphosis. It remains to be determined whether such an exceptional ability of the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis. Here we report that the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis. We demonstrate that larval newts use stem/progenitor cells such as satellite cells for new muscle in a regenerated limb, whereas metamorphosed newts recruit muscle fibre cells in the stump for the same purpose. We conclude that the newt has evolved novel strategies to secure its regenerative ability of the limbs after metamorphosis. Introduction In contrast to mammals, the newt, a urodele amphibian classified into the family of Salamandridae , has the ability to repeatedly regenerate its limbs independently of its age. When the limb is amputated, the newt generates at the stump a cell mass called the blastema, from which a new functional limb is eventually regenerated. On the other hand, other amphibians, which also have the ability to regenerate limbs in larval stage, deteriorate or lose such ability after metamorphosis. It remains to be determined whether such an exceptional ability of limb regeneration in the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis 1 . In urodeles, either skeletal muscle fibre cells (SMFCs) or muscle stem/progenitor cells (MPCs) such as satellite cells have been suggested to be contributing to new muscle in regenerated limbs. A recent study revealed that the adult newt uses SMFCs, whereas the axolotl (a neotenic species of the family Ambystomatidae ) uses satellite cells even after artificially metamorphosed by administration of thyroid hormone, raising the argument that such a difference in the origin of muscle is attributed to differences in species 2 . However, it is still not determined whether pre-metamorphosed newt limbs employ dedifferentiation of muscle fibres or not. Although the idea of species differences makes sense, it is imperative that other questions are asked. In this study, to address this issue, we created transgenic newts ( Cynops pyrrhogaster ) carrying a cassette, CreER T2 <CarA-CAGGs>[EGFP]mCherry, using the I-SceI protocol 3 . In these animals, SMFCs that differentiate in the larval stage (between St 34 and St 53) are labelled by mCherry after tamoxifen administration. Using this system, we tracked SMFCs during limb regeneration in both larval and metamorphosed newts. We found that larval newts did not require muscle fibre cells to regenerate their amputated limbs. New muscle in a regenerated limb seems to originate from stem/progenitor cells, because Pax7+ cells such as satellite cells, which are muscle progenitors, are recruited to the blastema. In contrast, after metamorphosis, the muscle fibre cells in the stump were mobilized to form the blastema, eventually giving rise to new muscle in the regenerated limb. To receive a whole picture of tissue fate during limb regeneration and to compare with similar studies in axolotl, we further followed regeneration of all other tissues in adult newt via grafting experiments. We found that the principal tissues of the adult limb such as the skin, bone, muscle and nerves strictly regenerate the same type of tissues. Our current results demonstrate that the newt developmentally switches cellular mechanism of limb regeneration, revealing novel strategies that have evolved in the newt to secure its regenerative ability of the limbs after metamorphosis. Results SMFC tracking in larval newt limb regeneration In larval newts at St 56–57 ( ∼ 3 months old; Fig. 1a ), whose forelimbs had grown with four digits, we found that SMFCs did not contribute to restoration of the missing part of the forelimb after amputation. When mCherry was monitored in living animals, it did not appear in the regenerating part of the limb (neither as cells from fragmented fibres nor as fibres) until ∼ 30 days when the amputated limb structure had almost been restored ( Fig. 1b,c and Supplementary Movie 1 ). We subsequently examined satellite cells. We carried out immunohistochemistry with Pax7 antibody (a marker of MPCs including satellite cells) 2 and found that Pax7-immunoreactive (Pax7+) mononucleated cells appeared in the blastema by day 12 post amputation ( Fig. 1d–f ; 3–17 cells per blastema, n =3) and increased in number in the next few days ( Fig. 1g ; 55–144 cells per blastema, n =3), suggesting that MPCs (potentially satellite cells) were recruited for new muscle during limb regeneration. Thus, these results suggest that SMFCs were not the primary source of new muscle in larval newts. Consequently, they also revealed close similarity between the larval newt and the axolotl, at least in terms of muscle regeneration ( Fig. 1h ). Figure 1: SMFC tracking in larval newt limb regeneration. ( a ) Larva (3 months old). It has four limbs, as well as the gills and tail fin. Scale bar, 4 mm. ( b ) Monitoring of SMFCs (mCherry+) during limb regeneration ( n =6). mCherry was not detected in the regenerating part of the limb until ∼ 30 days when the amputated limb had almost been recovered (see Supplementary Movie 1 ). Arrowheads: flexor muscle for digits (see Fig. 2 ). Scale bar, 1 mm. ( c ) Sections of regenerating limbs ( n =3 for each stage). SMFC-derived mCherry+ cells were not observed in the blastema. Lines: amputation site. m : muscle. Scale bar, 100 μm. ( d – f ) Pax7 immunolabelling of regenerating limbs on day 12 ( n =3) and ( g ) day 15 ( n =3) after amputation. ( d ) On day 12, a few Pax7+ nuclei (arrowheads) were detected in blastema cells and in satellite cells along the muscle fibres. Col IV, collagen type IV immunoreactivity. DAPI (4,6-diamidino-2-phenylindole), nuclei.<|im_end|> <|im_start|>assistant Imagine losing an eye, an arm or even your spinal cord. When we are wounded, our bodies, and those of other mammals, generally respond by sealing the wound with scar tissue. The newt, however, has evolved unique strategies that allow it to repeatedly regenerate lost tissues, even as an adult. Newts are the masters of regeneration. No other animal can match their regenerative abilities in body parts including the limbs, the tail and spinal cord, parts of the eye (such as the retina and the lens), the brain, the heart and the jaws. What happens when a newt loses, for example, a leg? A mass of cells, called a blastema, is generated at the stump, from which a new, fully functional leg is eventually regenerated. The newt is unique in having this ability even as an adult. Other amphibians with regenerative potential, such as axolotls, lose this ability once they metamorphose from a larva to a juvenile. Research led by Chikafumi Chiba at the University of Tsukuba, Japan and Panagiotis Tsonis at the University of Dayton, Ohio, and published in the current volume of the prestigious journal Nature Communications, has shed some light on the newt's exceptional regenerative ability and may provide further insight into regeneration in other species, including mammals. The researchers made the exciting discovery that the mechanism for regeneration in the larval newt is different to the one used after metamorphosis. This discovery was made using transgenic newts, the use of which has only recently been made possible. One of the researchers on the team, Martin Casco-Robles, from the Faculty of Life and Environmental Sciences, University of Tsukuba, is a pioneer in developing techniques for the creation of transgenic newts. Using transgenic Japanese fire bellied newts, the team were able to track different types of muscle cells during limb regeneration in both larval and metamorphosed animals. It had been suggested previously that either skeletal muscle fiber cells (SMFCs) or muscle stem/progenitor cells (MPCs) contribute to new muscle in regenerated limbs of newts. SMFCs make up skeletal muscles, which are one of the three major types of muscles. MPCs are the dormant predecessors of muscle fiber cells and are located within muscle fibers. They can be triggered to proliferate for both self-renewal and specialization into muscle fiber cells. The researchers inserted a gene known to be active in SMFCs into single-celled newt embryos. The transgenic newt embryos were then reared until the swimming larval stage, at 3 months of age, or the metamorphosed juvenile stage, at 16 months. The gene was linked to a red fluorescent protein which could be switched on and off at precise times with the addition of a particular chemical to the rearing solution.Selected transgenic newts had a limb removed under anesthesia. The fluorescence of the tissues in the living newts was monitored under a microscope during development and limb regeneration. In addition, tissue samples were collected for further MPC cell-specific staining. Lead author, Hibiki Tanaka, of the Graduate School of Life and Environmental Sciences, University of Tsukuba, explains that "we found that larval newts did not require muscle fiber cells to regenerate their amputated limbs." These experiments showed that the new muscle in larval newt regeneration tissue is primarily derived from muscle stem/progenitor cells, not skeletal muscle fiber cells. In contrast, after metamorphosis, the team found that the skeletal muscle fiber cells in the stump temporarily regress to a more primitive state, that is, they become dedifferentiated. The cells then re-enter the cell cycle and proliferate to produce more muscle cells. Hibiki Tanaka says "larval newts use stem/progenitor cells for new muscle in a regenerated limb while metamorphosed newts recruit muscle fiber cells in the stump for the same purpose." Next the researchers looked at whether or not the tissues in the limb strictly regenerated the same tissue types using reporter-gene expressing tissue transplantation experiments. The principal tissues of the adult limb, skin, bone, muscle and nerve tissues, were obtained from transgenic newts and grafted onto or into the corresponding regions of normal newts. These newts were then used in regeneration experiments. The team discovered that skin, bone, muscle and nerve tissues faithfully regenerated themselves. Chikafumi Chiba explains these remarkable discoveries, saying "the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis". He says "delineating the mechanisms of these strategies will undoubtedly provide clues for regeneration in other species including mammals". Thus, while we may never have the incredible regenerative powers of the newt, it is likely that this little amphibian will continue to provide us with insights into mammalian tissue regeneration, wound healing and repair. <|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 coupling (SOC) is pivotal for various fundamental spin-dependent phenomena in solids and their technological applications. In semiconductors, these phenomena have been so far studied in relatively weak electron–electron interaction regimes, where the single electron picture holds. However, SOC can profoundly compete against Coulomb interaction, which could lead to the emergence of unconventional electronic phases. Since SOC depends on the electric field in the crystal including contributions of itinerant electrons, electron–electron interactions can modify this coupling. Here we demonstrate the emergence of the SOC effect in a high-mobility two-dimensional electron system in a simple band structure MgZnO/ZnO semiconductor. This electron system also features strong electron–electron interaction effects. By changing the carrier density with Mg-content, we tune the SOC strength and achieve its interplay with electron–electron interaction. These systems pave a way to emergent spintronic phenomena in strong electron correlation regimes and to the formation of quasiparticles with the electron spin strongly coupled to the density. Introduction Spin–orbit coupling is a single particle relativistic effect producing in atomic physics a bilinear interaction between the electron spin and its orbital momentum. In solids the SOC is transformed into a symmetry-permitted coupling between the orientation of the electron spin and its crystal momentum. This coupling can lead to spin–momentum locking and establishes a spin-dependent band structure influenced by the crystal symmetry. Prominent examples here are the Rashba and Dresselhaus couplings, whose appearance requires the breaking of the structural and crystal inversion symmetries. By contrast, Coulomb interaction dictates collective electron behavior in solids, e.g., by establishing a Fermi liquid or a Mott insulator, and can also generate spin-polarized phases due to the Stoner instability 1 . Thus, SOC orients electron spin with respect to its momentum while the Coulomb interaction can counteract by aligning the spins in one direction, e.g., by producing a spin-depended exchange interaction. The usual single particle description of SOC-related effects in the presence of Coulomb interaction is poorly applicable, since the relativistic effect on quasiparticle excitations in strongly interacting systems is not known. Yet, the interplay of two mechanisms for spin orientation is suggested to have diverse manifestations encompassing the emergence of topological phases, spin textures, etc. 2 , 3 , 4 . An experimental realization of a system that shows both strong interaction between electrons, e.g., in the form of a Fermi liquid, and spin–orbit coupling is challenging. It requires a system with sufficiently strong relativistic effects to unfold the role of spin–orbit coupling and with a high mobility at a low carrier density to enhance the Coulomb interaction effect. Here we demonstrate a realization of such a regime in the two-dimensional electron system (2DES) at the Mg x Zn 1−x O/ZnO interface. The SOC effect is identified from the beatings of the Shubnikov-de Haas oscillations (SdH) in conductivity, which varies with the electron density N . Upon lowering N the system shows an enhancement of the electron effective mass, attributed to electron–electron interaction. Thus, we can tune the interplay between two interaction mechanisms and achieve an interaction regime for 2DESs, where the emergence of novel quantum states is anticipated. Results Formation of electron system We start with the discussion of the 2DES formation, since it is central for tuning the interplay between two interaction mechanisms. The 2DES is realized in the c -plane of wurtzite ZnO by interfacing it with Mg x Zn 1−x O (Fig. 1 a). Its formation is validated by our first-principles calculations, modeling the interface between two semi-infinite systems, ZnO and Mg x Zn 1−x O (Fig. 1 b). While Mg substitutes Zn stoichiometrically, its position is shifted from the original Zn atom position resulting in c -axis shrinking of the Mg x Zn 1−x O layer. This and the different chemical environment brought in by Mg atoms lead to a polarization discontinuity at the Mg x Zn 1−x O/ZnO interface, which is compensated by accumulating electrons at the interface. Respectively, the electron density depends on the Mg-content 5 . Fig. 1: Electronic structure of Mg x Zn 1−x O/ZnO interface. a Schematic view of high mobility MgZnO/ZnO heterostructure. Both wurtzite crystal structure of ZnO and Mg x Zn 1−x O/ZnO interface breaks the inversion symmetry. b The interface band structure is calculated using self consistent Green function method for semi-infinite systems considering x = 5%, a typical Mg content in the heterostructures. The conduction band (CB) of ZnO lowers at the interface forming the confinement potential for high mobility electrons. The size of the band gap in ZnO and Mg x Zn 1−x O is underestimated due to the lack of the conventional density functional theory. Full size image Spin–orbit coupling In such a wurtzite heterostructure the electrons are allowed to be polarized by the spin–orbit interaction, since both structural and crystal inversion symmetries are broken. The corresponding Hamiltonian for electrons in the c -plane is: $${H}_{{\\rm{SOC}}}=\\left[{\\alpha }_{{\\rm{R}}}+\\gamma (b\\langle {k}_{{\\rm{z}}}^{2}\\rangle -{k}_{\\parallel }^{2})\\right]({\\sigma }_{{\\rm{x}}}{k}_{{\\rm{y}}}-{\\sigma }_{{\\rm{y}}}{k}_{{\\rm{x}}}),$$ (1) where α R and γ are the Rashba and Dresselhaus coefficients respectively 6 , 7 , 8 . Here k z = − i ∂/∂ z acting on the electron wavefunction with 〈…〉 standing for the quantum expectation value, and k ∥ is the wavevector in the 2DES plane. We omit here higher k order terms, which can lead to the warping of the Fermi surface. They can become important at much higher charge carrier density values than considered in this work 9 . Equation 1 dictates that SOC effect, e.g., total spin structure and spin splitting, generated by Rashba and Dresselhaus interactions, is independent of their relative contributions to the total SOC effect. The expression in squared brackets acts as an effective SOC coefficient and for a free electron system it produces two Fermi surfaces with opposite spin chiralities. By contrast, due to the crystal symmetry of zinc blende the SOC Hamiltonian for 2DES formed in (001)-plane of GaAs has a different form than Eq. ( 1 ) 10 , 11 . Respectively, Rashba and Dresselhaus spin–orbit couplings produce different spin structures, so that the total", "role": "user" }, { "content": "In a finding that will help to identify exotic quantum states, RIKEN physicists have seen strongly competing factors that affect an electron's behavior in a high-quality quantum material. Electrons have a property called spin, which can be crudely thought of as the rotation of an electron about an axis. As an electron moves, its motion and spin can become linked through an effect known as spin–orbit coupling. This effect is useful because it offers a way to externally control the motion of an electron depending on its spin—a vital ability for an emerging technology called spintronics, which is seeking to use electron spin to realize low-power-consumption information processing. Spin–orbit coupling is a complex mix of quantum physics and relativity, but it becomes a little easier to understand by envisioning a round soccer ball. \"If a soccer player kicks the ball, it flies on a straight trajectory,\" explains Denis Maryenko of the RIKEN Center for Emergent Matter Science. \"But if the player gives the ball some rotation, or spin, its path bends.\" The ball's trajectory and its spinning motion are connected. If its spinning direction is reversed, the ball's path will bend in the opposite direction. Unlike soccer balls, electrons also interact with each other: two negatively charged particles will repel each other, for example. This mutual repulsion and the spin–orbit interaction compete with each other: the former can act to align an electron's spin with that of other electrons, whereas the latter tries to align an electron's spin with its motion. \"This interplay has recently attracted a lot of interest, since it could lead to the emergence of novel electronic and spin phases, which may be used in future quantum technologies,\" says Maryenko. \"It is thus important to understand the fundamentals of the interplay.\" But it is incredibly difficult to identify both effects at the same time. Now, Maryenko and his colleagues have succeeded in disentangling the two effects. They looked at electrons trapped between two semiconductors, magnesium zinc oxide and zinc oxide. Since the system had very few atomic impurities, there was a strong interaction between electrons. And the researchers could control the strength of the spin–orbit coupling by varying the magnesium content. \"We looked carefully at how the sample resistance changed when we applied a magnetic field,\" says Maryenko. In this way, they were able to identify signatures of both spin–orbit and the mutual repulsion due to the electrons' charges. This high-quality material system thus represents a great resource for testing theoretical predictions and it opens a path to develop spintronic phenomena in strong-electron-correlation regimes. ", "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 coupling (SOC) is pivotal for various fundamental spin-dependent phenomena in solids and their technological applications. In semiconductors, these phenomena have been so far studied in relatively weak electron–electron interaction regimes, where the single electron picture holds. However, SOC can profoundly compete against Coulomb interaction, which could lead to the emergence of unconventional electronic phases. Since SOC depends on the electric field in the crystal including contributions of itinerant electrons, electron–electron interactions can modify this coupling. Here we demonstrate the emergence of the SOC effect in a high-mobility two-dimensional electron system in a simple band structure MgZnO/ZnO semiconductor. This electron system also features strong electron–electron interaction effects. By changing the carrier density with Mg-content, we tune the SOC strength and achieve its interplay with electron–electron interaction. These systems pave a way to emergent spintronic phenomena in strong electron correlation regimes and to the formation of quasiparticles with the electron spin strongly coupled to the density. Introduction Spin–orbit coupling is a single particle relativistic effect producing in atomic physics a bilinear interaction between the electron spin and its orbital momentum. In solids the SOC is transformed into a symmetry-permitted coupling between the orientation of the electron spin and its crystal momentum. This coupling can lead to spin–momentum locking and establishes a spin-dependent band structure influenced by the crystal symmetry. Prominent examples here are the Rashba and Dresselhaus couplings, whose appearance requires the breaking of the structural and crystal inversion symmetries. By contrast, Coulomb interaction dictates collective electron behavior in solids, e.g., by establishing a Fermi liquid or a Mott insulator, and can also generate spin-polarized phases due to the Stoner instability 1 . Thus, SOC orients electron spin with respect to its momentum while the Coulomb interaction can counteract by aligning the spins in one direction, e.g., by producing a spin-depended exchange interaction. The usual single particle description of SOC-related effects in the presence of Coulomb interaction is poorly applicable, since the relativistic effect on quasiparticle excitations in strongly interacting systems is not known. Yet, the interplay of two mechanisms for spin orientation is suggested to have diverse manifestations encompassing the emergence of topological phases, spin textures, etc. 2 , 3 , 4 . An experimental realization of a system that shows both strong interaction between electrons, e.g., in the form of a Fermi liquid, and spin–orbit coupling is challenging. It requires a system with sufficiently strong relativistic effects to unfold the role of spin–orbit coupling and with a high mobility at a low carrier density to enhance the Coulomb interaction effect. Here we demonstrate a realization of such a regime in the two-dimensional electron system (2DES) at the Mg x Zn 1−x O/ZnO interface. The SOC effect is identified from the beatings of the Shubnikov-de Haas oscillations (SdH) in conductivity, which varies with the electron density N . Upon lowering N the system shows an enhancement of the electron effective mass, attributed to electron–electron interaction. Thus, we can tune the interplay between two interaction mechanisms and achieve an interaction regime for 2DESs, where the emergence of novel quantum states is anticipated. Results Formation of electron system We start with the discussion of the 2DES formation, since it is central for tuning the interplay between two interaction mechanisms. The 2DES is realized in the c -plane of wurtzite ZnO by interfacing it with Mg x Zn 1−x O (Fig. 1 a). Its formation is validated by our first-principles calculations, modeling the interface between two semi-infinite systems, ZnO and Mg x Zn 1−x O (Fig. 1 b). While Mg substitutes Zn stoichiometrically, its position is shifted from the original Zn atom position resulting in c -axis shrinking of the Mg x Zn 1−x O layer. This and the different chemical environment brought in by Mg atoms lead to a polarization discontinuity at the Mg x Zn 1−x O/ZnO interface, which is compensated by accumulating electrons at the interface. Respectively, the electron density depends on the Mg-content 5 . Fig. 1: Electronic structure of Mg x Zn 1−x O/ZnO interface. a Schematic view of high mobility MgZnO/ZnO heterostructure. Both wurtzite crystal structure of ZnO and Mg x Zn 1−x O/ZnO interface breaks the inversion symmetry. b The interface band structure is calculated using self consistent Green function method for semi-infinite systems considering x = 5%, a typical Mg content in the heterostructures. The conduction band (CB) of ZnO lowers at the interface forming the confinement potential for high mobility electrons. The size of the band gap in ZnO and Mg x Zn 1−x O is underestimated due to the lack of the conventional density functional theory. Full size image Spin–orbit coupling In such a wurtzite heterostructure the electrons are allowed to be polarized by the spin–orbit interaction, since both structural and crystal inversion symmetries are broken. The corresponding Hamiltonian for electrons in the c -plane is: $${H}_{{\rm{SOC}}}=\left[{\alpha }_{{\rm{R}}}+\gamma (b\langle {k}_{{\rm{z}}}^{2}\rangle -{k}_{\parallel }^{2})\right]({\sigma }_{{\rm{x}}}{k}_{{\rm{y}}}-{\sigma }_{{\rm{y}}}{k}_{{\rm{x}}}),$$ (1) where α R and γ are the Rashba and Dresselhaus coefficients respectively 6 , 7 , 8 . Here k z = − i ∂/∂ z acting on the electron wavefunction with 〈…〉 standing for the quantum expectation value, and k ∥ is the wavevector in the 2DES plane. We omit here higher k order terms, which can lead to the warping of the Fermi surface. They can become important at much higher charge carrier density values than considered in this work 9 . Equation 1 dictates that SOC effect, e.g., total spin structure and spin splitting, generated by Rashba and Dresselhaus interactions, is independent of their relative contributions to the total SOC effect. The expression in squared brackets acts as an effective SOC coefficient and for a free electron system it produces two Fermi surfaces with opposite spin chiralities. By contrast, due to the crystal symmetry of zinc blende the SOC Hamiltonian for 2DES formed in (001)-plane of GaAs has a different form than Eq. ( 1 ) 10 , 11 . Respectively, Rashba and Dresselhaus spin–orbit couplings produce different spin structures, so that the total<|im_end|> <|im_start|>assistant In a finding that will help to identify exotic quantum states, RIKEN physicists have seen strongly competing factors that affect an electron's behavior in a high-quality quantum material. Electrons have a property called spin, which can be crudely thought of as the rotation of an electron about an axis. As an electron moves, its motion and spin can become linked through an effect known as spin–orbit coupling. This effect is useful because it offers a way to externally control the motion of an electron depending on its spin—a vital ability for an emerging technology called spintronics, which is seeking to use electron spin to realize low-power-consumption information processing. Spin–orbit coupling is a complex mix of quantum physics and relativity, but it becomes a little easier to understand by envisioning a round soccer ball. "If a soccer player kicks the ball, it flies on a straight trajectory," explains Denis Maryenko of the RIKEN Center for Emergent Matter Science. "But if the player gives the ball some rotation, or spin, its path bends." The ball's trajectory and its spinning motion are connected. If its spinning direction is reversed, the ball's path will bend in the opposite direction. Unlike soccer balls, electrons also interact with each other: two negatively charged particles will repel each other, for example. This mutual repulsion and the spin–orbit interaction compete with each other: the former can act to align an electron's spin with that of other electrons, whereas the latter tries to align an electron's spin with its motion. "This interplay has recently attracted a lot of interest, since it could lead to the emergence of novel electronic and spin phases, which may be used in future quantum technologies," says Maryenko. "It is thus important to understand the fundamentals of the interplay." But it is incredibly difficult to identify both effects at the same time. Now, Maryenko and his colleagues have succeeded in disentangling the two effects. They looked at electrons trapped between two semiconductors, magnesium zinc oxide and zinc oxide. Since the system had very few atomic impurities, there was a strong interaction between electrons. And the researchers could control the strength of the spin–orbit coupling by varying the magnesium content. "We looked carefully at how the sample resistance changed when we applied a magnetic field," says Maryenko. In this way, they were able to identify signatures of both spin–orbit and the mutual repulsion due to the electrons' charges. This high-quality material system thus represents a great resource for testing theoretical predictions and it opens a path to develop spintronic phenomena in strong-electron-correlation regimes. <|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": "Abstracted & indexed Article level metrics FAQs Contact XML harvesting & OAI-PMH EGU publications Topbar <iframe frameborder=\"0\" id=\"co_auth_check_authiframecontainer\" style=\"width: 179px; height: 57px; margin: 0; margin-bottom: 5px; margin-left: 10px; margin-top: -15px; padding: 0; border: none; overflow: hidden; background-color: transparent; display: none;\" src=\"\"></iframe> End Topbar Article START_SEARCH END_SEARCH tpl: templates/get_functions/get_breadcrumbs/index Articles Volume 15, issue 4 TC, 15, 1751–1785, 2021 Authors Title Abstract Full text Website search $(function () { let searchField = $('#search_query'); function redirectToSearch(url) { let query = searchField.val(); let value = query.replace(/^\\s+|\\s+$/gm, ''); if (value.length > 0) { location.href = url + value; } } searchField.on('keyup', function (event) { if (event.key === 'Enter') { redirectToSearch(' } }); $('.search .dropdown-item').on('click', function (event) { event.stopPropagation(); event.preventDefault(); let url = $(this).attr('href'); redirectToSearch(url); return false; }); $('.search .dropdown-item').on('touchend', function (event) { event.stopPropagation(); event.preventDefault(); let url = $(this).attr('href'); redirectToSearch(url); return false; }); $('#search-wrapper .co-mobile-search:not(.active)').on('click', function (event) { let element = $(this); let parent = $(element).closest('div.col-12'); $(element).addClass('active'); let searchElementsWrapper = $('#search-wrapper').closest('div.col'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).removeClass('col'); $(searchElementsWrapper).addClass('col-12'); $(parent).addClass('d-none'); $('.search-fields-wrapper').removeClass('d-none'); } }); $('#search-wrapper .co-mobile-search:not(.active)').on('touchend', function (event) { let element = $(this); let parent = $(element).closest('div.col-12'); $(element).addClass('active'); let searchElementsWrapper = $('#search-wrapper').closest('div.col'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).removeClass('col'); $(searchElementsWrapper).addClass('col-12'); $(parent).addClass('d-none'); $('.search-fields-wrapper').removeClass('d-none'); } }); $('#search-wrapper .co-mobile-search.active').on('click', function (event) { let element = $(this); $(element).removeClass('active'); let parent = $(element).closest('div.col-12'); let searchElementsWrapper = $('#search-wrapper').closest('div.col-12'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).addClass('col-4'); $(searchElementsWrapper).removeClass('col-12'); $(parent).removeClass('d-none'); $('.search-fields-wrapper').addClass('d-none'); } }); $('#search-wrapper .co-mobile-search.active').on('touchend', function (event) { let element = $(this); $(element).removeClass('active'); let parent = $(element).closest('div.col-12'); let searchElementsWrapper = $('#search-wrapper').closest('div.col-12'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).addClass('col-4'); $(searchElementsWrapper).removeClass('col-12'); $(parent).removeClass('d-none'); $('.search-fields-wrapper').addClass('d-none'); } }); }); === Content === Articles | Volume 15, issue 4 Article Peer review Metrics Related articles Articles | Volume 15, issue 4 © Author(s) 2021. This work is distributed under the Creative Commons Attribution 4.0 License. © Author(s) 2021. This work is distributed under the Creative Commons Attribution 4.0 License. Articles | Volume 15, issue 4 Article Peer review Metrics Related articles Research article | Highlight paper | 12 Apr 2021 Research article | Highlight paper | | 12 Apr 2021 Sudden large-volume detachments of low-angle mountain glaciers – more frequent than thought? Sudden large-volume detachments of low-angle mountain glaciers – more frequent than thought? Sudden large-volume detachments of low-angle mountain glaciers – more frequent than thought? Andreas Kääb et al. Andreas Kääb , Mylène Jacquemart , Adrien Gilbert , Silvan Leinss , Luc Girod , Christian Huggel , Daniel Falaschi , Felipe Ugalde , Dmitry Petrakov , Sergey Chernomorets , Mikhail Dokukin , Frank Paul , Simon Gascoin , Etienne Berthier , and Jeffrey S. Kargel Andreas Kääb CORRESPONDING AUTHOR [email protected] × Department of Geosciences, University of Oslo, Oslo, Norway Invited contribution by Andreas Kääb, recipient of the EGU Louis Agassiz Medal 2019. Mylène Jacquemart × Cooperative Institute for Research in Environmental Sciences, University of Colorado at Boulder, Boulder, United States Adrien Gilbert × Université Grenoble Alpes, CNRS, IGE, Grenoble, France Silvan Leinss × Institute of Environmental Engineering, ETH Zurich, Zurich, Switzerland Luc Girod × Department of Geosciences, University of Oslo, Oslo, Norway Christian Huggel × Department of Geography, University of Zurich, Zurich, Switzerland Daniel Falaschi × Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales, Mendoza, Argentina Departamento de Geografía, Facultad de Filosofía y Letras, Universidad Nacional de Cuyo, Mendoza, Argentina Felipe Ugalde × Geoestudios, San José de Maipo, Chile Departamento de Geología, Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, Santiago, Chile Dmitry Petrakov × Faculty of Geography, M. V. Lomonosov Moscow State University, Moscow, Russia Sergey Chernomorets × Faculty of Geography, M. V. Lomonosov Moscow State University, Moscow, Russia Mikhail Dokukin × High-Mountain Geophysical Institute, Nalchik, Russia Frank Paul × Department of Geography, University of Zurich, Zurich, Switzerland Simon Gascoin × CESBIO, Université de Toulouse, CNES/CNRS/INRA/IRD/UPS, Toulouse, France Etienne Berthier × LEGOS, CNES, CNRS, IRD, UPS, Université de Toulouse, Toulouse, France Jeffrey S. Kargel × Planetary Science Institute, University of Arizona, Tucson, AZ, USA Abstract The detachment of large parts of low-angle mountain glaciers resulting in massive ice–rock avalanches have so far been believed to be a unique type of event, made known to the global scientific community first for the 2002 Kolka Glacier detachment, Caucasus Mountains, and then for the 2016 collapses of two glaciers in the Aru range, Tibet. Since 2016, several so-far unrecognized low-angle glacier detachments have been recognized and described, and new ones have occurred. In the current contribution, we compile, compare, and discuss 20 actual or suspected large-volume detachments of low-angle mountain glaciers at 10 different sites in the Caucasus, the Pamirs, Tibet, Altai, the North American Cordillera, and the Southern Andes. Many of the detachments reached volumes in the order of 10–100 million m 3 . The similarities and differences between the presented cases indicate that glacier detachments often involve a coincidental combination of factors related to the lowering of basal friction, high or increasing driving stresses, concentration of shear stress, or low resistance to exceed stability thresholds. Particularly soft glacier beds seem to be a common condition among the observed events as they offer smooth contact areas between the glacier and the underlying substrate and are prone to till-strength weakening and eventually basal failure under high pore-water pressure. Partially or fully thawed glacier bed conditions and the presence of liquid water could thus play an important role in the detachments. Surface slopes of the detached glaciers range between around 10 ∘ and 20 ∘ . This may be low enough to enable the development of thick and thus large-volume glaciers while also being steep enough to allow critical driving stresses to build up. We construct a simple slab model to estimate ranges of glacier slope and width above which a glacier may be able to detach when extensively losing basal resistance. From this model we estimate that all the detachments described in this study occurred due to a basal shear stress reduction of more than 50 %. Most of the ice–rock avalanches resulting from the detachments in this study have a particularly low angle of reach, down to around 5 ∘ , likely due to their high ice content and connected liquefaction potential, the", "role": "user" }, { "content": "One tends to think of mountain glaciers as slow moving, their gradual passage down a mountainside visible only through a long series of satellite imagery or years of time-lapse photography. However, new research shows that glacier flow can be much more dramatic, ranging from about 10 meters a day to speeds that are more like that of avalanches, with obvious potential dire consequences for those living below. Glaciers are generally slow-flowing rivers of ice, under the force of gravity transporting snow that has turned to ice at the top of the mountain to locations lower down the valley—a gradual process of balancing their upper-region mass gain with their lower-elevation mass loss. This process usually takes many decades. Since this is influenced by the climate, scientists use changes in the rate of glacier flow as an indicator of climate change. For some glaciers around the world this gradual flow can speed up, so that they advance several kilometers in just a few month or years, a process called glacier surging. After a surge, the glacier usually remains still and the displaced ice melts over a few decades. Although surges can block rivers and create lakes that may burst suddenly, these events don't often pose any danger, as by their very nature, they tend to be in remote and sparsely-populated regions—a fact that means that these events are often only known about thanks to data and images from satellites. For several years now, scientists have known that a glacier can also actually detach from the mountain rock and gush down to the valley at speeds of up to 300 kilometers an hour as a fluid ice-rock avalanche. In 2016, a glacier in Tibet’s Aru mountain range suddenly collapsed, killing 10 people and hundreds of livestock. A few months later, a second glacier in the same mountain range also unexpectedly collapsed. The image, based on data from the Copernicus Sentinel-1 mission, shows the traces left after these two avalanches. For several years now, scientists have known that glaciers can detach from the mountain rock like this and gush down to the valley at speeds of up to 300 kilometres an hour as a fluid ice-rock avalanche. However, a paper published recently in The Cryosphere describes how scientists working in ESA’s Climate Change Initiative Glaciers team has discovered, together with several colleagues, that these glacier detachments have happened much more often than had been known. Credit: contains modified Copernicus Sentinel-2 data (2016), processed by CCI Glacier team and ESA However, a paper published recently in The Cryosphere describes how scientists working in ESA's Climate Change Initiative Glaciers team has discovered, together with several colleagues, that these glacier detachments have happened much more often than had been known. Even more surprisingly, this is happening to glaciers resting on relatively flat beds. Andreas Kääb, from the University of Oslo, explained, \"We have known about debris flows originating from glaciers that break off at high elevations for several decades now, however, until relatively recently, we were extremely surprised to discover that glaciers resting on flatter beds can also detach as a whole. \"These events are reported only rarely. In fact, they only really came to light in 2002 after a huge chunk of the Kolka glacier, which sits in a gently sloping valley on the Russian–Georgian border, detached and thundered down the valley at about 80 meters a second, carrying around 130 million cubic meters of ice and rock that killed more than 100 people. \"Using satellite data, we have now discovered that such events are more common than we could have ever imagined, and this might be a consequence of a changing climate.\" The team of scientists from all over the world used data from different satellites including the Copernicus Sentinel-1 and Sentinel-2 missions and the US Landsat mission as well as digital elevation models to document and analyze events that were already known about, but also to identify glacier detachments that had not been recorded so far. Global occurrence of glacier detachments. Credit: CCI Glacier team/ESA They studied 20 glacier detachments that occurred in 10 different regions, from Alaska to the Andes and from the Caucasus to Tibet. Frank Paul, from the University of Zurich, said, \"We analyzed the timing of events, calculated volumes, run-out distances, elevation ranges, permafrost conditions as well as possible factors triggering these glacier avalanches. Although we found some common characteristics, there are diverse circumstances that may have led to these events. However, we have concluded that, at least for some events, the effects of a warmer climate, such as permafrost thawing and meltwater infiltration, may well be to blame.\" Andreas Kääb added, \"The bottom line is that detachment of glaciers resting on flat bedrock are more common than we thought. \"The current era of frequent high-resolution optical and radar data, not least from Sentinel-2 and Sentinel-1, has brought a step-change in detecting and understanding these events after they happen. Although we are still far away from having a prognostic tool to detect possible events before they happen, thanks to satellite data and this new understanding, we might be able to detect precursor signals in good time to potentially save 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 Abstracted & indexed Article level metrics FAQs Contact XML harvesting & OAI-PMH EGU publications Topbar <iframe frameborder="0" id="co_auth_check_authiframecontainer" style="width: 179px; height: 57px; margin: 0; margin-bottom: 5px; margin-left: 10px; margin-top: -15px; padding: 0; border: none; overflow: hidden; background-color: transparent; display: none;" src=""></iframe> End Topbar Article START_SEARCH END_SEARCH tpl: templates/get_functions/get_breadcrumbs/index Articles Volume 15, issue 4 TC, 15, 1751–1785, 2021 Authors Title Abstract Full text Website search $(function () { let searchField = $('#search_query'); function redirectToSearch(url) { let query = searchField.val(); let value = query.replace(/^\s+|\s+$/gm, ''); if (value.length > 0) { location.href = url + value; } } searchField.on('keyup', function (event) { if (event.key === 'Enter') { redirectToSearch(' } }); $('.search .dropdown-item').on('click', function (event) { event.stopPropagation(); event.preventDefault(); let url = $(this).attr('href'); redirectToSearch(url); return false; }); $('.search .dropdown-item').on('touchend', function (event) { event.stopPropagation(); event.preventDefault(); let url = $(this).attr('href'); redirectToSearch(url); return false; }); $('#search-wrapper .co-mobile-search:not(.active)').on('click', function (event) { let element = $(this); let parent = $(element).closest('div.col-12'); $(element).addClass('active'); let searchElementsWrapper = $('#search-wrapper').closest('div.col'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).removeClass('col'); $(searchElementsWrapper).addClass('col-12'); $(parent).addClass('d-none'); $('.search-fields-wrapper').removeClass('d-none'); } }); $('#search-wrapper .co-mobile-search:not(.active)').on('touchend', function (event) { let element = $(this); let parent = $(element).closest('div.col-12'); $(element).addClass('active'); let searchElementsWrapper = $('#search-wrapper').closest('div.col'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).removeClass('col'); $(searchElementsWrapper).addClass('col-12'); $(parent).addClass('d-none'); $('.search-fields-wrapper').removeClass('d-none'); } }); $('#search-wrapper .co-mobile-search.active').on('click', function (event) { let element = $(this); $(element).removeClass('active'); let parent = $(element).closest('div.col-12'); let searchElementsWrapper = $('#search-wrapper').closest('div.col-12'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).addClass('col-4'); $(searchElementsWrapper).removeClass('col-12'); $(parent).removeClass('d-none'); $('.search-fields-wrapper').addClass('d-none'); } }); $('#search-wrapper .co-mobile-search.active').on('touchend', function (event) { let element = $(this); $(element).removeClass('active'); let parent = $(element).closest('div.col-12'); let searchElementsWrapper = $('#search-wrapper').closest('div.col-12'); if(searchElementsWrapper.length > 0){ $(searchElementsWrapper).addClass('col-4'); $(searchElementsWrapper).removeClass('col-12'); $(parent).removeClass('d-none'); $('.search-fields-wrapper').addClass('d-none'); } }); }); === Content === Articles | Volume 15, issue 4 Article Peer review Metrics Related articles Articles | Volume 15, issue 4 © Author(s) 2021. This work is distributed under the Creative Commons Attribution 4.0 License. © Author(s) 2021. This work is distributed under the Creative Commons Attribution 4.0 License. Articles | Volume 15, issue 4 Article Peer review Metrics Related articles Research article | Highlight paper | 12 Apr 2021 Research article | Highlight paper | | 12 Apr 2021 Sudden large-volume detachments of low-angle mountain glaciers – more frequent than thought? Sudden large-volume detachments of low-angle mountain glaciers – more frequent than thought? Sudden large-volume detachments of low-angle mountain glaciers – more frequent than thought? Andreas Kääb et al. Andreas Kääb , Mylène Jacquemart , Adrien Gilbert , Silvan Leinss , Luc Girod , Christian Huggel , Daniel Falaschi , Felipe Ugalde , Dmitry Petrakov , Sergey Chernomorets , Mikhail Dokukin , Frank Paul , Simon Gascoin , Etienne Berthier , and Jeffrey S. Kargel Andreas Kääb CORRESPONDING AUTHOR [email protected] × Department of Geosciences, University of Oslo, Oslo, Norway Invited contribution by Andreas Kääb, recipient of the EGU Louis Agassiz Medal 2019. Mylène Jacquemart × Cooperative Institute for Research in Environmental Sciences, University of Colorado at Boulder, Boulder, United States Adrien Gilbert × Université Grenoble Alpes, CNRS, IGE, Grenoble, France Silvan Leinss × Institute of Environmental Engineering, ETH Zurich, Zurich, Switzerland Luc Girod × Department of Geosciences, University of Oslo, Oslo, Norway Christian Huggel × Department of Geography, University of Zurich, Zurich, Switzerland Daniel Falaschi × Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales, Mendoza, Argentina Departamento de Geografía, Facultad de Filosofía y Letras, Universidad Nacional de Cuyo, Mendoza, Argentina Felipe Ugalde × Geoestudios, San José de Maipo, Chile Departamento de Geología, Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, Santiago, Chile Dmitry Petrakov × Faculty of Geography, M. V. Lomonosov Moscow State University, Moscow, Russia Sergey Chernomorets × Faculty of Geography, M. V. Lomonosov Moscow State University, Moscow, Russia Mikhail Dokukin × High-Mountain Geophysical Institute, Nalchik, Russia Frank Paul × Department of Geography, University of Zurich, Zurich, Switzerland Simon Gascoin × CESBIO, Université de Toulouse, CNES/CNRS/INRA/IRD/UPS, Toulouse, France Etienne Berthier × LEGOS, CNES, CNRS, IRD, UPS, Université de Toulouse, Toulouse, France Jeffrey S. Kargel × Planetary Science Institute, University of Arizona, Tucson, AZ, USA Abstract The detachment of large parts of low-angle mountain glaciers resulting in massive ice–rock avalanches have so far been believed to be a unique type of event, made known to the global scientific community first for the 2002 Kolka Glacier detachment, Caucasus Mountains, and then for the 2016 collapses of two glaciers in the Aru range, Tibet. Since 2016, several so-far unrecognized low-angle glacier detachments have been recognized and described, and new ones have occurred. In the current contribution, we compile, compare, and discuss 20 actual or suspected large-volume detachments of low-angle mountain glaciers at 10 different sites in the Caucasus, the Pamirs, Tibet, Altai, the North American Cordillera, and the Southern Andes. Many of the detachments reached volumes in the order of 10–100 million m 3 . The similarities and differences between the presented cases indicate that glacier detachments often involve a coincidental combination of factors related to the lowering of basal friction, high or increasing driving stresses, concentration of shear stress, or low resistance to exceed stability thresholds. Particularly soft glacier beds seem to be a common condition among the observed events as they offer smooth contact areas between the glacier and the underlying substrate and are prone to till-strength weakening and eventually basal failure under high pore-water pressure. Partially or fully thawed glacier bed conditions and the presence of liquid water could thus play an important role in the detachments. Surface slopes of the detached glaciers range between around 10 ∘ and 20 ∘ . This may be low enough to enable the development of thick and thus large-volume glaciers while also being steep enough to allow critical driving stresses to build up. We construct a simple slab model to estimate ranges of glacier slope and width above which a glacier may be able to detach when extensively losing basal resistance. From this model we estimate that all the detachments described in this study occurred due to a basal shear stress reduction of more than 50 %. Most of the ice–rock avalanches resulting from the detachments in this study have a particularly low angle of reach, down to around 5 ∘ , likely due to their high ice content and connected liquefaction potential, the<|im_end|> <|im_start|>assistant One tends to think of mountain glaciers as slow moving, their gradual passage down a mountainside visible only through a long series of satellite imagery or years of time-lapse photography. However, new research shows that glacier flow can be much more dramatic, ranging from about 10 meters a day to speeds that are more like that of avalanches, with obvious potential dire consequences for those living below. Glaciers are generally slow-flowing rivers of ice, under the force of gravity transporting snow that has turned to ice at the top of the mountain to locations lower down the valley—a gradual process of balancing their upper-region mass gain with their lower-elevation mass loss. This process usually takes many decades. Since this is influenced by the climate, scientists use changes in the rate of glacier flow as an indicator of climate change. For some glaciers around the world this gradual flow can speed up, so that they advance several kilometers in just a few month or years, a process called glacier surging. After a surge, the glacier usually remains still and the displaced ice melts over a few decades. Although surges can block rivers and create lakes that may burst suddenly, these events don't often pose any danger, as by their very nature, they tend to be in remote and sparsely-populated regions—a fact that means that these events are often only known about thanks to data and images from satellites. For several years now, scientists have known that a glacier can also actually detach from the mountain rock and gush down to the valley at speeds of up to 300 kilometers an hour as a fluid ice-rock avalanche. In 2016, a glacier in Tibet’s Aru mountain range suddenly collapsed, killing 10 people and hundreds of livestock. A few months later, a second glacier in the same mountain range also unexpectedly collapsed. The image, based on data from the Copernicus Sentinel-1 mission, shows the traces left after these two avalanches. For several years now, scientists have known that glaciers can detach from the mountain rock like this and gush down to the valley at speeds of up to 300 kilometres an hour as a fluid ice-rock avalanche. However, a paper published recently in The Cryosphere describes how scientists working in ESA’s Climate Change Initiative Glaciers team has discovered, together with several colleagues, that these glacier detachments have happened much more often than had been known. Credit: contains modified Copernicus Sentinel-2 data (2016), processed by CCI Glacier team and ESA However, a paper published recently in The Cryosphere describes how scientists working in ESA's Climate Change Initiative Glaciers team has discovered, together with several colleagues, that these glacier detachments have happened much more often than had been known. Even more surprisingly, this is happening to glaciers resting on relatively flat beds. Andreas Kääb, from the University of Oslo, explained, "We have known about debris flows originating from glaciers that break off at high elevations for several decades now, however, until relatively recently, we were extremely surprised to discover that glaciers resting on flatter beds can also detach as a whole. "These events are reported only rarely. In fact, they only really came to light in 2002 after a huge chunk of the Kolka glacier, which sits in a gently sloping valley on the Russian–Georgian border, detached and thundered down the valley at about 80 meters a second, carrying around 130 million cubic meters of ice and rock that killed more than 100 people. "Using satellite data, we have now discovered that such events are more common than we could have ever imagined, and this might be a consequence of a changing climate." The team of scientists from all over the world used data from different satellites including the Copernicus Sentinel-1 and Sentinel-2 missions and the US Landsat mission as well as digital elevation models to document and analyze events that were already known about, but also to identify glacier detachments that had not been recorded so far. Global occurrence of glacier detachments. Credit: CCI Glacier team/ESA They studied 20 glacier detachments that occurred in 10 different regions, from Alaska to the Andes and from the Caucasus to Tibet. Frank Paul, from the University of Zurich, said, "We analyzed the timing of events, calculated volumes, run-out distances, elevation ranges, permafrost conditions as well as possible factors triggering these glacier avalanches. Although we found some common characteristics, there are diverse circumstances that may have led to these events. However, we have concluded that, at least for some events, the effects of a warmer climate, such as permafrost thawing and meltwater infiltration, may well be to blame." Andreas Kääb added, "The bottom line is that detachment of glaciers resting on flat bedrock are more common than we thought. "The current era of frequent high-resolution optical and radar data, not least from Sentinel-2 and Sentinel-1, has brought a step-change in detecting and understanding these events after they happen. Although we are still far away from having a prognostic tool to detect possible events before they happen, thanks to satellite data and this new understanding, we might be able to detect precursor signals in good time to potentially save lives." <|im_end|>

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315, 14812, 3090, 1436, 8617, 1514, 459, 3062, 3560, 304, 279, 47881, 1392, 13, 28061, 60108, 315, 279, 45017, 95790, 2134, 1990, 2212, 220, 605, 12264, 246, 323, 220, 508, 12264, 246, 662, 1115, 1253, 387, 3428, 3403, 311, 7431, 279, 4500, 315, 12314, 323, 8617, 3544, 67868, 95790, 1418, 1101, 1694, 32366, 3403, 311, 2187, 9200, 10043, 59623, 311, 1977, 709, 13, 1226, 9429, 264, 4382, 55791, 1646, 311, 16430, 21986, 315, 94867, 31332, 323, 2430, 3485, 902, 264, 94867, 1253, 387, 3025, 311, 47881, 994, 42817, 13490, 80710, 13957, 13, 5659, 420, 1646, 584, 16430, 430, 682, 279, 47881, 1392, 7633, 304, 420, 4007, 10222, 4245, 311, 264, 80710, 65344, 8631, 14278, 315, 810, 1109, 220, 1135, 19032, 7648, 315, 279, 10054, 4235, 21161, 41635, 83281, 13239, 505, 279, 47881, 1392, 304, 420, 4007, 617, 264, 8104, 3428, 9392, 315, 5662, 11, 1523, 311, 2212, 220, 20, 12264, 246, 1174, 4461, 4245, 311, 872, 1579, 10054, 2262, 323, 8599, 93542, 91409, 4754, 11, 279, 128257, 198, 128256, 78191, 198, 4054, 28335, 311, 1781, 315, 16700, 95790, 439, 6435, 7366, 11, 872, 53722, 21765, 1523, 264, 24405, 579, 9621, 1193, 1555, 264, 1317, 4101, 315, 24088, 41545, 477, 1667, 315, 892, 2922, 7629, 24685, 13, 4452, 11, 502, 3495, 5039, 430, 94867, 6530, 649, 387, 1790, 810, 22520, 11, 24950, 505, 922, 220, 605, 20645, 264, 1938, 311, 25753, 430, 527, 810, 1093, 430, 315, 41635, 83281, 11, 449, 8196, 4754, 13510, 16296, 369, 1884, 5496, 3770, 13, 8444, 582, 4918, 527, 8965, 6435, 62413, 287, 36617, 315, 10054, 11, 1234, 279, 5457, 315, 24128, 67757, 12056, 430, 706, 6656, 311, 10054, 520, 279, 1948, 315, 279, 16700, 311, 10687, 4827, 1523, 279, 34681, 29096, 53722, 1920, 315, 44463, 872, 8582, 61779, 3148, 8895, 449, 872, 4827, 5773, 44857, 3148, 4814, 13, 1115, 1920, 6118, 5097, 1690, 11026, 13, 8876, 420, 374, 28160, 555, 279, 10182, 11, 14248, 1005, 4442, 304, 279, 4478, 315, 94867, 6530, 439, 459, 21070, 315, 10182, 2349, 13, 1789, 1063, 95790, 2212, 279, 1917, 420, 53722, 6530, 649, 4732, 709, 11, 779, 430, 814, 12178, 3892, 41668, 304, 1120, 264, 2478, 2305, 477, 1667, 11, 264, 1920, 2663, 94867, 1765, 3252, 13, 4740, 264, 22531, 11, 279, 94867, 6118, 8625, 2103, 323, 279, 49246, 10054, 99191, 927, 264, 2478, 11026, 13, 10541, 1765, 4282, 649, 2565, 36617, 323, 1893, 44236, 430, 1253, 21165, 15187, 11, 1521, 4455, 1541, 956, 3629, 17477, 904, 8137, 11, 439, 555, 872, 1633, 7138, 11, 814, 8541, 311, 387, 304, 8870, 323, 993, 1590, 989, 41352, 7913, 13918, 29096, 2144, 430, 3445, 430, 1521, 4455, 527, 3629, 1193, 3967, 922, 9523, 311, 828, 323, 5448, 505, 47710, 13, 1789, 3892, 1667, 1457, 11, 14248, 617, 3967, 430, 264, 94867, 649, 1101, 3604, 47881, 505, 279, 16700, 7091, 323, 342, 1136, 1523, 311, 279, 34681, 520, 25753, 315, 709, 311, 220, 3101, 41668, 459, 6596, 439, 264, 15962, 10054, 80437, 96694, 13, 763, 220, 679, 21, 11, 264, 94867, 304, 45261, 753, 1676, 84, 16700, 2134, 15187, 29368, 11, 13419, 220, 605, 1274, 323, 11758, 315, 51876, 13, 362, 2478, 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3025, 311, 11388, 71261, 17738, 304, 1695, 892, 311, 13893, 3665, 6439, 1210, 220, 128257, 198 ]

2,965

[ { "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 Machine learning approaches are increasingly used to extract patterns and insights from the ever-increasing stream of geospatial data, but current approaches may not be optimal when system behaviour is dominated by spatial or temporal context. Here, rather than amending classical machine learning, we argue that these contextual cues should be used as part of deep learning (an approach that is able to extract spatio-temporal features automatically) to gain further process understanding of Earth system science problems, improving the predictive ability of seasonal forecasting and modelling of long-range spatial connections across multiple timescales, for example. The next step will be a hybrid modelling approach, coupling physical process models with the versatility of data-driven machine learning. Main Humans have always striven to predict and understand the world, and the ability to make better predictions has given competitive advantages in diverse contexts (such as weather, diseases or financial markets). Yet the tools for prediction have substantially changed over time, from ancient Greek philosophical reasoning to non-scientific medieval methods such as soothsaying, towards modern scientific discourse, which has come to include hypothesis testing, theory development and computer modelling underpinned by statistical and physical relationships, that is, laws 1 . A success story in the geosciences is weather prediction, which has greatly improved through the integration of better theory, increased computational power, and established observational systems, which allow for the assimilation of large amounts of data into the modelling system 2 . Nevertheless, we can accurately predict the evolution of the weather on a timescale of days, not months. Seasonal meteorological predictions, forecasting extreme events such as flooding or fire, and long-term climate projections are still major challenges. This is especially true for predicting dynamics in the biosphere, which is dominated by biologically mediated processes such as growth or reproduction, and is strongly controlled by seemingly stochastic disturbances such as fires and landslides. Such predictive problems have not seen much progress in the past few decades 3 . At the same time, a deluge of Earth system data has become available, with storage volumes already well beyond dozens of petabytes and rapidly increasing transmission rates exceeding hundreds of terabytes per day 4 . These data come from a plethora of sensors measuring states, fluxes and intensive or time/space-integrated variables, representing fifteen or more orders of temporal and spatial magnitude. They include remote sensing from a few metres to hundreds of kilometres above Earth as well as in situ observations (increasingly from autonomous sensors) at and below the surface and in the atmosphere, many of which are further being complemented by citizen science observations. Model simulation output adds to this deluge; the CMIP-5 dataset of the Climate Model Intercomparison Project, used extensively for scientific groundwork towards periodic climate assessments, is over 3 petabytes in size, and the next generation, CMIP-6, is estimated to reach up to 30 petabytes 5 . The data from models share many of the challenges and statistical properties of observational data, including many forms of uncertainty. In summary, Earth system data are exemplary of all four of the ‘four Vs’ of ‘big data’: volume, velocity, variety and veracity (see Fig. 1 ). One key challenge is to extract interpretable information and knowledge from this big data, possibly almost in real time and integrating between disciplines. Fig. 1: Big data challenges in the geoscientific context. Data size now exceeds 100 petabytes, and is growing quasi-exponentially (tapering of the figure to the right indicates decreasing data size.) The speed of change exceeds 5 petabytes a year; data are taken at frequencies of up to 10 Hz or more; reprocessing and versioning are common challenges. Data sources can be one- to four-dimensional, spatially integrated, from the organ level (such as leaves) to the global level. Earth has diverse observational systems, from remote sensing to in situ observation. The uncertainty of data can stem from observational errors or conceptual inconsistencies. Full size image Taken together, our ability to collect and create data far outpaces our ability to sensibly assimilate it, let alone understand it. Predictive ability in the last few decades has not increased apace with data availability. To get the most out of the explosive growth and diversity of Earth system data, we face two major tasks in the coming years: (1) extracting knowledge from the data deluge, and (2) deriving models that learn much more from data than traditional data assimilation approaches can, while still respecting our evolving understanding of nature’s laws. The combination of unprecedented data sources, increased computational power, and the recent advances in statistical modelling and machine learning offer exciting new opportunities for expanding our knowledge about the Earth system from data. In particular, many tools are available from the fields of machine learning and artificial intelligence, but they need to be further developed and adapted to geo-scientific analysis. Earth system science offers new opportunities, challenges and methodological demands, in particular for recent research lines focusing on spatio-temporal context and uncertainties (Box 1 ; see and for more complete glossaries). In the following sections we review the development of machine learning in the geoscientific context, and highlight how deep learning—that is, the automatic extraction of abstract (spatio-temporal) features—has the potential to overcome many of the limitations that have, until now, hindered a more wide-spread adoption of machine learning. We further lay out the most promising but also challenging approaches in combining machine learning with physical modelling. Box 1 Definition of terms Table 1 Full size table Show more State-of-the-art geoscientific machine learning Machine learning is now a successful part of several research-driven and operational geoscientific processing schemes, addressing the atmosphere, the land surface and the ocean, and has co-evolved with data availability over the past decade. Early landmarks in classification of land cover and clouds emerged almost 30 years ago through the coincidence of high-resolution satellite data and the first revival of neural networks 6 , 7 . Most major machine learning methodological development (for example, kernel methods or ‘random forests’) has subsequently been applied to geoscience and remote sensing", "role": "user" }, { "content": "A study by German scientists from Jena and Hamburg, published today in the journal Nature, shows that artificial intelligence (AI) can substantially improve our understanding of the climate and the Earth system. Especially the potential of deep learning has only partially been exhausted so far. In particular, complex dynamic processes such as hurricanes, fire propagation, and vegetation dynamics can be better described with the help of AI. As a result, climate and Earth system models will be improved, with new models combining artificial intelligence and physical modeling. In the past decades mainly static attributes have been investigated using machine learning approaches, such as the distribution of soil properties from the local to the global scale. For some time now, it has been possible to tackle more dynamic processes by using more sophisticated deep learning techniques. This allows for example to quantify the global photosynthesis on land with simultaneous consideration of seasonal and short term variations. Deducing underlying laws from observation data \"From a plethora of sensors, a deluge of Earth system data has become available, but so far we've been lagging behind in analysis and interpretation,\" explains Markus Reichstein, managing director of the Max Planck Institute for Biogeochemistry in Jena, directory board member of the Michael-Stifel-Center Jena (MSCJ) and first author of the publication. \"This is where deep learning techniques become a promising tool, beyond the classical machine learning applications such as image recognition, natural language processing or AlphaGo,\" adds co-author Joachim Denzler from the Computer Vision Group of the Friedrich Schiller University Jena (FSU) and member of MSCJ. Examples for application are extreme events such as fire spreads or hurricanes, which are very complex processes influenced by local conditions but also by their temporal and spatial context. This also applies to atmospheric and ocean transport, soil movement, and vegetation dynamics, some of the classic topics of Earth system science. Artificial intelligence to improve climate and Earth system models However, deep learning approaches are difficult. All data-driven and statistical approaches do not guarantee physical consistency per se, are highly dependent on data quality, and may experience difficulties with extrapolations. Besides, the requirement for data processing and storage capacity is very high. The publication discusses all these requirements and obstacles and develops a strategy to efficiently combine machine learning with physical modeling. If both techniques are brought together, so-called hybrid models are created. They can for example be used for modeling the motion of ocean water to predict sea surface temperature. While the temperatures are modelled physically, the ocean water movement is represented by a machine learning approach. \"The idea is to combine the best of two worlds, the consistency of physical models with the versatility of machine learning, to obtain greatly improved models,\" Markus Reichstein further explains. The scientists contend that detection and early warning of extreme events as well as seasonal and long-term prediction and projection of weather and climate will strongly benefit from the discussed deep-learning and hybrid modelling approaches. ", "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 Machine learning approaches are increasingly used to extract patterns and insights from the ever-increasing stream of geospatial data, but current approaches may not be optimal when system behaviour is dominated by spatial or temporal context. Here, rather than amending classical machine learning, we argue that these contextual cues should be used as part of deep learning (an approach that is able to extract spatio-temporal features automatically) to gain further process understanding of Earth system science problems, improving the predictive ability of seasonal forecasting and modelling of long-range spatial connections across multiple timescales, for example. The next step will be a hybrid modelling approach, coupling physical process models with the versatility of data-driven machine learning. Main Humans have always striven to predict and understand the world, and the ability to make better predictions has given competitive advantages in diverse contexts (such as weather, diseases or financial markets). Yet the tools for prediction have substantially changed over time, from ancient Greek philosophical reasoning to non-scientific medieval methods such as soothsaying, towards modern scientific discourse, which has come to include hypothesis testing, theory development and computer modelling underpinned by statistical and physical relationships, that is, laws 1 . A success story in the geosciences is weather prediction, which has greatly improved through the integration of better theory, increased computational power, and established observational systems, which allow for the assimilation of large amounts of data into the modelling system 2 . Nevertheless, we can accurately predict the evolution of the weather on a timescale of days, not months. Seasonal meteorological predictions, forecasting extreme events such as flooding or fire, and long-term climate projections are still major challenges. This is especially true for predicting dynamics in the biosphere, which is dominated by biologically mediated processes such as growth or reproduction, and is strongly controlled by seemingly stochastic disturbances such as fires and landslides. Such predictive problems have not seen much progress in the past few decades 3 . At the same time, a deluge of Earth system data has become available, with storage volumes already well beyond dozens of petabytes and rapidly increasing transmission rates exceeding hundreds of terabytes per day 4 . These data come from a plethora of sensors measuring states, fluxes and intensive or time/space-integrated variables, representing fifteen or more orders of temporal and spatial magnitude. They include remote sensing from a few metres to hundreds of kilometres above Earth as well as in situ observations (increasingly from autonomous sensors) at and below the surface and in the atmosphere, many of which are further being complemented by citizen science observations. Model simulation output adds to this deluge; the CMIP-5 dataset of the Climate Model Intercomparison Project, used extensively for scientific groundwork towards periodic climate assessments, is over 3 petabytes in size, and the next generation, CMIP-6, is estimated to reach up to 30 petabytes 5 . The data from models share many of the challenges and statistical properties of observational data, including many forms of uncertainty. In summary, Earth system data are exemplary of all four of the ‘four Vs’ of ‘big data’: volume, velocity, variety and veracity (see Fig. 1 ). One key challenge is to extract interpretable information and knowledge from this big data, possibly almost in real time and integrating between disciplines. Fig. 1: Big data challenges in the geoscientific context. Data size now exceeds 100 petabytes, and is growing quasi-exponentially (tapering of the figure to the right indicates decreasing data size.) The speed of change exceeds 5 petabytes a year; data are taken at frequencies of up to 10 Hz or more; reprocessing and versioning are common challenges. Data sources can be one- to four-dimensional, spatially integrated, from the organ level (such as leaves) to the global level. Earth has diverse observational systems, from remote sensing to in situ observation. The uncertainty of data can stem from observational errors or conceptual inconsistencies. Full size image Taken together, our ability to collect and create data far outpaces our ability to sensibly assimilate it, let alone understand it. Predictive ability in the last few decades has not increased apace with data availability. To get the most out of the explosive growth and diversity of Earth system data, we face two major tasks in the coming years: (1) extracting knowledge from the data deluge, and (2) deriving models that learn much more from data than traditional data assimilation approaches can, while still respecting our evolving understanding of nature’s laws. The combination of unprecedented data sources, increased computational power, and the recent advances in statistical modelling and machine learning offer exciting new opportunities for expanding our knowledge about the Earth system from data. In particular, many tools are available from the fields of machine learning and artificial intelligence, but they need to be further developed and adapted to geo-scientific analysis. Earth system science offers new opportunities, challenges and methodological demands, in particular for recent research lines focusing on spatio-temporal context and uncertainties (Box 1 ; see and for more complete glossaries). In the following sections we review the development of machine learning in the geoscientific context, and highlight how deep learning—that is, the automatic extraction of abstract (spatio-temporal) features—has the potential to overcome many of the limitations that have, until now, hindered a more wide-spread adoption of machine learning. We further lay out the most promising but also challenging approaches in combining machine learning with physical modelling. Box 1 Definition of terms Table 1 Full size table Show more State-of-the-art geoscientific machine learning Machine learning is now a successful part of several research-driven and operational geoscientific processing schemes, addressing the atmosphere, the land surface and the ocean, and has co-evolved with data availability over the past decade. Early landmarks in classification of land cover and clouds emerged almost 30 years ago through the coincidence of high-resolution satellite data and the first revival of neural networks 6 , 7 . Most major machine learning methodological development (for example, kernel methods or ‘random forests’) has subsequently been applied to geoscience and remote sensing<|im_end|> <|im_start|>assistant A study by German scientists from Jena and Hamburg, published today in the journal Nature, shows that artificial intelligence (AI) can substantially improve our understanding of the climate and the Earth system. Especially the potential of deep learning has only partially been exhausted so far. In particular, complex dynamic processes such as hurricanes, fire propagation, and vegetation dynamics can be better described with the help of AI. As a result, climate and Earth system models will be improved, with new models combining artificial intelligence and physical modeling. In the past decades mainly static attributes have been investigated using machine learning approaches, such as the distribution of soil properties from the local to the global scale. For some time now, it has been possible to tackle more dynamic processes by using more sophisticated deep learning techniques. This allows for example to quantify the global photosynthesis on land with simultaneous consideration of seasonal and short term variations. Deducing underlying laws from observation data "From a plethora of sensors, a deluge of Earth system data has become available, but so far we've been lagging behind in analysis and interpretation," explains Markus Reichstein, managing director of the Max Planck Institute for Biogeochemistry in Jena, directory board member of the Michael-Stifel-Center Jena (MSCJ) and first author of the publication. "This is where deep learning techniques become a promising tool, beyond the classical machine learning applications such as image recognition, natural language processing or AlphaGo," adds co-author Joachim Denzler from the Computer Vision Group of the Friedrich Schiller University Jena (FSU) and member of MSCJ. Examples for application are extreme events such as fire spreads or hurricanes, which are very complex processes influenced by local conditions but also by their temporal and spatial context. This also applies to atmospheric and ocean transport, soil movement, and vegetation dynamics, some of the classic topics of Earth system science. Artificial intelligence to improve climate and Earth system models However, deep learning approaches are difficult. All data-driven and statistical approaches do not guarantee physical consistency per se, are highly dependent on data quality, and may experience difficulties with extrapolations. Besides, the requirement for data processing and storage capacity is very high. The publication discusses all these requirements and obstacles and develops a strategy to efficiently combine machine learning with physical modeling. If both techniques are brought together, so-called hybrid models are created. They can for example be used for modeling the motion of ocean water to predict sea surface temperature. While the temperatures are modelled physically, the ocean water movement is represented by a machine learning approach. "The idea is to combine the best of two worlds, the consistency of physical models with the versatility of machine learning, to obtain greatly improved models," Markus Reichstein further explains. The scientists contend that detection and early warning of extreme events as well as seasonal and long-term prediction and projection of weather and climate will strongly benefit from the discussed deep-learning and hybrid modelling approaches. <|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 Bulk matrix stiffness has emerged as a key mechanical cue in stem cell differentiation. Here, we show that the commitment and differentiation of human mesenchymal stem cells encapsulated in physiologically soft ( ∼ 0.2–0.4 kPa), fully synthetic polyisocyanopeptide-based three-dimensional (3D) matrices that mimic the stiffness of adult stem cell niches and show biopolymer-like stress stiffening, can be readily switched from adipogenesis to osteogenesis by changing only the onset of stress stiffening. This mechanical behaviour can be tuned by simply altering the material’s polymer length whilst maintaining stiffness and ligand density. Our findings introduce stress stiffening as an important parameter that governs stem cell fate in a 3D microenvironment, and reveal a correlation between the onset of stiffening and the expression of the microtubule-associated protein DCAMKL1, thus implicating DCAMKL1 in a stress-stiffening-mediated, mechanotransduction pathway that involves microtubule dynamics in stem cell osteogenesis. Main Cellular interactions with the extracellular matrix (ECM) mediate important cell functions such as survival, proliferation, migration and differentiation 1 , 2 , 3 , 4 , 5 . The extracellular stimuli include soluble and adhesive ligands that provide chemical and mechanical cues which have been shown to govern cell physiology 1 . It has recently been demonstrated that physical cues from the matrix, especially the matrix stiffness and topography, can initiate intracellular biochemical signals through mechanotransduction and thus dictate the cell differentiation pathways 6 , 7 , 8 . Understanding the role of these microenvironmental physical cues has profound implications for realizing the full therapeutic potential of stem cell research in tissue engineering applications 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Three classical cell culture systems have been widely utilized to underpin the effect of the extracellular matrix mechanical properties on stem cell fate. First, natural ECM-protein-derived hydrogels prepared at different densities have been shown to significantly influence cell adhesion, cell shape and various cell functions 18 . However, changing density of these proteins not only changes the gel stiffness, but also alters the surface ligand concentration. Thus, in this type of culture systems, it is difficult to de-couple and interpret the effect of the matrix stiffness and ligand density on cellular response. The second class of culture systems employs synthetic polymer gels as ECM mimetic scaffolds for stem cell fate control 17 , 19 , 20 . In this case, the gel stiffness can be modulated by altering the amount of a crosslinker; however, the porosity and the polymer surface chemistry also change as a function of the crosslinker amount 21 , 22 . Thus, the stem cells are likely to interpret the combined effect of these parameters for their fate control, although it has recently been suggested that substrate porosity in 2D cell culture condition does not affect stem cell fate 23 . A third class of culture systems has been recently introduced, which is based on elastomeric micropost arrays, where different post heights are interpreted as different rigidities by the cells 16 . This system thus provides an approach to de-couple the effect of the substrate stiffness from alterations in the surface chemical properties. However, the micropost diameter dictates a focal adhesion limiting size, which restricts the focal contact maturation. In addition, the 2D nature of the micropost culture system limits its further applications to mimic a 3D physiological condition. We present a new class of cell culture systems based on fully synthetic biomimetic physically crosslinked soft ( ∼ 0.2–0.4 kPa) hydrogels derived from helical oligo(ethylene)glycol polyisocyanopeptides (PICs; ref. 24 ). We demonstrate the application of this novel 3D matrix for the study of stem cell functions. These soft thermoresponsive hydrogels are formed at extremely low polymer concentrations (99.95% water) and possess pore sizes of nanometre dimension ( ∼ 100–150 nm; ref. 25 ). Their mechanical properties are similar to those of gels prepared from filamentous biopolymers, such as microtubules, F-actin, fibrin and collagen, and exhibit nonlinear stress response beyond a critical stress σ C (stress stiffening) 25 . Thus, when the stress is increased beyond this value, the matrices become stiffer with increasing applied stress. Janmey et al. demonstrated that different types of cells, for example, fibroblasts and human mesenchymal stem cells (hMSCs), adopt a stretched morphology when cultured on soft fibrin gels (2D substrates), suggesting that the cells can deform these gels, allowing access to the high strain moduli in the strain stiffening regime 26 . It is important to note that the onset of stiffening for the ECM proteins occurs at extremely small applied stresses. Our synthetic PIC hydrogels show stress stiffening in the biologically relevant stress regime, as demonstrated in Fig. 1 , which has been constructed by adapting data from literature 27 and overlaying the data for the PIC gel obtained in the present work. It was therefore of interest to investigate how this biologically relevant parameter influences 3D stem cell differentiation as part of the mechanisms underlying the physiology of adult stem cell niches. Figure 1: Differential modulus, K ’, as a function of stress, σ , for intracellular and extracellular filamentous biopolymer gels that show stress stiffening. For comparison, the rheology data for a representative synthetic gel (polyacrylamide) and the biomimetic stress-stiffening polyisocyanopeptide hydrogel are included. G o indicates the equilibrium bulk stiffness and σ C denotes the critical stress for the onset of stress stiffening of the polymer gel. Full size image Here we show that for hMSCs encapsulated in these biomimetic gels (functionalized with cell-adhesive GRGDS peptides), preferential osteogenesis over adipogenesis can be induced in an extremely soft microenvironment by increasing the polymer length, thereby increasing σ C , without altering the bulk gel stiffness and ligand density of the matrix. Thus, this fully synthetic culture system presents a model to study the effect of this physiologically important parameter (stress stiffening) on cells encapsulated in a 3D microenvironment. We also demonstrate that stress-stiffening sensing implicates the microtubule-associated protein DCAMKL1 in the mechanotransduction pathway, suggesting a role of microtubule dynamics in hMSCs fate control. Synthesis", "role": "user" }, { "content": "(Phys.org)—Several properties of the extracellular matrix affect cellular interaction, including stem cell differentiation. Some of these are physical properties, such as topography and matrix stiffness. In an effort to investigate these physical properties, Rajat K. Das, Veronika Gocheva, Roel Hammink, Omar F. Zouani, and Alan E. Rowan from Radbound University in The Netherlands, and the company Histide in Switzerland designed a model 3D hydrogel polymer system that demonstrates how stress-stiffening in the extracellular matrix causes human mesenchymal stem cells to favor osteogenesis over adipogenesis. Using their new model system, they determined that the expression of DCAMKL1, a microtubule associated protein, is decreasing when stress-stiffness is higher, demonstrating a novel pathway in which microtubule dynamics affects cell fate. Their work appears in Nature Materials. The extracellular matrix (ECM) plays an important role in controlling what happens within a cell by way of physical properties like stiffness and topography. This type of interaction in which mechanical properties lead to a series of biochemical activity is known as mechanotransduction. One are of interest is how ECM stress-stiffness influences stem cell differentiation. In order to study the mechanism behind stiffness-induced cell differentiation, researchers have tried to mimic the ECM environment. Prior studies employed several different systems to do this, including ECM-protein-derived hydrogels, synthetic polymers, and elastomeric mircopost arrays. Each of these has its strengths and weakness in how well it replicates the ECM. Das, et al. have designed a new type of cell culture system to mimic a three-dimensional ECM. They developed a thermoresponsive hydrogel from oligo(ethylene)glycol polyisocyanopeptides (PICs) that they can use to study the effects of stress-stiffening on human mesenchymal stem cells (hMSCs) in a three-dimensional setting by changing the length of the ethylene glycol portion of the polymer. After making their synthetic polymers, they were functionalized with known stem cell adhesives. Analysis of the polymers showed that all of the polymers were soft and exhibited similar stiffness with critical stress measurements falling within a biologically relevant range. Additionally, critical stress was found to increase linearly as a function of polymer chain length. Das, et al. then used their hydrogel polymers to investigate how stress-stiffening affected hMSC differentiation. Cells were cultured in a 3D matrix of the hydrogel surrounding the hMSCs. Markers for differentiation appeared after 96 hours. The cultures were tested for markers for osteogenesis and adipogenesis. Das, et al. found that cells cultured in the gel with the lowest critical stress demonstrated adipogenesis, while cells cultured in higher critical stress progressively favored osteogenesis over adipogenesis. Additional studies using RGD-modified polymers in the presence of antibodies showed that ligand interactions played an important role in mediating how stress-stiffening informs differentiation. Das, et al. suspected that microtubule dynamics likely plays a role in stem cell fate based on the results of treating their cells with cytochalasin D, actin polymerization inhibitor, and Taxol, a microtubule stabilizing agent. They decided to investigate how exactly microtubule dynamics is at work in this system by looking at the role of DCAMKL1 and RUNX2 in stress-stiffening and hMSC cell fate. DCAMKL1 is a known microtubule-associated protein and represses RUNX2. RUNX2 is an early osteogenesis marker. They found that DCAMKL1 expression was lowest in the longest polymers, those with highest critical stress, and its expression increased in gels with lower critical stress. Additionally, RUNX2 expression was not observed in low critical stress polymers, but was in the higher ones. Analysis confirmed a switch-like relationship between DCAMKL1 and RUNX2 and correlates to hMSCs' preference for osteogenesis in the presence of higher stress-stiffening. The authors report that this is the first time DCAMKL1, a microtubule-associated protein, has been shown to be involved in stress-stiffening-mediated mechanotransduction pathway and demonstrates how microtubule dynamics is involved in hMSC cell fate. This study provides a new three-dimensional hydrogel for investigating stress-stiffening, and using this new hydrogel, Das, et al. were able to identify a new mechanotransduction pathway that controls hMSC differentiation that is distinctly different from two-dimensional systems. ", "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 Bulk matrix stiffness has emerged as a key mechanical cue in stem cell differentiation. Here, we show that the commitment and differentiation of human mesenchymal stem cells encapsulated in physiologically soft ( ∼ 0.2–0.4 kPa), fully synthetic polyisocyanopeptide-based three-dimensional (3D) matrices that mimic the stiffness of adult stem cell niches and show biopolymer-like stress stiffening, can be readily switched from adipogenesis to osteogenesis by changing only the onset of stress stiffening. This mechanical behaviour can be tuned by simply altering the material’s polymer length whilst maintaining stiffness and ligand density. Our findings introduce stress stiffening as an important parameter that governs stem cell fate in a 3D microenvironment, and reveal a correlation between the onset of stiffening and the expression of the microtubule-associated protein DCAMKL1, thus implicating DCAMKL1 in a stress-stiffening-mediated, mechanotransduction pathway that involves microtubule dynamics in stem cell osteogenesis. Main Cellular interactions with the extracellular matrix (ECM) mediate important cell functions such as survival, proliferation, migration and differentiation 1 , 2 , 3 , 4 , 5 . The extracellular stimuli include soluble and adhesive ligands that provide chemical and mechanical cues which have been shown to govern cell physiology 1 . It has recently been demonstrated that physical cues from the matrix, especially the matrix stiffness and topography, can initiate intracellular biochemical signals through mechanotransduction and thus dictate the cell differentiation pathways 6 , 7 , 8 . Understanding the role of these microenvironmental physical cues has profound implications for realizing the full therapeutic potential of stem cell research in tissue engineering applications 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Three classical cell culture systems have been widely utilized to underpin the effect of the extracellular matrix mechanical properties on stem cell fate. First, natural ECM-protein-derived hydrogels prepared at different densities have been shown to significantly influence cell adhesion, cell shape and various cell functions 18 . However, changing density of these proteins not only changes the gel stiffness, but also alters the surface ligand concentration. Thus, in this type of culture systems, it is difficult to de-couple and interpret the effect of the matrix stiffness and ligand density on cellular response. The second class of culture systems employs synthetic polymer gels as ECM mimetic scaffolds for stem cell fate control 17 , 19 , 20 . In this case, the gel stiffness can be modulated by altering the amount of a crosslinker; however, the porosity and the polymer surface chemistry also change as a function of the crosslinker amount 21 , 22 . Thus, the stem cells are likely to interpret the combined effect of these parameters for their fate control, although it has recently been suggested that substrate porosity in 2D cell culture condition does not affect stem cell fate 23 . A third class of culture systems has been recently introduced, which is based on elastomeric micropost arrays, where different post heights are interpreted as different rigidities by the cells 16 . This system thus provides an approach to de-couple the effect of the substrate stiffness from alterations in the surface chemical properties. However, the micropost diameter dictates a focal adhesion limiting size, which restricts the focal contact maturation. In addition, the 2D nature of the micropost culture system limits its further applications to mimic a 3D physiological condition. We present a new class of cell culture systems based on fully synthetic biomimetic physically crosslinked soft ( ∼ 0.2–0.4 kPa) hydrogels derived from helical oligo(ethylene)glycol polyisocyanopeptides (PICs; ref. 24 ). We demonstrate the application of this novel 3D matrix for the study of stem cell functions. These soft thermoresponsive hydrogels are formed at extremely low polymer concentrations (99.95% water) and possess pore sizes of nanometre dimension ( ∼ 100–150 nm; ref. 25 ). Their mechanical properties are similar to those of gels prepared from filamentous biopolymers, such as microtubules, F-actin, fibrin and collagen, and exhibit nonlinear stress response beyond a critical stress σ C (stress stiffening) 25 . Thus, when the stress is increased beyond this value, the matrices become stiffer with increasing applied stress. Janmey et al. demonstrated that different types of cells, for example, fibroblasts and human mesenchymal stem cells (hMSCs), adopt a stretched morphology when cultured on soft fibrin gels (2D substrates), suggesting that the cells can deform these gels, allowing access to the high strain moduli in the strain stiffening regime 26 . It is important to note that the onset of stiffening for the ECM proteins occurs at extremely small applied stresses. Our synthetic PIC hydrogels show stress stiffening in the biologically relevant stress regime, as demonstrated in Fig. 1 , which has been constructed by adapting data from literature 27 and overlaying the data for the PIC gel obtained in the present work. It was therefore of interest to investigate how this biologically relevant parameter influences 3D stem cell differentiation as part of the mechanisms underlying the physiology of adult stem cell niches. Figure 1: Differential modulus, K ’, as a function of stress, σ , for intracellular and extracellular filamentous biopolymer gels that show stress stiffening. For comparison, the rheology data for a representative synthetic gel (polyacrylamide) and the biomimetic stress-stiffening polyisocyanopeptide hydrogel are included. G o indicates the equilibrium bulk stiffness and σ C denotes the critical stress for the onset of stress stiffening of the polymer gel. Full size image Here we show that for hMSCs encapsulated in these biomimetic gels (functionalized with cell-adhesive GRGDS peptides), preferential osteogenesis over adipogenesis can be induced in an extremely soft microenvironment by increasing the polymer length, thereby increasing σ C , without altering the bulk gel stiffness and ligand density of the matrix. Thus, this fully synthetic culture system presents a model to study the effect of this physiologically important parameter (stress stiffening) on cells encapsulated in a 3D microenvironment. We also demonstrate that stress-stiffening sensing implicates the microtubule-associated protein DCAMKL1 in the mechanotransduction pathway, suggesting a role of microtubule dynamics in hMSCs fate control. Synthesis<|im_end|> <|im_start|>assistant (Phys.org)—Several properties of the extracellular matrix affect cellular interaction, including stem cell differentiation. Some of these are physical properties, such as topography and matrix stiffness. In an effort to investigate these physical properties, Rajat K. Das, Veronika Gocheva, Roel Hammink, Omar F. Zouani, and Alan E. Rowan from Radbound University in The Netherlands, and the company Histide in Switzerland designed a model 3D hydrogel polymer system that demonstrates how stress-stiffening in the extracellular matrix causes human mesenchymal stem cells to favor osteogenesis over adipogenesis. Using their new model system, they determined that the expression of DCAMKL1, a microtubule associated protein, is decreasing when stress-stiffness is higher, demonstrating a novel pathway in which microtubule dynamics affects cell fate. Their work appears in Nature Materials. The extracellular matrix (ECM) plays an important role in controlling what happens within a cell by way of physical properties like stiffness and topography. This type of interaction in which mechanical properties lead to a series of biochemical activity is known as mechanotransduction. One are of interest is how ECM stress-stiffness influences stem cell differentiation. In order to study the mechanism behind stiffness-induced cell differentiation, researchers have tried to mimic the ECM environment. Prior studies employed several different systems to do this, including ECM-protein-derived hydrogels, synthetic polymers, and elastomeric mircopost arrays. Each of these has its strengths and weakness in how well it replicates the ECM. Das, et al. have designed a new type of cell culture system to mimic a three-dimensional ECM. They developed a thermoresponsive hydrogel from oligo(ethylene)glycol polyisocyanopeptides (PICs) that they can use to study the effects of stress-stiffening on human mesenchymal stem cells (hMSCs) in a three-dimensional setting by changing the length of the ethylene glycol portion of the polymer. After making their synthetic polymers, they were functionalized with known stem cell adhesives. Analysis of the polymers showed that all of the polymers were soft and exhibited similar stiffness with critical stress measurements falling within a biologically relevant range. Additionally, critical stress was found to increase linearly as a function of polymer chain length. Das, et al. then used their hydrogel polymers to investigate how stress-stiffening affected hMSC differentiation. Cells were cultured in a 3D matrix of the hydrogel surrounding the hMSCs. Markers for differentiation appeared after 96 hours. The cultures were tested for markers for osteogenesis and adipogenesis. Das, et al. found that cells cultured in the gel with the lowest critical stress demonstrated adipogenesis, while cells cultured in higher critical stress progressively favored osteogenesis over adipogenesis. Additional studies using RGD-modified polymers in the presence of antibodies showed that ligand interactions played an important role in mediating how stress-stiffening informs differentiation. Das, et al. suspected that microtubule dynamics likely plays a role in stem cell fate based on the results of treating their cells with cytochalasin D, actin polymerization inhibitor, and Taxol, a microtubule stabilizing agent. They decided to investigate how exactly microtubule dynamics is at work in this system by looking at the role of DCAMKL1 and RUNX2 in stress-stiffening and hMSC cell fate. DCAMKL1 is a known microtubule-associated protein and represses RUNX2. RUNX2 is an early osteogenesis marker. They found that DCAMKL1 expression was lowest in the longest polymers, those with highest critical stress, and its expression increased in gels with lower critical stress. Additionally, RUNX2 expression was not observed in low critical stress polymers, but was in the higher ones. Analysis confirmed a switch-like relationship between DCAMKL1 and RUNX2 and correlates to hMSCs' preference for osteogenesis in the presence of higher stress-stiffening. The authors report that this is the first time DCAMKL1, a microtubule-associated protein, has been shown to be involved in stress-stiffening-mediated mechanotransduction pathway and demonstrates how microtubule dynamics is involved in hMSC cell fate. This study provides a new three-dimensional hydrogel for investigating stress-stiffening, and using this new hydrogel, Das, et al. were able to identify a new mechanotransduction pathway that controls hMSC differentiation that is distinctly different from two-dimensional systems. <|im_end|>

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2,378

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract To elucidate the genetic bases of mycorrhizal lifestyle evolution, we sequenced new fungal genomes, including 13 ectomycorrhizal (ECM), orchid (ORM) and ericoid (ERM) species, and five saprotrophs, which we analyzed along with other fungal genomes. Ectomycorrhizal fungi have a reduced complement of genes encoding plant cell wall–degrading enzymes (PCWDEs), as compared to their ancestral wood decayers. Nevertheless, they have retained a unique array of PCWDEs, thus suggesting that they possess diverse abilities to decompose lignocellulose. Similar functional categories of nonorthologous genes are induced in symbiosis. Of induced genes, 7–38% are orphan genes, including genes that encode secreted effector-like proteins. Convergent evolution of the mycorrhizal habit in fungi occurred via the repeated evolution of a 'symbiosis toolkit', with reduced numbers of PCWDEs and lineage-specific suites of mycorrhiza-induced genes. Main Fungi are often described as either saprotrophs, which degrade complex organic substrates, or biotrophs, which obtain carbon compounds from living hosts. Among the latter, ECM fungi provide crucial ecological services in interacting with forest trees. They are portrayed as mutualists trading host photoassimilates for nutrients and having limited capacity to decompose soil lignocellulose 1 , 2 , 3 , as a result of their reduced repertoire of PCWDEs 4 , 5 , 6 . However, recent studies are challenging this view 7 , 8 , 9 , 10 . An improved understanding of the ability of ECM fungi to decompose lignocellulose is needed to resolve mechanisms of nutrient cycling in forests. The ECM lifestyle in Laccaria bicolor is associated with the expression of new mycorrhiza-induced small secreted proteins (MiSSPs) that are required for establishment of symbiosis 11 , 12 . Mycorrhizal symbioses have arisen repeatedly during fungal evolution and include not only ECM associations but also those with ERM and ORM mycorrhizae 13 . It is not known whether these symbioses share the genomic features found in L. bicolor 4 and Tuber melanosporum 5 . Here we assess whether there are general evolutionary and functional properties of mycorrhizal Basidiomycota and Ascomycota, using comparative analysis of 18 newly sequenced genomes ( Supplementary Tables 1 and 2 ), including 13 from ECM, ERM and ORM fungal symbionts. Genomes of mycorrhizal fungi range in size from approximately 38 to 125 Mb, and their predicted gene contents range from approximately 15,000 to 23,000 genes ( Supplementary Tables 3 and 4 ). We combined the 18 new genomes with 31 others and performed phylogenomic analyses ( Supplementary Note , Supplementary Tables 1 and 5–10 and Supplementary Figs. 1–23 ). An organismal phylogeny resolved six to eight independent lineages of ECM and two lineages of ORM symbionts in Agaricomycetes as well as two mycorrhizal lineages in Ascomycota ( Fig. 1 ). Molecular-clock analyses have suggested that the Pezizomycotina and Agaricomycetes are approximately 400 and 300 million years old, respectively. In contrast, the Pinaceae (which may be the oldest ECM hosts), rosids and orchids are of Jurassic or Cretaceous origin ( ∼ 100 million years ago), according to fossil and molecular-clock evidence; this is consistent with the view that ECM and other mycorrhizal associations have evolved repeatedly across Dikarya 14 . Figure 1: Evolution of mycorrhizal symbiosis inferred from 49 fungal genomes. The tree is a chronogram estimated with r8s on the basis of a maximum-likelihood phylogeny inferred with RAxML. Nodes receiving less than maximal support in all analyses are indicated with asterisks. Curved arrows indicate alternate placements for Ustilaginomycotina and Auriculariales ( Supplementary Fig. 2 ). Mean ages (ma) are indicated adjacent to selected nodes. Circles indicate observed (right of tree) and reconstructed (left) copy numbers for selected genes encoding enzymes involved in decay of lignin (POD and GLX; blue circles) or crystalline cellulose (GH6, GH7 and LPMO; beige circles). Absence of gene copies is indicated with 'x'. Areas of circles are proportional to gene copy numbers. (Copy numbers are indicated for internal nodes; gene counts in terminal taxa are shown in Supplementary Table 9 .) Selected clades are labeled at internal nodes; 'st.' indicates the stem node for a taxon. Shading of terminal taxon names indicates nutritional modes (as shown in the key). Solid red triangles, estimated origins of ECM or ERM and ORM mycorrhizal symbioses; unfilled red triangle, alternate reconstruction with a single origin of ECM in Boletales and at least one reversal to saprotrophy; colored triangles below the geological timescale, ages of major ECM hosts based on fossils (solid triangles) and molecular-clock estimates (unfilled triangles); light-gray shading, temporal period when the origins of ECM are most plausible. Orch/eric/endomyc, orchid, ericoid or endomycorrhizae; litter/soil/other, litter, soil or other saprotroph; Cryog., Cryogenian; Ediac., Ediacaran; Cam., Cambrian; Ord., Ordovician; Sil., Silurian; Dev., Devonian; Carb., Carboniferous; Per., Permian; Tri., Triassic; Jur., Jurassic; Cret., Cretaceous; Cen., Cenozoic. Abbreviations for taxon names are defined in Supplementary Note . Full size image The first three sequenced mycorrhizal genomes, i.e., the ECM L. bicolor and T. melanosporum 4 , 5 and the arbuscular mycorrhizal fungus Rhizophagus irregularis 15 , demonstrated substantial losses in PCWDE genes. To assess the diversity of lignocellulose-decay capabilities of other mycorrhizal lineages, we cataloged 28 gene families and subfamilies encoding oxidoreductases and carbohydrate-active enzymes (CAZymes) associated with plant cell wall degradation ( Fig. 2 , Supplementary Note , Supplementary Tables 7 , 8 , 9 , 10 and Supplementary Fig. 3 ). Among Agaricomycetes, saprotrophs (including white-rot decayers, which can degrade lignin as well as cellulose), Botryobasidium botryosum , Jaapia argillacea and soil and litter saprotrophs possess on average 133 gene copies across all PCWDE families, whereas brown-rot species (which lack the ability to degrade lignin) possess 81 gene copies, and ECM species maintain 62 gene copies, on average. Thus, the evolution of ECM parallels that of brown-rot lineages, with both guilds having lost much of the plesiomorphic enzymatic apparatus of white rots ( Supplementary Note ). Figure 2: Summary of lignocellulose-degrading oxidoreductases, carbohydrate-active enzymes (CAZymes) and cellulose-binding modules in 49 fungal genomes. Relative abundance of genes is represented by a color scale, from the minimum (blue) to maximum (red) number of copies per species (excluding Sphaerobolus stellatus", "role": "user" }, { "content": "With apologies to the poet John Donne, and based on recent work from the U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science user facility, it can be said that no plant is an island, entire of itself. Unseen by the human eye, plants interact with many species of fungi and other microbes in the surrounding environment, and these exchanges can impact the plant's health and tolerance to stressors such as drought or disease, as well as the global carbon cycle. Mycorrhizal fungi live in the roots of host plants, where they exchange sugars that plants produce by photosynthesis for mineral nutrients that fungi absorb from the soil. They include some of the most conspicuous forest mushrooms, including the iconic, flaming red \"fly agaric,\" Amanita muscaria, and are of interest to bioenergy researchers, because they play roles in maintaining the health of candidate feedstock crop trees. Recent studies indicate that mycorrhizal fungi also play a significant role in belowground carbon sequestration, which may mitigate the effects of anthropogenic CO2 emissions. To understand the basis for fungal symbiotic relationships with plants, a team of DOE JGI researchers led by Igor Grigoriev and longtime collaborators at the French National Institute for Agricultural Research (INRA) and Clark University conducted the first broad, comparative phylogenomic analysis of mycorrhizal fungi, drawing on 49 fungal genomes, 18 of which were sequenced for this study. The 18 new fungal sequences included 13 mycorrhizal genomes, from ectomycorrhizal fungi that penetrate the host roots, and including species that comingle with orchid and heathland (which include blueberry, heather, and heath) plant roots. In the February 23, 2015 online edition of Nature Genetics, these researchers describe how the comparative analyses of these genomes allowed them to track the evolution of mycorrhizal fungi. The results help researchers understand how plants and fungi developed symbiotic relationships, and how the mutualistic association provides host plants with beneficial traits for environmental adaptation. Starting with previously sequenced mycorrhizal fungi \"Mycorrhizal symbioses are highly complex, but analyses of the 49 genomes indicate that they have evolved independently in many fungal lineages,\" said INRA's Francis Martin, one of the study's senior authors. To understand the genetic shifts underlying the repeated origins of mycorrhizal lifestyles, the researchers focused on enzymes that degrade plant cell walls from 16 gene families associated with plant cell wall degradation. They took their cue from the first sequenced ectomycorrhizal fungus, Laccaria bicolor and the first sequenced arbuscular mycorrhizal fungus Rhizophagus irregularis- all work done at the DOE JGI-which illuminates the origins and evolution of these enzymes, knowledge to be applied in collaboration for improving biomass breakdown for biofuels production. Through molecular clock analyses, which combine genome-scale molecular data with fossil calibrations, the team could work backwards to estimate when saprotrophic and mutualistic lineages last shared common ancestors based on the amount of divergence. The analyses of the fungal genomes and fossils suggested that in comparison to brown rot fungi and white rot fungi that evolved over 300 million years ago, ectomycorrhizal fungi emerged fairly recently from several species and then spread out across lineages less than 200 million years ago. The team also found that up to 40 percent of the symbiosis-induced genes were restricted to a single mycorrhizal species. Fungi evolving to break down plant cell walls David Hibbett of Clark University, another of the study's senior authors, compared the work to a previous collaboration with the DOE JGI detailed in Science to trace the evolution of white rot fungi, which are capable of breaking down cellulose, hemicellulose and lignin in plants. Prior to the emergence of white rot fungi hundreds of millions of years ago, fungi were not capable of breaking down lignin, and the undecayed plant mass became the basis of large coal deposits. \"Together these studies tell a story about how mushroom-forming fungi evolved a complex mechanism for breakdown of plant cell walls in 'white rot' and then cast it aside following the evolution of mycorrhizal associations, as well as the alternative decay mechanism of 'brown rot,'\" Hibbett said. \"The other major part of the story is that in mycorrhizal lineages there is a huge turnover in genes that are upregulated in the symbiosis-many of these have no homologs in even closely related species, suggesting that the evolution of the symbiosis is associated with massive genetic innovation.\" Martin chimed in: \"Many of these genes are likely used to control plant immunity during the massive colonization of root tissues by the fungus.\" DOE JGI's Igor Grigoriev also pointed out, \"This first large-scale study of mycorrhizal genomics is also the first step in both broader and deeper exploration of mycorrhizal diversity, their interactions with host plans, and roles in forest ecosystems using genomics tools, which are the focus areas for the JGI Fungal Genomics Program.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract To elucidate the genetic bases of mycorrhizal lifestyle evolution, we sequenced new fungal genomes, including 13 ectomycorrhizal (ECM), orchid (ORM) and ericoid (ERM) species, and five saprotrophs, which we analyzed along with other fungal genomes. Ectomycorrhizal fungi have a reduced complement of genes encoding plant cell wall–degrading enzymes (PCWDEs), as compared to their ancestral wood decayers. Nevertheless, they have retained a unique array of PCWDEs, thus suggesting that they possess diverse abilities to decompose lignocellulose. Similar functional categories of nonorthologous genes are induced in symbiosis. Of induced genes, 7–38% are orphan genes, including genes that encode secreted effector-like proteins. Convergent evolution of the mycorrhizal habit in fungi occurred via the repeated evolution of a 'symbiosis toolkit', with reduced numbers of PCWDEs and lineage-specific suites of mycorrhiza-induced genes. Main Fungi are often described as either saprotrophs, which degrade complex organic substrates, or biotrophs, which obtain carbon compounds from living hosts. Among the latter, ECM fungi provide crucial ecological services in interacting with forest trees. They are portrayed as mutualists trading host photoassimilates for nutrients and having limited capacity to decompose soil lignocellulose 1 , 2 , 3 , as a result of their reduced repertoire of PCWDEs 4 , 5 , 6 . However, recent studies are challenging this view 7 , 8 , 9 , 10 . An improved understanding of the ability of ECM fungi to decompose lignocellulose is needed to resolve mechanisms of nutrient cycling in forests. The ECM lifestyle in Laccaria bicolor is associated with the expression of new mycorrhiza-induced small secreted proteins (MiSSPs) that are required for establishment of symbiosis 11 , 12 . Mycorrhizal symbioses have arisen repeatedly during fungal evolution and include not only ECM associations but also those with ERM and ORM mycorrhizae 13 . It is not known whether these symbioses share the genomic features found in L. bicolor 4 and Tuber melanosporum 5 . Here we assess whether there are general evolutionary and functional properties of mycorrhizal Basidiomycota and Ascomycota, using comparative analysis of 18 newly sequenced genomes ( Supplementary Tables 1 and 2 ), including 13 from ECM, ERM and ORM fungal symbionts. Genomes of mycorrhizal fungi range in size from approximately 38 to 125 Mb, and their predicted gene contents range from approximately 15,000 to 23,000 genes ( Supplementary Tables 3 and 4 ). We combined the 18 new genomes with 31 others and performed phylogenomic analyses ( Supplementary Note , Supplementary Tables 1 and 5–10 and Supplementary Figs. 1–23 ). An organismal phylogeny resolved six to eight independent lineages of ECM and two lineages of ORM symbionts in Agaricomycetes as well as two mycorrhizal lineages in Ascomycota ( Fig. 1 ). Molecular-clock analyses have suggested that the Pezizomycotina and Agaricomycetes are approximately 400 and 300 million years old, respectively. In contrast, the Pinaceae (which may be the oldest ECM hosts), rosids and orchids are of Jurassic or Cretaceous origin ( ∼ 100 million years ago), according to fossil and molecular-clock evidence; this is consistent with the view that ECM and other mycorrhizal associations have evolved repeatedly across Dikarya 14 . Figure 1: Evolution of mycorrhizal symbiosis inferred from 49 fungal genomes. The tree is a chronogram estimated with r8s on the basis of a maximum-likelihood phylogeny inferred with RAxML. Nodes receiving less than maximal support in all analyses are indicated with asterisks. Curved arrows indicate alternate placements for Ustilaginomycotina and Auriculariales ( Supplementary Fig. 2 ). Mean ages (ma) are indicated adjacent to selected nodes. Circles indicate observed (right of tree) and reconstructed (left) copy numbers for selected genes encoding enzymes involved in decay of lignin (POD and GLX; blue circles) or crystalline cellulose (GH6, GH7 and LPMO; beige circles). Absence of gene copies is indicated with 'x'. Areas of circles are proportional to gene copy numbers. (Copy numbers are indicated for internal nodes; gene counts in terminal taxa are shown in Supplementary Table 9 .) Selected clades are labeled at internal nodes; 'st.' indicates the stem node for a taxon. Shading of terminal taxon names indicates nutritional modes (as shown in the key). Solid red triangles, estimated origins of ECM or ERM and ORM mycorrhizal symbioses; unfilled red triangle, alternate reconstruction with a single origin of ECM in Boletales and at least one reversal to saprotrophy; colored triangles below the geological timescale, ages of major ECM hosts based on fossils (solid triangles) and molecular-clock estimates (unfilled triangles); light-gray shading, temporal period when the origins of ECM are most plausible. Orch/eric/endomyc, orchid, ericoid or endomycorrhizae; litter/soil/other, litter, soil or other saprotroph; Cryog., Cryogenian; Ediac., Ediacaran; Cam., Cambrian; Ord., Ordovician; Sil., Silurian; Dev., Devonian; Carb., Carboniferous; Per., Permian; Tri., Triassic; Jur., Jurassic; Cret., Cretaceous; Cen., Cenozoic. Abbreviations for taxon names are defined in Supplementary Note . Full size image The first three sequenced mycorrhizal genomes, i.e., the ECM L. bicolor and T. melanosporum 4 , 5 and the arbuscular mycorrhizal fungus Rhizophagus irregularis 15 , demonstrated substantial losses in PCWDE genes. To assess the diversity of lignocellulose-decay capabilities of other mycorrhizal lineages, we cataloged 28 gene families and subfamilies encoding oxidoreductases and carbohydrate-active enzymes (CAZymes) associated with plant cell wall degradation ( Fig. 2 , Supplementary Note , Supplementary Tables 7 , 8 , 9 , 10 and Supplementary Fig. 3 ). Among Agaricomycetes, saprotrophs (including white-rot decayers, which can degrade lignin as well as cellulose), Botryobasidium botryosum , Jaapia argillacea and soil and litter saprotrophs possess on average 133 gene copies across all PCWDE families, whereas brown-rot species (which lack the ability to degrade lignin) possess 81 gene copies, and ECM species maintain 62 gene copies, on average. Thus, the evolution of ECM parallels that of brown-rot lineages, with both guilds having lost much of the plesiomorphic enzymatic apparatus of white rots ( Supplementary Note ). Figure 2: Summary of lignocellulose-degrading oxidoreductases, carbohydrate-active enzymes (CAZymes) and cellulose-binding modules in 49 fungal genomes. Relative abundance of genes is represented by a color scale, from the minimum (blue) to maximum (red) number of copies per species (excluding Sphaerobolus stellatus<|im_end|> <|im_start|>assistant With apologies to the poet John Donne, and based on recent work from the U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science user facility, it can be said that no plant is an island, entire of itself. Unseen by the human eye, plants interact with many species of fungi and other microbes in the surrounding environment, and these exchanges can impact the plant's health and tolerance to stressors such as drought or disease, as well as the global carbon cycle. Mycorrhizal fungi live in the roots of host plants, where they exchange sugars that plants produce by photosynthesis for mineral nutrients that fungi absorb from the soil. They include some of the most conspicuous forest mushrooms, including the iconic, flaming red "fly agaric," Amanita muscaria, and are of interest to bioenergy researchers, because they play roles in maintaining the health of candidate feedstock crop trees. Recent studies indicate that mycorrhizal fungi also play a significant role in belowground carbon sequestration, which may mitigate the effects of anthropogenic CO2 emissions. To understand the basis for fungal symbiotic relationships with plants, a team of DOE JGI researchers led by Igor Grigoriev and longtime collaborators at the French National Institute for Agricultural Research (INRA) and Clark University conducted the first broad, comparative phylogenomic analysis of mycorrhizal fungi, drawing on 49 fungal genomes, 18 of which were sequenced for this study. The 18 new fungal sequences included 13 mycorrhizal genomes, from ectomycorrhizal fungi that penetrate the host roots, and including species that comingle with orchid and heathland (which include blueberry, heather, and heath) plant roots. In the February 23, 2015 online edition of Nature Genetics, these researchers describe how the comparative analyses of these genomes allowed them to track the evolution of mycorrhizal fungi. The results help researchers understand how plants and fungi developed symbiotic relationships, and how the mutualistic association provides host plants with beneficial traits for environmental adaptation. Starting with previously sequenced mycorrhizal fungi "Mycorrhizal symbioses are highly complex, but analyses of the 49 genomes indicate that they have evolved independently in many fungal lineages," said INRA's Francis Martin, one of the study's senior authors. To understand the genetic shifts underlying the repeated origins of mycorrhizal lifestyles, the researchers focused on enzymes that degrade plant cell walls from 16 gene families associated with plant cell wall degradation. They took their cue from the first sequenced ectomycorrhizal fungus, Laccaria bicolor and the first sequenced arbuscular mycorrhizal fungus Rhizophagus irregularis- all work done at the DOE JGI-which illuminates the origins and evolution of these enzymes, knowledge to be applied in collaboration for improving biomass breakdown for biofuels production. Through molecular clock analyses, which combine genome-scale molecular data with fossil calibrations, the team could work backwards to estimate when saprotrophic and mutualistic lineages last shared common ancestors based on the amount of divergence. The analyses of the fungal genomes and fossils suggested that in comparison to brown rot fungi and white rot fungi that evolved over 300 million years ago, ectomycorrhizal fungi emerged fairly recently from several species and then spread out across lineages less than 200 million years ago. The team also found that up to 40 percent of the symbiosis-induced genes were restricted to a single mycorrhizal species. Fungi evolving to break down plant cell walls David Hibbett of Clark University, another of the study's senior authors, compared the work to a previous collaboration with the DOE JGI detailed in Science to trace the evolution of white rot fungi, which are capable of breaking down cellulose, hemicellulose and lignin in plants. Prior to the emergence of white rot fungi hundreds of millions of years ago, fungi were not capable of breaking down lignin, and the undecayed plant mass became the basis of large coal deposits. "Together these studies tell a story about how mushroom-forming fungi evolved a complex mechanism for breakdown of plant cell walls in 'white rot' and then cast it aside following the evolution of mycorrhizal associations, as well as the alternative decay mechanism of 'brown rot,'" Hibbett said. "The other major part of the story is that in mycorrhizal lineages there is a huge turnover in genes that are upregulated in the symbiosis-many of these have no homologs in even closely related species, suggesting that the evolution of the symbiosis is associated with massive genetic innovation." Martin chimed in: "Many of these genes are likely used to control plant immunity during the massive colonization of root tissues by the fungus." DOE JGI's Igor Grigoriev also pointed out, "This first large-scale study of mycorrhizal genomics is also the first step in both broader and deeper exploration of mycorrhizal diversity, their interactions with host plans, and roles in forest ecosystems using genomics tools, which are the focus areas for the JGI Fungal Genomics Program." <|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 supersolid is a counterintuitive phase of matter that combines the global phase coherence of a superfluid with a crystal-like self-modulation in space. Recently, such states have been experimentally realized using dipolar quantum gases. Here we investigate the response of a dipolar supersolid to an interaction quench that shatters the global phase coherence. We identify a parameter regime in which this out-of-equilibrium state rephases, indicating superfluid flow across the sample as well as an efficient dissipation mechanism. We find a crossover to a regime where the tendency to rephase gradually decreases until the system relaxes into an incoherent droplet array. Although a dipolar supersolid is, by its nature, ‘soft’, we capture the essential behaviour of the de- and rephasing process within a rigid Josephson junction array model. Yet, both experiment and simulation indicate that the interaction quench causes substantial collective mode excitations that connect to phonons in solids and affect the phase dynamics. Main The notion of phase coherence lies at the foundation of quantum physics. It is considered a key property in understanding many-body quantum phenomena, ranging from superfluidity and the Josephson effect to the more applied examples of matterwave interference, atom lasing processes and quantum transport in meso- and macroscopic systems 1 , 2 . Although phase-coherent states are well studied at equilibrium, understanding their out-of-equilibrium dynamics remains an open problem at the forefront of statistical and quantum physics, especially when interactions are present 3 . Rephasing dynamics of an initially incoherent many-body quantum system requires, first, the system to be conducting such that different parts can exchange energy and particles, and second, an efficient mechanism to dissipate the phase excitations. As for the first requirement, a famous example illustrating the inhibition of thermalization is many-body localization 4 . The second ingredient—dissipation—is more subtle and multifaceted, relating, for instance, to the growth of thermal correlations in isolated systems 5 , complex interaction-mediated dynamics 6 , 7 or the exponential growth of unstable modes and topological defects in connection with the Kibble–Zurek mechanism 8 , 9 , 10 . The interplay among coherence, self-localization and relaxation dynamics is an intriguing problem. In this respect, the recently discovered 11 , 12 , 13 supersolid states in dipolar quantum gases can potentially provide a new twist in studying non-equilibrium quantum phenomena, about which very little is known so far. A supersolid combines phase coherence and periodic localization in space, properties corresponding to the spontaneous and simultaneous breaking of both gauge and translational symmetry. Intuitively, a supersolid can be viewed as a fully coherent state, which self-establishes compressible density modulation. In this Article, we explore the evolution of a supersolid of ultracold dysprosium (Dy) atoms when brought out of equilibrium after an interaction quench that destroys its global phase coherence. Due to the dynamic formation of the supersolid, an interesting question is whether its phase dynamics are similar to or different from comparable rigid structures, such as a Bose–Einstein condensate (BEC) spliced in an optical lattice 14 , 15 , 16 , or if new phenomena can manifest. In a dipolar supersolid, the particle self-arrangement in space is largely dictated by the many-body interactions 17 , 18 , 19 , 20 , 21 , 22 and can be modified by either tuning the interatomic potentials or changing the atom number ( N ) in the system. Figure 1a shows the phase diagram of a cigar-shaped quantum gas of bosonic Dy atoms with transverse dipole orientation. It is constructed from the ground-state wavefunctions obtained by numerically solving the extended Gross–Pitaevskii equation (eGPE) 11 , 13 , 21 (Methods). Three distinct quantum phases can be accessed by changing N or the s -wave scattering length a s , which parametrizes the contact interaction. For a given N and large enough a s , the ground state of the system is a non-modulated dipolar BEC (grey region). By lowering a s , the influence of the dipolar interaction increases. When reaching a critical value of a s , the system undergoes a phase transition to a supersolid phase (SSP). Here density modulation at a wavelength close to the roton excitation 23 , 24 appears in the ground-state density profile (red region). By further lowering a s , the system evolves into an array of insulating droplets (IDs) with an exponentially vanishing density link between them (blue region). Fig. 1: Phase diagram, experimental sequence and starting condition. a , Ground-state phase diagram for our cigar-shaped trapped 164 Dy gas. The colour map encodes the density modulation via the link strength \${\\mathscr{L}}=1-({n}_{\\mathrm{max}}-{n}_{\\mathrm{min}})/({n}_{\\mathrm{max}}+{n}_{\\mathrm{min}})\$ , where n max ( n min ) is the density maximum (minimum) in the central region of the calculated in situ density distribution. \${\\mathscr{L}}\$ equals unity for a non-modulated state and zero for a fully modulated state. The grey colour indicates a non-modulated BEC, whereas the red and blue regions correspond to the SSP and ID phase, respectively. The insets show the density profiles along the weak axis for the different phases. b , Illustration of the phase-scrambling sequence: starting from an SSP (left) prepared at 2.43 G ( a s = 87.9 a 0 ), we reduce a s to enter the ID regime (middle). During t S the phases of the droplets evolve independently, leading to phase scrambling between the droplets. Eventually, we jump a s back into the supersolid regime (right), where the time evolution of the global phase coherence is studied. c , d , Amplitudes A M and A Φ ( c ) and Δ Φ ( d ) for our initial SSP (left panel in b ) when simply held for time t h . Each data point is derived from q ∈ [80, 90] individual experimental realizations. The error bars (partly covered by plot symbols) are the 1 σ confidence intervals from BCA bootstrapping (Methods) 39 . e , f , Polar scatter plot for P i ( e ) and histogram of the probability density function (PDF) ( f ) for Φ i at t", "role": "user" }, { "content": "Supersolids are materials that are fluid and solid at the same time. Physicists from Innsbruck and Geneva have for the first time investigated what happens when such a state is brought out of balance. They discovered a soft form of a solid of great interest for science. As the researchers led by Francesca Ferlaino and Thierry Giamarchi report in Nature Physics, they were also able to reverse the process and restore supersolidity. Last year, more than fifty years after initial theoretical proposals, researchers in Pisa, Stuttgart and Innsbruck independently succeeded for the first time in creating so-called supersolids using ultracold quantum gases of highly magnetic lanthanide atoms. This state of matter is, in a sense, solid and liquid at the same time. \"Due to quantum effects, a very cold gas of atoms can spontaneously develop both a crystalline order of a solid crystal and particle flow like a superfluid quantum liquid, i.e. a fluid able to flow without any friction,\" explains Francesca Ferlaino from the Institute for Quantum Optics and Quantum Information of the Austrian Academy of Sciences and the Department of Experimental Physics at the University of Innsbruck. \"Much simplified, a dipolar supersolid can be imagined as a chain of quantum droplets which communicate with each other via a superfluid background bath,\" says Thierry Giamarchi, theoretical physicist from the University of Geneva. Surprisingly reversible In Nature Physics, the researchers now report how such a supersolid state reacts if the superfluid bath between the droplets is drained by control of the external magnetic field. \"We were able to show that without the bath the droplets quickly lose knowledge about each other and start to behave like small independent quantum systems—they dephase. The supersolid turns into a normal solid,\" says Maximilian Sohmen from Francecsa Ferlaino's team. \"This 'solid,' however, is still soft, it can wobble and support many collective excitations, called phonons,\" adds Philipp Ilzhöfer from the Innsbruck team. \"This makes this state a very interesting but complex subject of study with strong connections to solid-state physics and other fields.\" Maybe surprisingly, the Innsbruck physicists were also able to reverse this dephasing process: When they replenished the background bath, the droplets renewed their communication by particle tunneling and re-established supersolidity. ", "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 supersolid is a counterintuitive phase of matter that combines the global phase coherence of a superfluid with a crystal-like self-modulation in space. Recently, such states have been experimentally realized using dipolar quantum gases. Here we investigate the response of a dipolar supersolid to an interaction quench that shatters the global phase coherence. We identify a parameter regime in which this out-of-equilibrium state rephases, indicating superfluid flow across the sample as well as an efficient dissipation mechanism. We find a crossover to a regime where the tendency to rephase gradually decreases until the system relaxes into an incoherent droplet array. Although a dipolar supersolid is, by its nature, ‘soft’, we capture the essential behaviour of the de- and rephasing process within a rigid Josephson junction array model. Yet, both experiment and simulation indicate that the interaction quench causes substantial collective mode excitations that connect to phonons in solids and affect the phase dynamics. Main The notion of phase coherence lies at the foundation of quantum physics. It is considered a key property in understanding many-body quantum phenomena, ranging from superfluidity and the Josephson effect to the more applied examples of matterwave interference, atom lasing processes and quantum transport in meso- and macroscopic systems 1 , 2 . Although phase-coherent states are well studied at equilibrium, understanding their out-of-equilibrium dynamics remains an open problem at the forefront of statistical and quantum physics, especially when interactions are present 3 . Rephasing dynamics of an initially incoherent many-body quantum system requires, first, the system to be conducting such that different parts can exchange energy and particles, and second, an efficient mechanism to dissipate the phase excitations. As for the first requirement, a famous example illustrating the inhibition of thermalization is many-body localization 4 . The second ingredient—dissipation—is more subtle and multifaceted, relating, for instance, to the growth of thermal correlations in isolated systems 5 , complex interaction-mediated dynamics 6 , 7 or the exponential growth of unstable modes and topological defects in connection with the Kibble–Zurek mechanism 8 , 9 , 10 . The interplay among coherence, self-localization and relaxation dynamics is an intriguing problem. In this respect, the recently discovered 11 , 12 , 13 supersolid states in dipolar quantum gases can potentially provide a new twist in studying non-equilibrium quantum phenomena, about which very little is known so far. A supersolid combines phase coherence and periodic localization in space, properties corresponding to the spontaneous and simultaneous breaking of both gauge and translational symmetry. Intuitively, a supersolid can be viewed as a fully coherent state, which self-establishes compressible density modulation. In this Article, we explore the evolution of a supersolid of ultracold dysprosium (Dy) atoms when brought out of equilibrium after an interaction quench that destroys its global phase coherence. Due to the dynamic formation of the supersolid, an interesting question is whether its phase dynamics are similar to or different from comparable rigid structures, such as a Bose–Einstein condensate (BEC) spliced in an optical lattice 14 , 15 , 16 , or if new phenomena can manifest. In a dipolar supersolid, the particle self-arrangement in space is largely dictated by the many-body interactions 17 , 18 , 19 , 20 , 21 , 22 and can be modified by either tuning the interatomic potentials or changing the atom number ( N ) in the system. Figure 1a shows the phase diagram of a cigar-shaped quantum gas of bosonic Dy atoms with transverse dipole orientation. It is constructed from the ground-state wavefunctions obtained by numerically solving the extended Gross–Pitaevskii equation (eGPE) 11 , 13 , 21 (Methods). Three distinct quantum phases can be accessed by changing N or the s -wave scattering length a s , which parametrizes the contact interaction. For a given N and large enough a s , the ground state of the system is a non-modulated dipolar BEC (grey region). By lowering a s , the influence of the dipolar interaction increases. When reaching a critical value of a s , the system undergoes a phase transition to a supersolid phase (SSP). Here density modulation at a wavelength close to the roton excitation 23 , 24 appears in the ground-state density profile (red region). By further lowering a s , the system evolves into an array of insulating droplets (IDs) with an exponentially vanishing density link between them (blue region). Fig. 1: Phase diagram, experimental sequence and starting condition. a , Ground-state phase diagram for our cigar-shaped trapped 164 Dy gas. The colour map encodes the density modulation via the link strength ${\mathscr{L}}=1-({n}_{\mathrm{max}}-{n}_{\mathrm{min}})/({n}_{\mathrm{max}}+{n}_{\mathrm{min}})$ , where n max ( n min ) is the density maximum (minimum) in the central region of the calculated in situ density distribution. ${\mathscr{L}}$ equals unity for a non-modulated state and zero for a fully modulated state. The grey colour indicates a non-modulated BEC, whereas the red and blue regions correspond to the SSP and ID phase, respectively. The insets show the density profiles along the weak axis for the different phases. b , Illustration of the phase-scrambling sequence: starting from an SSP (left) prepared at 2.43 G ( a s = 87.9 a 0 ), we reduce a s to enter the ID regime (middle). During t S the phases of the droplets evolve independently, leading to phase scrambling between the droplets. Eventually, we jump a s back into the supersolid regime (right), where the time evolution of the global phase coherence is studied. c , d , Amplitudes A M and A Φ ( c ) and Δ Φ ( d ) for our initial SSP (left panel in b ) when simply held for time t h . Each data point is derived from q ∈ [80, 90] individual experimental realizations. The error bars (partly covered by plot symbols) are the 1 σ confidence intervals from BCA bootstrapping (Methods) 39 . e , f , Polar scatter plot for P i ( e ) and histogram of the probability density function (PDF) ( f ) for Φ i at t<|im_end|> <|im_start|>assistant Supersolids are materials that are fluid and solid at the same time. Physicists from Innsbruck and Geneva have for the first time investigated what happens when such a state is brought out of balance. They discovered a soft form of a solid of great interest for science. As the researchers led by Francesca Ferlaino and Thierry Giamarchi report in Nature Physics, they were also able to reverse the process and restore supersolidity. Last year, more than fifty years after initial theoretical proposals, researchers in Pisa, Stuttgart and Innsbruck independently succeeded for the first time in creating so-called supersolids using ultracold quantum gases of highly magnetic lanthanide atoms. This state of matter is, in a sense, solid and liquid at the same time. "Due to quantum effects, a very cold gas of atoms can spontaneously develop both a crystalline order of a solid crystal and particle flow like a superfluid quantum liquid, i.e. a fluid able to flow without any friction," explains Francesca Ferlaino from the Institute for Quantum Optics and Quantum Information of the Austrian Academy of Sciences and the Department of Experimental Physics at the University of Innsbruck. "Much simplified, a dipolar supersolid can be imagined as a chain of quantum droplets which communicate with each other via a superfluid background bath," says Thierry Giamarchi, theoretical physicist from the University of Geneva. Surprisingly reversible In Nature Physics, the researchers now report how such a supersolid state reacts if the superfluid bath between the droplets is drained by control of the external magnetic field. "We were able to show that without the bath the droplets quickly lose knowledge about each other and start to behave like small independent quantum systems—they dephase. The supersolid turns into a normal solid," says Maximilian Sohmen from Francecsa Ferlaino's team. "This 'solid,' however, is still soft, it can wobble and support many collective excitations, called phonons," adds Philipp Ilzhöfer from the Innsbruck team. "This makes this state a very interesting but complex subject of study with strong connections to solid-state physics and other fields." Maybe surprisingly, the Innsbruck physicists were also able to reverse this dephasing process: When they replenished the background bath, the droplets renewed their communication by particle tunneling and re-established supersolidity. <|im_end|>

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1,896

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Preclinical and clinical evidence supports the concept of bidirectional brain-gut microbiome interactions. We aimed to determine if subgroups of irritable bowel syndrome (IBS) subjects can be identified based on differences in gut microbial composition, and if there are correlations between gut microbial measures and structural brain signatures in IBS. Methods Behavioral measures, stool samples, and structural brain images were collected from 29 adult IBS and 23 healthy control subjects (HCs). 16S ribosomal RNA (rRNA) gene sequencing was used to profile stool microbial communities, and various multivariate analysis approaches were used to quantitate microbial composition, abundance, and diversity. The metagenomic content of samples was inferred from 16S rRNA gene sequence data using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). T1-weighted brain images were acquired on a Siemens Allegra 3T scanner, and morphological measures were computed for 165 brain regions. Results Using unweighted Unifrac distances with hierarchical clustering on microbial data, samples were clustered into two IBS subgroups within the IBS population (IBS1 ( n = 13) and HC-like IBS ( n = 16)) and HCs ( n = 23) (AUROC = 0.96, sensitivity 0.95, specificity 0.67). A Random Forest classifier provided further support for the differentiation of IBS1 and HC groups. Microbes belonging to the genera Faecalibacterium , Blautia , and Bacteroides contributed to this subclassification. Clinical features distinguishing the groups included a history of early life trauma and duration of symptoms (greater in IBS1), but not self-reported bowel habits, anxiety, depression, or medication use. Gut microbial composition correlated with structural measures of brain regions including sensory- and salience-related regions, and with a history of early life trauma. Conclusions The results confirm previous reports of gut microbiome-based IBS subgroups and identify for the first time brain structural alterations associated with these subgroups. They provide preliminary evidence for the involvement of specific microbes and their predicted metabolites in these correlations. Background Alterations in gut microbial composition or “dysbiosis” have been implicated in the pathophysiology of irritable bowel syndrome (IBS) [ 1 , 2 , 3 ]. IBS is the most common chronic visceral pain syndrome. In the absence of agreed upon biomarkers, the syndrome is defined by symptom criteria which include the presence of chronically recurrent abdominal pain associated with alterations in bowel habits [ 4 ]. This hypothesis has been based on the reported findings of gut microbial differences between healthy control subjects (HCs) and IBS patients, on findings in rodent models of IBS, and on the theoretical appeal of such a hypothesis to explain various clinical observations. These include the observations in some patients that antibiotic treatment can both trigger and attenuate IBS symptoms [ 2 ], the development of IBS-like symptoms following gastroenteritis in a small percentage of patients [ 5 ], and the beneficial effects of the fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) elimination diet and probiotic ingestion [ 2 ]. In addition, the well described interactions between the gut microbiota with the brain and the gut-based immune system provide plausible mechanisms consistent with a role of altered gut microbiota in IBS [ 6 ]. However, to date, few consistent differences have been identified in the gut microbiota between HCs and IBS. This may be in part related to the clinical (age, sex, medications) and physiological (intestinal transit, history of early adverse life events [EALs], stress reactivity) heterogeneity of patients selected solely by symptom criteria. One exception is an increased ratio between the phyla Firmicutes and Bacteroidetes (F-B ratio) which has been reported by several investigators [ 7 , 8 , 9 , 10 ]. A recent study provided evidence for subgroups of IBS patients based on gut microbial composition, which were independent of predominant bowel habits and established symptoms criteria [ 10 ]. There is a growing consensus that alterations in the bidirectional interactions of the central nervous system with the gut (brain-gut axis) play an important role in IBS pathophysiology (reviewed in [ 6 ]). In animal models, early adverse life events have been shown to be associated with stress-induced alterations in intestinal transit (indexed by increased fecal pellet output, [ 11 ] and in the composition of the gut microbiota [ 12 , 13 ]. In addition to a growing list of abnormalities described by different investigators in the different components of the peripheral gut connectome [ 14 , 15 ], both structural and functional alterations of the brain have been identified in IBS subjects [ 16 ]. Recent analyses have identified widespread gray and white matter alterations in the brain of IBS patients, including extensive changes in the somatosensory system (thalamus, basal ganglia, S1, and M1). A history of early adversity has also been shown to be correlated with brain structural changes [ 17 ]. A recent study showed cross sectional correlations between brain structure and gut microbial composition [ 18 ]. The fact that functional activity in some of the same regions (somatosensory regions, basal ganglia) was increased when healthy women consumed a probiotic mix over 4 weeks [ 19 ] suggests the possibility of a link between gut microbial composition and sensory processing and integration in the brain, both in healthy control subjects (HCs) and in a subgroup of IBS patients. By studying a group of well phenotyped IBS subjects and HCs, we aimed to address three questions related to gut microbiota, clinical parameters, and brain signatures: 1. Can gut microbial composition be used to classify IBS patients and to identify subgroups with different clinical and behavioral symptoms, as recently suggested? 2. Is there an association between a history of early adverse life events (EALs) and gut microbial composition? 3. Is there a relationship between gut microbial composition and IBS-related brain biomarkers? Based on past clinical literature and brain regions altered in IBS, we expected to see a relationship between microbiota and emotion-related (amygdala, hippocampus) and sensory brain regions (basal ganglia, posterior insula, and primary sensory and motor regions). Methods Participants Stool samples were collected at UCLA from 29 right-handed adult IBS patients (22 females) and", "role": "user" }, { "content": "A new study by researchers at UCLA has revealed two key findings for people with irritable bowel syndrome about the relationship between the microorganisms that live in the gut and the brain. For people with IBS research shows for the first time that there is an association between the gut microbiota and the brain regions involved in the processing of sensory information from their bodies. The results suggest that signals generated by the brain can influence the composition of microbes residing in the intestine and that the chemicals in the gut can shape the human brain's structure. Additionally, the researchers gained insight into the connections among childhood trauma, brain development and the composition of the gut microbiome. Previous studies performed in mice have demonstrated effects of gut microbiota on brain function and behavior, as well as the influence of the brain on the composition of microbes in the gut. However, to date, only one study performed in human subjects has confirmed the translatability of such findings to the human brain. Studies have also reported evidence for alterations in the composition of gut microbiota in people with irritable bowel syndrome, but there has been little consistency among studies regarding the specific microbial alterations and the relationship of such alterations with the cardinal symptoms of IBS, recurring abdominal pain and altered bowel habits. In relation to a person's history with childhood trauma, it has been shown to be associated with structural and functional brain changes; trauma in young children has also been shown to alter gut microbial composition. But how they are related has been unknown. The UCLA researchers collected behavioral and clinical measures, stool samples and structural brain images from 29 adults diagnosed with IBS, and 23 healthy control subjects. They used DNA sequencing and various mathematical approaches to quantify composition, abundance and diversity of the gut microbiota. They also estimated the microbial gene content and gene products of the stool samples. Then the researchers cross-referenced these gut microbial measures with structural features of the brain. Based on the composition of the microbes in the gut, the samples from those diagnosed with IBS clustered into two subgroups. One group was indistinguishable from the healthy control subjects, while the other differed. Those in the group with an altered gut microbiota had more history of early life trauma and longer duration of IBS symptoms. The two groups also displayed differences in brain structure. Analysis of a person's gut microbiota may become a routine screening test for people with IBS in clinical practice, and in the future, therapies such as certain diets and probiotics may become personalized based on an individual's gut microbial profile. At the same time, subgroups of people with IBS distinguished by brain and microbial signatures may show different responsiveness to brain-directed therapies such as mindfulness-based stress reduction, cognitive behavioral therapy and targeted drugs. A history of early life trauma has been shown to be associated with structural and functional brain changes and to alter gut microbial composition. It is possible that the signals the gut and its microbes get from the brain of an individual with a history of childhood trauma may lead to lifelong changes in the gut microbiome. These alterations in the gut microbiota may feed back into sensory brain regions, altering the sensitivity to gut stimuli, a hallmark of people with IBS. The study was published online in the peer-reviewed journal Microbiome. ", "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 Preclinical and clinical evidence supports the concept of bidirectional brain-gut microbiome interactions. We aimed to determine if subgroups of irritable bowel syndrome (IBS) subjects can be identified based on differences in gut microbial composition, and if there are correlations between gut microbial measures and structural brain signatures in IBS. Methods Behavioral measures, stool samples, and structural brain images were collected from 29 adult IBS and 23 healthy control subjects (HCs). 16S ribosomal RNA (rRNA) gene sequencing was used to profile stool microbial communities, and various multivariate analysis approaches were used to quantitate microbial composition, abundance, and diversity. The metagenomic content of samples was inferred from 16S rRNA gene sequence data using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). T1-weighted brain images were acquired on a Siemens Allegra 3T scanner, and morphological measures were computed for 165 brain regions. Results Using unweighted Unifrac distances with hierarchical clustering on microbial data, samples were clustered into two IBS subgroups within the IBS population (IBS1 ( n = 13) and HC-like IBS ( n = 16)) and HCs ( n = 23) (AUROC = 0.96, sensitivity 0.95, specificity 0.67). A Random Forest classifier provided further support for the differentiation of IBS1 and HC groups. Microbes belonging to the genera Faecalibacterium , Blautia , and Bacteroides contributed to this subclassification. Clinical features distinguishing the groups included a history of early life trauma and duration of symptoms (greater in IBS1), but not self-reported bowel habits, anxiety, depression, or medication use. Gut microbial composition correlated with structural measures of brain regions including sensory- and salience-related regions, and with a history of early life trauma. Conclusions The results confirm previous reports of gut microbiome-based IBS subgroups and identify for the first time brain structural alterations associated with these subgroups. They provide preliminary evidence for the involvement of specific microbes and their predicted metabolites in these correlations. Background Alterations in gut microbial composition or “dysbiosis” have been implicated in the pathophysiology of irritable bowel syndrome (IBS) [ 1 , 2 , 3 ]. IBS is the most common chronic visceral pain syndrome. In the absence of agreed upon biomarkers, the syndrome is defined by symptom criteria which include the presence of chronically recurrent abdominal pain associated with alterations in bowel habits [ 4 ]. This hypothesis has been based on the reported findings of gut microbial differences between healthy control subjects (HCs) and IBS patients, on findings in rodent models of IBS, and on the theoretical appeal of such a hypothesis to explain various clinical observations. These include the observations in some patients that antibiotic treatment can both trigger and attenuate IBS symptoms [ 2 ], the development of IBS-like symptoms following gastroenteritis in a small percentage of patients [ 5 ], and the beneficial effects of the fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) elimination diet and probiotic ingestion [ 2 ]. In addition, the well described interactions between the gut microbiota with the brain and the gut-based immune system provide plausible mechanisms consistent with a role of altered gut microbiota in IBS [ 6 ]. However, to date, few consistent differences have been identified in the gut microbiota between HCs and IBS. This may be in part related to the clinical (age, sex, medications) and physiological (intestinal transit, history of early adverse life events [EALs], stress reactivity) heterogeneity of patients selected solely by symptom criteria. One exception is an increased ratio between the phyla Firmicutes and Bacteroidetes (F-B ratio) which has been reported by several investigators [ 7 , 8 , 9 , 10 ]. A recent study provided evidence for subgroups of IBS patients based on gut microbial composition, which were independent of predominant bowel habits and established symptoms criteria [ 10 ]. There is a growing consensus that alterations in the bidirectional interactions of the central nervous system with the gut (brain-gut axis) play an important role in IBS pathophysiology (reviewed in [ 6 ]). In animal models, early adverse life events have been shown to be associated with stress-induced alterations in intestinal transit (indexed by increased fecal pellet output, [ 11 ] and in the composition of the gut microbiota [ 12 , 13 ]. In addition to a growing list of abnormalities described by different investigators in the different components of the peripheral gut connectome [ 14 , 15 ], both structural and functional alterations of the brain have been identified in IBS subjects [ 16 ]. Recent analyses have identified widespread gray and white matter alterations in the brain of IBS patients, including extensive changes in the somatosensory system (thalamus, basal ganglia, S1, and M1). A history of early adversity has also been shown to be correlated with brain structural changes [ 17 ]. A recent study showed cross sectional correlations between brain structure and gut microbial composition [ 18 ]. The fact that functional activity in some of the same regions (somatosensory regions, basal ganglia) was increased when healthy women consumed a probiotic mix over 4 weeks [ 19 ] suggests the possibility of a link between gut microbial composition and sensory processing and integration in the brain, both in healthy control subjects (HCs) and in a subgroup of IBS patients. By studying a group of well phenotyped IBS subjects and HCs, we aimed to address three questions related to gut microbiota, clinical parameters, and brain signatures: 1. Can gut microbial composition be used to classify IBS patients and to identify subgroups with different clinical and behavioral symptoms, as recently suggested? 2. Is there an association between a history of early adverse life events (EALs) and gut microbial composition? 3. Is there a relationship between gut microbial composition and IBS-related brain biomarkers? Based on past clinical literature and brain regions altered in IBS, we expected to see a relationship between microbiota and emotion-related (amygdala, hippocampus) and sensory brain regions (basal ganglia, posterior insula, and primary sensory and motor regions). Methods Participants Stool samples were collected at UCLA from 29 right-handed adult IBS patients (22 females) and<|im_end|> <|im_start|>assistant A new study by researchers at UCLA has revealed two key findings for people with irritable bowel syndrome about the relationship between the microorganisms that live in the gut and the brain. For people with IBS research shows for the first time that there is an association between the gut microbiota and the brain regions involved in the processing of sensory information from their bodies. The results suggest that signals generated by the brain can influence the composition of microbes residing in the intestine and that the chemicals in the gut can shape the human brain's structure. Additionally, the researchers gained insight into the connections among childhood trauma, brain development and the composition of the gut microbiome. Previous studies performed in mice have demonstrated effects of gut microbiota on brain function and behavior, as well as the influence of the brain on the composition of microbes in the gut. However, to date, only one study performed in human subjects has confirmed the translatability of such findings to the human brain. Studies have also reported evidence for alterations in the composition of gut microbiota in people with irritable bowel syndrome, but there has been little consistency among studies regarding the specific microbial alterations and the relationship of such alterations with the cardinal symptoms of IBS, recurring abdominal pain and altered bowel habits. In relation to a person's history with childhood trauma, it has been shown to be associated with structural and functional brain changes; trauma in young children has also been shown to alter gut microbial composition. But how they are related has been unknown. The UCLA researchers collected behavioral and clinical measures, stool samples and structural brain images from 29 adults diagnosed with IBS, and 23 healthy control subjects. They used DNA sequencing and various mathematical approaches to quantify composition, abundance and diversity of the gut microbiota. They also estimated the microbial gene content and gene products of the stool samples. Then the researchers cross-referenced these gut microbial measures with structural features of the brain. Based on the composition of the microbes in the gut, the samples from those diagnosed with IBS clustered into two subgroups. One group was indistinguishable from the healthy control subjects, while the other differed. Those in the group with an altered gut microbiota had more history of early life trauma and longer duration of IBS symptoms. The two groups also displayed differences in brain structure. Analysis of a person's gut microbiota may become a routine screening test for people with IBS in clinical practice, and in the future, therapies such as certain diets and probiotics may become personalized based on an individual's gut microbial profile. At the same time, subgroups of people with IBS distinguished by brain and microbial signatures may show different responsiveness to brain-directed therapies such as mindfulness-based stress reduction, cognitive behavioral therapy and targeted drugs. A history of early life trauma has been shown to be associated with structural and functional brain changes and to alter gut microbial composition. It is possible that the signals the gut and its microbes get from the brain of an individual with a history of childhood trauma may lead to lifelong changes in the gut microbiome. These alterations in the gut microbiota may feed back into sensory brain regions, altering the sensitivity to gut stimuli, a hallmark of people with IBS. The study was published online in the peer-reviewed journal Microbiome. <|im_end|>

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2,030

[ { "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 There is debate as to whether quantum field theory is, at bottom, a quantum theory of fields or particles. One can take a field approach to the theory, using wave functionals over field configurations, or a particle approach, using wave functions over particle configurations. This article argues for a field approach, presenting three advantages over a particle approach: (1) particle wave functions are not available for photons, (2) a classical field model of the electron gives a superior account of both spin and self-interaction as compared to a classical particle model, and (3) the space of field wave functionals appears to be larger than the space of particle wave functions. The article also describes two important tasks facing proponents of a field approach: (1) legitimize or excise the use of Grassmann numbers for fermionic field values and in wave functional amplitudes, and (2) describe how quantum fields give rise to particle-like behavior. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction What replaces the wave functions of non-relativistic quantum mechanics in relativistic quantum field theory? According to what I will call the “particle approach,” we keep wave functions over particle configurations but modify the formalism to allow for (at least the appearance of) particle creation and annihilation—perhaps by moving from wave functions over configurations of a fixed number of particles to wave functions that assign amplitudes to different numbers of particles being in various possible configurations. According to the alternative “field approach,” we replace wave functions over particle configurations with wave functionals over field configurations—viewing quantum field theory as a theory of fields in quantum superpositions of different classical states. The debate between these approaches is a debate as to whether fields or particles are more fundamental. Footnote 1 The general view seems to be that fields are more fundamental than particles. But, wave functionals are rarely used Footnote 2 and the field approach (as described above) is rarely explicitly defended. Footnote 3 My goal here is to argue for the field approach, giving a number of reasons to favor the approach that I see as particularly compelling and also noting a few problems for the approach that I see as worthy of attention. We will be hovering high above some difficult technical terrain, taking a bird’s-eye view and pointing elsewhere for elaboration. Even as a zoomed-out survey, the treatment will be incomplete. I am only giving a selection of the many considerations that might be offered for and against the field approach. Footnote 4 In my assessment, the field approach is more attractive than the particle approach. But, I do not think that the case for the field approach can yet be considered decisive. There is still work to be done in developing and defending the approach. I hope to attract allies to those efforts. Up to now, the particle and field approaches have been debated most carefully in the literature on Bohmian quantum field theory, where one seeks to solve the quantum measurement problem by adding something to the quantum state (perhaps particles, perhaps fields). However, the debate between particle and field approaches crosscuts the debate as to the right way of solving the quantum measurement problem. A defender of the many-worlds interpretation might take a unitarily evolving wave functional as fundamental or a unitarily evolving wave function over different numbers and arrangements of particles. A proponent of collapse could modify the evolution of either kind of quantum state. To fully understand the ontology of quantum field theory (what exists according to the theory) and the laws of quantum field theory, we need to combine a particle or field approach with a particular solution to the measurement problem. As a first step, we can set the measurement problem aside and consider the merits of the particle and field approaches. In general, one might attempt to take a particle or field approach to the entirety of the standard model. To simplify the discussion here, we will focus on quantum electrodynamics, understood either as a theory of electrons, positrons, and photons, or, alternatively, as a theory of the quantum Dirac and electromagnetic fields. Although we will primarily be comparing a pure particle approach to a pure field approach, we will also consider a mixed approach, where one treats electrons and positrons as particles interacting with a quantum electromagnetic field, and a deflationary approach, where one views particle wave functions and field wave functionals as equivalent ways of representing the same states. The pure particle, pure field, mixed, and deflationary approaches are not the only options for understanding states in quantum field theory. There are other proposals that involve neither wave functions nor wave functionals, but they will not be considered here. Because some of these other proposals might legitimately claim to be called “particle” or “field” approaches, one could be more specific and call the two main approaches discussed here “particle wave function” and “field wave functional” approaches. This article is organized as follows: Sects. 2 and 3 introduce the particle and field approaches to quantum field theory. Section 4 presents three points in favor of the field approach. First, the particle approach is not available for photons because we do not have a relativistic single-photon quantum theory to build from (like Dirac’s single-electron relativistic quantum mechanics). Second, the classical pre-quantization starting point for the field approach (where the electron is modeled as a rotating cloud of energy and charge in the classical Dirac field) gives a superior account of both spin and self-interaction as compared to the classical pre-quantization starting point for the particle approach (where the electron is modeled as a point particle with intrinsic angular momentum and magnetic moment). Third, the particle approach appears to have a smaller space of states than the field approach and to lack the states necessary to represent ground and excited states in the presence of interactions. Section 5 begins by reviewing some gaps in the field approach that", "role": "user" }, { "content": "Deep inside all matter in the universe, electrons are buzzing around and behaving as if they are twirling around on their axes like spinning tops. These \"spinning\" electrons are fundamental to quantum physics and play a central role in our understanding of atoms and molecules. Other subatomic particles spin, too, and the study of spin has technical applications in the fields of chemistry, physics, medicine, and computer electronics. But many physicists will tell you that electrons are not really spinning—they merely act like it. For example, electrons have angular momentum, which is the tendency of something to keep rotating—like a moving bicycle wheel or a spinning skater—and because they have this property, one might conclude they are spinning. Further evidence comes from the fact that electrons act like little magnets, and magnetic fields arise from rotating charged bodies. The problem with the notion that electrons spin is, due to their miniscule size, the electrons would have to be spinning faster than the speed of light to match observed angular momentum values. (Think of an electron like a spinning skater with their arms folded inward: the smaller the overall size, the faster it spins.) Chip Sebens, assistant professor of philosophy at Caltech, wants to go back to the drawing board and rethink this notion. As a philosopher of physics, he wants to figure out what is really going on at the deepest levels of nature. \"Philosophers tend to be attracted to problems that have been unsolved for a really long time,\" Sebens explains. \"In quantum mechanics, we have ways of predicting the results of experiments that work very well for electrons and account for spin, but important foundational questions remain unanswered: Why do these methods work and what's happening inside an atom?\" To that end, Sebens has made arguments for why he thinks electrons and other subatomic particles are, in fact, spinning. The answer has to do with fields. In nature, there are both particles and fields. Physicists tend to think that fields are more fundamental than particles, but philosophers of physics still debate which entity is more fundamental. For example, light might be described as a beam of photons or as a wave in the electromagnetic field. This area of science is called quantum field theory. The late Richard Feynman, Caltech physicist and Nobel Laureate, worked on aspects of this theory by creating his famous Feynman diagrams, which map out interactions between particles like electrons and photons, indirectly describing fields. \"Quantum field theory is the best physics we have,\" Sebens says. In several studies, including a recent paper in the journal Synthese, Sebens outlines why he thinks an electron is not a point-size particle that merely acts like it is spinning but rather is a spread-out blob of charge that truly rotates. Going back to the ice skater analogy, the electron is instead like a skater with their arms spread outward. \"In an atom, the electron is often depicted as a cloud showing where the electron might be found, but I think that the electron is actually physically spread out over that cloud,\" Sebens says. With the electron's size spread out, the electron is now big enough to avoid the problem of having to move faster than the speed of light. In this case, explains Sebens, there are two important fields: the electromagnetic field as well as what is known as the Dirac field, after physicist Paul Dirac. \"Just as the electromagnetic field describes photons, the Dirac field describes electrons and positrons,\" he says. The positron is the antiparticle of the electron. The research is part of an overall effort by Sebens to answer the question of whether nature is, at the root, built from fields or particles. In the same Synthese paper, Sebens argues that fields are more fundamental in nature. Part of his argument is based on spin. As mentioned above, a field approach makes sense of the confusion that arises with rotating electrons. He also argues that the field approach helps with another important question regarding electrons: How do electrons respond to the electromagnetic fields that they create? If the electron is a point-size ball of charge, the field it creates is infinitely strong at the electron's location. This means the field would have no defined direction and thus no defined forces, which leads to problems in calculating the forces. But if the electron is instead an extended field of charge, the forces on the different parts of the electron would be finite with well-defined directions. \"This makes the self-interaction problem less severe,\" writes Sebens in an Aeon essay on the fundamental building blocks of nature. \"But it is not solved. If the electron's charge is spread out, why don't the various parts of the electron repel one another so that the electron rapidly explodes?\" Sebens is addressing this self-repulsion problem in his ongoing research. The answers to this and other problems he is investigating may ultimately lead to new and better ways to calculate and measure quantities in quantum physics. The work may even lead to new ways to answer an ongoing question in quantum physics called the quantum measurement problem. When measuring a quantum system, such as an electron in a state of superposition (in two states at once), the system will collapse and the electron will assume one state or another. Physicists still debate why this occurs. Research into the fundamental underpinnings of how particles and fields work may help settle the mystery. Writes Sebens in the Aeon essay, \"Sometimes progress in physics requires first backing up to reexamine, reinterpret and revise the theories that we already have. To do this kind of research, we need scholars who blend the roles of physicist and philosopher, as was done thousands of years ago in Ancient Greece.\" ", "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 There is debate as to whether quantum field theory is, at bottom, a quantum theory of fields or particles. One can take a field approach to the theory, using wave functionals over field configurations, or a particle approach, using wave functions over particle configurations. This article argues for a field approach, presenting three advantages over a particle approach: (1) particle wave functions are not available for photons, (2) a classical field model of the electron gives a superior account of both spin and self-interaction as compared to a classical particle model, and (3) the space of field wave functionals appears to be larger than the space of particle wave functions. The article also describes two important tasks facing proponents of a field approach: (1) legitimize or excise the use of Grassmann numbers for fermionic field values and in wave functional amplitudes, and (2) describe how quantum fields give rise to particle-like behavior. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction What replaces the wave functions of non-relativistic quantum mechanics in relativistic quantum field theory? According to what I will call the “particle approach,” we keep wave functions over particle configurations but modify the formalism to allow for (at least the appearance of) particle creation and annihilation—perhaps by moving from wave functions over configurations of a fixed number of particles to wave functions that assign amplitudes to different numbers of particles being in various possible configurations. According to the alternative “field approach,” we replace wave functions over particle configurations with wave functionals over field configurations—viewing quantum field theory as a theory of fields in quantum superpositions of different classical states. The debate between these approaches is a debate as to whether fields or particles are more fundamental. Footnote 1 The general view seems to be that fields are more fundamental than particles. But, wave functionals are rarely used Footnote 2 and the field approach (as described above) is rarely explicitly defended. Footnote 3 My goal here is to argue for the field approach, giving a number of reasons to favor the approach that I see as particularly compelling and also noting a few problems for the approach that I see as worthy of attention. We will be hovering high above some difficult technical terrain, taking a bird’s-eye view and pointing elsewhere for elaboration. Even as a zoomed-out survey, the treatment will be incomplete. I am only giving a selection of the many considerations that might be offered for and against the field approach. Footnote 4 In my assessment, the field approach is more attractive than the particle approach. But, I do not think that the case for the field approach can yet be considered decisive. There is still work to be done in developing and defending the approach. I hope to attract allies to those efforts. Up to now, the particle and field approaches have been debated most carefully in the literature on Bohmian quantum field theory, where one seeks to solve the quantum measurement problem by adding something to the quantum state (perhaps particles, perhaps fields). However, the debate between particle and field approaches crosscuts the debate as to the right way of solving the quantum measurement problem. A defender of the many-worlds interpretation might take a unitarily evolving wave functional as fundamental or a unitarily evolving wave function over different numbers and arrangements of particles. A proponent of collapse could modify the evolution of either kind of quantum state. To fully understand the ontology of quantum field theory (what exists according to the theory) and the laws of quantum field theory, we need to combine a particle or field approach with a particular solution to the measurement problem. As a first step, we can set the measurement problem aside and consider the merits of the particle and field approaches. In general, one might attempt to take a particle or field approach to the entirety of the standard model. To simplify the discussion here, we will focus on quantum electrodynamics, understood either as a theory of electrons, positrons, and photons, or, alternatively, as a theory of the quantum Dirac and electromagnetic fields. Although we will primarily be comparing a pure particle approach to a pure field approach, we will also consider a mixed approach, where one treats electrons and positrons as particles interacting with a quantum electromagnetic field, and a deflationary approach, where one views particle wave functions and field wave functionals as equivalent ways of representing the same states. The pure particle, pure field, mixed, and deflationary approaches are not the only options for understanding states in quantum field theory. There are other proposals that involve neither wave functions nor wave functionals, but they will not be considered here. Because some of these other proposals might legitimately claim to be called “particle” or “field” approaches, one could be more specific and call the two main approaches discussed here “particle wave function” and “field wave functional” approaches. This article is organized as follows: Sects. 2 and 3 introduce the particle and field approaches to quantum field theory. Section 4 presents three points in favor of the field approach. First, the particle approach is not available for photons because we do not have a relativistic single-photon quantum theory to build from (like Dirac’s single-electron relativistic quantum mechanics). Second, the classical pre-quantization starting point for the field approach (where the electron is modeled as a rotating cloud of energy and charge in the classical Dirac field) gives a superior account of both spin and self-interaction as compared to the classical pre-quantization starting point for the particle approach (where the electron is modeled as a point particle with intrinsic angular momentum and magnetic moment). Third, the particle approach appears to have a smaller space of states than the field approach and to lack the states necessary to represent ground and excited states in the presence of interactions. Section 5 begins by reviewing some gaps in the field approach that<|im_end|> <|im_start|>assistant Deep inside all matter in the universe, electrons are buzzing around and behaving as if they are twirling around on their axes like spinning tops. These "spinning" electrons are fundamental to quantum physics and play a central role in our understanding of atoms and molecules. Other subatomic particles spin, too, and the study of spin has technical applications in the fields of chemistry, physics, medicine, and computer electronics. But many physicists will tell you that electrons are not really spinning—they merely act like it. For example, electrons have angular momentum, which is the tendency of something to keep rotating—like a moving bicycle wheel or a spinning skater—and because they have this property, one might conclude they are spinning. Further evidence comes from the fact that electrons act like little magnets, and magnetic fields arise from rotating charged bodies. The problem with the notion that electrons spin is, due to their miniscule size, the electrons would have to be spinning faster than the speed of light to match observed angular momentum values. (Think of an electron like a spinning skater with their arms folded inward: the smaller the overall size, the faster it spins.) Chip Sebens, assistant professor of philosophy at Caltech, wants to go back to the drawing board and rethink this notion. As a philosopher of physics, he wants to figure out what is really going on at the deepest levels of nature. "Philosophers tend to be attracted to problems that have been unsolved for a really long time," Sebens explains. "In quantum mechanics, we have ways of predicting the results of experiments that work very well for electrons and account for spin, but important foundational questions remain unanswered: Why do these methods work and what's happening inside an atom?" To that end, Sebens has made arguments for why he thinks electrons and other subatomic particles are, in fact, spinning. The answer has to do with fields. In nature, there are both particles and fields. Physicists tend to think that fields are more fundamental than particles, but philosophers of physics still debate which entity is more fundamental. For example, light might be described as a beam of photons or as a wave in the electromagnetic field. This area of science is called quantum field theory. The late Richard Feynman, Caltech physicist and Nobel Laureate, worked on aspects of this theory by creating his famous Feynman diagrams, which map out interactions between particles like electrons and photons, indirectly describing fields. "Quantum field theory is the best physics we have," Sebens says. In several studies, including a recent paper in the journal Synthese, Sebens outlines why he thinks an electron is not a point-size particle that merely acts like it is spinning but rather is a spread-out blob of charge that truly rotates. Going back to the ice skater analogy, the electron is instead like a skater with their arms spread outward. "In an atom, the electron is often depicted as a cloud showing where the electron might be found, but I think that the electron is actually physically spread out over that cloud," Sebens says. With the electron's size spread out, the electron is now big enough to avoid the problem of having to move faster than the speed of light. In this case, explains Sebens, there are two important fields: the electromagnetic field as well as what is known as the Dirac field, after physicist Paul Dirac. "Just as the electromagnetic field describes photons, the Dirac field describes electrons and positrons," he says. The positron is the antiparticle of the electron. The research is part of an overall effort by Sebens to answer the question of whether nature is, at the root, built from fields or particles. In the same Synthese paper, Sebens argues that fields are more fundamental in nature. Part of his argument is based on spin. As mentioned above, a field approach makes sense of the confusion that arises with rotating electrons. He also argues that the field approach helps with another important question regarding electrons: How do electrons respond to the electromagnetic fields that they create? If the electron is a point-size ball of charge, the field it creates is infinitely strong at the electron's location. This means the field would have no defined direction and thus no defined forces, which leads to problems in calculating the forces. But if the electron is instead an extended field of charge, the forces on the different parts of the electron would be finite with well-defined directions. "This makes the self-interaction problem less severe," writes Sebens in an Aeon essay on the fundamental building blocks of nature. "But it is not solved. If the electron's charge is spread out, why don't the various parts of the electron repel one another so that the electron rapidly explodes?" Sebens is addressing this self-repulsion problem in his ongoing research. The answers to this and other problems he is investigating may ultimately lead to new and better ways to calculate and measure quantities in quantum physics. The work may even lead to new ways to answer an ongoing question in quantum physics called the quantum measurement problem. When measuring a quantum system, such as an electron in a state of superposition (in two states at once), the system will collapse and the electron will assume one state or another. Physicists still debate why this occurs. Research into the fundamental underpinnings of how particles and fields work may help settle the mystery. Writes Sebens in the Aeon essay, "Sometimes progress in physics requires first backing up to reexamine, reinterpret and revise the theories that we already have. To do this kind of research, we need scholars who blend the roles of physicist and philosopher, as was done thousands of years ago in Ancient Greece." <|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 report on the dynamics of collective alignment in groups of the cichlid fish Etroplus suratensis . Focusing on small- to intermediate-sized groups (10 ≲ N ≲ 100), we demonstrate that schooling (highly polarized and coherent motion) is noise induced, arising from the intrinsic stochasticity associated with finite numbers of interacting fish. The fewer the fish, the greater the (multiplicative) noise and therefore the greater the likelihood of alignment. Such rare empirical evidence tightly constrains the possible underlying interactions that govern fish alignment, suggesting that E. suratensis either spontaneously change their direction or copy the direction of another fish, without any local averaging (the otherwise canonical mechanism of collective alignment). Our study therefore highlights the importance of stochasticity in behavioural inference. Furthermore, rather than simply obscuring otherwise deterministic dynamics, noise can be fundamental to the characterization of emergent collective behaviours. Main Over the past decade, modern methods of image analysis and tracking have been used extensively to study the collective motion of animal groups, and by proxy the social interactions between their constituent individuals. Using a variety of techniques, a broad range of taxa have been investigated so far, including flocks of starlings 1 , 2 , 3 , shoals of fish 4 , 5 , 6 , 7 , 8 , marching locusts 9 , 10 , mice 11 and red deer 12 . However, aside from ref. 13 —a theoretical follow-up to the pioneering study of direction switching in locust nymphs 10 —such empirical studies have overlooked the intrinsic noise that arises in any finite collective, or group, whose underlying individuals interact in an inherently probabilistic way. We argue that this is a serious oversight; system-size expansions of master equations 14 readily demonstrate that probabilistic individual behaviours can conspire to produce collective features that are wholly surprising. Such approaches are typically referred to as mesoscopic, since they describe the properties of large but finite-sized groups, where the stochastic behaviour of the individuals cannot be completely ‘averaged out’. Notably, such residual stochasticity often manifests as a multiplicative, or state-dependent, noise at the collective level. In many cases, this can give rise to ‘finite-size noise-induced’ behaviour 15 , 16 , where the probability of finding the system in a particular state is concentrated away from the deterministic ( N → ∞) fixed point(s). For example, in a toy model of binary choice (between two food sources, say) where individuals can either copy each other at random or spontaneously change their mind, no consensus is ever reached in the N → ∞ limit. By contrast, at finite group sizes, noise-induced effects imply a clear consensus, with the group choosing either one of the options with equally high probability 17 . Such ideas are particularly relevant for the inference of individual behaviours from collective-level data: the important point being that, rather than simply obscuring the signature of otherwise deterministic dynamics, collective-level noise can actually encode important information about individual interactions 18 . Therefore, not only should fluctuations be extracted from data with care, but they are also pertinent to a major challenge of modern behavioural inference: how to distinguish between multiple mechanisms that ostensibly reproduce the same qualitative features of collective motion. It is in this context that we report on the stochastic dynamics of directional alignment in freshwater fish ( Etroplus suratensis ) under controlled laboratory conditions. We use a data-driven approach, formally extracting a stochastic differential equation (SDE) that describes the dynamics of collective alignment. We find that schooling in such fish—that is, highly polarized and coherent motion—bears all the hallmarks of a finite-size noise-induced effect, resulting from finite-sized groups of individuals that interact according to probabilistic rules. Put simply, the smaller the number of fish in a group, the larger the stochastic fluctuations and, surprisingly, the greater the ordering. This counterintuitive result can be traced back to an \$O(1/\\sqrt{N})\$ noise term that is multiplicative—that is, the strength of noise depends on the collective state of the group. Significantly, the type of finite-size noise-induced schooling that we observe tightly constrains the possible interactions between fish that might underpin it. Using both analysis and computer simulations, we find that all the salient features of our data are captured by a simple stochastic protocol for pairwise interactions, whereby a given fish interacts and aligns with other (single) fish, one at a time. Such features are not present if ternary or higher-order aligning interactions are dominant, including local directional averaging, as used in the Vicsek-like family of approaches 19 , 20 —the de facto standard for modelling collective motion. Experimental set-up Our experiments involved filming schools of freshwater juvenile E. suratensis in a large laboratory tank that was sufficiently shallow to constrain motion to two dimensions (Fig. 1 and Supplementary Section I ). We focused on small- to medium-sized groups— N = 15, N = 30 and N = 60—which ensured that schools were localized, with a spatial extent that was only a fraction of the overall tank size (see Supplementary Sections II and III , respectively, for details concerning larger schools and controls for the effects of the tank boundary). Fig. 1: Capturing the stochastic dynamics of ordering in small- to medium-sized groups of fish. a , Schools of juvenile E. suratensis were filmed in a large shallow tank (180 cm diameter, 10 cm height), under controlled laboratory conditions. b , Using particle-tracking methods, we obtained two-dimensional trajectories for each individual fish. This permits the construction of a stochastic time series for the group alignment, or M ( t ) (equation ( 1 )). c , For | M | ≈ 1 the fish are moving in a coherent direction, whereas for | M | ≈ 0 there is no prevailing direction and the shoal is effectively isotropic. Full size image Each group size was recorded for approximately 3.5 h in total, across four separate trials for N = 15 and 30 and three separate trials for N = 60. The temporal resolution was one frame every 0.04 s. However, at", "role": "user" }, { "content": "Fish school by copying each other and changing directions randomly, rather than calculating and adapting to an average direction of the group, a group of scientists co-led by UNSW has shown. In a study published today in Nature Physics, an international team from Australia, India and UK has shed light on the behavioural dynamics that govern alignment, or collective motion, of cichlid fish—offering new insights into the dynamics of schooling, and potentially the coordinated behaviour of other animals. \"In the fish that we have studied, schooling turns out to be noise-induced. It's not what anyone traditionally thought it was,\" says Dr. Richard Morris from UNSW Science, co-leader of the study and EMBL Australia group leader in UNSW's Single Molecule Science. \"Noise, in this setting, is simply the randomness arising from interactions between individual fish.\" In the study, the researchers present the first experimental evidence of noise-induced ordering, which previously only existed as a theoretical possibility. The interdisciplinary team of ecologists, physicists and mathematicians achieved this by combining the capabilities of their scientific disciplines to integrate experiments with computer simulations and analysis. \"Everyone's been aware of noise-induced phenomena, theoretically, but it's quite rare to find in practice. You can only observe it when the individuals in a study can actually make decisions. For example, you wouldn't find this type of noise-induced behaviour studying electrons or particles,\" says Dr. Morris. This new model proposed contradicts the standard 'moving average' theories for schooling and herding behaviour, which assume that the animals are capable of estimating the overall direction of the group. \"Every fish only interacts with one other fish at any given time. They either spontaneously change direction, or copy the direction of a different fish. Calculating an average direction of the group—which was the popular theory until now—is likely too complicated for a fish to compute,\" explains Dr. Morris. To study the behavioural dynamics, the researchers filmed schools of 15, 30 and 60 cichlid fish, tracking their trajectories to analyse the mechanism behind mutual alignment, or schooling. \"Smaller groups of fish schooled more coherently than large groups. This is counterintuitive, since the randomness, or noise, from individual interactions plays a bigger role in smaller groups than larger ones,\" Dr. Morris says. When researchers interpret data, noise is usually an unrelated factor that obscures and distracts from the information, like glare from the sun that you would try to eliminate to get a clearer photo. In this case, Dr. Morris explains that the random copying between pairs of fish gives rise to a different class of noise, and is actually what drives their highly coordinated behaviour. This new insight highlights the importance of noise, showing that noise may encode some important information about behavioural dynamics of fish and other animals. \"Here the signal is the noise. If you ignored the fluctuations completely, you couldn't explain schooling at all.\" Beyond fish behaviour, the discovery has the power to reshape the understanding of collective motion in animals, and calls for a revision of how noise is treated in studies of behaviour dynamics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We report on the dynamics of collective alignment in groups of the cichlid fish Etroplus suratensis . Focusing on small- to intermediate-sized groups (10 ≲ N ≲ 100), we demonstrate that schooling (highly polarized and coherent motion) is noise induced, arising from the intrinsic stochasticity associated with finite numbers of interacting fish. The fewer the fish, the greater the (multiplicative) noise and therefore the greater the likelihood of alignment. Such rare empirical evidence tightly constrains the possible underlying interactions that govern fish alignment, suggesting that E. suratensis either spontaneously change their direction or copy the direction of another fish, without any local averaging (the otherwise canonical mechanism of collective alignment). Our study therefore highlights the importance of stochasticity in behavioural inference. Furthermore, rather than simply obscuring otherwise deterministic dynamics, noise can be fundamental to the characterization of emergent collective behaviours. Main Over the past decade, modern methods of image analysis and tracking have been used extensively to study the collective motion of animal groups, and by proxy the social interactions between their constituent individuals. Using a variety of techniques, a broad range of taxa have been investigated so far, including flocks of starlings 1 , 2 , 3 , shoals of fish 4 , 5 , 6 , 7 , 8 , marching locusts 9 , 10 , mice 11 and red deer 12 . However, aside from ref. 13 —a theoretical follow-up to the pioneering study of direction switching in locust nymphs 10 —such empirical studies have overlooked the intrinsic noise that arises in any finite collective, or group, whose underlying individuals interact in an inherently probabilistic way. We argue that this is a serious oversight; system-size expansions of master equations 14 readily demonstrate that probabilistic individual behaviours can conspire to produce collective features that are wholly surprising. Such approaches are typically referred to as mesoscopic, since they describe the properties of large but finite-sized groups, where the stochastic behaviour of the individuals cannot be completely ‘averaged out’. Notably, such residual stochasticity often manifests as a multiplicative, or state-dependent, noise at the collective level. In many cases, this can give rise to ‘finite-size noise-induced’ behaviour 15 , 16 , where the probability of finding the system in a particular state is concentrated away from the deterministic ( N → ∞) fixed point(s). For example, in a toy model of binary choice (between two food sources, say) where individuals can either copy each other at random or spontaneously change their mind, no consensus is ever reached in the N → ∞ limit. By contrast, at finite group sizes, noise-induced effects imply a clear consensus, with the group choosing either one of the options with equally high probability 17 . Such ideas are particularly relevant for the inference of individual behaviours from collective-level data: the important point being that, rather than simply obscuring the signature of otherwise deterministic dynamics, collective-level noise can actually encode important information about individual interactions 18 . Therefore, not only should fluctuations be extracted from data with care, but they are also pertinent to a major challenge of modern behavioural inference: how to distinguish between multiple mechanisms that ostensibly reproduce the same qualitative features of collective motion. It is in this context that we report on the stochastic dynamics of directional alignment in freshwater fish ( Etroplus suratensis ) under controlled laboratory conditions. We use a data-driven approach, formally extracting a stochastic differential equation (SDE) that describes the dynamics of collective alignment. We find that schooling in such fish—that is, highly polarized and coherent motion—bears all the hallmarks of a finite-size noise-induced effect, resulting from finite-sized groups of individuals that interact according to probabilistic rules. Put simply, the smaller the number of fish in a group, the larger the stochastic fluctuations and, surprisingly, the greater the ordering. This counterintuitive result can be traced back to an $O(1/\sqrt{N})$ noise term that is multiplicative—that is, the strength of noise depends on the collective state of the group. Significantly, the type of finite-size noise-induced schooling that we observe tightly constrains the possible interactions between fish that might underpin it. Using both analysis and computer simulations, we find that all the salient features of our data are captured by a simple stochastic protocol for pairwise interactions, whereby a given fish interacts and aligns with other (single) fish, one at a time. Such features are not present if ternary or higher-order aligning interactions are dominant, including local directional averaging, as used in the Vicsek-like family of approaches 19 , 20 —the de facto standard for modelling collective motion. Experimental set-up Our experiments involved filming schools of freshwater juvenile E. suratensis in a large laboratory tank that was sufficiently shallow to constrain motion to two dimensions (Fig. 1 and Supplementary Section I ). We focused on small- to medium-sized groups— N = 15, N = 30 and N = 60—which ensured that schools were localized, with a spatial extent that was only a fraction of the overall tank size (see Supplementary Sections II and III , respectively, for details concerning larger schools and controls for the effects of the tank boundary). Fig. 1: Capturing the stochastic dynamics of ordering in small- to medium-sized groups of fish. a , Schools of juvenile E. suratensis were filmed in a large shallow tank (180 cm diameter, 10 cm height), under controlled laboratory conditions. b , Using particle-tracking methods, we obtained two-dimensional trajectories for each individual fish. This permits the construction of a stochastic time series for the group alignment, or M ( t ) (equation ( 1 )). c , For | M | ≈ 1 the fish are moving in a coherent direction, whereas for | M | ≈ 0 there is no prevailing direction and the shoal is effectively isotropic. Full size image Each group size was recorded for approximately 3.5 h in total, across four separate trials for N = 15 and 30 and three separate trials for N = 60. The temporal resolution was one frame every 0.04 s. However, at<|im_end|> <|im_start|>assistant Fish school by copying each other and changing directions randomly, rather than calculating and adapting to an average direction of the group, a group of scientists co-led by UNSW has shown. In a study published today in Nature Physics, an international team from Australia, India and UK has shed light on the behavioural dynamics that govern alignment, or collective motion, of cichlid fish—offering new insights into the dynamics of schooling, and potentially the coordinated behaviour of other animals. "In the fish that we have studied, schooling turns out to be noise-induced. It's not what anyone traditionally thought it was," says Dr. Richard Morris from UNSW Science, co-leader of the study and EMBL Australia group leader in UNSW's Single Molecule Science. "Noise, in this setting, is simply the randomness arising from interactions between individual fish." In the study, the researchers present the first experimental evidence of noise-induced ordering, which previously only existed as a theoretical possibility. The interdisciplinary team of ecologists, physicists and mathematicians achieved this by combining the capabilities of their scientific disciplines to integrate experiments with computer simulations and analysis. "Everyone's been aware of noise-induced phenomena, theoretically, but it's quite rare to find in practice. You can only observe it when the individuals in a study can actually make decisions. For example, you wouldn't find this type of noise-induced behaviour studying electrons or particles," says Dr. Morris. This new model proposed contradicts the standard 'moving average' theories for schooling and herding behaviour, which assume that the animals are capable of estimating the overall direction of the group. "Every fish only interacts with one other fish at any given time. They either spontaneously change direction, or copy the direction of a different fish. Calculating an average direction of the group—which was the popular theory until now—is likely too complicated for a fish to compute," explains Dr. Morris. To study the behavioural dynamics, the researchers filmed schools of 15, 30 and 60 cichlid fish, tracking their trajectories to analyse the mechanism behind mutual alignment, or schooling. "Smaller groups of fish schooled more coherently than large groups. This is counterintuitive, since the randomness, or noise, from individual interactions plays a bigger role in smaller groups than larger ones," Dr. Morris says. When researchers interpret data, noise is usually an unrelated factor that obscures and distracts from the information, like glare from the sun that you would try to eliminate to get a clearer photo. In this case, Dr. Morris explains that the random copying between pairs of fish gives rise to a different class of noise, and is actually what drives their highly coordinated behaviour. This new insight highlights the importance of noise, showing that noise may encode some important information about behavioural dynamics of fish and other animals. "Here the signal is the noise. If you ignored the fluctuations completely, you couldn't explain schooling at all." Beyond fish behaviour, the discovery has the power to reshape the understanding of collective motion in animals, and calls for a revision of how noise is treated in studies of behaviour dynamics. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Climate change is redistributing biodiversity globally and distributional shifts have been found to follow local climate velocities. It is largely assumed that marine endotherms such as cetaceans might shift more slowly than ectotherms in response to warming and would primarily follow changes in prey, but distributional shifts in cetaceans are difficult to quantify. Here we use data from fisheries bycatch and strandings to examine changes in the distribution of long-finned pilot whales ( Globicephala melas ), and assess shifts in pilot whales and their prey relative to climate velocity in a rapidly warming region of the Northwest Atlantic. We found a poleward shift in pilot whale distribution that exceeded climate velocity and occurred at more than three times the rate of fish and invertebrate prey species. Fish and invertebrates shifted at rates equal to or slower than expected based on climate velocity, with more slowly shifting species moving to deeper waters. We suggest that traits such as mobility, diet specialization, and thermoregulatory strategy are central to understanding and anticipating range shifts. Our findings highlight the potential for trait-mediated climate shifts to decouple relationships between endothermic cetaceans and their ectothermic prey, which has important implications for marine food web dynamics and ecosystem stability. Introduction While shifts in distribution 1 , 2 , 3 , 4 and productivity 5 , 6 in response to warming have been well documented in marine ectotherms 7 , 8 , direct impacts of climatic warming on marine endotherms are poorly understood 9 . As a result of differences in thermoregulatory mechanisms and energetic expenditure when faced with changing environmental temperatures, climate change may have fundamentally different impacts on ectotherms and endotherms 10 . It is largely assumed that ectotherms will respond more quickly to warming than endotherms 11 , 12 . The physiological performance of marine ectotherms is a function of water temperature and thus warming has had marked and measurable impacts on their growth, population productivity, and spatial distribution 13 , 14 , 15 . In contrast, endotherms have a greater capacity to maintain a constant body temperature by altering metabolic heat production in response to temperature fluctuations, but physiological thermal limits still constrain spatial distribution at broad scales 16 . Understanding the pace of climate change, or climate velocity, is key to understanding species responses in a given habitat 17 , 18 . It is generally thought that species must keep up with the pace of climate change in order to survive 4 , 17 . However, there is some controversy as to the relative degree to which climate velocity versus species traits explain range shifts. In marine ecosystems, previous studies have found that species traits do not strongly influence a species’ response to climate velocity 4 , 19 while others have found that species’ traits were key to explaining range shifts 20 . However, these studies focus on ectotherms. For endothermic marine predators, the relative importance of direct thermoregulatory responses vs. indirect effects mediated by prey dynamics in marine predators is critical to understanding how they may respond to climate change 21 , 22 . Since marine mammals are large and abundant endothermic predators with higher metabolic rates than ectotherms, their large prey requirements regulate marine foodwebs 23 , 24 , 25 and differential climate responses between these predators and their ectothermic prey would have formidable impacts on the resilience and stability of marine ecosystems 26 , 27 . Thus, considering traits including thermoregulatory strategy is critical to understanding species range shifts across many taxa. For endotherms, the use of elevated metabolism to maintain a constant body temperature consumes a major part of the energetic budget at environmental temperatures above or below the thermoneutral zone 28 . Cetaceans spend their whole life underwater, and thus warming waters may be more likely to directly impact thermoregulation in cetaceans than other marine endotherms such as flying seabirds that are not constantly immersed in a highly conductive environment. While thermal tolerances of cetaceans are not well understood, in broad terms, different taxonomic groups of cetaceans are known to vary considerably in their thermal tolerances. Baleen whales undertake long annual migrations between high latitude feeding grounds and tropical breeding grounds and are adapted to occur in a wide range of temperatures 29 . Conversely, most odontocetes have more limited ranges and their morphology and physiology reflect adaptations to the thermal conditions in their range. For example, cooler water species typically have lower surface area to volume ratios in their body core, and blubber with a higher lipid content, lower conductivity, and increased fatty acid stratification 30 , 31 . The larger appendages of long-finned pilot whales in comparison to short-finned pilot whales may reflect the need for enhanced mechanisms of heat dissipation in the large, well-insulated long-finned species, which occurs in cooler waters 32 . Distributions of many cetacean species are expected to move poleward under climate change 33 , 34 , resulting in range contractions for cool water species, poleward distributional shifts for temperate species, and range expansions for warm water species 21 . There is evidence that considerable distributional shifts have occurred in marine mammal species in recent decades, with changes in the occurrence of cool and warm water cetacean species occurring in association with warming waters 35 , 36 , 37 , 38 . However, our ability to quantify distributional shifts in marine mammals is limited by the lack of reliable time series of abundance and distribution for most species 36 . Measuring long-term changes in cetacean populations presents a considerable challenge for biologists and managers 39 , 40 ; at-sea sightings rates from line transect surveys used to assess abundance are low, necessitating high survey effort to produce abundance estimates 41 . Consistent, standardized surveys with sufficient temporal and spatial coverage to detect distributional shifts over decades are not typically feasible and standardized monitoring effort for cetaceans in US waters is likely insufficient for detecting trends in the abundance and distribution of cetacean populations 40 , 41 . Observations from stranding events", "role": "user" }, { "content": "Climate change is redistributing biodiversity globally, and distributional shifts of organisms often follow the speed and direction of environmental changes. Research by scientists at Stony Brook University's School of Marine and Atmospheric Sciences (SoMAS) reveals that this phenomenon is affecting where large marine mammals are distributed relative to their prey species, which could have important implications for marine food web dynamics. Their findings are published in Scientific Reports. Marine mammals (endotherms) such as whales and dolphins are often assumed to shift their movements and distribution in response to warming waters more slowly than their ectothermic prey, such as fish and squid, whose growth and productivity is directly impacted by water temperature. Since marine mammals are large, highly mobile and occur across wide geographic ranges, distributional shifts in these species are difficult to quantify. In this study, data from fisheries bycatch and stranding events is used to examine changes in the distribution of long-finned pilot whales and their prey relative to climate velocity in a rapidly warming region of the Northwest Atlantic. \"We found that long-finned pilot whales in the Northeast US shifted poleward over a 25-year period as water temperatures warmed rapidly—and at a very fast rate,\" says Lesley Thorne, Ph.D., Assistant Professor in SoMAS and lead author. \"The question was whether they were following rapidly shifting prey species or responding directly to environmental change.\" Thorne and co-author Janet Nye, Ph.D., Associate Professor at the University of North Carolina Institute of Marine Sciences and an Adjunct Professor at SoMAS, analyzed trends in water temperature and the distribution of fish, squid and long-finned pilot whales from 1992 to 2016. They found that the poleward shift in pilot whale distribution was faster than expected based on climate velocity, which describes the pace of climate change, and more than three times the rate of fish and invertebrate prey species. The authors said the four fish and squid prey species they examined were shifting as expected or slower than expected. \"Fish and squid species that were shifting slower than expected moved into deeper offshore waters, possibly seeking cooler waters by moving deeper in the water column. As air breathing vertebrates that undertake short, though deep, dives, pilot whales don't have the option of remaining at deep depths,\" says Thorne. Thorne and Nye explain that this case study suggests that species traits, such as body size, mobility, thermoregulatory strategy, and longitudinal range, rather than climate velocity alone, are key to understanding and anticipating climate responses in marine organisms. They also note that different responses of predator and prey species to warming could cause spatial mismatches in their distributions. \"Marine mammals are important consumers in marine ecosystems, and our analysis suggests that some species are shifting at a different rate than their prey,\" says Thorne. \"If climate change decouples relationships between marine mammals and their prey, this could have important implications for marine food web dynamics,\" she emphasizes. ", "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 Climate change is redistributing biodiversity globally and distributional shifts have been found to follow local climate velocities. It is largely assumed that marine endotherms such as cetaceans might shift more slowly than ectotherms in response to warming and would primarily follow changes in prey, but distributional shifts in cetaceans are difficult to quantify. Here we use data from fisheries bycatch and strandings to examine changes in the distribution of long-finned pilot whales ( Globicephala melas ), and assess shifts in pilot whales and their prey relative to climate velocity in a rapidly warming region of the Northwest Atlantic. We found a poleward shift in pilot whale distribution that exceeded climate velocity and occurred at more than three times the rate of fish and invertebrate prey species. Fish and invertebrates shifted at rates equal to or slower than expected based on climate velocity, with more slowly shifting species moving to deeper waters. We suggest that traits such as mobility, diet specialization, and thermoregulatory strategy are central to understanding and anticipating range shifts. Our findings highlight the potential for trait-mediated climate shifts to decouple relationships between endothermic cetaceans and their ectothermic prey, which has important implications for marine food web dynamics and ecosystem stability. Introduction While shifts in distribution 1 , 2 , 3 , 4 and productivity 5 , 6 in response to warming have been well documented in marine ectotherms 7 , 8 , direct impacts of climatic warming on marine endotherms are poorly understood 9 . As a result of differences in thermoregulatory mechanisms and energetic expenditure when faced with changing environmental temperatures, climate change may have fundamentally different impacts on ectotherms and endotherms 10 . It is largely assumed that ectotherms will respond more quickly to warming than endotherms 11 , 12 . The physiological performance of marine ectotherms is a function of water temperature and thus warming has had marked and measurable impacts on their growth, population productivity, and spatial distribution 13 , 14 , 15 . In contrast, endotherms have a greater capacity to maintain a constant body temperature by altering metabolic heat production in response to temperature fluctuations, but physiological thermal limits still constrain spatial distribution at broad scales 16 . Understanding the pace of climate change, or climate velocity, is key to understanding species responses in a given habitat 17 , 18 . It is generally thought that species must keep up with the pace of climate change in order to survive 4 , 17 . However, there is some controversy as to the relative degree to which climate velocity versus species traits explain range shifts. In marine ecosystems, previous studies have found that species traits do not strongly influence a species’ response to climate velocity 4 , 19 while others have found that species’ traits were key to explaining range shifts 20 . However, these studies focus on ectotherms. For endothermic marine predators, the relative importance of direct thermoregulatory responses vs. indirect effects mediated by prey dynamics in marine predators is critical to understanding how they may respond to climate change 21 , 22 . Since marine mammals are large and abundant endothermic predators with higher metabolic rates than ectotherms, their large prey requirements regulate marine foodwebs 23 , 24 , 25 and differential climate responses between these predators and their ectothermic prey would have formidable impacts on the resilience and stability of marine ecosystems 26 , 27 . Thus, considering traits including thermoregulatory strategy is critical to understanding species range shifts across many taxa. For endotherms, the use of elevated metabolism to maintain a constant body temperature consumes a major part of the energetic budget at environmental temperatures above or below the thermoneutral zone 28 . Cetaceans spend their whole life underwater, and thus warming waters may be more likely to directly impact thermoregulation in cetaceans than other marine endotherms such as flying seabirds that are not constantly immersed in a highly conductive environment. While thermal tolerances of cetaceans are not well understood, in broad terms, different taxonomic groups of cetaceans are known to vary considerably in their thermal tolerances. Baleen whales undertake long annual migrations between high latitude feeding grounds and tropical breeding grounds and are adapted to occur in a wide range of temperatures 29 . Conversely, most odontocetes have more limited ranges and their morphology and physiology reflect adaptations to the thermal conditions in their range. For example, cooler water species typically have lower surface area to volume ratios in their body core, and blubber with a higher lipid content, lower conductivity, and increased fatty acid stratification 30 , 31 . The larger appendages of long-finned pilot whales in comparison to short-finned pilot whales may reflect the need for enhanced mechanisms of heat dissipation in the large, well-insulated long-finned species, which occurs in cooler waters 32 . Distributions of many cetacean species are expected to move poleward under climate change 33 , 34 , resulting in range contractions for cool water species, poleward distributional shifts for temperate species, and range expansions for warm water species 21 . There is evidence that considerable distributional shifts have occurred in marine mammal species in recent decades, with changes in the occurrence of cool and warm water cetacean species occurring in association with warming waters 35 , 36 , 37 , 38 . However, our ability to quantify distributional shifts in marine mammals is limited by the lack of reliable time series of abundance and distribution for most species 36 . Measuring long-term changes in cetacean populations presents a considerable challenge for biologists and managers 39 , 40 ; at-sea sightings rates from line transect surveys used to assess abundance are low, necessitating high survey effort to produce abundance estimates 41 . Consistent, standardized surveys with sufficient temporal and spatial coverage to detect distributional shifts over decades are not typically feasible and standardized monitoring effort for cetaceans in US waters is likely insufficient for detecting trends in the abundance and distribution of cetacean populations 40 , 41 . Observations from stranding events<|im_end|> <|im_start|>assistant Climate change is redistributing biodiversity globally, and distributional shifts of organisms often follow the speed and direction of environmental changes. Research by scientists at Stony Brook University's School of Marine and Atmospheric Sciences (SoMAS) reveals that this phenomenon is affecting where large marine mammals are distributed relative to their prey species, which could have important implications for marine food web dynamics. Their findings are published in Scientific Reports. Marine mammals (endotherms) such as whales and dolphins are often assumed to shift their movements and distribution in response to warming waters more slowly than their ectothermic prey, such as fish and squid, whose growth and productivity is directly impacted by water temperature. Since marine mammals are large, highly mobile and occur across wide geographic ranges, distributional shifts in these species are difficult to quantify. In this study, data from fisheries bycatch and stranding events is used to examine changes in the distribution of long-finned pilot whales and their prey relative to climate velocity in a rapidly warming region of the Northwest Atlantic. "We found that long-finned pilot whales in the Northeast US shifted poleward over a 25-year period as water temperatures warmed rapidly—and at a very fast rate," says Lesley Thorne, Ph.D., Assistant Professor in SoMAS and lead author. "The question was whether they were following rapidly shifting prey species or responding directly to environmental change." Thorne and co-author Janet Nye, Ph.D., Associate Professor at the University of North Carolina Institute of Marine Sciences and an Adjunct Professor at SoMAS, analyzed trends in water temperature and the distribution of fish, squid and long-finned pilot whales from 1992 to 2016. They found that the poleward shift in pilot whale distribution was faster than expected based on climate velocity, which describes the pace of climate change, and more than three times the rate of fish and invertebrate prey species. The authors said the four fish and squid prey species they examined were shifting as expected or slower than expected. "Fish and squid species that were shifting slower than expected moved into deeper offshore waters, possibly seeking cooler waters by moving deeper in the water column. As air breathing vertebrates that undertake short, though deep, dives, pilot whales don't have the option of remaining at deep depths," says Thorne. Thorne and Nye explain that this case study suggests that species traits, such as body size, mobility, thermoregulatory strategy, and longitudinal range, rather than climate velocity alone, are key to understanding and anticipating climate responses in marine organisms. They also note that different responses of predator and prey species to warming could cause spatial mismatches in their distributions. "Marine mammals are important consumers in marine ecosystems, and our analysis suggests that some species are shifting at a different rate than their prey," says Thorne. "If climate change decouples relationships between marine mammals and their prey, this could have important implications for marine food web dynamics," she emphasizes. <|im_end|>

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1,872

[ { "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 Orthogonal to guided growth of nanoparticle (NP) crystals using DNA or supramolecules, a trace amount of polymeric impurities (<0.1 wt.%) leads to reproducible, rapid growth of 3D NP crystals in solution and on patterned substrates with high yield. When polymers preferentially precipitate on the NP surfaces, small NP clusters form and serve as nuclei for NP crystal growth in dilute solutions. This precipitation-induced NP crystallization process is applicable for a range of polymers, and the resultant 3-D NP crystals are tunable by varying polymeric additives loading, solvent evaporation rate, and NP size. The present study elucidates how to balance cohesive energy density and NP diffusivity to simultaneously favor nuclei formation energetically and kinetic growth in dilute solutions to rapidly crystalize NPs over multiple length scales. Furthermore, the amount of impurities needed to grow NP crystals (<0.1%) reminds us the importance of fine details to interpret experimental observations in nanoscience. Introduction Crystallization is a ubiquitous process seen in most, if not all, classes of matter. Nanoparticles (NPs) are ideal systems for visualizing and understanding crystallization processes 1 , 2 and can serve as building blocks for new classes of materials 3 , 4 . A dazzling array of NP crystals has been achieved by engineering complimentary interactions, e.g., by attaching DNA ligands 5 , 6 , 7 . To achieve highly ordered NP crystals, adequate system mobility must be maintained during the assembly process. While the initial stages of the nucleation process are still open to debate, it is commonly accepted that the critical nucleus size depends on the balance between the NP/solvent interfacial interactions and the NP/NP cohesive energy stored within the nucleus 8 . Nuclei are energetically stable at elevated NP concentrations 9 and/or with strong ligand interactions. The NP mobility scales inversely with the NP concentration and the strength of the ligand pair interactions. Different strategies have been employed to expand the processing window for NP crystallization, including controlled solvent evaporation, interface-mediated assembly 10 , 11 , 12 , emulsion-based assembly 13 , 14 , and slow cooling of concentrated/supersaturated solutions 15 . However, it remains challenging to control the crystallization kinetics so that high-quality NP crystals can be rapidly and reliably fabricated. Precipitating agents such as salts, solvents, and polymers have been used to drive and accelerate the crystallization of small molecules and proteins 16 , 17 , 18 , 19 . These additives can alter the molecular interactions to either stabilize the intermediate phase 19 , 20 or to reduce the solubility of the crystallizing species 21 . Adapting this concept for NP crystallization may lead to control over the assembly kinetics and pathways, but has not yet been experimentally explored. Here, we hypothesize that by introducing polymers with poor solubility, NP surfaces may be the preferred precipitating sites and the adsorbed polymers gradually change the NP surface chemistry. To minimize nonfavorable NP-solvent interactions, NPs form small clusters, which subsequently act as nuclei to initiate NP crystallization within a dilute solution (Fig. 1a ). Given sufficient NP mobility, rapid NP crystallization is realized, and the more attractive ligand–ligand interactions lead to desorption of the polymer precipitates to achieve a high degree of crystalline order. Here, we test this hypothesis and experimentally realize polymer precipitation-induced crystallization of polymer-grafted NPs (PGNPs). 3D PGNP clusters can be obtained rapidly (in a few to tens of minutes) using a range of polymers, including impurities from plastic containers. The polymeric precipitants indeed lead to small PGNP clusters with poor local order. These clusters subsequently grow into large 3D PGNP crystals. Detailed tomography analysis of a 3D PGNP crystal with single-particle resolution confirms the presence of defects and reduced positional order of NPs at the surfaces and edges, suggesting rather weak cohesive energy and slow local NP diffusion. This precipitating additive approach is facile where the PGNP crystal formation depends on polymeric additive loading, solvent evaporation rate, PGNP size, and nucleation sites. As an example, a patterned substrate is used to grow hierarchically ordered arrays of PGNP crystals with controlled size, location, and orientation. Fig. 1: Polymer precipitation-induced PGNP crystallization in solution during solvent evaporation. a Schematic of polymer precipitant-induced PGNP crystallization: the added polymers precipitate onto PGNP surfaces to form small PGNP clusters that grow into crystals. b Representative TEM images of PGNP assemblies of (1.7k) Au-PS 0.70 NPs with various polymer precipitants. See “Methods” for detailed polymer information. Scale bars are 100 nm for PNIPAM-COOH and PS-b-PHEMAC, 1 μm for PBd-COOH and PP/PE, and 20 nm for all inset images. c SAXS results of PGNP crystals in a toluene solution of (5.3k) Au-PS 0.60 NPs with PP/PE. A simulated scattering profile of a perfect bcc lattice is shown for reference. d In situ SAXS studies of toluene solutions of (1.7k) Au-PS 0.70 NPs and PP/PE during the drying process. Plots are offset for clarity. e PGNP crystal growth in a toluene solution of (1.7k) Au-PS 0.70 NPs and PP/PE over time. Data points reflect the peak integration ratio between the sharp diffraction peak at q ~ 0.1 Å −1 in d from PGNPs in crystals and the broad peak from PGNPs in the solution. f TEM images of (1.7k) Au-PS 0.70 NP assemblies with PP/PE upon fast solvent removal. Scale bars are 20 nm. PGNPs were dispersed at \${\\varnothing }_{{\\mathrm{NP}}}=0.1{\\rm{vol}}. \\%\$ with \${\\varnothing}_{{\\mathrm{PP}}/{{\\mathrm{PE}}}}\$ = \$0.08{\\rm{vol}}. \\%\$ and all other polymers at \${{{\\varnothing }}}_{{\\mathrm{polymer}}}\$ = \$0.2{\\rm{vol}}. \\%\$ . Full size image Results Polymer precipitation leads to PGNP crystallization in solution PGNPs were chosen as building blocks due to their programmability and diverse ligand chemistries 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . Gold NPs grafted with thiol end-functionalized polystyrene (PS) ligands were well dispersed in toluene (Supplementary Figs. S1 – 5 and Supplementary Table 1 ). A series of polymers were employed as precipitates with nonfavorable interactions with toluene and the PS ligands. Figure 1b shows the transmission electron microscopy (TEM) images of PGNP crystals in the presence of carboxylic acid terminated", "role": "user" }, { "content": "Crystallization is one of the most fundamental processes found in nature—and it's what gives minerals, gems, metals, and even proteins their structure. In the past couple of decades, scientists have tried to uncover how natural crystals self-assemble and grow—and their pioneering work has led to some exciting new technologies—from the quantum dots behind colorful QLED TV displays, to peptoids, a protein-mimic that has inspired dozens of biotech breakthroughs. Now, a research team led by scientists at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) and UC Berkeley has developed a nanoparticle composite that grows into 3-D crystals. The scientists say that the new material—which they call a 3D PGNP (polymer-grafted nanoparticle) crystal in their recently published Nature Communications study—could lead to new technologies that are 3D-grown rather than 3D-printed. \"We've demonstrated a new lever to turn, so to speak, to grow a crystalline material into a composite or structured material for applications ranging from nanoscale photonics for smart buildings to actuators for robotics,\" said Ting Xu, senior author of the study. Xu is a faculty senior scientist in Berkeley Lab's Materials Sciences Division and professor of chemistry and materials science and engineering at UC Berkeley. Xu said that their new method is compatible with the demands of mass manufacturing. \"Many smart minds have designed elegant chemistries, such as DNAs and supramolecules, to crystallize nanoparticles. Our system is essentially a blend of nanoparticle and polymers—which are similar to the ingredients people use to make airplane wings or automobile bumpers. But what's even more interesting is that we didn't expect our method to be so simple and so fast,\" Xu said. A chance discovery Lead author Yiwen Qian, a Ph.D. student researcher in the Xu Group at UC Berkeley, discovered the 3D PGNP nanocrystals by chance in an ordinary lab experiment. A couple of days before, she had left a solution of toluene solvent and gold nanoparticles grafted with polystyrene (Au-PS) in a centrifuge tube on a lab counter. When she looked at the sample under a transmission electron microscope (TEM), she noticed something odd. \"Nanoparticles had crystallized quickly. That was not a normal thing to expect,\" she said. To investigate, Xu collaborated with Peter Ercius, a staff scientist at Berkeley Lab's Molecular Foundry, and Wolfgang Theis and Alessandra DaSilva of the University of Birmingham, all of whom are widely regarded for their expertise in STEM (scanning transmission electron microscopy) tomography, an electron microscopy technique that uses a highly focused beam of electrons to reconstruct images of a material's 3D structure at high resolution. Using microscopes at the Molecular Foundry, a world-leading user facility in STEM tomography, the researchers first captured crystalline 3D patterns of the Au-PS nanoparticles. On the hunt for more clues, Xu and Qian then deployed nuclear magnetic resonance spectroscopy experiments at UC Berkeley, where they discovered that a tiny trace of polyolefin molecules from the centrifuge tube lining had somehow entered the mix. Polyolefins, which include polyethylene and polypropylene, are some of the most ubiquitous plastics in the world. Using microscopes at Berkeley Lab's Molecular Foundry, a world-leading user facility in STEM tomography, Ting Xu and her research team captured crystalline 3D patterns of gold-polystyrene nanoparticles. Credit: Berkeley Lab Qian repeated the experiment, adding more polyolefin to the Au-PS solution—and this time, they got bigger 3D PGNP crystals within minutes. Xu was surprised. \"I thought, 'This shouldn't be happening so fast,'\" she recalled. \"Crystals of nanoparticles usually take days to grow in the lab.\" A boon for industry: growing materials at the nanolevel Subsequent experiments revealed that as the toluene solvent quickly evaporates at room temperature, the polyolefin additive helps the Au-PS nanoparticles form into 3D PGNP crystals, and to \"grow into their favorite crystal structure,\" said Qian. In another key experiment, the researchers designed a self-assembling 100-200-nanometer crystalline disk that looks like the base of a pyramid. From this stunning demonstration of mastery over matter at the nanolevel, the researchers learned that the size and shape of the 3D PGNP crystals are driven by the kinetic energy of the polyolefins as they precipitate in the solution. Altogether, these findings \"provide a model for showing how you can control the crystal structure at the single particle level,\" Xu said, adding that their discovery is exciting because it provides new insight into how crystals form during the early stages of nucleation. \"And that's challenging to do because it's hard to make atoms sit next to each other,\" Ercius said. The new approach could grant researchers unprecedented control in fine-tuning electronic and optical devices at the nanolevel (billionths of a meter), Xu said. Such nanoparticle-scale precision, she added, could speed up production and eliminate errors in manufacturing. Looking ahead, Qian would like to use their new technique to probe the toughness of different crystal structures—and perhaps even make a hexagonal crystal. Xu plans to use their technique to grow bigger devices such as a transistor or perhaps 3D-print nanoparticles from a mix of materials. \"What can you do with different morphologies? We've shown that it's possible to generate a single-component composite from a mineral and a polymer. It's really exciting. Sometimes you just need to be in the right place at the right time,\" Xu said. Co-authors on the paper include Alessandra da Silva and Wolfgang Theis at the University of Birmingham in the United Kingdom; Emmy Yu, an undergraduate student researcher in the Xu Group at UC Berkeley; and Christopher L. Anderson and Yi Liu at Berkeley Lab's Molecular Foundry. ", "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 Orthogonal to guided growth of nanoparticle (NP) crystals using DNA or supramolecules, a trace amount of polymeric impurities (<0.1 wt.%) leads to reproducible, rapid growth of 3D NP crystals in solution and on patterned substrates with high yield. When polymers preferentially precipitate on the NP surfaces, small NP clusters form and serve as nuclei for NP crystal growth in dilute solutions. This precipitation-induced NP crystallization process is applicable for a range of polymers, and the resultant 3-D NP crystals are tunable by varying polymeric additives loading, solvent evaporation rate, and NP size. The present study elucidates how to balance cohesive energy density and NP diffusivity to simultaneously favor nuclei formation energetically and kinetic growth in dilute solutions to rapidly crystalize NPs over multiple length scales. Furthermore, the amount of impurities needed to grow NP crystals (<0.1%) reminds us the importance of fine details to interpret experimental observations in nanoscience. Introduction Crystallization is a ubiquitous process seen in most, if not all, classes of matter. Nanoparticles (NPs) are ideal systems for visualizing and understanding crystallization processes 1 , 2 and can serve as building blocks for new classes of materials 3 , 4 . A dazzling array of NP crystals has been achieved by engineering complimentary interactions, e.g., by attaching DNA ligands 5 , 6 , 7 . To achieve highly ordered NP crystals, adequate system mobility must be maintained during the assembly process. While the initial stages of the nucleation process are still open to debate, it is commonly accepted that the critical nucleus size depends on the balance between the NP/solvent interfacial interactions and the NP/NP cohesive energy stored within the nucleus 8 . Nuclei are energetically stable at elevated NP concentrations 9 and/or with strong ligand interactions. The NP mobility scales inversely with the NP concentration and the strength of the ligand pair interactions. Different strategies have been employed to expand the processing window for NP crystallization, including controlled solvent evaporation, interface-mediated assembly 10 , 11 , 12 , emulsion-based assembly 13 , 14 , and slow cooling of concentrated/supersaturated solutions 15 . However, it remains challenging to control the crystallization kinetics so that high-quality NP crystals can be rapidly and reliably fabricated. Precipitating agents such as salts, solvents, and polymers have been used to drive and accelerate the crystallization of small molecules and proteins 16 , 17 , 18 , 19 . These additives can alter the molecular interactions to either stabilize the intermediate phase 19 , 20 or to reduce the solubility of the crystallizing species 21 . Adapting this concept for NP crystallization may lead to control over the assembly kinetics and pathways, but has not yet been experimentally explored. Here, we hypothesize that by introducing polymers with poor solubility, NP surfaces may be the preferred precipitating sites and the adsorbed polymers gradually change the NP surface chemistry. To minimize nonfavorable NP-solvent interactions, NPs form small clusters, which subsequently act as nuclei to initiate NP crystallization within a dilute solution (Fig. 1a ). Given sufficient NP mobility, rapid NP crystallization is realized, and the more attractive ligand–ligand interactions lead to desorption of the polymer precipitates to achieve a high degree of crystalline order. Here, we test this hypothesis and experimentally realize polymer precipitation-induced crystallization of polymer-grafted NPs (PGNPs). 3D PGNP clusters can be obtained rapidly (in a few to tens of minutes) using a range of polymers, including impurities from plastic containers. The polymeric precipitants indeed lead to small PGNP clusters with poor local order. These clusters subsequently grow into large 3D PGNP crystals. Detailed tomography analysis of a 3D PGNP crystal with single-particle resolution confirms the presence of defects and reduced positional order of NPs at the surfaces and edges, suggesting rather weak cohesive energy and slow local NP diffusion. This precipitating additive approach is facile where the PGNP crystal formation depends on polymeric additive loading, solvent evaporation rate, PGNP size, and nucleation sites. As an example, a patterned substrate is used to grow hierarchically ordered arrays of PGNP crystals with controlled size, location, and orientation. Fig. 1: Polymer precipitation-induced PGNP crystallization in solution during solvent evaporation. a Schematic of polymer precipitant-induced PGNP crystallization: the added polymers precipitate onto PGNP surfaces to form small PGNP clusters that grow into crystals. b Representative TEM images of PGNP assemblies of (1.7k) Au-PS 0.70 NPs with various polymer precipitants. See “Methods” for detailed polymer information. Scale bars are 100 nm for PNIPAM-COOH and PS-b-PHEMAC, 1 μm for PBd-COOH and PP/PE, and 20 nm for all inset images. c SAXS results of PGNP crystals in a toluene solution of (5.3k) Au-PS 0.60 NPs with PP/PE. A simulated scattering profile of a perfect bcc lattice is shown for reference. d In situ SAXS studies of toluene solutions of (1.7k) Au-PS 0.70 NPs and PP/PE during the drying process. Plots are offset for clarity. e PGNP crystal growth in a toluene solution of (1.7k) Au-PS 0.70 NPs and PP/PE over time. Data points reflect the peak integration ratio between the sharp diffraction peak at q ~ 0.1 Å −1 in d from PGNPs in crystals and the broad peak from PGNPs in the solution. f TEM images of (1.7k) Au-PS 0.70 NP assemblies with PP/PE upon fast solvent removal. Scale bars are 20 nm. PGNPs were dispersed at ${\varnothing }_{{\mathrm{NP}}}=0.1{\rm{vol}}. \%$ with ${\varnothing}_{{\mathrm{PP}}/{{\mathrm{PE}}}}$ = $0.08{\rm{vol}}. \%$ and all other polymers at ${{{\varnothing }}}_{{\mathrm{polymer}}}$ = $0.2{\rm{vol}}. \%$ . Full size image Results Polymer precipitation leads to PGNP crystallization in solution PGNPs were chosen as building blocks due to their programmability and diverse ligand chemistries 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . Gold NPs grafted with thiol end-functionalized polystyrene (PS) ligands were well dispersed in toluene (Supplementary Figs. S1 – 5 and Supplementary Table 1 ). A series of polymers were employed as precipitates with nonfavorable interactions with toluene and the PS ligands. Figure 1b shows the transmission electron microscopy (TEM) images of PGNP crystals in the presence of carboxylic acid terminated<|im_end|> <|im_start|>assistant Crystallization is one of the most fundamental processes found in nature—and it's what gives minerals, gems, metals, and even proteins their structure. In the past couple of decades, scientists have tried to uncover how natural crystals self-assemble and grow—and their pioneering work has led to some exciting new technologies—from the quantum dots behind colorful QLED TV displays, to peptoids, a protein-mimic that has inspired dozens of biotech breakthroughs. Now, a research team led by scientists at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) and UC Berkeley has developed a nanoparticle composite that grows into 3-D crystals. The scientists say that the new material—which they call a 3D PGNP (polymer-grafted nanoparticle) crystal in their recently published Nature Communications study—could lead to new technologies that are 3D-grown rather than 3D-printed. "We've demonstrated a new lever to turn, so to speak, to grow a crystalline material into a composite or structured material for applications ranging from nanoscale photonics for smart buildings to actuators for robotics," said Ting Xu, senior author of the study. Xu is a faculty senior scientist in Berkeley Lab's Materials Sciences Division and professor of chemistry and materials science and engineering at UC Berkeley. Xu said that their new method is compatible with the demands of mass manufacturing. "Many smart minds have designed elegant chemistries, such as DNAs and supramolecules, to crystallize nanoparticles. Our system is essentially a blend of nanoparticle and polymers—which are similar to the ingredients people use to make airplane wings or automobile bumpers. But what's even more interesting is that we didn't expect our method to be so simple and so fast," Xu said. A chance discovery Lead author Yiwen Qian, a Ph.D. student researcher in the Xu Group at UC Berkeley, discovered the 3D PGNP nanocrystals by chance in an ordinary lab experiment. A couple of days before, she had left a solution of toluene solvent and gold nanoparticles grafted with polystyrene (Au-PS) in a centrifuge tube on a lab counter. When she looked at the sample under a transmission electron microscope (TEM), she noticed something odd. "Nanoparticles had crystallized quickly. That was not a normal thing to expect," she said. To investigate, Xu collaborated with Peter Ercius, a staff scientist at Berkeley Lab's Molecular Foundry, and Wolfgang Theis and Alessandra DaSilva of the University of Birmingham, all of whom are widely regarded for their expertise in STEM (scanning transmission electron microscopy) tomography, an electron microscopy technique that uses a highly focused beam of electrons to reconstruct images of a material's 3D structure at high resolution. Using microscopes at the Molecular Foundry, a world-leading user facility in STEM tomography, the researchers first captured crystalline 3D patterns of the Au-PS nanoparticles. On the hunt for more clues, Xu and Qian then deployed nuclear magnetic resonance spectroscopy experiments at UC Berkeley, where they discovered that a tiny trace of polyolefin molecules from the centrifuge tube lining had somehow entered the mix. Polyolefins, which include polyethylene and polypropylene, are some of the most ubiquitous plastics in the world. Using microscopes at Berkeley Lab's Molecular Foundry, a world-leading user facility in STEM tomography, Ting Xu and her research team captured crystalline 3D patterns of gold-polystyrene nanoparticles. Credit: Berkeley Lab Qian repeated the experiment, adding more polyolefin to the Au-PS solution—and this time, they got bigger 3D PGNP crystals within minutes. Xu was surprised. "I thought, 'This shouldn't be happening so fast,'" she recalled. "Crystals of nanoparticles usually take days to grow in the lab." A boon for industry: growing materials at the nanolevel Subsequent experiments revealed that as the toluene solvent quickly evaporates at room temperature, the polyolefin additive helps the Au-PS nanoparticles form into 3D PGNP crystals, and to "grow into their favorite crystal structure," said Qian. In another key experiment, the researchers designed a self-assembling 100-200-nanometer crystalline disk that looks like the base of a pyramid. From this stunning demonstration of mastery over matter at the nanolevel, the researchers learned that the size and shape of the 3D PGNP crystals are driven by the kinetic energy of the polyolefins as they precipitate in the solution. Altogether, these findings "provide a model for showing how you can control the crystal structure at the single particle level," Xu said, adding that their discovery is exciting because it provides new insight into how crystals form during the early stages of nucleation. "And that's challenging to do because it's hard to make atoms sit next to each other," Ercius said. The new approach could grant researchers unprecedented control in fine-tuning electronic and optical devices at the nanolevel (billionths of a meter), Xu said. Such nanoparticle-scale precision, she added, could speed up production and eliminate errors in manufacturing. Looking ahead, Qian would like to use their new technique to probe the toughness of different crystal structures—and perhaps even make a hexagonal crystal. Xu plans to use their technique to grow bigger devices such as a transistor or perhaps 3D-print nanoparticles from a mix of materials. "What can you do with different morphologies? We've shown that it's possible to generate a single-component composite from a mineral and a polymer. It's really exciting. Sometimes you just need to be in the right place at the right time," Xu said. Co-authors on the paper include Alessandra da Silva and Wolfgang Theis at the University of Birmingham in the United Kingdom; Emmy Yu, an undergraduate student researcher in the Xu Group at UC Berkeley; and Christopher L. Anderson and Yi Liu at Berkeley Lab's Molecular Foundry. <|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 Predators and their protection are controversial worldwide. Gray wolves, Canis lupus , lost U.S. federal protection (delisting) and the State of Wisconsin began lethal management first among all states and tribes that regained authority over wolves. Here we evaluated the initial success of reaching the state’s explicit objective, “…to allow for a sustainable harvest that neither increases nor decreases the state’s wolf population…” We used official state figures for hunter-killed wolves, population estimates from April 2017–2020, and the latest peer-reviewed model of individual wolf survival to estimate additional deaths resulting from federal delisting. More than half of the additional deaths were predicted to be cryptic poaching under the assumption that this period resembled past periods of liberalized wolf-killing in Wisconsin. We used a precautionary approach to construct three conservative scenarios to predict the current status of this wolf population and a minimum estimate of population decline since April 2020. From our scenarios that vary in growth rates and additional mortality estimates, we expect a maximum of 695–751 wolves to be alive in Wisconsin by 15 April 2021, a minimum 27–33% decline in the preceding 12 months. This contradicts the state expectation of no change in the population size. We draw a conclusion about the adequacy of regulatory mechanisms under state control of wolves and discuss the particular governance conditions met in Wisconsin. We recommend greater rigor and independent review of the science used by agencies to plan wolf hunting quotas and methods. We recommend clearer division of duties between state wildlife agencies, legislatures, and courts. We recommend federal governments reconsider the practice of sudden deregulation of wolf management and instead recommend they consider protecting predators as non-game or transition more slowly to subnational authority, to avoid the need for emergency relisting. Cite this as Treves A, Santiago-Ávila FJ, Putrevu K. 2021 . Quantifying the effects of delisting wolves after the first state began lethal management . PeerJ 9 : e11666 Main article text Introduction Wolves and their protection are controversial worldwide and across the U.S. ( Bruskotter et al., 2018 ; Manfredo et al., 2020 ; Treves & Martin, 2011 ; Chapron et al., 2014 ; Dressel, Sandström & Ericsson, 2014 ). The U.S. Endangered Species Act (ESA) aims to remove listed species (delist) from federal protection once recovered but contingent on adequate regulations in subnational jurisdictions to keep them off the federal list. Two U.S. Presidential Administrations have proposed the removal of federal protections for gray wolves ( Canis lupus ) nationwide but faced dissent by majorities (if not unanimity) of their official panels of scientists ( NCEAS, 2014 ; Atkins, 2019 ). The Trump administration went ahead anyway and announced on 3 November 2020 it would transfer authority to states and tribes on 3 November 2020, declaring gray wolves recovered across most of the country under the Endangered Species Act, ESA ( USFWS, 2020 ). That decision asserts that the species met the criteria of the five-factor analysis (ESA 16 USC § 1531 Sec. 4(a)) among others. The five factors necessary for delisting altogether ensure the delisted species remains secure for the foreseeable future. One of those criteria is the adequacy of state and tribal (subnational) regulatory mechanisms ( Zellmer, Panarella & Wood, 2020 ; Erickson, 2012 ). Whether delisted wolves are being managed with adequate regulatory mechanisms by subnational jurisdictions seems in part a scientific question (as opposed to a values-based question), because the adequacy of the mechanisms depends on their effectiveness in regulating factors that might reverse conditions and endanger wolves again. Chief among those factors for wolves has been human-caused mortality in five U.S. wolf populations, since modern monitoring ( Treves et al., 2017 ), as in other regions ( Chapron et al., 2014 ; Boitani, 1995 ). We present a data point to support scientific evaluations of the adequacy of regulatory mechanisms in subnational jurisdictions, for the first state to implement recreational hunting in the wake of federal wolf delisting announced on 3 November 2020. The State of Wisconsin wolf policy and management between 2020–2021 offers an interesting case study for the following reasons. Wisconsin was the first subnational jurisdiction to resume lethal management of wolves after delisting. The State wildlife agency (Department of Natural Resources, DNR, Annapolis, MD, USA) was explicit about its goals for regulated wolf-hunting, “The quota’s objective is to allow for a sustainable harvest that neither increases nor decreases the state’s wolf population…” ( , accessed 14 April 2021) and similar statements to media before the wolf-hunt ( Anderson, 2021 ). There are two phrases and two parts of that objective that can be evaluated scientifically, that of “a sustainable harvest” and “neither increases nor decreases the state’s wolf population”. This language mirrors recent reviews of the topic that have estimated the average expected, threshold rate of human-caused mortality predicted to result in stability of wolf populations (i.e., no increase or decrease). The estimates of stabilizing levels of human-induced mortality that would be sustainable ranges from 28–29% ( Adams et al., 2008 ) to 5–10% lower estimates by ( Fuller et al., 2003 ; Creel & Rotella, 2010 ; Vucetich, 2012 ). A higher estimate by Gude et al. (2012) has been questioned because of seeming errors in calculations ( Vucetich, 2012 ), so their higher estimate needs replication or correction. We use the preceding meaning of sustainability, not the other meaning of sustain suggesting a wolf population can withstand 1 or 2 years of higher rates of mortality before extirpation. Our justification apart from the literature comes from the Wisconsin DNR itself, using the Adams et al. (2008) estimate in prior wolf-hunting plans ( Natural Resources Board, 2012 ; Natural Resources Board, 2014 ), citation of those quota plans in 2021 ( Natural Resources Board, 2021a ), and explicit mention of using a 24% threshold on 15 February 2021 ( Natural Resources Board, 2021b ). Evaluating sustainability of natural resource uses demands long-term data, so here we only discuss the 1-year outcome in light of the objectives. Nevertheless,", "role": "user" }, { "content": "About 100 additional wolves died over the winter in Wisconsin as a result of the delisting of grey wolves under the Endangered Species Act, alongside the 218 wolves killed by licensed hunters during Wisconsin's first public wolf hunt, according to new research. The combined loss of 313 to 323 wolves represents a decline in the state's wolf population of between 27% and 33% between April 2020 and April 2021. Researchers estimate that a majority of these additional, uncounted deaths are due to something called cryptic poaching, where poachers hide evidence of illegal killings. The findings are the first estimate of Wisconsin's wolf population since the public hunt in February, which ended early after hunters exceeded the quota of 119 wolves within a few days. These population estimates can help the Wisconsin Department of Natural Resources (DNR) prepare for the next legally mandated wolf hunt this fall. They also provide guidance to other states planning wolf hunts following the removal of federal protections announced in November 2020 and effective January 2021. University of Wisconsin-Madison environmental studies scientists Adrian Treves, Francisco Santiago-Ávila and Karann Putrevu performed the research, which was published July 5 in the journal PeerJ. Under a variety of population growth scenarios, the researchers estimate that Wisconsin now hosts between 695 and 751 wolves, compared with at least 1,034 wolves last year. The scientists say this likely represents the maximum current wolf population, because they incorporated optimistic assumptions about population growth and low poaching rates into their models. This decline is despite the hunting quota of 119 wolves for non-native hunters, set with the goal of helping maintain but not reduce the state's wolf population. Ojibwe Tribes were granted a quota of 81 wolves, but they did not conduct a hunt. \"Although the DNR is aiming for a stable population, we estimate the population actually dropped significantly,\" says Treves, a professor in the Nelson Institute for Environmental Studies and director of the Carnivore Coexistence Lab at UW-Madison. The new study suggests that about one-third of the population decline is due to hidden deaths in the wolf population, resulting from relaxed legal protections. Previous research by the Treves lab showed that wolf population growth declined in Wisconsin and Michigan when legal protections were relaxed, regardless of the number of wolves legally killed. And Santiago-Ávila led research that found that Wisconsin's wolves and the heavily monitored Mexican wolves of the American Southwest disappeared at greater rates when lethal control methods were allowed. Other studies by the lab of attitudes toward wolves suggest that when governments allow lethal management, would-be poachers are inclined to kill more wolves because the relaxed policies signal that predators are less valued. Those previous findings helped Santiago-Ávila, Putrevu and Treves model the uncounted deaths in Wisconsin since last November. \"During these periods, we see an effect on poaching, both reported and cryptic. Those wolves disappear and you never find them again,\" says Santiago-Ávila, a postdoctoral researcher in the lab. \"Additional deaths are caused simply by the policy signal, and the wolf hunt adds to that.\" Treves and his team estimate that the population could recover in one to two years without hunting. Wisconsin law requires a wolf hunt between November and February when hunting is not prohibited by federal protections. Following the federal delisting of wolves that became effective in January 2021, the DNR initially planned to conduct the first hunt in November 2021. But after a lawsuit, the DNR immediately implemented a wolf hunt at the end of February. The research team hopes that the Wisconsin DNR and other states' natural resource agencies take advantage of their methods to develop a more complete assessment of the effect of new policies on predator populations. \"These methods and models are freely available to these agencies,\" says Putrevu, a doctoral student who also researches tiger populations in the Russian Far East. \"They should take advantage of the best available science to meet their stated goals.\" ", "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 Predators and their protection are controversial worldwide. Gray wolves, Canis lupus , lost U.S. federal protection (delisting) and the State of Wisconsin began lethal management first among all states and tribes that regained authority over wolves. Here we evaluated the initial success of reaching the state’s explicit objective, “…to allow for a sustainable harvest that neither increases nor decreases the state’s wolf population…” We used official state figures for hunter-killed wolves, population estimates from April 2017–2020, and the latest peer-reviewed model of individual wolf survival to estimate additional deaths resulting from federal delisting. More than half of the additional deaths were predicted to be cryptic poaching under the assumption that this period resembled past periods of liberalized wolf-killing in Wisconsin. We used a precautionary approach to construct three conservative scenarios to predict the current status of this wolf population and a minimum estimate of population decline since April 2020. From our scenarios that vary in growth rates and additional mortality estimates, we expect a maximum of 695–751 wolves to be alive in Wisconsin by 15 April 2021, a minimum 27–33% decline in the preceding 12 months. This contradicts the state expectation of no change in the population size. We draw a conclusion about the adequacy of regulatory mechanisms under state control of wolves and discuss the particular governance conditions met in Wisconsin. We recommend greater rigor and independent review of the science used by agencies to plan wolf hunting quotas and methods. We recommend clearer division of duties between state wildlife agencies, legislatures, and courts. We recommend federal governments reconsider the practice of sudden deregulation of wolf management and instead recommend they consider protecting predators as non-game or transition more slowly to subnational authority, to avoid the need for emergency relisting. Cite this as Treves A, Santiago-Ávila FJ, Putrevu K. 2021 . Quantifying the effects of delisting wolves after the first state began lethal management . PeerJ 9 : e11666 Main article text Introduction Wolves and their protection are controversial worldwide and across the U.S. ( Bruskotter et al., 2018 ; Manfredo et al., 2020 ; Treves & Martin, 2011 ; Chapron et al., 2014 ; Dressel, Sandström & Ericsson, 2014 ). The U.S. Endangered Species Act (ESA) aims to remove listed species (delist) from federal protection once recovered but contingent on adequate regulations in subnational jurisdictions to keep them off the federal list. Two U.S. Presidential Administrations have proposed the removal of federal protections for gray wolves ( Canis lupus ) nationwide but faced dissent by majorities (if not unanimity) of their official panels of scientists ( NCEAS, 2014 ; Atkins, 2019 ). The Trump administration went ahead anyway and announced on 3 November 2020 it would transfer authority to states and tribes on 3 November 2020, declaring gray wolves recovered across most of the country under the Endangered Species Act, ESA ( USFWS, 2020 ). That decision asserts that the species met the criteria of the five-factor analysis (ESA 16 USC § 1531 Sec. 4(a)) among others. The five factors necessary for delisting altogether ensure the delisted species remains secure for the foreseeable future. One of those criteria is the adequacy of state and tribal (subnational) regulatory mechanisms ( Zellmer, Panarella & Wood, 2020 ; Erickson, 2012 ). Whether delisted wolves are being managed with adequate regulatory mechanisms by subnational jurisdictions seems in part a scientific question (as opposed to a values-based question), because the adequacy of the mechanisms depends on their effectiveness in regulating factors that might reverse conditions and endanger wolves again. Chief among those factors for wolves has been human-caused mortality in five U.S. wolf populations, since modern monitoring ( Treves et al., 2017 ), as in other regions ( Chapron et al., 2014 ; Boitani, 1995 ). We present a data point to support scientific evaluations of the adequacy of regulatory mechanisms in subnational jurisdictions, for the first state to implement recreational hunting in the wake of federal wolf delisting announced on 3 November 2020. The State of Wisconsin wolf policy and management between 2020–2021 offers an interesting case study for the following reasons. Wisconsin was the first subnational jurisdiction to resume lethal management of wolves after delisting. The State wildlife agency (Department of Natural Resources, DNR, Annapolis, MD, USA) was explicit about its goals for regulated wolf-hunting, “The quota’s objective is to allow for a sustainable harvest that neither increases nor decreases the state’s wolf population…” ( , accessed 14 April 2021) and similar statements to media before the wolf-hunt ( Anderson, 2021 ). There are two phrases and two parts of that objective that can be evaluated scientifically, that of “a sustainable harvest” and “neither increases nor decreases the state’s wolf population”. This language mirrors recent reviews of the topic that have estimated the average expected, threshold rate of human-caused mortality predicted to result in stability of wolf populations (i.e., no increase or decrease). The estimates of stabilizing levels of human-induced mortality that would be sustainable ranges from 28–29% ( Adams et al., 2008 ) to 5–10% lower estimates by ( Fuller et al., 2003 ; Creel & Rotella, 2010 ; Vucetich, 2012 ). A higher estimate by Gude et al. (2012) has been questioned because of seeming errors in calculations ( Vucetich, 2012 ), so their higher estimate needs replication or correction. We use the preceding meaning of sustainability, not the other meaning of sustain suggesting a wolf population can withstand 1 or 2 years of higher rates of mortality before extirpation. Our justification apart from the literature comes from the Wisconsin DNR itself, using the Adams et al. (2008) estimate in prior wolf-hunting plans ( Natural Resources Board, 2012 ; Natural Resources Board, 2014 ), citation of those quota plans in 2021 ( Natural Resources Board, 2021a ), and explicit mention of using a 24% threshold on 15 February 2021 ( Natural Resources Board, 2021b ). Evaluating sustainability of natural resource uses demands long-term data, so here we only discuss the 1-year outcome in light of the objectives. Nevertheless,<|im_end|> <|im_start|>assistant About 100 additional wolves died over the winter in Wisconsin as a result of the delisting of grey wolves under the Endangered Species Act, alongside the 218 wolves killed by licensed hunters during Wisconsin's first public wolf hunt, according to new research. The combined loss of 313 to 323 wolves represents a decline in the state's wolf population of between 27% and 33% between April 2020 and April 2021. Researchers estimate that a majority of these additional, uncounted deaths are due to something called cryptic poaching, where poachers hide evidence of illegal killings. The findings are the first estimate of Wisconsin's wolf population since the public hunt in February, which ended early after hunters exceeded the quota of 119 wolves within a few days. These population estimates can help the Wisconsin Department of Natural Resources (DNR) prepare for the next legally mandated wolf hunt this fall. They also provide guidance to other states planning wolf hunts following the removal of federal protections announced in November 2020 and effective January 2021. University of Wisconsin-Madison environmental studies scientists Adrian Treves, Francisco Santiago-Ávila and Karann Putrevu performed the research, which was published July 5 in the journal PeerJ. Under a variety of population growth scenarios, the researchers estimate that Wisconsin now hosts between 695 and 751 wolves, compared with at least 1,034 wolves last year. The scientists say this likely represents the maximum current wolf population, because they incorporated optimistic assumptions about population growth and low poaching rates into their models. This decline is despite the hunting quota of 119 wolves for non-native hunters, set with the goal of helping maintain but not reduce the state's wolf population. Ojibwe Tribes were granted a quota of 81 wolves, but they did not conduct a hunt. "Although the DNR is aiming for a stable population, we estimate the population actually dropped significantly," says Treves, a professor in the Nelson Institute for Environmental Studies and director of the Carnivore Coexistence Lab at UW-Madison. The new study suggests that about one-third of the population decline is due to hidden deaths in the wolf population, resulting from relaxed legal protections. Previous research by the Treves lab showed that wolf population growth declined in Wisconsin and Michigan when legal protections were relaxed, regardless of the number of wolves legally killed. And Santiago-Ávila led research that found that Wisconsin's wolves and the heavily monitored Mexican wolves of the American Southwest disappeared at greater rates when lethal control methods were allowed. Other studies by the lab of attitudes toward wolves suggest that when governments allow lethal management, would-be poachers are inclined to kill more wolves because the relaxed policies signal that predators are less valued. Those previous findings helped Santiago-Ávila, Putrevu and Treves model the uncounted deaths in Wisconsin since last November. "During these periods, we see an effect on poaching, both reported and cryptic. Those wolves disappear and you never find them again," says Santiago-Ávila, a postdoctoral researcher in the lab. "Additional deaths are caused simply by the policy signal, and the wolf hunt adds to that." Treves and his team estimate that the population could recover in one to two years without hunting. Wisconsin law requires a wolf hunt between November and February when hunting is not prohibited by federal protections. Following the federal delisting of wolves that became effective in January 2021, the DNR initially planned to conduct the first hunt in November 2021. But after a lawsuit, the DNR immediately implemented a wolf hunt at the end of February. The research team hopes that the Wisconsin DNR and other states' natural resource agencies take advantage of their methods to develop a more complete assessment of the effect of new policies on predator populations. "These methods and models are freely available to these agencies," says Putrevu, a doctoral student who also researches tiger populations in the Russian Far East. "They should take advantage of the best available science to meet their stated goals." <|im_end|>

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2,208

[ { "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 research field of magnonics 1 , 2 , 3 , 4 , 5 , 6 , 7 , it is envisaged that spin waves will be used as information carriers, promoting operation based on their wave properties. However, the field still faces major challenges. To become fully competitive, novel schemes for energy-efficient control of spin-wave propagation in two dimensions have to be realized on much smaller length scales than used before. In this Letter, we address these challenges with the experimental realization of a novel approach to guide spin waves in reconfigurable, nano-sized magnonic waveguides. For this purpose, we make use of two inherent characteristics of magnetism: the non-volatility of magnetic remanence states and the nanometre dimensions of domain walls formed within these magnetic configurations. We present the experimental observation and micromagnetic simulations of spin-wave propagation inside nano-sized domain walls and realize a first step towards a reconfigurable domain-wall-based magnonic nanocircuitry. Main In the last few years, the scientific community in the field of magnonics has made huge efforts to realize concepts to use spin waves for data processing. Quite recently, remarkable progress has been made, leading to prototype building blocks of a spin-wave-based logic 8 , 9 , 10 . Despite this progress, most concepts are based on sample layouts that are limited regarding their further optimization. Previous studies on spin-wave propagation on the nanoscale have relied on confinement in geometrically patterned waveguides 11 , but these lack the flexibility for manipulating the propagation path that is required for reprogrammable devices. On the microscale, this dynamic control of spin waves in two-dimensional structures has been realized, but it is based on the continuous application of external fields and thus requires high energy consumption. Here, we will present a possible way to overcome these challenges. Spin waves impinging on domain walls are either reflected or phase-shifted when transmitted, depending on their wavelength and the nature of the domain wall 12 , 13 , 14 , 15 , 16 . Additional studies have been devoted to the domain wall dynamics, which was found to be on the order of 10 MHz (ref. 17 ). However, the possibility to send spin waves along a domain wall has only been addressed in one numerical study for out-of-plane magnetization and with a very specific domain wall that is difficult to realize in experimental scenarios 18 . Here, we experimentally explore the intrinsic spin-wave eigenmodes that are quantized across the width of a domain wall and possess a well-defined wave vector along the wall that enables information transport. By targeting this class of largely unknown spin-wave modes, we focus on the potential of using domain walls as nanometre-scaled spin-wave channels to open new perspectives for the energy-efficient control of spin-wave propagation in two dimensions. The top part of Fig. 1a shows a schematic of a 180° Néel wall. The magnetic moments rotate within the sample plane, giving rise to magnetic volume charges ∇ · M , with opposite sign on the two sides of the domain-wall centre. The red curve in Fig. 1a illustrates these volume charges calculated by means of micromagnetic simulations. The charges generate a strong magnetostatic field H demag (blue curve in Fig. 1a ) oriented antiparallel to the magnetization in the centre of the domain wall, resulting in a locally decreased effective magnetic field. Because spin-wave resonances depend on the effective field, locally decreased fields can form potential wells for localized modes 19 , 20 . Here, a potential well is created across the domain wall with a width of a few tens of nanometres. This width strongly depends on various parameters of magnetic materials and can be tuned towards even smaller sizes. In this Letter, we demonstrate experimentally and numerically that such a potential well leads to spin-wave modes that are strongly localized to the domain-wall width and travel freely along the wall. Moreover, and in contrast to the vast majority of experimentally realized scenarios, no energy-consuming external bias fields are needed to promote spin-wave propagation in the preferred geometry 10 along the domain wall. Figure 1: Channelling principle, sample geometry and magnetization configuration. a , Schematic illustration of a 180° Néel wall carrying a spin wave. The divergence of the magnetization ∇ · M across the width of the wall shows opposite sign on the two sides of the domain wall centre and results in a strong magnetostatic field H demag oriented antiparallel to the magnetization direction. This potential well confines the spin-wave propagation into the narrow region of the wall. b , SEM image of the investigated Py structure and the microwave antenna for the external excitation of spin dynamics. Inset (lower right): magnetic field sweep used to initialize the domain configuration. c , The black–white contrast of the Kerr microscopy image confirms the formation of a Landau-like domain pattern. Arrows indicate the magnetization direction in the domains. Full size image Figure 1b presents a scanning electron microscopy (SEM) image of the structure used in the experiment. A 40-nm-thick Ni 81 Fe 19 (permalloy, Py) film is patterned into a spin-wave waveguide that is 5 μm wide at one end and gradually broadens until it reaches a constant width of 10 μm. This variable width stabilizes the desired remanence state. A microwave antenna is positioned at the beginning of the 10-μm-wide part of the waveguide. Oscillating magnetic fields h rf generated by microwave currents in this antenna allow for the local excitation of spin waves with well-defined frequencies. To reproducibly prepare the aforementioned remanence state with the domain wall parallel to the long axis of the waveguide, we applied a sinusoidal, exponentially decaying magnetic field H ini, x parallel to its short axis, as depicted in the bottom right inset in Fig. 1b . We used magneto-optical Kerr microscopy to confirm the magnetic state of the waveguide. The overlay in Fig. 1c shows a Kerr image, with the black–white colour code representing the magnetization component along the y direction. A Landau-like domain pattern is formed", "role": "user" }, { "content": "The success story of information processing by way of moving electrons is slowly coming to an end. The trend towards more and more compact chips constitutes a major challenge for manufacturers, since the increasing miniaturization creates partly unsolvable physical problems. This is why magnetic spin waves could be the future: they are faster than electronic charge carriers and use less power. Researchers at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and TU Dresden have developed a method for controlling the propagation of these information carriers at the nanolevel in a targeted and simple way; so far, this required a lot of power. They have thus created a basis for nanocircuits that use spin waves. \"Our current information processing is based on electrons,\" explains Dr. Helmut Schultheiß from the HZDR's Institute of Ion Beam Physics and Materials Research. \"These charged particles flow through the wires, creating electric currents. Yet in the process they collide with atoms and lose energy, which escapes into the crystal lattice in the form of heat. This means that chips get all the warmer, the closer the elements on them are grouped together. Eventually they fail, because the heat cannot be conveyed anymore.\" This is why Schultheiß, head of an Emmy Noether Junior Research Group, pursues a different approach: information transport via spin waves, also known as magnons. The magnetic moment of electrons Spin is the term scientists use to describe the angular momentum of electrons revolving around their own axis. It makes the electric particles behave like extremely small magnets. This is why they align in a parallel manner in ferromagnetic materials. \"If one guides a spin in a different direction, this will have an impact also on the neighboring spins,\" Schultheiß explains. \"This creates a spin wave that travels through the solid body. It can be used to transport and process information just like flowing charge carriers.\" However, the electrons themselves do not move in this case. \"They do not collide with anything and therefore generate hardly any heat.\" Yet in order to prevail in the race for future information processing methods, systems are needed that allow for controlling the propagation of spin waves at the nanolevel. \"So far, approaches to a solution were based either on geometrically predefined conductor paths or on the permanent use of external magnetic fields,\" says Schultheiß, explaining the current state of research. \"In the case of the first solution, the propagation path cannot be changed; however this is necessary for the development of flexible circuits. The second method solves that problem, yet at the price of an enormous increase in power consumption.\" Controlled propagation path The scientists have successfully developed a new procedure for the targeted steering of spin waves by utilizing basic magnetic characteristics: remanence, that is, the residual magnetism that a solid body retains after the removal of a magnetic field, and the formation of so-called domain walls. \"This term denotes the area in solid bodies where differently aligned magnetic domains meet,\" Schultheiß explains. The HZDR researchers created such a domain wall within a nickel-iron alloy nanostructure in an experiment. They then triggered a spin wave using microwaves. As their tests have shown, the spin waves of a certain frequency got stuck in the domain wall, because the different magnetic domains act as barriers. \"In a sense, one could say that we created a road with a crash barrier along which the spin waves travel in a controlled manner,\" Schultheiß cheerfully describes the result. However, the Dresden physicists were able to celebrate yet another success. They manipulated the course of the domain wall by way of small external magnetic fields of far below one millitesla, about one hundred times weaker than a commercial horseshoe magnet. In doing so, they likewise manipulated the propagation of the spin waves. \"This could be the basis for a design of reconfigurable nanocircuits that uses magnons,\" Schultheiß says, sizing up the options. Even so, the researcher thinks that several years are likely to pass before application. \"We are still in the basic research phase. However, our results reveal that we are onto a good thing.\" ", "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 research field of magnonics 1 , 2 , 3 , 4 , 5 , 6 , 7 , it is envisaged that spin waves will be used as information carriers, promoting operation based on their wave properties. However, the field still faces major challenges. To become fully competitive, novel schemes for energy-efficient control of spin-wave propagation in two dimensions have to be realized on much smaller length scales than used before. In this Letter, we address these challenges with the experimental realization of a novel approach to guide spin waves in reconfigurable, nano-sized magnonic waveguides. For this purpose, we make use of two inherent characteristics of magnetism: the non-volatility of magnetic remanence states and the nanometre dimensions of domain walls formed within these magnetic configurations. We present the experimental observation and micromagnetic simulations of spin-wave propagation inside nano-sized domain walls and realize a first step towards a reconfigurable domain-wall-based magnonic nanocircuitry. Main In the last few years, the scientific community in the field of magnonics has made huge efforts to realize concepts to use spin waves for data processing. Quite recently, remarkable progress has been made, leading to prototype building blocks of a spin-wave-based logic 8 , 9 , 10 . Despite this progress, most concepts are based on sample layouts that are limited regarding their further optimization. Previous studies on spin-wave propagation on the nanoscale have relied on confinement in geometrically patterned waveguides 11 , but these lack the flexibility for manipulating the propagation path that is required for reprogrammable devices. On the microscale, this dynamic control of spin waves in two-dimensional structures has been realized, but it is based on the continuous application of external fields and thus requires high energy consumption. Here, we will present a possible way to overcome these challenges. Spin waves impinging on domain walls are either reflected or phase-shifted when transmitted, depending on their wavelength and the nature of the domain wall 12 , 13 , 14 , 15 , 16 . Additional studies have been devoted to the domain wall dynamics, which was found to be on the order of 10 MHz (ref. 17 ). However, the possibility to send spin waves along a domain wall has only been addressed in one numerical study for out-of-plane magnetization and with a very specific domain wall that is difficult to realize in experimental scenarios 18 . Here, we experimentally explore the intrinsic spin-wave eigenmodes that are quantized across the width of a domain wall and possess a well-defined wave vector along the wall that enables information transport. By targeting this class of largely unknown spin-wave modes, we focus on the potential of using domain walls as nanometre-scaled spin-wave channels to open new perspectives for the energy-efficient control of spin-wave propagation in two dimensions. The top part of Fig. 1a shows a schematic of a 180° Néel wall. The magnetic moments rotate within the sample plane, giving rise to magnetic volume charges ∇ · M , with opposite sign on the two sides of the domain-wall centre. The red curve in Fig. 1a illustrates these volume charges calculated by means of micromagnetic simulations. The charges generate a strong magnetostatic field H demag (blue curve in Fig. 1a ) oriented antiparallel to the magnetization in the centre of the domain wall, resulting in a locally decreased effective magnetic field. Because spin-wave resonances depend on the effective field, locally decreased fields can form potential wells for localized modes 19 , 20 . Here, a potential well is created across the domain wall with a width of a few tens of nanometres. This width strongly depends on various parameters of magnetic materials and can be tuned towards even smaller sizes. In this Letter, we demonstrate experimentally and numerically that such a potential well leads to spin-wave modes that are strongly localized to the domain-wall width and travel freely along the wall. Moreover, and in contrast to the vast majority of experimentally realized scenarios, no energy-consuming external bias fields are needed to promote spin-wave propagation in the preferred geometry 10 along the domain wall. Figure 1: Channelling principle, sample geometry and magnetization configuration. a , Schematic illustration of a 180° Néel wall carrying a spin wave. The divergence of the magnetization ∇ · M across the width of the wall shows opposite sign on the two sides of the domain wall centre and results in a strong magnetostatic field H demag oriented antiparallel to the magnetization direction. This potential well confines the spin-wave propagation into the narrow region of the wall. b , SEM image of the investigated Py structure and the microwave antenna for the external excitation of spin dynamics. Inset (lower right): magnetic field sweep used to initialize the domain configuration. c , The black–white contrast of the Kerr microscopy image confirms the formation of a Landau-like domain pattern. Arrows indicate the magnetization direction in the domains. Full size image Figure 1b presents a scanning electron microscopy (SEM) image of the structure used in the experiment. A 40-nm-thick Ni 81 Fe 19 (permalloy, Py) film is patterned into a spin-wave waveguide that is 5 μm wide at one end and gradually broadens until it reaches a constant width of 10 μm. This variable width stabilizes the desired remanence state. A microwave antenna is positioned at the beginning of the 10-μm-wide part of the waveguide. Oscillating magnetic fields h rf generated by microwave currents in this antenna allow for the local excitation of spin waves with well-defined frequencies. To reproducibly prepare the aforementioned remanence state with the domain wall parallel to the long axis of the waveguide, we applied a sinusoidal, exponentially decaying magnetic field H ini, x parallel to its short axis, as depicted in the bottom right inset in Fig. 1b . We used magneto-optical Kerr microscopy to confirm the magnetic state of the waveguide. The overlay in Fig. 1c shows a Kerr image, with the black–white colour code representing the magnetization component along the y direction. A Landau-like domain pattern is formed<|im_end|> <|im_start|>assistant The success story of information processing by way of moving electrons is slowly coming to an end. The trend towards more and more compact chips constitutes a major challenge for manufacturers, since the increasing miniaturization creates partly unsolvable physical problems. This is why magnetic spin waves could be the future: they are faster than electronic charge carriers and use less power. Researchers at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and TU Dresden have developed a method for controlling the propagation of these information carriers at the nanolevel in a targeted and simple way; so far, this required a lot of power. They have thus created a basis for nanocircuits that use spin waves. "Our current information processing is based on electrons," explains Dr. Helmut Schultheiß from the HZDR's Institute of Ion Beam Physics and Materials Research. "These charged particles flow through the wires, creating electric currents. Yet in the process they collide with atoms and lose energy, which escapes into the crystal lattice in the form of heat. This means that chips get all the warmer, the closer the elements on them are grouped together. Eventually they fail, because the heat cannot be conveyed anymore." This is why Schultheiß, head of an Emmy Noether Junior Research Group, pursues a different approach: information transport via spin waves, also known as magnons. The magnetic moment of electrons Spin is the term scientists use to describe the angular momentum of electrons revolving around their own axis. It makes the electric particles behave like extremely small magnets. This is why they align in a parallel manner in ferromagnetic materials. "If one guides a spin in a different direction, this will have an impact also on the neighboring spins," Schultheiß explains. "This creates a spin wave that travels through the solid body. It can be used to transport and process information just like flowing charge carriers." However, the electrons themselves do not move in this case. "They do not collide with anything and therefore generate hardly any heat." Yet in order to prevail in the race for future information processing methods, systems are needed that allow for controlling the propagation of spin waves at the nanolevel. "So far, approaches to a solution were based either on geometrically predefined conductor paths or on the permanent use of external magnetic fields," says Schultheiß, explaining the current state of research. "In the case of the first solution, the propagation path cannot be changed; however this is necessary for the development of flexible circuits. The second method solves that problem, yet at the price of an enormous increase in power consumption." Controlled propagation path The scientists have successfully developed a new procedure for the targeted steering of spin waves by utilizing basic magnetic characteristics: remanence, that is, the residual magnetism that a solid body retains after the removal of a magnetic field, and the formation of so-called domain walls. "This term denotes the area in solid bodies where differently aligned magnetic domains meet," Schultheiß explains. The HZDR researchers created such a domain wall within a nickel-iron alloy nanostructure in an experiment. They then triggered a spin wave using microwaves. As their tests have shown, the spin waves of a certain frequency got stuck in the domain wall, because the different magnetic domains act as barriers. "In a sense, one could say that we created a road with a crash barrier along which the spin waves travel in a controlled manner," Schultheiß cheerfully describes the result. However, the Dresden physicists were able to celebrate yet another success. They manipulated the course of the domain wall by way of small external magnetic fields of far below one millitesla, about one hundred times weaker than a commercial horseshoe magnet. In doing so, they likewise manipulated the propagation of the spin waves. "This could be the basis for a design of reconfigurable nanocircuits that uses magnons," Schultheiß says, sizing up the options. Even so, the researcher thinks that several years are likely to pass before application. "We are still in the basic research phase. However, our results reveal that we are onto a good thing." <|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 validity of the superposition principle and of Born’s rule are well-accepted tenants of quantum mechanics. Surprisingly, it has been predicted that the intensity pattern formed in a three-slit experiment is seemingly in contradiction with the most conventional form of the superposition principle when exotic looped trajectories are taken into account. However, the probability of observing such paths is typically very small, thus rendering them extremely difficult to measure. Here we confirm the validity of Born’s rule and present the first experimental observation of exotic trajectories as additional paths for the light by directly measuring their contribution to the formation of optical interference fringes. We accomplish this by enhancing the electromagnetic near-fields in the vicinity of the slits through the excitation of surface plasmons. This process increases the probability of occurrence of these exotic trajectories, demonstrating that they are related to the near-field component of the photon’s wavefunction. Introduction The phenomenon of interference has been recognized as ‘the only mystery’ of quantum mechanics 1 . The enormous interest and history of this fundamental effect can be traced back to the two-slit experiment devised by Thomas Young in the early 19th century. Young’s experiment is conceptually the simplest method for demonstrating the superposition principle, as the appearance of interference fringes in the far-field is unexplainable unless it is understood that the particle seemingly travels through both slits simultaneously. Such an experiment, originally performed with light, has since been conducted on particles ranging from individual photons, neutrons and atoms, to large molecules consisting of dozens of atoms 2 . As the superposition principle lies at the core of quantum physics, many of its counterintuitive features such as entanglement, non-locality, wave-particle duality, and delayed-choice concepts can be demonstrated or tested using a two-slit system 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . The standard interpretation of the two-slit experiment is given by solving the wave equation for an initially prepared complex wavefunction, . For example, if represents the wavefunction at the detector for a photon emerging from slit A , and is the wavefunction for a photon emerging from slit B , then the implementation of the superposition principle is to assume that the wavefunction is a superposition of the different paths given by = + . The probability of detection is given by Born’s rule as where P A = and P B = . From this equation it is clear that the outcome of the two-slit experiment is given by the sum of outcomes from each slit alone, plus an additional interference term. Due to the inherent structure of any wave theory, Born’s rule always bounds the complexity of any effect involving superpositions of an arbitrary number of wavefunctions to a sum of terms denoting the interference between pairs of wavefunctions 11 . For instance, in accordance with Born’s rule, the interference pattern obtained in a three-slit experiment can be described by the following probabilities Note that this expression does not include a probability term that involves three slits, but is entirely described by probabilities involving only one and two slits. Any possible contribution from higher-order interference terms (that is, a path involving the three slits) has been quantified by the so-called Sorkin parameter 11 , 12 which should be identically zero if only the direct paths through the three individual slits are considered. Sinha et al . 12 showed that can be evaluated experimentally by making a set of measurements for each term in equation (3). Although it might appear that the measurement of a non-zero implies a clear violation of quantum mechanics 12 , De Raedt et al . 13 demonstrated by numerically solving Maxwell’s equations that a non-zero value of can exist without such violation. Later it was found that this result is a consequence of the presence of exotic looped trajectories of light (for example, red curve in Fig. 1a ) that arise in the Feynman path integral formulation with extremely low probability of occurrence 14 . This interpretation was subsequently shown to agree with the exact numerical solution of the wave equation 15 . Figure 1: Trajectories of light in a three-slit interferometer. ( a ) The three-slit structure considered in this study. The red path going from point s to point d illustrates a possible looped trajectory of light. ( b ) Direct trajectories of light resulting from considering only the first term in equation (8). The widely used superposition principle, that is, equation (1), accounts only for these direct trajectories. ( c ) Examples of exotic looped trajectories arising from the higher order terms in equation (8). The red cloud in the vicinity of the slits depicts the near-field distribution, which increases the probability of photons to follow looped trajectories. ( d ) Normalized Poynting vector P in the vicinity of the three slits obtained through full wave simulations at a wavelength λ =810 nm, using a slit width w equals to 200 nm, slit separation p =4.6 μm, sample thickness t equals to 110 nm, and assuming infinite height, h =∞. The simulations consider a Gaussian beam excitation polarized along x , and focused onto slit A. The Poynting vector clearly exhibits a looped trajectory such as the solid path in c . ( e ) Far-field interference patterns calculated under x -polarized (solid) and y -polarized (dashed) optical excitation. Interference fringes are formed in the far field only when strong near fields are excited ( x -polarization), and occur from the interference of light following a direct trajectory and a looped trajectory. ( f ) Experimental evidence that shows the far-field pattern for a situation in which only one slit is illuminated with y -polarized heralded single-photons. ( g ) The presence of exotic looped trajectories leads to an increase in the visibility of the far-field pattern. This effect is observed when x -polarized light illuminates one of the slits. ( h ) The transverse profile of the patterns shown in f ,", "role": "user" }, { "content": "(Phys.org)—Physicists have performed a variation of the famous 200-year-old double-slit experiment that, for the first time, involves \"exotic looped trajectories\" of photons. These photons travel forward through one slit, then loop around and travel back through another slit, and then sometimes loop around again and travel forward through a third slit. Interestingly, the contribution of these looped trajectories to the overall interference pattern leads to an apparent deviation from the usual form of the superposition principle. This apparent deviation can be understood as an incorrect application of the superposition principle—once the additional interference between looped and straight trajectories is accounted for, the superposition can be correctly applied. The team of physicists, led by Omar S. Magaña-Loaiza and Israel De Leon, has published a paper on the new experiment in a recent issue of Nature Communications. Loops of light \"Our work is the first experimental observation of looped trajectories,\" De Leon told Phys.org. \"Looped trajectories are extremely difficult to detect because of their low probability of occurrence. Previously, researchers had suggested that these exotic trajectories could exist but failed to observe them.\" To increase the probability of the occurrence of looped trajectories, the researchers designed a three-slit structure that supports surface plasmons, which the scientists describe as \"strongly confined electromagnetic fields that can exist at the surface of metals.\" The presence of these electromagnetic fields near the three slits increases the contribution of looped trajectories to the overall interference pattern by almost two orders of magnitude. \"We provided a physical explanation that links the probability of these exotic trajectories to the near fields around the slits,\" De Leon said. \"As such, one can increase the strength of near fields around the slits to increase the probability of photons following looped trajectories.\" Superposition principle accounting for looped trajectories The new three-slit experiment with looped trajectories is just one of many variations of the original double-slit experiment, first performed by Thomas Young in 1801. Since then, researchers have been performing versions that use electrons, atoms, or molecules instead of photons. One of the reasons why the double-slit experiment has attracted so much attention is that it represents a physical manifestation of the principle of quantum superposition. The observation that individual particles can create an interference pattern implies that the particles must travel through both slits at the same time. This ability to occupy two places, or states, at once, is the defining feature of quantum superposition. Straight trajectories (green) and exotic looped trajectories (red, dashed, dotted) of light, where the red cloud near the surface depicts the near fields, which increase the probability of photons to follow looped trajectories. The graphs at left show simulations (top) and experimental results (bottom) of the large difference in interference patterns created by illuminating only one slit being treated independently (gray line) and the actual coupled system (blue line). The remarkable difference between the gray and blue lines is caused by the looped trajectories. Credit: Magaña-Loaiza et al. Nature Communications So far, all previous versions of the experiment have produced results that appear to be accurately described by the principle of superposition. This is because looped trajectories are so rare under normal conditions that their contribution to the overall interference pattern is typically negligible, and so applying the superposition principle to those cases results in a very good approximation. It is when the contribution of the looped trajectories becomes non-negligible that it becomes apparent that the total interference is not simply the superposition of individual wavefunctions of photons with straight trajectories, and so the interference pattern is not correctly described by the usual form of the superposition principle. Magaña-Loaiza explained this apparent deviation in more detail: \"The superposition principle is always valid—what is not valid is the inaccurate application of the superposition principle to a system with two or three slits,\" he said. \"For the past two centuries, scientists have assumed that one cannot observe interference if only one slit is illuminated in a two- or three-slit interferometer, and this is because this scenario represents the usual or typical case. \"However, in our paper we demonstrate that this is true only if the probability of photons to follow looped trajectories is negligible. Surprisingly, interference fringes are formed when photons following looped trajectories interfere with photons following straight (direct) trajectories, even when only one of the three slits is illuminated. \"The superposition principle can be applied to this surprising scenario by using the sum or 'superposition' of two wavefunctions; one describing a straight trajectory and the other describing looped trajectories. Not taking into account looped trajectories would represent an incorrect application of the superposition principle. \"To some extent, this effect is strange because scientists know that Thomas Young observed interference when he illuminated both slits and not only one. This is true only if the probability of photons following looped trajectories is negligible.\" In addition to impacting physicists' understanding of the superposition principle as it is applied to these experiments, the results also reveal new properties of light that could have applications for quantum simulators and other technologies that rely on interference effects. \"We believe that exotic looped paths can have important implications in the study of decoherence mechanisms in interferometry or to increase the complexity of certain protocols for quantum random walks, quantum simulators, and other algorithms used in quantum computation,\" De Leon said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The validity of the superposition principle and of Born’s rule are well-accepted tenants of quantum mechanics. Surprisingly, it has been predicted that the intensity pattern formed in a three-slit experiment is seemingly in contradiction with the most conventional form of the superposition principle when exotic looped trajectories are taken into account. However, the probability of observing such paths is typically very small, thus rendering them extremely difficult to measure. Here we confirm the validity of Born’s rule and present the first experimental observation of exotic trajectories as additional paths for the light by directly measuring their contribution to the formation of optical interference fringes. We accomplish this by enhancing the electromagnetic near-fields in the vicinity of the slits through the excitation of surface plasmons. This process increases the probability of occurrence of these exotic trajectories, demonstrating that they are related to the near-field component of the photon’s wavefunction. Introduction The phenomenon of interference has been recognized as ‘the only mystery’ of quantum mechanics 1 . The enormous interest and history of this fundamental effect can be traced back to the two-slit experiment devised by Thomas Young in the early 19th century. Young’s experiment is conceptually the simplest method for demonstrating the superposition principle, as the appearance of interference fringes in the far-field is unexplainable unless it is understood that the particle seemingly travels through both slits simultaneously. Such an experiment, originally performed with light, has since been conducted on particles ranging from individual photons, neutrons and atoms, to large molecules consisting of dozens of atoms 2 . As the superposition principle lies at the core of quantum physics, many of its counterintuitive features such as entanglement, non-locality, wave-particle duality, and delayed-choice concepts can be demonstrated or tested using a two-slit system 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . The standard interpretation of the two-slit experiment is given by solving the wave equation for an initially prepared complex wavefunction, . For example, if represents the wavefunction at the detector for a photon emerging from slit A , and is the wavefunction for a photon emerging from slit B , then the implementation of the superposition principle is to assume that the wavefunction is a superposition of the different paths given by = + . The probability of detection is given by Born’s rule as where P A = and P B = . From this equation it is clear that the outcome of the two-slit experiment is given by the sum of outcomes from each slit alone, plus an additional interference term. Due to the inherent structure of any wave theory, Born’s rule always bounds the complexity of any effect involving superpositions of an arbitrary number of wavefunctions to a sum of terms denoting the interference between pairs of wavefunctions 11 . For instance, in accordance with Born’s rule, the interference pattern obtained in a three-slit experiment can be described by the following probabilities Note that this expression does not include a probability term that involves three slits, but is entirely described by probabilities involving only one and two slits. Any possible contribution from higher-order interference terms (that is, a path involving the three slits) has been quantified by the so-called Sorkin parameter 11 , 12 which should be identically zero if only the direct paths through the three individual slits are considered. Sinha et al . 12 showed that can be evaluated experimentally by making a set of measurements for each term in equation (3). Although it might appear that the measurement of a non-zero implies a clear violation of quantum mechanics 12 , De Raedt et al . 13 demonstrated by numerically solving Maxwell’s equations that a non-zero value of can exist without such violation. Later it was found that this result is a consequence of the presence of exotic looped trajectories of light (for example, red curve in Fig. 1a ) that arise in the Feynman path integral formulation with extremely low probability of occurrence 14 . This interpretation was subsequently shown to agree with the exact numerical solution of the wave equation 15 . Figure 1: Trajectories of light in a three-slit interferometer. ( a ) The three-slit structure considered in this study. The red path going from point s to point d illustrates a possible looped trajectory of light. ( b ) Direct trajectories of light resulting from considering only the first term in equation (8). The widely used superposition principle, that is, equation (1), accounts only for these direct trajectories. ( c ) Examples of exotic looped trajectories arising from the higher order terms in equation (8). The red cloud in the vicinity of the slits depicts the near-field distribution, which increases the probability of photons to follow looped trajectories. ( d ) Normalized Poynting vector P in the vicinity of the three slits obtained through full wave simulations at a wavelength λ =810 nm, using a slit width w equals to 200 nm, slit separation p =4.6 μm, sample thickness t equals to 110 nm, and assuming infinite height, h =∞. The simulations consider a Gaussian beam excitation polarized along x , and focused onto slit A. The Poynting vector clearly exhibits a looped trajectory such as the solid path in c . ( e ) Far-field interference patterns calculated under x -polarized (solid) and y -polarized (dashed) optical excitation. Interference fringes are formed in the far field only when strong near fields are excited ( x -polarization), and occur from the interference of light following a direct trajectory and a looped trajectory. ( f ) Experimental evidence that shows the far-field pattern for a situation in which only one slit is illuminated with y -polarized heralded single-photons. ( g ) The presence of exotic looped trajectories leads to an increase in the visibility of the far-field pattern. This effect is observed when x -polarized light illuminates one of the slits. ( h ) The transverse profile of the patterns shown in f ,<|im_end|> <|im_start|>assistant (Phys.org)—Physicists have performed a variation of the famous 200-year-old double-slit experiment that, for the first time, involves "exotic looped trajectories" of photons. These photons travel forward through one slit, then loop around and travel back through another slit, and then sometimes loop around again and travel forward through a third slit. Interestingly, the contribution of these looped trajectories to the overall interference pattern leads to an apparent deviation from the usual form of the superposition principle. This apparent deviation can be understood as an incorrect application of the superposition principle—once the additional interference between looped and straight trajectories is accounted for, the superposition can be correctly applied. The team of physicists, led by Omar S. Magaña-Loaiza and Israel De Leon, has published a paper on the new experiment in a recent issue of Nature Communications. Loops of light "Our work is the first experimental observation of looped trajectories," De Leon told Phys.org. "Looped trajectories are extremely difficult to detect because of their low probability of occurrence. Previously, researchers had suggested that these exotic trajectories could exist but failed to observe them." To increase the probability of the occurrence of looped trajectories, the researchers designed a three-slit structure that supports surface plasmons, which the scientists describe as "strongly confined electromagnetic fields that can exist at the surface of metals." The presence of these electromagnetic fields near the three slits increases the contribution of looped trajectories to the overall interference pattern by almost two orders of magnitude. "We provided a physical explanation that links the probability of these exotic trajectories to the near fields around the slits," De Leon said. "As such, one can increase the strength of near fields around the slits to increase the probability of photons following looped trajectories." Superposition principle accounting for looped trajectories The new three-slit experiment with looped trajectories is just one of many variations of the original double-slit experiment, first performed by Thomas Young in 1801. Since then, researchers have been performing versions that use electrons, atoms, or molecules instead of photons. One of the reasons why the double-slit experiment has attracted so much attention is that it represents a physical manifestation of the principle of quantum superposition. The observation that individual particles can create an interference pattern implies that the particles must travel through both slits at the same time. This ability to occupy two places, or states, at once, is the defining feature of quantum superposition. Straight trajectories (green) and exotic looped trajectories (red, dashed, dotted) of light, where the red cloud near the surface depicts the near fields, which increase the probability of photons to follow looped trajectories. The graphs at left show simulations (top) and experimental results (bottom) of the large difference in interference patterns created by illuminating only one slit being treated independently (gray line) and the actual coupled system (blue line). The remarkable difference between the gray and blue lines is caused by the looped trajectories. Credit: Magaña-Loaiza et al. Nature Communications So far, all previous versions of the experiment have produced results that appear to be accurately described by the principle of superposition. This is because looped trajectories are so rare under normal conditions that their contribution to the overall interference pattern is typically negligible, and so applying the superposition principle to those cases results in a very good approximation. It is when the contribution of the looped trajectories becomes non-negligible that it becomes apparent that the total interference is not simply the superposition of individual wavefunctions of photons with straight trajectories, and so the interference pattern is not correctly described by the usual form of the superposition principle. Magaña-Loaiza explained this apparent deviation in more detail: "The superposition principle is always valid—what is not valid is the inaccurate application of the superposition principle to a system with two or three slits," he said. "For the past two centuries, scientists have assumed that one cannot observe interference if only one slit is illuminated in a two- or three-slit interferometer, and this is because this scenario represents the usual or typical case. "However, in our paper we demonstrate that this is true only if the probability of photons to follow looped trajectories is negligible. Surprisingly, interference fringes are formed when photons following looped trajectories interfere with photons following straight (direct) trajectories, even when only one of the three slits is illuminated. "The superposition principle can be applied to this surprising scenario by using the sum or 'superposition' of two wavefunctions; one describing a straight trajectory and the other describing looped trajectories. Not taking into account looped trajectories would represent an incorrect application of the superposition principle. "To some extent, this effect is strange because scientists know that Thomas Young observed interference when he illuminated both slits and not only one. This is true only if the probability of photons following looped trajectories is negligible." In addition to impacting physicists' understanding of the superposition principle as it is applied to these experiments, the results also reveal new properties of light that could have applications for quantum simulators and other technologies that rely on interference effects. "We believe that exotic looped paths can have important implications in the study of decoherence mechanisms in interferometry or to increase the complexity of certain protocols for quantum random walks, quantum simulators, and other algorithms used in quantum computation," De Leon said. <|im_end|>

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2,384

[ { "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 Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes. Main The three-dimensional organization of chromosomes is tightly related to their biological function 1 , 2 , 3 . Genome-wide chromosome conformation capture (Hi-C) maps have revealed key features of the 3D organization of metazoan chromosomes, including compartmentalization, TADs, and interaction peaks 4 , 5 ( Extended Data Fig. 1 ). Compartmentalization is visible as a characteristic checkerboard pattern of contact enrichment both in cis and in trans between megabase-sized genomic intervals of the same type, reflecting spatial segregation of transcriptionally active (type A) and inactive (type B) chromatin 6 . TADs appear as squares of enriched contact frequency with sharp boundaries; they usually span hundreds of kilobases and do not necessarily exhibit any checkering 7 , 8 . TADs are thought to contribute to gene expression, notably by promoting or preventing interactions between promoters and distant regulatory elements 9 , 10 , 11 . Finally, peaks (often termed loops 12 ) are visible as focal enrichments in contact frequency between pairs of loci, often at the corners of TAD squares. Despite a lack of supporting mechanistic experiments, compartments, TADs and peaks are typically assumed to constitute hierarchical levels of chromosome folding; however, the connection between them remains poorly understood. Architectural proteins, notably cohesin and the transcriptional insulator CTCF, are believed to have crucial roles in chromatin organization during interphase 13 . Cohesin and CTCF co-localize at TAD boundaries and the bases of Hi-C peaks 7 , 12 , but their roles have not been fully defined. The recently proposed loop extrusion model 14 , 15 yields predictions that are consistent with previous experimental results. In this model, TADs emerge from the progressive extrusion of chromatin loops by a protein complex (for example, cohesin) until it dissociates from chromatin or reaches a boundary element (for example, CTCF sites). Recent experimental manipulation of CTCF motifs 15 , 16 , 17 and CTCF depletion 18 support the proposed role of CTCFs as boundary elements, but the role of cohesin in interphase chromatin organization and the process of loop extrusion remains unclear, as experimental depletions of cohesin have shown limited impact on chromatin organization 19 , 20 , 21 . To identify the role of cohesin in interphase chromatin, we deleted Nipbl (yeast homologue Scc2 ), which is necessary for loading of cohesin onto chromatin 22 . As the turnover period of chromosome-bound cohesin is about 20 minutes 23 , 24 , constant loading is required for its presence on DNA. We achieved efficient deletion of Nipbl in non-dividing hepatocytes by using a liver-specific, tamoxifen-inducible Cre driver ( Fig. 1a ), which circumvents the lethality of Nipbl +/− mice and the essentiality of cohesin in dividing cells ( Extended Data Fig. 2 ). Ten days after tamoxifen injection, Nipbl expression was greatly reduced ( Fig. 1b ), leading to displacement of cohesin from the chromatin fraction to the soluble nuclear fraction, which indicates loss of cohesin from chromosomes ( Fig. 1c ). This strong depletion of chromatin-bound cohesin was also observed by calibrated chromatin immunoprecipitation and sequencing (ChIP–seq) 25 for RAD21 and SMC3 both genome-wide ( Extended Data Fig. 3 ) and at wild-type cohesin peaks ( Fig. 1d, e ). A conservative estimate indicates at least a fourfold to sixfold decrease in chromatin-associated cohesin. The liver showed no particular pathological signs compared to control mice (mock-injected Nipbl flox/flox ; Ttr-cre/Esr1 mice or tamoxifen-injected Nipbl +/+ ; Ttr-cre/Esr1 mice). Hepatocytes showed no sign of cell death or proliferation ( Extended Data Fig. 2 ). Figure 1: Overview of the experimental design. a , We deleted a conditional allele of Nipbl ( Extended Data Fig. 2 ) in adult hepatocytes using a liver-specific driver for the Cre–ERT2 fusion protein after injection of tamoxifen. In the absence of Nipbl , cohesin (red triangular ring) is not loaded on chromatin. b , Expression of Nipbl and Gapdh (control) by quantitative PCR with reverse transcription (RT–qPCR) in control ( n = 4) and Δ Nipbl ( n = 6 for Nipbl ; 4 for Gapdh ) hepatocytes. Mean normalized gene expression (using Pgk1 as internal control, and wild-type expression set as 1) is displayed as mean ± s.d. and compared using unpaired two-sided t -test (95% confidence interval (CI): control = (0.7033–1.297); Δ Nipbl = (0.05731–0.2198) for Nipbl expression). c , Western blots of hepatocyte protein extracts (WCL, whole cell lysate; Nsol, nuclear extract, soluble fraction; Nins, insoluble, chromatin fraction) showed displacement of cohesin structural subunits (SA-1 and SMC1) from the chromatin-bound fraction. Histone H2B and topoisomerase 2β (TOP2B) distributions serve as controls for loading and enrichment of two nuclear fractions. Experiment repeated on two biologically independent samples per condition. See Supplementary Data 1 for gel source data. d , Stacked heatmaps of calibrated chromatin immunoprecipitation and sequencing (ChIP–seq) signal (for Rad21 and SMC3) at wild-type Rad21 peaks ranked by fold change over input, in the TAM control condition. e , ChIP–seq tracks for Rad21 and SMC3 over representative genomic regions. f , g , Hi-C maps at 20 kb resolution of wild-type (left), TAM control (middle) and Δ Nipbl cells", "role": "user" }, { "content": "A molecular \"motor\" that organizes the genome into distinct neighborhoods by forming loops of DNA has been characterized by researchers at MIT and the Pasteur Institute in France. In a study published in 2016, a team led by Leonid Mirny, a professor of physics in MIT's Institute for Medical Engineering and Sciences, proposed that molecular motors transform chromosomes from a loosely tangled state into a dynamic series of expanding loops. The process, known as loop extrusion, is thought to bring regulatory elements together with the genes they control. The team also suggested that DNA is decorated with barriers—akin to stop signs—that limit the process of extrusion. In this way, loop extrusion divides chromosomes into separate regulatory neighborhoods, known as topologically associating domains (TADs). However, while the researchers suggested that a ring-like protein complex called cohesin was a likely candidate for these molecular motors, this had yet to be proven. Now, in a paper published in the journal Nature, a team led by Mirny and Francois Spitz at the Pasteur Institute, have demonstrated that cohesin does indeed play the role of a motor in the loop extrusion process. \"Each of these machines lands on the DNA and starts extruding loops, but there are boundaries on DNA that these motors cannot get through,\" Mirny says. \"So as a result of this motor activity, the genome is organized into many dynamic loops that do not cross the boundaries, so the genome becomes divided into a series of neighborhoods.\" The researchers also discovered that a different mechanism, that does not use cohesin, is at work organizing active and inactive regions of DNA into separate compartments in the cell's nucleus. To determine the role cohesin plays in genome formation, the team first deleted a molecule known as Nipbl, which is responsible for loading cohesin onto DNA. They then used an experimental technique known as Hi-C, in which parts of DNA that are close to one another in 3-D space are captured and sequenced, in a bid to measure the frequency of physical interactions between different spots along chromosomes. This technique, which was pioneered by Job Dekker, a professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical Center in Worcester, has previously been used to demonstrate the existence of TADs. The team first used the Hi-C technique to assess the organization of chromosomes before removing the Nipbl molecule from mice. They then removed the molecule and performed the same measurement again. They found that the neighborhoods had virtually disappeared. However, the compartmentalization between active and inactive regions of the genome had become even more marked. The team believes the cohesin motors allow each gene to reach out to its regulatory elements, which control whether genes should be switched on or off. What's more, it appears that the cohesin motors are stopped by another protein, CTCF, which demarcates the boundaries of each neighborhood. In a recent study in the journal Cell, the Mirny lab, in collaboration with researchers at the University of California at San Francisco and the University of Massachusetts Medical School has demonstrated that if this demarcating protein is removed, the borders between neighborhoods disappear, allowing genes in one neighborhood to talk to regulatory elements they should not be talking to in another neighborhood, and leading to misregulation of genes in the cell. \"Cohesin is central for gene regulation, and we emphasize that this is a motor function, so it is not just that they (genes and their regulatory elements) find each other somewhere randomly in space, but they were brought together by this motor activity,\" Mirny says. This paper provides important new molecular insights into the mechanisms by which cells fold their chromosomes, according to Dekker, who was not involved in the current study. \"In this work the Mirny and Spitz labs combine mouse models with genomic approaches to study chromosome folding to reveal that the machine that loads the cohesin complex is critical for TAD formation,\" Dekker says. \"From this and another previous study, a molecular mechanism is coming into view where TADs form by cohesin and Nipbl-dependent chromatin loop extrusion, which is blocked by sites bound by CTCF.\" The researchers are now attempting to characterize how the absence of the molecular motor would affect gene regulation. They are also carrying out computer simulations in a bid to determine how the cohesin-based loop extrusion takes place at the same time as the genome is undergoing the independent process of segregating into active and inactive compartments. \"It's like two pianists playing on the same piano,\" says Nezar Abdennur, a PhD student in the Mirny lab, who took part in the study alongside fellow PhD student Anton Goloborodko. \"They interfere and put constraints on each other, but together they can produce a beautiful piece of music.\" ", "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 Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes. Main The three-dimensional organization of chromosomes is tightly related to their biological function 1 , 2 , 3 . Genome-wide chromosome conformation capture (Hi-C) maps have revealed key features of the 3D organization of metazoan chromosomes, including compartmentalization, TADs, and interaction peaks 4 , 5 ( Extended Data Fig. 1 ). Compartmentalization is visible as a characteristic checkerboard pattern of contact enrichment both in cis and in trans between megabase-sized genomic intervals of the same type, reflecting spatial segregation of transcriptionally active (type A) and inactive (type B) chromatin 6 . TADs appear as squares of enriched contact frequency with sharp boundaries; they usually span hundreds of kilobases and do not necessarily exhibit any checkering 7 , 8 . TADs are thought to contribute to gene expression, notably by promoting or preventing interactions between promoters and distant regulatory elements 9 , 10 , 11 . Finally, peaks (often termed loops 12 ) are visible as focal enrichments in contact frequency between pairs of loci, often at the corners of TAD squares. Despite a lack of supporting mechanistic experiments, compartments, TADs and peaks are typically assumed to constitute hierarchical levels of chromosome folding; however, the connection between them remains poorly understood. Architectural proteins, notably cohesin and the transcriptional insulator CTCF, are believed to have crucial roles in chromatin organization during interphase 13 . Cohesin and CTCF co-localize at TAD boundaries and the bases of Hi-C peaks 7 , 12 , but their roles have not been fully defined. The recently proposed loop extrusion model 14 , 15 yields predictions that are consistent with previous experimental results. In this model, TADs emerge from the progressive extrusion of chromatin loops by a protein complex (for example, cohesin) until it dissociates from chromatin or reaches a boundary element (for example, CTCF sites). Recent experimental manipulation of CTCF motifs 15 , 16 , 17 and CTCF depletion 18 support the proposed role of CTCFs as boundary elements, but the role of cohesin in interphase chromatin organization and the process of loop extrusion remains unclear, as experimental depletions of cohesin have shown limited impact on chromatin organization 19 , 20 , 21 . To identify the role of cohesin in interphase chromatin, we deleted Nipbl (yeast homologue Scc2 ), which is necessary for loading of cohesin onto chromatin 22 . As the turnover period of chromosome-bound cohesin is about 20 minutes 23 , 24 , constant loading is required for its presence on DNA. We achieved efficient deletion of Nipbl in non-dividing hepatocytes by using a liver-specific, tamoxifen-inducible Cre driver ( Fig. 1a ), which circumvents the lethality of Nipbl +/− mice and the essentiality of cohesin in dividing cells ( Extended Data Fig. 2 ). Ten days after tamoxifen injection, Nipbl expression was greatly reduced ( Fig. 1b ), leading to displacement of cohesin from the chromatin fraction to the soluble nuclear fraction, which indicates loss of cohesin from chromosomes ( Fig. 1c ). This strong depletion of chromatin-bound cohesin was also observed by calibrated chromatin immunoprecipitation and sequencing (ChIP–seq) 25 for RAD21 and SMC3 both genome-wide ( Extended Data Fig. 3 ) and at wild-type cohesin peaks ( Fig. 1d, e ). A conservative estimate indicates at least a fourfold to sixfold decrease in chromatin-associated cohesin. The liver showed no particular pathological signs compared to control mice (mock-injected Nipbl flox/flox ; Ttr-cre/Esr1 mice or tamoxifen-injected Nipbl +/+ ; Ttr-cre/Esr1 mice). Hepatocytes showed no sign of cell death or proliferation ( Extended Data Fig. 2 ). Figure 1: Overview of the experimental design. a , We deleted a conditional allele of Nipbl ( Extended Data Fig. 2 ) in adult hepatocytes using a liver-specific driver for the Cre–ERT2 fusion protein after injection of tamoxifen. In the absence of Nipbl , cohesin (red triangular ring) is not loaded on chromatin. b , Expression of Nipbl and Gapdh (control) by quantitative PCR with reverse transcription (RT–qPCR) in control ( n = 4) and Δ Nipbl ( n = 6 for Nipbl ; 4 for Gapdh ) hepatocytes. Mean normalized gene expression (using Pgk1 as internal control, and wild-type expression set as 1) is displayed as mean ± s.d. and compared using unpaired two-sided t -test (95% confidence interval (CI): control = (0.7033–1.297); Δ Nipbl = (0.05731–0.2198) for Nipbl expression). c , Western blots of hepatocyte protein extracts (WCL, whole cell lysate; Nsol, nuclear extract, soluble fraction; Nins, insoluble, chromatin fraction) showed displacement of cohesin structural subunits (SA-1 and SMC1) from the chromatin-bound fraction. Histone H2B and topoisomerase 2β (TOP2B) distributions serve as controls for loading and enrichment of two nuclear fractions. Experiment repeated on two biologically independent samples per condition. See Supplementary Data 1 for gel source data. d , Stacked heatmaps of calibrated chromatin immunoprecipitation and sequencing (ChIP–seq) signal (for Rad21 and SMC3) at wild-type Rad21 peaks ranked by fold change over input, in the TAM control condition. e , ChIP–seq tracks for Rad21 and SMC3 over representative genomic regions. f , g , Hi-C maps at 20 kb resolution of wild-type (left), TAM control (middle) and Δ Nipbl cells<|im_end|> <|im_start|>assistant A molecular "motor" that organizes the genome into distinct neighborhoods by forming loops of DNA has been characterized by researchers at MIT and the Pasteur Institute in France. In a study published in 2016, a team led by Leonid Mirny, a professor of physics in MIT's Institute for Medical Engineering and Sciences, proposed that molecular motors transform chromosomes from a loosely tangled state into a dynamic series of expanding loops. The process, known as loop extrusion, is thought to bring regulatory elements together with the genes they control. The team also suggested that DNA is decorated with barriers—akin to stop signs—that limit the process of extrusion. In this way, loop extrusion divides chromosomes into separate regulatory neighborhoods, known as topologically associating domains (TADs). However, while the researchers suggested that a ring-like protein complex called cohesin was a likely candidate for these molecular motors, this had yet to be proven. Now, in a paper published in the journal Nature, a team led by Mirny and Francois Spitz at the Pasteur Institute, have demonstrated that cohesin does indeed play the role of a motor in the loop extrusion process. "Each of these machines lands on the DNA and starts extruding loops, but there are boundaries on DNA that these motors cannot get through," Mirny says. "So as a result of this motor activity, the genome is organized into many dynamic loops that do not cross the boundaries, so the genome becomes divided into a series of neighborhoods." The researchers also discovered that a different mechanism, that does not use cohesin, is at work organizing active and inactive regions of DNA into separate compartments in the cell's nucleus. To determine the role cohesin plays in genome formation, the team first deleted a molecule known as Nipbl, which is responsible for loading cohesin onto DNA. They then used an experimental technique known as Hi-C, in which parts of DNA that are close to one another in 3-D space are captured and sequenced, in a bid to measure the frequency of physical interactions between different spots along chromosomes. This technique, which was pioneered by Job Dekker, a professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical Center in Worcester, has previously been used to demonstrate the existence of TADs. The team first used the Hi-C technique to assess the organization of chromosomes before removing the Nipbl molecule from mice. They then removed the molecule and performed the same measurement again. They found that the neighborhoods had virtually disappeared. However, the compartmentalization between active and inactive regions of the genome had become even more marked. The team believes the cohesin motors allow each gene to reach out to its regulatory elements, which control whether genes should be switched on or off. What's more, it appears that the cohesin motors are stopped by another protein, CTCF, which demarcates the boundaries of each neighborhood. In a recent study in the journal Cell, the Mirny lab, in collaboration with researchers at the University of California at San Francisco and the University of Massachusetts Medical School has demonstrated that if this demarcating protein is removed, the borders between neighborhoods disappear, allowing genes in one neighborhood to talk to regulatory elements they should not be talking to in another neighborhood, and leading to misregulation of genes in the cell. "Cohesin is central for gene regulation, and we emphasize that this is a motor function, so it is not just that they (genes and their regulatory elements) find each other somewhere randomly in space, but they were brought together by this motor activity," Mirny says. This paper provides important new molecular insights into the mechanisms by which cells fold their chromosomes, according to Dekker, who was not involved in the current study. "In this work the Mirny and Spitz labs combine mouse models with genomic approaches to study chromosome folding to reveal that the machine that loads the cohesin complex is critical for TAD formation," Dekker says. "From this and another previous study, a molecular mechanism is coming into view where TADs form by cohesin and Nipbl-dependent chromatin loop extrusion, which is blocked by sites bound by CTCF." The researchers are now attempting to characterize how the absence of the molecular motor would affect gene regulation. They are also carrying out computer simulations in a bid to determine how the cohesin-based loop extrusion takes place at the same time as the genome is undergoing the independent process of segregating into active and inactive compartments. "It's like two pianists playing on the same piano," says Nezar Abdennur, a PhD student in the Mirny lab, who took part in the study alongside fellow PhD student Anton Goloborodko. "They interfere and put constraints on each other, but together they can produce a beautiful piece of music." <|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 Laser cooling is a fundamental technique used in primary atomic frequency standards, quantum computers, quantum condensed matter physics and tests of fundamental physics, among other areas. It has been known since the early 1990s that laser cooling can, in principle, be improved by using squeezed light as an electromagnetic reservoir; while quantum feedback control using a squeezed light probe is also predicted to allow improved cooling. Here we show the implementation of quantum feedback control of a micro-mechanical oscillator using squeezed probe light. This allows quantum-enhanced feedback cooling with a measurement rate greater than it is possible with classical light, and a consequent reduction in the final oscillator temperature. Our results have significance for future applications in areas ranging from quantum information networks, to quantum-enhanced force and displacement measurements and fundamental tests of macroscopic quantum mechanics. Introduction Real-time quantum feedback control 1 often involves time-continuous measurements of a quantum state followed by control of a physical system with the aim of steering that system into a desired state. Such control has been demonstrated in numerous experiments, including the preparation of microwave Fock states 2 and the generation of deterministic entanglement in quantum superconducting circuits 3 . Quantum feedback control also allows the control of motional states via continuous measurements of a probe field followed by actuation back on the motional degree of freedom. It has been used to steer single trapped atoms 4 , levitated microspheres 5 , micromechanical oscillators 6 , 7 and suspended kilogram-scale mirrors 8 towards their motional ground states. Furthermore, quantum feedback control was proposed as a means to prepare both mechanical Fock 9 and superposition states 10 . However, to-date, all such experiments have used a classical probe field. The use of a nonclassical probe field for quantum control can both increase the effectiveness of steering to the desired quantum state and introduce new functionalities. For instance, it can be used to prepare a mechanical oscillator in a non-Gaussian quantum state even in the linear coupling regime 11 , 12 , 13 , thereby circumventing the usual requirement to reach the single-photon strong coupling regime 14 . Moreover, quantum feedback control using squeezed light can enable an efficient interface for quantum information networks 15 , 16 , and allow the standard quantum limit of force measurements to be surpassed via squeezing-enhanced measurements 17 . Here we demonstrate the first critical step towards such functionalities by realising a quantum-enhanced cooling rate using a squeezed probe field and real-time feedback control of a mechanical mode. The basic idea is to continuously monitor the position of the mechanical oscillator and subsequently use the measurement record to steer the oscillator towards the ground state with real-time feedback 18 . The cooling rate is limited by the precision with which the position of the oscillator can be monitored, which in turn is often limited by the noise of the tracking laser beam 19 . Therefore, by engineering the quantum state of the laser beam to reduce the measurement noise, an enhanced cooling rate can be expected. Using squeezed light with variance V sqz to continuously monitor the mechanical motion, a feedback loop with signal detection efficiency η , an overall detection efficiency η d for the squeezed light, and feedback gain G Fb , can lower the temperature to where V d is the detected variance η d V sqz +(1− η d )/2, T 0 is the equilibrium temperature of the mechanical oscillator before feedback cooling, n th the corresponding mean phonon occupancy and we have neglected radiation pressure induced heating due to the measurement process. Considering a cavity optomechanical system with cavity energy decay rate κ and mechanical dissipation rate Γ m , the linearized interaction is characterized by the cooperativity , where g 0 is the single-photon optomechanical coupling strength and N c the mean intra-cavity photon number. As the feedback gain is increased, the temperature drops, reaching a minimum for . At higher gain, the oscillator begins to heat up due to the imparted measurement noise. In essence, the application of squeezed measurement noise acts to shift this onset of heating to higher gain values, thereby allowing cooling to temperatures below the shot noise imposed limit, as illustrated in Fig. 1d . Alternatively, the improved cooling efficiency can be appreciated as a consequence of an increased measurement rate , resulting from the squeezing-enhanced signal-to-noise ratio of the transduced mechanical motion 20 . In comparison to a coherent state probe, the improvement is directly given by the degree of squeezing as μ sqz / μ coh =(2 V d ) −1 . As the measurement rate is intimately related to the ability to achieve ground state cooling, requiring μ >Γ th ∼ Γ m n th , squeezing-enhanced feedback cooling can greatly relax the structural requirements for the mechanical oscillator and thereby facilitate the preparation of macroscopic oscillators in their motional ground state. It should be noted that improved cooling can be also realised by increasing the power of the probe beam. However, it is challenging, in practice, to achieve cooling rates sufficient for ground state cooling due to localized bulk heating introduced by absorption of the probe field. Figure 1: Experimental and conceptual details. ( a ) Sketch of the experimental setup. The mechanical motion in a microtoroid was sensed using a squeezed or coherent state coupled evanescently to the microtoroid via a tapered fibre. The electrical output of a homodyne detector was bandpass filtered around the mechanical resonance frequency, delayed, amplified and fed back to the mechanical resonator via an electrical actuator. An electrode tip held close above the toroid combined with a grounded base plate formed the actuator. ESA, Electrical Spectrum Analyser. ( b ) Scanning electron microscope picture of the microtoroidal resonator with a radius of 37.5 μm and an optical Q value of 1 × 10 6 . The scale bar corresponds to 10 μm. ( c ) Mechanical spectrum of the microtoroid measured with a coherent probe beam of 50", "role": "user" }, { "content": "How does the tightrope walker manage to maintain her balance and avoid that fatal drop from the sky? She carefully senses the motion of her body and vibrations of the rope and accordingly compensates any deviation from equilibrium by shifting her center of gravity. In a thermally excited system, the amplitude of the mechanical vibrations are directly linked to the system's temperature. Thus, by eliminating vibrations the system is cooled to a lower effective temperature. In recent experiments at DTU Physics, researchers have employed a quantum-enhanced feedback technique to dampen the motion of a micron-sized mechanical oscillator, thereby cooling its temperature by more than 140 degrees below room temperature. Most importantly, this work demonstrates a novel application of squeezed light allowing an improved sensitivity to the mechanical motion and thereby a more efficient extraction of information on how the damping feedback should be tailored. In the experiment, the mechanical motion of a microtoroidal resonator was continuously sensed using laser light circulating inside the resonator. Using that information an electric feedback force that was always out of phase with the instantaneous motion was tailored and applied - that is, when the motion was directed upwards the feedback force would counteract this by pushing the toroid downwards and vice versa. Using ordinary - classical - laser light, this technique is ultimately limited by the intrinsic quantum noise of the probe laser, and that sets the classical limit for how efficient the feedback cooling can be. As now demonstrated by DTU researchers, this limit can be surpassed by using quantum-engineered squeezed light. In the experiment, an improvement of more than 12% over the classical limiting temperature was achieved. This improvement was limited by inefficiencies of the specific system resulting in a loss of information on the mechanical motion. The full potential of the demonstrated technique can be unfolded by application to state-of-the-art optomechanical systems, holding promises for reaching the motional quantum ground state of a mechanical oscillator in room temperature experiments. Achieving this would pave the way for a plethora of new optomechanical investigations of fundamental quantum physics and constitute a crucial step towards development of new quantum technologies for sensing and information processing based on micromechanical oscillators. ", "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 cooling is a fundamental technique used in primary atomic frequency standards, quantum computers, quantum condensed matter physics and tests of fundamental physics, among other areas. It has been known since the early 1990s that laser cooling can, in principle, be improved by using squeezed light as an electromagnetic reservoir; while quantum feedback control using a squeezed light probe is also predicted to allow improved cooling. Here we show the implementation of quantum feedback control of a micro-mechanical oscillator using squeezed probe light. This allows quantum-enhanced feedback cooling with a measurement rate greater than it is possible with classical light, and a consequent reduction in the final oscillator temperature. Our results have significance for future applications in areas ranging from quantum information networks, to quantum-enhanced force and displacement measurements and fundamental tests of macroscopic quantum mechanics. Introduction Real-time quantum feedback control 1 often involves time-continuous measurements of a quantum state followed by control of a physical system with the aim of steering that system into a desired state. Such control has been demonstrated in numerous experiments, including the preparation of microwave Fock states 2 and the generation of deterministic entanglement in quantum superconducting circuits 3 . Quantum feedback control also allows the control of motional states via continuous measurements of a probe field followed by actuation back on the motional degree of freedom. It has been used to steer single trapped atoms 4 , levitated microspheres 5 , micromechanical oscillators 6 , 7 and suspended kilogram-scale mirrors 8 towards their motional ground states. Furthermore, quantum feedback control was proposed as a means to prepare both mechanical Fock 9 and superposition states 10 . However, to-date, all such experiments have used a classical probe field. The use of a nonclassical probe field for quantum control can both increase the effectiveness of steering to the desired quantum state and introduce new functionalities. For instance, it can be used to prepare a mechanical oscillator in a non-Gaussian quantum state even in the linear coupling regime 11 , 12 , 13 , thereby circumventing the usual requirement to reach the single-photon strong coupling regime 14 . Moreover, quantum feedback control using squeezed light can enable an efficient interface for quantum information networks 15 , 16 , and allow the standard quantum limit of force measurements to be surpassed via squeezing-enhanced measurements 17 . Here we demonstrate the first critical step towards such functionalities by realising a quantum-enhanced cooling rate using a squeezed probe field and real-time feedback control of a mechanical mode. The basic idea is to continuously monitor the position of the mechanical oscillator and subsequently use the measurement record to steer the oscillator towards the ground state with real-time feedback 18 . The cooling rate is limited by the precision with which the position of the oscillator can be monitored, which in turn is often limited by the noise of the tracking laser beam 19 . Therefore, by engineering the quantum state of the laser beam to reduce the measurement noise, an enhanced cooling rate can be expected. Using squeezed light with variance V sqz to continuously monitor the mechanical motion, a feedback loop with signal detection efficiency η , an overall detection efficiency η d for the squeezed light, and feedback gain G Fb , can lower the temperature to where V d is the detected variance η d V sqz +(1− η d )/2, T 0 is the equilibrium temperature of the mechanical oscillator before feedback cooling, n th the corresponding mean phonon occupancy and we have neglected radiation pressure induced heating due to the measurement process. Considering a cavity optomechanical system with cavity energy decay rate κ and mechanical dissipation rate Γ m , the linearized interaction is characterized by the cooperativity , where g 0 is the single-photon optomechanical coupling strength and N c the mean intra-cavity photon number. As the feedback gain is increased, the temperature drops, reaching a minimum for . At higher gain, the oscillator begins to heat up due to the imparted measurement noise. In essence, the application of squeezed measurement noise acts to shift this onset of heating to higher gain values, thereby allowing cooling to temperatures below the shot noise imposed limit, as illustrated in Fig. 1d . Alternatively, the improved cooling efficiency can be appreciated as a consequence of an increased measurement rate , resulting from the squeezing-enhanced signal-to-noise ratio of the transduced mechanical motion 20 . In comparison to a coherent state probe, the improvement is directly given by the degree of squeezing as μ sqz / μ coh =(2 V d ) −1 . As the measurement rate is intimately related to the ability to achieve ground state cooling, requiring μ >Γ th ∼ Γ m n th , squeezing-enhanced feedback cooling can greatly relax the structural requirements for the mechanical oscillator and thereby facilitate the preparation of macroscopic oscillators in their motional ground state. It should be noted that improved cooling can be also realised by increasing the power of the probe beam. However, it is challenging, in practice, to achieve cooling rates sufficient for ground state cooling due to localized bulk heating introduced by absorption of the probe field. Figure 1: Experimental and conceptual details. ( a ) Sketch of the experimental setup. The mechanical motion in a microtoroid was sensed using a squeezed or coherent state coupled evanescently to the microtoroid via a tapered fibre. The electrical output of a homodyne detector was bandpass filtered around the mechanical resonance frequency, delayed, amplified and fed back to the mechanical resonator via an electrical actuator. An electrode tip held close above the toroid combined with a grounded base plate formed the actuator. ESA, Electrical Spectrum Analyser. ( b ) Scanning electron microscope picture of the microtoroidal resonator with a radius of 37.5 μm and an optical Q value of 1 × 10 6 . The scale bar corresponds to 10 μm. ( c ) Mechanical spectrum of the microtoroid measured with a coherent probe beam of 50<|im_end|> <|im_start|>assistant How does the tightrope walker manage to maintain her balance and avoid that fatal drop from the sky? She carefully senses the motion of her body and vibrations of the rope and accordingly compensates any deviation from equilibrium by shifting her center of gravity. In a thermally excited system, the amplitude of the mechanical vibrations are directly linked to the system's temperature. Thus, by eliminating vibrations the system is cooled to a lower effective temperature. In recent experiments at DTU Physics, researchers have employed a quantum-enhanced feedback technique to dampen the motion of a micron-sized mechanical oscillator, thereby cooling its temperature by more than 140 degrees below room temperature. Most importantly, this work demonstrates a novel application of squeezed light allowing an improved sensitivity to the mechanical motion and thereby a more efficient extraction of information on how the damping feedback should be tailored. In the experiment, the mechanical motion of a microtoroidal resonator was continuously sensed using laser light circulating inside the resonator. Using that information an electric feedback force that was always out of phase with the instantaneous motion was tailored and applied - that is, when the motion was directed upwards the feedback force would counteract this by pushing the toroid downwards and vice versa. Using ordinary - classical - laser light, this technique is ultimately limited by the intrinsic quantum noise of the probe laser, and that sets the classical limit for how efficient the feedback cooling can be. As now demonstrated by DTU researchers, this limit can be surpassed by using quantum-engineered squeezed light. In the experiment, an improvement of more than 12% over the classical limiting temperature was achieved. This improvement was limited by inefficiencies of the specific system resulting in a loss of information on the mechanical motion. The full potential of the demonstrated technique can be unfolded by application to state-of-the-art optomechanical systems, holding promises for reaching the motional quantum ground state of a mechanical oscillator in room temperature experiments. Achieving this would pave the way for a plethora of new optomechanical investigations of fundamental quantum physics and constitute a crucial step towards development of new quantum technologies for sensing and information processing based on micromechanical oscillators. <|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 Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a nearly complete loss of β cells 1 . Restoration of insulin-producing β cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D 2 , 3 , 4 . Here we report that enhancing β-cell mass early in life, in two models of female non-obese diabetic (NOD) mice, results in immunomodulation of T cells, reduced islet infiltration and lower β-cell apoptosis, which together protect them from developing T1D. The animals displayed altered β-cell antigens; islet transplantation studies showed prolonged graft survival in the NOD-liver-specific insulin receptor knockout (LIRKO) model. Adoptive transfer of splenocytes from NOD-LIRKO mice prevented development of diabetes in prediabetic NOD mice. A substantial increase in the splenic CD4 + CD25 + Foxp3 + regulatory T cell (T reg ) population was observed to underlie the protected phenotype since T reg -cell depletion rendered NOD-LIRKO mice diabetic. An increase in T reg cells coupled with activation of transforming growth factor-β/SMAD family member 3 signalling pathway in pathogenic T cells favoured reduced ability to kill β cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, before islet infiltration by immune cells alters the identity of β cells, decreases pathological self-reactivity of effector T cells and increases T reg cells to prevent the progression of T1D. Main To determine whether enhanced β-cell proliferation, starting before an immune attack, would provide protection against type 1 diabetes (T1D) development, we backcrossed the liver-specific insulin receptor knockout (LIRKO) mouse 5 , a model characterized by robust β-cell proliferation, onto the non-obese diabetic (NOD) 6 background. Achieving >99.5% isogenicity while maintaining key NOD modifiers intact, we followed only female mice (hereafter NOD-Lox and NOD-LIRKO) for up to 24 months (Supplementary Fig. 1a,b ) since traditionally NOD female mice exhibit a higher incidence of diabetes 7 . While most of the NOD-Lox (IRLox control) mice developed severe diabetes between 20 and 35 weeks of age, surprisingly, virtually all NOD-LIRKO mice survived through the follow-up period (Fig. 1a ). Moreover, NOD-Lox mice exhibited progressive hyperglycaemia starting at age 16–18 weeks and began to succumb similarly to wild-type NOD mice (Fig. 1b and Supplementary Fig. 1c ); however, NOD-LIRKO mice exhibited transient hyperglycaemia at age 4–5 weeks that reverted to normoglycaemia from approximately 10 weeks and during the entire follow-up period (Fig. 1b ). A transient increase in blood glucose was also observed in LIRKO mice on the original background (Supplementary Fig. 1c ). Fig. 1: NOD-LIRKO mice are protected from progressing to diabetes development. a , Kaplan–Meier survival curve showing NOD-Lox and NOD-LIRKO mice monitored for mortality rates (NOD-Lox: n = 19; NOD-LIRKO: n = 26; P < 0.0001, log-rank (Mantel–Cox) test). b , Weekly blood glucose values of mice in a . The dashed line shows the upper limit of normoglycaemia. c , d , Immunohistochemistry (from three or four mice per genotype from two independent experimental cohorts) showing mononuclear cell infiltration in pancreatic islets from 1-, 2-, 4-, 6-, 12- and 24-month-old mice (the insets show the enlarged islets) ( c ), and quantification of insulitis scores of pancreatic sections from c (scale bar, 200 µm) ( d ). e , Representative immunofluorescence images (from three or four mice per genotype from a single experimental cohort) showing proliferation in 15-day-old or 1-, 2-, 4-, 6- or 24-month-old NOD-Lox and NOD-LIRKO mice (scale bar, 200 µm). f , Quantification of Ki67 + β cells in e (NOD-Lox: 0.5, 1, 2, 4 and 6 months; n = 3 per group; NOD-LIRKO: 0.5, 1, 2, 4 and 6 months; n = 4, 3, 3, 4 and 4 per group respectively). g , h , Representative TUNEL staining (from three or four mice per genotype from a single experimental cohort) showing β-cell apoptosis (scale bar, 200 µm) ( g ) and quantification of percentage β-cell apoptosis (NOD-Lox: 0.5, 1, 2, 4 and 6 months; n = 3 per group; NOD-LIRKO: 0.5, 1, 2, 4 and 6 months; n = 4, 3, 3, 4 and 4 per group respectively) ( h ) in NOD-Lox and NOD-LIRKO mice. i , Representative pancreas sections (from three mice per genotype from a single experimental cohort) with the insets showing insulin-positive (red) islets (scale bar, 2 mm). j , Morphometric analysis of β-cell mass as described in the Methods . n = 3 mice per group. k , Representative H&E staining (from four or five mice per genotype from a single experimental cohort) showing immune cell infiltration in salivary glands in NSG, NOD-Lox and NOD-LIRKO mice (scale bar, 1 mm). l , Representative images (from three mice per genotype from a single experimental cohort) of FACS analyses for splenic B, NK, NKT, CD4 + and CD8 + T cells from NOD-Lox and NOD-LIRKO mice. FSC-H, forward scatter height. m , Percentage of immune cell subsets shown in l (NOD-Lox: n = 3; NOD-LIRKO: n = 3). n , Representative images of FACS analyses for thymic DN, DP, CD4SP and CD8SP cells from NOD-Lox and NOD-LIRKO mice. FSC, forward scatter; SSC, side scatter. o , Percentage of immune cell subsets shown in n (NOD-Lox: n = 4; NOD-LIRKO: n = 4). All samples in each panel are biologically independent. §, NOD-Lox versus NOD-LIRKO. Data are expressed as means ± s.e.m. *, § P < 0.05, **, §§ P < 0.01, ***, §§§ P < 0.001. Statistical analyses were performed using two-tailed, unpaired Student’s t -tests. Full size image To exclude the potential interactions between the insertion of loxP sites and T1D susceptibility loci, we phenotyped age-matched, Cre + and Cre female mice heterozygous for the floxed insulin receptor (NOD-IRLox HET) . The presence of hyperglycaemia starting at approximately 16 weeks of age, in both NOD-IRLox HET Cre + and Cre − mice, similarly to NOD-Lox controls, indicated that the phenotype in the NOD-LIRKO mice is independent of potential epistatic interactions due to backcrossing (Supplementary Fig. 1d", "role": "user" }, { "content": "Many in-development cures for type 1 diabetes have understandably focused on tackling the autoimmune aspect of the disease before figuring out a way to replace the destroyed beta cells. But what if focusing on the beta cells first could prevent their destruction altogether? Researchers at Joslin have found that increasing the proliferation and turnover of beta cells before signs of type 1 diabetes could halt the development of the disease. In animal models, researchers in the lab of Rohit N. Kulkarni MD Ph.D., HMS Professor of Medicine and Co-Section Head of Islet and Regenerative Biology in the Joslin Diabetes Center, pushed the growth of beta cells while the animals were still young—meaning organs of the immune system were still developing, and still susceptible to manipulation. The results were published today in Nature Metabolism. \"We are clearly the first to show that if you push the proliferation to continuously generate new insulin producing beta-cells before the immune cell invasion starts then, for some reason we are still trying to figure out, immune cells stop attacking the beta cell,\" says Dr. Kulkarni. This surprising finding was thoroughly interrogated in Dr. Kulkarni's lab in experiments led by Ercument Dirice Ph.D., HMS Instructor in Medicine and Research Associate at the Joslin Diabetes Center. The studies were completed in two different diabetes-prone mouse models. One was a genetically engineered model that showed increased beta cell growth soon after birth while the second model was injected at an early age with an agent known to increase beta cell proliferation. Then, they collected samples from the spleen to monitor the numbers of T cells and B cells, both of which are involved in the autoimmune reactions associated with type 1 diabetes. When the researchers transplanted the the islet cells harvested from the protected animals to a different mouse, the recipients showed protection from the autoimmune reaction for a longer time. \"It is very exciting to observe that inducing beta cell replication in a timely manner resulted in a reshaped immune profile which specifically protects beta cells being targeted,\" said Dr. Dirice, who has recently been appointed to the faculty of the New York Medical College, School of Medicine. \"Even [in a highly susceptible mouse model], when you push the proliferation to generate new beta cells, 99 percent of the animals survived—and almost up to two years, which is very unusual,\" says Dr. Kulkarni. Something about the rapid turning over of the beta cells \"confuses\" the autoimmune reaction, in a sense. The beta cells do not seem to be presenting the autoantibodies typical of type 1 diabetes progression. They also seem to be more resistant to stress, which was a secondary discovery of the transplant portion of the experiments. This resistance to stress could factor into their ability to withstand any autoimmune attack. \"We believe there are some alterations in the new beta cells where a number of cells being presented as autoantigens are reduced or diluted, and therefore, because of the slow presentation of the antigens, the number of autoreactive T cells are less pathogenic,\" says Dr. Kulkarni. \"Clearly there's a link between these two processes. A precise mechanism and the pathways and the proteins involved will require a follow up study.\" This is not the first clue that beta cell proliferation could be a sort of protective factor for people with type 1 diabetes. Joslin's Medalist Study showed that many of those with long-duration type 1 diabetes still retain some beta cell function and growth more than 50 years after their diagnosis. Once the process of using beta cell proliferation as a preventative measure is better understood, it could move to human studies and clinical trials. Finding the right window to force beta cell proliferation in humans could delay or even prevent the destruction of beta cells by autoimmune cells. Some degree of autoimmunity would still exist in the body, however, so it would still require appropriate treatment to suppress the immune system. This study was supported in part by a grant from JDRF. \"As we work to develop strategies to replace or regrow insulin producing cells to cure T1D, this work from Drs. Kulkarni and Dirice gives us important insight into how we could protect these new cells from autoimmune attack. This is a great example of the importance of JDRF's training program in developing successful new T1D scientists.\" Said Frank Martin, Ph.D., JDRF Associate Director, Research. \"We're really excited to move things forward,\" says Dr. Kulkarni. \"We hope that we can now begin to think about how to translate this to 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 Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a nearly complete loss of β cells 1 . Restoration of insulin-producing β cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D 2 , 3 , 4 . Here we report that enhancing β-cell mass early in life, in two models of female non-obese diabetic (NOD) mice, results in immunomodulation of T cells, reduced islet infiltration and lower β-cell apoptosis, which together protect them from developing T1D. The animals displayed altered β-cell antigens; islet transplantation studies showed prolonged graft survival in the NOD-liver-specific insulin receptor knockout (LIRKO) model. Adoptive transfer of splenocytes from NOD-LIRKO mice prevented development of diabetes in prediabetic NOD mice. A substantial increase in the splenic CD4 + CD25 + Foxp3 + regulatory T cell (T reg ) population was observed to underlie the protected phenotype since T reg -cell depletion rendered NOD-LIRKO mice diabetic. An increase in T reg cells coupled with activation of transforming growth factor-β/SMAD family member 3 signalling pathway in pathogenic T cells favoured reduced ability to kill β cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, before islet infiltration by immune cells alters the identity of β cells, decreases pathological self-reactivity of effector T cells and increases T reg cells to prevent the progression of T1D. Main To determine whether enhanced β-cell proliferation, starting before an immune attack, would provide protection against type 1 diabetes (T1D) development, we backcrossed the liver-specific insulin receptor knockout (LIRKO) mouse 5 , a model characterized by robust β-cell proliferation, onto the non-obese diabetic (NOD) 6 background. Achieving >99.5% isogenicity while maintaining key NOD modifiers intact, we followed only female mice (hereafter NOD-Lox and NOD-LIRKO) for up to 24 months (Supplementary Fig. 1a,b ) since traditionally NOD female mice exhibit a higher incidence of diabetes 7 . While most of the NOD-Lox (IRLox control) mice developed severe diabetes between 20 and 35 weeks of age, surprisingly, virtually all NOD-LIRKO mice survived through the follow-up period (Fig. 1a ). Moreover, NOD-Lox mice exhibited progressive hyperglycaemia starting at age 16–18 weeks and began to succumb similarly to wild-type NOD mice (Fig. 1b and Supplementary Fig. 1c ); however, NOD-LIRKO mice exhibited transient hyperglycaemia at age 4–5 weeks that reverted to normoglycaemia from approximately 10 weeks and during the entire follow-up period (Fig. 1b ). A transient increase in blood glucose was also observed in LIRKO mice on the original background (Supplementary Fig. 1c ). Fig. 1: NOD-LIRKO mice are protected from progressing to diabetes development. a , Kaplan–Meier survival curve showing NOD-Lox and NOD-LIRKO mice monitored for mortality rates (NOD-Lox: n = 19; NOD-LIRKO: n = 26; P < 0.0001, log-rank (Mantel–Cox) test). b , Weekly blood glucose values of mice in a . The dashed line shows the upper limit of normoglycaemia. c , d , Immunohistochemistry (from three or four mice per genotype from two independent experimental cohorts) showing mononuclear cell infiltration in pancreatic islets from 1-, 2-, 4-, 6-, 12- and 24-month-old mice (the insets show the enlarged islets) ( c ), and quantification of insulitis scores of pancreatic sections from c (scale bar, 200 µm) ( d ). e , Representative immunofluorescence images (from three or four mice per genotype from a single experimental cohort) showing proliferation in 15-day-old or 1-, 2-, 4-, 6- or 24-month-old NOD-Lox and NOD-LIRKO mice (scale bar, 200 µm). f , Quantification of Ki67 + β cells in e (NOD-Lox: 0.5, 1, 2, 4 and 6 months; n = 3 per group; NOD-LIRKO: 0.5, 1, 2, 4 and 6 months; n = 4, 3, 3, 4 and 4 per group respectively). g , h , Representative TUNEL staining (from three or four mice per genotype from a single experimental cohort) showing β-cell apoptosis (scale bar, 200 µm) ( g ) and quantification of percentage β-cell apoptosis (NOD-Lox: 0.5, 1, 2, 4 and 6 months; n = 3 per group; NOD-LIRKO: 0.5, 1, 2, 4 and 6 months; n = 4, 3, 3, 4 and 4 per group respectively) ( h ) in NOD-Lox and NOD-LIRKO mice. i , Representative pancreas sections (from three mice per genotype from a single experimental cohort) with the insets showing insulin-positive (red) islets (scale bar, 2 mm). j , Morphometric analysis of β-cell mass as described in the Methods . n = 3 mice per group. k , Representative H&E staining (from four or five mice per genotype from a single experimental cohort) showing immune cell infiltration in salivary glands in NSG, NOD-Lox and NOD-LIRKO mice (scale bar, 1 mm). l , Representative images (from three mice per genotype from a single experimental cohort) of FACS analyses for splenic B, NK, NKT, CD4 + and CD8 + T cells from NOD-Lox and NOD-LIRKO mice. FSC-H, forward scatter height. m , Percentage of immune cell subsets shown in l (NOD-Lox: n = 3; NOD-LIRKO: n = 3). n , Representative images of FACS analyses for thymic DN, DP, CD4SP and CD8SP cells from NOD-Lox and NOD-LIRKO mice. FSC, forward scatter; SSC, side scatter. o , Percentage of immune cell subsets shown in n (NOD-Lox: n = 4; NOD-LIRKO: n = 4). All samples in each panel are biologically independent. §, NOD-Lox versus NOD-LIRKO. Data are expressed as means ± s.e.m. *, § P < 0.05, **, §§ P < 0.01, ***, §§§ P < 0.001. Statistical analyses were performed using two-tailed, unpaired Student’s t -tests. Full size image To exclude the potential interactions between the insertion of loxP sites and T1D susceptibility loci, we phenotyped age-matched, Cre + and Cre female mice heterozygous for the floxed insulin receptor (NOD-IRLox HET) . The presence of hyperglycaemia starting at approximately 16 weeks of age, in both NOD-IRLox HET Cre + and Cre − mice, similarly to NOD-Lox controls, indicated that the phenotype in the NOD-LIRKO mice is independent of potential epistatic interactions due to backcrossing (Supplementary Fig. 1d<|im_end|> <|im_start|>assistant Many in-development cures for type 1 diabetes have understandably focused on tackling the autoimmune aspect of the disease before figuring out a way to replace the destroyed beta cells. But what if focusing on the beta cells first could prevent their destruction altogether? Researchers at Joslin have found that increasing the proliferation and turnover of beta cells before signs of type 1 diabetes could halt the development of the disease. In animal models, researchers in the lab of Rohit N. Kulkarni MD Ph.D., HMS Professor of Medicine and Co-Section Head of Islet and Regenerative Biology in the Joslin Diabetes Center, pushed the growth of beta cells while the animals were still young—meaning organs of the immune system were still developing, and still susceptible to manipulation. The results were published today in Nature Metabolism. "We are clearly the first to show that if you push the proliferation to continuously generate new insulin producing beta-cells before the immune cell invasion starts then, for some reason we are still trying to figure out, immune cells stop attacking the beta cell," says Dr. Kulkarni. This surprising finding was thoroughly interrogated in Dr. Kulkarni's lab in experiments led by Ercument Dirice Ph.D., HMS Instructor in Medicine and Research Associate at the Joslin Diabetes Center. The studies were completed in two different diabetes-prone mouse models. One was a genetically engineered model that showed increased beta cell growth soon after birth while the second model was injected at an early age with an agent known to increase beta cell proliferation. Then, they collected samples from the spleen to monitor the numbers of T cells and B cells, both of which are involved in the autoimmune reactions associated with type 1 diabetes. When the researchers transplanted the the islet cells harvested from the protected animals to a different mouse, the recipients showed protection from the autoimmune reaction for a longer time. "It is very exciting to observe that inducing beta cell replication in a timely manner resulted in a reshaped immune profile which specifically protects beta cells being targeted," said Dr. Dirice, who has recently been appointed to the faculty of the New York Medical College, School of Medicine. "Even [in a highly susceptible mouse model], when you push the proliferation to generate new beta cells, 99 percent of the animals survived—and almost up to two years, which is very unusual," says Dr. Kulkarni. Something about the rapid turning over of the beta cells "confuses" the autoimmune reaction, in a sense. The beta cells do not seem to be presenting the autoantibodies typical of type 1 diabetes progression. They also seem to be more resistant to stress, which was a secondary discovery of the transplant portion of the experiments. This resistance to stress could factor into their ability to withstand any autoimmune attack. "We believe there are some alterations in the new beta cells where a number of cells being presented as autoantigens are reduced or diluted, and therefore, because of the slow presentation of the antigens, the number of autoreactive T cells are less pathogenic," says Dr. Kulkarni. "Clearly there's a link between these two processes. A precise mechanism and the pathways and the proteins involved will require a follow up study." This is not the first clue that beta cell proliferation could be a sort of protective factor for people with type 1 diabetes. Joslin's Medalist Study showed that many of those with long-duration type 1 diabetes still retain some beta cell function and growth more than 50 years after their diagnosis. Once the process of using beta cell proliferation as a preventative measure is better understood, it could move to human studies and clinical trials. Finding the right window to force beta cell proliferation in humans could delay or even prevent the destruction of beta cells by autoimmune cells. Some degree of autoimmunity would still exist in the body, however, so it would still require appropriate treatment to suppress the immune system. This study was supported in part by a grant from JDRF. "As we work to develop strategies to replace or regrow insulin producing cells to cure T1D, this work from Drs. Kulkarni and Dirice gives us important insight into how we could protect these new cells from autoimmune attack. This is a great example of the importance of JDRF's training program in developing successful new T1D scientists." Said Frank Martin, Ph.D., JDRF Associate Director, Research. "We're really excited to move things forward," says Dr. Kulkarni. "We hope that we can now begin to think about how to translate this to humans." <|im_end|>

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279, 28978, 3817, 53689, 5955, 11, 15753, 279, 6650, 315, 13746, 7917, 1418, 279, 10099, 1051, 2103, 3995, 2345, 57865, 36853, 315, 279, 22852, 1887, 1051, 2103, 11469, 11, 323, 2103, 47281, 311, 34786, 13, 578, 3135, 1051, 4756, 3432, 304, 22037, 6344, 53904, 2191, 13, 330, 1687, 527, 9539, 279, 1176, 311, 1501, 430, 422, 499, 4585, 279, 53840, 311, 31978, 7068, 502, 32152, 17843, 13746, 1824, 6572, 1603, 279, 22852, 2849, 30215, 8638, 1243, 11, 369, 1063, 2944, 584, 527, 2103, 4560, 311, 7216, 704, 11, 22852, 7917, 3009, 23664, 279, 13746, 2849, 1359, 2795, 2999, 13, 735, 22537, 1923, 72, 13, 1115, 15206, 9455, 574, 27461, 37539, 660, 304, 2999, 13, 735, 22537, 1923, 72, 596, 10278, 304, 21896, 6197, 555, 469, 1310, 1143, 31194, 560, 2405, 920, 2637, 97170, 63462, 304, 19152, 323, 8483, 33468, 520, 279, 28978, 3817, 53689, 5955, 13, 578, 7978, 1051, 8308, 304, 1403, 2204, 20335, 27748, 606, 8814, 4211, 13, 3861, 574, 264, 52033, 46036, 1646, 430, 8710, 7319, 13746, 2849, 6650, 5246, 1306, 7342, 1418, 279, 2132, 1646, 574, 41772, 520, 459, 4216, 4325, 449, 459, 8479, 3967, 311, 5376, 13746, 2849, 53840, 13, 5112, 11, 814, 14890, 10688, 505, 279, 87450, 268, 311, 8891, 279, 5219, 315, 350, 7917, 323, 426, 7917, 11, 2225, 315, 902, 527, 6532, 304, 279, 88191, 25481, 5938, 449, 955, 220, 16, 20335, 13, 3277, 279, 12074, 1380, 501, 7719, 279, 279, 374, 1169, 7917, 67572, 505, 279, 2682, 10099, 311, 264, 2204, 8814, 11, 279, 34876, 8710, 9313, 505, 279, 88191, 13010, 369, 264, 5129, 892, 13, 330, 2181, 374, 1633, 13548, 311, 23846, 430, 96811, 13746, 2849, 48891, 304, 264, 32100, 11827, 19543, 304, 264, 64793, 10395, 22852, 5643, 902, 11951, 36236, 13746, 7917, 1694, 17550, 1359, 1071, 2999, 13, 31194, 560, 11, 889, 706, 6051, 1027, 21489, 311, 279, 22291, 315, 279, 1561, 4356, 13235, 9304, 11, 6150, 315, 19152, 13, 330, 13461, 510, 258, 264, 7701, 47281, 8814, 1646, 1145, 994, 499, 4585, 279, 53840, 311, 7068, 502, 13746, 7917, 11, 220, 1484, 3346, 315, 279, 10099, 26968, 17223, 4661, 709, 311, 1403, 1667, 11, 902, 374, 1633, 19018, 1359, 2795, 2999, 13, 735, 22537, 1923, 72, 13, 25681, 922, 279, 11295, 13353, 927, 315, 279, 13746, 7917, 330, 6263, 4881, 1, 279, 88191, 13010, 11, 304, 264, 5647, 13, 578, 13746, 7917, 656, 539, 2873, 311, 387, 32644, 279, 3313, 519, 581, 10233, 14595, 315, 955, 220, 16, 20335, 33824, 13, 2435, 1101, 2873, 311, 387, 810, 31785, 311, 8631, 11, 902, 574, 264, 14580, 18841, 315, 279, 43929, 13651, 315, 279, 21896, 13, 1115, 13957, 311, 8631, 1436, 8331, 1139, 872, 5845, 311, 51571, 904, 88191, 3440, 13, 330, 1687, 4510, 1070, 527, 1063, 61086, 304, 279, 502, 13746, 7917, 1405, 264, 1396, 315, 7917, 1694, 10666, 439, 3313, 519, 343, 729, 527, 11293, 477, 80703, 11, 323, 9093, 11, 1606, 315, 279, 6435, 15864, 315, 279, 68937, 729, 11, 279, 1396, 315, 3154, 461, 3104, 350, 7917, 527, 2753, 1853, 29569, 1359, 2795, 2999, 13, 735, 22537, 1923, 72, 13, 330, 75471, 1070, 596, 264, 2723, 1990, 1521, 1403, 11618, 13, 362, 24473, 17383, 323, 279, 44014, 323, 279, 28896, 6532, 690, 1397, 264, 1833, 709, 4007, 1210, 1115, 374, 539, 279, 1176, 31089, 430, 13746, 2849, 53840, 1436, 387, 264, 3460, 315, 29219, 8331, 369, 1274, 449, 955, 220, 16, 20335, 13, 28978, 3817, 596, 17867, 380, 19723, 8710, 430, 1690, 315, 1884, 449, 1317, 65483, 955, 220, 16, 20335, 2103, 14389, 1063, 13746, 2849, 734, 323, 6650, 810, 1109, 220, 1135, 1667, 1306, 872, 23842, 13, 9843, 279, 1920, 315, 1701, 13746, 2849, 53840, 439, 264, 97420, 6767, 374, 2731, 16365, 11, 433, 1436, 3351, 311, 3823, 7978, 323, 14830, 19622, 13, 43897, 279, 1314, 3321, 311, 5457, 13746, 2849, 53840, 304, 12966, 1436, 7781, 477, 1524, 5471, 279, 19814, 315, 13746, 7917, 555, 88191, 7917, 13, 4427, 8547, 315, 3313, 12828, 2498, 1053, 2103, 3073, 304, 279, 2547, 11, 4869, 11, 779, 433, 1053, 2103, 1397, 8475, 6514, 311, 28321, 279, 22852, 1887, 13, 1115, 4007, 574, 7396, 304, 961, 555, 264, 13500, 505, 622, 7842, 37, 13, 330, 2170, 584, 990, 311, 2274, 15174, 311, 8454, 477, 1239, 654, 32152, 17843, 7917, 311, 27208, 350, 16, 35, 11, 420, 990, 505, 2999, 82, 13, 735, 22537, 1923, 72, 323, 31194, 560, 6835, 603, 3062, 20616, 1139, 1268, 584, 1436, 6144, 1521, 502, 7917, 505, 88191, 3440, 13, 1115, 374, 264, 2294, 3187, 315, 279, 12939, 315, 622, 7842, 37, 596, 4967, 2068, 304, 11469, 6992, 502, 350, 16, 35, 14248, 1210, 51224, 9454, 11826, 11, 2405, 920, 2637, 622, 7842, 37, 33468, 10783, 11, 8483, 13, 330, 1687, 2351, 2216, 12304, 311, 3351, 2574, 4741, 1359, 2795, 2999, 13, 735, 22537, 1923, 72, 13, 330, 1687, 3987, 430, 584, 649, 1457, 3240, 311, 1781, 922, 1268, 311, 15025, 420, 311, 12966, 1210, 220, 128257, 198 ]

2,623

[ { "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 2015, the International Association of Geodesy defined the International Height Reference System (IHRS) as the conventional gravity field-related global height system. The IHRS is a geopotential reference system co-rotating with the Earth. Coordinates of points or objects close to or on the Earth’s surface are given by geopotential numbers C ( P ) referring to an equipotential surface defined by the conventional value W 0 = 62,636,853.4 m 2 s −2 , and geocentric Cartesian coordinates X referring to the International Terrestrial Reference System (ITRS). Current efforts concentrate on an accurate, consistent, and well-defined realisation of the IHRS to provide an international standard for the precise determination of physical coordinates worldwide. Accordingly, this study focuses on the strategy for the realisation of the IHRS; i.e. the establishment of the International Height Reference Frame (IHRF). Four main aspects are considered: (1) methods for the determination of IHRF physical coordinates; (2) standards and conventions needed to ensure consistency between the definition and the realisation of the reference system; (3) criteria for the IHRF reference network design and station selection; and (4) operational infrastructure to guarantee a reliable and long-term sustainability of the IHRF. A highlight of this work is the evaluation of different approaches for the determination and accuracy assessment of IHRF coordinates based on the existing resources, namely (1) global gravity models of high resolution, (2) precise regional gravity field modelling, and (3) vertical datum unification of the local height systems into the IHRF. After a detailed discussion of the advantages, current limitations, and possibilities of improvement in the coordinate determination using these options, we define a strategy for the establishment of the IHRF including data requirements, a set of minimum standards/conventions for the determination of potential coordinates, a first IHRF reference network configuration, and a proposal to create a component of the International Gravity Field Service (IGFS) dedicated to the maintenance and servicing of the IHRS/IHRF. Working on a manuscript? Avoid the common mistakes 1 Introduction A current main objective of Geodesy is the implementation of an integrated global geodetic reference system that simultaneously supports the consistent determination and monitoring of the Earth’s geometry, rotation, and gravity field changes with high accuracy worldwide (IAG 2017 ). This objective is in accordance with the resolution adopted by the United Nations General Assembly on a Global Geodetic Reference Frame (GGRF-UN) for Sustainable Development (A/RES/69/266) on February 26, 2015. During the last decades, a huge progress in the realisation of the International Celestial Reference System (ICRS, Ma and Feissel 1997 ) and the International Terrestrial Reference System (ITRS, Petit and Luzum 2010 ) has been achieved. The definition, realisation, and maintenance of these two systems guarantee a globally unified geometric reference frame with reliability at the centimetre level. An equivalent high-precision gravity field-related global height system is missing. Most countries today use regional or local height systems, which have been implemented individually, applying in general diverse procedures. At present, there are some hundred local and regional physical height systems in use. They refer to local sea surface levels, are usually stationary (do not consider variations in time), and realise different physical height types (orthometric or normal heights), and their combination in a global frame presents uncertainties at the metre level. The geodetic data depending on them (e.g. physical heights, gravity anomalies, geoid models, digital terrain models, etc.) are usable in limited geographical areas only, and their global combination or with satellite-based data (especially Global Navigation Satellite Systems’ (GNSS) positioning) shows discrepancies with magnitudes much higher than the accuracy required today. An accurate, consistent and well-defined global vertical reference system that is in accordance with the increased precision of modern observational techniques and is capable of supporting the present needs of science and society regarding geo-referenced data of high resolution has yet to be established as an international standard (IAG 2017 ). The International Association of Geodesy (IAG), as the organisation responsible for the advancement of the science of Geodesy, introduced in 2015 the International Height Reference System (IHRS) as the conventional gravity field-related global height system (see IAG Resolution No. 1 (2015) in Drewes et al. 2016 ). The theoretical foundations for the definition of the IHRS are described in Ihde et al. ( 2017 ). Based on this work, this study concentrates on the strategy for the realisation of the IHRS; i.e. the implementation of the International Height Reference Frame (IHRF). Given that a reference frame realises a reference system physically by a solid materialisation of points or observing instruments, and mathematically by the determination of coordinates referring to that reference system (Drewes 2009 ), this study considers four main aspects: (1) methods for the determination of IHRF physical coordinates (e.g. geopotential numbers referring to the conventional reference W 0 value); (2) standards and conventions needed to ensure consistency between the definition and the realisation of the reference system; (3) station selection for the IHRF reference network; and (4) Operational infrastructure to guarantee a reliable and long-term sustainability of the IHRS/IHRF. Accordingly, Sect. 2 summarises the definition of the IHRS. Sections 3 – 5 concentrate on the determination and accuracy assessment of IHRF coordinates based on the existing resources: global gravity models of high resolution (GGM-HR in Sect. 3 ), regional gravity field modelling (Sect. 4 ), and existing physical height systems (Sect. 5 ). These sections also provide a description of current limitations and possibilities of improvement in the coordinate determination using each method. The outcome of this analysis is presented in two parts: Sect. 6 proposes the standards and conventions identified as the minimum requirements for the determination of IHRF coordinates. It includes a standardised strategy for the treatment of the permanent tide in the determination of IHRF coordinates in the mean-tide system. Section 7 recommends the strategy for the implementation of the IHRF, which covers (1) the determination and evaluation of IHRF coordinates depending on the data availability; (2) improvement of the input data required for the determination of IHRF coordinates; (3) the criteria for the IHRF", "role": "user" }, { "content": "Maps generally indicate elevation in meters above sea level. But sea level is not the same everywhere. A group of experts headed by the Technical University of Munich (TUM), has developed an International Height Reference System (IHRS) that will unify geodetic measurements worldwide. How high is Mount Everest? 8848 meters? 8844 meters? Or 8850 meters? For years, China and Nepal could not agree. In 2019, Nepal sent a team of geodesists to measure the world's highest mountain. A year later a team from China climbed the peak. Last December the two governments jointly announced the outcome of the new measurement: 8848.86 meters. The fact that both China and Nepal recognize this result must be seen as a diplomatic success. It was made possible by the new International Height Reference System (IHRS), used for the first time by the geodetic specialists conducting the new measurement. Scientists from TUM played a leading role in developing the new system. It establishes a generally agreed zero level as a basis for all future measurements. It thus replaces the mean sea level, which has traditionally served as the zero level for surveyors and thus for all topographical maps. A paper in the Journal of Geodesy, jointly authored by TUM scientists and international research groups, outlines the scientific background and theoretical concept of the IHRS as well as the strategy for implementing it. When zero is not always zero The standard used until now—the mean sea level—was flawed from the outset: There was never a fixed definition. Every country could use arbitrary tide gauges to define its own zero level. As a result, Germany's official sea level is 31 centimeters higher than Italy's, 50 cm higher than that used in Spain and actually 2.33 m higher than in Belgium, where the zero height is based on low water in Ostend. When topographical maps are only used for hiking, no one is bothered by such differences. But for geodetics specialists trying to arrive at a universally agreed height—for Mount Everest, for example, half in Nepal and half in China—the inconsistent zero levels are a bigger problem. And it can be very costly when planners of cross-border structures such as bridges and tunnels forget to check the different coordinates used by the teams and convert them as needed. On the Hochrheinbrücke, a bridge connecting Germany and Switzerland, a discrepancy of this kind was noticed just in time. Surveys from orbit \"The introduction of an internationally valid height reference system was long overdue,\" says TUM researcher Dr. Laura Sánchez of the Deutsches Geodätisches Forschungsinstitut (DGFI-TUM), who has headed working groups studying theoretical aspects and implementing the new global height reference system at the International Association of Geodesy for several years. What is needed is obvious: a universally accepted zero level. The new International Height Reference System (IHRS) defines how it can be calculated: It takes into account the shape of the Earth—which is close to spherical, but flattened at the poles and bulging slightly at the equator due to its rotation—and the uneven distribution of masses in the interior and on the surface. The resulting irregularities in the gravity field are the basis for calculating the height system because the strength and direction of the force determine the distribution of water in the oceans. If we assume that the Earth's surface is completely covered with water, the height of a hypothetical sea level and thus the zero level for the entire globe can be calculated precisely. In construction projects, even the smallest deviations can be crucial \"It became possible to realize the IHRS only with the availability of global data from satellite missions such as the ESA earth observation satellite GOCE (Gravity field and steady-state Ocean Circulation Explorer),\" says Prof. Roland Pail of the TUM Chair of Astronomical and Physical Geodesy (APG). His team played an integral role in analyzing the GOCE measurements and using them to calculate global models of the Earth's gravity field. \"The information gained in this way provides the basis to calculate the mean sea level for every point on Earth with the new International Height Reference System, regardless of whether it is on a continent or in an ocean, and thus to compute the internationally accepted zero level,\" explains Sánchez. Does every map have to be redrawn? \"It won't be that dramatic,\" says Sánchez. \"In the industrial countries, where they have been making gravity measurements for decades, the deviations are quite small—only in the decimeter range.\" But with construction projects, for example, even small deviations can cause serious troubles. Consequently, the scientist is confident that the new reference system will gain acceptance quickly. ", "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 2015, the International Association of Geodesy defined the International Height Reference System (IHRS) as the conventional gravity field-related global height system. The IHRS is a geopotential reference system co-rotating with the Earth. Coordinates of points or objects close to or on the Earth’s surface are given by geopotential numbers C ( P ) referring to an equipotential surface defined by the conventional value W 0 = 62,636,853.4 m 2 s −2 , and geocentric Cartesian coordinates X referring to the International Terrestrial Reference System (ITRS). Current efforts concentrate on an accurate, consistent, and well-defined realisation of the IHRS to provide an international standard for the precise determination of physical coordinates worldwide. Accordingly, this study focuses on the strategy for the realisation of the IHRS; i.e. the establishment of the International Height Reference Frame (IHRF). Four main aspects are considered: (1) methods for the determination of IHRF physical coordinates; (2) standards and conventions needed to ensure consistency between the definition and the realisation of the reference system; (3) criteria for the IHRF reference network design and station selection; and (4) operational infrastructure to guarantee a reliable and long-term sustainability of the IHRF. A highlight of this work is the evaluation of different approaches for the determination and accuracy assessment of IHRF coordinates based on the existing resources, namely (1) global gravity models of high resolution, (2) precise regional gravity field modelling, and (3) vertical datum unification of the local height systems into the IHRF. After a detailed discussion of the advantages, current limitations, and possibilities of improvement in the coordinate determination using these options, we define a strategy for the establishment of the IHRF including data requirements, a set of minimum standards/conventions for the determination of potential coordinates, a first IHRF reference network configuration, and a proposal to create a component of the International Gravity Field Service (IGFS) dedicated to the maintenance and servicing of the IHRS/IHRF. Working on a manuscript? Avoid the common mistakes 1 Introduction A current main objective of Geodesy is the implementation of an integrated global geodetic reference system that simultaneously supports the consistent determination and monitoring of the Earth’s geometry, rotation, and gravity field changes with high accuracy worldwide (IAG 2017 ). This objective is in accordance with the resolution adopted by the United Nations General Assembly on a Global Geodetic Reference Frame (GGRF-UN) for Sustainable Development (A/RES/69/266) on February 26, 2015. During the last decades, a huge progress in the realisation of the International Celestial Reference System (ICRS, Ma and Feissel 1997 ) and the International Terrestrial Reference System (ITRS, Petit and Luzum 2010 ) has been achieved. The definition, realisation, and maintenance of these two systems guarantee a globally unified geometric reference frame with reliability at the centimetre level. An equivalent high-precision gravity field-related global height system is missing. Most countries today use regional or local height systems, which have been implemented individually, applying in general diverse procedures. At present, there are some hundred local and regional physical height systems in use. They refer to local sea surface levels, are usually stationary (do not consider variations in time), and realise different physical height types (orthometric or normal heights), and their combination in a global frame presents uncertainties at the metre level. The geodetic data depending on them (e.g. physical heights, gravity anomalies, geoid models, digital terrain models, etc.) are usable in limited geographical areas only, and their global combination or with satellite-based data (especially Global Navigation Satellite Systems’ (GNSS) positioning) shows discrepancies with magnitudes much higher than the accuracy required today. An accurate, consistent and well-defined global vertical reference system that is in accordance with the increased precision of modern observational techniques and is capable of supporting the present needs of science and society regarding geo-referenced data of high resolution has yet to be established as an international standard (IAG 2017 ). The International Association of Geodesy (IAG), as the organisation responsible for the advancement of the science of Geodesy, introduced in 2015 the International Height Reference System (IHRS) as the conventional gravity field-related global height system (see IAG Resolution No. 1 (2015) in Drewes et al. 2016 ). The theoretical foundations for the definition of the IHRS are described in Ihde et al. ( 2017 ). Based on this work, this study concentrates on the strategy for the realisation of the IHRS; i.e. the implementation of the International Height Reference Frame (IHRF). Given that a reference frame realises a reference system physically by a solid materialisation of points or observing instruments, and mathematically by the determination of coordinates referring to that reference system (Drewes 2009 ), this study considers four main aspects: (1) methods for the determination of IHRF physical coordinates (e.g. geopotential numbers referring to the conventional reference W 0 value); (2) standards and conventions needed to ensure consistency between the definition and the realisation of the reference system; (3) station selection for the IHRF reference network; and (4) Operational infrastructure to guarantee a reliable and long-term sustainability of the IHRS/IHRF. Accordingly, Sect. 2 summarises the definition of the IHRS. Sections 3 – 5 concentrate on the determination and accuracy assessment of IHRF coordinates based on the existing resources: global gravity models of high resolution (GGM-HR in Sect. 3 ), regional gravity field modelling (Sect. 4 ), and existing physical height systems (Sect. 5 ). These sections also provide a description of current limitations and possibilities of improvement in the coordinate determination using each method. The outcome of this analysis is presented in two parts: Sect. 6 proposes the standards and conventions identified as the minimum requirements for the determination of IHRF coordinates. It includes a standardised strategy for the treatment of the permanent tide in the determination of IHRF coordinates in the mean-tide system. Section 7 recommends the strategy for the implementation of the IHRF, which covers (1) the determination and evaluation of IHRF coordinates depending on the data availability; (2) improvement of the input data required for the determination of IHRF coordinates; (3) the criteria for the IHRF<|im_end|> <|im_start|>assistant Maps generally indicate elevation in meters above sea level. But sea level is not the same everywhere. A group of experts headed by the Technical University of Munich (TUM), has developed an International Height Reference System (IHRS) that will unify geodetic measurements worldwide. How high is Mount Everest? 8848 meters? 8844 meters? Or 8850 meters? For years, China and Nepal could not agree. In 2019, Nepal sent a team of geodesists to measure the world's highest mountain. A year later a team from China climbed the peak. Last December the two governments jointly announced the outcome of the new measurement: 8848.86 meters. The fact that both China and Nepal recognize this result must be seen as a diplomatic success. It was made possible by the new International Height Reference System (IHRS), used for the first time by the geodetic specialists conducting the new measurement. Scientists from TUM played a leading role in developing the new system. It establishes a generally agreed zero level as a basis for all future measurements. It thus replaces the mean sea level, which has traditionally served as the zero level for surveyors and thus for all topographical maps. A paper in the Journal of Geodesy, jointly authored by TUM scientists and international research groups, outlines the scientific background and theoretical concept of the IHRS as well as the strategy for implementing it. When zero is not always zero The standard used until now—the mean sea level—was flawed from the outset: There was never a fixed definition. Every country could use arbitrary tide gauges to define its own zero level. As a result, Germany's official sea level is 31 centimeters higher than Italy's, 50 cm higher than that used in Spain and actually 2.33 m higher than in Belgium, where the zero height is based on low water in Ostend. When topographical maps are only used for hiking, no one is bothered by such differences. But for geodetics specialists trying to arrive at a universally agreed height—for Mount Everest, for example, half in Nepal and half in China—the inconsistent zero levels are a bigger problem. And it can be very costly when planners of cross-border structures such as bridges and tunnels forget to check the different coordinates used by the teams and convert them as needed. On the Hochrheinbrücke, a bridge connecting Germany and Switzerland, a discrepancy of this kind was noticed just in time. Surveys from orbit "The introduction of an internationally valid height reference system was long overdue," says TUM researcher Dr. Laura Sánchez of the Deutsches Geodätisches Forschungsinstitut (DGFI-TUM), who has headed working groups studying theoretical aspects and implementing the new global height reference system at the International Association of Geodesy for several years. What is needed is obvious: a universally accepted zero level. The new International Height Reference System (IHRS) defines how it can be calculated: It takes into account the shape of the Earth—which is close to spherical, but flattened at the poles and bulging slightly at the equator due to its rotation—and the uneven distribution of masses in the interior and on the surface. The resulting irregularities in the gravity field are the basis for calculating the height system because the strength and direction of the force determine the distribution of water in the oceans. If we assume that the Earth's surface is completely covered with water, the height of a hypothetical sea level and thus the zero level for the entire globe can be calculated precisely. In construction projects, even the smallest deviations can be crucial "It became possible to realize the IHRS only with the availability of global data from satellite missions such as the ESA earth observation satellite GOCE (Gravity field and steady-state Ocean Circulation Explorer)," says Prof. Roland Pail of the TUM Chair of Astronomical and Physical Geodesy (APG). His team played an integral role in analyzing the GOCE measurements and using them to calculate global models of the Earth's gravity field. "The information gained in this way provides the basis to calculate the mean sea level for every point on Earth with the new International Height Reference System, regardless of whether it is on a continent or in an ocean, and thus to compute the internationally accepted zero level," explains Sánchez. Does every map have to be redrawn? "It won't be that dramatic," says Sánchez. "In the industrial countries, where they have been making gravity measurements for decades, the deviations are quite small—only in the decimeter range." But with construction projects, for example, even small deviations can cause serious troubles. Consequently, the scientist is confident that the new reference system will gain acceptance quickly. <|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 probabilistic nature of single-photon sources and photon–photon interactions encourages encoding as much quantum information as possible in every photon for the purpose of photonic quantum information processing. Here, by encoding high-dimensional units of information (qudits) in time and frequency degrees of freedom using on-chip sources, we report deterministic two-qudit gates in a single photon with fidelities exceeding 0.90 in the computational basis. Constructing a two-qudit modulo SUM gate, we generate and measure a single-photon state with nonseparability between time and frequency qudits. We then employ this SUM operation on two frequency-bin entangled photons—each carrying two 32-dimensional qudits—to realize a four-party high-dimensional Greenberger–Horne–Zeilinger state, occupying a Hilbert space equivalent to that of 20 qubits. Although high-dimensional coding alone is ultimately not scalable for universal quantum computing, our design shows the potential of deterministic optical quantum operations in large encoding spaces for practical and compact quantum information processing protocols. Introduction Quantum information processing has drawn massive attention due to its power in solving some crucial algorithms exponentially faster than their classical counterparts, 1 as well as its ability to transmit information in a fully secure fashion, two capabilities looked to be combined in the emerging quantum internet. 2 Among the platforms that can exhibit quantum behavior, optical states have the advantages of low decoherence and suitability for long-distance communications, yet the weak coupling of photons to their surroundings also makes it extremely difficult to manipulate the state of one photon based on the state of another. This operation, needed for a two-qubit gate, is probabilistic with standard linear optics and photon counting. 3 Quantum gates have been demonstrated in a number of different photonic degrees of freedom, such as polarization, 4 orbital angular momentum, 5 time, 6 and frequency, 7 , 8 and to sidestep the challenges of probabilistic multiphoton interactions, encoding qubits in different degrees of freedom (DoFs) in a single photon has been demonstrated, where each DoF carries one qubit and, now, operations between different qubits can be made deterministic. 9 , 10 This scheme allows encoding more quantum information in single photons, and can find use in stand-alone processing tasks or be subsequently incorporated into larger systems built on true photon–photon interactions, thus offering a potentially more efficient method for photonic quantum information processing. Even though in this case two- and three-qubit operations can be executed with unity success probability, each DoF contains only one qubit, and the number of a photon’s DoFs are limited; thus the size of the Hilbert space in which these deterministic transformations can happen is fairly moderate (e.g., an eight-dimensional Hilbert space has been demonstrated by encoding three qubits in three different DoFs of a single photon 10 ). In this article, we take advantage of the high dimensionality in two particular DoFs of a single photon—namely, time and frequency, which are both compatible with fiber optical transmission—to encode one qudit in each DoF. We consider multiple time bins and frequency bins; as long as the frequency spacing between different modes (Δ f ) and the time-bin spacing (Δ t ) are chosen such that they exceed the Fourier transform limit (i.e., Δ f Δ t > 1), we are able to manipulate the time and frequency DoFs independently in a hyper-encoding fashion, using concepts developed in time-division and wavelength-division multiplexing, respectively. 11 , 12 In other words, each time–frequency mode pair constitutes a well-defined entity, or plaquette, 11 , 12 which is sufficiently separated from its neighbors to provide stable encoding (Fig. 1 ). Alternatively, this can be understood by considering bandwidth-limited plaquettes with individual spectral linewidth δf (corresponding to temporal duration ~1/ δf ). These will not overlap in time–frequency space as long as the chosen bin separations satisfy Δ f > δf and Δ t > 1/ δf . Combined, then, these two equations yield the aforementioned condition Δ f Δ t > 1. An analogous process is at work in the advanced optical modulation formats gaining adoption in modern digital communications, where many bits are encoded in a single symbol via modulation of canonically conjugate quadratures. 13 Since our single photons can potentially be generated in a superposition of many time and frequency bins, multiple qubits can be encoded in each DoF, making our proposed scheme a favorable platform for deterministic optical quantum information processing on Hilbert spaces dramatically larger than previously demonstrated deterministic qubit-based gates. Ultimately, the total number of DoFs carried by a single photon is limited, so one cannot increase the Hilbert space indefinitely by encoding in increasingly more properties within individual photons. The Hilbert space can be increased, though, by expanding the dimensionality within each DoF. While enabling only linear scaling of the Hilbert space with the number of modes, 14 and thereby not facilitating the exponential scaling required for fault-tolerant quantum computing, qudit encoding promises significant potential in the current generation of quantum circuits. It has been shown, for example, that two-qudit optical gates are useful in transmitting quantum states with higher information content per photon by means of qudit teleportation, 15 a task that requires two-qudit gates which can operate on the different degrees of freedom of a single photon 16 , 17 —precisely the functionality we demonstrate here. Fig. 1 Illustration of the scheme. Two qudits encoded in d time bins and frequency bins in a single photon, going through a deterministic quantum process. The single photon can be encoded in an arbitrary superposition of different time and frequency bins; the unused time–frequency slots are shown with dashed circles. After the deterministic quantum process operates on the two-qudit state, the orientation of the time–frequency superpositions change to a new two-qudit state Full size image Results To enable the realization of all single-qudit unitaries, it is sufficient to demonstrate the generalized Pauli gates X (cyclic shift) and Z (state-dependent phase), which are universal for single-qudit operations, 5 and from which all d -dimensional Weyl operators can be constructed. 18 The Z gate applies a unique phase shift to each of the d", "role": "user" }, { "content": "Quantum information processing promises to be much faster and more secure than what today's supercomputers can achieve, but doesn't exist yet because its building blocks, qubits, are notoriously unstable. Purdue University researchers are among the first to build a gate—what could be a quantum version of a transistor, used in today's computers for processing information—with qudits. Whereas qubits can exist only in superpositions of 0 and 1 states, qudits exist in multiple states, such as 0 and 1 and 2. More states mean that more data can be encoded and processed. The gate would not only be inherently more efficient than qubit gates, but also more stable because the researchers packed the qudits into photons, particles of light that aren't easily disturbed by their environment. The researchers' findings appear in npj Quantum Information. The gate also creates one of the largest entangled states of quantum particles to date—in this case, photons. Entanglement is a quantum phenomenon that allows measurements on one particle to automatically affect measurements on another particle, bringing the ability to make communication between parties unbreakable or to teleport quantum information from one point to another, for example. The more entanglement in the so-called Hilbert space—the realm where quantum information processing can take place—the better. Previous photonic approaches were able to reach 18 qubits encoded in six entangled photons in the Hilbert space. Purdue researchers maximized entanglement with a gate using four qudits—the equivalent of 20 qubits—encoded in only two photons. In quantum communication, less is more. \"Photons are expensive in the quantum sense because they're hard to generate and control, so it's ideal to pack as much information as possible into each photon,\" said Poolad Imany, a postdoctoral researcher in Purdue's School of Electrical and Computer Engineering. The team achieved more entanglement with fewer photons by encoding one qudit in the time domain and the other in the frequency domain of each of the two photons. They built a gate using the two qudits encoded in each photon, for a total of four qudits in 32 dimensions, or possibilities, of both time and frequency. The more dimensions, the more entanglement. Starting from two photons entangled in the frequency domain and then operating the gate to entangle the time and frequency domains of each photon generates four fully-entangled qudits, which occupy a Hilbert space of 1,048,576 dimensions, or 32 to the fourth power. Typically, gates built on photonic platforms to manipulate quantum information encoded in separate photons work only some of the time because photons naturally don't interact with each other very well, making it extremely difficult to manipulate the state of one photon based on the state of another. By encoding quantum information in the time and frequency domains of photons, Purdue researchers made operating the quantum gate deterministic as opposed to probabilistic. The team implemented the gate with a set of standard off-the-shelf equipment used daily in the optical communication industry. \"This gate allows us to manipulate information in a predictable and deterministic way, which means that it could perform the operations necessary for certain quantum information processing tasks,\" said Andrew Weiner, Purdue's Scifres Family Distinguished Professor of Electrical and Computer Engineering, whose lab specializes in ultrafast optics. Next, the team wants to use the gate in quantum communications tasks such as high-dimensional quantum teleportation as well as for performing quantum algorithms in applications such as quantum machine learning or simulating molecules. ", "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 probabilistic nature of single-photon sources and photon–photon interactions encourages encoding as much quantum information as possible in every photon for the purpose of photonic quantum information processing. Here, by encoding high-dimensional units of information (qudits) in time and frequency degrees of freedom using on-chip sources, we report deterministic two-qudit gates in a single photon with fidelities exceeding 0.90 in the computational basis. Constructing a two-qudit modulo SUM gate, we generate and measure a single-photon state with nonseparability between time and frequency qudits. We then employ this SUM operation on two frequency-bin entangled photons—each carrying two 32-dimensional qudits—to realize a four-party high-dimensional Greenberger–Horne–Zeilinger state, occupying a Hilbert space equivalent to that of 20 qubits. Although high-dimensional coding alone is ultimately not scalable for universal quantum computing, our design shows the potential of deterministic optical quantum operations in large encoding spaces for practical and compact quantum information processing protocols. Introduction Quantum information processing has drawn massive attention due to its power in solving some crucial algorithms exponentially faster than their classical counterparts, 1 as well as its ability to transmit information in a fully secure fashion, two capabilities looked to be combined in the emerging quantum internet. 2 Among the platforms that can exhibit quantum behavior, optical states have the advantages of low decoherence and suitability for long-distance communications, yet the weak coupling of photons to their surroundings also makes it extremely difficult to manipulate the state of one photon based on the state of another. This operation, needed for a two-qubit gate, is probabilistic with standard linear optics and photon counting. 3 Quantum gates have been demonstrated in a number of different photonic degrees of freedom, such as polarization, 4 orbital angular momentum, 5 time, 6 and frequency, 7 , 8 and to sidestep the challenges of probabilistic multiphoton interactions, encoding qubits in different degrees of freedom (DoFs) in a single photon has been demonstrated, where each DoF carries one qubit and, now, operations between different qubits can be made deterministic. 9 , 10 This scheme allows encoding more quantum information in single photons, and can find use in stand-alone processing tasks or be subsequently incorporated into larger systems built on true photon–photon interactions, thus offering a potentially more efficient method for photonic quantum information processing. Even though in this case two- and three-qubit operations can be executed with unity success probability, each DoF contains only one qubit, and the number of a photon’s DoFs are limited; thus the size of the Hilbert space in which these deterministic transformations can happen is fairly moderate (e.g., an eight-dimensional Hilbert space has been demonstrated by encoding three qubits in three different DoFs of a single photon 10 ). In this article, we take advantage of the high dimensionality in two particular DoFs of a single photon—namely, time and frequency, which are both compatible with fiber optical transmission—to encode one qudit in each DoF. We consider multiple time bins and frequency bins; as long as the frequency spacing between different modes (Δ f ) and the time-bin spacing (Δ t ) are chosen such that they exceed the Fourier transform limit (i.e., Δ f Δ t > 1), we are able to manipulate the time and frequency DoFs independently in a hyper-encoding fashion, using concepts developed in time-division and wavelength-division multiplexing, respectively. 11 , 12 In other words, each time–frequency mode pair constitutes a well-defined entity, or plaquette, 11 , 12 which is sufficiently separated from its neighbors to provide stable encoding (Fig. 1 ). Alternatively, this can be understood by considering bandwidth-limited plaquettes with individual spectral linewidth δf (corresponding to temporal duration ~1/ δf ). These will not overlap in time–frequency space as long as the chosen bin separations satisfy Δ f > δf and Δ t > 1/ δf . Combined, then, these two equations yield the aforementioned condition Δ f Δ t > 1. An analogous process is at work in the advanced optical modulation formats gaining adoption in modern digital communications, where many bits are encoded in a single symbol via modulation of canonically conjugate quadratures. 13 Since our single photons can potentially be generated in a superposition of many time and frequency bins, multiple qubits can be encoded in each DoF, making our proposed scheme a favorable platform for deterministic optical quantum information processing on Hilbert spaces dramatically larger than previously demonstrated deterministic qubit-based gates. Ultimately, the total number of DoFs carried by a single photon is limited, so one cannot increase the Hilbert space indefinitely by encoding in increasingly more properties within individual photons. The Hilbert space can be increased, though, by expanding the dimensionality within each DoF. While enabling only linear scaling of the Hilbert space with the number of modes, 14 and thereby not facilitating the exponential scaling required for fault-tolerant quantum computing, qudit encoding promises significant potential in the current generation of quantum circuits. It has been shown, for example, that two-qudit optical gates are useful in transmitting quantum states with higher information content per photon by means of qudit teleportation, 15 a task that requires two-qudit gates which can operate on the different degrees of freedom of a single photon 16 , 17 —precisely the functionality we demonstrate here. Fig. 1 Illustration of the scheme. Two qudits encoded in d time bins and frequency bins in a single photon, going through a deterministic quantum process. The single photon can be encoded in an arbitrary superposition of different time and frequency bins; the unused time–frequency slots are shown with dashed circles. After the deterministic quantum process operates on the two-qudit state, the orientation of the time–frequency superpositions change to a new two-qudit state Full size image Results To enable the realization of all single-qudit unitaries, it is sufficient to demonstrate the generalized Pauli gates X (cyclic shift) and Z (state-dependent phase), which are universal for single-qudit operations, 5 and from which all d -dimensional Weyl operators can be constructed. 18 The Z gate applies a unique phase shift to each of the d<|im_end|> <|im_start|>assistant Quantum information processing promises to be much faster and more secure than what today's supercomputers can achieve, but doesn't exist yet because its building blocks, qubits, are notoriously unstable. Purdue University researchers are among the first to build a gate—what could be a quantum version of a transistor, used in today's computers for processing information—with qudits. Whereas qubits can exist only in superpositions of 0 and 1 states, qudits exist in multiple states, such as 0 and 1 and 2. More states mean that more data can be encoded and processed. The gate would not only be inherently more efficient than qubit gates, but also more stable because the researchers packed the qudits into photons, particles of light that aren't easily disturbed by their environment. The researchers' findings appear in npj Quantum Information. The gate also creates one of the largest entangled states of quantum particles to date—in this case, photons. Entanglement is a quantum phenomenon that allows measurements on one particle to automatically affect measurements on another particle, bringing the ability to make communication between parties unbreakable or to teleport quantum information from one point to another, for example. The more entanglement in the so-called Hilbert space—the realm where quantum information processing can take place—the better. Previous photonic approaches were able to reach 18 qubits encoded in six entangled photons in the Hilbert space. Purdue researchers maximized entanglement with a gate using four qudits—the equivalent of 20 qubits—encoded in only two photons. In quantum communication, less is more. "Photons are expensive in the quantum sense because they're hard to generate and control, so it's ideal to pack as much information as possible into each photon," said Poolad Imany, a postdoctoral researcher in Purdue's School of Electrical and Computer Engineering. The team achieved more entanglement with fewer photons by encoding one qudit in the time domain and the other in the frequency domain of each of the two photons. They built a gate using the two qudits encoded in each photon, for a total of four qudits in 32 dimensions, or possibilities, of both time and frequency. The more dimensions, the more entanglement. Starting from two photons entangled in the frequency domain and then operating the gate to entangle the time and frequency domains of each photon generates four fully-entangled qudits, which occupy a Hilbert space of 1,048,576 dimensions, or 32 to the fourth power. Typically, gates built on photonic platforms to manipulate quantum information encoded in separate photons work only some of the time because photons naturally don't interact with each other very well, making it extremely difficult to manipulate the state of one photon based on the state of another. By encoding quantum information in the time and frequency domains of photons, Purdue researchers made operating the quantum gate deterministic as opposed to probabilistic. The team implemented the gate with a set of standard off-the-shelf equipment used daily in the optical communication industry. "This gate allows us to manipulate information in a predictable and deterministic way, which means that it could perform the operations necessary for certain quantum information processing tasks," said Andrew Weiner, Purdue's Scifres Family Distinguished Professor of Electrical and Computer Engineering, whose lab specializes in ultrafast optics. Next, the team wants to use the gate in quantum communications tasks such as high-dimensional quantum teleportation as well as for performing quantum algorithms in applications such as quantum machine learning or simulating molecules. <|im_end|>

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2,061

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective To project the proportion of population 65+ years with severe long-term activity limitations from 2017 to 2047. Design Large population study. Setting Population living in private households of the European Union (EU) and neighbouring countries. Participants Participants from the EU Statistics on Income and Living Conditions aged 55 years and older and living in one of 26 EU and neighbouring countries, who answered the health section of the questionnaire. Outcome measures Prevalence of severe long-term activity limitations of particular subpopulations (ie, 55+, 65+, 75+ and 85+ years) by sex and country. Results We find a huge variation in the prevalence of self-reported severe long-term limitations across Europe for both sexes. However, in 2017, about 20% of the female population aged 65 years and above and about 16% of their male counterparts are expected to report severe long-term activity limitations after accounting for differences in reporting. Accounting for cultural differences in reporting, we expect that European countries will have about 21% (decile 1: 19.5%; decile 9: 22.9%) of female and about 16.8% (decile 1: 15.4%; decile 9: 18.1%) of male 65+ years population with severe long-term activity limitations by 2047. Conclusions Overall, despite the expected increase of life expectancy in European countries, our results suggest almost constant shares of older adults with severe long-term activity limitations within the next 30 years. disability activity limitations Eu-silc europe health expectancy ageing 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 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 14 news outlets Blogged by 1 Tweeted by 8 On 2 Facebook pages 25 readers on Mendeley Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions disability activity limitations Eu-silc europe health expectancy ageing Strengths and limitations of this study We used data on 26 European countries collected annually between 2008 and 2014. Applying the Sullivan method, we computed life expectancy without severe long-term activity limitations (healthy life years (HLYs)) by sex and 5-year age groups. We model the ratio of HLYs and life expectancy to predict prevalence of severe activity limitations among older adults. Cultural differences in self-reports are acknowledged, so we used a random intercept approach to consider those properly. Introduction Worldwide populations are growing older. In upper middle-income and high-income countries, life expectancy is increasing and fertility rates are declining, leading to an increase of older populations. However, there is a lack of evidence whether these demographic changes are accompanied by an increase of frail or morbid people. The health status of older population is of raising public interest and a broadly discussed issue since many countries fear a rise in economic costs caused by ageing. During the last decades, a large body of literature focused on health trends, which were often analysed with indicators using health-specific life expectancies. 1–3 Research on trends in healthy life years (HLYs) and disability-free life expectancy showed an inconsistent pattern. For instance, in the early 2000s, healthy life expectancy showed only little change for European men and women in contrast to their life expectancy, 4 whereas it increased significantly between the early 1980s and 2000s in Austria. 5 Other studies showed that in the USA, higher educated population experienced some compression of morbidity, whereas their lower educated counterparts showed an expansion. 6 There are inequalities in health expectancies at older ages across the European Union (EU) and even within countries, and there are discrepancies between men and women. 1 Even though women benefit from their mortality advantage over men when it comes to HLYs, the situation is sometimes the opposite. Women in general report higher prevalence of disabilities and frailty. 7 Some research already explored this health-survival paradox. 8 9 Less research was focused on the impact of possible future trends in healthy and disability-free life expectancy on the socioeconomic development of a country. For instance, are European health systems prepared for higher shares of older adults? Should we expect higher proportions of unhealthy older population? The objective of this study is to provide an outlook on the future health status of older population measured by living with severe long-term limitations in daily activities. Based on the EU Statistics on Income and Living Conditions (SILC) survey, we project the share of the 65+ years population living with severe long-term activity limitations for 26 European countries by 2047. Data and method Data We used the EU-SILC data, which are conducted annually within EU member states and a few additional European states. 10 This cross-sectional and longitudinal microdata provide information on income, poverty, social exclusion and living conditions. Eurostat has coordinated the EU-SILC data since 2003, whereas national statistical institutes have collected the information, first in 6 countries and by 2014 in 31 countries. 11 Although the sampling procedure varies across countries, the samples are considered nationally representative of individuals aged at least 16 years living in private households. 10 11 In our study, we focus on the global activity limitation indicator (GALI), which was designed for monitoring HLYs (ie, life expectancy without long-term activity limitations) within the EU. 12 This measure of general activity limitations was shown to be significantly associated with other health measures such as functional limitations, activities of daily living and instrumental activity of daily living. 13 Since 2008, GALI addresses the long-term activity limitations with the question ‘For at least the past 6 months, to what extent have you been limited because of a health problem in activities people usually do?’. There are some minor variations", "role": "user" }, { "content": "By 2047 one in four women and one in six men aged 65 and above is expected to be living with a physical disability that will severely restrict everyday activities, reveals an analysis published in the online journal BMJ Open. The proportions of those affected are set to change little over the next 30 years, despite the overall expected increase in longevity, the projections show. But the absolute numbers will rise significantly as European populations age. This is likely to have considerable implications for the provision of supported care and the training of healthcare professionals, warn the researchers. They base their findings on SILC (EU Statistics on Income and Living Conditions) survey data on 26 high and middle income European countries, collected annually between 2008 and 2014, and sex specific life expectancy tables and population projections from 2015 to 2050 provided by the United Nations. The nationally representative SILC survey does not cover people in care homes, but it includes a question on long term health problems that restrict routine activities of daily living. The researchers focused on the responses from those aged at least 55, up to the age of 85+. They combined all the data to calculate remaining life expectancy free of severe limitations on physical function (healthy life years) by sex, age, and country, to predict the proportion of older people whose daily lives would be severely restricted as a result of long term health issues. They took account of cultural differences and the generosity of welfare systems, both of which may influence those who identify themselves as physically incapacitated. The analysis confirms the findings of other studies, say the researchers: more women than men reported severe limitations in physical capacity as a result of long term health issues in all the countries studied. Women tend to live longer than men. However, both men's and women's health seemed to worsen with increasing age at the same pace. The figures also indicated wide variations in the self reported health of older adults for both sexes. For example, around one in 10 Swedish women over the age of 65 said their daily lives were severely restricted by health issues, compared with around one in three of their peers in Slovakia. But on the basis of the calculations, by 2047 around one four (21%) women and around one in six (just under 17%) men aged 65 and above will be expected to have a long term health issue that will severely restrict activities of daily living. The proportion of the 'unhealthy' population was very similar across the 26 countries, once cultural differences had been accounted for. This is expected to remain fairly constant over time, even though life expectancy is set to increase, the figures suggest. The trends will still require action to be taken, say the researchers. \"Even though the trends in the proportion of people with limitations will remain constant, the absolute number of people with severe long term activity limitations will definitely increase since the number of people at older ages is expected to increase in most European countries,\" they write. \"It might require several measures to accommodate the needs of an increasing number of people with activity limitations such as expanding infrastructure for disabled people in the public as well as private sectors, training of medical specialists and care professionals.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective To project the proportion of population 65+ years with severe long-term activity limitations from 2017 to 2047. Design Large population study. Setting Population living in private households of the European Union (EU) and neighbouring countries. Participants Participants from the EU Statistics on Income and Living Conditions aged 55 years and older and living in one of 26 EU and neighbouring countries, who answered the health section of the questionnaire. Outcome measures Prevalence of severe long-term activity limitations of particular subpopulations (ie, 55+, 65+, 75+ and 85+ years) by sex and country. Results We find a huge variation in the prevalence of self-reported severe long-term limitations across Europe for both sexes. However, in 2017, about 20% of the female population aged 65 years and above and about 16% of their male counterparts are expected to report severe long-term activity limitations after accounting for differences in reporting. Accounting for cultural differences in reporting, we expect that European countries will have about 21% (decile 1: 19.5%; decile 9: 22.9%) of female and about 16.8% (decile 1: 15.4%; decile 9: 18.1%) of male 65+ years population with severe long-term activity limitations by 2047. Conclusions Overall, despite the expected increase of life expectancy in European countries, our results suggest almost constant shares of older adults with severe long-term activity limitations within the next 30 years. disability activity limitations Eu-silc europe health expectancy ageing 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 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 14 news outlets Blogged by 1 Tweeted by 8 On 2 Facebook pages 25 readers on Mendeley Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions disability activity limitations Eu-silc europe health expectancy ageing Strengths and limitations of this study We used data on 26 European countries collected annually between 2008 and 2014. Applying the Sullivan method, we computed life expectancy without severe long-term activity limitations (healthy life years (HLYs)) by sex and 5-year age groups. We model the ratio of HLYs and life expectancy to predict prevalence of severe activity limitations among older adults. Cultural differences in self-reports are acknowledged, so we used a random intercept approach to consider those properly. Introduction Worldwide populations are growing older. In upper middle-income and high-income countries, life expectancy is increasing and fertility rates are declining, leading to an increase of older populations. However, there is a lack of evidence whether these demographic changes are accompanied by an increase of frail or morbid people. The health status of older population is of raising public interest and a broadly discussed issue since many countries fear a rise in economic costs caused by ageing. During the last decades, a large body of literature focused on health trends, which were often analysed with indicators using health-specific life expectancies. 1–3 Research on trends in healthy life years (HLYs) and disability-free life expectancy showed an inconsistent pattern. For instance, in the early 2000s, healthy life expectancy showed only little change for European men and women in contrast to their life expectancy, 4 whereas it increased significantly between the early 1980s and 2000s in Austria. 5 Other studies showed that in the USA, higher educated population experienced some compression of morbidity, whereas their lower educated counterparts showed an expansion. 6 There are inequalities in health expectancies at older ages across the European Union (EU) and even within countries, and there are discrepancies between men and women. 1 Even though women benefit from their mortality advantage over men when it comes to HLYs, the situation is sometimes the opposite. Women in general report higher prevalence of disabilities and frailty. 7 Some research already explored this health-survival paradox. 8 9 Less research was focused on the impact of possible future trends in healthy and disability-free life expectancy on the socioeconomic development of a country. For instance, are European health systems prepared for higher shares of older adults? Should we expect higher proportions of unhealthy older population? The objective of this study is to provide an outlook on the future health status of older population measured by living with severe long-term limitations in daily activities. Based on the EU Statistics on Income and Living Conditions (SILC) survey, we project the share of the 65+ years population living with severe long-term activity limitations for 26 European countries by 2047. Data and method Data We used the EU-SILC data, which are conducted annually within EU member states and a few additional European states. 10 This cross-sectional and longitudinal microdata provide information on income, poverty, social exclusion and living conditions. Eurostat has coordinated the EU-SILC data since 2003, whereas national statistical institutes have collected the information, first in 6 countries and by 2014 in 31 countries. 11 Although the sampling procedure varies across countries, the samples are considered nationally representative of individuals aged at least 16 years living in private households. 10 11 In our study, we focus on the global activity limitation indicator (GALI), which was designed for monitoring HLYs (ie, life expectancy without long-term activity limitations) within the EU. 12 This measure of general activity limitations was shown to be significantly associated with other health measures such as functional limitations, activities of daily living and instrumental activity of daily living. 13 Since 2008, GALI addresses the long-term activity limitations with the question ‘For at least the past 6 months, to what extent have you been limited because of a health problem in activities people usually do?’. There are some minor variations<|im_end|> <|im_start|>assistant By 2047 one in four women and one in six men aged 65 and above is expected to be living with a physical disability that will severely restrict everyday activities, reveals an analysis published in the online journal BMJ Open. The proportions of those affected are set to change little over the next 30 years, despite the overall expected increase in longevity, the projections show. But the absolute numbers will rise significantly as European populations age. This is likely to have considerable implications for the provision of supported care and the training of healthcare professionals, warn the researchers. They base their findings on SILC (EU Statistics on Income and Living Conditions) survey data on 26 high and middle income European countries, collected annually between 2008 and 2014, and sex specific life expectancy tables and population projections from 2015 to 2050 provided by the United Nations. The nationally representative SILC survey does not cover people in care homes, but it includes a question on long term health problems that restrict routine activities of daily living. The researchers focused on the responses from those aged at least 55, up to the age of 85+. They combined all the data to calculate remaining life expectancy free of severe limitations on physical function (healthy life years) by sex, age, and country, to predict the proportion of older people whose daily lives would be severely restricted as a result of long term health issues. They took account of cultural differences and the generosity of welfare systems, both of which may influence those who identify themselves as physically incapacitated. The analysis confirms the findings of other studies, say the researchers: more women than men reported severe limitations in physical capacity as a result of long term health issues in all the countries studied. Women tend to live longer than men. However, both men's and women's health seemed to worsen with increasing age at the same pace. The figures also indicated wide variations in the self reported health of older adults for both sexes. For example, around one in 10 Swedish women over the age of 65 said their daily lives were severely restricted by health issues, compared with around one in three of their peers in Slovakia. But on the basis of the calculations, by 2047 around one four (21%) women and around one in six (just under 17%) men aged 65 and above will be expected to have a long term health issue that will severely restrict activities of daily living. The proportion of the 'unhealthy' population was very similar across the 26 countries, once cultural differences had been accounted for. This is expected to remain fairly constant over time, even though life expectancy is set to increase, the figures suggest. The trends will still require action to be taken, say the researchers. "Even though the trends in the proportion of people with limitations will remain constant, the absolute number of people with severe long term activity limitations will definitely increase since the number of people at older ages is expected to increase in most European countries," they write. "It might require several measures to accommodate the needs of an increasing number of people with activity limitations such as expanding infrastructure for disabled people in the public as well as private sectors, training of medical specialists and care professionals." <|im_end|>

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2,007

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV + interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM + interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV + and SOM + interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons. Main Fear conditioning is a powerful model system for investigating plasticity of neuronal circuits and the mechanisms of associative learning, as the basic underlying circuitry has been thoroughly studied over the last decades 1 , 2 , 3 , 4 . The basolateral amygdala (BLA) has been identified as a key brain area involved in auditory fear conditioning, where associative synaptic plasticity at glutamatergic sensory afferents is induced by the pairing of a neutral tone (conditioned stimulus (CS)) and a mild aversive footshock (unconditioned stimulus (US)) during conditioning 1 , 4 , 5 . As a cortex-like structure 6 , the BLA contains a variety of interneurons with marker expression, basic properties and connectivity very similar to neocortical circuits 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , and inhibition has been shown to have a role in fear conditioning 8 . Functionally, salient sensory stimuli lead to cell-type-specific responses in different interneuron subtypes in anaesthetized animals 14 . Moreover, fear conditioning and extinction have been shown to induce opposing changes in the strength of inhibitory transmission and in the expression of inhibition-related genes 8 , 15 , 16 , 17 . However, besides the general notion that inhibition is involved in fear learning, knowledge about the role of individual interneuron subtypes is still lacking. One of the major interneuron subclasses in cortical and cortex-like structures such as the BLA is defined by the expression of the calcium-binding protein parvalbumin (PV; also called PVALB) 9 , 10 , 18 , 19 , 20 . Most PV + interneurons feature a fast-spiking phenotype with narrow spike widths and high firing rates 21 , 22 . PV + interneurons preferentially form synapses at the perisomatic region of their target cells, thereby controlling neuronal activity and spike output 10 , 18 , 23 , 24 . In addition to glutamatergic principal neurons, PV + cells contact both other PV + interneurons and different interneuron types 21 , 25 . In the hippocampus, PV + cells have been shown to interact with interneurons expressing somatostatin (SOM; also called SST) to regulate pyramidal cell output 26 . In contrast to PV + cells, SOM + interneurons preferentially contact the distal dendrites 27 , which allows them to efficiently control the impact of inputs to their target cells 28 , 29 . Here, we address the role of interneuron subtypes using a combination of optogenetic manipulations and single-unit recordings from identified BLA interneurons during fear learning. Our results reveal that BLA PV + and SOM + interneurons exert bidirectional control over fear acquisition resulting in differential changes in inhibition along the somatodendritic axis of principal neurons. We identify inhibition of SOM + interneurons by PV + interneurons as a crucial mechanism for dendritic disinhibition of principal neurons. Our findings indicate that exquisitely organized inhibitory and disinhibitory microcircuits comprising defined subtypes of interneurons have important and distinct roles during associative learning. PV + interneurons in the BLA control fear learning To examine a possible role of PV + cells in fear learning, we selectively expressed channelrhodopsin-2 (ChR2 (ref. 30 )) in PV + interneurons in the BLA 31 ( Fig. 1a–c ; see Methods), and used bilaterally implanted optic fibres for light stimulation ( Fig. 1a and Extended Data Fig. 1a ). Importantly, stimulation of PV + interneurons alone did not have any effect on freezing or locomotion ( Extended Data Fig. 2a ). Mice were conditioned to two distinct CS (tones of different frequencies, counterbalanced between experiments). Whereas PV + cell activity was manipulated during one entire CS–US pairing, the other CS–US pair served as a within-animal control ( Fig. 1d , left). A fear memory retrieval test on the next day without optogenetic stimulation revealed that PV + interneuron activation during acquisition significantly attenuated the CS-induced freezing response when compared with the internal control CS ( Fig. 1d , right and Extended Data Fig. 2b ). These results indicate that the level of PV + interneuron activity in the BLA can control the acquisition of conditioned fear responses. Figure 1: BLA PV + interneurons control fear learning. a , Optogenetic manipulation and simultaneous single-unit recordings using an optrode in freely behaving mice. b , Co-expression of ChR2 and Venus (green) in PV + interneurons in the BLA, using PV–Cre mice and conditional rAAVs. Counterstains: DAPI (blue) and NeuN (red). CeL, central lateral amygdala. c , Restriction of ChR2 and Venus expression (green) to PV + interneurons is verified by PV immunohistochemistry (IHC) (red). d , Left, fear conditioning paradigm to test for effects of PV + manipulation on fear learning. Animals were conditioned to two distinct auditory CSs. CS2 was paired with blue light for ChR2 activation during the entire CS–US pairing. During retrieval on the next day, both CSs were presented without light. CS order and light-pairing were counterbalanced. Right, animals displayed significantly less freezing to the light-paired CS2 during retrieval compared to CS1, indicating that PV + activation during the entire CS–US pairing impairs fear acquisition. Light stimulation had no effect on control animals", "role": "user" }, { "content": "(Medical Xpress)—Learning can only occur if certain neuronal \"brakes\" are released. As the group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research has now discovered, learning processes in the brain are dynamically regulated by various types of interneurons. The new connections essential for learning can only be established if inhibitory inputs from interneurons are reduced at the right moment. These findings have now been published in Nature. For some years, most neurobiologists studying learning processes have assumed that the new connections required for learning can only be established and ultimately reinforced if certain neuronal \"brakes\" are released – a process known as disinhibition. It has also been supposed for some time that various types of interneurons could be involved in disinhibition. Interneurons are nerve cells that surround and – via their connections – inhibit the activity of principal neurons. It has not been clear, however, whether these cell types actually play a role in disinhibition and how they control learning. Andreas Lüthi and his group at the Friedrich Miescher Institute for Biomedical Research have now demonstrated for the first time how a learning process is dynamically regulated by specific types of interneurons. In Lüthi's experiments, mice were trained to associate a sound with an unpleasant stimulus, so that the animals subsequently knew what would happen when they heard the auditory cue. The researchers showed that, during the learning process, the sound stimulus released a brake in some of the principal neurons. More precisely, it induced the activation of parvalbumin-positive (PV+) interneurons, leading indirectly – via somatostatin-positive (SOM+) interneurons – to disinhibition of the principal neurons. The latter thus became receptive to further sensory inputs. If this was immediately followed by the unpleasant stimulus, then another brake was released. Once again, PV+ interneurons were involved, but this time the principal neurons were directly disinhibited. Steffen Wolff, a postdoc in Lüthi's group and first author of the publication, explains: \"The principal neurons temporarily reached a level of activation enabling neuronal connections to be reinforced in such a way that the animal could learn the association between the sound and the unpleasant stimulus.\" Lüthi comments: \"This is the first time we've been able to identify so clearly the function of defined interneurons in a learning process, and to show how successive disinhibition can enable this process. We assume that interneurons disinhibit the principal neurons in a highly dynamic manner. They integrate, as it were, the state of numerous different neural networks, activated for example by sensory input, earlier experiences or emotional states, and thus permit or prevent learning. I think these findings are also of interest in the context of conditions where learning processes are impaired or dysfunctional, as in the case of anxiety disorders.\" ", "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 Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV + interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM + interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV + and SOM + interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons. Main Fear conditioning is a powerful model system for investigating plasticity of neuronal circuits and the mechanisms of associative learning, as the basic underlying circuitry has been thoroughly studied over the last decades 1 , 2 , 3 , 4 . The basolateral amygdala (BLA) has been identified as a key brain area involved in auditory fear conditioning, where associative synaptic plasticity at glutamatergic sensory afferents is induced by the pairing of a neutral tone (conditioned stimulus (CS)) and a mild aversive footshock (unconditioned stimulus (US)) during conditioning 1 , 4 , 5 . As a cortex-like structure 6 , the BLA contains a variety of interneurons with marker expression, basic properties and connectivity very similar to neocortical circuits 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , and inhibition has been shown to have a role in fear conditioning 8 . Functionally, salient sensory stimuli lead to cell-type-specific responses in different interneuron subtypes in anaesthetized animals 14 . Moreover, fear conditioning and extinction have been shown to induce opposing changes in the strength of inhibitory transmission and in the expression of inhibition-related genes 8 , 15 , 16 , 17 . However, besides the general notion that inhibition is involved in fear learning, knowledge about the role of individual interneuron subtypes is still lacking. One of the major interneuron subclasses in cortical and cortex-like structures such as the BLA is defined by the expression of the calcium-binding protein parvalbumin (PV; also called PVALB) 9 , 10 , 18 , 19 , 20 . Most PV + interneurons feature a fast-spiking phenotype with narrow spike widths and high firing rates 21 , 22 . PV + interneurons preferentially form synapses at the perisomatic region of their target cells, thereby controlling neuronal activity and spike output 10 , 18 , 23 , 24 . In addition to glutamatergic principal neurons, PV + cells contact both other PV + interneurons and different interneuron types 21 , 25 . In the hippocampus, PV + cells have been shown to interact with interneurons expressing somatostatin (SOM; also called SST) to regulate pyramidal cell output 26 . In contrast to PV + cells, SOM + interneurons preferentially contact the distal dendrites 27 , which allows them to efficiently control the impact of inputs to their target cells 28 , 29 . Here, we address the role of interneuron subtypes using a combination of optogenetic manipulations and single-unit recordings from identified BLA interneurons during fear learning. Our results reveal that BLA PV + and SOM + interneurons exert bidirectional control over fear acquisition resulting in differential changes in inhibition along the somatodendritic axis of principal neurons. We identify inhibition of SOM + interneurons by PV + interneurons as a crucial mechanism for dendritic disinhibition of principal neurons. Our findings indicate that exquisitely organized inhibitory and disinhibitory microcircuits comprising defined subtypes of interneurons have important and distinct roles during associative learning. PV + interneurons in the BLA control fear learning To examine a possible role of PV + cells in fear learning, we selectively expressed channelrhodopsin-2 (ChR2 (ref. 30 )) in PV + interneurons in the BLA 31 ( Fig. 1a–c ; see Methods), and used bilaterally implanted optic fibres for light stimulation ( Fig. 1a and Extended Data Fig. 1a ). Importantly, stimulation of PV + interneurons alone did not have any effect on freezing or locomotion ( Extended Data Fig. 2a ). Mice were conditioned to two distinct CS (tones of different frequencies, counterbalanced between experiments). Whereas PV + cell activity was manipulated during one entire CS–US pairing, the other CS–US pair served as a within-animal control ( Fig. 1d , left). A fear memory retrieval test on the next day without optogenetic stimulation revealed that PV + interneuron activation during acquisition significantly attenuated the CS-induced freezing response when compared with the internal control CS ( Fig. 1d , right and Extended Data Fig. 2b ). These results indicate that the level of PV + interneuron activity in the BLA can control the acquisition of conditioned fear responses. Figure 1: BLA PV + interneurons control fear learning. a , Optogenetic manipulation and simultaneous single-unit recordings using an optrode in freely behaving mice. b , Co-expression of ChR2 and Venus (green) in PV + interneurons in the BLA, using PV–Cre mice and conditional rAAVs. Counterstains: DAPI (blue) and NeuN (red). CeL, central lateral amygdala. c , Restriction of ChR2 and Venus expression (green) to PV + interneurons is verified by PV immunohistochemistry (IHC) (red). d , Left, fear conditioning paradigm to test for effects of PV + manipulation on fear learning. Animals were conditioned to two distinct auditory CSs. CS2 was paired with blue light for ChR2 activation during the entire CS–US pairing. During retrieval on the next day, both CSs were presented without light. CS order and light-pairing were counterbalanced. Right, animals displayed significantly less freezing to the light-paired CS2 during retrieval compared to CS1, indicating that PV + activation during the entire CS–US pairing impairs fear acquisition. Light stimulation had no effect on control animals<|im_end|> <|im_start|>assistant (Medical Xpress)—Learning can only occur if certain neuronal "brakes" are released. As the group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research has now discovered, learning processes in the brain are dynamically regulated by various types of interneurons. The new connections essential for learning can only be established if inhibitory inputs from interneurons are reduced at the right moment. These findings have now been published in Nature. For some years, most neurobiologists studying learning processes have assumed that the new connections required for learning can only be established and ultimately reinforced if certain neuronal "brakes" are released – a process known as disinhibition. It has also been supposed for some time that various types of interneurons could be involved in disinhibition. Interneurons are nerve cells that surround and – via their connections – inhibit the activity of principal neurons. It has not been clear, however, whether these cell types actually play a role in disinhibition and how they control learning. Andreas Lüthi and his group at the Friedrich Miescher Institute for Biomedical Research have now demonstrated for the first time how a learning process is dynamically regulated by specific types of interneurons. In Lüthi's experiments, mice were trained to associate a sound with an unpleasant stimulus, so that the animals subsequently knew what would happen when they heard the auditory cue. The researchers showed that, during the learning process, the sound stimulus released a brake in some of the principal neurons. More precisely, it induced the activation of parvalbumin-positive (PV+) interneurons, leading indirectly – via somatostatin-positive (SOM+) interneurons – to disinhibition of the principal neurons. The latter thus became receptive to further sensory inputs. If this was immediately followed by the unpleasant stimulus, then another brake was released. Once again, PV+ interneurons were involved, but this time the principal neurons were directly disinhibited. Steffen Wolff, a postdoc in Lüthi's group and first author of the publication, explains: "The principal neurons temporarily reached a level of activation enabling neuronal connections to be reinforced in such a way that the animal could learn the association between the sound and the unpleasant stimulus." Lüthi comments: "This is the first time we've been able to identify so clearly the function of defined interneurons in a learning process, and to show how successive disinhibition can enable this process. We assume that interneurons disinhibit the principal neurons in a highly dynamic manner. They integrate, as it were, the state of numerous different neural networks, activated for example by sensory input, earlier experiences or emotional states, and thus permit or prevent learning. I think these findings are also of interest in the context of conditions where learning processes are impaired or dysfunctional, as in the case of anxiety disorders." <|im_end|>

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2,049

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Alzheimer’s disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles 1 . The amyloid hypothesis of Alzheimer’s disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau 2 , 3 . However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology 4 , 5 . Human neurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles 6 , 7 , 8 , 9 , 10 , 11 . Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders. Main To develop human neural progenitor cells (hNPCs) that produce high levels of toxic amyloid-β species, we overexpressed human β-amyloid precursor protein (APP) or APP and presenilin 1 (PSEN1), containing FAD mutations. We first generated polycistronic lentiviral constructs designed to express human APP with both K670N/M671L (Swedish) and V717I (London) FAD mutations (APPSL) or APPSL and PSEN1 with ΔE9 FAD mutation (PSEN1(ΔE9)) ( Fig. 1a ). These FAD lentiviral constructs were transfected into ReNcell VM human neural stem (ReN) cells (Millipore). The transfected cells with GFP (ReN-G), mCherry (ReN-m), APPSL-GFP (ReN-GA), APPSL-GFP/PSEN1(ΔE9)-mCherry (ReN-mGAP), APPSL-PSEN1(ΔE9)-mCherry (ReN-mAP) or GFP/APPSL-PSEN1(ΔE9)-mCherry (HReN-mGAP) were enriched on the basis of GFP and/or mCherry signals using fluorescence-activated cell sorting (FACS) ( Extended Data Fig. 1a–c, f ). Western blot analysis revealed high expression of PSEN1(ΔE9), APP and APP carboxy-terminal fragments in ReN cells with FAD mutations (FAD ReN cells, Extended Data Fig. 1e ). As previously reported 12 , 13 , 14 , most ReN cells differentiated into neuronal and glial cells within 3 weeks ( Extended Data Figs 1d and 2a ). Immunofluorescence staining confirmed punctate localization of VGluT1 (vesicular glutamate transporter 1), a presynaptic marker, along with dendritic processes ( Extended Data Fig. 2b ). Quantitative real-time PCR (qPCR) array analysis showed robust increases of neuronal and glial marker genes ( Extended Data Fig. 2c ). Reverse-transcription–PCR (RT–PCR) analysis also showed a dramatic increase of 4-repeat adult tau isoforms following differentiation ( Extended Data Fig. 2d ). The differentiated ReN cells exhibit voltage-gated potassium and sodium currents after 29 days of differentiation ( Extended Data Fig. 2e–h ), as previously reported 12 , 13 . Figure 1: Generation of hNPCs with multiple FAD mutations. a , Diagrams showing lentiviral internal ribosome entry sites (IRES) constructs. CMV, cytomegalovirus. b , Increased Aβ 40 and Aβ 42 levels in 6-week differentiated FAD ReN cells. Amyloid-β levels in conditioned media were normalized to total protein levels. * P < 0.05; ** P < 0.01; *** P < 0.001; ANOVA followed by a post hoc Dunnett’s test; n = 3 per each sample. c , Amyloid-β levels are dramatically decreased in FAD ReN cells after treatment with 1 μM β-secretase inhibitor IV or 3.7 nM compound E. Mean ± s.e.m.; * P < 0.05; ** P < 0.01; *** P < 0.001; ANOVA followed by a post hoc Dunnett’s test; n = 3 per each sample; ND, not detected. PowerPoint slide Source data Full size image We measured levels of the 40-amino-acid and 42-amino-acid amyloid-β isoforms (Aβ 40 and Aβ 42 ) in conditioned media after 6-week differentiation. FAD ReN cells revealed dramatic increases in Aβ 40 ( ∼ 9-fold) and Aβ 42 ( ∼ 17-fold) levels as compared to the control ReN cells ( Fig. 1b and Extended Data Fig. 2i ). The Aβ 42 :Aβ 40 ratio was also increased ( ∼ 5-fold) in ReN cells expressing PSEN1(ΔE9) ( Fig. 1b ). Treatment with β- or γ-secretase inhibitors markedly decreased amyloid-β levels ( Fig. 1c ) with no appreciable toxicity (data not shown). We confirmed that ReN cells carry the APOE ε3/ε3 genotype, not the ε4 allele associated with Alzheimer’s disease ( Extended Data Fig. 2j ). In conventional 2D cultures, secreted amyloid-β diffuses into a large volume of media. We hypothesized that a 3D culture would accelerate amyloid-β deposition by limiting diffusion of amyloid-β, allowing for aggregation 15 , 16 , 17 . We chose BD Matrigel (BD Biosciences) as a 3D support matrix since it contains high levels of brain extracellular matrix proteins. For immunofluorescence and biochemical analyses, we set up thin- ( ∼ 100–300 μm) and thick-layer ( ∼ 4 mm) 3D culture models ( Figs 2a and 3a ). 3D-differentiated ReN cells displayed extensive processes after 2–6 weeks of differentiation ( Supplementary Videos 1 , 2 and 3 ). To demonstrate ReN-cell differentiation in thick-layer 3D cultures, paraffin-sectioned thick-layer 3D cultures were analysed by immunofluorescence with various neuronal markers ( Extended Data Fig. 3 ). qPCR array data indicated that 3D cultures promote more neuronal and glial differentiation than 2D cultures ( Extended Data Fig. 2c ). We also observed a dramatic increase in the levels of 4-repeat adult tau isoforms in 3D cultures versus 2D ( Extended Data Fig. 2d ).", "role": "user" }, { "content": "A breakthrough in Alzheimer's disease research based on state-of-the-art human-relevant research techniques that replace scientifically unsatisfactory animal tests has been welcomed by the science team at Humane Society International. The research was published in Nature. Dr Gill Langley, senior science adviser to Humane Society International, said: \"The Alzheimer's in a dish breakthrough is a very exciting development that could transform neurodegenerative disease research and be the beginning of the end for poor-performing animal models. For decades, Alzheimer's research has been dominated by artificially creating symptoms in monkeys and, more recently, genetically modified mice. But fundamental species differences make these animal models poor replicas of this uniquely human disease and consequently, despite years of animal experiments, researchers have failed to find a single cure that works in human patients. \"Tens of millions of people have dementia worldwide, and continuing to focus on failing animal models is a waste of time and resources. So, human biology-based tools such as this are a huge leap forward, and could vastly improve our chances of cracking this debilitating brain disease. With research outcomes so poor in so many neurodegenerative areas, it's vital we embark on a new research roadmap that dispenses with poor quality animal tests and utilises instead state-of-the-art tools. From patient-derived human brain cells in culture, to powerful neuroimaging machines, and super-computers combining multiple data to reconstruct the disease pathways, we could map true human Alzheimer's in all its complexity that is simply impossible using animal models.\" The scientists at Massachusetts General Hospital in Boston used human stem cells that can be turned into any cell of the body. Using a chemical-infused gel they were able to develop the stem cells into neurons or other brain cells, which were altered with genes associated with Alzheimer's. The cells went on to form networks as happened in the brain. Unlike animal models, the cells developed the signature plaques and tangles seen in the brains of human Alzheimer's patients. This breakthrough is a major step forward in Alzheimer's disease research and could significantly improve chances of discovering a drug that is effective in people. A number of different animal species have featured in Alzheimer's research, including rabbits, dogs and monkeys. But for the last two decades, the dominant animal 'model' has been transgenic mice – mice with inserted faulty human genes that produce a few symptoms similar to the real disease. The problem is simply that the condition developed in these mice differs from the human disease in how causation, how the disease progresses, and the sequence and complexity of symptoms that occur. Despite basic similarities in all mammalian brains, the different evolutionary paths of mice and humans mean that our brains differ in genetics, proteins, chemistry and 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 Alzheimer’s disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles 1 . The amyloid hypothesis of Alzheimer’s disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau 2 , 3 . However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology 4 , 5 . Human neurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles 6 , 7 , 8 , 9 , 10 , 11 . Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders. Main To develop human neural progenitor cells (hNPCs) that produce high levels of toxic amyloid-β species, we overexpressed human β-amyloid precursor protein (APP) or APP and presenilin 1 (PSEN1), containing FAD mutations. We first generated polycistronic lentiviral constructs designed to express human APP with both K670N/M671L (Swedish) and V717I (London) FAD mutations (APPSL) or APPSL and PSEN1 with ΔE9 FAD mutation (PSEN1(ΔE9)) ( Fig. 1a ). These FAD lentiviral constructs were transfected into ReNcell VM human neural stem (ReN) cells (Millipore). The transfected cells with GFP (ReN-G), mCherry (ReN-m), APPSL-GFP (ReN-GA), APPSL-GFP/PSEN1(ΔE9)-mCherry (ReN-mGAP), APPSL-PSEN1(ΔE9)-mCherry (ReN-mAP) or GFP/APPSL-PSEN1(ΔE9)-mCherry (HReN-mGAP) were enriched on the basis of GFP and/or mCherry signals using fluorescence-activated cell sorting (FACS) ( Extended Data Fig. 1a–c, f ). Western blot analysis revealed high expression of PSEN1(ΔE9), APP and APP carboxy-terminal fragments in ReN cells with FAD mutations (FAD ReN cells, Extended Data Fig. 1e ). As previously reported 12 , 13 , 14 , most ReN cells differentiated into neuronal and glial cells within 3 weeks ( Extended Data Figs 1d and 2a ). Immunofluorescence staining confirmed punctate localization of VGluT1 (vesicular glutamate transporter 1), a presynaptic marker, along with dendritic processes ( Extended Data Fig. 2b ). Quantitative real-time PCR (qPCR) array analysis showed robust increases of neuronal and glial marker genes ( Extended Data Fig. 2c ). Reverse-transcription–PCR (RT–PCR) analysis also showed a dramatic increase of 4-repeat adult tau isoforms following differentiation ( Extended Data Fig. 2d ). The differentiated ReN cells exhibit voltage-gated potassium and sodium currents after 29 days of differentiation ( Extended Data Fig. 2e–h ), as previously reported 12 , 13 . Figure 1: Generation of hNPCs with multiple FAD mutations. a , Diagrams showing lentiviral internal ribosome entry sites (IRES) constructs. CMV, cytomegalovirus. b , Increased Aβ 40 and Aβ 42 levels in 6-week differentiated FAD ReN cells. Amyloid-β levels in conditioned media were normalized to total protein levels. * P < 0.05; ** P < 0.01; *** P < 0.001; ANOVA followed by a post hoc Dunnett’s test; n = 3 per each sample. c , Amyloid-β levels are dramatically decreased in FAD ReN cells after treatment with 1 μM β-secretase inhibitor IV or 3.7 nM compound E. Mean ± s.e.m.; * P < 0.05; ** P < 0.01; *** P < 0.001; ANOVA followed by a post hoc Dunnett’s test; n = 3 per each sample; ND, not detected. PowerPoint slide Source data Full size image We measured levels of the 40-amino-acid and 42-amino-acid amyloid-β isoforms (Aβ 40 and Aβ 42 ) in conditioned media after 6-week differentiation. FAD ReN cells revealed dramatic increases in Aβ 40 ( ∼ 9-fold) and Aβ 42 ( ∼ 17-fold) levels as compared to the control ReN cells ( Fig. 1b and Extended Data Fig. 2i ). The Aβ 42 :Aβ 40 ratio was also increased ( ∼ 5-fold) in ReN cells expressing PSEN1(ΔE9) ( Fig. 1b ). Treatment with β- or γ-secretase inhibitors markedly decreased amyloid-β levels ( Fig. 1c ) with no appreciable toxicity (data not shown). We confirmed that ReN cells carry the APOE ε3/ε3 genotype, not the ε4 allele associated with Alzheimer’s disease ( Extended Data Fig. 2j ). In conventional 2D cultures, secreted amyloid-β diffuses into a large volume of media. We hypothesized that a 3D culture would accelerate amyloid-β deposition by limiting diffusion of amyloid-β, allowing for aggregation 15 , 16 , 17 . We chose BD Matrigel (BD Biosciences) as a 3D support matrix since it contains high levels of brain extracellular matrix proteins. For immunofluorescence and biochemical analyses, we set up thin- ( ∼ 100–300 μm) and thick-layer ( ∼ 4 mm) 3D culture models ( Figs 2a and 3a ). 3D-differentiated ReN cells displayed extensive processes after 2–6 weeks of differentiation ( Supplementary Videos 1 , 2 and 3 ). To demonstrate ReN-cell differentiation in thick-layer 3D cultures, paraffin-sectioned thick-layer 3D cultures were analysed by immunofluorescence with various neuronal markers ( Extended Data Fig. 3 ). qPCR array data indicated that 3D cultures promote more neuronal and glial differentiation than 2D cultures ( Extended Data Fig. 2c ). We also observed a dramatic increase in the levels of 4-repeat adult tau isoforms in 3D cultures versus 2D ( Extended Data Fig. 2d ).<|im_end|> <|im_start|>assistant A breakthrough in Alzheimer's disease research based on state-of-the-art human-relevant research techniques that replace scientifically unsatisfactory animal tests has been welcomed by the science team at Humane Society International. The research was published in Nature. Dr Gill Langley, senior science adviser to Humane Society International, said: "The Alzheimer's in a dish breakthrough is a very exciting development that could transform neurodegenerative disease research and be the beginning of the end for poor-performing animal models. For decades, Alzheimer's research has been dominated by artificially creating symptoms in monkeys and, more recently, genetically modified mice. But fundamental species differences make these animal models poor replicas of this uniquely human disease and consequently, despite years of animal experiments, researchers have failed to find a single cure that works in human patients. "Tens of millions of people have dementia worldwide, and continuing to focus on failing animal models is a waste of time and resources. So, human biology-based tools such as this are a huge leap forward, and could vastly improve our chances of cracking this debilitating brain disease. With research outcomes so poor in so many neurodegenerative areas, it's vital we embark on a new research roadmap that dispenses with poor quality animal tests and utilises instead state-of-the-art tools. From patient-derived human brain cells in culture, to powerful neuroimaging machines, and super-computers combining multiple data to reconstruct the disease pathways, we could map true human Alzheimer's in all its complexity that is simply impossible using animal models." The scientists at Massachusetts General Hospital in Boston used human stem cells that can be turned into any cell of the body. Using a chemical-infused gel they were able to develop the stem cells into neurons or other brain cells, which were altered with genes associated with Alzheimer's. The cells went on to form networks as happened in the brain. Unlike animal models, the cells developed the signature plaques and tangles seen in the brains of human Alzheimer's patients. This breakthrough is a major step forward in Alzheimer's disease research and could significantly improve chances of discovering a drug that is effective in people. A number of different animal species have featured in Alzheimer's research, including rabbits, dogs and monkeys. But for the last two decades, the dominant animal 'model' has been transgenic mice – mice with inserted faulty human genes that produce a few symptoms similar to the real disease. The problem is simply that the condition developed in these mice differs from the human disease in how causation, how the disease progresses, and the sequence and complexity of symptoms that occur. Despite basic similarities in all mammalian brains, the different evolutionary paths of mice and humans mean that our brains differ in genetics, proteins, chemistry and physiology. <|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 interstellar medium (ISM) comprises gases at different temperatures and densities, including ionized, atomic and molecular species, and dust particles 1 . The neutral ISM is dominated by neutral hydrogen 2 and has ionization fractions of up to eight per cent 3 . The concentration of chemical elements heavier than helium (metallicity) spans orders of magnitudes in Galactic stars 4 , because they formed at different times. However, the gas in the vicinity of the Sun is assumed to be well mixed and to have a solar metallicity in traditional chemical evolution models 5 . The ISM chemical abundances can be accurately measured with ultraviolet absorption-line spectroscopy. However, the effects of dust depletion 6 , 7 , 8 , 9 —which removes part of the metals from the observable gaseous phase and incorporates it into solid grains—have prevented, until recently, a deeper investigation of the ISM metallicity. Here we report the dust-corrected metallicity of the neutral ISM measured towards 25 stars in our Galaxy. We find large variations in metallicity over a factor of ten (with an average of 55 ± 7 per cent solar metallicity and a standard deviation of 0.28 dex), including many regions of low metallicity, down to about 17 per cent solar metallicity and possibly below. Pristine gas falling onto the Galactic disk in the form of high-velocity clouds can cause the observed chemical inhomogeneities on scales of tens of parsecs. Our results suggest that this low-metallicity accreting gas does not efficiently mix into the ISM, which may help us understand metallicity deviations in nearby coeval stars. Main We analyse Hubble Space Telescope (HST) Space Telescope Imaging Spectrograph (STIS) near-ultraviolet spectra of 25 bright type-O and type-B stars in the Galaxy. When available, we include archival Very Large Telescope (VLT) Ultraviolet and Visual Echelle Spectrograph (UVES) high-resolution optical spectra of these targets. The selection of the 25 stars in our sample, as well as the data collection and handling, is described in Methods and the sample properties are listed in Extended Data Table 1 . The locations of our targets on the Galactic plane are visualized in Fig. 1 . Fig. 1: Location of our targets on the Galactic plane. Left, artistic impression of the Galaxy, face-on. Image courtesy of NASA/JPL-Caltech/R. Hurt (SSC/Caltech). Right, the location of our targets is marked on the same illustration of the Galaxy, but zoomed-in on the star-forming spiral arms in the Solar neighbourhood. The metallicity of the neutral gas along these lines of sight (Extended Data Table 3 ) is highlighted with the greyscale. 1 kpc ≈ 3.09 × 10 19 m. Source data Full size image We identify and analyse the absorption lines from Mg i , Al ii , Si ii , Cr ii , Fe ii , Co ii , Ni ii , Zn ii and Ti ii . A selection of absorption lines in the spectra of our targets are shown in Extended Data Fig. 1 . The column density measurements are explained in Methods and reported in Extended Data Table 2 . We report 3 σ significance levels for the quoted limits and 1 σ for the quoted errors, unless otherwise stated. We determine the neutral gas metallicity using two independent approaches and with different assumptions, which we call the ‘relative’ method and the ‘ F *’ method. Both methods aim to characterize the strength of dust depletion along Galactic lines of sight, and are described in Methods (equations ( 1 )–( 8 )). We use both methods to cross-check our results. In brief, the F * and relative methods use either the gas-phase abundances or the relative abundances to estimate by how much the observations are affected by dust depletion based on the empirical relations of ref. 8 or ref. 9 , respectively. Each method uses a specific parameter to estimate the overall amount of dust depletion in a system, either [Zn/Fe] fit or F *, as explained in Methods. The individual dust-corrected abundances derived with the relative method are shown in Fig. 2 , for individual metals. Figure 3 shows the total metallicities towards the 25 lines of sight in our sample, which are listed in Extended Data Table 3 and derived with the relative and F * methods from the fit to the data in Extended Data Figs. 2 , 3 , respectively. We measure total metallicities [M/H] tot ranging between −0.76 dex and +0.26 dex, where about two-thirds of our sample show subsolar metallicities. The average metallicity in our sample is −0.26 ± 0.06 dex (that is, 55 ± 7% solar) with a standard deviation of 0.28 dex. The most notable result is that the maximum variations between lines of sight are more than an order of magnitude, mostly subsolar. In Methods, we test this result for different assumptions. The result holds regardless of the assumptions. It is possible that the low metallicities that we measure represent a mix of two different gases, namely a nearly solar interstellar medium (ISM) component with high depletion levels with the injection of significant amounts of pristine gas with zero depletion and metallicities even lower than what we measure (Methods). Fig. 2: Dust-corrected abundances in the neutral ISM. Dust-corrected abundances of Si (light-blue triangles), Ti (blue stars), Cr (green diamonds), Fe (vermilion squares), Ni (pink crosses) and Zn (yellow squares) using the relative method. Stars are labelled in order of HD number (Extended Data Table 1 ). The error bars show the 1 σ uncertainties. Source data Full size image Fig. 3: Metallicities in the neutral ISM. Dust-corrected metallicities are marked with circles: the filled blue circles are derived with the relative method and the open green circles with the F * method. The open yellow triangles show the observed [Zn/H], and thus represent a lower limit to the true metallicity. Stars are ordered with increasing metallicity. In our sample, 15 out of 25 lines of sight are more than 3 σ away from solar metallicity (horizontal dashed line). The error bars show the", "role": "user" }, { "content": "In order to better understand the history and evolution of the Milky Way, astronomers are studying the composition of the gases and metals that make up an important part of our galaxy. Three main elements stand out: the initial gas coming from outside our galaxy, the gas between the stars inside our galaxy—enriched with chemical elements –, and the dust created by the condensation of the metals present in this gas. Until now, theoretical models assumed that these three elements were homogeneously mixed throughout the Milky Way and reached a level of chemical enrichment similar to the sun's atmosphere, called the solar metallicity. Today, a team of astronomers from the University of Geneva (UNIGE) demonstrates that these gases are not mixed as much as previously thought, which has a strong impact on the current understanding of the evolution of galaxies. As a result, simulations of the Milky Way's evolution will have to be modified. These results can be read in the journal Nature. Galaxies are made up of a collection of stars and are formed by the condensation of the gas of the intergalactic medium composed of mostly hydrogen and a bit of helium. This gas does not contain metals unlike the gas in galaxies—in astronomy, all chemical elements heavier than helium are collectively called metals, although they are atoms in gaseous form. \"Galaxies are fueled by 'virgin' gas that falls in from the outside, which rejuvenates them and allows new stars to form,\" explains Annalisa De Cia, a professor in the Department of Astronomy at the UNIGE Faculty of Science and first author of the study. At the same time, stars burn the hydrogen that constitutes them throughout their life and form other elements through nucleosynthesis. When a star that has reached the end of its life explodes, it expels the metals it has produced, such as iron, zinc, carbon and silicon, feeding these elements into the gas of the galaxy. These atoms can then condense into dust, especially in the colder, denser parts of the galaxy. \"Initially, when the Milky Way was formed, more than 10 billion years ago, it had no metals. Then the stars gradually enriched the environment with the metals they produced,\" continues the researcher. When the amount of metals in this gas reaches the level that is present in the sun, astronomers speak of solar metallicity. A not so homogeneous environment The environment that makes up the Milky Way thus brings together the metals produced by the stars, the dust particles that have formed from these metals, but also gases from outside the galaxy that regularly enter it. \"Until now, theoretical models considered that these three elements were homogeneously mixed and reached the solar composition everywhere in our galaxy, with a slight increase in metallicity in the center, where the stars are more numerous,\" explains Patrick Petitjean, a researcher at the Institut d'Astrophysique de Paris, Sorbonne University. \"We wanted to observe this in detail using an Ultraviolet spectrograph on the Hubble Space Telescope.\" Spectroscopy allows the light from stars to be separated in its individual colors or frequencies, a bit like a with prism or in a rainbow. In this decomposed light, astronomers are particularly interested in absorption lines: \"When we observe a star, the metals that make up the gas between the star and ourselves absorb a very small part of the light in a characteristic way, at a specific frequency, which allows us not only to identify their presence, but also to say which metal it is, and how abundant it is,\" he continues. A new method developed to observe the total metallicity For 25 hours, the team of scientists observed the atmosphere of 25 stars using Hubble and the Very Large Telescope (VLT) in Chile. The problem? The dust cannot be counted with these spectrographs, even though it contains metals. Annalisa De Cia's team has therefore developed a new observational technique. \"It involves taking into account the total composition of the gas and dust by simultaneously observing several elements such as iron, zinc, titanium, silicon and oxygen,\" explains the Geneva researcher. \"Then we can trace the quantity of metals present in the dust and add it to that already quantified by the previous observations to get the total.\" Thanks to this dual observation technique, the astronomers have found that not only is the Milky Way's environment not homogeneous, but that some of the areas studied reach only 10% of the solar metallicity. \"This discovery plays a key role in the design of theoretical models on the formation and evolution of galaxies,\" says Jens-Kristian Krogager, researcher at the UNIGE's Department of Astronomy. \"From now on, we will have to refine the simulations by increasing the resolution, so that we can include these changes in metallicity at different locations in the Milky Way.\" These results have a strong impact on our understanding of the evolution of galaxies and of our own in particular. Indeed, metals play a fundamental role in the formation of stars, cosmic dust, molecules and planets. And we now know that new stars and planets could be formed today from gases with very different compositions. ", "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 interstellar medium (ISM) comprises gases at different temperatures and densities, including ionized, atomic and molecular species, and dust particles 1 . The neutral ISM is dominated by neutral hydrogen 2 and has ionization fractions of up to eight per cent 3 . The concentration of chemical elements heavier than helium (metallicity) spans orders of magnitudes in Galactic stars 4 , because they formed at different times. However, the gas in the vicinity of the Sun is assumed to be well mixed and to have a solar metallicity in traditional chemical evolution models 5 . The ISM chemical abundances can be accurately measured with ultraviolet absorption-line spectroscopy. However, the effects of dust depletion 6 , 7 , 8 , 9 —which removes part of the metals from the observable gaseous phase and incorporates it into solid grains—have prevented, until recently, a deeper investigation of the ISM metallicity. Here we report the dust-corrected metallicity of the neutral ISM measured towards 25 stars in our Galaxy. We find large variations in metallicity over a factor of ten (with an average of 55 ± 7 per cent solar metallicity and a standard deviation of 0.28 dex), including many regions of low metallicity, down to about 17 per cent solar metallicity and possibly below. Pristine gas falling onto the Galactic disk in the form of high-velocity clouds can cause the observed chemical inhomogeneities on scales of tens of parsecs. Our results suggest that this low-metallicity accreting gas does not efficiently mix into the ISM, which may help us understand metallicity deviations in nearby coeval stars. Main We analyse Hubble Space Telescope (HST) Space Telescope Imaging Spectrograph (STIS) near-ultraviolet spectra of 25 bright type-O and type-B stars in the Galaxy. When available, we include archival Very Large Telescope (VLT) Ultraviolet and Visual Echelle Spectrograph (UVES) high-resolution optical spectra of these targets. The selection of the 25 stars in our sample, as well as the data collection and handling, is described in Methods and the sample properties are listed in Extended Data Table 1 . The locations of our targets on the Galactic plane are visualized in Fig. 1 . Fig. 1: Location of our targets on the Galactic plane. Left, artistic impression of the Galaxy, face-on. Image courtesy of NASA/JPL-Caltech/R. Hurt (SSC/Caltech). Right, the location of our targets is marked on the same illustration of the Galaxy, but zoomed-in on the star-forming spiral arms in the Solar neighbourhood. The metallicity of the neutral gas along these lines of sight (Extended Data Table 3 ) is highlighted with the greyscale. 1 kpc ≈ 3.09 × 10 19 m. Source data Full size image We identify and analyse the absorption lines from Mg i , Al ii , Si ii , Cr ii , Fe ii , Co ii , Ni ii , Zn ii and Ti ii . A selection of absorption lines in the spectra of our targets are shown in Extended Data Fig. 1 . The column density measurements are explained in Methods and reported in Extended Data Table 2 . We report 3 σ significance levels for the quoted limits and 1 σ for the quoted errors, unless otherwise stated. We determine the neutral gas metallicity using two independent approaches and with different assumptions, which we call the ‘relative’ method and the ‘ F *’ method. Both methods aim to characterize the strength of dust depletion along Galactic lines of sight, and are described in Methods (equations ( 1 )–( 8 )). We use both methods to cross-check our results. In brief, the F * and relative methods use either the gas-phase abundances or the relative abundances to estimate by how much the observations are affected by dust depletion based on the empirical relations of ref. 8 or ref. 9 , respectively. Each method uses a specific parameter to estimate the overall amount of dust depletion in a system, either [Zn/Fe] fit or F *, as explained in Methods. The individual dust-corrected abundances derived with the relative method are shown in Fig. 2 , for individual metals. Figure 3 shows the total metallicities towards the 25 lines of sight in our sample, which are listed in Extended Data Table 3 and derived with the relative and F * methods from the fit to the data in Extended Data Figs. 2 , 3 , respectively. We measure total metallicities [M/H] tot ranging between −0.76 dex and +0.26 dex, where about two-thirds of our sample show subsolar metallicities. The average metallicity in our sample is −0.26 ± 0.06 dex (that is, 55 ± 7% solar) with a standard deviation of 0.28 dex. The most notable result is that the maximum variations between lines of sight are more than an order of magnitude, mostly subsolar. In Methods, we test this result for different assumptions. The result holds regardless of the assumptions. It is possible that the low metallicities that we measure represent a mix of two different gases, namely a nearly solar interstellar medium (ISM) component with high depletion levels with the injection of significant amounts of pristine gas with zero depletion and metallicities even lower than what we measure (Methods). Fig. 2: Dust-corrected abundances in the neutral ISM. Dust-corrected abundances of Si (light-blue triangles), Ti (blue stars), Cr (green diamonds), Fe (vermilion squares), Ni (pink crosses) and Zn (yellow squares) using the relative method. Stars are labelled in order of HD number (Extended Data Table 1 ). The error bars show the 1 σ uncertainties. Source data Full size image Fig. 3: Metallicities in the neutral ISM. Dust-corrected metallicities are marked with circles: the filled blue circles are derived with the relative method and the open green circles with the F * method. The open yellow triangles show the observed [Zn/H], and thus represent a lower limit to the true metallicity. Stars are ordered with increasing metallicity. In our sample, 15 out of 25 lines of sight are more than 3 σ away from solar metallicity (horizontal dashed line). The error bars show the<|im_end|> <|im_start|>assistant In order to better understand the history and evolution of the Milky Way, astronomers are studying the composition of the gases and metals that make up an important part of our galaxy. Three main elements stand out: the initial gas coming from outside our galaxy, the gas between the stars inside our galaxy—enriched with chemical elements –, and the dust created by the condensation of the metals present in this gas. Until now, theoretical models assumed that these three elements were homogeneously mixed throughout the Milky Way and reached a level of chemical enrichment similar to the sun's atmosphere, called the solar metallicity. Today, a team of astronomers from the University of Geneva (UNIGE) demonstrates that these gases are not mixed as much as previously thought, which has a strong impact on the current understanding of the evolution of galaxies. As a result, simulations of the Milky Way's evolution will have to be modified. These results can be read in the journal Nature. Galaxies are made up of a collection of stars and are formed by the condensation of the gas of the intergalactic medium composed of mostly hydrogen and a bit of helium. This gas does not contain metals unlike the gas in galaxies—in astronomy, all chemical elements heavier than helium are collectively called metals, although they are atoms in gaseous form. "Galaxies are fueled by 'virgin' gas that falls in from the outside, which rejuvenates them and allows new stars to form," explains Annalisa De Cia, a professor in the Department of Astronomy at the UNIGE Faculty of Science and first author of the study. At the same time, stars burn the hydrogen that constitutes them throughout their life and form other elements through nucleosynthesis. When a star that has reached the end of its life explodes, it expels the metals it has produced, such as iron, zinc, carbon and silicon, feeding these elements into the gas of the galaxy. These atoms can then condense into dust, especially in the colder, denser parts of the galaxy. "Initially, when the Milky Way was formed, more than 10 billion years ago, it had no metals. Then the stars gradually enriched the environment with the metals they produced," continues the researcher. When the amount of metals in this gas reaches the level that is present in the sun, astronomers speak of solar metallicity. A not so homogeneous environment The environment that makes up the Milky Way thus brings together the metals produced by the stars, the dust particles that have formed from these metals, but also gases from outside the galaxy that regularly enter it. "Until now, theoretical models considered that these three elements were homogeneously mixed and reached the solar composition everywhere in our galaxy, with a slight increase in metallicity in the center, where the stars are more numerous," explains Patrick Petitjean, a researcher at the Institut d'Astrophysique de Paris, Sorbonne University. "We wanted to observe this in detail using an Ultraviolet spectrograph on the Hubble Space Telescope." Spectroscopy allows the light from stars to be separated in its individual colors or frequencies, a bit like a with prism or in a rainbow. In this decomposed light, astronomers are particularly interested in absorption lines: "When we observe a star, the metals that make up the gas between the star and ourselves absorb a very small part of the light in a characteristic way, at a specific frequency, which allows us not only to identify their presence, but also to say which metal it is, and how abundant it is," he continues. A new method developed to observe the total metallicity For 25 hours, the team of scientists observed the atmosphere of 25 stars using Hubble and the Very Large Telescope (VLT) in Chile. The problem? The dust cannot be counted with these spectrographs, even though it contains metals. Annalisa De Cia's team has therefore developed a new observational technique. "It involves taking into account the total composition of the gas and dust by simultaneously observing several elements such as iron, zinc, titanium, silicon and oxygen," explains the Geneva researcher. "Then we can trace the quantity of metals present in the dust and add it to that already quantified by the previous observations to get the total." Thanks to this dual observation technique, the astronomers have found that not only is the Milky Way's environment not homogeneous, but that some of the areas studied reach only 10% of the solar metallicity. "This discovery plays a key role in the design of theoretical models on the formation and evolution of galaxies," says Jens-Kristian Krogager, researcher at the UNIGE's Department of Astronomy. "From now on, we will have to refine the simulations by increasing the resolution, so that we can include these changes in metallicity at different locations in the Milky Way." These results have a strong impact on our understanding of the evolution of galaxies and of our own in particular. Indeed, metals play a fundamental role in the formation of stars, cosmic dust, molecules and planets. And we now know that new stars and planets could be formed today from gases with very different compositions. <|im_end|>

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315, 14254, 527, 810, 1109, 459, 2015, 315, 26703, 11, 10213, 5258, 7569, 13, 763, 19331, 11, 584, 1296, 420, 1121, 369, 2204, 32946, 13, 578, 1121, 10187, 15851, 315, 279, 32946, 13, 1102, 374, 3284, 430, 279, 3428, 46258, 1385, 430, 584, 6767, 4097, 264, 6651, 315, 1403, 2204, 45612, 11, 32125, 264, 7154, 13238, 958, 78393, 11298, 320, 47905, 8, 3777, 449, 1579, 92948, 5990, 449, 279, 26127, 315, 5199, 15055, 315, 66085, 6962, 449, 7315, 92948, 323, 46258, 1385, 1524, 4827, 1109, 1148, 584, 6767, 320, 18337, 570, 23966, 13, 220, 17, 25, 33093, 1824, 28132, 291, 23325, 3095, 304, 279, 21277, 3507, 44, 13, 33093, 1824, 28132, 291, 23325, 3095, 315, 12095, 320, 4238, 32754, 43546, 705, 23126, 320, 12481, 9958, 705, 4656, 320, 13553, 49151, 705, 3926, 320, 424, 76, 50012, 32440, 705, 22652, 320, 64349, 50535, 8, 323, 127265, 320, 28969, 32440, 8, 1701, 279, 8844, 1749, 13, 25676, 527, 61336, 304, 2015, 315, 12445, 1396, 320, 54290, 2956, 6771, 220, 16, 7609, 578, 1493, 16283, 1501, 279, 220, 16, 48823, 69867, 13, 8922, 828, 8797, 1404, 2217, 23966, 13, 220, 18, 25, 87971, 1385, 304, 279, 21277, 3507, 44, 13, 33093, 1824, 28132, 291, 46258, 1385, 527, 13160, 449, 26432, 25, 279, 10409, 6437, 26432, 527, 14592, 449, 279, 8844, 1749, 323, 279, 1825, 6307, 26432, 449, 279, 435, 353, 1749, 13, 578, 1825, 14071, 43546, 1501, 279, 13468, 510, 57, 77, 24240, 1145, 323, 8617, 4097, 264, 4827, 4017, 311, 279, 837, 9501, 25814, 13, 25676, 527, 11713, 449, 7859, 9501, 25814, 13, 763, 1057, 6205, 11, 220, 868, 704, 315, 220, 914, 5238, 315, 14254, 527, 810, 1109, 220, 18, 48823, 3201, 505, 13238, 9501, 25814, 320, 31729, 67822, 1584, 570, 578, 1493, 16283, 1501, 279, 128257, 198, 128256, 78191, 198, 644, 2015, 311, 2731, 3619, 279, 3925, 323, 15740, 315, 279, 89819, 12424, 11, 87887, 527, 21630, 279, 18528, 315, 279, 45612, 323, 37182, 430, 1304, 709, 459, 3062, 961, 315, 1057, 34261, 13, 14853, 1925, 5540, 2559, 704, 25, 279, 2926, 6962, 5108, 505, 4994, 1057, 34261, 11, 279, 6962, 1990, 279, 9958, 4871, 1057, 34261, 2345, 268, 14172, 291, 449, 11742, 5540, 1389, 11, 323, 279, 16174, 3549, 555, 279, 9955, 42725, 315, 279, 37182, 3118, 304, 420, 6962, 13, 30070, 1457, 11, 32887, 4211, 19655, 430, 1521, 2380, 5540, 1051, 5105, 34224, 7162, 9709, 6957, 279, 89819, 12424, 323, 8813, 264, 2237, 315, 11742, 70272, 4528, 311, 279, 7160, 596, 16975, 11, 2663, 279, 13238, 9501, 25814, 13, 11450, 11, 264, 2128, 315, 87887, 505, 279, 3907, 315, 45345, 320, 1899, 1953, 36, 8, 32216, 430, 1521, 45612, 527, 539, 9709, 439, 1790, 439, 8767, 3463, 11, 902, 706, 264, 3831, 5536, 389, 279, 1510, 8830, 315, 279, 15740, 315, 66017, 13, 1666, 264, 1121, 11, 47590, 315, 279, 89819, 12424, 596, 15740, 690, 617, 311, 387, 11041, 13, 4314, 3135, 649, 387, 1373, 304, 279, 8486, 22037, 13, 10845, 58088, 527, 1903, 709, 315, 264, 4526, 315, 9958, 323, 527, 14454, 555, 279, 9955, 42725, 315, 279, 6962, 315, 279, 958, 16876, 24045, 11298, 24306, 315, 10213, 35784, 323, 264, 2766, 315, 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1065, 2428, 409, 12366, 11, 30631, 6098, 818, 3907, 13, 330, 1687, 4934, 311, 23846, 420, 304, 7872, 1701, 459, 67957, 85311, 66425, 4539, 389, 279, 473, 14942, 11746, 87062, 1210, 27726, 299, 51856, 6276, 279, 3177, 505, 9958, 311, 387, 19180, 304, 1202, 3927, 8146, 477, 34873, 11, 264, 2766, 1093, 264, 449, 94710, 477, 304, 264, 48713, 13, 763, 420, 29602, 3950, 3177, 11, 87887, 527, 8104, 8173, 304, 44225, 5238, 25, 330, 4599, 584, 23846, 264, 6917, 11, 279, 37182, 430, 1304, 709, 279, 6962, 1990, 279, 6917, 323, 13520, 35406, 264, 1633, 2678, 961, 315, 279, 3177, 304, 264, 29683, 1648, 11, 520, 264, 3230, 11900, 11, 902, 6276, 603, 539, 1193, 311, 10765, 872, 9546, 11, 719, 1101, 311, 2019, 902, 9501, 433, 374, 11, 323, 1268, 44611, 433, 374, 1359, 568, 9731, 13, 362, 502, 1749, 8040, 311, 23846, 279, 2860, 9501, 25814, 1789, 220, 914, 4207, 11, 279, 2128, 315, 14248, 13468, 279, 16975, 315, 220, 914, 9958, 1701, 473, 14942, 323, 279, 15668, 20902, 87062, 320, 53, 28504, 8, 304, 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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 Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics. Introduction Since their characterization as COX inhibitors 1 , non-steroidal anti-inflammatory drugs (NSAIDs) have been used to treat a wide variety of diseases with relatively limited side effects 2 . NSAID inhibition of COX prevents the conversion of arachidonic acid to eicosanoids resulting in a reduction in the synthesis of proinflammatory prostaglandins 3 . Evidence indicates a polyvalent effect of NSAIDs with some research suggesting COX-independent activity 4 . One such important action may be to directly limit the production of proinflammatory cytokines. Many inflammatory diseases are driven by the proinflammatory cytokine interleukin-1β (IL-1β) 5 . IL-1β is produced in myeloid cells as an inactive precursor (pro-IL-1β) that requires cleavage by the protease caspase-1 for its activation and secretion 6 . Caspase-1 is also produced as an inactive precursor, which is activated following recruitment to a large multi-protein complex called the inflammasome 6 . Inflammasomes are defined by the presence of a pattern recognition receptor. The best characterized inflammasome-forming pattern recognition receptor, and the most commonly associated with disease is NLRP3 (NLR family, pyrin domain containing 3). In response to pathogen-associated molecular patterns or damage-associated molecular patterns NLRP3 nucleates the oligomerization of ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) molecules 7 , 8 into large ‘specks’ that serve as platforms for caspase-1 activation and subsequent release of IL-1β. The NLRP3 inflammasome is an important contributor to inflammatory diseases, including Alzheimer’s disease 9 , atherosclerosis 10 , metabolic diseases such as type 2 diabetes 11 and others 12 . Hence, there is substantial interest in the discovery of potentially therapeutic inflammasome inhibitors. One such compound, MCC950, has been identified as a potent NLRP3-selective inhibitor 13 , but is not yet available for clinical use. Fenamate NSAIDs have been shown to inhibit IL-1β secretion from macrophages 14 , although the significance of COX inhibition remains unclear 15 . Here we show that the fenamate class of NSAIDs inhibit the NLRP3 inflammasome via reversible blockade of volume-regulated anion channels (VRAC) in the plasma membrane, and inhibit cognitive impairments in models of Alzheimer’s disease in rodents, thus offering a safe and rapidly translatable option to treat NLRP3-related inflammatory diseases. Results Fenamate NSAIDs selectively inhibit the NLRP3 inflammasome Immortalized mouse bone marrow-derived macrophages (iBMDMs) were primed with lipopolysaccharide (LPS; 1 μg ml −1 , 2 h), after which the media was replaced with serum-free media. At this point the cells were incubated with a range of NSAIDs ( Supplementary Fig. 1 ) for 15 min before 1 h stimulation with 5 mM ATP to activate the P2X7 receptor and induce NLRP3 inflammasome activation 16 . ELISA analysis of cell supernatants revealed that of the NSAIDs tested the fenamates (N-phenyl-substituted anthranilic acid derivatives such as flufenamic acid, meclofenamic acid, mefenamic acid) were most effective at inhibiting IL-1β release ( Fig. 1a ). The selective COX-2 inhibitor celecoxib did not inhibit IL-1β release, nor did ibuprofen, even at concentrations supra-maximal for COX inhibition. Western blot analysis of the supernatants also showed that caspase-1-dependent processing of IL-1β was also inhibited by the fenamates ( Supplementary Fig. 2 ). Fenamate NSAIDs had no effect on ATP-induced cell death ( Supplementary Fig. 3 ) suggesting that their effects were specific to IL-1β release, and independent of the stability of ATP. As early studies indicated multiple sites of action for the fenamate NSAIDs 17 , these data reveal the fenamates as inhibitors of IL-1β processing and release and suggest that this effect is independent of COX inhibition. Figure 1: Fenamate NSAIDs inhibit IL-1β processing and release. ( a ) iBMDMs were primed with LPS (1 μg ml −1 , 2 h) then pre-treated with NSAID at indicated concentration before stimulating with ATP (5 mM, 1 h). ( b – d ) Murine primary BMDMs from WT ( b ) or NLRP3 −/− ( c , d ) mice were primed with LPS (1 μg ml −1 , 4 h) and pre-treated with NSAID (100 μM, 15 min) before stimulating with monosodium urate (MSU) crystals (250 μg ml −1 , 4 h) ( b ), transfected ultrapure flagellin from Salmonella typhimurium (1 ng per 1,000 cells, 2 h) ( c ), or transfected DNA (0.66 ng per 1,000 cells, 4 h) ( d ). Supernatants were analysed by ELISA. Data are presented as mean % IL-1β release versus vehicle (DMSO) control+s.e.m ( n =3 or 4). NS, not significantly different, * P <0.05, ** P <0.01 determined by one-sample t -test versus hypothetical value of 100%. Full size image Flufenamic acid, but not ibuprofen, also inhibited IL-1β release induced by the NLRP3 inflammasome activator monosodium urate (MSU) in primary mouse BMDMs ( Fig. 1b ), suggesting that their effect was not due to direct inhibition of the P2X7 receptor or a direct effect on ATP. To determine whether the fenamates were selective inhibitors of NLRP3-dependent IL-1β release, we tested their effects against other well-characterized inflammasomes in primary BMDMs. NLRC4 inflammasome activation by transfected Salmonella typhimurium flagellin in BMDMs induced IL-1β release, which was not inhibited by flufenamic or mefenamic acid ( Fig. 1c ). AIM2 inflammasome activation by transfected double-stranded DNA was also unaffected by flufenamic or mefenamic acid ( Fig. 1d ). These data suggest that the fenamates selectively", "role": "user" }, { "content": "A research project has shown that an experimental model of Alzheimer's disease can be successfully treated with a commonly used anti-inflammatory drug. A team led by Dr David Brough from The University of Manchester found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice. Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain. The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and Dr Catherine Lawrence supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments. Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use. The research, funded by the Medical Research Council and the Alzheimer's Society, paves the way for human trials which the team hope to conduct in the future. Around 500,000 people in the UK have Alzheimer's disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions. In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo. The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month. Credit: University of Manchester Memory loss was completely reversed back to the levels seen in mice without the disease. Dr Brough said: \"There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse. \"Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells.\" He added: \"Until now, no drug has been available to target this pathway, so we are very excited by this result. \"However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease. \"Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs. \"We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans.\" Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: \"Testing drugs already in use for other conditions is a priority for Alzheimer's Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch. \"These promising lab results identify a class of existing drugs that have potential to treat Alzheimer's disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer's disease at this stage – studies in people are needed first.\" ", "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 Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics. Introduction Since their characterization as COX inhibitors 1 , non-steroidal anti-inflammatory drugs (NSAIDs) have been used to treat a wide variety of diseases with relatively limited side effects 2 . NSAID inhibition of COX prevents the conversion of arachidonic acid to eicosanoids resulting in a reduction in the synthesis of proinflammatory prostaglandins 3 . Evidence indicates a polyvalent effect of NSAIDs with some research suggesting COX-independent activity 4 . One such important action may be to directly limit the production of proinflammatory cytokines. Many inflammatory diseases are driven by the proinflammatory cytokine interleukin-1β (IL-1β) 5 . IL-1β is produced in myeloid cells as an inactive precursor (pro-IL-1β) that requires cleavage by the protease caspase-1 for its activation and secretion 6 . Caspase-1 is also produced as an inactive precursor, which is activated following recruitment to a large multi-protein complex called the inflammasome 6 . Inflammasomes are defined by the presence of a pattern recognition receptor. The best characterized inflammasome-forming pattern recognition receptor, and the most commonly associated with disease is NLRP3 (NLR family, pyrin domain containing 3). In response to pathogen-associated molecular patterns or damage-associated molecular patterns NLRP3 nucleates the oligomerization of ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) molecules 7 , 8 into large ‘specks’ that serve as platforms for caspase-1 activation and subsequent release of IL-1β. The NLRP3 inflammasome is an important contributor to inflammatory diseases, including Alzheimer’s disease 9 , atherosclerosis 10 , metabolic diseases such as type 2 diabetes 11 and others 12 . Hence, there is substantial interest in the discovery of potentially therapeutic inflammasome inhibitors. One such compound, MCC950, has been identified as a potent NLRP3-selective inhibitor 13 , but is not yet available for clinical use. Fenamate NSAIDs have been shown to inhibit IL-1β secretion from macrophages 14 , although the significance of COX inhibition remains unclear 15 . Here we show that the fenamate class of NSAIDs inhibit the NLRP3 inflammasome via reversible blockade of volume-regulated anion channels (VRAC) in the plasma membrane, and inhibit cognitive impairments in models of Alzheimer’s disease in rodents, thus offering a safe and rapidly translatable option to treat NLRP3-related inflammatory diseases. Results Fenamate NSAIDs selectively inhibit the NLRP3 inflammasome Immortalized mouse bone marrow-derived macrophages (iBMDMs) were primed with lipopolysaccharide (LPS; 1 μg ml −1 , 2 h), after which the media was replaced with serum-free media. At this point the cells were incubated with a range of NSAIDs ( Supplementary Fig. 1 ) for 15 min before 1 h stimulation with 5 mM ATP to activate the P2X7 receptor and induce NLRP3 inflammasome activation 16 . ELISA analysis of cell supernatants revealed that of the NSAIDs tested the fenamates (N-phenyl-substituted anthranilic acid derivatives such as flufenamic acid, meclofenamic acid, mefenamic acid) were most effective at inhibiting IL-1β release ( Fig. 1a ). The selective COX-2 inhibitor celecoxib did not inhibit IL-1β release, nor did ibuprofen, even at concentrations supra-maximal for COX inhibition. Western blot analysis of the supernatants also showed that caspase-1-dependent processing of IL-1β was also inhibited by the fenamates ( Supplementary Fig. 2 ). Fenamate NSAIDs had no effect on ATP-induced cell death ( Supplementary Fig. 3 ) suggesting that their effects were specific to IL-1β release, and independent of the stability of ATP. As early studies indicated multiple sites of action for the fenamate NSAIDs 17 , these data reveal the fenamates as inhibitors of IL-1β processing and release and suggest that this effect is independent of COX inhibition. Figure 1: Fenamate NSAIDs inhibit IL-1β processing and release. ( a ) iBMDMs were primed with LPS (1 μg ml −1 , 2 h) then pre-treated with NSAID at indicated concentration before stimulating with ATP (5 mM, 1 h). ( b – d ) Murine primary BMDMs from WT ( b ) or NLRP3 −/− ( c , d ) mice were primed with LPS (1 μg ml −1 , 4 h) and pre-treated with NSAID (100 μM, 15 min) before stimulating with monosodium urate (MSU) crystals (250 μg ml −1 , 4 h) ( b ), transfected ultrapure flagellin from Salmonella typhimurium (1 ng per 1,000 cells, 2 h) ( c ), or transfected DNA (0.66 ng per 1,000 cells, 4 h) ( d ). Supernatants were analysed by ELISA. Data are presented as mean % IL-1β release versus vehicle (DMSO) control+s.e.m ( n =3 or 4). NS, not significantly different, * P <0.05, ** P <0.01 determined by one-sample t -test versus hypothetical value of 100%. Full size image Flufenamic acid, but not ibuprofen, also inhibited IL-1β release induced by the NLRP3 inflammasome activator monosodium urate (MSU) in primary mouse BMDMs ( Fig. 1b ), suggesting that their effect was not due to direct inhibition of the P2X7 receptor or a direct effect on ATP. To determine whether the fenamates were selective inhibitors of NLRP3-dependent IL-1β release, we tested their effects against other well-characterized inflammasomes in primary BMDMs. NLRC4 inflammasome activation by transfected Salmonella typhimurium flagellin in BMDMs induced IL-1β release, which was not inhibited by flufenamic or mefenamic acid ( Fig. 1c ). AIM2 inflammasome activation by transfected double-stranded DNA was also unaffected by flufenamic or mefenamic acid ( Fig. 1d ). These data suggest that the fenamates selectively<|im_end|> <|im_start|>assistant A research project has shown that an experimental model of Alzheimer's disease can be successfully treated with a commonly used anti-inflammatory drug. A team led by Dr David Brough from The University of Manchester found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice. Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain. The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and Dr Catherine Lawrence supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments. Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use. The research, funded by the Medical Research Council and the Alzheimer's Society, paves the way for human trials which the team hope to conduct in the future. Around 500,000 people in the UK have Alzheimer's disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions. In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo. The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month. Credit: University of Manchester Memory loss was completely reversed back to the levels seen in mice without the disease. Dr Brough said: "There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse. "Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells." He added: "Until now, no drug has been available to target this pathway, so we are very excited by this result. "However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease. "Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs. "We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans." Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: "Testing drugs already in use for other conditions is a priority for Alzheimer's Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch. "These promising lab results identify a class of existing drugs that have potential to treat Alzheimer's disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer's disease at this stage – studies in people are needed first." <|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 Child development research on overconfidence suggests that the bias is present and persistent in preschoolers and kindergartners. However, little is known about what drives overconfidence among young decision-makers, how it changes over a large number of repetitions, and whether such changes differ by gender or age. The current experimental study analyzes data from 60 children, aged 4 years 0 months to 6 years 10 months, who played 60 turns of the Children’s Gambling Task and provided regular estimates on their performance. A video intervention, designed to demonstrate the consequences of disadvantageous choices, was tested in a double-blind randomized controlled trial to assess its impact on overconfidence. The results show that every third participant remained overconfident even after 60 trials and constant feedback. Unlike previously reported, gender seems to be a determining factor in this process. Lastly, providing additional information through a video intervention appears to have no impact on participants’ overconfidence levels. Introduction Overconfidence describes the tendency to overestimate one’s skills and underestimate the impact of risk and ambiguity on a given outcome 1 . The presence and influence of overconfidence on young decision-makers (4 years 0 months and older) has been consistently shown in a multitude of empirical studies over the course of several decades. The majority of these studies relied on memory tasks that compared children’s predicted performance to their actual, observed outcome (e.g., performance on a picture recall task) 2 , 3 , 4 . In all of these studies, the average participant significantly overestimated their own performance which resulted in a substantial discrepancy between prediction and actual recall. Additionally, there is evidence that overconfidence in early childhood and primary education slightly decreases with age 3 , 5 , 6 . For instance, preschoolers and kindergartners seem to be more likely to overstate their recall performance compared to third-graders. A possible explanation for this finding is superior metacognitive abilities among older children who have a greater capacity to accurately recall and evaluate their past performance and assess their own predictions 7 . Younger decision-makers also exhibit more persistence in excessively confident predictions, even after repeating the task, recalling their past performance before providing an estimate for the repetition, or assessing the performance of another child 8 . The former aspect suggests that children do not develop underconfidence with practice (UWP) at an early age. UWP describes the propensity to initially observe excessively confident behavior which shifts to underconfidence after a sufficiently large number of repetitions. However, the approximate age range may be disputable, as Finn and Metcalfe 9 found that even fifth-graders at a mean age of 10 years 0 months showed consistent overconfidence, while Lipko and colleagues 5 concluded that third- (mean age: 8 years 11 months) but not first-graders (mean age: 6; 11) exhibited UWP. It may be noted that the majority of the aforementioned studies did not report or find any discrepancy between the performance or self-assessment of girls and boys in their samples 3 , 4 , 5 , 6 , 8 , 9 . This stands in stark contrast to empirical work assessing overconfidence among adults that commonly find a gender effect 10 , 11 , 12 . Even if an effect among young decision-makers was detected, it might have been deemed spurious or described as “[not] very credible, interpretable, or interesting ” 2 (p. 334). That being said, Pressley and Ghatala 7 found that girls in first and second grade can be associated with a more precise assessment of their performance compared to their male counterparts. It is unclear whether these deviating findings are sample-specific or arise from the difference in the underlying procedures (i.e., memory task in the former studies and a picture vocabulary test in the latter). Furthermore, few studies used randomized controlled designs to identify mechanisms underlying age-related changes in overconfidence. These studies provide conflicting evidence with some suggesting that interventions designed to engage metamemory processes (i.e., reflection and knowledge about one’s memory) can reduce the bias. For instance, Stipek et al . 13 played a game of deception with sixty 4-year-olds. Participants were asked to lift a metal ball up a tower on a cart that was secretly controlled by magnetic force. The preschoolers were randomly allocated into experimental arms that either had to make prediction about their own performance or about the performance of a gender-matched child who played the same game on TV. Both arms included three groups receiving incentives in the form of marbles, explicit feedback regarding their past “performance” (which could not be influenced by the participants), or no intervention (i.e., control condition). If incentivized, mean predictions between self and others did not differ. However, if participants did not receive any intervention, their own future performance was perceived to be superior to the outcome of the other child. The reverse is true when preschoolers were explicitly reminded about their past performance. Yet, small intragroup sample sizes of 10 participants and a notable absence of influence on the actual outcome, diminish the generalizability of the findings. Powel and colleagues 14 asked 22 children (aged 4; 2–6; 9) to provide confidence estimates about their ability to throw 10 beanbags into a basket. All participants showed overconfidence in their throwing skills, but accuracy seems to improve with age. Lastly, Lagatutta and Sayfan 15 used a narrative of positive, negative, or ambiguous events to assess attitude and predictions of 265 children (mean age 4; 6–8; 11) and adults (mean age 20; 0). Contrary to previous studies, the results suggested that unjustifiable confidence in past events with limited information value increased with age. A possible explanation for these conflicting results may be found in the underlying experimental tasks. The former studies that reported a decrease of the bias with age utilize physically executable tasks (e.g., lifting a metal ball, throwing beanbags, etc.) while the latter work relied on an abstract assessment of a future event that required a judgment under uncertainty without any physically executable actions. Prior research suggests that overconfidence is domain specific which might explain", "role": "user" }, { "content": "Overconfidence in one's own abilities despite clear evidence to the contrary is present and persistent in children as young as four, a new study by the University of Sussex Business School has revealed. The cognitive bias has been consistently observed among a number of professions including business executives, bankers and physicians across different countries and cultures but a new study led by Dr. Dominik Piehlmaier indicates that overconfidence is persistent and widespread during early childhood. The research also found that girls were more successful than boys at a card game in the study thanks to a more low-risk strategy but also experienced greater swings between overconfidence and lack of confidence in their abilities. Dr. Dominik Piehlmaier, Lecturer in Marketing at the University of Sussex Business School and the study's author, said: \"Much of our knowledge on judgment and decision-making is based on adult participants but there is no reason to believe that humans only develop such an omnipresent cognitive illusion once we reach adulthood. \"My findings indicate that effective interventions that increase an individual's knowledge about their own knowledge and its boundaries might be needed to target much younger individuals if one wants to efficiently calibrate a person's irrational confidence.\" In the study, children were asked to play a card game known as the Children's Gambling Task where they choose cards from one of two packs. The card is then turned over to reveal how many stickers the participant has won and lost. One pack had cards with significantly higher wins and losses than the other. At intervals, children had to decide whether they thought they would win more, about the same, or fewer stickers than previously in the game. Each participant started off with four stickers after the initial six practice trials. On average, every participant gained 0.3 stickers per turn and left the game with an average of 6.67 stickers, ranging from zero to 33. The study showed that more than 70% of four-year-olds and half of all five and six-year-olds were overconfident in their expectations after playing ten turns and six practice trials. Dr. Piehlmaier said: \"A vast number of repetitions, learning, and feedback in the study did not diminish the misplaced confidence in the success of the majority of participants. \"The children played more than 60 turns and saw their payoff balance rose and fell, yet every third child still thought that they could do better than they had done in the previous 50 turns. \"The Children's Gambling Task closely resembles a very simplified version of the financial markets with relatively safe options providing low but steady average return rates and highly risky assets that promise much higher short-term gains with a catastrophic long-term yield. \"The finding that overconfidence is persistent even in the face of own shortcomings mirrors results from previous studies that looked at the performance of investors.\" Overconfidence is widely seen as a male trait but the study also had interesting findings when it came to the general performance of boys and girls. In general, girls outperformed boys by an average of 2.87 stickers thanks to a less high-risk strategy of choosing relatively more safe cards which offered smaller but more sustainable gains. Dr. Piehlmaier added: \"Boys seem to follow a negative trend line that indicates slow but steady learning on what might be considered 'reasonable expectations'. \"Girls' behaviour is much more unpredictable. When the girls' overconfidence plot is compared to their payoffs, it can be noticed that they closely align. \"This indicates that girls overestimate their abilities if they have a winning streak and underestimate themselves whenever they lose a few times in a row. \"By the end of the experiment, there were relatively more overconfident girls than boys; a finding that contradicts previous reports regarding more calibrated girls in metamemory tasks.\" ", "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 Child development research on overconfidence suggests that the bias is present and persistent in preschoolers and kindergartners. However, little is known about what drives overconfidence among young decision-makers, how it changes over a large number of repetitions, and whether such changes differ by gender or age. The current experimental study analyzes data from 60 children, aged 4 years 0 months to 6 years 10 months, who played 60 turns of the Children’s Gambling Task and provided regular estimates on their performance. A video intervention, designed to demonstrate the consequences of disadvantageous choices, was tested in a double-blind randomized controlled trial to assess its impact on overconfidence. The results show that every third participant remained overconfident even after 60 trials and constant feedback. Unlike previously reported, gender seems to be a determining factor in this process. Lastly, providing additional information through a video intervention appears to have no impact on participants’ overconfidence levels. Introduction Overconfidence describes the tendency to overestimate one’s skills and underestimate the impact of risk and ambiguity on a given outcome 1 . The presence and influence of overconfidence on young decision-makers (4 years 0 months and older) has been consistently shown in a multitude of empirical studies over the course of several decades. The majority of these studies relied on memory tasks that compared children’s predicted performance to their actual, observed outcome (e.g., performance on a picture recall task) 2 , 3 , 4 . In all of these studies, the average participant significantly overestimated their own performance which resulted in a substantial discrepancy between prediction and actual recall. Additionally, there is evidence that overconfidence in early childhood and primary education slightly decreases with age 3 , 5 , 6 . For instance, preschoolers and kindergartners seem to be more likely to overstate their recall performance compared to third-graders. A possible explanation for this finding is superior metacognitive abilities among older children who have a greater capacity to accurately recall and evaluate their past performance and assess their own predictions 7 . Younger decision-makers also exhibit more persistence in excessively confident predictions, even after repeating the task, recalling their past performance before providing an estimate for the repetition, or assessing the performance of another child 8 . The former aspect suggests that children do not develop underconfidence with practice (UWP) at an early age. UWP describes the propensity to initially observe excessively confident behavior which shifts to underconfidence after a sufficiently large number of repetitions. However, the approximate age range may be disputable, as Finn and Metcalfe 9 found that even fifth-graders at a mean age of 10 years 0 months showed consistent overconfidence, while Lipko and colleagues 5 concluded that third- (mean age: 8 years 11 months) but not first-graders (mean age: 6; 11) exhibited UWP. It may be noted that the majority of the aforementioned studies did not report or find any discrepancy between the performance or self-assessment of girls and boys in their samples 3 , 4 , 5 , 6 , 8 , 9 . This stands in stark contrast to empirical work assessing overconfidence among adults that commonly find a gender effect 10 , 11 , 12 . Even if an effect among young decision-makers was detected, it might have been deemed spurious or described as “[not] very credible, interpretable, or interesting ” 2 (p. 334). That being said, Pressley and Ghatala 7 found that girls in first and second grade can be associated with a more precise assessment of their performance compared to their male counterparts. It is unclear whether these deviating findings are sample-specific or arise from the difference in the underlying procedures (i.e., memory task in the former studies and a picture vocabulary test in the latter). Furthermore, few studies used randomized controlled designs to identify mechanisms underlying age-related changes in overconfidence. These studies provide conflicting evidence with some suggesting that interventions designed to engage metamemory processes (i.e., reflection and knowledge about one’s memory) can reduce the bias. For instance, Stipek et al . 13 played a game of deception with sixty 4-year-olds. Participants were asked to lift a metal ball up a tower on a cart that was secretly controlled by magnetic force. The preschoolers were randomly allocated into experimental arms that either had to make prediction about their own performance or about the performance of a gender-matched child who played the same game on TV. Both arms included three groups receiving incentives in the form of marbles, explicit feedback regarding their past “performance” (which could not be influenced by the participants), or no intervention (i.e., control condition). If incentivized, mean predictions between self and others did not differ. However, if participants did not receive any intervention, their own future performance was perceived to be superior to the outcome of the other child. The reverse is true when preschoolers were explicitly reminded about their past performance. Yet, small intragroup sample sizes of 10 participants and a notable absence of influence on the actual outcome, diminish the generalizability of the findings. Powel and colleagues 14 asked 22 children (aged 4; 2–6; 9) to provide confidence estimates about their ability to throw 10 beanbags into a basket. All participants showed overconfidence in their throwing skills, but accuracy seems to improve with age. Lastly, Lagatutta and Sayfan 15 used a narrative of positive, negative, or ambiguous events to assess attitude and predictions of 265 children (mean age 4; 6–8; 11) and adults (mean age 20; 0). Contrary to previous studies, the results suggested that unjustifiable confidence in past events with limited information value increased with age. A possible explanation for these conflicting results may be found in the underlying experimental tasks. The former studies that reported a decrease of the bias with age utilize physically executable tasks (e.g., lifting a metal ball, throwing beanbags, etc.) while the latter work relied on an abstract assessment of a future event that required a judgment under uncertainty without any physically executable actions. Prior research suggests that overconfidence is domain specific which might explain<|im_end|> <|im_start|>assistant Overconfidence in one's own abilities despite clear evidence to the contrary is present and persistent in children as young as four, a new study by the University of Sussex Business School has revealed. The cognitive bias has been consistently observed among a number of professions including business executives, bankers and physicians across different countries and cultures but a new study led by Dr. Dominik Piehlmaier indicates that overconfidence is persistent and widespread during early childhood. The research also found that girls were more successful than boys at a card game in the study thanks to a more low-risk strategy but also experienced greater swings between overconfidence and lack of confidence in their abilities. Dr. Dominik Piehlmaier, Lecturer in Marketing at the University of Sussex Business School and the study's author, said: "Much of our knowledge on judgment and decision-making is based on adult participants but there is no reason to believe that humans only develop such an omnipresent cognitive illusion once we reach adulthood. "My findings indicate that effective interventions that increase an individual's knowledge about their own knowledge and its boundaries might be needed to target much younger individuals if one wants to efficiently calibrate a person's irrational confidence." In the study, children were asked to play a card game known as the Children's Gambling Task where they choose cards from one of two packs. The card is then turned over to reveal how many stickers the participant has won and lost. One pack had cards with significantly higher wins and losses than the other. At intervals, children had to decide whether they thought they would win more, about the same, or fewer stickers than previously in the game. Each participant started off with four stickers after the initial six practice trials. On average, every participant gained 0.3 stickers per turn and left the game with an average of 6.67 stickers, ranging from zero to 33. The study showed that more than 70% of four-year-olds and half of all five and six-year-olds were overconfident in their expectations after playing ten turns and six practice trials. Dr. Piehlmaier said: "A vast number of repetitions, learning, and feedback in the study did not diminish the misplaced confidence in the success of the majority of participants. "The children played more than 60 turns and saw their payoff balance rose and fell, yet every third child still thought that they could do better than they had done in the previous 50 turns. "The Children's Gambling Task closely resembles a very simplified version of the financial markets with relatively safe options providing low but steady average return rates and highly risky assets that promise much higher short-term gains with a catastrophic long-term yield. "The finding that overconfidence is persistent even in the face of own shortcomings mirrors results from previous studies that looked at the performance of investors." Overconfidence is widely seen as a male trait but the study also had interesting findings when it came to the general performance of boys and girls. In general, girls outperformed boys by an average of 2.87 stickers thanks to a less high-risk strategy of choosing relatively more safe cards which offered smaller but more sustainable gains. Dr. Piehlmaier added: "Boys seem to follow a negative trend line that indicates slow but steady learning on what might be considered 'reasonable expectations'. "Girls' behaviour is much more unpredictable. When the girls' overconfidence plot is compared to their payoffs, it can be noticed that they closely align. "This indicates that girls overestimate their abilities if they have a winning streak and underestimate themselves whenever they lose a few times in a row. "By the end of the experiment, there were relatively more overconfident girls than boys; a finding that contradicts previous reports regarding more calibrated girls in metamemory tasks." <|im_end|>

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2,056

[ { "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 Natural and anthropogenic disasters can have long-lasting impacts on the genetics and structure of impacted populations. The 1986 Chernobyl Nuclear Power Plant disaster led to extensive contamination of the local environment and the wildlife therein. Several ecological, environmental, and genetic studies reported various effects of this disaster on animal, insect, and plant species; however, little work has been done to investigate the genetics of the free-breeding dogs that occupy the Chernobyl Exclusion Zone (CEZ). Results We define the population genetic structure of two groups of dogs that reside within the CEZ, one around the reactor site itself and another living within Chernobyl City. We found little evidence of gene flow and a significant degree of genetic differentiation between the two populations dogs, suggesting that these are two distinct populations despite occupying areas located just 16 km apart. With an F ST -based outlier analysis, we then performed a genome-wide scan for evidence of directional selection within the dog populations. We found 391 outlier loci associated with genomic regions influenced by directional selection, from which we identified 52 candidate genes. Conclusions Our genome scan highlighted outlier loci within or near genomic regions under directional selection, possibly in response to the multi-generational exposure faced. In defining the population structure and identifying candidate genes for these dog populations, we take steps towards understanding how these types of prolonged exposures have impacted these populations. Plain English Summary Wildlife populations can be greatly affected by disasters, whether they are natural or man-made. Disasters that result in contamination or habitat destruction can result in population declines or influence wildlife adaptation to these adverse environmental changes. The Chernobyl nuclear power plant disaster released an enormous quantity of ionizing radiation into the surrounding environment. Abandonment of military and industrial facilities, as well as subsequent cleanup and remediation efforts, resulted in further environmental contamination by a variety of non-radioactive toxic metals, chemicals, and compounds. Earlier studies investigated local wildlife responses to some of these exposures. In this study, we address the impact of this disaster on the population structure of free-breeding dogs that live around the power plant and in the nearby city of Chernobyl. In particular, we use genetic approaches to understand how these two populations of dogs interact and their breed composition, so that we may begin to understand how these populations have adapted to over 30 years of exposure to this harsh environment. In this foundational study we determined that while the two local populations of dogs are separated by only 16 km, they have very low rates of interpopulation migration. We also detected genetic evidence that suggests that these population may have adapted to exposures faced over many generations. In future studies, we aim to determine if the genetic variation detected is indeed a biological response to enable survival after multi-generational exposures to radiation, heavy metals, organic toxins, or other environmental contaminants. In this way, we then understand how the impact of environmental catastrophes such as the Chernobyl nuclear disaster can influence animal populations. Background Large-scale disasters, both natural and anthropogenic, can have multiple direct and indirect impacts on wildlife populations. Natural disasters such as tornadoes, volcanic eruptions, and hurricanes, as well as man-made disasters such as oil spills, chemical leaks, and nuclear accidents can have detrimental impacts on local species, lasting for months or even years after the incident [ 1 , 2 , 3 , 4 ]. Environmental contamination, habitat destruction, and other stressors brought on by disasters can shape the local wildlife populations quickly, especially when the ecological changes can be extreme. These stressors can prompt changes in the genetic population structure, including loss of genetic diversity or selective sweeps. For example, drastic changes such as pollution of the local environment can induce rapid evolution, as evidenced by adaptive toxicant resistance in Gulf killifish [ 5 ]. Carcinogenic contaminants can also have direct impacts on the DNA of individuals in the population, such as inducing deleterious point mutations or chromosomal rearrangements [ 6 , 7 ]. One such disaster with lasting effects was the nuclear disaster in the former Soviet Union at the Chernobyl Nuclear Power Plant (CNPP) on April 26, 1986. This catastrophe resulted in the release of over 5,000 petabecquerels (PBq) of radioisotopes, including 134-Iodine, 90-Strontium and 137-Cesium, into the surrounding environment [ 8 ]. Within 48 h of the accident, tens of thousands of residents from nearby towns and villages were evacuated. An area of approximately 700 km 2 (~ 30 km radius from the power plant) that spans regions of northeastern Ukraine and southern Belarus was established as the Chernobyl Exclusion Zone (CEZ). Heavy metals, organics, and other environmental toxins left behind following decontamination and remediation efforts, along with the abandonment of military bases and industrial complexes, contributes to ongoing contamination of the locale [ 9 , 10 , 11 , 12 ]. About 150,000 km 2 of land throughout Ukraine, Belarus, and Russia, and especially in the area surrounding the now decommissioned reactors of the CNPP, remains contaminated and predominantly abandoned, other than a few remaining elderly residents [ 13 ]. Though 36 years have passed, the roughly 30-year half-life of the predominant radionuclides, 137-Cs and 90-Sr, means that the threat posed by radioactive contamination will continue for another century. Some areas, especially regions of the former “Red Forest”, remain significantly more contaminated than others. In addition, spontaneous periodic wildfires near the power plant contribute to resuspension of radionuclides and these events are likely to continue [ 14 ]. The Russian army occupation of the CNPP in Spring 2022 also led to soil disturbances and a reported increase in radioactivity from around 1 millisievert (mSv) per year to 6.5 mSv/yr in the immediate vicinity of the CNPP, although this increase does not warrant a threat to public health according to a recent assessment by the International Atomic Energy Agency (IAEA) assessment [ 13 , 15 ]. The potential of natural disasters and anthropogenic disturbances to increase the local radioactivity raises concern about our understanding of", "role": "user" }, { "content": "In the first step toward understanding how dogs—and perhaps humans—might adapt to intense environmental pressures such as exposure to radiation, heavy metals, or toxic chemicals, researchers have found that two groups of dogs living within the Chernobyl Exclusion Zone, one at the site of the former Chernobyl reactors, and another 16.5 km away in Chernobyl City, showed significant genetic differences between them. The results indicate that these are two distinct populations that rarely interbreed. While earlier studies focused on the effects of the Chernobyl Nuclear Power Plant disaster on various species of wildlife, this is the first investigation into the genetic structure of stray dogs living near the Chernobyl nuclear power plant. The 1986 Chernobyl nuclear power plant disaster displaced more than 300,000 people living nearby and led to the establishment of an Exclusion Zone, a \"no man's land\" of an approximately 30 km radius surrounding the damaged reactor complex. While a massive steam explosion releasing enormous amounts of ionizing radiation into the air, water, and soil was the direct cause of the catastrophe, radiation exposure is not the only environmental hazard resulting from the disaster. Chemicals, toxic metals, pesticides, and organic compounds left behind by years-long cleanup efforts and from abandoned and decaying structures, including the nearby abandoned city of Pripyat and the Duga-1 military base, all contribute to an ecological and environmental disaster. \"Somehow, two small populations of dogs managed to survive in that highly toxic environment,\" noted Norman J. Kleiman, Ph.D., assistant professor of Environmental Health Sciences at Columbia Mailman School of Public Health, and a co-author. \"In addition to classifying the population dynamics within these dogs at both locations, we took the first steps towards understanding how chronic exposure to multiple environmental hazards may have impacted these populations.\" \"The overarching question here is: does an environmental disaster of this magnitude have a genetic impact on life in the region?\" says Matthew Breen, Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics at NC State, and a corresponding author. \"And we have two populations of dogs living at and near the site of a major environmental disaster that may provide key information to help us answer that question.\" Earlier research by the co-authors, led by collaborators at NIH, used a much smaller set of genetic variants, but a larger number of dogs, to show that the two populations were separate and that each had complicated family structures. In this parallel study, the team analyzed the dog DNA samples with four times the number of genetic variants, which provided a closer look at the genomes. In addition to confirming that the two populations are indeed genetically distinct, the team were also able to identify 391 outlier regions in the genomes of the dogs that differed between dogs living at the two locations. \"Think of these regions as markers, or signposts, on a highway,\" Breen says. \"They identify areas within the genome where we should look more closely at nearby genes. Moreover, some of these markers are pointing to genes associated with genetic repair; specifically, with genetic repair after exposures similar to those experienced by the dogs in Chernobyl.\" He went on to say \"at this stage we cannot say for sure that any genetic alterations are in response to the multigenerational and complex exposures; we have a lot more work to do to determine if that is the case\" \"The question we must answer now are why are there striking genetic differences between the two dog populations?\" says Megan Dillion, Ph.D. candidate at NC State and a lead author of the published study. \"Are the differences just due to genetic drift, or are they due to the unique environmental stressors at each location?\" \"The dog is a sentinel species,\" Breen says. \"By and teasing out whether or not the genetic changes we detected in these dogs are the canine genome's response to the exposures the populations have faced, we may be able to understand how the dogs survived in such a hostile environment and what that might mean for any population—animal or human—that experiences similar exposures.\" \"Though 37 years have passed since the accident, the ~30-year-long half-lives of lingering radioisotopes means the danger posed by radiation exposure is still very much real,\" notes Kleiman, who is also director of the Columbia University Radiation Safety Officer Training course. \"When radiation exposure is combined with a complex toxic chemical mixture of uncertain composition, there are very real human health concerns raised for the thousands of people who continue to work within the Exclusion Zone on continuing cleanup efforts as well as at two newly constructed nuclear fuel reprocessing plants.\" \"Understanding the genetic and health impacts of these chronic exposures in the dogs will strengthen our broader understanding of how these types of environmental hazards can impact humans and how best to mitigate health risks.\" The research appears in Canine Medicine and Genetics. ", "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 Natural and anthropogenic disasters can have long-lasting impacts on the genetics and structure of impacted populations. The 1986 Chernobyl Nuclear Power Plant disaster led to extensive contamination of the local environment and the wildlife therein. Several ecological, environmental, and genetic studies reported various effects of this disaster on animal, insect, and plant species; however, little work has been done to investigate the genetics of the free-breeding dogs that occupy the Chernobyl Exclusion Zone (CEZ). Results We define the population genetic structure of two groups of dogs that reside within the CEZ, one around the reactor site itself and another living within Chernobyl City. We found little evidence of gene flow and a significant degree of genetic differentiation between the two populations dogs, suggesting that these are two distinct populations despite occupying areas located just 16 km apart. With an F ST -based outlier analysis, we then performed a genome-wide scan for evidence of directional selection within the dog populations. We found 391 outlier loci associated with genomic regions influenced by directional selection, from which we identified 52 candidate genes. Conclusions Our genome scan highlighted outlier loci within or near genomic regions under directional selection, possibly in response to the multi-generational exposure faced. In defining the population structure and identifying candidate genes for these dog populations, we take steps towards understanding how these types of prolonged exposures have impacted these populations. Plain English Summary Wildlife populations can be greatly affected by disasters, whether they are natural or man-made. Disasters that result in contamination or habitat destruction can result in population declines or influence wildlife adaptation to these adverse environmental changes. The Chernobyl nuclear power plant disaster released an enormous quantity of ionizing radiation into the surrounding environment. Abandonment of military and industrial facilities, as well as subsequent cleanup and remediation efforts, resulted in further environmental contamination by a variety of non-radioactive toxic metals, chemicals, and compounds. Earlier studies investigated local wildlife responses to some of these exposures. In this study, we address the impact of this disaster on the population structure of free-breeding dogs that live around the power plant and in the nearby city of Chernobyl. In particular, we use genetic approaches to understand how these two populations of dogs interact and their breed composition, so that we may begin to understand how these populations have adapted to over 30 years of exposure to this harsh environment. In this foundational study we determined that while the two local populations of dogs are separated by only 16 km, they have very low rates of interpopulation migration. We also detected genetic evidence that suggests that these population may have adapted to exposures faced over many generations. In future studies, we aim to determine if the genetic variation detected is indeed a biological response to enable survival after multi-generational exposures to radiation, heavy metals, organic toxins, or other environmental contaminants. In this way, we then understand how the impact of environmental catastrophes such as the Chernobyl nuclear disaster can influence animal populations. Background Large-scale disasters, both natural and anthropogenic, can have multiple direct and indirect impacts on wildlife populations. Natural disasters such as tornadoes, volcanic eruptions, and hurricanes, as well as man-made disasters such as oil spills, chemical leaks, and nuclear accidents can have detrimental impacts on local species, lasting for months or even years after the incident [ 1 , 2 , 3 , 4 ]. Environmental contamination, habitat destruction, and other stressors brought on by disasters can shape the local wildlife populations quickly, especially when the ecological changes can be extreme. These stressors can prompt changes in the genetic population structure, including loss of genetic diversity or selective sweeps. For example, drastic changes such as pollution of the local environment can induce rapid evolution, as evidenced by adaptive toxicant resistance in Gulf killifish [ 5 ]. Carcinogenic contaminants can also have direct impacts on the DNA of individuals in the population, such as inducing deleterious point mutations or chromosomal rearrangements [ 6 , 7 ]. One such disaster with lasting effects was the nuclear disaster in the former Soviet Union at the Chernobyl Nuclear Power Plant (CNPP) on April 26, 1986. This catastrophe resulted in the release of over 5,000 petabecquerels (PBq) of radioisotopes, including 134-Iodine, 90-Strontium and 137-Cesium, into the surrounding environment [ 8 ]. Within 48 h of the accident, tens of thousands of residents from nearby towns and villages were evacuated. An area of approximately 700 km 2 (~ 30 km radius from the power plant) that spans regions of northeastern Ukraine and southern Belarus was established as the Chernobyl Exclusion Zone (CEZ). Heavy metals, organics, and other environmental toxins left behind following decontamination and remediation efforts, along with the abandonment of military bases and industrial complexes, contributes to ongoing contamination of the locale [ 9 , 10 , 11 , 12 ]. About 150,000 km 2 of land throughout Ukraine, Belarus, and Russia, and especially in the area surrounding the now decommissioned reactors of the CNPP, remains contaminated and predominantly abandoned, other than a few remaining elderly residents [ 13 ]. Though 36 years have passed, the roughly 30-year half-life of the predominant radionuclides, 137-Cs and 90-Sr, means that the threat posed by radioactive contamination will continue for another century. Some areas, especially regions of the former “Red Forest”, remain significantly more contaminated than others. In addition, spontaneous periodic wildfires near the power plant contribute to resuspension of radionuclides and these events are likely to continue [ 14 ]. The Russian army occupation of the CNPP in Spring 2022 also led to soil disturbances and a reported increase in radioactivity from around 1 millisievert (mSv) per year to 6.5 mSv/yr in the immediate vicinity of the CNPP, although this increase does not warrant a threat to public health according to a recent assessment by the International Atomic Energy Agency (IAEA) assessment [ 13 , 15 ]. The potential of natural disasters and anthropogenic disturbances to increase the local radioactivity raises concern about our understanding of<|im_end|> <|im_start|>assistant In the first step toward understanding how dogs—and perhaps humans—might adapt to intense environmental pressures such as exposure to radiation, heavy metals, or toxic chemicals, researchers have found that two groups of dogs living within the Chernobyl Exclusion Zone, one at the site of the former Chernobyl reactors, and another 16.5 km away in Chernobyl City, showed significant genetic differences between them. The results indicate that these are two distinct populations that rarely interbreed. While earlier studies focused on the effects of the Chernobyl Nuclear Power Plant disaster on various species of wildlife, this is the first investigation into the genetic structure of stray dogs living near the Chernobyl nuclear power plant. The 1986 Chernobyl nuclear power plant disaster displaced more than 300,000 people living nearby and led to the establishment of an Exclusion Zone, a "no man's land" of an approximately 30 km radius surrounding the damaged reactor complex. While a massive steam explosion releasing enormous amounts of ionizing radiation into the air, water, and soil was the direct cause of the catastrophe, radiation exposure is not the only environmental hazard resulting from the disaster. Chemicals, toxic metals, pesticides, and organic compounds left behind by years-long cleanup efforts and from abandoned and decaying structures, including the nearby abandoned city of Pripyat and the Duga-1 military base, all contribute to an ecological and environmental disaster. "Somehow, two small populations of dogs managed to survive in that highly toxic environment," noted Norman J. Kleiman, Ph.D., assistant professor of Environmental Health Sciences at Columbia Mailman School of Public Health, and a co-author. "In addition to classifying the population dynamics within these dogs at both locations, we took the first steps towards understanding how chronic exposure to multiple environmental hazards may have impacted these populations." "The overarching question here is: does an environmental disaster of this magnitude have a genetic impact on life in the region?" says Matthew Breen, Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics at NC State, and a corresponding author. "And we have two populations of dogs living at and near the site of a major environmental disaster that may provide key information to help us answer that question." Earlier research by the co-authors, led by collaborators at NIH, used a much smaller set of genetic variants, but a larger number of dogs, to show that the two populations were separate and that each had complicated family structures. In this parallel study, the team analyzed the dog DNA samples with four times the number of genetic variants, which provided a closer look at the genomes. In addition to confirming that the two populations are indeed genetically distinct, the team were also able to identify 391 outlier regions in the genomes of the dogs that differed between dogs living at the two locations. "Think of these regions as markers, or signposts, on a highway," Breen says. "They identify areas within the genome where we should look more closely at nearby genes. Moreover, some of these markers are pointing to genes associated with genetic repair; specifically, with genetic repair after exposures similar to those experienced by the dogs in Chernobyl." He went on to say "at this stage we cannot say for sure that any genetic alterations are in response to the multigenerational and complex exposures; we have a lot more work to do to determine if that is the case" "The question we must answer now are why are there striking genetic differences between the two dog populations?" says Megan Dillion, Ph.D. candidate at NC State and a lead author of the published study. "Are the differences just due to genetic drift, or are they due to the unique environmental stressors at each location?" "The dog is a sentinel species," Breen says. "By and teasing out whether or not the genetic changes we detected in these dogs are the canine genome's response to the exposures the populations have faced, we may be able to understand how the dogs survived in such a hostile environment and what that might mean for any population—animal or human—that experiences similar exposures." "Though 37 years have passed since the accident, the ~30-year-long half-lives of lingering radioisotopes means the danger posed by radiation exposure is still very much real," notes Kleiman, who is also director of the Columbia University Radiation Safety Officer Training course. "When radiation exposure is combined with a complex toxic chemical mixture of uncertain composition, there are very real human health concerns raised for the thousands of people who continue to work within the Exclusion Zone on continuing cleanup efforts as well as at two newly constructed nuclear fuel reprocessing plants." "Understanding the genetic and health impacts of these chronic exposures in the dogs will strengthen our broader understanding of how these types of environmental hazards can impact humans and how best to mitigate health risks." The research appears in Canine Medicine and Genetics. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As use and availability of mobile health apps have increased, so too has the need for a thorough, accessible framework for app evaluation. The American Psychiatric Association’s app evaluation model has emerged as a way to critically assess an app by considering accessibility, privacy and security, clinical foundation, engagement, and interoperability; however, there is no centralized database where users can view how various health apps perform when assessed via the APA model. In this perspective, we propose and outline our effort to translate the APA’s model for the evaluation of health apps into a set of objective metrics that can be published online, making the framework actionable and accessible to a broad audience. The questions from the APA model were operationalized into 105 objective questions that are either binary or numeric. These questions serve as the foundation of an online database, where app evaluation consists of answering these 105 questions and can be crowdsourced. While the database has yet to be published and crowdsourced, initial internal testing demonstrated excellent interrater reliability. The database proposed here introduces a public and interactive approach to data collection that is guided by the APA model. The published product enables users to sort through the many mobile health apps and filter them according to individual preferences and priorities, making the ever-growing health app market more navigable. The need for a comprehensive app evaluation framework The need for accessible mental healthcare is more urgent than ever. For example, in 2016, mental health conditions impacted more than a billion people worldwide and depression in 2020 is recognized by the World Health Organization as a leading global cause of disability 1 . Despite efforts to improve access, significant disparities in access to mental healthcare persist in every country in the world. In recent years, digital health interventions such as smartphone apps have emerged as potentially cost-effective, evidence-based, and scalable tools to expand access to mental healthcare worldwide. The proliferation of healthcare apps, potentiated by expanding smartphone ownership and internet connectivity 2 , has been rapid: there are already an estimated 350,000 health apps with 10,000 focused on mental health 3 . Yet, despite the vast numbers of mobile apps available, the adoption of these tools is variable, with associated challenges within the context of standardization, provider, and patient levels. The marketplace of mental health apps continues to grow and change at a rapid pace, prompting questions about how to assess quality and effectiveness. Given the dynamic nature of the digital health app space, it is difficult for service users, peer support specialists, and clinical providers alike to stay updated and ensure that apps are safe, evidence based, usable, and clinically meaningful. As an example of the challenge, a clinically relevant app for depression becomes unavailable and deleted from the app stores every 2.9 days 4 . Providers seeking to utilize apps to support patient management have reservations in recommending apps as a treatment given the limited oversight and accountability that exists with any one app 5 . Complicating matters further, for the general public today, healthcare providers are not the main source of information regarding health apps—individuals are more likely to rely upon app store reviews and rankings to decide on an app for health 6 . However, these app store rankings are marketing metrics not aligned with clinical guidelines or utility 7 . There are mounting concerns about quality and safety even among top-ranked apps in the commercial marketplaces 8 . Despite broad regulatory efforts in the digital health space, health apps have largely escaped oversight. The US Food and Drug Administration (FDA) released a set of guidelines for regulating mobile medical apps in 2015 9 . The guidelines impose a thorough set of standards, including those for labeling, medical claims, safety, and effectiveness. Because most apps are categorized as “health and wellness” apps, however, they are not designated as medical devices and thus fall outside the purview of these FDA guidelines. Those which may be medical apps have utilized the regulatory discretion pathway to avoid scrutiny. The app stores, which have emerged as the major sources of information in the absence of FDA assessment, are ill-equipped to provide the thorough expert analysis of accreditation in their current format of user rankings and reviews. Various app ranking models have emerged to fill this void and provide a source of clarity and objectivity in app evaluation. Although there are now upwards of forty-five different frameworks for the evaluation of mobile apps, none of the existing frameworks are suitable for use in health technology assessment (HTA) to inform policymakers, individuals, and providers because they neglect to evaluate both the potential for harm and the effect of software updates 10 . Many of these ranking systems rely upon expert consensus, which can be opaque and difficult to understand for both users and clinicians. Furthermore, there is still significant inconsistency in their outcomes. For example, a study of three different ranking systems (Psyberguide, ORCHA, MindTools.io) demonstrated a lack of correspondence in evaluating top apps, with Fleiss’ Exact Kappa scores for three domains ranging from 0.147 (for data use and security) to 0.228 (for credibility and evidence base), indicating weak reliability 11 . As a potential solution, the FDA has amended its effort towards evaluation of mobile health apps, adopting a “Pre-Certification” model that will focus efforts on app developers more than the evaluation of individual apps themselves 12 . While the FDA’s Pre-cert initiative holds promise, it is already the topic of political debate and proving its utility, as well as engaging developers may prove to be a slow process. In the meantime, there is a necessity for a framework tailored to clinicians and individuals’ needs today as they determine what apps suit their needs. We sought to develop a framework for the assessment of health apps that would augment available evaluation models and help individuals harness the potential of digital health by choosing a relevant, safe, and effective app. This model was developed in collaboration with the American Psychiatric", "role": "user" }, { "content": "About one in five U.S. adults, an estimated 47 million people, lives with a mental illness. Fewer than half of them receive treatment, counseling or medication. In recent years, smartphone apps have emerged as potentially cost-effective means of expanding access to mental healthcare. But with some 10,000 mental health apps—which are not subject to FDA oversight—available in mobile app stores today, the task of determining which apps are safe and effective can seem overwhelming to patients and providers alike. Now, researcher-clinicians from Beth Israel Deaconess Medical Center (BIDMC) and Lahey Hospital and Medical Center, both part of Beth Israel Lahey Health, have collaborated to develop an online assessment tool , currently available in its beta version, to help patients and providers make more informed decisions about choosing and using a mental health app. The 105-question interactive tool does not endorse or recommend specific apps, but rather helps potential users weigh apps' safety, ease of use, and commitment to user privacy, the scientists re-ported in npj Digital Medicine. \"The absence of regulatory oversight leaves the app stores' user reviews and rankings as the major sources of information for consumers interested in mental health apps,\" said corresponding author John Torous, MD, Direc-tor of Digital Psychiatry at Beth Israel Deaconess Medical Center. \"To fill that void, we developed a database of mental health apps that is grounded in principles of medical ethics. Rather than focusing on what is the 'best' app we aim to help people find one that is the 'best match\" through guiding them through informed decision making.\" The largest database of its kind, the assessment tool currently features more than 200 apps and allows users to easily filter and find apps by the criteria that matter most to them. The six-step, 105-question interactive tool—developed in collaboration with the American Psychiatry Association (APA)—incorporates concepts from nearly 1,000 questions from 45 existing but non-standardized app evaluation frameworks. By boiling these concepts down to just 105 questions with yes/no or numeric answers, the assessment provides objective guidance that allow users to sort and filter mental health apps according to individual preferences and priorities. \"We remain focused on growing the database to encompass more apps and more diseases and to enhance the user experience for patients and providers,\" said Patrick Aquino, MD, Chair, Division of Psychiatry & Behavioral Medicine, Lahey Hospital & Medical Center. \"This collaborative effort shows what is possible through our new health 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 As use and availability of mobile health apps have increased, so too has the need for a thorough, accessible framework for app evaluation. The American Psychiatric Association’s app evaluation model has emerged as a way to critically assess an app by considering accessibility, privacy and security, clinical foundation, engagement, and interoperability; however, there is no centralized database where users can view how various health apps perform when assessed via the APA model. In this perspective, we propose and outline our effort to translate the APA’s model for the evaluation of health apps into a set of objective metrics that can be published online, making the framework actionable and accessible to a broad audience. The questions from the APA model were operationalized into 105 objective questions that are either binary or numeric. These questions serve as the foundation of an online database, where app evaluation consists of answering these 105 questions and can be crowdsourced. While the database has yet to be published and crowdsourced, initial internal testing demonstrated excellent interrater reliability. The database proposed here introduces a public and interactive approach to data collection that is guided by the APA model. The published product enables users to sort through the many mobile health apps and filter them according to individual preferences and priorities, making the ever-growing health app market more navigable. The need for a comprehensive app evaluation framework The need for accessible mental healthcare is more urgent than ever. For example, in 2016, mental health conditions impacted more than a billion people worldwide and depression in 2020 is recognized by the World Health Organization as a leading global cause of disability 1 . Despite efforts to improve access, significant disparities in access to mental healthcare persist in every country in the world. In recent years, digital health interventions such as smartphone apps have emerged as potentially cost-effective, evidence-based, and scalable tools to expand access to mental healthcare worldwide. The proliferation of healthcare apps, potentiated by expanding smartphone ownership and internet connectivity 2 , has been rapid: there are already an estimated 350,000 health apps with 10,000 focused on mental health 3 . Yet, despite the vast numbers of mobile apps available, the adoption of these tools is variable, with associated challenges within the context of standardization, provider, and patient levels. The marketplace of mental health apps continues to grow and change at a rapid pace, prompting questions about how to assess quality and effectiveness. Given the dynamic nature of the digital health app space, it is difficult for service users, peer support specialists, and clinical providers alike to stay updated and ensure that apps are safe, evidence based, usable, and clinically meaningful. As an example of the challenge, a clinically relevant app for depression becomes unavailable and deleted from the app stores every 2.9 days 4 . Providers seeking to utilize apps to support patient management have reservations in recommending apps as a treatment given the limited oversight and accountability that exists with any one app 5 . Complicating matters further, for the general public today, healthcare providers are not the main source of information regarding health apps—individuals are more likely to rely upon app store reviews and rankings to decide on an app for health 6 . However, these app store rankings are marketing metrics not aligned with clinical guidelines or utility 7 . There are mounting concerns about quality and safety even among top-ranked apps in the commercial marketplaces 8 . Despite broad regulatory efforts in the digital health space, health apps have largely escaped oversight. The US Food and Drug Administration (FDA) released a set of guidelines for regulating mobile medical apps in 2015 9 . The guidelines impose a thorough set of standards, including those for labeling, medical claims, safety, and effectiveness. Because most apps are categorized as “health and wellness” apps, however, they are not designated as medical devices and thus fall outside the purview of these FDA guidelines. Those which may be medical apps have utilized the regulatory discretion pathway to avoid scrutiny. The app stores, which have emerged as the major sources of information in the absence of FDA assessment, are ill-equipped to provide the thorough expert analysis of accreditation in their current format of user rankings and reviews. Various app ranking models have emerged to fill this void and provide a source of clarity and objectivity in app evaluation. Although there are now upwards of forty-five different frameworks for the evaluation of mobile apps, none of the existing frameworks are suitable for use in health technology assessment (HTA) to inform policymakers, individuals, and providers because they neglect to evaluate both the potential for harm and the effect of software updates 10 . Many of these ranking systems rely upon expert consensus, which can be opaque and difficult to understand for both users and clinicians. Furthermore, there is still significant inconsistency in their outcomes. For example, a study of three different ranking systems (Psyberguide, ORCHA, MindTools.io) demonstrated a lack of correspondence in evaluating top apps, with Fleiss’ Exact Kappa scores for three domains ranging from 0.147 (for data use and security) to 0.228 (for credibility and evidence base), indicating weak reliability 11 . As a potential solution, the FDA has amended its effort towards evaluation of mobile health apps, adopting a “Pre-Certification” model that will focus efforts on app developers more than the evaluation of individual apps themselves 12 . While the FDA’s Pre-cert initiative holds promise, it is already the topic of political debate and proving its utility, as well as engaging developers may prove to be a slow process. In the meantime, there is a necessity for a framework tailored to clinicians and individuals’ needs today as they determine what apps suit their needs. We sought to develop a framework for the assessment of health apps that would augment available evaluation models and help individuals harness the potential of digital health by choosing a relevant, safe, and effective app. This model was developed in collaboration with the American Psychiatric<|im_end|> <|im_start|>assistant About one in five U.S. adults, an estimated 47 million people, lives with a mental illness. Fewer than half of them receive treatment, counseling or medication. In recent years, smartphone apps have emerged as potentially cost-effective means of expanding access to mental healthcare. But with some 10,000 mental health apps—which are not subject to FDA oversight—available in mobile app stores today, the task of determining which apps are safe and effective can seem overwhelming to patients and providers alike. Now, researcher-clinicians from Beth Israel Deaconess Medical Center (BIDMC) and Lahey Hospital and Medical Center, both part of Beth Israel Lahey Health, have collaborated to develop an online assessment tool , currently available in its beta version, to help patients and providers make more informed decisions about choosing and using a mental health app. The 105-question interactive tool does not endorse or recommend specific apps, but rather helps potential users weigh apps' safety, ease of use, and commitment to user privacy, the scientists re-ported in npj Digital Medicine. "The absence of regulatory oversight leaves the app stores' user reviews and rankings as the major sources of information for consumers interested in mental health apps," said corresponding author John Torous, MD, Direc-tor of Digital Psychiatry at Beth Israel Deaconess Medical Center. "To fill that void, we developed a database of mental health apps that is grounded in principles of medical ethics. Rather than focusing on what is the 'best' app we aim to help people find one that is the 'best match" through guiding them through informed decision making." The largest database of its kind, the assessment tool currently features more than 200 apps and allows users to easily filter and find apps by the criteria that matter most to them. The six-step, 105-question interactive tool—developed in collaboration with the American Psychiatry Association (APA)—incorporates concepts from nearly 1,000 questions from 45 existing but non-standardized app evaluation frameworks. By boiling these concepts down to just 105 questions with yes/no or numeric answers, the assessment provides objective guidance that allow users to sort and filter mental health apps according to individual preferences and priorities. "We remain focused on growing the database to encompass more apps and more diseases and to enhance the user experience for patients and providers," said Patrick Aquino, MD, Chair, Division of Psychiatry & Behavioral Medicine, Lahey Hospital & Medical Center. "This collaborative effort shows what is possible through our new health system." <|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 Carbon monoxide as an endogenous signaling molecule exhibits pharmacological efficacy in various animal models of organ injury. To address the difficulty in using CO gas as a therapeutic agent for widespread applications, we are interested in developing CO prodrugs through bioreversible caging of CO in an organic compound. Specifically, we have explored the decarboxylation–decarbonylation chemistry of 1,2-dicarbonyl compounds. Examination and optimization of factors favorable for maximal CO release under physiological conditions led to organic CO prodrugs using non-calorific sweeteners as leaving groups attached to the 1,2-dicarbonyl core. Attaching a leaving group with appropriate properties promotes the desired hydrolysis–decarboxylation–decarbonylation sequence of reactions that leads to CO generation. One such CO prodrug was selected to recapitulate the anti-inflammatory effects of CO against LPS-induced TNF-α production in cell culture studies. Oral administration in mice elevated COHb levels to the safe and efficacious levels established in various preclinical and clinical studies. Furthermore, its pharmacological efficacy was demonstrated in mouse models of acute kidney injury. These studies demonstrate the potential of these prodrugs with benign carriers as orally active CO-based therapeutics. This represents the very first example of orally active organic CO prodrugs with a benign carrier that is an FDA-approved sweetener with demonstrated safety profiles in vivo . This article is part of the themed collection: Most popular 2021 organic chemistry articles, 2021 Introduction With the firm establishment of carbon monoxide (CO) as an endogenous signaling molecule, there has been an increasing level of interest in developing CO-based therapeutics by taking advantage of its demonstrated cyto- and organ-protective effects. 1–3 Along this line, the organ protective effects of CO have been demonstrated in injury models of the kidneys, 4,5 lungs, 6 the gastrointestinal tract, 7,8 and the liver, 9 among others. Because of the gaseous nature of CO, the difficulty in delivering a gas as a therapeutic to patients, and the potential risks it poses to healthcare workers as well as patients in terms of accidental poisoning, there have been intense efforts in developing alternative delivery forms. 1,10,11 Earlier efforts focused on metal-based CO releasing molecules (CORMs), 1 photo-sensitive-organic CO donors, 11–13 CO in solution, 14,15 and CO immobilized on modified hemoglobin. 16 There are several reviews discussing in detail the various existing delivery forms of CO. 1,10,11 We are interested in developing organic CO prodrugs as donors for developing CO-based therapeutics as “CO in a pill” for eventual clinical applications. 17 Along this line, we 18 and Larsen's lab 19 developed cheletropic extrusion-based CO prodrugs with tunable release rates, triggered release, and the ability to target the mitochondria. 20 Fig. 1 shows some representative CO donors. In terms of drug-like features, each class has its own features that need improvement including metal reactivity for some metal-based CO-RMs ( Fig. 1A ), 21,22 high hydrophobicity for some of the organic prodrugs due to the presence of multiple aryl groups ( Fig. 1B ), 18 and the known and unknown toxicity of transition metals 23,24 and the organic “carrier” portions of the organic CO prodrugs. Fig. 1 Examples of CO donors that are activated by physiological stimuli – (A) ligand exchange from endogenous nucleophiles, and (B) exposure to an aqueous environment and/or at pH 7.4. In search of CO prodrugs with improved pharmaceutical properties, we are especially interested in those that use a “carrier” moiety with known safety profiles. Along this line, we look to known decarbonylation chemistry for our design. Several types of decarbonylation chemistry are known in synthetic chemistry in organic solvents, including decarbonylation of formic acid and its derivatives, α-hydroxyacid, 5-(hydroxymethyl)furfural 25,26 and other aldehydes and carbonyl-containing compounds. 27–33 However, most of these reactions happen under non-physiological conditions or require harsh acids, heating, or metal catalysis for CO release. In most cases, especially those that require metal catalysis, application under near physiological conditions is hard to achieve. The hydrolysis, decarboxylation, decarbonylation reaction sequence characteristic of 1,2-dicarbonyl compounds with appropriate leaving groups, presented an opportunity to install benign carriers as leaving groups. As a literature precedent, oxalyl chloride, one of the simplest 1,2-dicarbonyl compounds in the form of oxalates, is known to decompose in water to produce CO, HCl, and CO 2 through first hydrolysis of one acyl chloride, then decarboxylation, and finally decarbonylation to release CO ( Fig. 2A ). 34 Because of the reliability of this chemistry, oxalyl chloride has been used as a convenient CO gas donor in carbonylation reactions. 35,36 However, its use for biological and therapeutic applications presents significant challenges because of the release of HCl, and its corrosive and acutely toxic nature. 37 With CO fixed in the 1,2-dicarbonyl moieties, our goal was to design a new class of CO donors involving benign carriers ( Fig. 2B ). Fig. 2 (A) Decomposition of oxalyl chloride to produce CO. (B) Design of CO donors based on the hydrolysis, decarboxylation, decarbonylation chemistry of oxalyl derivatives. (C) Competing paths by which 1,2-dicarbonyl CO prodrugs can breakdown in aqueous solution – (i) a CO-generating pathway; (ii) non-CO producing pathway that generates oxalic acid as the product. Results and discussion Because of enhanced electrophilicity arising from vicinal keto groups, 1,2-dicarbonyl compounds with appropriate leaving groups are susceptible to hydrolysis, expelling one leaving group and generating a ketoacid intermediate ( Fig. 2C ). CO is generated once this ketoacid intermediate undergoes a decarboxylation–decarbonylation sequence of reactions. For oxalyl chloride, this path predominates and thus forms CO, CO 2 , and HCl as end-products when placed in water. However, when the chloride leaving group is replaced by other leaving groups, another decomposition path may compete with the CO generating path. 38,39 The ketoacid intermediate can undergo hydrolysis to expel the second leaving group and form oxalic acid without CO generation. Therefore, the identity of the leaving group must be carefully selected to tune the reaction in favor of the CO generating path. For understanding the basic chemistry and parameters that control the partitioning between the two pathways, chloride was replaced by various leaving groups having different p K a values to survey the", "role": "user" }, { "content": "An oral prodrug developed by a team of scientists led by Binghe Wang, Regents' Professor of Chemistry at Georgia State University, delivers carbon monoxide to protect against acute kidney injury, according to a new paper published in Chemical Science. Although carbon monoxide (CO) gas is toxic in large doses, scientists have discovered it can have beneficial effects by reducing inflammation and protecting cells against injury. Previous studies have demonstrated the protective effects of CO against injury in the kidneys, lungs, gastrointestinal tract and liver, among other organs. For the past five years, Wang and his collaborators have worked to design a safe way to deliver CO to human patients via prodrugs—inactive compounds that must undergo a chemical process in the body before releasing the active pharmacological agent. Wang's team developed prodrugs that allow for oral administration of CO using two common artificial sweeteners—saccharine (an ingredient in Sweet'N Low) and acesulfame (an ingredient in Splenda)—as 'carrier' molecules. They designed the molecules to release CO in the process of decomposition, which is triggered by exposure to water. These are the first examples of orally active, organic CO prodrugs using a benign carrier that is approved by the Food & Drug Administration with a demonstrated safety profile. \"It's difficult to deliver a gas, much less a poisonous gas, as a therapeutic to patients, and this work represents a pivotal step forward in developing alternative delivery forms,\" said Wang, senior author of the paper and a Georgia Research Alliance Eminent Scholar. \"We wanted to work with a carrier that has a very well characterized safety profile, which confers a higher degree of certainty that it will be safe to use in a pill for human consumption.\" Of the two prodrugs, the scientists tested one, CO-306, for pharmacological efficacy against acute kidney damage. The researchers administered CO-306, which uses saccharine as a carrier molecule, to mice and found it reduced biomarkers associated with kidney injury, indicating it could be developed into a viable therapy. The mouse model mimicked the mechanisms of kidney tissue damage that occur in patients with extensive muscle damage, sickle cell disease, a common type of malaria, cardiopulmonary bypass surgery and severe sepsis. Wang and his collaborators at Georgia State's Center for Diagnostics and Therapeutics, Vanderbilt University, Harvard Medical School and the University of Mississippi plan to conduct more extensive animal model studies and safety assessments on CO-306 before progressing to human clinical studies. They also plan to test CO-306 for efficacy against other types of organ injuries. Wang says CO-based therapies particularly hold promise as a method of reducing the likelihood of organ damage during transplantation and improving outcomes for transplant patients. \"Science shows that exposing organs to CO gas can help preserve organs and prevent them from deteriorating during the process of transplantation,\" he said. \"Now we need to demonstrate that these prodrugs can have a similar effect.\" ", "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 Carbon monoxide as an endogenous signaling molecule exhibits pharmacological efficacy in various animal models of organ injury. To address the difficulty in using CO gas as a therapeutic agent for widespread applications, we are interested in developing CO prodrugs through bioreversible caging of CO in an organic compound. Specifically, we have explored the decarboxylation–decarbonylation chemistry of 1,2-dicarbonyl compounds. Examination and optimization of factors favorable for maximal CO release under physiological conditions led to organic CO prodrugs using non-calorific sweeteners as leaving groups attached to the 1,2-dicarbonyl core. Attaching a leaving group with appropriate properties promotes the desired hydrolysis–decarboxylation–decarbonylation sequence of reactions that leads to CO generation. One such CO prodrug was selected to recapitulate the anti-inflammatory effects of CO against LPS-induced TNF-α production in cell culture studies. Oral administration in mice elevated COHb levels to the safe and efficacious levels established in various preclinical and clinical studies. Furthermore, its pharmacological efficacy was demonstrated in mouse models of acute kidney injury. These studies demonstrate the potential of these prodrugs with benign carriers as orally active CO-based therapeutics. This represents the very first example of orally active organic CO prodrugs with a benign carrier that is an FDA-approved sweetener with demonstrated safety profiles in vivo . This article is part of the themed collection: Most popular 2021 organic chemistry articles, 2021 Introduction With the firm establishment of carbon monoxide (CO) as an endogenous signaling molecule, there has been an increasing level of interest in developing CO-based therapeutics by taking advantage of its demonstrated cyto- and organ-protective effects. 1–3 Along this line, the organ protective effects of CO have been demonstrated in injury models of the kidneys, 4,5 lungs, 6 the gastrointestinal tract, 7,8 and the liver, 9 among others. Because of the gaseous nature of CO, the difficulty in delivering a gas as a therapeutic to patients, and the potential risks it poses to healthcare workers as well as patients in terms of accidental poisoning, there have been intense efforts in developing alternative delivery forms. 1,10,11 Earlier efforts focused on metal-based CO releasing molecules (CORMs), 1 photo-sensitive-organic CO donors, 11–13 CO in solution, 14,15 and CO immobilized on modified hemoglobin. 16 There are several reviews discussing in detail the various existing delivery forms of CO. 1,10,11 We are interested in developing organic CO prodrugs as donors for developing CO-based therapeutics as “CO in a pill” for eventual clinical applications. 17 Along this line, we 18 and Larsen's lab 19 developed cheletropic extrusion-based CO prodrugs with tunable release rates, triggered release, and the ability to target the mitochondria. 20 Fig. 1 shows some representative CO donors. In terms of drug-like features, each class has its own features that need improvement including metal reactivity for some metal-based CO-RMs ( Fig. 1A ), 21,22 high hydrophobicity for some of the organic prodrugs due to the presence of multiple aryl groups ( Fig. 1B ), 18 and the known and unknown toxicity of transition metals 23,24 and the organic “carrier” portions of the organic CO prodrugs. Fig. 1 Examples of CO donors that are activated by physiological stimuli – (A) ligand exchange from endogenous nucleophiles, and (B) exposure to an aqueous environment and/or at pH 7.4. In search of CO prodrugs with improved pharmaceutical properties, we are especially interested in those that use a “carrier” moiety with known safety profiles. Along this line, we look to known decarbonylation chemistry for our design. Several types of decarbonylation chemistry are known in synthetic chemistry in organic solvents, including decarbonylation of formic acid and its derivatives, α-hydroxyacid, 5-(hydroxymethyl)furfural 25,26 and other aldehydes and carbonyl-containing compounds. 27–33 However, most of these reactions happen under non-physiological conditions or require harsh acids, heating, or metal catalysis for CO release. In most cases, especially those that require metal catalysis, application under near physiological conditions is hard to achieve. The hydrolysis, decarboxylation, decarbonylation reaction sequence characteristic of 1,2-dicarbonyl compounds with appropriate leaving groups, presented an opportunity to install benign carriers as leaving groups. As a literature precedent, oxalyl chloride, one of the simplest 1,2-dicarbonyl compounds in the form of oxalates, is known to decompose in water to produce CO, HCl, and CO 2 through first hydrolysis of one acyl chloride, then decarboxylation, and finally decarbonylation to release CO ( Fig. 2A ). 34 Because of the reliability of this chemistry, oxalyl chloride has been used as a convenient CO gas donor in carbonylation reactions. 35,36 However, its use for biological and therapeutic applications presents significant challenges because of the release of HCl, and its corrosive and acutely toxic nature. 37 With CO fixed in the 1,2-dicarbonyl moieties, our goal was to design a new class of CO donors involving benign carriers ( Fig. 2B ). Fig. 2 (A) Decomposition of oxalyl chloride to produce CO. (B) Design of CO donors based on the hydrolysis, decarboxylation, decarbonylation chemistry of oxalyl derivatives. (C) Competing paths by which 1,2-dicarbonyl CO prodrugs can breakdown in aqueous solution – (i) a CO-generating pathway; (ii) non-CO producing pathway that generates oxalic acid as the product. Results and discussion Because of enhanced electrophilicity arising from vicinal keto groups, 1,2-dicarbonyl compounds with appropriate leaving groups are susceptible to hydrolysis, expelling one leaving group and generating a ketoacid intermediate ( Fig. 2C ). CO is generated once this ketoacid intermediate undergoes a decarboxylation–decarbonylation sequence of reactions. For oxalyl chloride, this path predominates and thus forms CO, CO 2 , and HCl as end-products when placed in water. However, when the chloride leaving group is replaced by other leaving groups, another decomposition path may compete with the CO generating path. 38,39 The ketoacid intermediate can undergo hydrolysis to expel the second leaving group and form oxalic acid without CO generation. Therefore, the identity of the leaving group must be carefully selected to tune the reaction in favor of the CO generating path. For understanding the basic chemistry and parameters that control the partitioning between the two pathways, chloride was replaced by various leaving groups having different p K a values to survey the<|im_end|> <|im_start|>assistant An oral prodrug developed by a team of scientists led by Binghe Wang, Regents' Professor of Chemistry at Georgia State University, delivers carbon monoxide to protect against acute kidney injury, according to a new paper published in Chemical Science. Although carbon monoxide (CO) gas is toxic in large doses, scientists have discovered it can have beneficial effects by reducing inflammation and protecting cells against injury. Previous studies have demonstrated the protective effects of CO against injury in the kidneys, lungs, gastrointestinal tract and liver, among other organs. For the past five years, Wang and his collaborators have worked to design a safe way to deliver CO to human patients via prodrugs—inactive compounds that must undergo a chemical process in the body before releasing the active pharmacological agent. Wang's team developed prodrugs that allow for oral administration of CO using two common artificial sweeteners—saccharine (an ingredient in Sweet'N Low) and acesulfame (an ingredient in Splenda)—as 'carrier' molecules. They designed the molecules to release CO in the process of decomposition, which is triggered by exposure to water. These are the first examples of orally active, organic CO prodrugs using a benign carrier that is approved by the Food & Drug Administration with a demonstrated safety profile. "It's difficult to deliver a gas, much less a poisonous gas, as a therapeutic to patients, and this work represents a pivotal step forward in developing alternative delivery forms," said Wang, senior author of the paper and a Georgia Research Alliance Eminent Scholar. "We wanted to work with a carrier that has a very well characterized safety profile, which confers a higher degree of certainty that it will be safe to use in a pill for human consumption." Of the two prodrugs, the scientists tested one, CO-306, for pharmacological efficacy against acute kidney damage. The researchers administered CO-306, which uses saccharine as a carrier molecule, to mice and found it reduced biomarkers associated with kidney injury, indicating it could be developed into a viable therapy. The mouse model mimicked the mechanisms of kidney tissue damage that occur in patients with extensive muscle damage, sickle cell disease, a common type of malaria, cardiopulmonary bypass surgery and severe sepsis. Wang and his collaborators at Georgia State's Center for Diagnostics and Therapeutics, Vanderbilt University, Harvard Medical School and the University of Mississippi plan to conduct more extensive animal model studies and safety assessments on CO-306 before progressing to human clinical studies. They also plan to test CO-306 for efficacy against other types of organ injuries. Wang says CO-based therapies particularly hold promise as a method of reducing the likelihood of organ damage during transplantation and improving outcomes for transplant patients. "Science shows that exposing organs to CO gas can help preserve organs and prevent them from deteriorating during the process of transplantation," he said. "Now we need to demonstrate that these prodrugs can have a similar effect." <|im_end|>

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2,121

[ { "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 Fossil material in amber from Myanmar can provide important insights into mid-Cretaceous forest ecosystems. However, Myanmar amber has been receiving increased international attention due to reported links between amber mining and the ongoing humanitarian crisis in northern Myanmar, as well as the legal issues associated with its exportation. Here, we conduct a bibliometric analysis of Myanmar amber publications (1990–2021) and demonstrate how research interest in Myanmar amber is explicitly linked to major political, legal, and economic changes. An analysis of the authorship networks for publications on amber inclusions reveals how current research practices have excluded Myanmar researchers from the field. In addition, the international trade of Myanmar amber with fossil inclusions falls into a legal ‘grey-zone’ which continues to be exploited. This case study vividly demonstrates that systemic changes, alongside an increased awareness of inequitable research practices amongst the broader scientific and allied communities, are urgently needed to curb illegal practices in palaeontology. Background Fossils entombed in amber provide exceptional and unique insights into the morphology and evolution of organisms that inhabited past forest ecosystems 1 . Amber, which is fossilised plant resin, of various geological ages can be found in several parts of the world, including the Baltic region of Europe, Alaska, Madagascar, Lebanon, the Dominican Republic, and Canada. Amber from Myanmar (formerly Burma) is particularly famous for preserving the remains of insects, plants, and reptiles that lived alongside the dinosaurs during the mid-Cretaceous, approximately 99 million years ago 2 . However, Myanmar amber has more recently gained international attention due to legal and ethical issues in the discovery, collection, trade, and research of this material 3 , 4 , 5 . Myanmar has a rich palaeontological heritage, including fossils of the oldest representatives of anthropoid primates 6 . But by far the most popular fossil finds from the country are those in amber. Most amber is mined in the northern state of Kachin, with many fossils coming from the Hukawng Valley (Fig. 1 ), though amber is also mined from several other regions 7 , 8 . To the international palaeontological community, this region is highly productive in terms of amber fossils, but on the ground, it has endured armed conflict between the Kachin Independence Army (KIA) and the Myanmar government military forces, the Tatmadaw, since the 1960s, only two decades after the country gained independence from British rule in 1948. Both the KIA and the Myanmar military have funded their activities through profits from the mining industry for decades, through both legal and illegal routes 9 . The most recent attempt by the military to seize control of the amber mining areas in Kachin State from the KIA occurred in 2017, and soon after, a UN Human Rights Council fact-finding mission reported on the violations of international human rights law and international humanitarian law perpetrated by the military in these areas 10 . These events have led recent media reports to describe working on Myanmar amber as an ‘ethical minefield’, and to question the ‘human cost’ of working on this material 3 , 4 , 11 . Fig. 1: Locations in Myanmar associated with Myanmar amber and areas of major conflict. Location of Myanmar in Southeast Asia (inset) and location of Kachin state in Northern Myanmar (main). Many amber mines are located in Hukawng Valley (circled), close to the city of Tanai. Also included are the major amber trading cities of Myitkyina in Myanmar and Tengchong in Yunnan, China. Star icons denote major areas where conflict (e.g. armed clashes and violence against civilians) has been reported in July 2020 to December 2021 (sourced from The Armed Conflict Location & Event Data Project; ). Full size image Several countries have legislation in place to protect fossils from being exported illegally or studied without the involvement of local researchers 12 . More generally, this kind of legislation protects against extractive research practices, often referred to collectively as ‘parachute science’ (or scientific colonialism), whereby researchers from higher income countries collect specimens or data from lower income countries without engaging with local researchers or communities 13 , 14 , 15 . While Myanmar has national laws and is a signatory of several international conventions that could apply to fossil material in amber (Table 1 , Box 1 ), the domestic regulation of this material’s export has a major loophole 16 . Most of the amber mined in Kachin State is sent across the Chinese border to Tengchong, where it is sold in large markets to jewellers, private collectors, and palaeontologists 4 . Permanent export of fossil material from Myanmar is prohibited under the 2015 Protection and Preservation of Antique Objects Law. The 1970 UNESCO Convention on the Means of Prohibiting and Preventing the Illicit Import, Export and Transfer of Ownership of Cultural Property 17 , an international treaty that entered into force for Myanmar in 2013, also protects cultural property from illicit trafficking (Table 1 ). For this purpose, the Convention obligates states parties to pass and enforce domestic legislation. However, under the 2019 Myanmar Gemstone Law (and its previous versions) amber is classified as a gemstone and its export can be legal if accompanied with the appropriate paperwork (Table 1 ). Neither the antiquities law (2015 The Protection and Preservation of Antique Objects Law; Table 1 ) nor the gemstone law (2019 Myanmar Gem Law; Table 1 ) explicitly mention amber with fossil inclusions, leading to it falling within a legal grey zone, where the gemstone can in principle be legally exported (with accompanying documentation), but not its fossilised contents. Table 1 National laws and international treaties that apply to fossil specimens in amber uncovered in Myanmar. Full size table Due to this seemingly complex legal and ethical situation, the palaeontological community has not yet united on a stance towards the issues surrounding Myanmar amber. In 2020, the Society of Vertebrate Paleontology (SVP) released a letter to editors of palaeontological journal editors, calling for a moratorium on publishing material in Myanmar amber, particularly that acquired after the military took", "role": "user" }, { "content": "Myanmar, a country in Southeast Asia, is plagued by political and economic crises. The fall of a president, a military putsch and the crackdown on religious minorities have had an impact not only on life but also on research in the country. One area of research that has been particularly affected is research into fossils preserved in amber. Researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have conducted a case study proving the negative impact political conflicts have on research. They examined scientific publications from the last three decades describing fossils in amber from Myanmar. Their results indicate that the increased research interest in Myanmar amber is explicitly linked to major political, legal and economic changes. The results were published in the journal Communications Biology. Myanmar is dominated by political and economic crises, and reports show a connection between amber mining and the ongoing humanitarian crisis in the north of the country. The unrelenting conflict between the Kachin Independence Army (KIA) and the Myanmar military forces has a direct impact on the life of the civilian population and on research. Certain areas of research have been particularly affected, including research into amber fossils. Amber from Myanmar contains remnants of forest ecosystems from the mid Cretaceous, the same ecosystem in which the dinosaurs lived. In order to gain a better understanding of the affects on research into amber fossils from Myanmar, researchers from FAU have analyzed academic publications describing fossils in Myanmar amber from 1990 to 2021. Gemstones in crisis Their findings reveal that the increasing interest in amber from Myanmar correlates exactly with the ongoing political, legal and economic changes within the country and on the international scene. Demand for amber has increased rapidly since 2010 and mining in the northern region of Kachin has been extended. The armed conflict has led to amber mines becoming sites for human rights violations, and the local population has been forced to leave their homes. Furthermore, the analysis shows that researchers from Myanmar are largely excluded from conducting research into the amber from their own country. Amber fossils fetch a high price. As a result, amber tends to be sold abroad and made available for researchers based outside Myanmar. The strict restrictions within the country mean that researchers have scarcely any opportunity to acquire amber for research purposes. The case study makes it clear that systemic changes and a greater awareness of unfair research practices in the paleontological community and in wider academic circles are urgently required in order to curb exploitative and illegal practices in paleontology. ", "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 Fossil material in amber from Myanmar can provide important insights into mid-Cretaceous forest ecosystems. However, Myanmar amber has been receiving increased international attention due to reported links between amber mining and the ongoing humanitarian crisis in northern Myanmar, as well as the legal issues associated with its exportation. Here, we conduct a bibliometric analysis of Myanmar amber publications (1990–2021) and demonstrate how research interest in Myanmar amber is explicitly linked to major political, legal, and economic changes. An analysis of the authorship networks for publications on amber inclusions reveals how current research practices have excluded Myanmar researchers from the field. In addition, the international trade of Myanmar amber with fossil inclusions falls into a legal ‘grey-zone’ which continues to be exploited. This case study vividly demonstrates that systemic changes, alongside an increased awareness of inequitable research practices amongst the broader scientific and allied communities, are urgently needed to curb illegal practices in palaeontology. Background Fossils entombed in amber provide exceptional and unique insights into the morphology and evolution of organisms that inhabited past forest ecosystems 1 . Amber, which is fossilised plant resin, of various geological ages can be found in several parts of the world, including the Baltic region of Europe, Alaska, Madagascar, Lebanon, the Dominican Republic, and Canada. Amber from Myanmar (formerly Burma) is particularly famous for preserving the remains of insects, plants, and reptiles that lived alongside the dinosaurs during the mid-Cretaceous, approximately 99 million years ago 2 . However, Myanmar amber has more recently gained international attention due to legal and ethical issues in the discovery, collection, trade, and research of this material 3 , 4 , 5 . Myanmar has a rich palaeontological heritage, including fossils of the oldest representatives of anthropoid primates 6 . But by far the most popular fossil finds from the country are those in amber. Most amber is mined in the northern state of Kachin, with many fossils coming from the Hukawng Valley (Fig. 1 ), though amber is also mined from several other regions 7 , 8 . To the international palaeontological community, this region is highly productive in terms of amber fossils, but on the ground, it has endured armed conflict between the Kachin Independence Army (KIA) and the Myanmar government military forces, the Tatmadaw, since the 1960s, only two decades after the country gained independence from British rule in 1948. Both the KIA and the Myanmar military have funded their activities through profits from the mining industry for decades, through both legal and illegal routes 9 . The most recent attempt by the military to seize control of the amber mining areas in Kachin State from the KIA occurred in 2017, and soon after, a UN Human Rights Council fact-finding mission reported on the violations of international human rights law and international humanitarian law perpetrated by the military in these areas 10 . These events have led recent media reports to describe working on Myanmar amber as an ‘ethical minefield’, and to question the ‘human cost’ of working on this material 3 , 4 , 11 . Fig. 1: Locations in Myanmar associated with Myanmar amber and areas of major conflict. Location of Myanmar in Southeast Asia (inset) and location of Kachin state in Northern Myanmar (main). Many amber mines are located in Hukawng Valley (circled), close to the city of Tanai. Also included are the major amber trading cities of Myitkyina in Myanmar and Tengchong in Yunnan, China. Star icons denote major areas where conflict (e.g. armed clashes and violence against civilians) has been reported in July 2020 to December 2021 (sourced from The Armed Conflict Location & Event Data Project; ). Full size image Several countries have legislation in place to protect fossils from being exported illegally or studied without the involvement of local researchers 12 . More generally, this kind of legislation protects against extractive research practices, often referred to collectively as ‘parachute science’ (or scientific colonialism), whereby researchers from higher income countries collect specimens or data from lower income countries without engaging with local researchers or communities 13 , 14 , 15 . While Myanmar has national laws and is a signatory of several international conventions that could apply to fossil material in amber (Table 1 , Box 1 ), the domestic regulation of this material’s export has a major loophole 16 . Most of the amber mined in Kachin State is sent across the Chinese border to Tengchong, where it is sold in large markets to jewellers, private collectors, and palaeontologists 4 . Permanent export of fossil material from Myanmar is prohibited under the 2015 Protection and Preservation of Antique Objects Law. The 1970 UNESCO Convention on the Means of Prohibiting and Preventing the Illicit Import, Export and Transfer of Ownership of Cultural Property 17 , an international treaty that entered into force for Myanmar in 2013, also protects cultural property from illicit trafficking (Table 1 ). For this purpose, the Convention obligates states parties to pass and enforce domestic legislation. However, under the 2019 Myanmar Gemstone Law (and its previous versions) amber is classified as a gemstone and its export can be legal if accompanied with the appropriate paperwork (Table 1 ). Neither the antiquities law (2015 The Protection and Preservation of Antique Objects Law; Table 1 ) nor the gemstone law (2019 Myanmar Gem Law; Table 1 ) explicitly mention amber with fossil inclusions, leading to it falling within a legal grey zone, where the gemstone can in principle be legally exported (with accompanying documentation), but not its fossilised contents. Table 1 National laws and international treaties that apply to fossil specimens in amber uncovered in Myanmar. Full size table Due to this seemingly complex legal and ethical situation, the palaeontological community has not yet united on a stance towards the issues surrounding Myanmar amber. In 2020, the Society of Vertebrate Paleontology (SVP) released a letter to editors of palaeontological journal editors, calling for a moratorium on publishing material in Myanmar amber, particularly that acquired after the military took<|im_end|> <|im_start|>assistant Myanmar, a country in Southeast Asia, is plagued by political and economic crises. The fall of a president, a military putsch and the crackdown on religious minorities have had an impact not only on life but also on research in the country. One area of research that has been particularly affected is research into fossils preserved in amber. Researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have conducted a case study proving the negative impact political conflicts have on research. They examined scientific publications from the last three decades describing fossils in amber from Myanmar. Their results indicate that the increased research interest in Myanmar amber is explicitly linked to major political, legal and economic changes. The results were published in the journal Communications Biology. Myanmar is dominated by political and economic crises, and reports show a connection between amber mining and the ongoing humanitarian crisis in the north of the country. The unrelenting conflict between the Kachin Independence Army (KIA) and the Myanmar military forces has a direct impact on the life of the civilian population and on research. Certain areas of research have been particularly affected, including research into amber fossils. Amber from Myanmar contains remnants of forest ecosystems from the mid Cretaceous, the same ecosystem in which the dinosaurs lived. In order to gain a better understanding of the affects on research into amber fossils from Myanmar, researchers from FAU have analyzed academic publications describing fossils in Myanmar amber from 1990 to 2021. Gemstones in crisis Their findings reveal that the increasing interest in amber from Myanmar correlates exactly with the ongoing political, legal and economic changes within the country and on the international scene. Demand for amber has increased rapidly since 2010 and mining in the northern region of Kachin has been extended. The armed conflict has led to amber mines becoming sites for human rights violations, and the local population has been forced to leave their homes. Furthermore, the analysis shows that researchers from Myanmar are largely excluded from conducting research into the amber from their own country. Amber fossils fetch a high price. As a result, amber tends to be sold abroad and made available for researchers based outside Myanmar. The strict restrictions within the country mean that researchers have scarcely any opportunity to acquire amber for research purposes. The case study makes it clear that systemic changes and a greater awareness of unfair research practices in the paleontological community and in wider academic circles are urgently required in order to curb exploitative and illegal practices in paleontology. <|im_end|>

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1,804

[ { "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 Hum-noise-based touch sensors (HumTouch) are capable of recognizing human touch on semiconductive materials using the current leaking from the finger to the surface. Thus far, calibration for these hum-noise-based touch sensors has been performed for individual users because of the individual differences in hum-driven electric currents in human bodies. However, for applications designed for unknown users, time-consuming calibration for individual users is not preferred, and a new user should be able to use the sensor immediately. For this purpose, we propose a new calibration method for HumTouch. In this method, learning datasets collected from multiple people and a few extra samples from a new user are collectively used to establish a touch localization estimator. The estimator is computed using the kernel regression method with weighted samples from the new user. For a 20 \\times \\times 18 cm ^2 ^2 paper, the mean localization error is reduced from 1.24 cm to 0.90 cm with only one sample from the new user. Hence, a new user can establish a semipersonalized localization estimator by touching only one point on the surface. This method improves the localization performance of HumTouch sensors in an easy-to-access manner. Introduction Capacitive sensing has been adopted in most commonly-used and commercially successful touch-sensitive methods. This sensing method detects the changes in the electric charges within a uniform electrostatic field [ 1 , 2 , 3 ], and is extensively used in touch panels and buttons. Recently, touch localization technology that can be applied to nonspecialized surfaces or objects has attracted the attention of researchers. Most of these techniques are aimed at furniture and cloth, rather than touch panels for electronic appliances. An example is the electrical tomography method [ 4 , 5 , 6 , 7 ], which uses several pairs of electrodes to apply voltages to a resistive surface. The touched location can be computed by recording the changes in the electrical impedance between the electrodes. Optical methods such as cameras, which detect and trace human fingertips, can be applied to any surface as long as the occlusion problem is not severe [ 8 , 9 , 10 , 11 , 12 ]. In addition, soft or thin pressure-sensitive sheets have been used for constructing touch-sensitive areas on free-form surfaces [ 13 , 14 , 15 , 16 , 17 ]. Other approaches include radio-frequency identification tags for sensing touch events and localization [ 18 ], inertial measurement unit sensors for tracking fingertips and recognizing gestures [ 19 ], and methods utilizing the propagation of acoustic waves in solid materials [ 20 ]. Multi-axial force sensors can also turn objects such as furniture into touch sensitive interfaces [ 21 , 22 , 23 ]. Furthermore, a method based on spray coating conductive substances can be easily applied to objects with complex shapes for forming a touch-sensitive surface [ 6 , 7 , 24 ]. Moreover, wearable sensors, such as [ 25 , 26 ], are a potential approach to detect a touch on objects without sensory instruments. We focus on a sensing method that utilizes environmental AC-hum-noise [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. For example, Cohn et al. demonstrated that the touch positions on a wall could be discriminated by monitoring the voltage at an electrode on human skin [ 27 ]. In their experiment, the hum-noise in the wall was detected through human skin when a person touched the wall. The hum-noise-based sensing method employed in this study is called HumTouch [ 34 , 35 , 36 , 37 ], which uses the environmental noise leaking from human fingers onto the surfaces of conductive or semiconductive objects. Touch or finger localization is achieved based on the voltages recorded at multiple electrodes attached to the surface [ 35 , 36 , 37 ]. In previous studies on hum-noise-based touch sensors, calibration for localization was performed for individual users, using machine learning or statistical approaches comprising support vector machines and regression analysis [ 27 , 28 , 29 , 30 , 35 , 36 , 37 ]. Because of the individual differences in human bodies, the voltages recorded on material surfaces differ among users, leading to inaccurate localization of touch. For certain applications, calibration for individual users before using the sensors is acceptable or suitable; however, other applications require easy access to hum-noise-based touch sensors by unknown users with less effort for sensor calibration. Fig. 1 Principle of HumTouch. HumTouch utilizes the current leaking from a human body when conductive substances in the body react with the electromagnetic waves generated by AC power lines in buildings Full size image Herein, we propose a calibration method in which only one or a few samples from a new unknown user and many samples collected from various people are combined to build a semipersonalized calibration model. The extra samples from the new user are weighted to tailor the calibration model to the user. We examine a method that uses 20 \\times 18~\\text {cm}^2 20 \\times 18~\\text {cm}^2 paper coated with conductive ink. We investigate the suitable weighting values and the extra samples required for improving the localization accuracy. To the best of our knowledge, a method similar to our semipersonalized method for touch sensors has not yet been developed. This is mainly because, in principle, most of the previous touch sensors do not require calibration for individuals because their measurement accuracy does not depend on individual users. For example, electrical tomography methods utilize the changes in the electrical impedance caused by the deformation of the surface touched by the user. Hence, calibration models are required for individual surfaces, but not for individual users. Touch-sensing methods utilizing hum-noise have distinctive features from other sensing methods. First, this method does not require any sensing structures on the surface to be measured. It does not require any resistive or capacitive materials and layers installed on the surface as long as the surface material is semiconductive. Hence, HumTouch may allow us to turn wooden products [", "role": "user" }, { "content": "Researchers from Tokyo Metropolitan University have developed a new calibration algorithm for technology that turns common materials into touch sensors. HumTouch detects the current that runs from our fingertips to any partially conductive surface and locates where it was touched. The new algorithm speeds up calibration for new users, solving a major drawback of existing versions of the technology. It also improves the accuracy, bringing HumTouch a step closer to practical applications. In the span of a few decades, touch sensing has gone from being bleeding edge tech to becoming an ubiquitous part of everyday life. This is particularly apparent in the profusion of touchscreens that surround us, from smartphones and tablets to everyday interactive tasks like checking out groceries, making a payment, controlling household appliances or even playing games. But the sensing capabilities of a touchscreen are confined to the area of the screen. Capacitive touchscreens, for example, feature a set of tiny circuits all over the screen which detect small, local changes in capacitance when we touch it; the point is, there's a static, preinstalled set of circuitry over which the screen can act as a sensor. A team of researchers from Tokyo Metropolitan University led by Associate Professor Shogo Okamoto have been working on technology that might turn any slightly conductive surface into a touch sensor. By wiring electrodes to the edges of any surface, whether it be made of cloth, wood or stone, they have developed sensing technology that can not only detect when the surface has been touched, but where it has been touched, just like a touchscreen. The research is published in the ROBOMECH Journal. The principle they use is based on AC hum noise. Any location with a mains power supply is full of electromagnetic waves emitted from sources; these induce tiny currents in our body which can leak into a surface when we touch them. The technology, called HumTouch, can convert accurate measurements of this current to a location. This could potentially turn nearly any surface into a touch sensor. A major drawback of HumTouch, however, has been how sensitive the conversion is to the person. A lengthy calibration process is required for new users, requiring touching the surface at more than 20 locations before accurate touch location could be achieved. Now, the team have discovered that data collected from multiple users could be combined with data from a single touch from a new user to generate much more accurate location than before for the newcomer. They tested their new algorithm by wiring up a paper towel and collecting data from different users. Any new user could then touch the paper once, have the measurement mixed with preexisting calibration data from other users, and enjoy accurate location of subsequent touches up to an accuracy of less than a centimeter. Importantly, that is less than the width of a finger. In principle, the technology is very close to deployment in practical applications. The team hopes that HumTouch will be able to bring currently inanimate, offline objects into the network infrastructure of the Internet of Things, adding unprecedented interactive capabilities to our immediate 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 Hum-noise-based touch sensors (HumTouch) are capable of recognizing human touch on semiconductive materials using the current leaking from the finger to the surface. Thus far, calibration for these hum-noise-based touch sensors has been performed for individual users because of the individual differences in hum-driven electric currents in human bodies. However, for applications designed for unknown users, time-consuming calibration for individual users is not preferred, and a new user should be able to use the sensor immediately. For this purpose, we propose a new calibration method for HumTouch. In this method, learning datasets collected from multiple people and a few extra samples from a new user are collectively used to establish a touch localization estimator. The estimator is computed using the kernel regression method with weighted samples from the new user. For a 20 \times \times 18 cm ^2 ^2 paper, the mean localization error is reduced from 1.24 cm to 0.90 cm with only one sample from the new user. Hence, a new user can establish a semipersonalized localization estimator by touching only one point on the surface. This method improves the localization performance of HumTouch sensors in an easy-to-access manner. Introduction Capacitive sensing has been adopted in most commonly-used and commercially successful touch-sensitive methods. This sensing method detects the changes in the electric charges within a uniform electrostatic field [ 1 , 2 , 3 ], and is extensively used in touch panels and buttons. Recently, touch localization technology that can be applied to nonspecialized surfaces or objects has attracted the attention of researchers. Most of these techniques are aimed at furniture and cloth, rather than touch panels for electronic appliances. An example is the electrical tomography method [ 4 , 5 , 6 , 7 ], which uses several pairs of electrodes to apply voltages to a resistive surface. The touched location can be computed by recording the changes in the electrical impedance between the electrodes. Optical methods such as cameras, which detect and trace human fingertips, can be applied to any surface as long as the occlusion problem is not severe [ 8 , 9 , 10 , 11 , 12 ]. In addition, soft or thin pressure-sensitive sheets have been used for constructing touch-sensitive areas on free-form surfaces [ 13 , 14 , 15 , 16 , 17 ]. Other approaches include radio-frequency identification tags for sensing touch events and localization [ 18 ], inertial measurement unit sensors for tracking fingertips and recognizing gestures [ 19 ], and methods utilizing the propagation of acoustic waves in solid materials [ 20 ]. Multi-axial force sensors can also turn objects such as furniture into touch sensitive interfaces [ 21 , 22 , 23 ]. Furthermore, a method based on spray coating conductive substances can be easily applied to objects with complex shapes for forming a touch-sensitive surface [ 6 , 7 , 24 ]. Moreover, wearable sensors, such as [ 25 , 26 ], are a potential approach to detect a touch on objects without sensory instruments. We focus on a sensing method that utilizes environmental AC-hum-noise [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. For example, Cohn et al. demonstrated that the touch positions on a wall could be discriminated by monitoring the voltage at an electrode on human skin [ 27 ]. In their experiment, the hum-noise in the wall was detected through human skin when a person touched the wall. The hum-noise-based sensing method employed in this study is called HumTouch [ 34 , 35 , 36 , 37 ], which uses the environmental noise leaking from human fingers onto the surfaces of conductive or semiconductive objects. Touch or finger localization is achieved based on the voltages recorded at multiple electrodes attached to the surface [ 35 , 36 , 37 ]. In previous studies on hum-noise-based touch sensors, calibration for localization was performed for individual users, using machine learning or statistical approaches comprising support vector machines and regression analysis [ 27 , 28 , 29 , 30 , 35 , 36 , 37 ]. Because of the individual differences in human bodies, the voltages recorded on material surfaces differ among users, leading to inaccurate localization of touch. For certain applications, calibration for individual users before using the sensors is acceptable or suitable; however, other applications require easy access to hum-noise-based touch sensors by unknown users with less effort for sensor calibration. Fig. 1 Principle of HumTouch. HumTouch utilizes the current leaking from a human body when conductive substances in the body react with the electromagnetic waves generated by AC power lines in buildings Full size image Herein, we propose a calibration method in which only one or a few samples from a new unknown user and many samples collected from various people are combined to build a semipersonalized calibration model. The extra samples from the new user are weighted to tailor the calibration model to the user. We examine a method that uses 20 \times 18~\text {cm}^2 20 \times 18~\text {cm}^2 paper coated with conductive ink. We investigate the suitable weighting values and the extra samples required for improving the localization accuracy. To the best of our knowledge, a method similar to our semipersonalized method for touch sensors has not yet been developed. This is mainly because, in principle, most of the previous touch sensors do not require calibration for individuals because their measurement accuracy does not depend on individual users. For example, electrical tomography methods utilize the changes in the electrical impedance caused by the deformation of the surface touched by the user. Hence, calibration models are required for individual surfaces, but not for individual users. Touch-sensing methods utilizing hum-noise have distinctive features from other sensing methods. First, this method does not require any sensing structures on the surface to be measured. It does not require any resistive or capacitive materials and layers installed on the surface as long as the surface material is semiconductive. Hence, HumTouch may allow us to turn wooden products [<|im_end|> <|im_start|>assistant Researchers from Tokyo Metropolitan University have developed a new calibration algorithm for technology that turns common materials into touch sensors. HumTouch detects the current that runs from our fingertips to any partially conductive surface and locates where it was touched. The new algorithm speeds up calibration for new users, solving a major drawback of existing versions of the technology. It also improves the accuracy, bringing HumTouch a step closer to practical applications. In the span of a few decades, touch sensing has gone from being bleeding edge tech to becoming an ubiquitous part of everyday life. This is particularly apparent in the profusion of touchscreens that surround us, from smartphones and tablets to everyday interactive tasks like checking out groceries, making a payment, controlling household appliances or even playing games. But the sensing capabilities of a touchscreen are confined to the area of the screen. Capacitive touchscreens, for example, feature a set of tiny circuits all over the screen which detect small, local changes in capacitance when we touch it; the point is, there's a static, preinstalled set of circuitry over which the screen can act as a sensor. A team of researchers from Tokyo Metropolitan University led by Associate Professor Shogo Okamoto have been working on technology that might turn any slightly conductive surface into a touch sensor. By wiring electrodes to the edges of any surface, whether it be made of cloth, wood or stone, they have developed sensing technology that can not only detect when the surface has been touched, but where it has been touched, just like a touchscreen. The research is published in the ROBOMECH Journal. The principle they use is based on AC hum noise. Any location with a mains power supply is full of electromagnetic waves emitted from sources; these induce tiny currents in our body which can leak into a surface when we touch them. The technology, called HumTouch, can convert accurate measurements of this current to a location. This could potentially turn nearly any surface into a touch sensor. A major drawback of HumTouch, however, has been how sensitive the conversion is to the person. A lengthy calibration process is required for new users, requiring touching the surface at more than 20 locations before accurate touch location could be achieved. Now, the team have discovered that data collected from multiple users could be combined with data from a single touch from a new user to generate much more accurate location than before for the newcomer. They tested their new algorithm by wiring up a paper towel and collecting data from different users. Any new user could then touch the paper once, have the measurement mixed with preexisting calibration data from other users, and enjoy accurate location of subsequent touches up to an accuracy of less than a centimeter. Importantly, that is less than the width of a finger. In principle, the technology is very close to deployment in practical applications. The team hopes that HumTouch will be able to bring currently inanimate, offline objects into the network infrastructure of the Internet of Things, adding unprecedented interactive capabilities to our immediate environment. <|im_end|>

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1,878

[ { "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 distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma. We generate eight conditional, knock-in mouse models and show that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation, whereas common melanoma mutants (NRAS Q61R, Q61K, or Q61L) induce rapid tumor onset with high penetrance. Molecular dynamics simulations, combined with cell-based protein–protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma. Introduction It is unclear why the profile of oncogenic RAS mutations differs between tumor types. It was once thought that differences in tumor etiology determined the preferred location (codon 12, 13, or 61) and amino acid identity of oncogenic mutations in RAS . However, apart from KRAS 12C mutations which are linked to cigarette carcinogens in lung cancer 1 , tumor type-specific mutational processes do not explain the enrichment of specific RAS mutations in many cancers. This trend is particularly evident in melanoma where the most common NRAS mutations (Q61R and Q61K) are not caused by direct damage from ultraviolet (UVB) light 2 . These observations suggest that each RAS mutant may fulfill different requirements for tumor initiation. Emerging evidence shows that RAS mutants have distinct biochemical and tumorigenic properties. While all oncogenic RAS mutants are constitutively active, differential positioning of the switch I and II domains leads to variations in GTP binding and hydrolysis 3 . These structural differences can also influence effector interactions as evidenced by the positioning of switch II in KRAS 12R , which prevents PI3Kα binding and the subsequent induction of micropinocytosis 4 , 5 . Such mechanistic differences may also explain the tissue-specific potential of RAS mutants to initiate tumorigenesis in genetically engineered mouse models (GEMMs). For example, we have shown that endogenous levels of NRAS 61R or NRAS 12D exhibit distinct tumorigenic potential in GEMMs of melanoma and leukemia 6 . Finally, mutation-specific functions of oncogenic RAS may influence patient outcomes as the efficacy of targeted therapies in colorectal and non-small cell lung cancer is dependent upon the underlying KRAS mutant 7 , 8 , 9 . Therefore, understanding functional differences that drive the selection of specific RAS mutants in each cancer type may identify pharmacologically tractable targets required for tumor initiation. Technical challenges have made it hard to identify differences between RAS alleles that drive tumorigenesis. For example, exogenous gene expression is a commonly used tool, yet RAS gene dosage has been shown to affect signaling 10 , localization 11 and in vivo functionality 12 , 13 . The biological consequences of mutant RAS expression also differ based on the isoform (H-, K- or N-RAS) and cell-type examined 6 , 14 , 15 , 16 , 17 . Therefore, it is essential to assess the differences between endogenous RAS mutants under physiologically relevant conditions. Here, we report the development of eight NRAS - mutant mouse alleles, each of which enables the conditional expression of a distinct NRAS mutant from the endogenous gene locus. Crossing these alleles to a melanocyte-specific Cre, we find that the melanomagenic potential of NRAS mutants parallels their frequency in human melanoma. We link the melanomagenic potential of NRAS mutants to enhanced BRAF binding, dimerization, and MAPK > ERK signaling. Results The tumorigenic potential of NRAS mutants parallels allelic frequency in human melanoma We used CRISPR-Cas9 to zygotically modify the Nras mutation in Tyr::CreER T2 ; LSL-Nras 61R/R ( TN 61R/R ) mice (Supplementary Figs. 1a , b, 2a ; refs. 6 , 18 ). This process yielded eight mouse models in which induction of Cre recombinase triggers the melanocyte-specific expression of a modified Nras gene from the endogenous locus: TN 61K/K , TN 61L/L , TN 61H/H , TN 61P/P , TN 61Q/Q , TN 12D/D , TN 13D/D , and TN 13R/R . Each LSL-Nras allele was sequenced and functionally validated in mouse embryonic fibroblasts (MEFs) (Supplementary Figs. 1c –e, 2b–d ). Founder animals were backcrossed two generations to TN 61R/R mice to limit any off-target effects of CRISPR-Cas9. We used this suite of TN mice to determine if NRAS oncogenes common to human melanoma (Fig. 1a ) drive melanocyte transformation better than those present in other tumor types. Experimental TN 61X/X cohorts were generated by intercrossing Tyr::CreER T2 transgenic mice carrying one LSL-Nras 61R and one LSL-Nras 61X allele, where X = K, L, H, P, or Q (Supplementary Fig. 1f ). The resulting offspring were topically treated with 4-hydroxytamoxifen (4-OHT) on postnatal days 1 and 2 to drive CreER T2 -mediated excision of the LSL transcriptional stop sequence and initiate expression of each Nras variant (Supplementary Fig. 1g ). The mice were then subjected to a single, 4.5 kJ/m 2 dose of ultraviolet B (UVB) irradiation on postnatal day 3 to mimic the role of sunlight in melanoma formation (Supplementary Fig. 1g ; ref. 18 ). Fig. 1: Frequency of NRAS mutants in human melanoma parallels tumorigenic potential in mice. a Frequency of NRAS mutations in the TCGA PanCancer Atlas dataset for human cutaneous melanoma. Melanoma-free survival ( b ), total tumor burden ( c ), and tumor growth rates ( d ) for mice expressing the indicated melanocyte-specific NRAS mutants. Tumor burden and growth rate data are presented as mean values +/− SD. The following number biologically independent animals were evaluated per genotype (61R = 72, 61K = 19, 61L = 17, 61H = 17, 61P = 16, 61Q = 22). Log-rank (Mantel–Cox) ( b ) or ANOVA ( c , d ) with a Tukey’s multiple comparisons test was used to compare measurements between each genotype. TN X/X samples statistically different", "role": "user" }, { "content": "A new study reveals important molecular information that could help scientists develop more effective treatment and prevention strategies for a difficult-to-treat form of melanoma skin cancer. In this new report, The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC—James) researchers identify and describe key features of a gene mutation responsible for 15 to 20% of all melanomas. Using a preclinical laboratory model, the team establishes that the frequency at which a specific NRAS gene mutation occurs in human melanoma is directly related to the ability of that gene mutation to initiate spontaneous melanoma formation. \"This means that properties of the mutant itself—rather than the ease at which that specific gene mutation occurs—is the cause of cancer formation,\" said corresponding author Christin Burd who serves an associate professor of molecular genetics in The Ohio State University College of Arts and Sciences, Department of Molecular Genetics and a member of the OSUCCC—James Molecular Carcinogenesis and Chemoprevention Program. \"NRAS-mutant cancers are challenging to treat because effective therapies beyond immunotherapy don't exist yet,\" said Burd. \"Each cancer type seems to prefer a specific 'flavor' of mutant NRAS, and it has not been clear why this is.\" The OSUCCC—James wanted to know what made the melanoma-promoting NRAS mutants different than those that promote other cancer types. Scientists say this knowledge could help investigators pinpoint the early events required for melanoma formation and develop treatments that prevent the disease. Burd and colleagues report their findings in the June 7, 2022, issue of Nature Communications. Study design and methods To conduct this study, OSUCCC-James researchers developed genetically engineered models that would allow them to activate one of nine different NRAS-mutant variations in melanocytes, the pigment cells that form melanoma. \"Amazingly, when we activated these gene mutations only those found in the human disease caused melanoma to develop,\" said Burd. \"Some mutants never led to melanoma, yet we know that they cause leukemia. This finding shows that selection of NRAS mutations is specific to each tumor type and occurs during cancer initiation, rather than in response to a specific mutagenic event like sun exposure.\" Collaborating with Sharon Campbell, a structural biologist at the University of North Carolina (UNC) Chapel Hill, and Debbie Morrison at the National Institutes of Health, Burd's team identified that slight variances in the outward facing structure of NRAS mutants capable of initiating melanoma that made these proteins better able to interact with the signaling pathways that drive melanoma growth. \"Now we will work to target this unique structural feature of the melanoma-inducing NRAS mutants to prevent and/or treat the disease,\" said Burd. \"Our work also demonstrates and confirms what was—until now—only speculation: that minor differences between the RAS mutants determine which 'flavors' can cause a particular cancer. Such a concept could be used to find vulnerabilities in other RAS-driven tumor types.\" To facilitate similar discoveries, the team generated eight new and publicly available genetically engineered mouse models that will serve as an essential toolkit for the entire RAS community. Burd says these models can be used to activate and study the role of NRAS is other relevant cancer types such as colon cancer, leukemia, myeloma, and thyroid cancer. They can also be used to investigate new drugs for these diseases. The preclinical research models developed in Burd's lab and used for this research are publicly available to scientists conducting research about other RAS-driven cancer types or working to develop new cancer therapies through the National Institute of Health's repository. ", "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 distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma. We generate eight conditional, knock-in mouse models and show that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation, whereas common melanoma mutants (NRAS Q61R, Q61K, or Q61L) induce rapid tumor onset with high penetrance. Molecular dynamics simulations, combined with cell-based protein–protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma. Introduction It is unclear why the profile of oncogenic RAS mutations differs between tumor types. It was once thought that differences in tumor etiology determined the preferred location (codon 12, 13, or 61) and amino acid identity of oncogenic mutations in RAS . However, apart from KRAS 12C mutations which are linked to cigarette carcinogens in lung cancer 1 , tumor type-specific mutational processes do not explain the enrichment of specific RAS mutations in many cancers. This trend is particularly evident in melanoma where the most common NRAS mutations (Q61R and Q61K) are not caused by direct damage from ultraviolet (UVB) light 2 . These observations suggest that each RAS mutant may fulfill different requirements for tumor initiation. Emerging evidence shows that RAS mutants have distinct biochemical and tumorigenic properties. While all oncogenic RAS mutants are constitutively active, differential positioning of the switch I and II domains leads to variations in GTP binding and hydrolysis 3 . These structural differences can also influence effector interactions as evidenced by the positioning of switch II in KRAS 12R , which prevents PI3Kα binding and the subsequent induction of micropinocytosis 4 , 5 . Such mechanistic differences may also explain the tissue-specific potential of RAS mutants to initiate tumorigenesis in genetically engineered mouse models (GEMMs). For example, we have shown that endogenous levels of NRAS 61R or NRAS 12D exhibit distinct tumorigenic potential in GEMMs of melanoma and leukemia 6 . Finally, mutation-specific functions of oncogenic RAS may influence patient outcomes as the efficacy of targeted therapies in colorectal and non-small cell lung cancer is dependent upon the underlying KRAS mutant 7 , 8 , 9 . Therefore, understanding functional differences that drive the selection of specific RAS mutants in each cancer type may identify pharmacologically tractable targets required for tumor initiation. Technical challenges have made it hard to identify differences between RAS alleles that drive tumorigenesis. For example, exogenous gene expression is a commonly used tool, yet RAS gene dosage has been shown to affect signaling 10 , localization 11 and in vivo functionality 12 , 13 . The biological consequences of mutant RAS expression also differ based on the isoform (H-, K- or N-RAS) and cell-type examined 6 , 14 , 15 , 16 , 17 . Therefore, it is essential to assess the differences between endogenous RAS mutants under physiologically relevant conditions. Here, we report the development of eight NRAS - mutant mouse alleles, each of which enables the conditional expression of a distinct NRAS mutant from the endogenous gene locus. Crossing these alleles to a melanocyte-specific Cre, we find that the melanomagenic potential of NRAS mutants parallels their frequency in human melanoma. We link the melanomagenic potential of NRAS mutants to enhanced BRAF binding, dimerization, and MAPK > ERK signaling. Results The tumorigenic potential of NRAS mutants parallels allelic frequency in human melanoma We used CRISPR-Cas9 to zygotically modify the Nras mutation in Tyr::CreER T2 ; LSL-Nras 61R/R ( TN 61R/R ) mice (Supplementary Figs. 1a , b, 2a ; refs. 6 , 18 ). This process yielded eight mouse models in which induction of Cre recombinase triggers the melanocyte-specific expression of a modified Nras gene from the endogenous locus: TN 61K/K , TN 61L/L , TN 61H/H , TN 61P/P , TN 61Q/Q , TN 12D/D , TN 13D/D , and TN 13R/R . Each LSL-Nras allele was sequenced and functionally validated in mouse embryonic fibroblasts (MEFs) (Supplementary Figs. 1c –e, 2b–d ). Founder animals were backcrossed two generations to TN 61R/R mice to limit any off-target effects of CRISPR-Cas9. We used this suite of TN mice to determine if NRAS oncogenes common to human melanoma (Fig. 1a ) drive melanocyte transformation better than those present in other tumor types. Experimental TN 61X/X cohorts were generated by intercrossing Tyr::CreER T2 transgenic mice carrying one LSL-Nras 61R and one LSL-Nras 61X allele, where X = K, L, H, P, or Q (Supplementary Fig. 1f ). The resulting offspring were topically treated with 4-hydroxytamoxifen (4-OHT) on postnatal days 1 and 2 to drive CreER T2 -mediated excision of the LSL transcriptional stop sequence and initiate expression of each Nras variant (Supplementary Fig. 1g ). The mice were then subjected to a single, 4.5 kJ/m 2 dose of ultraviolet B (UVB) irradiation on postnatal day 3 to mimic the role of sunlight in melanoma formation (Supplementary Fig. 1g ; ref. 18 ). Fig. 1: Frequency of NRAS mutants in human melanoma parallels tumorigenic potential in mice. a Frequency of NRAS mutations in the TCGA PanCancer Atlas dataset for human cutaneous melanoma. Melanoma-free survival ( b ), total tumor burden ( c ), and tumor growth rates ( d ) for mice expressing the indicated melanocyte-specific NRAS mutants. Tumor burden and growth rate data are presented as mean values +/− SD. The following number biologically independent animals were evaluated per genotype (61R = 72, 61K = 19, 61L = 17, 61H = 17, 61P = 16, 61Q = 22). Log-rank (Mantel–Cox) ( b ) or ANOVA ( c , d ) with a Tukey’s multiple comparisons test was used to compare measurements between each genotype. TN X/X samples statistically different<|im_end|> <|im_start|>assistant A new study reveals important molecular information that could help scientists develop more effective treatment and prevention strategies for a difficult-to-treat form of melanoma skin cancer. In this new report, The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC—James) researchers identify and describe key features of a gene mutation responsible for 15 to 20% of all melanomas. Using a preclinical laboratory model, the team establishes that the frequency at which a specific NRAS gene mutation occurs in human melanoma is directly related to the ability of that gene mutation to initiate spontaneous melanoma formation. "This means that properties of the mutant itself—rather than the ease at which that specific gene mutation occurs—is the cause of cancer formation," said corresponding author Christin Burd who serves an associate professor of molecular genetics in The Ohio State University College of Arts and Sciences, Department of Molecular Genetics and a member of the OSUCCC—James Molecular Carcinogenesis and Chemoprevention Program. "NRAS-mutant cancers are challenging to treat because effective therapies beyond immunotherapy don't exist yet," said Burd. "Each cancer type seems to prefer a specific 'flavor' of mutant NRAS, and it has not been clear why this is." The OSUCCC—James wanted to know what made the melanoma-promoting NRAS mutants different than those that promote other cancer types. Scientists say this knowledge could help investigators pinpoint the early events required for melanoma formation and develop treatments that prevent the disease. Burd and colleagues report their findings in the June 7, 2022, issue of Nature Communications. Study design and methods To conduct this study, OSUCCC-James researchers developed genetically engineered models that would allow them to activate one of nine different NRAS-mutant variations in melanocytes, the pigment cells that form melanoma. "Amazingly, when we activated these gene mutations only those found in the human disease caused melanoma to develop," said Burd. "Some mutants never led to melanoma, yet we know that they cause leukemia. This finding shows that selection of NRAS mutations is specific to each tumor type and occurs during cancer initiation, rather than in response to a specific mutagenic event like sun exposure." Collaborating with Sharon Campbell, a structural biologist at the University of North Carolina (UNC) Chapel Hill, and Debbie Morrison at the National Institutes of Health, Burd's team identified that slight variances in the outward facing structure of NRAS mutants capable of initiating melanoma that made these proteins better able to interact with the signaling pathways that drive melanoma growth. "Now we will work to target this unique structural feature of the melanoma-inducing NRAS mutants to prevent and/or treat the disease," said Burd. "Our work also demonstrates and confirms what was—until now—only speculation: that minor differences between the RAS mutants determine which 'flavors' can cause a particular cancer. Such a concept could be used to find vulnerabilities in other RAS-driven tumor types." To facilitate similar discoveries, the team generated eight new and publicly available genetically engineered mouse models that will serve as an essential toolkit for the entire RAS community. Burd says these models can be used to activate and study the role of NRAS is other relevant cancer types such as colon cancer, leukemia, myeloma, and thyroid cancer. They can also be used to investigate new drugs for these diseases. The preclinical research models developed in Burd's lab and used for this research are publicly available to scientists conducting research about other RAS-driven cancer types or working to develop new cancer therapies through the National Institute of Health's repository. <|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 organoids maintain cell–cell interactions, heterogeneity, microenvironment, and drug response of the sample they originate from. Thus, there is increasing interest in developing tumor organoid models for drug development and personalized medicine applications. Although organoids are in principle amenable to high-throughput screenings, progress has been hampered by technical constraints and extensive manipulations required by current methods. Here we introduce a miniaturized method that uses a simplified geometry by seeding cells around the rim of the wells (mini-rings). This allows high-throughput screenings in a format compatible with automation as shown using four patient-derived tumor organoids established from two ovarian and one peritoneal high-grade serous carcinomas and one carcinosarcoma of the ovary. Using our automated screening platform, we identified personalized responses by measuring viability, number, and size of organoids after exposure to 240 kinase inhibitors. Results are available within a week from surgery, a timeline compatible with therapeutic decision-making. Introduction Cancer therapy is rapidly progressing toward individualized regimens not based on the organ of origin, but rather on the molecular characteristics of tumors. Next-generation sequencing is typically regarded as the key to access this potentially actionable molecular information 1 , 2 . However, recent studies showed how only a small number of cancers can be singled out and targeted with this approach, in part because very few gene alteration–drug pairs are unequivocally established and few accurate predictive biomarkers are available 3 , 4 , 5 , 6 , 7 . Thus, functional precision therapy approaches where the primary tumor tissue is directly exposed to drugs, to determine which may be efficacious, have the potential to boost personalized medicine efforts and influence clinical decisions 3 , 4 . Establishing patient-derived xenografts (PDXs) is a costly and time-consuming option that only allows to screen very few potential drugs. Conversely, ex vivo three-dimensional (3D) tumor spheroids or organoids derived from primary cancers can be easily established and potentially scaled to screen hundreds to thousands of different conditions. 3D cancer models have been consistently shown to faithfully recapitulate features of the tumor of origin in terms of cell differentiation, heterogeneity, histoarchitecture, and clinical drug response 4 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Various methods to set up tumor spheroids or organoids have been proposed, including using low-attachment U-bottom plates, feeding layers, or various biological and artificial matrices 9 , 12 , 13 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Methods using low-attachment U-bottom plates ideally only carry one organoid per well and have limited automation and final assay capabilities 19 , 20 , 21 . In addition, not all cells are capable of forming organized 3D structures with this method. Approaches that include a bio-matrix, such as Matrigel, have the potential to offer a scalable alternative in which cancer cells thrive 9 , 14 , 24 , 25 . However, most methods proposed so far rely on thick volumes of matrix, which is not cost-effective, potentially hard for drugs to efficiently penetrate, and difficult to dissolve fully at the end of the experiment 4 , 24 . In other applications, organoids are first formed and then transferred to different plates for drug treatment or final readout, which can result in the tumor spheres sticking to plastic or breaking 14 , 25 . In addition, some assays require to disrupt the organoids to single-cell suspensions at the end of the experiment 17 , 23 . All of these manipulations introduce large variability, limiting applicability in screening efforts 12 . To overcome these limitations, we introduce a facile assay system to screen 3D tumor organoids that takes advantage of a specific geometry. Our miniaturized ring methodology does not require functionalized plates. Organoids are assayed in the same plate where they are seeded, with no need for sample transfer at any stage or dissociation of the pre-formed tumor organoids to a single-cell suspension. Here we show that the mini-ring approach is simple, robust, requires few cells, and can be easily automated for high-throughput applications. Using this method, we were able to rapidly identify clinically actionable drug sensitivities for several ovarian cancers and high-grade serous tumors by testing two different drug concentrations and a library of 240 protein kinase inhibitor compounds. Results Establishment of 3D tumor models in ring format To rapidly screen organoids, we first established a miniaturized system that allows the setup of hundreds of wells and perform assays with minimal manipulation. We adapted the geometry used to plate tumor cells in Matrigel, to generate mini-rings around the rim of the wells. This is attained by plating single-cell suspensions obtained from a cell line or a surgical specimen pre-mixed with cold Matrigel (3:4 ratio) in a ring shape around the rim in 96-well plates (Fig. 1a ). Rings can be established using a single-well or multichannel pipette. Use of a robotic system or automated 96-well pipettor is theoretically feasible as long as temperature and plate positioning can be effectively controlled. The combination of small volume plated (10 µl) and surface tension holds the cells in place until the Matrigel solidifies upon incubation at 37 °C and prevents two-dimensional (2D) growth at the center of the wells. The ring configuration allows for media addition and removal so that changes of conditions or treatment addition to be easily performed by pipetting directly in the center of the well, preventing any disruption of the gel. Cancer cell lines grown in mini-ring format give rise to organized tumor organoids that recapitulate features of the original histology (Supplementary Fig. 1 and Supplementary Table 1 ). Fig. 1 The mini-ring method for 3D tumor cell biology. a Schematics of the mini-ring setup. Cells are plated to form a solid thin ring as depicted in 1 and photographed in 2. The picture in 3 acquired with a cell imager shows tumor organoids growing at the periphery of the well as desired, with no invasion of the center. b Proliferation of primary", "role": "user" }, { "content": "UCLA scientists have developed a new method to quickly screen hundreds of drugs in order to identify treatments that can target specific tumors. The approach could help scientists understand how a person's tumor would respond to a certain drug or drug combination, and it could help guide treatment decisions for people with rare and hard-to-treat cancers. A paper detailing the new technique was published in Communications Biology. \"We always focus on how we need new and better drugs to treat cancer,\" said Alice Soragni, the senior author of the study and a scientist at the UCLA Jonsson Comprehensive Cancer Center. \"While that's true, we also have many drugs currently available—we just haven't been able to figure out who is going to respond to which ones for most of them.\" The screening method uses patients' own cells, collected during surgery, to create miniature tumor organoids. Organoids are simpler, smaller versions of bodily organs or tumors that scientists can grow in a lab to replicate the full-function structures; researchers create them to study diseases and possible treatments. \"We obtain cancer cells directly from surgery and that same day we can seed them to generate tumor organoids,\" said Soragni, an assistant professor in the division of hematology/oncology at the David Geffen School of Medicine at UCLA and member of the Molecular Biology Institute at UCLA. \"We created a miniaturized system that allows the setup of hundreds of wells for testing with minimal manipulation.\" After the tumor organoids are established, typically in three to five days, the lab screens hundreds of drugs to determine which ones are effective. The approach developed by Soragni's lab uses an automated feed—instead of testing one drug at a time, scientists use robots to simultaneously screen hundreds of different treatments. The method is fast and efficient: The entire process, from surgery to final results, can take as little as one to two weeks. To test the technique, Soragni's team took cells from four patients—three with ovarian cancer and one with peritoneal cancer—to grow tumor organoids. The test enabled the researchers to produce personalized snapshots of which drugs were effective for each patient's organoids. For example, one of the four participants in the study was a woman with an extremely rare type of ovarian cancer. (The specific subtype of cancer is diagnosed in fewer than 200 U.S. women each year.) The organoids developed from her cancer cells responded to a class of drugs called cyclin-kinase inhibitors, which can target cancer by preventing it from growing. Soragni said there are currently no known biomarkers to predict the effect of the specific cyclin-kinase inhibitors identified by the screening on tumor growth. So without the test, it would have been impossible to know that the drugs would work on that specific subtype of cancer. For many rare types of cancer, scientists know little about drug susceptibilities. But being able to create models of rare tumors in the lab can help scientists identify patients who could benefit the most from a specific treatment. In addition to identifying personalized treatments, the technique could also help scientists select patients to participate in clinical trials for potential new cancer therapies. \"This could become a powerful tool to help guide therapies for people who really have no known treatment options left,\" Soragni 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 Tumor organoids maintain cell–cell interactions, heterogeneity, microenvironment, and drug response of the sample they originate from. Thus, there is increasing interest in developing tumor organoid models for drug development and personalized medicine applications. Although organoids are in principle amenable to high-throughput screenings, progress has been hampered by technical constraints and extensive manipulations required by current methods. Here we introduce a miniaturized method that uses a simplified geometry by seeding cells around the rim of the wells (mini-rings). This allows high-throughput screenings in a format compatible with automation as shown using four patient-derived tumor organoids established from two ovarian and one peritoneal high-grade serous carcinomas and one carcinosarcoma of the ovary. Using our automated screening platform, we identified personalized responses by measuring viability, number, and size of organoids after exposure to 240 kinase inhibitors. Results are available within a week from surgery, a timeline compatible with therapeutic decision-making. Introduction Cancer therapy is rapidly progressing toward individualized regimens not based on the organ of origin, but rather on the molecular characteristics of tumors. Next-generation sequencing is typically regarded as the key to access this potentially actionable molecular information 1 , 2 . However, recent studies showed how only a small number of cancers can be singled out and targeted with this approach, in part because very few gene alteration–drug pairs are unequivocally established and few accurate predictive biomarkers are available 3 , 4 , 5 , 6 , 7 . Thus, functional precision therapy approaches where the primary tumor tissue is directly exposed to drugs, to determine which may be efficacious, have the potential to boost personalized medicine efforts and influence clinical decisions 3 , 4 . Establishing patient-derived xenografts (PDXs) is a costly and time-consuming option that only allows to screen very few potential drugs. Conversely, ex vivo three-dimensional (3D) tumor spheroids or organoids derived from primary cancers can be easily established and potentially scaled to screen hundreds to thousands of different conditions. 3D cancer models have been consistently shown to faithfully recapitulate features of the tumor of origin in terms of cell differentiation, heterogeneity, histoarchitecture, and clinical drug response 4 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Various methods to set up tumor spheroids or organoids have been proposed, including using low-attachment U-bottom plates, feeding layers, or various biological and artificial matrices 9 , 12 , 13 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Methods using low-attachment U-bottom plates ideally only carry one organoid per well and have limited automation and final assay capabilities 19 , 20 , 21 . In addition, not all cells are capable of forming organized 3D structures with this method. Approaches that include a bio-matrix, such as Matrigel, have the potential to offer a scalable alternative in which cancer cells thrive 9 , 14 , 24 , 25 . However, most methods proposed so far rely on thick volumes of matrix, which is not cost-effective, potentially hard for drugs to efficiently penetrate, and difficult to dissolve fully at the end of the experiment 4 , 24 . In other applications, organoids are first formed and then transferred to different plates for drug treatment or final readout, which can result in the tumor spheres sticking to plastic or breaking 14 , 25 . In addition, some assays require to disrupt the organoids to single-cell suspensions at the end of the experiment 17 , 23 . All of these manipulations introduce large variability, limiting applicability in screening efforts 12 . To overcome these limitations, we introduce a facile assay system to screen 3D tumor organoids that takes advantage of a specific geometry. Our miniaturized ring methodology does not require functionalized plates. Organoids are assayed in the same plate where they are seeded, with no need for sample transfer at any stage or dissociation of the pre-formed tumor organoids to a single-cell suspension. Here we show that the mini-ring approach is simple, robust, requires few cells, and can be easily automated for high-throughput applications. Using this method, we were able to rapidly identify clinically actionable drug sensitivities for several ovarian cancers and high-grade serous tumors by testing two different drug concentrations and a library of 240 protein kinase inhibitor compounds. Results Establishment of 3D tumor models in ring format To rapidly screen organoids, we first established a miniaturized system that allows the setup of hundreds of wells and perform assays with minimal manipulation. We adapted the geometry used to plate tumor cells in Matrigel, to generate mini-rings around the rim of the wells. This is attained by plating single-cell suspensions obtained from a cell line or a surgical specimen pre-mixed with cold Matrigel (3:4 ratio) in a ring shape around the rim in 96-well plates (Fig. 1a ). Rings can be established using a single-well or multichannel pipette. Use of a robotic system or automated 96-well pipettor is theoretically feasible as long as temperature and plate positioning can be effectively controlled. The combination of small volume plated (10 µl) and surface tension holds the cells in place until the Matrigel solidifies upon incubation at 37 °C and prevents two-dimensional (2D) growth at the center of the wells. The ring configuration allows for media addition and removal so that changes of conditions or treatment addition to be easily performed by pipetting directly in the center of the well, preventing any disruption of the gel. Cancer cell lines grown in mini-ring format give rise to organized tumor organoids that recapitulate features of the original histology (Supplementary Fig. 1 and Supplementary Table 1 ). Fig. 1 The mini-ring method for 3D tumor cell biology. a Schematics of the mini-ring setup. Cells are plated to form a solid thin ring as depicted in 1 and photographed in 2. The picture in 3 acquired with a cell imager shows tumor organoids growing at the periphery of the well as desired, with no invasion of the center. b Proliferation of primary<|im_end|> <|im_start|>assistant UCLA scientists have developed a new method to quickly screen hundreds of drugs in order to identify treatments that can target specific tumors. The approach could help scientists understand how a person's tumor would respond to a certain drug or drug combination, and it could help guide treatment decisions for people with rare and hard-to-treat cancers. A paper detailing the new technique was published in Communications Biology. "We always focus on how we need new and better drugs to treat cancer," said Alice Soragni, the senior author of the study and a scientist at the UCLA Jonsson Comprehensive Cancer Center. "While that's true, we also have many drugs currently available—we just haven't been able to figure out who is going to respond to which ones for most of them." The screening method uses patients' own cells, collected during surgery, to create miniature tumor organoids. Organoids are simpler, smaller versions of bodily organs or tumors that scientists can grow in a lab to replicate the full-function structures; researchers create them to study diseases and possible treatments. "We obtain cancer cells directly from surgery and that same day we can seed them to generate tumor organoids," said Soragni, an assistant professor in the division of hematology/oncology at the David Geffen School of Medicine at UCLA and member of the Molecular Biology Institute at UCLA. "We created a miniaturized system that allows the setup of hundreds of wells for testing with minimal manipulation." After the tumor organoids are established, typically in three to five days, the lab screens hundreds of drugs to determine which ones are effective. The approach developed by Soragni's lab uses an automated feed—instead of testing one drug at a time, scientists use robots to simultaneously screen hundreds of different treatments. The method is fast and efficient: The entire process, from surgery to final results, can take as little as one to two weeks. To test the technique, Soragni's team took cells from four patients—three with ovarian cancer and one with peritoneal cancer—to grow tumor organoids. The test enabled the researchers to produce personalized snapshots of which drugs were effective for each patient's organoids. For example, one of the four participants in the study was a woman with an extremely rare type of ovarian cancer. (The specific subtype of cancer is diagnosed in fewer than 200 U.S. women each year.) The organoids developed from her cancer cells responded to a class of drugs called cyclin-kinase inhibitors, which can target cancer by preventing it from growing. Soragni said there are currently no known biomarkers to predict the effect of the specific cyclin-kinase inhibitors identified by the screening on tumor growth. So without the test, it would have been impossible to know that the drugs would work on that specific subtype of cancer. For many rare types of cancer, scientists know little about drug susceptibilities. But being able to create models of rare tumors in the lab can help scientists identify patients who could benefit the most from a specific treatment. In addition to identifying personalized treatments, the technique could also help scientists select patients to participate in clinical trials for potential new cancer therapies. "This could become a powerful tool to help guide therapies for people who really have no known treatment options left," Soragni said. <|im_end|>

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1,999

[ { "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 binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design. Introduction Proteins are central to biology as they carry out a wide range of essential functions, from gene regulation to enzymatic catalysis, where their ability to specifically interact with other biomolecules is crucial. In pharmacology, inhibiting their interactions using drug-like small molecules is a common approach to modulate biological functions relevant to disease. In cases where the binding partner is another protein, the binding interfaces are usually flat and extended 1 , making it challenging to inhibit the interactions with small molecules 2 , and it is generally preferable to target them with antibodies. Yet, despite recent progress in intracellular antibody delivery 3 , their clinical applications have been limited to targeting extracellular proteins, highlighting the need to develop new molecular tools to inhibit intracellular protein-protein interactions. Peptides have some of the advantages of small molecules, such as their ease of synthesis, and some of the advantages of antibodies, such as their relatively large size. Peptides, therefore, have at least in principle great potential as modulators of protein-protein interactions for pharmacological applications 4 , 5 . Protein-protein interactions where one partner is in a helical conformation are particularly common and especially amenable to inhibition by peptides: an excised linear peptide comprising a suitable sequence can, in principle, inhibit the interaction if it can bind to its partner with high affinity 6 . Linear peptides have a low propensity to fold into stable α-helices, however, and the entropic cost of folding decreases both their affinity for their targets and their stability against proteolytic degradation, highlighting the need to develop new tools to stabilize their helical conformation. Introducing non-natural amino acids that act as potent N-caps 7 or substituting the i + 4 → i hydrogen bonds stabilizing this secondary structure by covalent, and therefore permanent, surrogates 8 can be used to achieve this goal. Alternatively, specific amino acids can be introduced at positions i and i + 3 , i and i + 4 or i and i + 7 , that are close in space in α-helices, and linked by different means 9 , 10 such as by peptide stapling 11 , 12 . Peptide stapling is based on the use of pairs of synthetic α-methyl, α-alkenyl amino acids at relative positions i,i + 3 , i,i + 4 or i,i + 7 where their side chains can react by ring-closing metathesis when the peptide folds into an α-helix, thus greatly stabilizing this conformation 11 , 12 ; in some cases, two such connections have been concatenated to obtain especially long and stable helices 13 . Although these approaches have shown applicability to inhibit protein-protein interactions, they have drawbacks that limit their range of applicability, such as their costly synthesis, limited solubility, and high rigidity. We recently reported that Gln side chain to main chain hydrogen bonds stabilize the polyglutamine (polyQ) helix, a helical secondary structure formed by the polyQ tract of the androgen receptor (AR) 14 , 15 . In this structure both the main and side chain amide groups of Gln residues at position i donate hydrogens to the main chain CO group of the residues at position i-4; the strength of this bifurcate interaction depends on the residue at position i-4 , with Leu performing particularly well. Equivalent interactions have also been observed in the polyQ tract of the protein huntingtin, indicating that it is not specific to AR and can therefore be used in design 16 . As the relative donor and acceptor positions of such interactions are equivalent to those of the residues linked covalently in stapled peptides, we reasoned that side chain to main chain hydrogen bonds could be used to stabilize the α-helical conformation of linear peptides to enhance their interaction with globular proteins. Here, to address this hypothesis we design a series of linear, uncharged, and highly soluble peptides and confirm their cooperative folding into single α-helices under physiological conditions. To evaluate the versatility and range of applicability of the design rules we analyze their tolerance towards changes of the acceptor residue, with bulky hydrophobic residues performing best, and introduce a pH-dependent conformational switch; in addition we explore how such bifurcated hydrogen bonds can be combined with electrostatic interactions between side chains to further stabilize α-helices. Most importantly, we show that the sequences of such peptides can be tailored to interact with specific globular proteins. In summary, the simple design rules that we propose can be used to engineer a class of linear, cooperatively folded helical peptides for use as templates in applications in pharmacology, materials science, synthetic biology and, more generally, in bioengineering. Results Design of Gln-based single α-helices The helicity of peptides and intrinsically disordered (ID) proteins can be predicted by secondary structure prediction algorithms such as Agadir 17 . This algorithm, similar to the Zimm-Bragg 18 and Lifson-Roig 19 helix-coil transition models, is based on statistical mechanics. The statistical weight of the helical state of any peptide segment depends on the free energy of it folding into an α-helix, that Agadir computes as the sum of different terms including one accounting for interactions between residues at positions i and i + 4 , close in space in α-helices, that requires experimental", "role": "user" }, { "content": "Inside cells, proteins constantly interact with each other to carry out different functions. For some diseases in which these functions are altered, blocking the binding between two or more proteins emerges as a possible therapeutic approach. Scientists led by ICREA researcher Dr. Xavier Salvatella at IRB Barcelona have published guidelines for designing synthetic molecules that block the interaction between two proteins in the journal Nature Communications. In brief, the researchers have focused on the interactions characterized by the binding of an α-helix of one of the proteins on the surface of the other. This interaction mechanism is very common and prevalent in cell functions of therapeutic interest related to diseases such as prostate cancer. The guidelines presented in this work allow scientists to develop molecules in a relatively straightforward manner that block (potentially) any interaction between a globular protein and an α-helix, thus offering high versatility. These synthetic molecules also show high stability, are soluble in water, and can reach the interior of the cell. Such characteristics make them ideal drug candidates. \"Our work proposes a simple way to block interactions between globular proteins mediated by α-helices and it can benefit both protein engineering and drug development efforts,\" explains Dr. Salvatella, head of the Molecular Biophysics Laboratory at IRB Barcelona. \"It's an approach based on research performed by our lab addressing the natural interactions of certain proteins, and it proposes using this knowledge to achieve therapeutic objectives through the design of small molecules with artificial sequences,\" he adds. Competition for a binding site When two proteins recognize each other in the cell and interact, it is because a region on their surfaces fits, thus allowing binding. The molecules addressed in this work, like many commonly used drugs, mimic this site on the surface of one of the proteins involved in the interaction, such that they compete to bind to the site of the other protein, which is also referred to as the target protein. Thus, if the competitor molecule is present at a higher concentration or has a greater affinity for the target protein, it will occupy all the binding sites and block any possible interaction with the original protein that the drug is mimicking. However, the size of large protein interaction interfaces makes it difficult to mimic the binding surface between them. \"What we propose in this work is to create molecules in the form of α-helices that offer a configurable surface to fit the target protein, and we explain how to ensure that this helix maintains a stable structure in the cellular context,\" explains Dr. Albert Escobedo, currently a postdoctoral researcher at the Center for Genomic Regulation (CRG), who led the work together with Dr. Salvatella at IRB Barcelona. Describing the interactions and searching for a stable structure The researchers have focused their efforts on detailing the characteristics that these synthetic molecules must meet to show stability and be able to perform their function of inhibiting the interaction between two proteins. In the study, they describe how several consecutive repetitions with a certain pattern of pairs of the amino acid glutamine and another hydrophobic amino acid confer stability to the helix. In contrast to other approaches with the same purpose, the exclusive use of natural amino acids and the absence of chemical modifications to stabilize the helix can enhance the biocompatibility and safety of the drugs designed using the new guidelines described. In another study published in Nature Communications in 2019, the researchers had already observed that, for a given protein, the number of glutamine residues present in the structure condition the stability of its helix-shaped structure. In this new study, they have confirmed that the same thing also occurs in other proteins, they explain why and use the knowledge acquired to increase the versatility of the molecules designed. Also, they propose how changes in the number of glutamine residues present in different proteins can cause different diseases. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design. Introduction Proteins are central to biology as they carry out a wide range of essential functions, from gene regulation to enzymatic catalysis, where their ability to specifically interact with other biomolecules is crucial. In pharmacology, inhibiting their interactions using drug-like small molecules is a common approach to modulate biological functions relevant to disease. In cases where the binding partner is another protein, the binding interfaces are usually flat and extended 1 , making it challenging to inhibit the interactions with small molecules 2 , and it is generally preferable to target them with antibodies. Yet, despite recent progress in intracellular antibody delivery 3 , their clinical applications have been limited to targeting extracellular proteins, highlighting the need to develop new molecular tools to inhibit intracellular protein-protein interactions. Peptides have some of the advantages of small molecules, such as their ease of synthesis, and some of the advantages of antibodies, such as their relatively large size. Peptides, therefore, have at least in principle great potential as modulators of protein-protein interactions for pharmacological applications 4 , 5 . Protein-protein interactions where one partner is in a helical conformation are particularly common and especially amenable to inhibition by peptides: an excised linear peptide comprising a suitable sequence can, in principle, inhibit the interaction if it can bind to its partner with high affinity 6 . Linear peptides have a low propensity to fold into stable α-helices, however, and the entropic cost of folding decreases both their affinity for their targets and their stability against proteolytic degradation, highlighting the need to develop new tools to stabilize their helical conformation. Introducing non-natural amino acids that act as potent N-caps 7 or substituting the i + 4 → i hydrogen bonds stabilizing this secondary structure by covalent, and therefore permanent, surrogates 8 can be used to achieve this goal. Alternatively, specific amino acids can be introduced at positions i and i + 3 , i and i + 4 or i and i + 7 , that are close in space in α-helices, and linked by different means 9 , 10 such as by peptide stapling 11 , 12 . Peptide stapling is based on the use of pairs of synthetic α-methyl, α-alkenyl amino acids at relative positions i,i + 3 , i,i + 4 or i,i + 7 where their side chains can react by ring-closing metathesis when the peptide folds into an α-helix, thus greatly stabilizing this conformation 11 , 12 ; in some cases, two such connections have been concatenated to obtain especially long and stable helices 13 . Although these approaches have shown applicability to inhibit protein-protein interactions, they have drawbacks that limit their range of applicability, such as their costly synthesis, limited solubility, and high rigidity. We recently reported that Gln side chain to main chain hydrogen bonds stabilize the polyglutamine (polyQ) helix, a helical secondary structure formed by the polyQ tract of the androgen receptor (AR) 14 , 15 . In this structure both the main and side chain amide groups of Gln residues at position i donate hydrogens to the main chain CO group of the residues at position i-4; the strength of this bifurcate interaction depends on the residue at position i-4 , with Leu performing particularly well. Equivalent interactions have also been observed in the polyQ tract of the protein huntingtin, indicating that it is not specific to AR and can therefore be used in design 16 . As the relative donor and acceptor positions of such interactions are equivalent to those of the residues linked covalently in stapled peptides, we reasoned that side chain to main chain hydrogen bonds could be used to stabilize the α-helical conformation of linear peptides to enhance their interaction with globular proteins. Here, to address this hypothesis we design a series of linear, uncharged, and highly soluble peptides and confirm their cooperative folding into single α-helices under physiological conditions. To evaluate the versatility and range of applicability of the design rules we analyze their tolerance towards changes of the acceptor residue, with bulky hydrophobic residues performing best, and introduce a pH-dependent conformational switch; in addition we explore how such bifurcated hydrogen bonds can be combined with electrostatic interactions between side chains to further stabilize α-helices. Most importantly, we show that the sequences of such peptides can be tailored to interact with specific globular proteins. In summary, the simple design rules that we propose can be used to engineer a class of linear, cooperatively folded helical peptides for use as templates in applications in pharmacology, materials science, synthetic biology and, more generally, in bioengineering. Results Design of Gln-based single α-helices The helicity of peptides and intrinsically disordered (ID) proteins can be predicted by secondary structure prediction algorithms such as Agadir 17 . This algorithm, similar to the Zimm-Bragg 18 and Lifson-Roig 19 helix-coil transition models, is based on statistical mechanics. The statistical weight of the helical state of any peptide segment depends on the free energy of it folding into an α-helix, that Agadir computes as the sum of different terms including one accounting for interactions between residues at positions i and i + 4 , close in space in α-helices, that requires experimental<|im_end|> <|im_start|>assistant Inside cells, proteins constantly interact with each other to carry out different functions. For some diseases in which these functions are altered, blocking the binding between two or more proteins emerges as a possible therapeutic approach. Scientists led by ICREA researcher Dr. Xavier Salvatella at IRB Barcelona have published guidelines for designing synthetic molecules that block the interaction between two proteins in the journal Nature Communications. In brief, the researchers have focused on the interactions characterized by the binding of an α-helix of one of the proteins on the surface of the other. This interaction mechanism is very common and prevalent in cell functions of therapeutic interest related to diseases such as prostate cancer. The guidelines presented in this work allow scientists to develop molecules in a relatively straightforward manner that block (potentially) any interaction between a globular protein and an α-helix, thus offering high versatility. These synthetic molecules also show high stability, are soluble in water, and can reach the interior of the cell. Such characteristics make them ideal drug candidates. "Our work proposes a simple way to block interactions between globular proteins mediated by α-helices and it can benefit both protein engineering and drug development efforts," explains Dr. Salvatella, head of the Molecular Biophysics Laboratory at IRB Barcelona. "It's an approach based on research performed by our lab addressing the natural interactions of certain proteins, and it proposes using this knowledge to achieve therapeutic objectives through the design of small molecules with artificial sequences," he adds. Competition for a binding site When two proteins recognize each other in the cell and interact, it is because a region on their surfaces fits, thus allowing binding. The molecules addressed in this work, like many commonly used drugs, mimic this site on the surface of one of the proteins involved in the interaction, such that they compete to bind to the site of the other protein, which is also referred to as the target protein. Thus, if the competitor molecule is present at a higher concentration or has a greater affinity for the target protein, it will occupy all the binding sites and block any possible interaction with the original protein that the drug is mimicking. However, the size of large protein interaction interfaces makes it difficult to mimic the binding surface between them. "What we propose in this work is to create molecules in the form of α-helices that offer a configurable surface to fit the target protein, and we explain how to ensure that this helix maintains a stable structure in the cellular context," explains Dr. Albert Escobedo, currently a postdoctoral researcher at the Center for Genomic Regulation (CRG), who led the work together with Dr. Salvatella at IRB Barcelona. Describing the interactions and searching for a stable structure The researchers have focused their efforts on detailing the characteristics that these synthetic molecules must meet to show stability and be able to perform their function of inhibiting the interaction between two proteins. In the study, they describe how several consecutive repetitions with a certain pattern of pairs of the amino acid glutamine and another hydrophobic amino acid confer stability to the helix. In contrast to other approaches with the same purpose, the exclusive use of natural amino acids and the absence of chemical modifications to stabilize the helix can enhance the biocompatibility and safety of the drugs designed using the new guidelines described. In another study published in Nature Communications in 2019, the researchers had already observed that, for a given protein, the number of glutamine residues present in the structure condition the stability of its helix-shaped structure. In this new study, they have confirmed that the same thing also occurs in other proteins, they explain why and use the knowledge acquired to increase the versatility of the molecules designed. Also, they propose how changes in the number of glutamine residues present in different proteins can cause different diseases. <|im_end|>

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5353, 2204, 19338, 13, 220, 128257, 198 ]

2,089

[ { "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 Genetic data are increasingly used for fast, efficient, and cost-effective monitoring of natural populations and assessment of extinction risk in species management. A single modern molecular snapshot is typically used to infer population size and vulnerability, yet for species with unknown and potentially complex genetic metapopulation structure, this technique may not effectively predict vulnerability. Darwin’s finches, which are well-represented in museum collections, offer a unique opportunity to test the effectiveness of predicting extinction vulnerability in species with complex structure, such as naturally fragmented populations. In this study, we compared ancient DNA from ~ 100 year old extinct and extant Darwin’s finch populations in the Galápagos Islands to determine whether single time point genetic assessments in the past accurately predicted extinction risk, or if other factors such as metapopulation dynamics could mask population declines. Of eight extinct populations, only one had significantly reduced genetic variation compared to an extant population of similar characteristics. Contrary to our prediction that populations would have decreased genetic diversity prior to extinction when compared to persisting populations, at least one measure of genetic diversity was significantly higher in six of the eight extinct populations when compared to extant populations. Simulations lend support to the hypothesis that unaccounted for metapopulation structure may explain the observed pattern in many species. Therefore, models of genetic diversity reflecting population extinction potential may be inadequate for highly-mobile species with metapopulation dynamics such as the Galápagos finches. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction As the number of threatened and endangered species rises worldwide, there is an increasing demand for fast, efficient and cost-effective ways to monitor natural populations and assess extinction risk. One measure commonly used to approximate extinction risk for populations or species is genetic diversity. Typically, as few species have historical specimens available for comparison, a single modern genetic snapshot is used to determine if a population has patterns of genetic diversity that fit a model of a declining population. For those populations or species that have gone extinct, low genetic diversity is strongly associated with extinction risk (Spielman et al. 2004 ; Evans and Sheldon 2008 ; Hieb et al. 2014 ). These declines in genetic richness are rapidly detectable (Antao et al. 2011 ), and can be used to evaluate effective population sizes and trends, and detect recent bottlenecks in individual populations (Schwartz et al. 2007 ; Antao et al. 2011 ; Méndez et al. 2014 ). In cases of extreme decline, where only remnants of a single population remain, the connection between lower genetic diversity, decline in population size, and increased extinction risk is clear. Little is known, however, about whether allelic richness and diversity alone can differentiate lineages that will survive from those that will perish in complex ecosystems, particularly when only a modern genetic assessment is available. The use of genetic diversity as a measure of extinction potential in vulnerable species has a number of shortcomings in its application, foremost being that in most studies the ultimate fate of the population of interest is unknown. Low or declining genetic diversity does not guarantee imminent extinction as there have been several examples of species persisting over extended time periods despite low genetic diversity (e.g., Johnson et al. 2009 ; Reed 2010 ). Without sampling through time using historical samples, the performance of theoretical models of extinction risk or population declines (e.g., VORTEX (Lacy 1993 , 2000 ), BOTTLENECK (Cornuet and Luikart 1996 )) remains largely untested. Additionally, in species with a metapopulation structure of populations with ongoing gene flow, measuring genetic diversity of individual populations without taking into account the dynamics of gene flow from healthy populations (sources) into vulnerable ones (sinks) can lead to erroneous results (Keller et al. 2001 ; Caplins et al. 2014 ; Frankham et al. 2017 ). Continuous monitoring in vertebrates shows that declining populations may have inflated measures of genetic diversity if receiving immigration from other populations (e.g., Smyser et al. 2016 ). Thus, by measuring single populations, their standing genetic diversity may be unrelated to extinction risk (Hanski and Gilpin 1991 ). Due to these limitations, a test of extinction dynamics in a natural system of fragmented populations with both historical and modern genetic sampling would be valuable for gaining a better understanding of the genetic signatures found in localized populations approaching extinction within complex systems. The adaptive radiation of Darwin’s finches in the Galápagos Islands provides a unique opportunity to study population vulnerability in a complex system with many codistributed species for comparisons. There are approximately 19 species currently recognized within this radiation (Lamichhaney et al. 2015 ), and besides a few island endemics (e.g., Camarhynchus heliobates on Isabela Island and C. pauper of Floreana Island), most species within the radiation have distributions spanning many islands (e.g., Geospiza scandens is found on 10 major islands, G. fuliginosa on 12, Camarhynchus parvulus on 10). These populations appear to act as metapopulations, with non-inconsequential estimates of migration (Petren et al. 2005 ; Farrington and Petren 2011 ). As these islands have been sampled for over 100 years since Darwin’s first visit, this system provides unique access to both historical and current genetic samples and distribution data. Based on avian models from other remote islands (Steadman 2006 ; Pratt 2009 ), there is a strong expectation that Galápagos bird communities should be in decline due to recent human-induced ecological changes such as invasive species (Eckhardt 1972 ), habitat alteration (Watson et al. 2010 ; O’Connor et al. 2010a , b ), introduced diseases and parasites (Wikelski et al. 2004 ; Dudaniec and Kleindorfer 2006 ; Parker et al. 2011 ; Kleindorfer et al. 2014b ; Rivera-Parra et al. 2014 ; Kleindorfer and Dudaniec 2016 ), and hybridization (Kleindorfer et al. 2014a ; Lawson et al. 2017 ). Although there have been no known avian species extinctions in the Galápagos, current population extinction rates are approximately 100 times greater than those during the era prior to human colonization (across vertebrate species:", "role": "user" }, { "content": "Scientists who are trying to save species at the brink of extinction are finding help in an unexpected place. Heather Farrington, curator of zoology for the Cincinnati Museum Center, is using DNA from specimens collected more than 100 years ago to help understand the evolution and stresses faced by today's animals. Farrington runs the museum's new state-of-the-art genetics laboratory, which helps researchers study populations of animals over time. Researchers increasingly are embracing the power of ancient DNA from old museum specimens to answer questions about climate change, habitat loss and other stresses on surviving populations. Ancient DNA has been used to explain the diversity of livestock in Africa and the first domestication of wild horses in Asia. Farrington earned her doctorate in biological sciences from the University of Cincinnati, where she charted the family trees of Galapagos finches and used the latest DNA tools to gain fresh insights about the birds from century-old museum specimens. The museum's genetics lab works with researchers and government agencies on a variety of projects that require DNA analysis, from conserving wildlife to improving our understanding of the natural world. Recently, the lab helped with a conservation project on the Allegheny woodrat, a small rock-loving rodent that is in decline across much of its historic range from Indiana to New Jersey. In Ohio it's found in only one place, the Richard and Lucille Durrell Edge of Appalachia Preserve, a mix of mature forest and limestone cliffs along the Ohio River. Heather Farrington, curator of zoology for the Cincinnati Museum Center, opens a cabinet containing extinct specimens of passenger pigeons, Carolina parakeets, Eskimo curlews and ivory-billed woodpeckers. The museum is using ancient DNA today to help save species on the brink of extinction. Credit: Jay Yocis/UC Creative Services The museum's lab analysis found that Ohio's woodrats are maintaining their genetic diversity so far despite their geographic isolation. The lab also has studied the genetics of Ohio's crayfish and a beautiful yellow-and-black songbird called a hooded warbler. The museum's DNA lab has glass walls on two sides so the public can watch scientists at work. Next door, visitors also can watch museum staff and volunteers prepare fossils from a public gallery at the paleontology lab. Farrington's colleague, museum collections manager Emily Imhoff, explained how the sensitive equipment works. The lab keeps DNA samples in refrigerators, including one set to a chilly minus-112 degrees Fahrenheit. Scientists can identify the concentration of DNA, amplify the sample and sequence it to understand the lineage and relationships of species. \"We definitely feel our work is useful when we take on projects with other researchers,\" Imhoff said. \"Heather and I are both passionate about our work.\" Farrington was looking for a graduate program in aquatic ecology that could satisfy her growing curiosity about genetics. UC biology professor Kenneth Petren, who served as dean of UC's McMicken College of Arts and Sciences, reached out to recruit her to UC. The Cincinnati Museum Center has specimens of extinct species such as this Carolina parakeet. The museum is working with government and academic partners to conserve species with help from its genetics lab. Credit: Jay Yocis/UC Creative Services \"He said, 'Well, I do genetics, but I don't do fish. I work on Darwin's finches,'\" Farrington said. At UC, Petren has conducted two decades of research on descendants of birds that shaped Charles Darwin's understanding of evolution through natural selection in the Galapagos Islands of Ecuador. \"I thought, 'Oh, my gosh, I can't say no to Darwin's finches,'\" Farrington said. Farrington, Petren and UC biology professor Lucinda Lawson authored a study of finch populations that was published recently in the journal Conservation Genetics. Moreover, at UC Farrington also realized what a valuable resource museum collections are for genetic research. For her dissertation, she examined museum specimens gathered more than 100 years ago to understand how Galapagos finch populations have changed over time. Farrington developed many of the important lab techniques she uses at the museum while conducting research at UC, Petren said. \"While at UC, Heather worked very hard to pioneer the use of museum specimens for population genetics analysis,\" Petren said. \"Our lab was a leader in this field because of Heather's efforts. \"She used the techniques she developed to address issues of conservation in several different species of Galapagos finches,\" Petren said. \"She went on to become a leader in the field of environmental DNA in her role working for the U.S. Department of Defense, which was interested in monitoring rare species or to provide early warnings of problematic invasive species like the Asian carp.\" Farrington said her experience while researching museum specimens for her dissertation at UC convinced her of how valuable these resources can be for future study. \"That is really what got me into museum work and the amazing things you can learn from museum specimens,\" Farrington 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 Genetic data are increasingly used for fast, efficient, and cost-effective monitoring of natural populations and assessment of extinction risk in species management. A single modern molecular snapshot is typically used to infer population size and vulnerability, yet for species with unknown and potentially complex genetic metapopulation structure, this technique may not effectively predict vulnerability. Darwin’s finches, which are well-represented in museum collections, offer a unique opportunity to test the effectiveness of predicting extinction vulnerability in species with complex structure, such as naturally fragmented populations. In this study, we compared ancient DNA from ~ 100 year old extinct and extant Darwin’s finch populations in the Galápagos Islands to determine whether single time point genetic assessments in the past accurately predicted extinction risk, or if other factors such as metapopulation dynamics could mask population declines. Of eight extinct populations, only one had significantly reduced genetic variation compared to an extant population of similar characteristics. Contrary to our prediction that populations would have decreased genetic diversity prior to extinction when compared to persisting populations, at least one measure of genetic diversity was significantly higher in six of the eight extinct populations when compared to extant populations. Simulations lend support to the hypothesis that unaccounted for metapopulation structure may explain the observed pattern in many species. Therefore, models of genetic diversity reflecting population extinction potential may be inadequate for highly-mobile species with metapopulation dynamics such as the Galápagos finches. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction As the number of threatened and endangered species rises worldwide, there is an increasing demand for fast, efficient and cost-effective ways to monitor natural populations and assess extinction risk. One measure commonly used to approximate extinction risk for populations or species is genetic diversity. Typically, as few species have historical specimens available for comparison, a single modern genetic snapshot is used to determine if a population has patterns of genetic diversity that fit a model of a declining population. For those populations or species that have gone extinct, low genetic diversity is strongly associated with extinction risk (Spielman et al. 2004 ; Evans and Sheldon 2008 ; Hieb et al. 2014 ). These declines in genetic richness are rapidly detectable (Antao et al. 2011 ), and can be used to evaluate effective population sizes and trends, and detect recent bottlenecks in individual populations (Schwartz et al. 2007 ; Antao et al. 2011 ; Méndez et al. 2014 ). In cases of extreme decline, where only remnants of a single population remain, the connection between lower genetic diversity, decline in population size, and increased extinction risk is clear. Little is known, however, about whether allelic richness and diversity alone can differentiate lineages that will survive from those that will perish in complex ecosystems, particularly when only a modern genetic assessment is available. The use of genetic diversity as a measure of extinction potential in vulnerable species has a number of shortcomings in its application, foremost being that in most studies the ultimate fate of the population of interest is unknown. Low or declining genetic diversity does not guarantee imminent extinction as there have been several examples of species persisting over extended time periods despite low genetic diversity (e.g., Johnson et al. 2009 ; Reed 2010 ). Without sampling through time using historical samples, the performance of theoretical models of extinction risk or population declines (e.g., VORTEX (Lacy 1993 , 2000 ), BOTTLENECK (Cornuet and Luikart 1996 )) remains largely untested. Additionally, in species with a metapopulation structure of populations with ongoing gene flow, measuring genetic diversity of individual populations without taking into account the dynamics of gene flow from healthy populations (sources) into vulnerable ones (sinks) can lead to erroneous results (Keller et al. 2001 ; Caplins et al. 2014 ; Frankham et al. 2017 ). Continuous monitoring in vertebrates shows that declining populations may have inflated measures of genetic diversity if receiving immigration from other populations (e.g., Smyser et al. 2016 ). Thus, by measuring single populations, their standing genetic diversity may be unrelated to extinction risk (Hanski and Gilpin 1991 ). Due to these limitations, a test of extinction dynamics in a natural system of fragmented populations with both historical and modern genetic sampling would be valuable for gaining a better understanding of the genetic signatures found in localized populations approaching extinction within complex systems. The adaptive radiation of Darwin’s finches in the Galápagos Islands provides a unique opportunity to study population vulnerability in a complex system with many codistributed species for comparisons. There are approximately 19 species currently recognized within this radiation (Lamichhaney et al. 2015 ), and besides a few island endemics (e.g., Camarhynchus heliobates on Isabela Island and C. pauper of Floreana Island), most species within the radiation have distributions spanning many islands (e.g., Geospiza scandens is found on 10 major islands, G. fuliginosa on 12, Camarhynchus parvulus on 10). These populations appear to act as metapopulations, with non-inconsequential estimates of migration (Petren et al. 2005 ; Farrington and Petren 2011 ). As these islands have been sampled for over 100 years since Darwin’s first visit, this system provides unique access to both historical and current genetic samples and distribution data. Based on avian models from other remote islands (Steadman 2006 ; Pratt 2009 ), there is a strong expectation that Galápagos bird communities should be in decline due to recent human-induced ecological changes such as invasive species (Eckhardt 1972 ), habitat alteration (Watson et al. 2010 ; O’Connor et al. 2010a , b ), introduced diseases and parasites (Wikelski et al. 2004 ; Dudaniec and Kleindorfer 2006 ; Parker et al. 2011 ; Kleindorfer et al. 2014b ; Rivera-Parra et al. 2014 ; Kleindorfer and Dudaniec 2016 ), and hybridization (Kleindorfer et al. 2014a ; Lawson et al. 2017 ). Although there have been no known avian species extinctions in the Galápagos, current population extinction rates are approximately 100 times greater than those during the era prior to human colonization (across vertebrate species:<|im_end|> <|im_start|>assistant Scientists who are trying to save species at the brink of extinction are finding help in an unexpected place. Heather Farrington, curator of zoology for the Cincinnati Museum Center, is using DNA from specimens collected more than 100 years ago to help understand the evolution and stresses faced by today's animals. Farrington runs the museum's new state-of-the-art genetics laboratory, which helps researchers study populations of animals over time. Researchers increasingly are embracing the power of ancient DNA from old museum specimens to answer questions about climate change, habitat loss and other stresses on surviving populations. Ancient DNA has been used to explain the diversity of livestock in Africa and the first domestication of wild horses in Asia. Farrington earned her doctorate in biological sciences from the University of Cincinnati, where she charted the family trees of Galapagos finches and used the latest DNA tools to gain fresh insights about the birds from century-old museum specimens. The museum's genetics lab works with researchers and government agencies on a variety of projects that require DNA analysis, from conserving wildlife to improving our understanding of the natural world. Recently, the lab helped with a conservation project on the Allegheny woodrat, a small rock-loving rodent that is in decline across much of its historic range from Indiana to New Jersey. In Ohio it's found in only one place, the Richard and Lucille Durrell Edge of Appalachia Preserve, a mix of mature forest and limestone cliffs along the Ohio River. Heather Farrington, curator of zoology for the Cincinnati Museum Center, opens a cabinet containing extinct specimens of passenger pigeons, Carolina parakeets, Eskimo curlews and ivory-billed woodpeckers. The museum is using ancient DNA today to help save species on the brink of extinction. Credit: Jay Yocis/UC Creative Services The museum's lab analysis found that Ohio's woodrats are maintaining their genetic diversity so far despite their geographic isolation. The lab also has studied the genetics of Ohio's crayfish and a beautiful yellow-and-black songbird called a hooded warbler. The museum's DNA lab has glass walls on two sides so the public can watch scientists at work. Next door, visitors also can watch museum staff and volunteers prepare fossils from a public gallery at the paleontology lab. Farrington's colleague, museum collections manager Emily Imhoff, explained how the sensitive equipment works. The lab keeps DNA samples in refrigerators, including one set to a chilly minus-112 degrees Fahrenheit. Scientists can identify the concentration of DNA, amplify the sample and sequence it to understand the lineage and relationships of species. "We definitely feel our work is useful when we take on projects with other researchers," Imhoff said. "Heather and I are both passionate about our work." Farrington was looking for a graduate program in aquatic ecology that could satisfy her growing curiosity about genetics. UC biology professor Kenneth Petren, who served as dean of UC's McMicken College of Arts and Sciences, reached out to recruit her to UC. The Cincinnati Museum Center has specimens of extinct species such as this Carolina parakeet. The museum is working with government and academic partners to conserve species with help from its genetics lab. Credit: Jay Yocis/UC Creative Services "He said, 'Well, I do genetics, but I don't do fish. I work on Darwin's finches,'" Farrington said. At UC, Petren has conducted two decades of research on descendants of birds that shaped Charles Darwin's understanding of evolution through natural selection in the Galapagos Islands of Ecuador. "I thought, 'Oh, my gosh, I can't say no to Darwin's finches,'" Farrington said. Farrington, Petren and UC biology professor Lucinda Lawson authored a study of finch populations that was published recently in the journal Conservation Genetics. Moreover, at UC Farrington also realized what a valuable resource museum collections are for genetic research. For her dissertation, she examined museum specimens gathered more than 100 years ago to understand how Galapagos finch populations have changed over time. Farrington developed many of the important lab techniques she uses at the museum while conducting research at UC, Petren said. "While at UC, Heather worked very hard to pioneer the use of museum specimens for population genetics analysis," Petren said. "Our lab was a leader in this field because of Heather's efforts. "She used the techniques she developed to address issues of conservation in several different species of Galapagos finches," Petren said. "She went on to become a leader in the field of environmental DNA in her role working for the U.S. Department of Defense, which was interested in monitoring rare species or to provide early warnings of problematic invasive species like the Asian carp." Farrington said her experience while researching museum specimens for her dissertation at UC convinced her of how valuable these resources can be for future study. "That is really what got me into museum work and the amazing things you can learn from museum specimens," Farrington 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 Synthetic chemistry aims to build up molecular complexity from simple feedstocks 1 . However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space 2 , 3 . Here we report a reaction that ‘deletes’ nitrogen from organic molecules. We show that N -pivaloyloxy- N -alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon–carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon–carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon–carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds. Main Retrosynthetic analysis is the cornerstone of synthesis. As chemical transformations are discovered, they can be evaluated in terms of the retrosynthetic disconnections that they enable, and the forward progress of synthesis—broadly speaking—can be assessed by inspection of the total set of available disconnections. Accordingly, the identification and realization of synthetically attractive transformations that represent inaccessible or otherwise underused molecular changes is paramount to the continued advancement of the chemical sciences, and as such the advancement of all allied fields that design and deploy purpose-built molecules. Molecular editing and late-stage functionalization have emerged as appealing strategies for the identification of such ‘missing’ transformations 4 , 5 , 6 , 7 , and represent the ideals of modern synthesis—including the ability to build and tolerate complexity. However, their intellectual deployment has so far largely focused on C–H functionalization chemistry (peripheral editing). Conversely, modification of the underlying molecular skeleton (skeletal editing) has not achieved the same level of refinement, despite receiving increasing interest from many laboratories 8 , 9 , 10 , 11 , 12 . In our own assessment, such skeletal transformations represent a large untapped pool of potentially transformative chemical reactions, should they be realized (Fig. 1a ). Among these, single-atom insertions and deletions are particularly attractive from the standpoint of retrosynthetic simplicity, in contrast to many known skeletal rearrangements for which complex patterns of reactivity require substantial skill and insight to recognize as disconnections. Indeed, many classic reactions—especially in the context of carbonyl chemistry—enable the insertion or deletion of carbon, nitrogen or oxygen into molecular skeletons (for example the Wolff, Favorskii and Bayer–Villiger rearrangements) 13 , 14 . Nonetheless, broadly speaking, accessible single-step skeletal transformations remain limited. Here we report a reaction that excises nitrogen atoms from secondary amines, liberating N 2 and forging a new C–C bond between the remaining molecular fragments. Fig. 1: Background. a , Conceptual overview of skeletal editing and peripheral editing techniques as used in molecular optimization campaigns. b , Mechanistic hypothesis for direct nitrogen deletion enabled by anomeric amide reagents. c , Precedent for isodiazene generation from anomeric amides, and for nitrogen extrusion from isodiazenes. Full size image Our approach was based on the mechanistic hypothesis outlined in Fig. 1b . This hypothesis was in turn supported by precedented chemistry of anomeric amides, which—in analogy to the anomeric centres of carbohydrates—bear two oxygen substituents on the amide nitrogen 15 . Bis-heteroatom-substituted amides have been studied in detail and display unusual pyramidalization at nitrogen as well as notable electrophilic reactivity 16 . In particular, N -methylaniline was observed to form a tetrazene product upon reaction with reagent 1a , which is strongly suggestive of an isodiazene intermediate 15 (Fig. 1c ). These latter species piqued our interest owing to their known N 2 -extrusion reactivity, providing diradical species that undergo rapid, intramolecular C-C bond formation 17 , 18 , 19 . Classical routes to such intermediates involve multistep protocols that use hazardous reagents—one frequently used synthesis involves a sequence of N -nitrosation (requiring isolation of carcinogenic N -nitrosamine compounds), reduction to the 1,1-hydrazine and oxidation with stoichiometric mercuric oxide or lead tetraacetate 20 . We reasoned that the combination of anomeric amide reagents with suitable secondary amine nucleophiles would enable a single-step protocol for nitrogen deletion directly from secondary amines. Crucially, this would facilitate the examination of skeletal edits by circumventing the laborious and undesirable features of existing protocols 21 , 22 . From a retrosynthetic perspective, this strategy would enable aliphatic C–N bond-forming reactions to serve formally as C–C bond-forming surrogates. This is advantageous in part because of the reliability and broad scope of iminium-based transformations that feature prominently among the medicinal chemistry toolbox. For example, reductive amination consistently ranks in the top ten most-used reactions in drug discovery, and iminium-based cyclization methods are broadly applied for the synthesis of cyclic amines 23 . These methods have led to the proliferation of amines as feedstock chemicals, and thousands of derivatives are now commercially available 24 , 25 . Our investigation began with the N -benzyloxy- N -acetoxybenzamide 1a (ref. 15 ) (Fig. 2a ). Reaction with the model substrate 2a in tetrahydrofuran solution at 45 °C resulted in a 35% yield of nitrogen deletion product 3a . However, acetamide 4a was observed as a major side product, which probably formed through competitive substitution at the acyl carbon. To ameliorate this, we synthesized the N -pivaloxy derivative 1b . When used under identical conditions, none of the corresponding pivalamide side product 4b could be detected and 3a was produced in an improved yield of 57%. Further evaluation of substituent effects revealed that para -trifluoromethyl-substituted reagent 1c reacted more rapidly, leading to complete conversion of 2a within 5 h, in comparison to the 18-h reaction time required for 1b . This was representative of a general trend: a competition Hammett study revealed a slope of 0.60 (corresponding to the reaction constant ρ ) when rate data were plotted against the electrophilic substituent constant (σ + ) 26 (Fig. 2b ). However, the preparation of reagents that are more electron-poor than", "role": "user" }, { "content": "Molecules are the building blocks for our modern world, from phones to cars to Doritos. But coming up with new ones is still an incredibly costly and time-consuming process. A group of University of Chicago chemists wants to find a better way. \"If you look at a diagram of a molecule, it seems like you should be able to just snap them together like Tinkertoys, but you can't,\" said Asst. Prof. Mark Levin. \"We'd like to change that.\" Their new discovery, published May 12 in Nature, represents a first step towards that transformation: a way to easily cut nitrogen atoms from molecules. Despite decades of experiments, chemistry remains an art in many ways because molecules are built in a long, iterative process: attaching some parts, then breaking others so that you can patch new parts in. Every molecule we use, from the fibers in your rug to the dyes that colored it to the detergents you use to clean it, is built this way. But sometimes, the molecules created in the intermediate steps or as byproducts are very toxic, or the whole process takes a lot of time and electricity. This process becomes even more laborious when scientists or drugmakers are looking for a new chemical, Levin said, since they have to create so many options to test. \"Say you want to make a new drug that targets a part of the cell that biologists have identified as important for heart disease,\" he said. \"Typically, you screen thousands of molecules just to find a few that latch on to that part of the cell. Then you go about modifying them, to make the molecules easier for the body to absorb or to avoid side effects. Every time that you think, say, 'Would it work better with a carbon atom on one side instead of a nitrogen?' you have to go back to the beginning and start over with how to build it.\" Levin's group wants to transform the field by introducing ways to directly edit the molecule of interest. There are a few ways to make minor edits around the edges, Levin said, but scientists are still searching for techniques to make major changes to the skeletons of molecules. The UChicago chemists made a breakthrough in this quest, finding a way to \"delete\" a nitrogen atom from a molecule. Similar processes currently use generate a very toxic molecule—but Levin's group instead adds a key reagent, or reactive chemical, which bypasses the intermediate step. The nitrogen is released as N2, and two carbon atoms forge a bond in its place. As a new foundational method, the discovery opens up avenues for constructing molecules. \"One thing it lets you do is think about making rings in a new way, with potentially fewer steps. That lets you change the logic of how you make things,\" Levin said. (Rings of molecules are a frequent ingredient in chemicals.) The process doesn't work for every single molecule, but it does for many important ones. For example, Levin's group tested the method on lapatinib, a molecule approved by the FDA as a cancer drug, and was able to edit its composition quickly and easily. \"One side of this discovery is being able to actually work with a class of reactions that was largely underused because they're just awful to work with,\" Levin said. \"But more broadly speaking, we hope it represents a transformation in thinking about how you optimize a molecule.\" ", "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 Synthetic chemistry aims to build up molecular complexity from simple feedstocks 1 . However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space 2 , 3 . Here we report a reaction that ‘deletes’ nitrogen from organic molecules. We show that N -pivaloyloxy- N -alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon–carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon–carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon–carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds. Main Retrosynthetic analysis is the cornerstone of synthesis. As chemical transformations are discovered, they can be evaluated in terms of the retrosynthetic disconnections that they enable, and the forward progress of synthesis—broadly speaking—can be assessed by inspection of the total set of available disconnections. Accordingly, the identification and realization of synthetically attractive transformations that represent inaccessible or otherwise underused molecular changes is paramount to the continued advancement of the chemical sciences, and as such the advancement of all allied fields that design and deploy purpose-built molecules. Molecular editing and late-stage functionalization have emerged as appealing strategies for the identification of such ‘missing’ transformations 4 , 5 , 6 , 7 , and represent the ideals of modern synthesis—including the ability to build and tolerate complexity. However, their intellectual deployment has so far largely focused on C–H functionalization chemistry (peripheral editing). Conversely, modification of the underlying molecular skeleton (skeletal editing) has not achieved the same level of refinement, despite receiving increasing interest from many laboratories 8 , 9 , 10 , 11 , 12 . In our own assessment, such skeletal transformations represent a large untapped pool of potentially transformative chemical reactions, should they be realized (Fig. 1a ). Among these, single-atom insertions and deletions are particularly attractive from the standpoint of retrosynthetic simplicity, in contrast to many known skeletal rearrangements for which complex patterns of reactivity require substantial skill and insight to recognize as disconnections. Indeed, many classic reactions—especially in the context of carbonyl chemistry—enable the insertion or deletion of carbon, nitrogen or oxygen into molecular skeletons (for example the Wolff, Favorskii and Bayer–Villiger rearrangements) 13 , 14 . Nonetheless, broadly speaking, accessible single-step skeletal transformations remain limited. Here we report a reaction that excises nitrogen atoms from secondary amines, liberating N 2 and forging a new C–C bond between the remaining molecular fragments. Fig. 1: Background. a , Conceptual overview of skeletal editing and peripheral editing techniques as used in molecular optimization campaigns. b , Mechanistic hypothesis for direct nitrogen deletion enabled by anomeric amide reagents. c , Precedent for isodiazene generation from anomeric amides, and for nitrogen extrusion from isodiazenes. Full size image Our approach was based on the mechanistic hypothesis outlined in Fig. 1b . This hypothesis was in turn supported by precedented chemistry of anomeric amides, which—in analogy to the anomeric centres of carbohydrates—bear two oxygen substituents on the amide nitrogen 15 . Bis-heteroatom-substituted amides have been studied in detail and display unusual pyramidalization at nitrogen as well as notable electrophilic reactivity 16 . In particular, N -methylaniline was observed to form a tetrazene product upon reaction with reagent 1a , which is strongly suggestive of an isodiazene intermediate 15 (Fig. 1c ). These latter species piqued our interest owing to their known N 2 -extrusion reactivity, providing diradical species that undergo rapid, intramolecular C-C bond formation 17 , 18 , 19 . Classical routes to such intermediates involve multistep protocols that use hazardous reagents—one frequently used synthesis involves a sequence of N -nitrosation (requiring isolation of carcinogenic N -nitrosamine compounds), reduction to the 1,1-hydrazine and oxidation with stoichiometric mercuric oxide or lead tetraacetate 20 . We reasoned that the combination of anomeric amide reagents with suitable secondary amine nucleophiles would enable a single-step protocol for nitrogen deletion directly from secondary amines. Crucially, this would facilitate the examination of skeletal edits by circumventing the laborious and undesirable features of existing protocols 21 , 22 . From a retrosynthetic perspective, this strategy would enable aliphatic C–N bond-forming reactions to serve formally as C–C bond-forming surrogates. This is advantageous in part because of the reliability and broad scope of iminium-based transformations that feature prominently among the medicinal chemistry toolbox. For example, reductive amination consistently ranks in the top ten most-used reactions in drug discovery, and iminium-based cyclization methods are broadly applied for the synthesis of cyclic amines 23 . These methods have led to the proliferation of amines as feedstock chemicals, and thousands of derivatives are now commercially available 24 , 25 . Our investigation began with the N -benzyloxy- N -acetoxybenzamide 1a (ref. 15 ) (Fig. 2a ). Reaction with the model substrate 2a in tetrahydrofuran solution at 45 °C resulted in a 35% yield of nitrogen deletion product 3a . However, acetamide 4a was observed as a major side product, which probably formed through competitive substitution at the acyl carbon. To ameliorate this, we synthesized the N -pivaloxy derivative 1b . When used under identical conditions, none of the corresponding pivalamide side product 4b could be detected and 3a was produced in an improved yield of 57%. Further evaluation of substituent effects revealed that para -trifluoromethyl-substituted reagent 1c reacted more rapidly, leading to complete conversion of 2a within 5 h, in comparison to the 18-h reaction time required for 1b . This was representative of a general trend: a competition Hammett study revealed a slope of 0.60 (corresponding to the reaction constant ρ ) when rate data were plotted against the electrophilic substituent constant (σ + ) 26 (Fig. 2b ). However, the preparation of reagents that are more electron-poor than<|im_end|> <|im_start|>assistant Molecules are the building blocks for our modern world, from phones to cars to Doritos. But coming up with new ones is still an incredibly costly and time-consuming process. A group of University of Chicago chemists wants to find a better way. "If you look at a diagram of a molecule, it seems like you should be able to just snap them together like Tinkertoys, but you can't," said Asst. Prof. Mark Levin. "We'd like to change that." Their new discovery, published May 12 in Nature, represents a first step towards that transformation: a way to easily cut nitrogen atoms from molecules. Despite decades of experiments, chemistry remains an art in many ways because molecules are built in a long, iterative process: attaching some parts, then breaking others so that you can patch new parts in. Every molecule we use, from the fibers in your rug to the dyes that colored it to the detergents you use to clean it, is built this way. But sometimes, the molecules created in the intermediate steps or as byproducts are very toxic, or the whole process takes a lot of time and electricity. This process becomes even more laborious when scientists or drugmakers are looking for a new chemical, Levin said, since they have to create so many options to test. "Say you want to make a new drug that targets a part of the cell that biologists have identified as important for heart disease," he said. "Typically, you screen thousands of molecules just to find a few that latch on to that part of the cell. Then you go about modifying them, to make the molecules easier for the body to absorb or to avoid side effects. Every time that you think, say, 'Would it work better with a carbon atom on one side instead of a nitrogen?' you have to go back to the beginning and start over with how to build it." Levin's group wants to transform the field by introducing ways to directly edit the molecule of interest. There are a few ways to make minor edits around the edges, Levin said, but scientists are still searching for techniques to make major changes to the skeletons of molecules. The UChicago chemists made a breakthrough in this quest, finding a way to "delete" a nitrogen atom from a molecule. Similar processes currently use generate a very toxic molecule—but Levin's group instead adds a key reagent, or reactive chemical, which bypasses the intermediate step. The nitrogen is released as N2, and two carbon atoms forge a bond in its place. As a new foundational method, the discovery opens up avenues for constructing molecules. "One thing it lets you do is think about making rings in a new way, with potentially fewer steps. That lets you change the logic of how you make things," Levin said. (Rings of molecules are a frequent ingredient in chemicals.) The process doesn't work for every single molecule, but it does for many important ones. For example, Levin's group tested the method on lapatinib, a molecule approved by the FDA as a cancer drug, and was able to edit its composition quickly and easily. "One side of this discovery is being able to actually work with a class of reactions that was largely underused because they're just awful to work with," Levin said. "But more broadly speaking, we hope it represents a transformation in thinking about how you optimize a molecule." <|im_end|>

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2,165

[ { "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 resistance of cancer cells to therapy is responsible for the death of most patients with cancer 1 . Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells 2 , 3 . However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ—a small GTPase that is preferentially expressed in EMT cancer cells—controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy. Main Cancer is one of the main causes of mortality worldwide and resistance to therapy is responsible for treatment failure in the majority of patients 1 . EMT is a developmental process in which epithelial cancer cells lose cell–cell adhesion and acquire mesenchymal features, including increased invasiveness and motility 4 . EMT in cancer controls tumour initiation, progression, metastasis and resistance to anti-cancer therapies 2 , 5 . Transcription factors that promote EMT, such as Zeb1, Zeb2 and Twist1, mediate resistance to chemotherapy and radiotherapy in different cancer cell lines in vitro and after their transplantation into immunocompromised mice 6 , 7 . The conditional deletion of Twist1 or Snai1 in a mouse model of pancreatic adenocarcinoma sensitizes tumour cells to gemcitabine 8 . EMT in a mammary tumour model promotes resistance to different chemotherapeutic drugs 9 . Several mechanisms have been proposed to account for the resistance to therapy associated with EMT in cancer cell lines in vitro 3 , 8 , 9 . However, whether these mechanisms are responsible for EMT-induced resistance to therapy in primary tumours in vivo remains unclear. Here we used a genetic mouse model of squamous cell carcinoma (SCC) presenting spontaneous EMT to determine the functional response of different cell populations to chemotherapy. We found that, in primary skin SCCs presenting EMT, EPCAM − tumour cells were highly resistant to chemotherapy. Using genetic gain and loss of function studies, we identified RHOJ, a small Rho GTPase, as a key regulator that promotes resistance to a broad range of chemotherapeutic agents in EMT tumour cells. Proteomic analysis combined with functional assays revealed that RHOJ controls the formation of nuclear F-actin fibres and the activation of dormant origins of replication, which promotes DNA repair and prevents chemotherapy induced cell death. EMT-associated chemotherapy resistance in SCC To investigate the role and the mechanisms of resistance to therapy in EMT tumour cells in vivo, we used a genetically induced mouse model of skin SCCs combining the expression of oncogenic Kras ( Kras G12D ) with the deletion of Trp53 and the expression of a YFP reporter in hair follicle lineages 10 ( Lgr5 creER Kras G12D Trp53 cKO Rosa-YFP ). The YFP reporter, combined with EPCAM staining, enables us to identify tumour cells that undergo EMT and lose the expression of epithelial markers (YFP + EPCAM − ) (Extended Data Fig. 1a ). To assess whether EMT is associated with resistance to chemotherapy in skin SCC, we treated Lgr5 creER Kras G12D Trp53 cKO Rosa-YFP mice that were induced with tamoxifen and presented primary SCCs with cisplatin and 5-fluorouracil (5FU), the standard chemotherapy used to treat human patients with metastatic SCCs 11 . About 14% of SCCs were very sensitive to chemotherapy and completely disappeared after 4 weeks of treatment (fully responding tumours). About 32% of SCCs did not respond and progressed during chemotherapy (non-responding tumours). Most SCCs (54%) presented a partial response to chemotherapy. Using immunostaining and fluorescence-activated cell sorting (FACS) analysis, we found that responding tumours consisted of YFP + epithelial tumour cells expressing the epithelial marker K14 or a mixture of epithelial and EMT tumour cells. The tumours that did not respond were enriched for EMT tumour cells (K14 − VIM + or EPCAM − ) (Extended Data Fig. 1b–j ). These data suggest that chemotherapy either preferentially kills EPCAM + tumour cells or induces EMT promoting the switch from EPCAM + to EPCAM − tumour cells during chemotherapy. To distinguish between these two possibilities, we investigated apoptosis in EPCAM + and EPCAM − tumour cells 24 h after chemotherapy administration. EPCAM − tumour cells were very resistant to chemotherapy-induced cell death in vivo as only 2% of EPCAM − tumour cells were caspase-3 positive compared with 9% of epithelial EPCAM + tumour cells. We recently identified EMT subpopulations of tumour cells presenting different degrees of EMT in mouse skin SCCs 12 . We found that the different EMT subpopulations were similarly resistant to chemotherapy (Fig. 1a and Extended Data Fig. 1k–p ). Similar to what we found in vivo, EMT tumour cells were profoundly resistant to chemotherapy in vitro in the absence of the tumour microenvironment, whereas EPCAM + epithelial tumour cells were even more sensitive (Fig. 1b,c ). In addition to cisplatin/5FU treatment, EPCAM − tumour cells were resistant to the topoisomerase I inhibitor topotecan, the topoisomerase II inhibitor etoposide and the anti-metabolite gemcitabine. EPCAM − tumour cells were also resistant to the anti-microtubule paclitaxel, the DNA intercalant and topoisomerase II inhibitor doxorubicin and ionizing radiation, although these treatments were less efficient in inducing cell death in EPCAM + tumour cells (Fig. 1d ). Together, these data demonstrate that EMT in skin SCCs is associated with resistance to a wide range of genotoxic drugs in a cellular autonomous manner both in", "role": "user" }, { "content": "Despite the recent development of new targeted therapies, chemotherapies remain the most frequently used treatment to treat patients suffering from advanced cancers. Chemotherapy resistance is one of the main causes of treatment failure and death in cancer patients. It has been suggested that the epithelial-mesenchymal transition (EMT), a process by which epithelial cells detach from their neighboring cells and acquire invasive properties, plays a role in the acquisition of resistance to anti-cancer therapy. However, the mechanism by which cancer cells presenting EMT resist to anti-cancer therapy is currently unknown. In a study published in Nature, researchers led by Prof. Cédric Blanpain, MD/Ph.D., WELBIO investigator, Director of the Stem Cells and Cancer Laboratory and Professor at the Université Libre de Bruxelles, discovered that a protein named RHOJ allows cancer cells presenting EMT to resist anti-cancer treatments by stimulating the repair of DNA damage caused by the chemotherapy. Maud Debaugnies and her colleagues showed that cancer cells presenting EMT become resistant to chemotherapeutic treatment. They found that RHOJ expression was particularly high in chemotherapy-resistant cells. They then showed that by silencing RHOJ, cancer cells became sensitive to chemotherapy. \"It was particularly exciting to understand the mechanisms that allow cancer cells to resist chemotherapy, paving the way for the development of novel and more effective therapeutic strategies to treat cancer,\" says Maud Debaugnies, the first author of this study. Maud Debaugnies and her colleagues then studied by which mechanisms RHOJ makes cancer cells resistant to chemotherapy. Chemotherapy induces DNA damage in cancer cells which activates the death of these cells. They discovered that RHOJ can activate the DNA damage repair pathway induced by chemotherapy, allowing cancer cells to repair the DNA lesions and escape cell death. \"Our discovery that the inhibition of a single gene can make cancer cells sensitive to chemotherapy opens new avenues for the development of drugs targeting RHOJ that should decrease the resistance to chemotherapy in patients with cancers presenting EMT,\" says Prof. Cedric Blanpain, the director of this study. ", "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 resistance of cancer cells to therapy is responsible for the death of most patients with cancer 1 . Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells 2 , 3 . However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ—a small GTPase that is preferentially expressed in EMT cancer cells—controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy. Main Cancer is one of the main causes of mortality worldwide and resistance to therapy is responsible for treatment failure in the majority of patients 1 . EMT is a developmental process in which epithelial cancer cells lose cell–cell adhesion and acquire mesenchymal features, including increased invasiveness and motility 4 . EMT in cancer controls tumour initiation, progression, metastasis and resistance to anti-cancer therapies 2 , 5 . Transcription factors that promote EMT, such as Zeb1, Zeb2 and Twist1, mediate resistance to chemotherapy and radiotherapy in different cancer cell lines in vitro and after their transplantation into immunocompromised mice 6 , 7 . The conditional deletion of Twist1 or Snai1 in a mouse model of pancreatic adenocarcinoma sensitizes tumour cells to gemcitabine 8 . EMT in a mammary tumour model promotes resistance to different chemotherapeutic drugs 9 . Several mechanisms have been proposed to account for the resistance to therapy associated with EMT in cancer cell lines in vitro 3 , 8 , 9 . However, whether these mechanisms are responsible for EMT-induced resistance to therapy in primary tumours in vivo remains unclear. Here we used a genetic mouse model of squamous cell carcinoma (SCC) presenting spontaneous EMT to determine the functional response of different cell populations to chemotherapy. We found that, in primary skin SCCs presenting EMT, EPCAM − tumour cells were highly resistant to chemotherapy. Using genetic gain and loss of function studies, we identified RHOJ, a small Rho GTPase, as a key regulator that promotes resistance to a broad range of chemotherapeutic agents in EMT tumour cells. Proteomic analysis combined with functional assays revealed that RHOJ controls the formation of nuclear F-actin fibres and the activation of dormant origins of replication, which promotes DNA repair and prevents chemotherapy induced cell death. EMT-associated chemotherapy resistance in SCC To investigate the role and the mechanisms of resistance to therapy in EMT tumour cells in vivo, we used a genetically induced mouse model of skin SCCs combining the expression of oncogenic Kras ( Kras G12D ) with the deletion of Trp53 and the expression of a YFP reporter in hair follicle lineages 10 ( Lgr5 creER Kras G12D Trp53 cKO Rosa-YFP ). The YFP reporter, combined with EPCAM staining, enables us to identify tumour cells that undergo EMT and lose the expression of epithelial markers (YFP + EPCAM − ) (Extended Data Fig. 1a ). To assess whether EMT is associated with resistance to chemotherapy in skin SCC, we treated Lgr5 creER Kras G12D Trp53 cKO Rosa-YFP mice that were induced with tamoxifen and presented primary SCCs with cisplatin and 5-fluorouracil (5FU), the standard chemotherapy used to treat human patients with metastatic SCCs 11 . About 14% of SCCs were very sensitive to chemotherapy and completely disappeared after 4 weeks of treatment (fully responding tumours). About 32% of SCCs did not respond and progressed during chemotherapy (non-responding tumours). Most SCCs (54%) presented a partial response to chemotherapy. Using immunostaining and fluorescence-activated cell sorting (FACS) analysis, we found that responding tumours consisted of YFP + epithelial tumour cells expressing the epithelial marker K14 or a mixture of epithelial and EMT tumour cells. The tumours that did not respond were enriched for EMT tumour cells (K14 − VIM + or EPCAM − ) (Extended Data Fig. 1b–j ). These data suggest that chemotherapy either preferentially kills EPCAM + tumour cells or induces EMT promoting the switch from EPCAM + to EPCAM − tumour cells during chemotherapy. To distinguish between these two possibilities, we investigated apoptosis in EPCAM + and EPCAM − tumour cells 24 h after chemotherapy administration. EPCAM − tumour cells were very resistant to chemotherapy-induced cell death in vivo as only 2% of EPCAM − tumour cells were caspase-3 positive compared with 9% of epithelial EPCAM + tumour cells. We recently identified EMT subpopulations of tumour cells presenting different degrees of EMT in mouse skin SCCs 12 . We found that the different EMT subpopulations were similarly resistant to chemotherapy (Fig. 1a and Extended Data Fig. 1k–p ). Similar to what we found in vivo, EMT tumour cells were profoundly resistant to chemotherapy in vitro in the absence of the tumour microenvironment, whereas EPCAM + epithelial tumour cells were even more sensitive (Fig. 1b,c ). In addition to cisplatin/5FU treatment, EPCAM − tumour cells were resistant to the topoisomerase I inhibitor topotecan, the topoisomerase II inhibitor etoposide and the anti-metabolite gemcitabine. EPCAM − tumour cells were also resistant to the anti-microtubule paclitaxel, the DNA intercalant and topoisomerase II inhibitor doxorubicin and ionizing radiation, although these treatments were less efficient in inducing cell death in EPCAM + tumour cells (Fig. 1d ). Together, these data demonstrate that EMT in skin SCCs is associated with resistance to a wide range of genotoxic drugs in a cellular autonomous manner both in<|im_end|> <|im_start|>assistant Despite the recent development of new targeted therapies, chemotherapies remain the most frequently used treatment to treat patients suffering from advanced cancers. Chemotherapy resistance is one of the main causes of treatment failure and death in cancer patients. It has been suggested that the epithelial-mesenchymal transition (EMT), a process by which epithelial cells detach from their neighboring cells and acquire invasive properties, plays a role in the acquisition of resistance to anti-cancer therapy. However, the mechanism by which cancer cells presenting EMT resist to anti-cancer therapy is currently unknown. In a study published in Nature, researchers led by Prof. Cédric Blanpain, MD/Ph.D., WELBIO investigator, Director of the Stem Cells and Cancer Laboratory and Professor at the Université Libre de Bruxelles, discovered that a protein named RHOJ allows cancer cells presenting EMT to resist anti-cancer treatments by stimulating the repair of DNA damage caused by the chemotherapy. Maud Debaugnies and her colleagues showed that cancer cells presenting EMT become resistant to chemotherapeutic treatment. They found that RHOJ expression was particularly high in chemotherapy-resistant cells. They then showed that by silencing RHOJ, cancer cells became sensitive to chemotherapy. "It was particularly exciting to understand the mechanisms that allow cancer cells to resist chemotherapy, paving the way for the development of novel and more effective therapeutic strategies to treat cancer," says Maud Debaugnies, the first author of this study. Maud Debaugnies and her colleagues then studied by which mechanisms RHOJ makes cancer cells resistant to chemotherapy. Chemotherapy induces DNA damage in cancer cells which activates the death of these cells. They discovered that RHOJ can activate the DNA damage repair pathway induced by chemotherapy, allowing cancer cells to repair the DNA lesions and escape cell death. "Our discovery that the inhibition of a single gene can make cancer cells sensitive to chemotherapy opens new avenues for the development of drugs targeting RHOJ that should decrease the resistance to chemotherapy in patients with cancers presenting EMT," says Prof. Cedric Blanpain, the director of this study. <|im_end|>

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11, 584, 12020, 445, 911, 20, 1922, 643, 735, 13075, 480, 717, 35, 1183, 79, 4331, 272, 56047, 47930, 30237, 11960, 24548, 430, 1051, 36572, 449, 26555, 5241, 56439, 323, 10666, 6156, 80399, 82, 449, 67504, 501, 15111, 323, 220, 20, 12556, 84, 269, 414, 582, 321, 320, 20, 82313, 705, 279, 5410, 62730, 1511, 311, 4322, 3823, 6978, 449, 68370, 780, 80399, 82, 220, 806, 662, 10180, 220, 975, 4, 315, 80399, 82, 1051, 1633, 16614, 311, 62730, 323, 6724, 29496, 1306, 220, 19, 5672, 315, 6514, 320, 3725, 30438, 15756, 2530, 570, 10180, 220, 843, 4, 315, 80399, 82, 1550, 539, 6013, 323, 62916, 2391, 62730, 320, 6414, 12, 6961, 287, 15756, 2530, 570, 7648, 80399, 82, 320, 4370, 11587, 10666, 264, 7276, 2077, 311, 62730, 13, 12362, 33119, 537, 2101, 323, 97332, 12, 31262, 2849, 29373, 320, 37, 63787, 8, 6492, 11, 584, 1766, 430, 30438, 15756, 2530, 44660, 315, 816, 11960, 489, 64779, 59544, 15756, 414, 7917, 37810, 279, 64779, 59544, 11381, 735, 975, 477, 264, 21655, 315, 64779, 59544, 323, 469, 8673, 15756, 414, 7917, 13, 578, 15756, 2530, 430, 1550, 539, 6013, 1051, 69671, 369, 469, 8673, 15756, 414, 7917, 320, 42, 975, 25173, 650, 1829, 489, 477, 469, 4977, 1428, 25173, 883, 320, 54290, 2956, 23966, 13, 220, 16, 65, 4235, 73, 7609, 4314, 828, 4284, 430, 62730, 3060, 10932, 31668, 29910, 469, 4977, 1428, 489, 15756, 414, 7917, 477, 90974, 469, 8673, 22923, 279, 3480, 505, 469, 4977, 1428, 489, 311, 469, 4977, 1428, 25173, 15756, 414, 7917, 2391, 62730, 13, 2057, 33137, 1990, 1521, 1403, 24525, 11, 584, 27313, 95874, 304, 469, 4977, 1428, 489, 323, 469, 4977, 1428, 25173, 15756, 414, 7917, 220, 1187, 305, 1306, 62730, 8735, 13, 469, 4977, 1428, 25173, 15756, 414, 7917, 1051, 1633, 31785, 311, 62730, 38973, 2849, 4648, 304, 41294, 439, 1193, 220, 17, 4, 315, 469, 4977, 1428, 25173, 15756, 414, 7917, 1051, 4865, 79, 521, 12, 18, 6928, 7863, 449, 220, 24, 4, 315, 64779, 59544, 469, 4977, 1428, 489, 15756, 414, 7917, 13, 1226, 6051, 11054, 469, 8673, 1207, 8539, 7607, 315, 15756, 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4007, 13, 220, 128257, 198 ]

1,919

[ { "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 Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE ‘variant-to-gene’ maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome. Introduction Genome-wide association studies (GWAS) is an important tool in understanding the genetic basis of complex, heritable diseases and traits. However, GWAS is typically powered to identify large blocks of the genome containing hundreds of single nucleotide polymorphisms (SNP) in linkage disequilibrium (LD), any one of which could be responsible for the association of the entire locus with disease susceptibility. Moreover, ~90% of GWAS-implicated SNPs are non-coding, and per se do not identify the culprit genes. Examples of this are the FTO signal in obesity 1 , 2 , and the TCF7L2 signal in type 2 diabetes 3 , where the suspected causal variant resides in an intron of the local gene, but instead regulates expression of the distant genes. Systemic lupus erythematosus (SLE) is a complex inflammatory disease mediated by autoreactive antibodies that damage multiple tissues in children and adults 4 . An inflammatory leukocyte required for the development of SLE is the follicular helper T cell (TFH). TFH differentiate from naive CD4+ T cells in the lymph nodes, spleen, and tonsil, where they license B cells to produce high affinity protective or pathogenic antibodies 5 , 6 . Given their central role in regulation of humoral immune responses, genetic susceptibility to SLE is highly likely to manifest functionally in TFH. GWAS has associated >60 loci with SLE susceptibility 7 , 8 . Given the paucity of immune cell eQTL data represented in GTEx, we mapped the open chromatin landscape of TFH from human tonsil to identify potentially functional SLE variants. Here, we conduct a genome-wide, promoter-focused Capture-C analysis of chromatin contacts at ~42,000 annotated human genes at ~270 bp resolution to map these variants to the genes they likely regulate. This approach, which we used recently to identify new effector genes at bone mineral density loci 9 , only requires three samples to make valid interaction calls, and does not require material from SLE patients or genotyped individuals. By design, this approach does not determine the effect of variants in the system, but rather, uses reported variants as ‘signposts’ to identify potential gene enhancers in normal tissue. We show that most SLE-associated variants do not interact with the nearest promoter, but instead connect to distant genes, many of which have known roles in TFH and SLE. Using CRISPR/CAS9 genome editing, we validate several of these SLE-associated regions, revealing a requisite role in regulating their connected genes. Finally, we experimentally verify roles for two kinases implicated by this variant-to-gene mapping approach in TFH differentiation and function, identifying potential drug targets for SLE and other antibody-mediated diseases. Results Human tonsillar naive T cell and TFH open chromatin landscapes The vast majority (>90%) of the human genome is packed tightly into cellular chromatin and is not accessible to the nuclear machinery that regulates gene expression 10 . Consequently, >95% of transcription factor and RNA polymerase occupancy is concentrated at regions of open chromatin 10 , and thus the map of accessible chromatin in a cell essentially defines its potential gene regulatory landscape. As a step toward defining the disease-associated regulatory architecture of SLE, we focused on human TFH cells, which are required for the production of pathogenic antibodies by autoreactive B cells 4 . Tonsillar TFH are derived from naive CD4+ T cell precursors, and represent a population of cells in healthy subjects that are ‘caught in the act’ of helping B cells to produce high-affinity, class-switched antibodies. We sorted naive CD4+CD45RO− T cells and differentiated CD4+CD45RO+CD25−CXCR5 hi PD1 hi TFH 11 from human tonsil and generated open chromatin maps of both cell types from three donors using ATAC-seq 12 . A peak calling approach identified 91,222 open chromatin regions (OCR); 75,268 OCR in naive cells and 74,627 OCR in TFH (Supplementary Data 1 ). Further quantitative analysis of the accessibility signal at each OCR revealed a similar overall degree of genomic accessibility (~1.4%) in both cell types (Supplementary Fig. 1 ), however, differentiation of naive cells into TFH is associated with remodeling of 22% of the T cell open chromatin landscape, with 11,228 OCR becoming more accessible, and 8,804 becoming less accessible (Fig. 1a , Supplementary Data 1 ). Among all 20,032 differentially accessible regions, 20.5% (4100) reside in the promoters of genes that tended to be differentially expressed between TFH and naive cells (Fig. 1b , 1496 DEG, GSEA enrichment p < 0.05, absNES > 3.5, Supplementary Data 2 ). The functions of genes more accessible in TFH were enriched for CD28 costimulatory, G-protein, Rho GTPase, semaphorin, and TLR signaling pathways (hypergeometric test, FDR < 0.05, Supplementary Fig. 2a ). Promoters less accessible in TFH are enriched for chemokine and G protein-coupled signaling pathways (Supplementary Fig. 2b ). These data show that global chromatin remodeling dynamics faithfully reflect dynamic changes in gene expression during the differentiation of follicular helper T cells from their naive precursors. Fig. 1: ATAC-seq analysis of open chromatin landscapes in naive and follicular helper T cells from human tonsil. a Quantitative differences between naive and follicular helper T cell open chromatin landscapes. A total of 91,222 OCR were used as reference for differential analysis", "role": "user" }, { "content": "A team of researchers from Children's Hospital of Philadelphia (CHOP) used a new method of pinpointing potential disease-causing changes in the genome to identify two new potential therapeutic targets for lupus, while also paving the way for more accurately identifying disease-causing variations in other autoimmune disorders. The findings were published online in Nature Communications. Genome-wide association studies (GWAS) leverage variations across the genome, the complete set of a person's genes and associated DNA, in order to learn more about heritable diseases and traits. These studies typically identify clusters of hundreds of single-nucleotide polymorophisms, or variants, that could cause a particular disease, but the studies themselves are unable to identify which ones are responsible. This is because the vast majority of variants are not in the genes themselves, but in the intervening DNA, and GWAS does not necessarily solve which genes are impacted by disease-associated polymorphisms. Systemic Lupus Erythematosus is an autoimmune disorder with no known cure that affects both children and adults, with greater prevalence among racial minorities. While several studies on lupus have focused on naive helper T cells and other blood cells, this study was designed to focus on follicular helper T cells, which play a more central role in immune responses related to lupus. Rather than use a typical GWAS approach, the researchers set out to create three-dimensional maps that match variants with the genes they likely regulate. Their approach used variants as \"signposts\" to identify potential gene enhancers in normal tissue. \"Prior to this study, no 3-D structural genomic maps had been generated for this lupus-relevant cell type before,\" said Andrew D. Wells, Ph.D., Co-Director of the Center for Spatial and Functional Genomics at CHOP, and co-senior author of the study together with Struan F. A. Grant, Ph.D. \"With our approach, we believe we were in a position to identify genes and pathways that had no prior known role in lupus.\" Using this method, the study team identified 393 variants in proximity to genes in 3-D, and therefore potentially involved in their regulation. Approximately 90% of those variants would have been considered distant to their gene in one dimension, but were actually close in the proper three-dimensional map created by the team. The researchers were able to pinpoint two kinases, HIPK1 and MINK1, that had no previously known role in lupus. When these enzymes are targeted in follicular helper T cells, they inhibit the production of interleukin-21, a cytokine involved in regulating antibody production. \"We believe that HIPK1 and MINK1 may serve as valuable therapeutic targets for lupus, a disease that is in dire need of new treatment options,\" Wells said. \"We also want to take the methods we used in this study and apply them to other autoimmune diseases and help pinpoint more causal variations that may have otherwise remained obscured by GWAS alone.\" Wells also said their team hopes to develop HIPK1 transgenic mouse models to study their susceptibility to experimental lupus, as well as the potential impact of HIPK1 on antiviral immunity. ", "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 Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE ‘variant-to-gene’ maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome. Introduction Genome-wide association studies (GWAS) is an important tool in understanding the genetic basis of complex, heritable diseases and traits. However, GWAS is typically powered to identify large blocks of the genome containing hundreds of single nucleotide polymorphisms (SNP) in linkage disequilibrium (LD), any one of which could be responsible for the association of the entire locus with disease susceptibility. Moreover, ~90% of GWAS-implicated SNPs are non-coding, and per se do not identify the culprit genes. Examples of this are the FTO signal in obesity 1 , 2 , and the TCF7L2 signal in type 2 diabetes 3 , where the suspected causal variant resides in an intron of the local gene, but instead regulates expression of the distant genes. Systemic lupus erythematosus (SLE) is a complex inflammatory disease mediated by autoreactive antibodies that damage multiple tissues in children and adults 4 . An inflammatory leukocyte required for the development of SLE is the follicular helper T cell (TFH). TFH differentiate from naive CD4+ T cells in the lymph nodes, spleen, and tonsil, where they license B cells to produce high affinity protective or pathogenic antibodies 5 , 6 . Given their central role in regulation of humoral immune responses, genetic susceptibility to SLE is highly likely to manifest functionally in TFH. GWAS has associated >60 loci with SLE susceptibility 7 , 8 . Given the paucity of immune cell eQTL data represented in GTEx, we mapped the open chromatin landscape of TFH from human tonsil to identify potentially functional SLE variants. Here, we conduct a genome-wide, promoter-focused Capture-C analysis of chromatin contacts at ~42,000 annotated human genes at ~270 bp resolution to map these variants to the genes they likely regulate. This approach, which we used recently to identify new effector genes at bone mineral density loci 9 , only requires three samples to make valid interaction calls, and does not require material from SLE patients or genotyped individuals. By design, this approach does not determine the effect of variants in the system, but rather, uses reported variants as ‘signposts’ to identify potential gene enhancers in normal tissue. We show that most SLE-associated variants do not interact with the nearest promoter, but instead connect to distant genes, many of which have known roles in TFH and SLE. Using CRISPR/CAS9 genome editing, we validate several of these SLE-associated regions, revealing a requisite role in regulating their connected genes. Finally, we experimentally verify roles for two kinases implicated by this variant-to-gene mapping approach in TFH differentiation and function, identifying potential drug targets for SLE and other antibody-mediated diseases. Results Human tonsillar naive T cell and TFH open chromatin landscapes The vast majority (>90%) of the human genome is packed tightly into cellular chromatin and is not accessible to the nuclear machinery that regulates gene expression 10 . Consequently, >95% of transcription factor and RNA polymerase occupancy is concentrated at regions of open chromatin 10 , and thus the map of accessible chromatin in a cell essentially defines its potential gene regulatory landscape. As a step toward defining the disease-associated regulatory architecture of SLE, we focused on human TFH cells, which are required for the production of pathogenic antibodies by autoreactive B cells 4 . Tonsillar TFH are derived from naive CD4+ T cell precursors, and represent a population of cells in healthy subjects that are ‘caught in the act’ of helping B cells to produce high-affinity, class-switched antibodies. We sorted naive CD4+CD45RO− T cells and differentiated CD4+CD45RO+CD25−CXCR5 hi PD1 hi TFH 11 from human tonsil and generated open chromatin maps of both cell types from three donors using ATAC-seq 12 . A peak calling approach identified 91,222 open chromatin regions (OCR); 75,268 OCR in naive cells and 74,627 OCR in TFH (Supplementary Data 1 ). Further quantitative analysis of the accessibility signal at each OCR revealed a similar overall degree of genomic accessibility (~1.4%) in both cell types (Supplementary Fig. 1 ), however, differentiation of naive cells into TFH is associated with remodeling of 22% of the T cell open chromatin landscape, with 11,228 OCR becoming more accessible, and 8,804 becoming less accessible (Fig. 1a , Supplementary Data 1 ). Among all 20,032 differentially accessible regions, 20.5% (4100) reside in the promoters of genes that tended to be differentially expressed between TFH and naive cells (Fig. 1b , 1496 DEG, GSEA enrichment p < 0.05, absNES > 3.5, Supplementary Data 2 ). The functions of genes more accessible in TFH were enriched for CD28 costimulatory, G-protein, Rho GTPase, semaphorin, and TLR signaling pathways (hypergeometric test, FDR < 0.05, Supplementary Fig. 2a ). Promoters less accessible in TFH are enriched for chemokine and G protein-coupled signaling pathways (Supplementary Fig. 2b ). These data show that global chromatin remodeling dynamics faithfully reflect dynamic changes in gene expression during the differentiation of follicular helper T cells from their naive precursors. Fig. 1: ATAC-seq analysis of open chromatin landscapes in naive and follicular helper T cells from human tonsil. a Quantitative differences between naive and follicular helper T cell open chromatin landscapes. A total of 91,222 OCR were used as reference for differential analysis<|im_end|> <|im_start|>assistant A team of researchers from Children's Hospital of Philadelphia (CHOP) used a new method of pinpointing potential disease-causing changes in the genome to identify two new potential therapeutic targets for lupus, while also paving the way for more accurately identifying disease-causing variations in other autoimmune disorders. The findings were published online in Nature Communications. Genome-wide association studies (GWAS) leverage variations across the genome, the complete set of a person's genes and associated DNA, in order to learn more about heritable diseases and traits. These studies typically identify clusters of hundreds of single-nucleotide polymorophisms, or variants, that could cause a particular disease, but the studies themselves are unable to identify which ones are responsible. This is because the vast majority of variants are not in the genes themselves, but in the intervening DNA, and GWAS does not necessarily solve which genes are impacted by disease-associated polymorphisms. Systemic Lupus Erythematosus is an autoimmune disorder with no known cure that affects both children and adults, with greater prevalence among racial minorities. While several studies on lupus have focused on naive helper T cells and other blood cells, this study was designed to focus on follicular helper T cells, which play a more central role in immune responses related to lupus. Rather than use a typical GWAS approach, the researchers set out to create three-dimensional maps that match variants with the genes they likely regulate. Their approach used variants as "signposts" to identify potential gene enhancers in normal tissue. "Prior to this study, no 3-D structural genomic maps had been generated for this lupus-relevant cell type before," said Andrew D. Wells, Ph.D., Co-Director of the Center for Spatial and Functional Genomics at CHOP, and co-senior author of the study together with Struan F. A. Grant, Ph.D. "With our approach, we believe we were in a position to identify genes and pathways that had no prior known role in lupus." Using this method, the study team identified 393 variants in proximity to genes in 3-D, and therefore potentially involved in their regulation. Approximately 90% of those variants would have been considered distant to their gene in one dimension, but were actually close in the proper three-dimensional map created by the team. The researchers were able to pinpoint two kinases, HIPK1 and MINK1, that had no previously known role in lupus. When these enzymes are targeted in follicular helper T cells, they inhibit the production of interleukin-21, a cytokine involved in regulating antibody production. "We believe that HIPK1 and MINK1 may serve as valuable therapeutic targets for lupus, a disease that is in dire need of new treatment options," Wells said. "We also want to take the methods we used in this study and apply them to other autoimmune diseases and help pinpoint more causal variations that may have otherwise remained obscured by GWAS alone." Wells also said their team hopes to develop HIPK1 transgenic mouse models to study their susceptibility to experimental lupus, as well as the potential impact of HIPK1 on antiviral immunity. <|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 Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions 1 , 2 . By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes 3 , 4 , 5 . However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans 6 , showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2 , in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity. Main SOX9 is a developmental transcription factor with important functions in chondrocyte differentiation and male sex determination 7 . The SOX9 locus is a genomic region that has been linked to various human diseases with a broad range of phenotypes 6 , 8 , 9 . We investigated how genomic duplications in this region affect higher-order chromatin organization and, in particular, the formation of TADs. Hi-C, a technology to quantify chromatin contacts genome-wide, shows a compartmentalization of the human locus in two major TADs, one containing SOX9 (referred to hereafter as SOX9 TAD), the other containing the two potassium channels KCNJ2 and KCNJ16 (referred to hereafter as KCNJ TAD) ( Fig. 1a ) 2 . The large gene desert corresponding to the SOX9 TAD has been shown to contain multiple regulatory elements and human-disease-related sites ( Fig. 1a ) 9 . Duplications including a region 0.5 megabases (Mb) upstream of SOX9 (referred to as the RevSex region) lead to female-to-male sex reversal ( Fig. 1a ), indicating that the RevSex region contains a critical regulator of SOX9 expression in the developing gonads 6 , 10 . Surprisingly, duplications that include the RevSex region but extend further upstream towards the neighbouring genes KCNJ2 and KCNJ16 have no effect on sexual development. Instead, they result in Cooks syndrome, a congenital limb malformation characterized by aplasia of nails and short digits 8 . We identified a family (mother and daughter) with a third type of duplication that includes the RevSex region and the entire gene desert upstream of SOX9 , but not the KCNJ2 and KCNJ16 genes ( Fig. 1a ). In spite of complete overlap with the reported sex reversal duplications and large parts of the Cooks syndrome duplication, carriers of this variant are phenotypically normal. According to the Hi-C profile, all sex reversal associated duplications are located within the SOX9 TAD, whereas the duplication with no phenotype and also the Cooks syndrome duplications extend into the neighbouring KCNJ TAD thereby spanning two TADs and their boundary. We refer two these two types of duplications as intra-TAD and inter-TAD, respectively. Figure 1: 4C-seq from human fibroblasts with intra-TAD and inter-TAD duplications. a , SOX9 locus with Hi-C interaction profile (H1 embryonic stem cells 2 ). Schematic shows KCNJ TAD (blue), SOX9 TAD (brown) and TAD boundaries (red hexagons). Ovals indicate regions associated with sex reversal (RevSex) or Pierre Robin syndrome (PRS), human duplications with corresponding phenotypes are indicated above (line thickness indicates maximum/minimum size). b , 4C-seq from control skin fibroblasts using SOX9 and KCNJ2 as viewpoints (triangles). c , 4C-seq from fibroblasts of an individual with sex reversal and intra-TAD duplication shows no change in overall interaction profile (below, log 2 ratio to control). 4C-seq from duplication breakpoint (below, in purple) shows increased interaction with the duplicated part and the rest of the SOX9 TAD. d , 4C-seq from fibroblasts of individual with no phenotype and inter-TAD duplication. Note unchanged interaction profiles from SOX9 and KCNJ2 viewpoints. 4C-seq from duplication breakpoint shows interactions restricted to the duplicated region. All reads mapped to a wild-type genome (resulting in split viewpoint for duplication breakpoints). See Methods for sample collection. PowerPoint slide Full size image To investigate the difference between the intra-TAD (sex reversal) and the inter-TAD (no phenotype) duplications, we performed 4C-seq of patient fibroblasts and compared them to controls. In control cells, the SOX9 and the KCNJ2 viewpoint showed an interaction profile restricted to their Hi-C predicted TADs ( Fig. 1b ). 4C-seq from a patient with sex reversal and a 150 kilobase (kb) intra-TAD duplication showed a slight increase with the duplicated part from SOX9 , but an overall unchanged profile from both viewpoints ( Fig. 1c ). Similarly, no change in the configuration of the interaction profiles was observed with the larger inter-TAD (no phenotype) duplication ( Fig. 1d ). To identify the region specifically contacted by the duplicated part, we used the unique sequence created by the duplication breakpoints to perform allele-specific 4C-seq. In the intra-TAD duplication, we observed high interaction with the entire SOX9 TAD (purple track, Fig. 1c ). Similar results were obtained with fibroblasts from a second individual with a", "role": "user" }, { "content": "Duplications of DNA segments are common in the human genome. Duplications have been proposed as an evolutionary mechanism but they can also be associated with human disease. Scientists from the Max Planck Institute for Molecular Genetics and the Charité – Universitätsmedizin Berlin have now shown that, depending on their position in the genome, duplications can lead to the formation of new functional units known as topologically associated domains (TADs). In the journal Nature, the researchers describe how the duplication of DNA segments of various sizes gives rise to new TADs and how duplicated genes can acquire new functions. This mechanism represents a possible mechanism how new gene functions can arise in the course of evolution and has far-reaching implications for the interpretation of genetic mutations in humans. Topologically associated domains – or TADs for short – are spatially separated regions in the genome. They are DNA segments that are a million base pairs long on average and contain one or more genes and their regulatory elements, called enhancers. The latter control when and in which cells a gene is switched on or off. TADs are separated from each other by boundary elements, so that gene activity in one TAD is independent from that in neighbouring TADs. By studying duplications of various sizes in the region of the SOX9 gene, scientists of the Research Group Development & Disease at the Max Planck Institute for Molecular Genetics have discovered a previously unknown function of TADs. The SOX9 gene is responsible for the expression of a transcription factor that has important functions in skeletal and male sexual development. By analyzing the three-dimensional structure of the genome, the researchers were able to show that two large TADs are located in the SOX9 region. One of them contains the SOX9 gene and its regulatory elements; the other contains two genes, KCNJ2 and KCNJ16, two potassium channels, and their regulatory elements. Various types of duplications Duplications in the region of the SOX9 gene can lead to radically different clinical pictures. In order to understand these differences, the researchers investigated three duplications, all of which include regulatory elements of the SOX9 gene as well as other DNA segments of various lengths. The first of the duplications examined leads in humans to a reversal of gender from female to male. Affected individuals are morphologically male despite possessing two X chromosomes. The scientists showed that this duplication only affects the DNA and regulatory elements that occur within the SOX9 TAD. Surprisingly, however, larger duplications that include this region but extend up to the neighbouring genes KCNJ2 and KCNJ16 and therefore contain sections of the adjacent TAD have no clinical effects on sex determination. By contrast, even bigger duplications that include not only the non-coding DNA in the SOX9 region but also the neighbouring KCNJ2 gene lead to Cooks syndrome, a hereditary abnormality of the hands and feet characterized by the absence of fingernails and shortened fingers and toes. Intra-TAD and inter-TAD duplications \"We have to distinguish between intra-TAD and inter-TAD duplications, depending on their location,\" says Stefan Mundlos, head of the research group that carried out the work. \"In the case of sex reversal, regulatory elements within a TAD (intra-TAD) are duplicated, and the effect remains limited to that TAD. Thus, only the gene in the TAD is misregulated, meaning that it is activated either too much or too little. In the case of the SOX9 gene, the activity of the gene is increased, resulting in the development of the male gender, even if the affected individual is genetically female.\" Because TADs are functionally separated from each other, intra-TAD duplications only affect one TAD and have no impact on neighbouring TADs. In the case of inter-TAD duplications, by contrast, not only the regulatory elements of the SOX9 region are duplicated, but also the boundary between two TADs. The duplicated boundary defines a new TAD (called neo-TAD) that includes the duplicated region of the genome and insulates it from the rest of the genome. \"The effects of a neo-TAD depend on which elements of the genome it contains,\" says Mundlos. \"If the neo-TAD contains only regulatory elements but no genes, it has no effects on the organism. Neighbouring genes are shielded from the regulatory elements by the TAD boundaries and remain unaffected. However, if a neo-TAD contains both regulatory elements and a gene from a neighbouring TAD, the latter can be regulated by the regulatory elements (enhancer) within the neo-TAD, resulting in gene misexpression, which might trigger abnormalities or disease. TAD duplication with gene and regulatory elements This was exactly the case for the third duplication studied by the researchers, which triggers Cooks syndrome. The new TAD contains not only the regulatory elements of the SOX9 gene, but also a copy of the KCNJ2 gene. The KCNJ2 gene in the neo-TAD is then regulated by the regulatory elements of the SOX9 gene. As a result, it is activated at the wrong time and in the wrong tissues during development, giving rise to the abnormalities associated with this syndrome. By including the TAD structure in the interpretation of genetic alterations, scientists can make much more precise predictions about the effects of mutations than it was previously the case. This relates, for example, to duplications that cause hereditary diseases as well as alterations in cancer cells, in which duplications commonly occur. Duplications are one of the driving forces of evolution. The duplication of a gene makes it possible for the copy to develop new and different properties from the original gene, which remains unaffected by this process. By enabling new combinations of regulatory elements and genes in neo-TADs, duplications could represent an evolutionary mechanism for the emergence of new gene functions. ", "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 Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions 1 , 2 . By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes 3 , 4 , 5 . However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans 6 , showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2 , in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity. Main SOX9 is a developmental transcription factor with important functions in chondrocyte differentiation and male sex determination 7 . The SOX9 locus is a genomic region that has been linked to various human diseases with a broad range of phenotypes 6 , 8 , 9 . We investigated how genomic duplications in this region affect higher-order chromatin organization and, in particular, the formation of TADs. Hi-C, a technology to quantify chromatin contacts genome-wide, shows a compartmentalization of the human locus in two major TADs, one containing SOX9 (referred to hereafter as SOX9 TAD), the other containing the two potassium channels KCNJ2 and KCNJ16 (referred to hereafter as KCNJ TAD) ( Fig. 1a ) 2 . The large gene desert corresponding to the SOX9 TAD has been shown to contain multiple regulatory elements and human-disease-related sites ( Fig. 1a ) 9 . Duplications including a region 0.5 megabases (Mb) upstream of SOX9 (referred to as the RevSex region) lead to female-to-male sex reversal ( Fig. 1a ), indicating that the RevSex region contains a critical regulator of SOX9 expression in the developing gonads 6 , 10 . Surprisingly, duplications that include the RevSex region but extend further upstream towards the neighbouring genes KCNJ2 and KCNJ16 have no effect on sexual development. Instead, they result in Cooks syndrome, a congenital limb malformation characterized by aplasia of nails and short digits 8 . We identified a family (mother and daughter) with a third type of duplication that includes the RevSex region and the entire gene desert upstream of SOX9 , but not the KCNJ2 and KCNJ16 genes ( Fig. 1a ). In spite of complete overlap with the reported sex reversal duplications and large parts of the Cooks syndrome duplication, carriers of this variant are phenotypically normal. According to the Hi-C profile, all sex reversal associated duplications are located within the SOX9 TAD, whereas the duplication with no phenotype and also the Cooks syndrome duplications extend into the neighbouring KCNJ TAD thereby spanning two TADs and their boundary. We refer two these two types of duplications as intra-TAD and inter-TAD, respectively. Figure 1: 4C-seq from human fibroblasts with intra-TAD and inter-TAD duplications. a , SOX9 locus with Hi-C interaction profile (H1 embryonic stem cells 2 ). Schematic shows KCNJ TAD (blue), SOX9 TAD (brown) and TAD boundaries (red hexagons). Ovals indicate regions associated with sex reversal (RevSex) or Pierre Robin syndrome (PRS), human duplications with corresponding phenotypes are indicated above (line thickness indicates maximum/minimum size). b , 4C-seq from control skin fibroblasts using SOX9 and KCNJ2 as viewpoints (triangles). c , 4C-seq from fibroblasts of an individual with sex reversal and intra-TAD duplication shows no change in overall interaction profile (below, log 2 ratio to control). 4C-seq from duplication breakpoint (below, in purple) shows increased interaction with the duplicated part and the rest of the SOX9 TAD. d , 4C-seq from fibroblasts of individual with no phenotype and inter-TAD duplication. Note unchanged interaction profiles from SOX9 and KCNJ2 viewpoints. 4C-seq from duplication breakpoint shows interactions restricted to the duplicated region. All reads mapped to a wild-type genome (resulting in split viewpoint for duplication breakpoints). See Methods for sample collection. PowerPoint slide Full size image To investigate the difference between the intra-TAD (sex reversal) and the inter-TAD (no phenotype) duplications, we performed 4C-seq of patient fibroblasts and compared them to controls. In control cells, the SOX9 and the KCNJ2 viewpoint showed an interaction profile restricted to their Hi-C predicted TADs ( Fig. 1b ). 4C-seq from a patient with sex reversal and a 150 kilobase (kb) intra-TAD duplication showed a slight increase with the duplicated part from SOX9 , but an overall unchanged profile from both viewpoints ( Fig. 1c ). Similarly, no change in the configuration of the interaction profiles was observed with the larger inter-TAD (no phenotype) duplication ( Fig. 1d ). To identify the region specifically contacted by the duplicated part, we used the unique sequence created by the duplication breakpoints to perform allele-specific 4C-seq. In the intra-TAD duplication, we observed high interaction with the entire SOX9 TAD (purple track, Fig. 1c ). Similar results were obtained with fibroblasts from a second individual with a<|im_end|> <|im_start|>assistant Duplications of DNA segments are common in the human genome. Duplications have been proposed as an evolutionary mechanism but they can also be associated with human disease. Scientists from the Max Planck Institute for Molecular Genetics and the Charité – Universitätsmedizin Berlin have now shown that, depending on their position in the genome, duplications can lead to the formation of new functional units known as topologically associated domains (TADs). In the journal Nature, the researchers describe how the duplication of DNA segments of various sizes gives rise to new TADs and how duplicated genes can acquire new functions. This mechanism represents a possible mechanism how new gene functions can arise in the course of evolution and has far-reaching implications for the interpretation of genetic mutations in humans. Topologically associated domains – or TADs for short – are spatially separated regions in the genome. They are DNA segments that are a million base pairs long on average and contain one or more genes and their regulatory elements, called enhancers. The latter control when and in which cells a gene is switched on or off. TADs are separated from each other by boundary elements, so that gene activity in one TAD is independent from that in neighbouring TADs. By studying duplications of various sizes in the region of the SOX9 gene, scientists of the Research Group Development & Disease at the Max Planck Institute for Molecular Genetics have discovered a previously unknown function of TADs. The SOX9 gene is responsible for the expression of a transcription factor that has important functions in skeletal and male sexual development. By analyzing the three-dimensional structure of the genome, the researchers were able to show that two large TADs are located in the SOX9 region. One of them contains the SOX9 gene and its regulatory elements; the other contains two genes, KCNJ2 and KCNJ16, two potassium channels, and their regulatory elements. Various types of duplications Duplications in the region of the SOX9 gene can lead to radically different clinical pictures. In order to understand these differences, the researchers investigated three duplications, all of which include regulatory elements of the SOX9 gene as well as other DNA segments of various lengths. The first of the duplications examined leads in humans to a reversal of gender from female to male. Affected individuals are morphologically male despite possessing two X chromosomes. The scientists showed that this duplication only affects the DNA and regulatory elements that occur within the SOX9 TAD. Surprisingly, however, larger duplications that include this region but extend up to the neighbouring genes KCNJ2 and KCNJ16 and therefore contain sections of the adjacent TAD have no clinical effects on sex determination. By contrast, even bigger duplications that include not only the non-coding DNA in the SOX9 region but also the neighbouring KCNJ2 gene lead to Cooks syndrome, a hereditary abnormality of the hands and feet characterized by the absence of fingernails and shortened fingers and toes. Intra-TAD and inter-TAD duplications "We have to distinguish between intra-TAD and inter-TAD duplications, depending on their location," says Stefan Mundlos, head of the research group that carried out the work. "In the case of sex reversal, regulatory elements within a TAD (intra-TAD) are duplicated, and the effect remains limited to that TAD. Thus, only the gene in the TAD is misregulated, meaning that it is activated either too much or too little. In the case of the SOX9 gene, the activity of the gene is increased, resulting in the development of the male gender, even if the affected individual is genetically female." Because TADs are functionally separated from each other, intra-TAD duplications only affect one TAD and have no impact on neighbouring TADs. In the case of inter-TAD duplications, by contrast, not only the regulatory elements of the SOX9 region are duplicated, but also the boundary between two TADs. The duplicated boundary defines a new TAD (called neo-TAD) that includes the duplicated region of the genome and insulates it from the rest of the genome. "The effects of a neo-TAD depend on which elements of the genome it contains," says Mundlos. "If the neo-TAD contains only regulatory elements but no genes, it has no effects on the organism. Neighbouring genes are shielded from the regulatory elements by the TAD boundaries and remain unaffected. However, if a neo-TAD contains both regulatory elements and a gene from a neighbouring TAD, the latter can be regulated by the regulatory elements (enhancer) within the neo-TAD, resulting in gene misexpression, which might trigger abnormalities or disease. TAD duplication with gene and regulatory elements This was exactly the case for the third duplication studied by the researchers, which triggers Cooks syndrome. The new TAD contains not only the regulatory elements of the SOX9 gene, but also a copy of the KCNJ2 gene. The KCNJ2 gene in the neo-TAD is then regulated by the regulatory elements of the SOX9 gene. As a result, it is activated at the wrong time and in the wrong tissues during development, giving rise to the abnormalities associated with this syndrome. By including the TAD structure in the interpretation of genetic alterations, scientists can make much more precise predictions about the effects of mutations than it was previously the case. This relates, for example, to duplications that cause hereditary diseases as well as alterations in cancer cells, in which duplications commonly occur. Duplications are one of the driving forces of evolution. The duplication of a gene makes it possible for the copy to develop new and different properties from the original gene, which remains unaffected by this process. By enabling new combinations of regulatory elements and genes in neo-TADs, duplications could represent an evolutionary mechanism for the emergence of new gene functions. <|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 Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (−)-variabilin, (−)-homopterocarpin, (−)-medicarpin, (−)-3,9-dihydroxypterocarpan, and (−)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (−)-glyceollin I and (−)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2′-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton. Introduction Due to the diverse pharmacological properties, the pterocarpan [syllable division ptero-carpan] scaffold is an interesting target for research 1 , 2 , 3 , 4 . The 6a-hydroxypterocarpans (−)-glyceollin I ( 1 ) and (−)-glyceollin II ( 2 ) are phytoalexins isolated from stressed soybeans (Fig. 1 ). Klarman and Sanford were the first to isolate a single compound with antifungal properties from soybeans in 1968, and the correct structures of 1 and 2 were assigned in the 1970s 5 , 6 , 7 . In soy plants, the glyceollins are synthesised de novo from the isoflavone daidzein in response to pathogen attack such as fungi, bacteria, UV irradiation, or abiotic elicitors such as silver nitrate or aluminium chloride 8 , 9 , 10 , 11 . 1 and 2 belong to a group of at least eight A-ring prenylated 6a-hydroxypterocarpans, which are referred to as glyceollins 12 . In addition to the antifungal, antibacterial, and anti-nematode activities, which are important for the soy plant itself, the glyceollins have attracted much attention recently due to their activity as selective oestrogen receptor modulators and their anti-inflammatory, antiproliferative, anti-oxidative, and anti-cholesterolemic activities 13 , 14 . The antitumour activity of 1 is not limited to oestrogen-positive cancers such as mammary carcinoma or ovarian cancer, as it exhibits an antiangiogenic and anti-vasculogenic activity, too 15 , 16 , as well as other non-oestrogen related anticancer mechanisms 13 . Fig. 1: Examples of isoflavonoids. Bioactive natural products with 6a-hydroxypterocarpan skeleton ( 1 – 3 ) and selected other phytoalexins. Full size image Due to the interesting bioactivity of glyceollins and the difficulties to isolate them in pure form from soy, the asymmetric total synthesis of these compounds became desirable. In 2008, the first total synthesis of (−)-glyceollin I ( 1 ), which also yielded minor amounts of (−)-glyceollin II ( 2 ), was published by the group of Erhardt and scaled up in 2011 to a multigram synthesis 17 , 18 , 19 , 20 . These studies utilised a Sharpless asymmetric dihydroxylation of an isoflav-3-ene with stoichiometric amounts of osmium tetroxide and the chiral ligand 21 . In 2014, Kohno et al. published an alternative approach to the isoflav-3-ene intermediate of the Erhardt synthesis 22 . Malik et al. also utilised a benzoin condensation for the synthesis of racemic glyceollin II ( 2 ) 23 . In our research group, a strategy relying on the epoxidation of an isoflav-3-ene led to racemic 1 and 2 , only 24 . The phytoalexin (−)-variabilin ( 3 ) 25 , 26 is a natural product with antifungal properties, which promotes the differentiation of neural stem cells, and influences the reabsorption of glucose in the kidneys 27 , 28 , 29 . Possessing the susceptible 6a-hydroxypterocarpan skeleton it represents a suitable model structure to establish a synthetic pathway toward the glyceollins I ( 1 ) and II ( 2 ). Our previous strategy to this 6a-hydroxypterocarpan via epoxidation of a 2 H -chromene involved several unstable intermediates ruling out an upscaling of the synthesis 30 , and thus encouraged us to attempt a different approach, which also enabled the synthesis of the phytoalexins (−)-homopterocarpin ( 4 ), (−)-medicarpin ( 5 ) 31 , 32 , 33 , 34 , (−)-3,9-dihydroxypterocarpan ( 6 ) 35 , and (−)-vestitol ( 7 ) 33 , 36 . Here, we communicate the asymmetric syntheses of the natural isoflavonoids 1 – 7 by means of an asymmetric transfer hydrogenation (ATH). Results The synthetic plan As one of the key transformations of our approach, we envisioned the introduction of the sensitive tertiary alcohol functionality of variabilin ( 3 ) by a regioselective biomimetic oxidation at the benzylic carbon atom 6a of the pterocarpan 4 (Fig. 2a ). Pterocarpan 4 , obtained from 5 by simple methylation, might be accessible by acid-catalysed cyclisation of an isoflavan-4-ol after debenzylation of 8 21 . We aimed to form 8 by ATH with dynamic kinetic resolution from the racemic 2′-hydroxyisoflavanone 9 . The ATH has proved to be an exceptionally powerful tool to establish the two consecutive stereogenic centres of isoflavan-4-ols from isoflavanones 37 , but 2′-substituted isoflavanones proved to be less reactive under these conditions 38 . Racemic 9 might be accessible via 1,4-reduction of the corresponding isoflavone 10 . Isoflavones with a wide range of substituents are readily prepared by Suzuki coupling of iodochromones and phenylboronic acids 39 . Fig. 2: Retrosynthetic analysis of 6a-hydroxypterocarpans. a Synthesis of (−)-variabilin ( 3 ) via biomimetic benzylic oxidation of (−)-homopterocarpin ( 4 ). The pterocarpan skeleton is traced back to isoflavan-4-ol 8 which is generated by asymmetric transfer hydrogenation (ATH). b Synthesis of (−)-glyceollin I ( 1 ) and (−)-glyceollin II ( 2 ) via a one-pot transformation from isoflavone 13 to pterocarpan 12 involving an ATH cascade and acid-catalysed cyclisation. Full size image Based on the successful execution of this synthetic plan for variabilin ( 3 ), we traced back the glyceollins I ( 1 ) and II ( 2 ) to the common intermediate 11 by pyran ring annellation and subsequent desilylation (Fig. 2b ). The 6a-hydroxy", "role": "user" }, { "content": "Phytoalexins are bioactive phytochemicals that have attracted much attention in recent years due to their health-promoting effects in humans and their vital role in plant health. Chemists at TU Dresden have now developed a new and very efficient synthesis for these substances. With the new method, they are paving the way for a simpler production of phytoalexins and thus for large-scale investigations into their effects, especially with regard to their positive influence in the fight against cancer. Through a balanced diet, we consume larger quantities of phytoalexins every day—in a natural and healthy way. Phytoalexins (gr. phytos = plant, alekein = \"repel\") are phytochemicals that plants produce as an immune response to certain stimuli in order to maintain their own health. Numerous scientific studies have already shown that these bioactive natural products also have a health-promoting effect on humans. However, in order to investigate the mechanisms of action in detail, it is important to obtain the individual phytoalexins simply, which has so far been done with little efficiency and using toxic substances. Dr. Philipp Ciesielski and Prof. Peter Metz from the Chair of Organic Chemistry I at TU Dresden have now presented a novel and extremely efficient synthesis for phytoalexins in the renowned journal Nature Communications. In particular, the low-level synthesis of the phytoalexins Glyceollin I and Glyceollin II, which are produced as part of the immune response in soybean plants, is a decisive innovation. These two natural compounds are characterized by a broad spectrum of bioactivities, including antitumour activity and health-promoting, anti-oxidant and anti-cholesterolemic effects against Western diseases. The previous syntheses of Glyceollin I and II use large amounts of the very toxic and expensive oxidizing agent osmium tetroxide as well as large amounts of a comparatively expensive excipient as ligand in the key step. The newly presented synthesis route, on the other hand, manages without osmium tetroxide and at the same time proves to be much more efficient. \"Our synthesis pathway to various phytoalexins now allows easier access to these substances. This is an important basis for further investigations into the biological activity of these natural compounds and may well form the basis for their further development as therapeutics. The path we have described to the basic structure of phytoalexins can also be used by other research groups in the synthesis of related natural and active compounds,\" concludes Prof. Metz. ", "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 Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (−)-variabilin, (−)-homopterocarpin, (−)-medicarpin, (−)-3,9-dihydroxypterocarpan, and (−)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (−)-glyceollin I and (−)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2′-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton. Introduction Due to the diverse pharmacological properties, the pterocarpan [syllable division ptero-carpan] scaffold is an interesting target for research 1 , 2 , 3 , 4 . The 6a-hydroxypterocarpans (−)-glyceollin I ( 1 ) and (−)-glyceollin II ( 2 ) are phytoalexins isolated from stressed soybeans (Fig. 1 ). Klarman and Sanford were the first to isolate a single compound with antifungal properties from soybeans in 1968, and the correct structures of 1 and 2 were assigned in the 1970s 5 , 6 , 7 . In soy plants, the glyceollins are synthesised de novo from the isoflavone daidzein in response to pathogen attack such as fungi, bacteria, UV irradiation, or abiotic elicitors such as silver nitrate or aluminium chloride 8 , 9 , 10 , 11 . 1 and 2 belong to a group of at least eight A-ring prenylated 6a-hydroxypterocarpans, which are referred to as glyceollins 12 . In addition to the antifungal, antibacterial, and anti-nematode activities, which are important for the soy plant itself, the glyceollins have attracted much attention recently due to their activity as selective oestrogen receptor modulators and their anti-inflammatory, antiproliferative, anti-oxidative, and anti-cholesterolemic activities 13 , 14 . The antitumour activity of 1 is not limited to oestrogen-positive cancers such as mammary carcinoma or ovarian cancer, as it exhibits an antiangiogenic and anti-vasculogenic activity, too 15 , 16 , as well as other non-oestrogen related anticancer mechanisms 13 . Fig. 1: Examples of isoflavonoids. Bioactive natural products with 6a-hydroxypterocarpan skeleton ( 1 – 3 ) and selected other phytoalexins. Full size image Due to the interesting bioactivity of glyceollins and the difficulties to isolate them in pure form from soy, the asymmetric total synthesis of these compounds became desirable. In 2008, the first total synthesis of (−)-glyceollin I ( 1 ), which also yielded minor amounts of (−)-glyceollin II ( 2 ), was published by the group of Erhardt and scaled up in 2011 to a multigram synthesis 17 , 18 , 19 , 20 . These studies utilised a Sharpless asymmetric dihydroxylation of an isoflav-3-ene with stoichiometric amounts of osmium tetroxide and the chiral ligand 21 . In 2014, Kohno et al. published an alternative approach to the isoflav-3-ene intermediate of the Erhardt synthesis 22 . Malik et al. also utilised a benzoin condensation for the synthesis of racemic glyceollin II ( 2 ) 23 . In our research group, a strategy relying on the epoxidation of an isoflav-3-ene led to racemic 1 and 2 , only 24 . The phytoalexin (−)-variabilin ( 3 ) 25 , 26 is a natural product with antifungal properties, which promotes the differentiation of neural stem cells, and influences the reabsorption of glucose in the kidneys 27 , 28 , 29 . Possessing the susceptible 6a-hydroxypterocarpan skeleton it represents a suitable model structure to establish a synthetic pathway toward the glyceollins I ( 1 ) and II ( 2 ). Our previous strategy to this 6a-hydroxypterocarpan via epoxidation of a 2 H -chromene involved several unstable intermediates ruling out an upscaling of the synthesis 30 , and thus encouraged us to attempt a different approach, which also enabled the synthesis of the phytoalexins (−)-homopterocarpin ( 4 ), (−)-medicarpin ( 5 ) 31 , 32 , 33 , 34 , (−)-3,9-dihydroxypterocarpan ( 6 ) 35 , and (−)-vestitol ( 7 ) 33 , 36 . Here, we communicate the asymmetric syntheses of the natural isoflavonoids 1 – 7 by means of an asymmetric transfer hydrogenation (ATH). Results The synthetic plan As one of the key transformations of our approach, we envisioned the introduction of the sensitive tertiary alcohol functionality of variabilin ( 3 ) by a regioselective biomimetic oxidation at the benzylic carbon atom 6a of the pterocarpan 4 (Fig. 2a ). Pterocarpan 4 , obtained from 5 by simple methylation, might be accessible by acid-catalysed cyclisation of an isoflavan-4-ol after debenzylation of 8 21 . We aimed to form 8 by ATH with dynamic kinetic resolution from the racemic 2′-hydroxyisoflavanone 9 . The ATH has proved to be an exceptionally powerful tool to establish the two consecutive stereogenic centres of isoflavan-4-ols from isoflavanones 37 , but 2′-substituted isoflavanones proved to be less reactive under these conditions 38 . Racemic 9 might be accessible via 1,4-reduction of the corresponding isoflavone 10 . Isoflavones with a wide range of substituents are readily prepared by Suzuki coupling of iodochromones and phenylboronic acids 39 . Fig. 2: Retrosynthetic analysis of 6a-hydroxypterocarpans. a Synthesis of (−)-variabilin ( 3 ) via biomimetic benzylic oxidation of (−)-homopterocarpin ( 4 ). The pterocarpan skeleton is traced back to isoflavan-4-ol 8 which is generated by asymmetric transfer hydrogenation (ATH). b Synthesis of (−)-glyceollin I ( 1 ) and (−)-glyceollin II ( 2 ) via a one-pot transformation from isoflavone 13 to pterocarpan 12 involving an ATH cascade and acid-catalysed cyclisation. Full size image Based on the successful execution of this synthetic plan for variabilin ( 3 ), we traced back the glyceollins I ( 1 ) and II ( 2 ) to the common intermediate 11 by pyran ring annellation and subsequent desilylation (Fig. 2b ). The 6a-hydroxy<|im_end|> <|im_start|>assistant Phytoalexins are bioactive phytochemicals that have attracted much attention in recent years due to their health-promoting effects in humans and their vital role in plant health. Chemists at TU Dresden have now developed a new and very efficient synthesis for these substances. With the new method, they are paving the way for a simpler production of phytoalexins and thus for large-scale investigations into their effects, especially with regard to their positive influence in the fight against cancer. Through a balanced diet, we consume larger quantities of phytoalexins every day—in a natural and healthy way. Phytoalexins (gr. phytos = plant, alekein = "repel") are phytochemicals that plants produce as an immune response to certain stimuli in order to maintain their own health. Numerous scientific studies have already shown that these bioactive natural products also have a health-promoting effect on humans. However, in order to investigate the mechanisms of action in detail, it is important to obtain the individual phytoalexins simply, which has so far been done with little efficiency and using toxic substances. Dr. Philipp Ciesielski and Prof. Peter Metz from the Chair of Organic Chemistry I at TU Dresden have now presented a novel and extremely efficient synthesis for phytoalexins in the renowned journal Nature Communications. In particular, the low-level synthesis of the phytoalexins Glyceollin I and Glyceollin II, which are produced as part of the immune response in soybean plants, is a decisive innovation. These two natural compounds are characterized by a broad spectrum of bioactivities, including antitumour activity and health-promoting, anti-oxidant and anti-cholesterolemic effects against Western diseases. The previous syntheses of Glyceollin I and II use large amounts of the very toxic and expensive oxidizing agent osmium tetroxide as well as large amounts of a comparatively expensive excipient as ligand in the key step. The newly presented synthesis route, on the other hand, manages without osmium tetroxide and at the same time proves to be much more efficient. "Our synthesis pathway to various phytoalexins now allows easier access to these substances. This is an important basis for further investigations into the biological activity of these natural compounds and may well form the basis for their further development as therapeutics. The path we have described to the basic structure of phytoalexins can also be used by other research groups in the synthesis of related natural and active compounds," concludes Prof. Metz. <|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 Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53 , CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification. Main DLBCL is the most common lymphoid malignancy in adults, accounting for up to 35% of non-Hodgkin lymphomas. Although DLBCL is curable with combination therapy (R-CHOP) in over 60% of patients, the remainder develop recurrent or progressive disease that is often fatal. DLBCL is also a genetically heterogeneous disorder with multiple low-frequency mutations, somatic copy number alterations (SCNAs), and structural variants (SVs) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . These tumors are currently thought to arise from antigen-exposed B cells that transit through the germinal center (GC) 1 . Aspects of the GC environment, including the high proliferation rate, physiologic activation-induced cytidine deaminase (AID)-mediated immunoglobulin receptor editing, and aberrant somatic hypermutation (SHM) are conducive to malignant transformation 1 . The heterogeneity of DLBCL is reflected in transcriptionally defined subtypes that provide insights into disease pathogenesis and candidate treatment targets 9 , 10 , 11 , 12 , 13 , 14 . The cell-of-origin (COO) classification identifies ABC- and GCB-type DLBCLs 1 , 9 . ABC-DLBCLs are currently thought to be derived from B cells that have passaged through the GC and are committed to plasmablastic differentiation 1 . These tumors have increased NF-kB activity, and a subset exhibit genetic alterations in NF-kB modifiers and proximal components of the B cell receptor (BCR) pathway and perturbed terminal B cell differentiation 1 , 11 , 13 , 15 . In contrast, GCB-DLBCLs are postulated to originate from light-zone GCBs 1 . A subset of these tumors have alterations in chromatin-modifying enzymes, PI3K signaling, and Gα-migration pathway components and frequent SVs of BCL2 (refs 1 , 16 , 17 , 18 ). Although patients with ABC-DLBCLs have been reported to have less favorable responses to standard therapy than those with GCB-DLBCLs 8 , 9 , 19 , targeted analyses of select alterations have suggested that additional genetic complexity remains to be defined 2 , 11 , 18 , 20 , 21 . Despite the recognized clinical and molecular heterogeneity in DLBCL, previous genomic studies of this disease have largely focused on single types of alterations: mutations, SCNAs, or SVs. To address these issues, we performed whole-exome sequencing (WES) with an expanded bait set to capture known SVs in 304 DLBCLs from newly diagnosed patients. Of the patients, 85% were uniformly treated with R-CHOP and had long-term follow-up; a subset of these patients were enrolled in the prospective multi-center RICOVER60 trial 22 . This representative and clinically annotated DLBCL cohort was used to comprehensively detect mutations, SCNAs, and SVs, and to identify five groups of patients with outcome-associated coordinate genetic signatures, three of which were previously undescribed. Results Significantly mutated driver genes We detected mutations using WES data from 304 primary DLBCLs, 55% of which lacked patient-matched normal samples ( Methods , Supplementary Fig. 1 , and Supplementary Tables 1 and 2 ). To include all 304 samples in the discovery cohort for candidate cancer genes (CCGs), we developed new computational methods to filter germline variants and artifacts from tumor-only samples ( Methods and Supplementary Figs. 2 and 3 ). After filtering, we found a median of 3.3 and 6.6 mutations/Mb in the paired and tumor-only samples, respectively, suggesting that an average of 3.3 germline variants per megabase persisted after filtering. Multiple lines of evidence indicate that these rare germline variants are spread throughout the genome and have minimal effect on the detection of CCGs (beta-binomial test, P = 0.4; Methods and Supplementary Figs. 2 and 3 ). We applied MutSig2CV 23 to the 304 DLBCLs and detected 98 CCGs (q value < 0.1; Fig. 1 and Supplementary Table 3a ). Our CCG list includes previously reported mutational drivers, including the tumor suppressor TP53 ; the chromatin modifiers KMT2D ( MLL2 ), CREBBP , and EP300 ; the components of the BCR, Toll-like receptor (TLR), and NF-kB signaling pathways CD79B , MYD88 , CARD11 , and TNFAIP3 ( A20 ); certain components of the RAS pathway, KRAS , and BRAF ; NOTCH2 and the NOTCH signaling modifier SPEN ; and the immunomodulatory pathway components, B2M , CD58 , CD70 , and CIITA (Fig. 1a ) 3 , 4 , 5 , 6 , 7 , 8 . As a result of the improved methodology and increased sample size, we identified 40 additional previously undescribed CCGs in DLBCL 8 , many of which have defined roles in other lymphoid malignancies or cancers (Supplementary Fig. 3r,s ). These include the additional modifiers of the BCR and TLR signaling pathways PTPN6 ( SHP1 ), LYN , HVCN1 , PRKCB , and TLR2 ; the histone genes HIST1H1B , HIST1H1C , HIST1H1D , HIST1H2AC , HIST1H2AM , HIST1H2BK , HIST1H3B , and HIST2H2BE ; BCL11A , IL6 , CCL4 ( MIP-1β ), and the PD-1 ligand CD274 (PD-L1) (Fig. 1a and Supplementary Fig. 4 ). Fig. 1: Recurrently mutated genes in 304 primary DLBCLs. a ,", "role": "user" }, { "content": "The majority of patients with diffuse large B cell lymphoma (DLBCL) can be treated effectively. However, people whose disease recurs face a shortage of good options, especially because the disease is driven by a complicated mix of genetic alterations. Genomic analysis by scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard now offers a better framework for understanding the disease's many forms, which will help to predict individual patient outcomes and guide personalized treatment. Analyzing 304 patient samples, the study showed that DLBCL tumors can be divided into five genetic subtypes, says Margaret Shipp, MD, chief of Dana-Farber's Hematologic Neoplasia division and director of the Lymphoma Program of the Dana-Farber/Harvard Cancer Center. These genetic subtypes can help in identifying likely therapeutic targets, some of which can be inhibited by drugs that already are approved for other conditions or in clinical trials, says Shipp, who, along with Broad Institute's Gad Getz, is co-corresponding author on a Nature Medicine paper presenting the work. \"These genetic signatures also clearly suggest that we want to think about using a combination of targeted agents, because in DLBCL, combinations of genetic alterations occur together in specific subtypes,\" she says. DLBCL is the most common form of lymphoma among adults, with roughly 25,000 people diagnosed with the disease each year in the United States. About 60% of patients can be treated successfully with a combination of four chemotherapies plus a targeted drug that inhibits a B cell surface protein. \"But the other very substantial fraction of patients develops recurrent disease, and their treatment options are far less successful,\" says Shipp. Current clinical tests do a relatively good job of predicting which patients with DLBCL can be treated effectively with standard treatments, but the tests do not offer insights into how treatments could be improved for other patients. The Dana-Farber/Broad collaboration is among several research groups bringing genomic tools to this task. An earlier effort led by National Cancer Institute (NCI) scientists established a widely used \"cell of origin\" classification scheme for DLBCL, which employed RNA profiling to categorize tumor cells by stages of normal B-cell development. Unlike previous DLBCL research efforts, Shipp says, the Dana-Farber/Broad collaboration sought to integrate data on three types of genetic alterations that can drive tumors-mutations to genes, changes in gene copy numbers and chromosomal rearrangements-and define previously unappreciated disease substructure. \"Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all three types of genetic alterations,\" Shipp notes. \"Most importantly, we saw that there were five discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.\" The investigators followed up to examine these tumor subtypes by RNA data associated with cell of origin. They found that each of the two major cell-of-origin subtypes could be split into separate categories with distinct genetic signatures. An additional subtype defined by TP53 gene alterations and associated genomic instability was unrelated to cell of origin. The team then went on to discover clear links between given genetic subtypes and how patients responded to standard treatment. \"We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,\" says Shipp. The study underlined the high genetic diversity in DLBCL—for instance, the median number of genetic driver alterations in individual tumors was 17. \"That large number of alterations tells us that we need to understand the complexity of the genetic signature, because it's unlikely that simply focusing on one genetic alteration will be enough to target therapeutically,\" Shipp points out. \"By understanding the genetic basis of that heterogeneity, we will be able to apply more specifically targeted agents that have the highest likelihood of impacting the right pathways in the right patients.\" She and her collaborators are now working on creating a clinical tool to identify these genetic signatures in patients. Studying related biological mechanisms in the lab, the team also is developing clinical trials that will match patients with given genetic signatures to treatment that includes appropriate targeted agents. Dana-Farber's Bjoern Chapuy and Broad's Chip Stewart and Andrew Dunford are co-first authors on the paper, and Broad's Gad Getz is co-corresponding author. Clinical investigators from the German High-Grade Lymphoma Study Group and the Mayo Clinic also participated. \"This was very much a collaborative effort of a multidisciplinary group of investigators who approached the problem with complementary skill sets,\" Shipp emphasizes. \"This multidisciplinary model, which is increasingly used to investigate cancers, will bring practical benefits for patients.\" ", "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 Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53 , CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification. Main DLBCL is the most common lymphoid malignancy in adults, accounting for up to 35% of non-Hodgkin lymphomas. Although DLBCL is curable with combination therapy (R-CHOP) in over 60% of patients, the remainder develop recurrent or progressive disease that is often fatal. DLBCL is also a genetically heterogeneous disorder with multiple low-frequency mutations, somatic copy number alterations (SCNAs), and structural variants (SVs) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . These tumors are currently thought to arise from antigen-exposed B cells that transit through the germinal center (GC) 1 . Aspects of the GC environment, including the high proliferation rate, physiologic activation-induced cytidine deaminase (AID)-mediated immunoglobulin receptor editing, and aberrant somatic hypermutation (SHM) are conducive to malignant transformation 1 . The heterogeneity of DLBCL is reflected in transcriptionally defined subtypes that provide insights into disease pathogenesis and candidate treatment targets 9 , 10 , 11 , 12 , 13 , 14 . The cell-of-origin (COO) classification identifies ABC- and GCB-type DLBCLs 1 , 9 . ABC-DLBCLs are currently thought to be derived from B cells that have passaged through the GC and are committed to plasmablastic differentiation 1 . These tumors have increased NF-kB activity, and a subset exhibit genetic alterations in NF-kB modifiers and proximal components of the B cell receptor (BCR) pathway and perturbed terminal B cell differentiation 1 , 11 , 13 , 15 . In contrast, GCB-DLBCLs are postulated to originate from light-zone GCBs 1 . A subset of these tumors have alterations in chromatin-modifying enzymes, PI3K signaling, and Gα-migration pathway components and frequent SVs of BCL2 (refs 1 , 16 , 17 , 18 ). Although patients with ABC-DLBCLs have been reported to have less favorable responses to standard therapy than those with GCB-DLBCLs 8 , 9 , 19 , targeted analyses of select alterations have suggested that additional genetic complexity remains to be defined 2 , 11 , 18 , 20 , 21 . Despite the recognized clinical and molecular heterogeneity in DLBCL, previous genomic studies of this disease have largely focused on single types of alterations: mutations, SCNAs, or SVs. To address these issues, we performed whole-exome sequencing (WES) with an expanded bait set to capture known SVs in 304 DLBCLs from newly diagnosed patients. Of the patients, 85% were uniformly treated with R-CHOP and had long-term follow-up; a subset of these patients were enrolled in the prospective multi-center RICOVER60 trial 22 . This representative and clinically annotated DLBCL cohort was used to comprehensively detect mutations, SCNAs, and SVs, and to identify five groups of patients with outcome-associated coordinate genetic signatures, three of which were previously undescribed. Results Significantly mutated driver genes We detected mutations using WES data from 304 primary DLBCLs, 55% of which lacked patient-matched normal samples ( Methods , Supplementary Fig. 1 , and Supplementary Tables 1 and 2 ). To include all 304 samples in the discovery cohort for candidate cancer genes (CCGs), we developed new computational methods to filter germline variants and artifacts from tumor-only samples ( Methods and Supplementary Figs. 2 and 3 ). After filtering, we found a median of 3.3 and 6.6 mutations/Mb in the paired and tumor-only samples, respectively, suggesting that an average of 3.3 germline variants per megabase persisted after filtering. Multiple lines of evidence indicate that these rare germline variants are spread throughout the genome and have minimal effect on the detection of CCGs (beta-binomial test, P = 0.4; Methods and Supplementary Figs. 2 and 3 ). We applied MutSig2CV 23 to the 304 DLBCLs and detected 98 CCGs (q value < 0.1; Fig. 1 and Supplementary Table 3a ). Our CCG list includes previously reported mutational drivers, including the tumor suppressor TP53 ; the chromatin modifiers KMT2D ( MLL2 ), CREBBP , and EP300 ; the components of the BCR, Toll-like receptor (TLR), and NF-kB signaling pathways CD79B , MYD88 , CARD11 , and TNFAIP3 ( A20 ); certain components of the RAS pathway, KRAS , and BRAF ; NOTCH2 and the NOTCH signaling modifier SPEN ; and the immunomodulatory pathway components, B2M , CD58 , CD70 , and CIITA (Fig. 1a ) 3 , 4 , 5 , 6 , 7 , 8 . As a result of the improved methodology and increased sample size, we identified 40 additional previously undescribed CCGs in DLBCL 8 , many of which have defined roles in other lymphoid malignancies or cancers (Supplementary Fig. 3r,s ). These include the additional modifiers of the BCR and TLR signaling pathways PTPN6 ( SHP1 ), LYN , HVCN1 , PRKCB , and TLR2 ; the histone genes HIST1H1B , HIST1H1C , HIST1H1D , HIST1H2AC , HIST1H2AM , HIST1H2BK , HIST1H3B , and HIST2H2BE ; BCL11A , IL6 , CCL4 ( MIP-1β ), and the PD-1 ligand CD274 (PD-L1) (Fig. 1a and Supplementary Fig. 4 ). Fig. 1: Recurrently mutated genes in 304 primary DLBCLs. a ,<|im_end|> <|im_start|>assistant The majority of patients with diffuse large B cell lymphoma (DLBCL) can be treated effectively. However, people whose disease recurs face a shortage of good options, especially because the disease is driven by a complicated mix of genetic alterations. Genomic analysis by scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard now offers a better framework for understanding the disease's many forms, which will help to predict individual patient outcomes and guide personalized treatment. Analyzing 304 patient samples, the study showed that DLBCL tumors can be divided into five genetic subtypes, says Margaret Shipp, MD, chief of Dana-Farber's Hematologic Neoplasia division and director of the Lymphoma Program of the Dana-Farber/Harvard Cancer Center. These genetic subtypes can help in identifying likely therapeutic targets, some of which can be inhibited by drugs that already are approved for other conditions or in clinical trials, says Shipp, who, along with Broad Institute's Gad Getz, is co-corresponding author on a Nature Medicine paper presenting the work. "These genetic signatures also clearly suggest that we want to think about using a combination of targeted agents, because in DLBCL, combinations of genetic alterations occur together in specific subtypes," she says. DLBCL is the most common form of lymphoma among adults, with roughly 25,000 people diagnosed with the disease each year in the United States. About 60% of patients can be treated successfully with a combination of four chemotherapies plus a targeted drug that inhibits a B cell surface protein. "But the other very substantial fraction of patients develops recurrent disease, and their treatment options are far less successful," says Shipp. Current clinical tests do a relatively good job of predicting which patients with DLBCL can be treated effectively with standard treatments, but the tests do not offer insights into how treatments could be improved for other patients. The Dana-Farber/Broad collaboration is among several research groups bringing genomic tools to this task. An earlier effort led by National Cancer Institute (NCI) scientists established a widely used "cell of origin" classification scheme for DLBCL, which employed RNA profiling to categorize tumor cells by stages of normal B-cell development. Unlike previous DLBCL research efforts, Shipp says, the Dana-Farber/Broad collaboration sought to integrate data on three types of genetic alterations that can drive tumors-mutations to genes, changes in gene copy numbers and chromosomal rearrangements-and define previously unappreciated disease substructure. "Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all three types of genetic alterations," Shipp notes. "Most importantly, we saw that there were five discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination." The investigators followed up to examine these tumor subtypes by RNA data associated with cell of origin. They found that each of the two major cell-of-origin subtypes could be split into separate categories with distinct genetic signatures. An additional subtype defined by TP53 gene alterations and associated genomic instability was unrelated to cell of origin. The team then went on to discover clear links between given genetic subtypes and how patients responded to standard treatment. "We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies," says Shipp. The study underlined the high genetic diversity in DLBCL—for instance, the median number of genetic driver alterations in individual tumors was 17. "That large number of alterations tells us that we need to understand the complexity of the genetic signature, because it's unlikely that simply focusing on one genetic alteration will be enough to target therapeutically," Shipp points out. "By understanding the genetic basis of that heterogeneity, we will be able to apply more specifically targeted agents that have the highest likelihood of impacting the right pathways in the right patients." She and her collaborators are now working on creating a clinical tool to identify these genetic signatures in patients. Studying related biological mechanisms in the lab, the team also is developing clinical trials that will match patients with given genetic signatures to treatment that includes appropriate targeted agents. Dana-Farber's Bjoern Chapuy and Broad's Chip Stewart and Andrew Dunford are co-first authors on the paper, and Broad's Gad Getz is co-corresponding author. Clinical investigators from the German High-Grade Lymphoma Study Group and the Mayo Clinic also participated. "This was very much a collaborative effort of a multidisciplinary group of investigators who approached the problem with complementary skill sets," Shipp emphasizes. "This multidisciplinary model, which is increasingly used to investigate cancers, will bring practical benefits for patients." <|im_end|>

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2,587

[ { "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 Live birth has evolved many times independently in vertebrates, such as mammals and diverse groups of lizards and snakes. However, live birth is unknown in the major clade Archosauromorpha, a group that first evolved some 260 million years ago and is represented today by birds and crocodilians. Here we report the discovery of a pregnant long-necked marine reptile ( Dinocephalosaurus ) from the Middle Triassic ( ∼ 245 million years ago) of southwest China showing live birth in archosauromorphs. Our discovery pushes back evidence of reproductive biology in the clade by roughly 50 million years, and shows that there is no fundamental reason that archosauromorphs could not achieve live birth. Our phylogenetic models indicate that Dinocephalosaurus determined the sex of their offspring by sex chromosomes rather than by environmental temperature like crocodilians. Our results provide crucial evidence for genotypic sex determination facilitating land-water transitions in amniotes. Introduction Adaptations related to reproduction directly affect the ability of organisms to produce subsequent generations and persist over evolutionary time scales 1 . The evolutionary transition from egg-laying (oviparity) to live birth (viviparity) involves subtle changes to maternal morphology, physiology, and behaviour, which can lead to matrotrophy (feeding by the mother, for example through a placenta) and shifts in ecological and evolutionary trajectories 1 , 2 , 3 . Despite the complexity of this transition, viviparity has evolved at least 115 times in extant squamates (lizards and snakes), in addition to a single time in the common ancestor of therian mammals 2 , 4 . Moreover, viviparity is a common reproductive mode in extinct aquatic reptiles 5 including eosauropterygians 6 , 7 , ichthyosaurs 8 , 9 , 10 , 11 , 12 , mosasauroids 13 , 14 , some choristoderans 15 and likely mesosaurs 16 , 17 . However, all of the above viviparous reptile lineages are concentrated within one of the three major lineages of extant reptiles—the Lepidosauromorpha—plus some completely extinct aquatic groups with uncertain affinities ( Fig. 1 ). No evidence for viviparity has been discovered in the two other major lineages, Testudines (turtles) and Archosauromorpha. Figure 1: Evolution of reproductive modes in major groups of amniotes. The phylogenetic tree is derived from a combination of published sources 18 , 45 . O, egg-laying (oviparous); V, live-bearing (viviparous). Full size image Basal archosauromorph reptiles first appeared in the Late Permian and diversified in the Triassic 18 . They include trilophosaurs, protorosaurs, rhynchosaurs and archosauriforms, the latter of which includes the ancestors of the crown-group, namely the birds and crocodilians, and their extinct relatives including non-avian dinosaurs and pterosaurs among others 18 . All crown-group archosauromorphs lay calcified eggs 19 , the fossil record of which can be traced back at least to the Early Jurassic 20 , 21 . However, the reproductive biology of stem-group archosauromorphs remains unknown. Here we report a new specimen of the aquatic protorosaur Dinocephalosaurus 22 from the Middle Triassic of South China containing an embryo in the abdominal region. The pregnant specimen provides evidence of live birth in a reptile with undoubted archosauromorph affinity and insight into the reproductive biology of stem-group archosauromorphs. Results Geological background The new specimen belongs to the recently discovered Luoping biota 23 , 24 , which is preserved in an intraplatform basin of the Yangtze Platform in the South China Block ( Fig. 2a ). Conodont analysis dates the biota to the Pelsonian substage of the Anisian in the Middle Triassic 25 , corresponding to an age of ∼ 244–245 million years ago (Ma). The Luoping biota comprises thousands of extremely well preserved fossil specimens 23 , 24 . The specimen was collected in 2008 from Bed 74 of the Dawazi section ( Fig. 2b ) in Luoping County, Yunnan Province, China. The thin micritic limestone layer bearing the specimen immediately overlies a set of thick-bedded siliceous nodular limestones ( Fig. 2b ). Before collection, the specimen had already been weathered into three blocks in the field, the fractures of which were filled with modern soils. The specimen was then transferred from Luoping to the Chengdu Center of China Geological Survey for routine mechanical preparation. Figure 2: Locality and horizon of the new Dinocephalosaurus specimen LPV 30280. ( a ) Paleotectonic map showing the location of the Luoping biota where LPV 30280 is preserved 23 . Scale bar, 60 km. ( b ) Stratigraphic column of the Dawazi section 23 showing the horizon of LPV 30280. Scale bar, 2 m. Full size image Systematic palaeontology and phylogenetic analysis The Luoping specimen ( Fig. 3 ) is catalogued as LPV 30280 in the Chengdu Center of China Geological Survey. It shares several unequivocally derived characters with published Dinocephalosaurus specimens among protorosaurs, including a remarkably elongated neck formed by an increased number of cervical vertebrate, free sacral and caudal ribs from relevant vertebrae, round tarsus ossifications and moderate hyperphalangy in the pes. These distinct synapomorphies make the identification of the new material as Dinocephalosaurus unambiguous. Slight differences exist, but currently the available specimens are not enough to reach a firm conclusion that these differences are stable between specimens from two different locations (see Supplementary Note 1 for detailed description of the specimen). Using both parsimony and Bayesian methods, phylogenetic analyses incorporating all well-known protorosaurian genera reveal a closer phylogenetic relationship of Dinocephalosaurus to the derived tanystropheids than to other protorosaurs ( Fig. 4 ; Supplementary Figs 1 and 2 ). Figure 3: Skeleton of the new Dinocephalosaurus specimen LPV 30280. ( a ) Photograph. The three separate blocks are arranged following their original positions in the field. ( b ) Interpretive drawing. Dotted line indicates the rough course of the vertebral column of the adult. The different colour in the cervical region aims to facilitate the association of cervical ribs with corresponding vertebrae. ( c ) Photo showing a close-up of the embryo preserved in the stomach region of LPV 30280. ( d ) Interpretive drawing of the embryo. ( e ) Photo showing a close-up of the perleidid fish preserved in", "role": "user" }, { "content": "A remarkable 250 million-year-old \"terrible-headed lizard\" fossil found in China shows an embryo inside the mother—clear evidence for live birth. Head of The University of Queensland's School of Earth and Environmental Sciences and co-author Professor Jonathan Aitchison said the fossil unexpectedly provided the first evidence for live birth in an animal group previously thought to exclusively lay eggs. \"Live birth is well known in mammals, where the mother has a placenta to nourish the developing embryo,\" Professor Aitchison said. \"Live birth is also very common among lizards and snakes, where the babies sometimes 'hatch' inside their mother and emerge without a shelled egg.\" Until recently it was thought the third major group of living land vertebrates, the crocodiles and birds (part of the wider group Archosauromorpha) only laid eggs. \"Indeed, egg-laying is the primitive state, seen at the base of reptiles, and in their ancestors such as amphibians and fishes,\" Professor Aitchison said. He said the new fossil was an unusual, long-necked marine animal called an archosauromorph that flourished in shallow seas of South China in the Middle Triassic Period. The creature was a fish-eater, snaking its long neck from side to side to snatch its prey. Its fossil was one of many astonishingly well-preserved specimens from new \"Luoping biota\" locations in south-western China. There were no known fossils like this (marine vertebrates of this age) from Australia. Lead author Professor Jun Liu from Hefei University of Technology China, said the researchers were \"excited\" when they first saw this embryonic specimen. \"We were not sure if the embryonic specimen was the mother's last lunch or its unborn baby,\" Professor Liu said. \"Upon further preparation and closer inspection, we discovered something unusual.\" He said the embryo was inside the mother's rib cage, and it faced forward; swallowed animals generally face backward because the predator swallows its prey head-first to help it go down its throat. Furthermore, the small reptile inside the mother was an example of the same species. \"Further evolutionary analysis revealed the first case of live birth in such a wide group containing birds, crocodilians, dinosaurs and pterosaurs among others, and pushes back evidence of reproductive biology in the group by 50 million years,\" Professor Liu said. \"Information on reproductive biology of archosauromorphs before the Jurassic Period was not available until our discovery, despite a 260 million-year history of the group.\" Professor Chris Organ from Montana State University said evolutionary analysis showed that this instance of live birth was also associated with genetic sex determination. \"Some reptiles today, such as crocodiles, determine the sex of their offspring by the temperature inside the nest,\" he said. \"We identified that Dinocephalosaurus, a distant ancestor of crocodiles, determined the sex of its babies genetically, like mammals and birds. \"This new specimen from China rewrites our understanding of the evolution of reproductive systems.\" Professor Mike Benton of the University of Bristol said analysis of the evolutionary position of the new specimens showed no fundamental reason why archosauromorphs could not have evolved live birth. \"This combination of live birth and genotypic sex determination seems to have been necessary for animals such as Dinocephalosaurus to become aquatic,\" he said. \"It's great to see such an important step forward in our understanding of the evolution of a major group coming from a chance fossil find in a Chinese field.\" The work is part of ongoing wider collaborations between palaeontologists in China, the United States, the UK and Australia. The paper is published in the journal, Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Live birth has evolved many times independently in vertebrates, such as mammals and diverse groups of lizards and snakes. However, live birth is unknown in the major clade Archosauromorpha, a group that first evolved some 260 million years ago and is represented today by birds and crocodilians. Here we report the discovery of a pregnant long-necked marine reptile ( Dinocephalosaurus ) from the Middle Triassic ( ∼ 245 million years ago) of southwest China showing live birth in archosauromorphs. Our discovery pushes back evidence of reproductive biology in the clade by roughly 50 million years, and shows that there is no fundamental reason that archosauromorphs could not achieve live birth. Our phylogenetic models indicate that Dinocephalosaurus determined the sex of their offspring by sex chromosomes rather than by environmental temperature like crocodilians. Our results provide crucial evidence for genotypic sex determination facilitating land-water transitions in amniotes. Introduction Adaptations related to reproduction directly affect the ability of organisms to produce subsequent generations and persist over evolutionary time scales 1 . The evolutionary transition from egg-laying (oviparity) to live birth (viviparity) involves subtle changes to maternal morphology, physiology, and behaviour, which can lead to matrotrophy (feeding by the mother, for example through a placenta) and shifts in ecological and evolutionary trajectories 1 , 2 , 3 . Despite the complexity of this transition, viviparity has evolved at least 115 times in extant squamates (lizards and snakes), in addition to a single time in the common ancestor of therian mammals 2 , 4 . Moreover, viviparity is a common reproductive mode in extinct aquatic reptiles 5 including eosauropterygians 6 , 7 , ichthyosaurs 8 , 9 , 10 , 11 , 12 , mosasauroids 13 , 14 , some choristoderans 15 and likely mesosaurs 16 , 17 . However, all of the above viviparous reptile lineages are concentrated within one of the three major lineages of extant reptiles—the Lepidosauromorpha—plus some completely extinct aquatic groups with uncertain affinities ( Fig. 1 ). No evidence for viviparity has been discovered in the two other major lineages, Testudines (turtles) and Archosauromorpha. Figure 1: Evolution of reproductive modes in major groups of amniotes. The phylogenetic tree is derived from a combination of published sources 18 , 45 . O, egg-laying (oviparous); V, live-bearing (viviparous). Full size image Basal archosauromorph reptiles first appeared in the Late Permian and diversified in the Triassic 18 . They include trilophosaurs, protorosaurs, rhynchosaurs and archosauriforms, the latter of which includes the ancestors of the crown-group, namely the birds and crocodilians, and their extinct relatives including non-avian dinosaurs and pterosaurs among others 18 . All crown-group archosauromorphs lay calcified eggs 19 , the fossil record of which can be traced back at least to the Early Jurassic 20 , 21 . However, the reproductive biology of stem-group archosauromorphs remains unknown. Here we report a new specimen of the aquatic protorosaur Dinocephalosaurus 22 from the Middle Triassic of South China containing an embryo in the abdominal region. The pregnant specimen provides evidence of live birth in a reptile with undoubted archosauromorph affinity and insight into the reproductive biology of stem-group archosauromorphs. Results Geological background The new specimen belongs to the recently discovered Luoping biota 23 , 24 , which is preserved in an intraplatform basin of the Yangtze Platform in the South China Block ( Fig. 2a ). Conodont analysis dates the biota to the Pelsonian substage of the Anisian in the Middle Triassic 25 , corresponding to an age of ∼ 244–245 million years ago (Ma). The Luoping biota comprises thousands of extremely well preserved fossil specimens 23 , 24 . The specimen was collected in 2008 from Bed 74 of the Dawazi section ( Fig. 2b ) in Luoping County, Yunnan Province, China. The thin micritic limestone layer bearing the specimen immediately overlies a set of thick-bedded siliceous nodular limestones ( Fig. 2b ). Before collection, the specimen had already been weathered into three blocks in the field, the fractures of which were filled with modern soils. The specimen was then transferred from Luoping to the Chengdu Center of China Geological Survey for routine mechanical preparation. Figure 2: Locality and horizon of the new Dinocephalosaurus specimen LPV 30280. ( a ) Paleotectonic map showing the location of the Luoping biota where LPV 30280 is preserved 23 . Scale bar, 60 km. ( b ) Stratigraphic column of the Dawazi section 23 showing the horizon of LPV 30280. Scale bar, 2 m. Full size image Systematic palaeontology and phylogenetic analysis The Luoping specimen ( Fig. 3 ) is catalogued as LPV 30280 in the Chengdu Center of China Geological Survey. It shares several unequivocally derived characters with published Dinocephalosaurus specimens among protorosaurs, including a remarkably elongated neck formed by an increased number of cervical vertebrate, free sacral and caudal ribs from relevant vertebrae, round tarsus ossifications and moderate hyperphalangy in the pes. These distinct synapomorphies make the identification of the new material as Dinocephalosaurus unambiguous. Slight differences exist, but currently the available specimens are not enough to reach a firm conclusion that these differences are stable between specimens from two different locations (see Supplementary Note 1 for detailed description of the specimen). Using both parsimony and Bayesian methods, phylogenetic analyses incorporating all well-known protorosaurian genera reveal a closer phylogenetic relationship of Dinocephalosaurus to the derived tanystropheids than to other protorosaurs ( Fig. 4 ; Supplementary Figs 1 and 2 ). Figure 3: Skeleton of the new Dinocephalosaurus specimen LPV 30280. ( a ) Photograph. The three separate blocks are arranged following their original positions in the field. ( b ) Interpretive drawing. Dotted line indicates the rough course of the vertebral column of the adult. The different colour in the cervical region aims to facilitate the association of cervical ribs with corresponding vertebrae. ( c ) Photo showing a close-up of the embryo preserved in the stomach region of LPV 30280. ( d ) Interpretive drawing of the embryo. ( e ) Photo showing a close-up of the perleidid fish preserved in<|im_end|> <|im_start|>assistant A remarkable 250 million-year-old "terrible-headed lizard" fossil found in China shows an embryo inside the mother—clear evidence for live birth. Head of The University of Queensland's School of Earth and Environmental Sciences and co-author Professor Jonathan Aitchison said the fossil unexpectedly provided the first evidence for live birth in an animal group previously thought to exclusively lay eggs. "Live birth is well known in mammals, where the mother has a placenta to nourish the developing embryo," Professor Aitchison said. "Live birth is also very common among lizards and snakes, where the babies sometimes 'hatch' inside their mother and emerge without a shelled egg." Until recently it was thought the third major group of living land vertebrates, the crocodiles and birds (part of the wider group Archosauromorpha) only laid eggs. "Indeed, egg-laying is the primitive state, seen at the base of reptiles, and in their ancestors such as amphibians and fishes," Professor Aitchison said. He said the new fossil was an unusual, long-necked marine animal called an archosauromorph that flourished in shallow seas of South China in the Middle Triassic Period. The creature was a fish-eater, snaking its long neck from side to side to snatch its prey. Its fossil was one of many astonishingly well-preserved specimens from new "Luoping biota" locations in south-western China. There were no known fossils like this (marine vertebrates of this age) from Australia. Lead author Professor Jun Liu from Hefei University of Technology China, said the researchers were "excited" when they first saw this embryonic specimen. "We were not sure if the embryonic specimen was the mother's last lunch or its unborn baby," Professor Liu said. "Upon further preparation and closer inspection, we discovered something unusual." He said the embryo was inside the mother's rib cage, and it faced forward; swallowed animals generally face backward because the predator swallows its prey head-first to help it go down its throat. Furthermore, the small reptile inside the mother was an example of the same species. "Further evolutionary analysis revealed the first case of live birth in such a wide group containing birds, crocodilians, dinosaurs and pterosaurs among others, and pushes back evidence of reproductive biology in the group by 50 million years," Professor Liu said. "Information on reproductive biology of archosauromorphs before the Jurassic Period was not available until our discovery, despite a 260 million-year history of the group." Professor Chris Organ from Montana State University said evolutionary analysis showed that this instance of live birth was also associated with genetic sex determination. "Some reptiles today, such as crocodiles, determine the sex of their offspring by the temperature inside the nest," he said. "We identified that Dinocephalosaurus, a distant ancestor of crocodiles, determined the sex of its babies genetically, like mammals and birds. "This new specimen from China rewrites our understanding of the evolution of reproductive systems." Professor Mike Benton of the University of Bristol said analysis of the evolutionary position of the new specimens showed no fundamental reason why archosauromorphs could not have evolved live birth. "This combination of live birth and genotypic sex determination seems to have been necessary for animals such as Dinocephalosaurus to become aquatic," he said. "It's great to see such an important step forward in our understanding of the evolution of a major group coming from a chance fossil find in a Chinese field." The work is part of ongoing wider collaborations between palaeontologists in China, the United States, the UK and Australia. The paper is published in the journal, Nature Communications. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Workplace incivility (i.e., rudeness and disrespect) is a pervasive problem that impacts a number of important employee workplace outcomes. This study expands past research on outcomes of experienced incivility by proposing a spillover-crossover model in which experienced incivility is associated with negative work rumination outside of work as well as insomnia symptoms (i.e., spillover). We further propose that rumination in one employee is also linked to insomnia symptoms in the employee’s partner (i.e., crossover). The moderating effect of being work-linked (working in the same organization or occupation as one’s partner) was also investigated. We tested the hypothesized Actor-Partner Interdependence Mediation Model in the context of dual-earner couples ( N = 305). To test moderation effects, we conducted a multi-group analysis by comparing our hypothesized model across work-linked and non-linked couples. Our results support the spillover effect, suggesting that experienced incivility is linked to employee insomnia symptoms through rumination. However, the crossover effect was only found among work-linked couples. By connecting the sleep and workplace incivility literatures, our findings support a dyadic model in which workplace incivility, as an interpersonal stressor, is linked to employee as well as partner insomnia through negative work rumination. Interventions aimed at alleviating negative work rumination may help reduce work-home spillover as well as crossover, particularly for work-linked, dual-earner couples. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes The experience of workplace incivility (i.e., rudeness and disrespect) has been linked to employee strain, affecting employees’ willingness and ability to remain a productive member of their organization. Employee surveys indicate that 98% of sampled workers had experienced incivility at work (Porath and Pearson 2013 ) and 71% of employees experienced workplace incivility in the last 5 years (Cortina et al. 2001 ). The experience of incivility has been linked to a vast variety of employee outcomes including impaired well-being and increased counterproductive work behaviors (see Schilpzand et al. 2014 , for a review). Despite the continually growing research on workplace incivility, we still lack understanding of the potential links between workplace incivility and employee experiences outside of work. Therefore, our study contributes to past research by examining the relationship between workplace incivility – a common work stressor – and employee insomnia symptoms – an employee experience in the home domain. Impaired sleep in employees has been linked to a variety of employee outcomes (e.g. accidents, lower productivity, impaired communication, impaired self-regulation; Barnes 2012 ) suggesting that individuals and organizations should make sufficient, high-quality sleep a priority. Therefore, understanding the link between workplace incivility and employee sleep will help clarify the harmful nature of incivility experiences and provide suggestions for job design and specific organizational interventions. In addition, our study examines a possible mechanism linking incivility and sleep problems, namely negative work rumination outside of work. Specifically, we propose that cognitive activation, in the form of negative work rumination, will help explain the relationship between experienced workplace incivility and employee sleep problems. Finding and understanding mechanisms linking workplace incivility and employee outcomes outside of work is crucial for theory building as well as the development of workplace interventions. We examine this proposed mediation in the context of dual-earner couples, suggesting that negative work rumination does not occur in a vacuum. Accordingly, Miner et al. ( 2017 ) suggests that incivility experiences can impact others in the victim’s social network such as coworkers, customers, or family members. Thus, while past research has focused mostly on individual outcomes of incivility it is important to examine how the incivility experiences cross over from an employee to their partner at home. Applying the idea of cognitive activation, we propose that negative work rumination outside of work in one employee will mediate the relationship between that the person’s experienced incivility and sleep problems in his or her partner. Thus, incivility experienced by one employee may be related to impaired sleep in two individuals! The negative outcomes of impaired sleep in both partners may then result in a variety of negative outcomes in two workplaces (Litwiller et al. 2017 ). Recent research on workplace incivility has pointed to links between experienced incivility, and partner as well as family outcomes (Ferguson 2012 ; Lim et al. 2016 ). Our study extends the focus on partner outcomes by examining a moderator of the proposed mediation to better understand the context in which these crossover processes occur. Specifically, we suggest that the effects on partner sleep problems will be stronger for partners who are work-linked (i.e., working in the same organization or occupation). While being work-linked can provide unique resources for dual-earner couples due to higher integration of work and family roles (Halbesleben et al. 2010 ) it can also create additional demands and challenges for both partners. Understanding these challenges as well as associated outcomes for both partners will expand the current literature on work-family dynamics thereby providing important information for theory and practice. In summary, we are expanding past research on outcomes of workplace incivility by proposing a moderated mediation model in dual-earner couples. Specifically, we propose that experienced incivility in the workplace will be associated with rumination outside of work as well as insomnia symptoms. We further suggest that rumination in one employee will also linked to insomnia symptoms in the employee’s partner and this relationship will be stronger in couples who are work-linked. Figure 1 displays our conceptual model. Fig. 1 Conceptual model. The discontinuous lines indicate unhypothesized effects. The subscript A refers to actor effects while the subscript P refers to partner effects. Circles represent error terms. The hypothesized actor-to-actor mediation refers to a A b A (H3) while the actor-to-partner mediation refers to a A b P (H4). The direct actor effect, c A is drawn as the mediation effects are expected to be partial. For simplicity, this Figure does not include work-linked relationship as a moderator of the path, b P , as well as the indirect effect of a A b P Full size image Theory", "role": "user" }, { "content": "Rudeness. Sarcastic comments. Demeaning language. Interrupting or talking over someone in a meeting. Workplace incivilities such as these are becoming increasingly common, and a new study from Portland State University and University of Illinois researchers found this behavior has the potential to not only negatively affect an employee's sleep but their partner's as well. The study, recently published in the journal Occupational Health Science, builds on previous research by examining the relationship between workplace incivility—a common stressful work event—and employee sleep in the context of dual-earner couples. The researchers surveyed 305 couples in a variety of jobs. Charlotte Fritz, the lead author of the study and associate professor of industrial and organizational psychology in PSU's College of Liberal Arts and Sciences, said when one spouse experiences workplace incivility, they tend to ruminate more about work at home and report insomnia symptoms whether it's trouble falling asleep or waking up in the middle of the night. But the study went a step further examining sleep problems in the employee's spouse and found their sleep is also affected—but only if the couple works in the same company or occupation. \"Because work-linked couples have a better idea of what's going on in each other's work, they can be better supporters,\" Fritz said. \"They probably know more about the context of the incivil act and might be more pulled into the venting or problem-solving process.\" Fritz recommends that organizations do everything in their power to create a culture of civility by imposing zero-tolerance policies or offering civility training. But given that workplace incivilities aren't completely avoidable, Fritz also suggests a number of strategies to help employees cope, including mentally detaching from work during non-work hours by spending time with family and friends or enjoying hobbies, and practicing meditation at work and home. The same is true of the employee's spouse. \"Not talking about work or not supporting your spouse is not the solution,\" Fritz said. \"They can talk about work, vent about it, discuss it, but then they should make an explicit attempt to unwind together and create good conditions for sleep.\" ", "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 Workplace incivility (i.e., rudeness and disrespect) is a pervasive problem that impacts a number of important employee workplace outcomes. This study expands past research on outcomes of experienced incivility by proposing a spillover-crossover model in which experienced incivility is associated with negative work rumination outside of work as well as insomnia symptoms (i.e., spillover). We further propose that rumination in one employee is also linked to insomnia symptoms in the employee’s partner (i.e., crossover). The moderating effect of being work-linked (working in the same organization or occupation as one’s partner) was also investigated. We tested the hypothesized Actor-Partner Interdependence Mediation Model in the context of dual-earner couples ( N = 305). To test moderation effects, we conducted a multi-group analysis by comparing our hypothesized model across work-linked and non-linked couples. Our results support the spillover effect, suggesting that experienced incivility is linked to employee insomnia symptoms through rumination. However, the crossover effect was only found among work-linked couples. By connecting the sleep and workplace incivility literatures, our findings support a dyadic model in which workplace incivility, as an interpersonal stressor, is linked to employee as well as partner insomnia through negative work rumination. Interventions aimed at alleviating negative work rumination may help reduce work-home spillover as well as crossover, particularly for work-linked, dual-earner couples. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes The experience of workplace incivility (i.e., rudeness and disrespect) has been linked to employee strain, affecting employees’ willingness and ability to remain a productive member of their organization. Employee surveys indicate that 98% of sampled workers had experienced incivility at work (Porath and Pearson 2013 ) and 71% of employees experienced workplace incivility in the last 5 years (Cortina et al. 2001 ). The experience of incivility has been linked to a vast variety of employee outcomes including impaired well-being and increased counterproductive work behaviors (see Schilpzand et al. 2014 , for a review). Despite the continually growing research on workplace incivility, we still lack understanding of the potential links between workplace incivility and employee experiences outside of work. Therefore, our study contributes to past research by examining the relationship between workplace incivility – a common work stressor – and employee insomnia symptoms – an employee experience in the home domain. Impaired sleep in employees has been linked to a variety of employee outcomes (e.g. accidents, lower productivity, impaired communication, impaired self-regulation; Barnes 2012 ) suggesting that individuals and organizations should make sufficient, high-quality sleep a priority. Therefore, understanding the link between workplace incivility and employee sleep will help clarify the harmful nature of incivility experiences and provide suggestions for job design and specific organizational interventions. In addition, our study examines a possible mechanism linking incivility and sleep problems, namely negative work rumination outside of work. Specifically, we propose that cognitive activation, in the form of negative work rumination, will help explain the relationship between experienced workplace incivility and employee sleep problems. Finding and understanding mechanisms linking workplace incivility and employee outcomes outside of work is crucial for theory building as well as the development of workplace interventions. We examine this proposed mediation in the context of dual-earner couples, suggesting that negative work rumination does not occur in a vacuum. Accordingly, Miner et al. ( 2017 ) suggests that incivility experiences can impact others in the victim’s social network such as coworkers, customers, or family members. Thus, while past research has focused mostly on individual outcomes of incivility it is important to examine how the incivility experiences cross over from an employee to their partner at home. Applying the idea of cognitive activation, we propose that negative work rumination outside of work in one employee will mediate the relationship between that the person’s experienced incivility and sleep problems in his or her partner. Thus, incivility experienced by one employee may be related to impaired sleep in two individuals! The negative outcomes of impaired sleep in both partners may then result in a variety of negative outcomes in two workplaces (Litwiller et al. 2017 ). Recent research on workplace incivility has pointed to links between experienced incivility, and partner as well as family outcomes (Ferguson 2012 ; Lim et al. 2016 ). Our study extends the focus on partner outcomes by examining a moderator of the proposed mediation to better understand the context in which these crossover processes occur. Specifically, we suggest that the effects on partner sleep problems will be stronger for partners who are work-linked (i.e., working in the same organization or occupation). While being work-linked can provide unique resources for dual-earner couples due to higher integration of work and family roles (Halbesleben et al. 2010 ) it can also create additional demands and challenges for both partners. Understanding these challenges as well as associated outcomes for both partners will expand the current literature on work-family dynamics thereby providing important information for theory and practice. In summary, we are expanding past research on outcomes of workplace incivility by proposing a moderated mediation model in dual-earner couples. Specifically, we propose that experienced incivility in the workplace will be associated with rumination outside of work as well as insomnia symptoms. We further suggest that rumination in one employee will also linked to insomnia symptoms in the employee’s partner and this relationship will be stronger in couples who are work-linked. Figure 1 displays our conceptual model. Fig. 1 Conceptual model. The discontinuous lines indicate unhypothesized effects. The subscript A refers to actor effects while the subscript P refers to partner effects. Circles represent error terms. The hypothesized actor-to-actor mediation refers to a A b A (H3) while the actor-to-partner mediation refers to a A b P (H4). The direct actor effect, c A is drawn as the mediation effects are expected to be partial. For simplicity, this Figure does not include work-linked relationship as a moderator of the path, b P , as well as the indirect effect of a A b P Full size image Theory<|im_end|> <|im_start|>assistant Rudeness. Sarcastic comments. Demeaning language. Interrupting or talking over someone in a meeting. Workplace incivilities such as these are becoming increasingly common, and a new study from Portland State University and University of Illinois researchers found this behavior has the potential to not only negatively affect an employee's sleep but their partner's as well. The study, recently published in the journal Occupational Health Science, builds on previous research by examining the relationship between workplace incivility—a common stressful work event—and employee sleep in the context of dual-earner couples. The researchers surveyed 305 couples in a variety of jobs. Charlotte Fritz, the lead author of the study and associate professor of industrial and organizational psychology in PSU's College of Liberal Arts and Sciences, said when one spouse experiences workplace incivility, they tend to ruminate more about work at home and report insomnia symptoms whether it's trouble falling asleep or waking up in the middle of the night. But the study went a step further examining sleep problems in the employee's spouse and found their sleep is also affected—but only if the couple works in the same company or occupation. "Because work-linked couples have a better idea of what's going on in each other's work, they can be better supporters," Fritz said. "They probably know more about the context of the incivil act and might be more pulled into the venting or problem-solving process." Fritz recommends that organizations do everything in their power to create a culture of civility by imposing zero-tolerance policies or offering civility training. But given that workplace incivilities aren't completely avoidable, Fritz also suggests a number of strategies to help employees cope, including mentally detaching from work during non-work hours by spending time with family and friends or enjoying hobbies, and practicing meditation at work and home. The same is true of the employee's spouse. "Not talking about work or not supporting your spouse is not the solution," Fritz said. "They can talk about work, vent about it, discuss it, but then they should make an explicit attempt to unwind together and create good conditions for sleep." <|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 Rice ( Oriza sativa ) feeds nearly half of the world’s population. Regional and national studies in Asia suggest that rice production will suffer under climate change, but researchers conducted few studies for other parts of the world. This research identifies suitable areas for cultivating irrigated rice in Colombia under current climates and for the 2050s, according to the Representative Concentration Pathway (RCP) 8.5 scenario. The methodology uses known locations of the crop, environmental variables, and maximum entropy and probabilistic methods to develop niche-based models for estimating the potential geographic distribution of irrigated rice. Results indicate that future climate change in Colombia could reduce the area that is suitable for rice production by 60%, from 4.4 to 1.8 million hectares. Low-lying rice production regions could be the most susceptible to changing environmental conditions, while mid-altitude valleys could see improvements in rice-growing conditions. In contrast to a country like China where rice production can move to higher latitudes, rice adaptation in tropical Colombia will favor higher elevations. These results suggest adaptation strategies for the Colombian rice sector. Farmers can adopt climate-resilient varieties or change water and agronomic management practices, or both. Other farmers may consider abandoning rice production for some other crop or activity. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes 1 Introduction Half of the world’s population consumes rice, making it the most important food crop in the developing world (Seck et al. 2012 ). A constant supply of rice ( Oriza sativa ) supports food security and societal stability in both rice-producing and rice-consuming countries (Degiovanni et al. 2010 ; Godfray et al. 2010a , b ). One hundred thirteen countries produce substantial amounts of rice. Twenty-six countries in Latin American and the Caribbean (LAC) produce 24 million tons of rice on 5.9 million hectares, equivalent to 4% of world production (FAOSTAT 2004 ; Sanint 2010 ). Experts anticipate that climate change will have large impacts on rice and other crops. The most recent report of the Intergovernmental Panel on Climate Change (IPCC) suggests average global crop productivity will likely decline between 1 and 2.5%/°C of warming (Porter et al. 2014 ; Challinor et al. 2014 ). At the global scale, Zabel et al. ( 2014 ) identified the climate change impact on geographic distribution for several crops, including rice. They projected that an area of 6.4 million square kilometers would become unsuitable for agricultural production, and another 4.8 million square kilometers would become marginally suitable for global agriculture, if adaptation measures are not widely adopted. At regional scale, David Lobell et al. ( 2008 ) projected 10% yield reductions in rice in the Andean region in their study of climatic risk for seven crops in 12 regions of the world. Based on the ORYZA crop model, Matthews et al. ( 1997 ) projected yield reductions as high as 31% in Asia under a scenario where temperatures increase by 4 °C temperature. At national scales, studies of rice and climate change have almost exclusively focused on Asian countries. Three studies have assessed the impact of climate change on rice in China. Zhang et al. ( 2017 ) simulated the migration of rice and maize planting areas in China by analyzing movement of the geographic mean of rice production under current and future climate scenarios. They project the suitable areas for rice and maize to shift northward in the future, while the area suitable for irrigated cultivation will gradually increase, mainly in northwestern and northern China. Ye et al. ( 2015 ) explored the influence of climate change on suitable rice cropping areas, rice cropping systems and crop water requirements during the growing season for historical (1951–2010) and future (2011–2100) time periods in China. Their results showed that the land areas suitable for rice cropping systems shifted northward and westward from 1951 to 2010. Yao et al. ( 2007 ) estimates large rice yield reductions in China, based on the CERES crop model. Paul Teng et al. ( 2016 ) estimated rice yield reductions of 23%, 32%, and 33% in Vietnam, Thailand, and India, respectively. In one study of India, Auffhammer et al. ( 2012 ) show that climate change has already affected millions of rice producers and consumers and will continue to do so in the future. Only one study estimated that there would be yield increases for irrigated rice in India in the future (Aggarwal and Mall 2002 ). Reilly et al. ( 2003 ) estimate large yield reductions in the southernmost rice-producing regions of the USA. The review of studies above shows the lack of research on the impacts of climate change on rice in Latin America. Colombia lacks a study of this type, despite the importance of rice in the diet and expectations for significant climate change. This study—the first analysis of its type for a Latin American country—fills a gap in research on climate change by analyzing expected impact on rice production in Colombia. Colombian farmers cultivated 570,802 ha of rice in 2016, producing 5.7 million tons. Current production represents an increase compared to the previous two rice censuses, when national production was 2.8 million tons on 493,237 ha in 1999 and 2.5 million tons on 400,451 ha in 2007 (FEDEARROZ 2008 ; FEDEARROZ 2016 ). Average yields rose from 5.7 tons ha −1 in 1999 to 6.2 tons ha −1 in 2007, falling back to 5.7 tons ha −1 in 2016 (FEDEARROZ 2008 ; FEDEARROZ 2016 ). Nevertheless, Colombia remains among the Latin American countries with the lowest yields, lower than countries such as Peru (7.3 tons ha −1 ) and Uruguay (7.1 tons ha −1 ), among others (GRISP 2013 ). Low yields and increases in per capita rice consumption led Colombia to import rice from countries such as Ecuador, Peru, and the USA (DANE 2015 ; Pulver et al. 2008 ; Espinal et al. 2005 ; Tilman and Clark 2014 ). The increasing dependence on rice imports poses important challenges to Colombian food", "role": "user" }, { "content": "Without significant global reductions in greenhouse gas emissions, Colombia will have 60 percent less land suitable for rice production by the 2050s, according to a new study by the CGIAR Research Program on Climate Change, Agriculture and Food Security (CCAFS). Due primarily to increased temperatures and decreased rainfall—as opposed to sea-level rise, which is the driver of projected change to rice production in some Asian countries—the research shows suitable conditions will need to be found at higher elevations when low-altitude fields are too hot or dry for irrigated rice production. The study found that Colombia's suitable arable land for rice is currently 4.4 million hectares but could be reduced to 1.8 million hectares in a few decades. Mitigation could require complex decisions around land-use change, changes in crop cultivation, and food security, said the authors. The study is the first of its kind for a Latin American country and was published in Mitigation and Adaptation Strategies for Global Change. \"Many of these impacts can be avoided if we act on time by facilitating strategies so that our farmers are better prepared, and reducing the emissions of greenhouse gases from agriculture and other sectors,\" said Fabio Castro, the study's lead author and researcher at the International Center for Tropical Agriculture (CIAT) in Colombia. The study highlights the climate-change challenges faced by many tropical countries that grow rice, which is the most important food crop in the developing world. Whereas China, the world's largest rice producer, has lots of land and can move production further north to mitigate climate impacts, many countries do not have the same options. \"India, which is a little bit closer to the equator, doesn't have as much flexibility as China does, but they still have some flexibility, as do some Southeast Asian countries,\" said Glenn Hyman, a co-author at the Spatial Informatics Group. \"Indonesia, Western Africa, Peru, Ecuador and Central America are similar to Colombia but may lack land at cooler, higher altitudes.\" Rice trial plots on the International Center for Tropical Agriculture campus in Colombia. Credit: Neil Palmer / CIAT Mitigate quickly The researchers examined current and projected climate conditions in Colombia's various rice-growing regions. Under the projections, some low-altitude areas are projected to become environmentally incompatible with rice production. Other areas, which are cooler and have higher elevations, will become more suitable. Mitigation strategies for the most extreme future climates include adoption of heat-tolerant rice varieties and more efficient water management. Researchers also recommend careful development of new rice-growing areas. They emphasize that global action to reduce greenhouse gas emissions will significantly decrease the extent of adaptation measures. \"This is a warning that Colombia's suitability for rice will change,\" said Castro, who is also a researcher at Colombia's Universidad del Valle. \"If cultivation continues in the same areas, with the same seeds and the same agronomic practices, perhaps future yields will be reduced or simply the current varieties will not adapt.\" The study's future scenario, 2049-2060, is based on Representative Concentration Pathway (RCP) 8.5, a greenhouse gas concentration trajectory that considers business-as-usual emissions scenarios. RCPs were adopted by the Intergovernmental Panel on Climate Change to help standardize research related to projected impacts of increased greenhouse gases in the atmosphere. Future land suitability was determined by climate models for temperature, precipitation, soil types, and socioeconomic variables. \"Areas that are projected to be less suitable for rice may need to switch to other crops or otherwise develop new livelihood strategies. In other areas where rice production is projected to thrive, land-use changes need to be considered carefully in the light of sustainability and profitability,\" wrote the authors. \"Food security and food sovereignty issues may also be important considerations in land-use planning in these regions. Planning efforts will require more research on the economic and social aspects of agricultural production in the country.\" ", "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 Rice ( Oriza sativa ) feeds nearly half of the world’s population. Regional and national studies in Asia suggest that rice production will suffer under climate change, but researchers conducted few studies for other parts of the world. This research identifies suitable areas for cultivating irrigated rice in Colombia under current climates and for the 2050s, according to the Representative Concentration Pathway (RCP) 8.5 scenario. The methodology uses known locations of the crop, environmental variables, and maximum entropy and probabilistic methods to develop niche-based models for estimating the potential geographic distribution of irrigated rice. Results indicate that future climate change in Colombia could reduce the area that is suitable for rice production by 60%, from 4.4 to 1.8 million hectares. Low-lying rice production regions could be the most susceptible to changing environmental conditions, while mid-altitude valleys could see improvements in rice-growing conditions. In contrast to a country like China where rice production can move to higher latitudes, rice adaptation in tropical Colombia will favor higher elevations. These results suggest adaptation strategies for the Colombian rice sector. Farmers can adopt climate-resilient varieties or change water and agronomic management practices, or both. Other farmers may consider abandoning rice production for some other crop or activity. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes 1 Introduction Half of the world’s population consumes rice, making it the most important food crop in the developing world (Seck et al. 2012 ). A constant supply of rice ( Oriza sativa ) supports food security and societal stability in both rice-producing and rice-consuming countries (Degiovanni et al. 2010 ; Godfray et al. 2010a , b ). One hundred thirteen countries produce substantial amounts of rice. Twenty-six countries in Latin American and the Caribbean (LAC) produce 24 million tons of rice on 5.9 million hectares, equivalent to 4% of world production (FAOSTAT 2004 ; Sanint 2010 ). Experts anticipate that climate change will have large impacts on rice and other crops. The most recent report of the Intergovernmental Panel on Climate Change (IPCC) suggests average global crop productivity will likely decline between 1 and 2.5%/°C of warming (Porter et al. 2014 ; Challinor et al. 2014 ). At the global scale, Zabel et al. ( 2014 ) identified the climate change impact on geographic distribution for several crops, including rice. They projected that an area of 6.4 million square kilometers would become unsuitable for agricultural production, and another 4.8 million square kilometers would become marginally suitable for global agriculture, if adaptation measures are not widely adopted. At regional scale, David Lobell et al. ( 2008 ) projected 10% yield reductions in rice in the Andean region in their study of climatic risk for seven crops in 12 regions of the world. Based on the ORYZA crop model, Matthews et al. ( 1997 ) projected yield reductions as high as 31% in Asia under a scenario where temperatures increase by 4 °C temperature. At national scales, studies of rice and climate change have almost exclusively focused on Asian countries. Three studies have assessed the impact of climate change on rice in China. Zhang et al. ( 2017 ) simulated the migration of rice and maize planting areas in China by analyzing movement of the geographic mean of rice production under current and future climate scenarios. They project the suitable areas for rice and maize to shift northward in the future, while the area suitable for irrigated cultivation will gradually increase, mainly in northwestern and northern China. Ye et al. ( 2015 ) explored the influence of climate change on suitable rice cropping areas, rice cropping systems and crop water requirements during the growing season for historical (1951–2010) and future (2011–2100) time periods in China. Their results showed that the land areas suitable for rice cropping systems shifted northward and westward from 1951 to 2010. Yao et al. ( 2007 ) estimates large rice yield reductions in China, based on the CERES crop model. Paul Teng et al. ( 2016 ) estimated rice yield reductions of 23%, 32%, and 33% in Vietnam, Thailand, and India, respectively. In one study of India, Auffhammer et al. ( 2012 ) show that climate change has already affected millions of rice producers and consumers and will continue to do so in the future. Only one study estimated that there would be yield increases for irrigated rice in India in the future (Aggarwal and Mall 2002 ). Reilly et al. ( 2003 ) estimate large yield reductions in the southernmost rice-producing regions of the USA. The review of studies above shows the lack of research on the impacts of climate change on rice in Latin America. Colombia lacks a study of this type, despite the importance of rice in the diet and expectations for significant climate change. This study—the first analysis of its type for a Latin American country—fills a gap in research on climate change by analyzing expected impact on rice production in Colombia. Colombian farmers cultivated 570,802 ha of rice in 2016, producing 5.7 million tons. Current production represents an increase compared to the previous two rice censuses, when national production was 2.8 million tons on 493,237 ha in 1999 and 2.5 million tons on 400,451 ha in 2007 (FEDEARROZ 2008 ; FEDEARROZ 2016 ). Average yields rose from 5.7 tons ha −1 in 1999 to 6.2 tons ha −1 in 2007, falling back to 5.7 tons ha −1 in 2016 (FEDEARROZ 2008 ; FEDEARROZ 2016 ). Nevertheless, Colombia remains among the Latin American countries with the lowest yields, lower than countries such as Peru (7.3 tons ha −1 ) and Uruguay (7.1 tons ha −1 ), among others (GRISP 2013 ). Low yields and increases in per capita rice consumption led Colombia to import rice from countries such as Ecuador, Peru, and the USA (DANE 2015 ; Pulver et al. 2008 ; Espinal et al. 2005 ; Tilman and Clark 2014 ). The increasing dependence on rice imports poses important challenges to Colombian food<|im_end|> <|im_start|>assistant Without significant global reductions in greenhouse gas emissions, Colombia will have 60 percent less land suitable for rice production by the 2050s, according to a new study by the CGIAR Research Program on Climate Change, Agriculture and Food Security (CCAFS). Due primarily to increased temperatures and decreased rainfall—as opposed to sea-level rise, which is the driver of projected change to rice production in some Asian countries—the research shows suitable conditions will need to be found at higher elevations when low-altitude fields are too hot or dry for irrigated rice production. The study found that Colombia's suitable arable land for rice is currently 4.4 million hectares but could be reduced to 1.8 million hectares in a few decades. Mitigation could require complex decisions around land-use change, changes in crop cultivation, and food security, said the authors. The study is the first of its kind for a Latin American country and was published in Mitigation and Adaptation Strategies for Global Change. "Many of these impacts can be avoided if we act on time by facilitating strategies so that our farmers are better prepared, and reducing the emissions of greenhouse gases from agriculture and other sectors," said Fabio Castro, the study's lead author and researcher at the International Center for Tropical Agriculture (CIAT) in Colombia. The study highlights the climate-change challenges faced by many tropical countries that grow rice, which is the most important food crop in the developing world. Whereas China, the world's largest rice producer, has lots of land and can move production further north to mitigate climate impacts, many countries do not have the same options. "India, which is a little bit closer to the equator, doesn't have as much flexibility as China does, but they still have some flexibility, as do some Southeast Asian countries," said Glenn Hyman, a co-author at the Spatial Informatics Group. "Indonesia, Western Africa, Peru, Ecuador and Central America are similar to Colombia but may lack land at cooler, higher altitudes." Rice trial plots on the International Center for Tropical Agriculture campus in Colombia. Credit: Neil Palmer / CIAT Mitigate quickly The researchers examined current and projected climate conditions in Colombia's various rice-growing regions. Under the projections, some low-altitude areas are projected to become environmentally incompatible with rice production. Other areas, which are cooler and have higher elevations, will become more suitable. Mitigation strategies for the most extreme future climates include adoption of heat-tolerant rice varieties and more efficient water management. Researchers also recommend careful development of new rice-growing areas. They emphasize that global action to reduce greenhouse gas emissions will significantly decrease the extent of adaptation measures. "This is a warning that Colombia's suitability for rice will change," said Castro, who is also a researcher at Colombia's Universidad del Valle. "If cultivation continues in the same areas, with the same seeds and the same agronomic practices, perhaps future yields will be reduced or simply the current varieties will not adapt." The study's future scenario, 2049-2060, is based on Representative Concentration Pathway (RCP) 8.5, a greenhouse gas concentration trajectory that considers business-as-usual emissions scenarios. RCPs were adopted by the Intergovernmental Panel on Climate Change to help standardize research related to projected impacts of increased greenhouse gases in the atmosphere. Future land suitability was determined by climate models for temperature, precipitation, soil types, and socioeconomic variables. "Areas that are projected to be less suitable for rice may need to switch to other crops or otherwise develop new livelihood strategies. In other areas where rice production is projected to thrive, land-use changes need to be considered carefully in the light of sustainability and profitability," wrote the authors. "Food security and food sovereignty issues may also be important considerations in land-use planning in these regions. Planning efforts will require more research on the economic and social aspects of agricultural production in the country." <|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 Premorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS). There is evidence of shared genetic risk between ALS and lipid metabolism. A very large prospective longitudinal population cohort permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS. Methods The risk of subsequent ALS diagnosis in those enrolled prospectively to the UK Biobank (n=502 409) was examined in relation to baseline levels of blood high and low density lipoprotein (HDL, LDL), total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B (apoA1, apoB), triglycerides, glycated haemoglobin A1c (HbA1c) and creatinine, plus self-reported exercise and body mass index. Results Controlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS. Conclusions The association of HDL, apoA1 and LDL levels with risk of ALS contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in pathogenesis. Understanding the molecular basis for these changes will inform presymptomatic biomarker development and therapeutic targeting. epidemiology cholesterol Data availability statement Data may be obtained from a third party and are not publicly available. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 18 news outlets Blogged by 3 Tweeted by 15 On 3 Facebook pages 27 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 epidemiology cholesterol Introduction Beyond the few monogenetic variants that account for less than 15% of cases, the precise factors underpinning the development of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS) remain unclear. 1 2 ALS has a consistent incidence of ~2/100 000/year across Europe 3 and involves a relatively selective degeneration of motor system function, extending to wider cerebral networks in a clinicopathological spectrum with frontotemporal dementia. 4 Numerous epidemiological studies have considered the role of metabolic factors in the development of ALS. Relative cardiovascular health and lower premorbid body mass index (BMI) have been associated with an increased risk of developing ALS. 5–8 Physical activity has been inconsistently associated with an increased risk of developing ALS, with a suggestion that strenuous exercise is more specific and may be causally related to susceptibility to ALS. 9–11 Diabetes appears to modulate the risk of developing ALS in a relationship that varies with age. 12–14 Higher levels of low density lipoprotein cholesterol (LDL) and apolipoprotein B:A1 have been associated with an increased risk of subsequent ALS, with temporal changes in the lipid biomarker profile observed in the decade prior to diagnosis. 15 Mendelian randomisation studies have also provided evidence of a causal link for some lipid biomarker levels and ALS. 16 17 Much of the epidemiological research in ALS has been based on case–control studies, which carry inherent risks of referral, selection and recall bias, issues which can in part be circumvented by prospective cohort studies. 18 This study sought to examine the relationship between previously highlighted metabolic factors, including blood markers of lipid and carbohydrate metabolism, physical exercise and BMI, with the risk of subsequent development of ALS using data from a very large prospective longitudinal population cohort. Methods Participants and consent The UK Biobank is a prospective cohort study of over 500 000 people aged between 39 and 72 years ( ). All people within the specified age range registered with the National Health Service and living within approximately 25 miles of one of the 22 assessment centres distributed around the UK were invited to take part. 19 Participants underwent initial assessment between March 2006 and October 2010 and were followed for a median of 11.9 years (11.1–12.6 years; table 1 ). Ethical approval was granted by the Health Research Authority (North West – Haydock Research Ethics Committee reference 16/NW/0274). All participants provided informed electronic consent. View this table: View inline View popup Table 1 Cohort baseline demographic and metabolic data Participants provided demographic and health information alongside donated blood for biochemical analysis performed by the UK Biobank according to standard protocols ( ), which included measurement of blood total cholesterol, high density lipoprotein cholesterol (HDL), LDL, triglycerides, apolipoprotein A1 (apoA1), apolipoprotein B (apoB), HbA1c and creatinine. Excess metabolic equivalent task (MET) hours were calculated based on self-reported walking, moderate and vigorous activity per week. 20 Participants reported how many days per week they undertook each category of exercise for more than 10 min. The reported duration of activity on a typical day was then multiplied by the number of reported days per week. Excess MET was calculated by subtracting one unit per hour from the total hourly MET values given for each category according to the International Physical Activity Questionnaire (walking 2.3, moderate activity 3.0 and vigorous activity 7.0 excess MET), representing the energy expenditure in excess of that of an inactive person. 21 A diagnosis of ALS made at some", "role": "user" }, { "content": "Some blood lipid biomarkers linked to cardiovascular disease risk are also associated with a lower risk of amyotrophic lateral sclerosis (ALS) suggest the findings of a large epidemiology study published online in the Journal of Neurology Neurosurgery & Psychiatry. ALS is the commonest form of motor neuron disease—a progressive nervous system disease that destroys nerve cells responsible for voluntary movement such as walking and talking. Single gene factors drive only a minority of cases of ALS, and in the remainder the causes of the condition are not well understood. Lower weight, higher levels of strenuous physical activity levels, and relatively good cardiovascular health have been shown by some studies to be risk factors for ALS, but the relationships are complex and the evidence inconsistent. Researchers are keen to identify biomarkers linked to ALS, which could ultimately lead to much earlier diagnosis, potentially before symptoms appear, and the hope of preventative treatments. The authors were able to use data from a very large epidemiological study to try to determine with more certainty the nature of any relationships between levels of biomarkers associated with cardiovascular disease and subsequent diagnosis of ALS. They used data for 502,409 people who enrolled in the UK Biobank study between March 2006 and October 2010 when aged 39 to 72 years. All had blood tests at enrolment and were followed for a median of 11.9 years. The authors looked at the relationship between ALS and baseline blood levels of high and low density lipoprotein (HDL and LDL), total cholesterol, apolipoproteins A1 and B (apoA1 and apoB), triglycerides, glycated hemoglobin A1c (HbA1c) and creatinine. They also looked at the relationship between ALS and self-reported exercise and body mass index. After controlling for age and sex, the authors found that higher HDL and apoA1 were associated with a lower risk of ALS. A higher total cholesterol:HDL ratio was associated with a higher risk of ALS. When models incorporating multiple metabolic markers were used to assess risk of the condition, HDL and apoA1 continued to be associated with a reduced risk of ALS independent of other factors. Lower LDL and apoB levels were also associated with a decreased risk of ALS. In further analysis, levels of LDL and apoB were shown to be higher long before diagnosis but lower in people closer to diagnosis, whereas HDL and apoA1 levels showed no such differences. \"The persistence of these findings in models controlling for statin use, smoking and vascular disease indicates that the association of lipid levels and ALS is not attributable to a confounding association between lipids, ALS and these factors,\" the authors say. This is an observational study, and as such, can't establish cause. The researchers also acknowledge certain limitations, including differences between study participants and the general population due to the nature of the Biobank recruitment processes, use of ICD10 and ICD9 diagnostic codes to identify ALS cases meant that some non-ALS motor neuron disease cases might be incorrectly included, and lack of data on common genetic causes of ALS. There remain some inconsistencies across other published studies, reflecting different methodologies. Nevertheless, the authors conclude: \"This study adds to a growing literature documenting differences in the premorbid metabolic profile of those who eventually develop ALS.\" \"In addition to providing novel insights into pathogenesis, this emphasizes the need to consider a broader set of potential pre-symptomatic ALS biomarkers. Such markers might help to target population screening for ALS and also build confidence in future trials of preventative therapy.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Premorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS). There is evidence of shared genetic risk between ALS and lipid metabolism. A very large prospective longitudinal population cohort permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS. Methods The risk of subsequent ALS diagnosis in those enrolled prospectively to the UK Biobank (n=502 409) was examined in relation to baseline levels of blood high and low density lipoprotein (HDL, LDL), total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B (apoA1, apoB), triglycerides, glycated haemoglobin A1c (HbA1c) and creatinine, plus self-reported exercise and body mass index. Results Controlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS. Conclusions The association of HDL, apoA1 and LDL levels with risk of ALS contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in pathogenesis. Understanding the molecular basis for these changes will inform presymptomatic biomarker development and therapeutic targeting. epidemiology cholesterol Data availability statement Data may be obtained from a third party and are not publicly available. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 18 news outlets Blogged by 3 Tweeted by 15 On 3 Facebook pages 27 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 epidemiology cholesterol Introduction Beyond the few monogenetic variants that account for less than 15% of cases, the precise factors underpinning the development of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS) remain unclear. 1 2 ALS has a consistent incidence of ~2/100 000/year across Europe 3 and involves a relatively selective degeneration of motor system function, extending to wider cerebral networks in a clinicopathological spectrum with frontotemporal dementia. 4 Numerous epidemiological studies have considered the role of metabolic factors in the development of ALS. Relative cardiovascular health and lower premorbid body mass index (BMI) have been associated with an increased risk of developing ALS. 5–8 Physical activity has been inconsistently associated with an increased risk of developing ALS, with a suggestion that strenuous exercise is more specific and may be causally related to susceptibility to ALS. 9–11 Diabetes appears to modulate the risk of developing ALS in a relationship that varies with age. 12–14 Higher levels of low density lipoprotein cholesterol (LDL) and apolipoprotein B:A1 have been associated with an increased risk of subsequent ALS, with temporal changes in the lipid biomarker profile observed in the decade prior to diagnosis. 15 Mendelian randomisation studies have also provided evidence of a causal link for some lipid biomarker levels and ALS. 16 17 Much of the epidemiological research in ALS has been based on case–control studies, which carry inherent risks of referral, selection and recall bias, issues which can in part be circumvented by prospective cohort studies. 18 This study sought to examine the relationship between previously highlighted metabolic factors, including blood markers of lipid and carbohydrate metabolism, physical exercise and BMI, with the risk of subsequent development of ALS using data from a very large prospective longitudinal population cohort. Methods Participants and consent The UK Biobank is a prospective cohort study of over 500 000 people aged between 39 and 72 years ( ). All people within the specified age range registered with the National Health Service and living within approximately 25 miles of one of the 22 assessment centres distributed around the UK were invited to take part. 19 Participants underwent initial assessment between March 2006 and October 2010 and were followed for a median of 11.9 years (11.1–12.6 years; table 1 ). Ethical approval was granted by the Health Research Authority (North West – Haydock Research Ethics Committee reference 16/NW/0274). All participants provided informed electronic consent. View this table: View inline View popup Table 1 Cohort baseline demographic and metabolic data Participants provided demographic and health information alongside donated blood for biochemical analysis performed by the UK Biobank according to standard protocols ( ), which included measurement of blood total cholesterol, high density lipoprotein cholesterol (HDL), LDL, triglycerides, apolipoprotein A1 (apoA1), apolipoprotein B (apoB), HbA1c and creatinine. Excess metabolic equivalent task (MET) hours were calculated based on self-reported walking, moderate and vigorous activity per week. 20 Participants reported how many days per week they undertook each category of exercise for more than 10 min. The reported duration of activity on a typical day was then multiplied by the number of reported days per week. Excess MET was calculated by subtracting one unit per hour from the total hourly MET values given for each category according to the International Physical Activity Questionnaire (walking 2.3, moderate activity 3.0 and vigorous activity 7.0 excess MET), representing the energy expenditure in excess of that of an inactive person. 21 A diagnosis of ALS made at some<|im_end|> <|im_start|>assistant Some blood lipid biomarkers linked to cardiovascular disease risk are also associated with a lower risk of amyotrophic lateral sclerosis (ALS) suggest the findings of a large epidemiology study published online in the Journal of Neurology Neurosurgery & Psychiatry. ALS is the commonest form of motor neuron disease—a progressive nervous system disease that destroys nerve cells responsible for voluntary movement such as walking and talking. Single gene factors drive only a minority of cases of ALS, and in the remainder the causes of the condition are not well understood. Lower weight, higher levels of strenuous physical activity levels, and relatively good cardiovascular health have been shown by some studies to be risk factors for ALS, but the relationships are complex and the evidence inconsistent. Researchers are keen to identify biomarkers linked to ALS, which could ultimately lead to much earlier diagnosis, potentially before symptoms appear, and the hope of preventative treatments. The authors were able to use data from a very large epidemiological study to try to determine with more certainty the nature of any relationships between levels of biomarkers associated with cardiovascular disease and subsequent diagnosis of ALS. They used data for 502,409 people who enrolled in the UK Biobank study between March 2006 and October 2010 when aged 39 to 72 years. All had blood tests at enrolment and were followed for a median of 11.9 years. The authors looked at the relationship between ALS and baseline blood levels of high and low density lipoprotein (HDL and LDL), total cholesterol, apolipoproteins A1 and B (apoA1 and apoB), triglycerides, glycated hemoglobin A1c (HbA1c) and creatinine. They also looked at the relationship between ALS and self-reported exercise and body mass index. After controlling for age and sex, the authors found that higher HDL and apoA1 were associated with a lower risk of ALS. A higher total cholesterol:HDL ratio was associated with a higher risk of ALS. When models incorporating multiple metabolic markers were used to assess risk of the condition, HDL and apoA1 continued to be associated with a reduced risk of ALS independent of other factors. Lower LDL and apoB levels were also associated with a decreased risk of ALS. In further analysis, levels of LDL and apoB were shown to be higher long before diagnosis but lower in people closer to diagnosis, whereas HDL and apoA1 levels showed no such differences. "The persistence of these findings in models controlling for statin use, smoking and vascular disease indicates that the association of lipid levels and ALS is not attributable to a confounding association between lipids, ALS and these factors," the authors say. This is an observational study, and as such, can't establish cause. The researchers also acknowledge certain limitations, including differences between study participants and the general population due to the nature of the Biobank recruitment processes, use of ICD10 and ICD9 diagnostic codes to identify ALS cases meant that some non-ALS motor neuron disease cases might be incorrectly included, and lack of data on common genetic causes of ALS. There remain some inconsistencies across other published studies, reflecting different methodologies. Nevertheless, the authors conclude: "This study adds to a growing literature documenting differences in the premorbid metabolic profile of those who eventually develop ALS." "In addition to providing novel insights into pathogenesis, this emphasizes the need to consider a broader set of potential pre-symptomatic ALS biomarkers. Such markers might help to target population screening for ALS and also build confidence in future trials of preventative therapy." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Food system technologies (FSTs) are being developed to accelerate the transformation towards sustainable food systems. Here we conducted a systematic scoping review that accounts for multiple dimensions of sustainability to describe the extent, range and nature of peer-reviewed literature that assesses the sustainability performance of four FSTs: plant-based alternatives, vertical farming, food deliveries and blockchain technology. Included literature had a dominant focus on environmental sustainability and less on public health and socio-economic sustainability. Gaps in the literature include empirical assessments on the sustainability of blockchain technology, plant-based seafood alternatives, public health consequences of food deliveries and socio-economic consequences of vertical farming. The development of a holistic sustainability assessment framework that demonstrates the impact of deploying FSTs is needed to guide investments in and the development of sustainable food innovation. Main Technologies in the food sector, such as cellular agriculture, are being developed at a considerable pace to facilitate the transformation towards achieving food system sustainability 1 . We here define them as food system technologies (FSTs) that have been recently introduced at various parts of the food supply chains to address current systemic challenges that prevent sustainable food systems. Data on investment trends show that their development has been accelerated by the COVID-19 pandemic and has generated strong interest from venture capital firms 2 . These FSTs are often surrounded by a sustainability halo, a socio-psychological phenomenon of perceiving a product as sustainable based on positive attributes, leading to a higher willingness to pay (WTP). This has created an innovation space that often strives to reduce climate impact from the food sector but disregards other dimensions of sustainability. As outlined in the Sustainable Development Goals (SDGs), the comprehensive concept of sustainability addresses multiple environmental, economic and social impact factors 3 , with synergies and trade-offs within and across them 4 . Innovations in the food industry can impact all these sustainability pillars, potentially leading to unintended consequences 5 . Yet, while many well-defined tools exist to study the food system as a whole 6 , 7 , 8 , there is no such defined toolset and inventory of sustainability indicators to empirically assess the sustainability performance of FSTs. Considering the three pillars of sustainability, this multidisciplinary scoping review examines the extent, range and nature of the peer-reviewed literature that assessed the sustainability performance of FSTs and summarizes the research findings. To accomplish this, we first identify sustainability indicators that have been used in the literature to assess FSTs and then synthesize empirical evidence indicating FSTs sustainability performance compared with the technologies they intend to replace. Finally, we identify implications for research and practice in relation to the development of comprehensive sustainability assessments. We focus on four divergent but representative FSTs that aim to address sustainability-related issues at different parts of the food supply chain: plant-based alternatives (PBAs), vertical farming (VF), food deliveries (FD) and blockchain technology (BT) (Fig. 1 ). We selected these FSTs by mapping investment flows into food start-ups in the Nordic region and selected the four FSTs that received the most investments in the first half of 2021 (Supplementary Material Section 2 ). Fig. 1: Conceptual framework of included FSTs. Overview of the FSTs included in this review that are driving food system transformation at different entry points of the food supply chain. Credit: This figure has been designed using icons provided by Flaticon.com. Full size image Results We retrieved 1,493 studies from the initial search, of which 79 articles met our inclusion criteria and have been included in the analysis (Fig. 2 ). Fig. 2: PRISMA flow chart (Preferred reporting items for systemic reviews and meta-analyses). Indicating the selection process of eligible studies. Full size image Extent and range of evidence The majority of the included papers assessed PBAs ( n = 37), dominated by meat alternatives (PBMA) and dairy alternatives, while only two studies assessed seafood or egg alternatives. This was followed by literature that assessed VF ( n = 16), BT ( n = 14) and FD ( n = 11). Fig. 3: Sustainability indicators assessed in the included literature. The heat map cross-references all the included studies on PBAs, VF and FD to show the frequency of studies that investigated sustainability indicators. Impact domains are split by social, environmental and economic sustainability, from the left. Source data are provided in the Supplementary Data . HTP, human toxicity potential; WTB, willingness to buy; WTP, willingness to pay. Full size image The retrieved literature represents a wide geographical scope, with case studies spanning 40 countries across six continents. Regional representation varied across the different FSTs, visualized in Supplementary Material Section 5 . Case studies on VF had a dominant focus on Europe (63%), FD on Asia (60%) and PBAs on Europe (55%) and northern America (19%). Literature on BT mainly elaborated a global perspective, with some case studies focusing on different countries, primarily from Asia (56%). Nature of evidence The sustainability of these FSTs has been addressed using a range of study designs assessing different indicators. The majority of the literature employed life cycle assessment (LCA) to study the environmental impact ( n = 26), cross-sectional and intervention studies for consumer behaviour ( n = 11), nutritional analysis to determine the nutritional content of foods ( n = 10) and modelling studies for economic indicators ( n = 7). We captured systematic and non-systematic reviews ( n = 13), mostly focusing on BT ( n = 8). Other methods that have been applied to case studies ( n = 12) are detailed in the Supplementary Data . Indicators to assess the sustainability of FSTs For PBAs, VF and FD we observed a wide range of indicators empirically assessing all three dimensions of sustainability, with clear differences across FSTs (Fig. 3 ). The results for BT are presented separately (Fig. 4 ) and are not analysed further as the contribution of BT to sustainability was described using different indicators and was not empirically investigated. Fig. 4: Benefits and limitations of deploying BT to the food", "role": "user" }, { "content": "A new analysis reveals significant gaps in evidence related to the sustainability claims of new food technologies such as vertical farming, blockchain, food deliveries and plant-based alternatives to animal products. Money is pouring into food tech. But despite rosy claims, food innovations are rarely empirically assessed from a broader sustainability perspective. \"Food system technologies are often surrounded by a sustainability halo. And many of them strive to reduce climate impact, but they disregard other dimensions of sustainability,\" says Anne Charlotte Bunge, researcher at the Stockholm Resilience Centre at Stockholm University and lead author of a recent study published in Nature Food. In the study, the research team compared the scientific evidence behind sustainability claims of four food system technologies: plant-based substitutes for meat, dairy, eggs or sea food; vertical farming; food deliveries; and blockchain technology. All four receive considerable interest from venture capital firms across Scandinavia, and all are frequently framed as new sustainable solutions. However, the scientific evidence to back these claims up is limited, according to the new study. For blockchain technology, no research has shown any tangible sustainability improvements related to its usage in the food industry. Studies that have been published so far only discussed theoretical benefits. Plant-based substitutes are found to have lower environmental impacts than conventional animal-based products. But research on their nutritional aspects has not been studied over the long term, and other socioeconomic factors, such as pricing, are rarely discussed. \"Plant-based alternatives are higher in costs than conventional animal products, which could generate the impression that a plant-based diet is more expensive and seen as a luxury, leading to social inequalities,\" warns lead author Anne Charlotte Bunge. Vertical farming has a mixed sustainability performance. Vertical farms outperform on-field cultivation and greenhouses in some aspects, such as land and water use. However, they often require more energy and emit more greenhouse gases than field agriculture. And regarding other aspects of sustainability, there is little research: \"We found a distinct lack of evidence modeling the socioeconomic implications of scaling vertical farming,\" says Anne Charlotte Bunge. Food deliveries performed worse in most aspects of sustainability, except that delivered groceries are better than making individual trips to the supermarket by car—but not by foot or public transport. Having meals delivered to one's home did not have any benefits, according to the analysis. \"Research demonstrates that walking to the restaurant and consuming the meal there instead of having it delivered could reduce the total amount of greenhouse gas emissions by 68% per meal,\" says Anne Charlotte Bunge. Even here, significant gaps in research exist on other environmental issues and social sustainability. To prevent misled investments in the future, the researchers call for a new sustainability assessment framework. \"Guiding transformative investments requires a more rigorous, quantitative assessment of the sustainability implications of food system technologies,\" says co-author Line Gordon, professor at the Stockholm Resilience Centre at Stockholm University. What are the four food technologies? Plant-based alternatives: Vegan substitutes of meat, dairy, seafood, and eggs, that mimic the structure, taste, and sensory profile of conventional animal-based products.Vertical farming: Multi-layer vertical indoor crop production systems with controlled growth conditions and without solar light.Blockchain technology: A decentralized distributed ledger technology that traces the supply chain to create transparency.Food deliveries: The delivery of meals and groceries that have been purchased online by various means of transport. Part of the wider digital food 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 Food system technologies (FSTs) are being developed to accelerate the transformation towards sustainable food systems. Here we conducted a systematic scoping review that accounts for multiple dimensions of sustainability to describe the extent, range and nature of peer-reviewed literature that assesses the sustainability performance of four FSTs: plant-based alternatives, vertical farming, food deliveries and blockchain technology. Included literature had a dominant focus on environmental sustainability and less on public health and socio-economic sustainability. Gaps in the literature include empirical assessments on the sustainability of blockchain technology, plant-based seafood alternatives, public health consequences of food deliveries and socio-economic consequences of vertical farming. The development of a holistic sustainability assessment framework that demonstrates the impact of deploying FSTs is needed to guide investments in and the development of sustainable food innovation. Main Technologies in the food sector, such as cellular agriculture, are being developed at a considerable pace to facilitate the transformation towards achieving food system sustainability 1 . We here define them as food system technologies (FSTs) that have been recently introduced at various parts of the food supply chains to address current systemic challenges that prevent sustainable food systems. Data on investment trends show that their development has been accelerated by the COVID-19 pandemic and has generated strong interest from venture capital firms 2 . These FSTs are often surrounded by a sustainability halo, a socio-psychological phenomenon of perceiving a product as sustainable based on positive attributes, leading to a higher willingness to pay (WTP). This has created an innovation space that often strives to reduce climate impact from the food sector but disregards other dimensions of sustainability. As outlined in the Sustainable Development Goals (SDGs), the comprehensive concept of sustainability addresses multiple environmental, economic and social impact factors 3 , with synergies and trade-offs within and across them 4 . Innovations in the food industry can impact all these sustainability pillars, potentially leading to unintended consequences 5 . Yet, while many well-defined tools exist to study the food system as a whole 6 , 7 , 8 , there is no such defined toolset and inventory of sustainability indicators to empirically assess the sustainability performance of FSTs. Considering the three pillars of sustainability, this multidisciplinary scoping review examines the extent, range and nature of the peer-reviewed literature that assessed the sustainability performance of FSTs and summarizes the research findings. To accomplish this, we first identify sustainability indicators that have been used in the literature to assess FSTs and then synthesize empirical evidence indicating FSTs sustainability performance compared with the technologies they intend to replace. Finally, we identify implications for research and practice in relation to the development of comprehensive sustainability assessments. We focus on four divergent but representative FSTs that aim to address sustainability-related issues at different parts of the food supply chain: plant-based alternatives (PBAs), vertical farming (VF), food deliveries (FD) and blockchain technology (BT) (Fig. 1 ). We selected these FSTs by mapping investment flows into food start-ups in the Nordic region and selected the four FSTs that received the most investments in the first half of 2021 (Supplementary Material Section 2 ). Fig. 1: Conceptual framework of included FSTs. Overview of the FSTs included in this review that are driving food system transformation at different entry points of the food supply chain. Credit: This figure has been designed using icons provided by Flaticon.com. Full size image Results We retrieved 1,493 studies from the initial search, of which 79 articles met our inclusion criteria and have been included in the analysis (Fig. 2 ). Fig. 2: PRISMA flow chart (Preferred reporting items for systemic reviews and meta-analyses). Indicating the selection process of eligible studies. Full size image Extent and range of evidence The majority of the included papers assessed PBAs ( n = 37), dominated by meat alternatives (PBMA) and dairy alternatives, while only two studies assessed seafood or egg alternatives. This was followed by literature that assessed VF ( n = 16), BT ( n = 14) and FD ( n = 11). Fig. 3: Sustainability indicators assessed in the included literature. The heat map cross-references all the included studies on PBAs, VF and FD to show the frequency of studies that investigated sustainability indicators. Impact domains are split by social, environmental and economic sustainability, from the left. Source data are provided in the Supplementary Data . HTP, human toxicity potential; WTB, willingness to buy; WTP, willingness to pay. Full size image The retrieved literature represents a wide geographical scope, with case studies spanning 40 countries across six continents. Regional representation varied across the different FSTs, visualized in Supplementary Material Section 5 . Case studies on VF had a dominant focus on Europe (63%), FD on Asia (60%) and PBAs on Europe (55%) and northern America (19%). Literature on BT mainly elaborated a global perspective, with some case studies focusing on different countries, primarily from Asia (56%). Nature of evidence The sustainability of these FSTs has been addressed using a range of study designs assessing different indicators. The majority of the literature employed life cycle assessment (LCA) to study the environmental impact ( n = 26), cross-sectional and intervention studies for consumer behaviour ( n = 11), nutritional analysis to determine the nutritional content of foods ( n = 10) and modelling studies for economic indicators ( n = 7). We captured systematic and non-systematic reviews ( n = 13), mostly focusing on BT ( n = 8). Other methods that have been applied to case studies ( n = 12) are detailed in the Supplementary Data . Indicators to assess the sustainability of FSTs For PBAs, VF and FD we observed a wide range of indicators empirically assessing all three dimensions of sustainability, with clear differences across FSTs (Fig. 3 ). The results for BT are presented separately (Fig. 4 ) and are not analysed further as the contribution of BT to sustainability was described using different indicators and was not empirically investigated. Fig. 4: Benefits and limitations of deploying BT to the food<|im_end|> <|im_start|>assistant A new analysis reveals significant gaps in evidence related to the sustainability claims of new food technologies such as vertical farming, blockchain, food deliveries and plant-based alternatives to animal products. Money is pouring into food tech. But despite rosy claims, food innovations are rarely empirically assessed from a broader sustainability perspective. "Food system technologies are often surrounded by a sustainability halo. And many of them strive to reduce climate impact, but they disregard other dimensions of sustainability," says Anne Charlotte Bunge, researcher at the Stockholm Resilience Centre at Stockholm University and lead author of a recent study published in Nature Food. In the study, the research team compared the scientific evidence behind sustainability claims of four food system technologies: plant-based substitutes for meat, dairy, eggs or sea food; vertical farming; food deliveries; and blockchain technology. All four receive considerable interest from venture capital firms across Scandinavia, and all are frequently framed as new sustainable solutions. However, the scientific evidence to back these claims up is limited, according to the new study. For blockchain technology, no research has shown any tangible sustainability improvements related to its usage in the food industry. Studies that have been published so far only discussed theoretical benefits. Plant-based substitutes are found to have lower environmental impacts than conventional animal-based products. But research on their nutritional aspects has not been studied over the long term, and other socioeconomic factors, such as pricing, are rarely discussed. "Plant-based alternatives are higher in costs than conventional animal products, which could generate the impression that a plant-based diet is more expensive and seen as a luxury, leading to social inequalities," warns lead author Anne Charlotte Bunge. Vertical farming has a mixed sustainability performance. Vertical farms outperform on-field cultivation and greenhouses in some aspects, such as land and water use. However, they often require more energy and emit more greenhouse gases than field agriculture. And regarding other aspects of sustainability, there is little research: "We found a distinct lack of evidence modeling the socioeconomic implications of scaling vertical farming," says Anne Charlotte Bunge. Food deliveries performed worse in most aspects of sustainability, except that delivered groceries are better than making individual trips to the supermarket by car—but not by foot or public transport. Having meals delivered to one's home did not have any benefits, according to the analysis. "Research demonstrates that walking to the restaurant and consuming the meal there instead of having it delivered could reduce the total amount of greenhouse gas emissions by 68% per meal," says Anne Charlotte Bunge. Even here, significant gaps in research exist on other environmental issues and social sustainability. To prevent misled investments in the future, the researchers call for a new sustainability assessment framework. "Guiding transformative investments requires a more rigorous, quantitative assessment of the sustainability implications of food system technologies," says co-author Line Gordon, professor at the Stockholm Resilience Centre at Stockholm University. What are the four food technologies? Plant-based alternatives: Vegan substitutes of meat, dairy, seafood, and eggs, that mimic the structure, taste, and sensory profile of conventional animal-based products.Vertical farming: Multi-layer vertical indoor crop production systems with controlled growth conditions and without solar light.Blockchain technology: A decentralized distributed ledger technology that traces the supply chain to create transparency.Food deliveries: The delivery of meals and groceries that have been purchased online by various means of transport. Part of the wider digital food 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 Objectives To disaggregate the crime impact of visitor inflows. There is increasing evidence that visitors can make a major contribution to levels of crime in a given neighbourhood: crimes by visiting offenders may add to those committed by local offenders, while visitors (and their property) may provide local offenders with additional opportunities for crime. Methods Using police-recorded crime data for a large Eastern Canadian city we determined whether individuals charged or chargeable for property and violent crimes were visitors or residents of census tracts (CT) where crimes had been committed. This information was combined with data from a large transportation survey, allowing us to estimate daily population flows into each CT for four purposes (work, shopping, recreation, and education). Negative binomial regression models including spatial lags were used. Results An increase in visitor inflow not only increases the number of visitors charged with crimes but also the number of local residents charged. These effects vary significantly by visit purpose: more infractions are committed in tracts where visits are for recreation and, to a lesser extent, for shopping. Findings for work and education are mixed. Conclusions One important implication of our results is that, because most studies of aggregate crime counts or rates fail to account for whether crimes have been committed by visitors or residents, previous research may have provided hasty, partial, or even erroneous explanations for crime concentrations. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Since the 1980s, Sherman and other researchers have explored the idea of hot spots of crime and their analyses have had clear benefits for crime prevention (see Weisburd ( 2015 ) for a recent review of this body of work). Work on concentrations of crime is still today an important part of published work in criminology (e.g. Bones and Hope 2015 ; Shiode et al. 2015 ). Different types of crimes have been analyzed, at various (or even multiple) levels of aggregation, in different cultural contexts (e.g. Australia: Livingston 2008 ; Canada: Andresen 2007 ; Cape Verde: Petrosino and Pace 2015 ; Japan: Takagi and Kawachi 2014 ; the Netherlands: Bruinsma et al. 2013 ). Fairly consistent results have been found: crime tends to be concentrated in relation to disadvantage and opportunities. Surprisingly, very little has been said about those who create such concentrations: are crimes committed by residents of an area or by visitors? Are crimes by local and outside residents equally and randomly distributed across space? The Crime–Population Link The relationship between crime and population size is one of the few accepted “facts” in criminology (e.g., Siegel 2003 ): crime is assumed to be more frequent in more populated areas, a statement that has usually been confirmed by cross-sectional research (Ousey 2000 ). We argue that such a statement is too vague, for at least two reasons. First, the population of urban environments, especially large cities, includes not only residents but also a considerable number of visitors. For example, there are more than 2.5 million residents in Chicago, Illinois but, according to public officials, the city also had over 50 million visitors in 2014. While traditional indicators of crime account for residential population, measures that look at ambient populations may provide a different picture (Andresen 2006 ). Second, as argued by Johnson and Summers ( 2015 ), an unresolved issue in most previous studies of spatial variations is that crime locations are analyzed without regard to who committed the infraction, despite early recognition (Schmid 1960a , b ). Yet, the issue is of primary importance to law enforcement agencies and other organisations if, for example, they hope to offer effective crime prevention programs: there is no point in developing a prevention program that aims at residents of an area if crimes are committed largely by non-residents, and policymakers must have limited expectations with regard to the effect if many non-residents commit crime. Theoretical Perspectives Two prominent theories frequently cited to explain spatial variations of crime in urban settings provide meaningful propositions to explain crime by both residents and outsiders: routine activity (RA) and social disorganization (SD). According to routine activity, crime occurs where criminal opportunities arise, i.e., where likely offenders meet suitable targets in the absence of capable guardianship (Cohen and Felson 1979 ). Routine activity considers residents of an area to be both potential offenders and potential targets and, thus, posits a positive relationship between residential population and crime. The same logic applies to non-resident populations: visitors are potential offenders and targets, and the number of crimes should be positively related to the number of visitors in an area. However, residents and visitors may also act as guardians by their simple presence (Felson and Eckert 2015 ); the size of a population in an area could, therefore, be associated with a decrease in the number of crimes committed by residents and/or visitors. In sum, the number of crimes in an area would, therefore, be positively related to the number of offenders and targets in an area, and negatively related to the number of potential guardians. Any factor that influences the presence of offenders, targets, or guardians is expected to have a corresponding effect on the number of crimes in an area. Social disorganization theory holds that social controls have an important effect on crime rates (Kornhauser 1978 ). Areas where structural conditions are conducive to higher levels of social disorganization—and weaker social controls—should experience higher levels of crime: in other words, any factor that leads to a deterioration in social controls is expected to increase crime. Social disorganization has been measured in various ways, including through indicators of residential mobility: areas where individuals tend to be residents for longer periods (“stable” residential population) have been found to have more effective systems of social organization (Bursik 1988). Thus, areas with a stable residential population are expected to have less crime, while an unstable residential population should arguably increase crime. In social disorganization theory, visitors can be seen as threats to effective collective", "role": "user" }, { "content": "When a city district is said to have a \"high crime rate,\" it's often assumed the criminals are \"insiders,\" people who live in the area. But what if the criminals are actually outsiders, people who live somewhere else? That's what University of Montreal criminology professor Rémi Boivin is trying to figure out. In a new study, published in the Journal of Quantitative Criminology, Boivin takes a novel approach to analyzing violent and property crimes using police and population data. With co-author Marcus Felson of Texas State University, Boivin looked at Montreal police crime data on people charged with or awaiting charge for property or violent crimes in the federal census year 2011. The researchers wanted to see how many were residents of the area where the crime was committed and how many were just visiting. Then, using data from a telephone survey on the transportation habits of 156,000 people in and around the city in 2013, the researchers estimated how many had come for a specific type of activity: recreational (e.g. going to nightclubs and bars), shopping, work or education (going to school). Their conclusion: An increase in visitors not only increases the number of crimes, it also results in more residents in these high-traffic areas getting involved in crimes. In other words, a city's \"crime rate\" reflects the criminality both of the people who live there and of those who don't. \"The novelty of this paper is we focus on visitors,\" Boivin said. \"Criminologists have been studying so-called 'ambient' populations for about a decade, but we try to push that a little further. When it comes to crime, it's always good to know how many people are doing it, but we also need to know who they are.\" 'Visitors matter' Following up on a previous study Boivin published in 2013 in the Canadian Journal of Criminology and Criminal Justice, he and Felson had an advantage over researchers in the U.S., where precise residency data is almost impossible to come by, and even over researchers in most Canadian cities, where transportation survey data is not collected. \"When we look at crime rates, we forget that people move, that people are visitors of other areas all the time,\" said Boivin, himself an \"outsider\" to Montreal (he lives on the city's South Shore and commutes to work at the university) and also an \"insider\" with the city's police force (he worked there as an analyst until 2012 while doing his PhD). \"Our new study is unique in two ways,\" Boivin said. \"The first is that we had very detailed data from the police; having the location of crime incidences is not rare, but having the home address of offenders is. The second is we use transportation data, which is something that's not widely available; only four other Canadian cites collect it.\" What did they learn? \"Our main finding, if I had to just sum up in one sentence, is that visitors matter. We need to know more about visitors to better understand crime, and the good news is that we are learning more, from social media and other sources. Visitor data is increasingly available, and our paper is just one of the first on the subject.\" 'A boom in criminology' One other surprising finding: Not only do parts of the city with high numbers of visitors also have higher crime rates by both visitors and residents, there's also more violent crime in areas that have what Boivin calls \"an unstable population,\" places where there's a high number of recent arrivals, over the last five years or less. Violent crimes include homicide, sexual and non-sexual assault, robbery and kidnapping; property crimes include breaking and entering, various forms of theft, and fraud. Most violent crimes have a high \"clearance rate,\" meaning a suspect is charged or identified; in Montreal, the rate in 2011 was 63 per cent. Property crimes, by contrast are rarely cleared: in Montreal in 2011, the rate was only 12 per cent.Boivin anticipates \"there will be a boom in criminology as new data become available,\" and hopes that more research will buttress his finding that mobility is just as important for property and violent crime as the usual factors related to \"social disadvantage\" in cities: how many single-parent families live in an area, how many visible minorities, how many recent arrivals, how many low-income households. Twitter data coming next Two further studies are coming this year from Boivin and colleagues at UdeM: The first, co-authored with Patricia Obartel, looks at the relationship between visitor inflows to Montreal and the police's use of force between 2008 and 2011. The paper has been accepted for publication in the CJCCJ.The second involves Twitter. Boivin and criminologist Francis Fortin are looking at where tweets are sent from and how they might relate to crime trends; the scholars plan to submit their findings for publication this summer. The Twitter data, all publicly available, could prove to particularly rich in information. \"Transportation survey data is not that specific; we don't really know precisely where people are, just where they say they've been,\" said Boivin. \"Twitter data is something else entirely. They have x/y coordinates, so we can know exactly where people are, as close to five metres away. We can look at the content and see if and how it relates to patterns in crime.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objectives To disaggregate the crime impact of visitor inflows. There is increasing evidence that visitors can make a major contribution to levels of crime in a given neighbourhood: crimes by visiting offenders may add to those committed by local offenders, while visitors (and their property) may provide local offenders with additional opportunities for crime. Methods Using police-recorded crime data for a large Eastern Canadian city we determined whether individuals charged or chargeable for property and violent crimes were visitors or residents of census tracts (CT) where crimes had been committed. This information was combined with data from a large transportation survey, allowing us to estimate daily population flows into each CT for four purposes (work, shopping, recreation, and education). Negative binomial regression models including spatial lags were used. Results An increase in visitor inflow not only increases the number of visitors charged with crimes but also the number of local residents charged. These effects vary significantly by visit purpose: more infractions are committed in tracts where visits are for recreation and, to a lesser extent, for shopping. Findings for work and education are mixed. Conclusions One important implication of our results is that, because most studies of aggregate crime counts or rates fail to account for whether crimes have been committed by visitors or residents, previous research may have provided hasty, partial, or even erroneous explanations for crime concentrations. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Since the 1980s, Sherman and other researchers have explored the idea of hot spots of crime and their analyses have had clear benefits for crime prevention (see Weisburd ( 2015 ) for a recent review of this body of work). Work on concentrations of crime is still today an important part of published work in criminology (e.g. Bones and Hope 2015 ; Shiode et al. 2015 ). Different types of crimes have been analyzed, at various (or even multiple) levels of aggregation, in different cultural contexts (e.g. Australia: Livingston 2008 ; Canada: Andresen 2007 ; Cape Verde: Petrosino and Pace 2015 ; Japan: Takagi and Kawachi 2014 ; the Netherlands: Bruinsma et al. 2013 ). Fairly consistent results have been found: crime tends to be concentrated in relation to disadvantage and opportunities. Surprisingly, very little has been said about those who create such concentrations: are crimes committed by residents of an area or by visitors? Are crimes by local and outside residents equally and randomly distributed across space? The Crime–Population Link The relationship between crime and population size is one of the few accepted “facts” in criminology (e.g., Siegel 2003 ): crime is assumed to be more frequent in more populated areas, a statement that has usually been confirmed by cross-sectional research (Ousey 2000 ). We argue that such a statement is too vague, for at least two reasons. First, the population of urban environments, especially large cities, includes not only residents but also a considerable number of visitors. For example, there are more than 2.5 million residents in Chicago, Illinois but, according to public officials, the city also had over 50 million visitors in 2014. While traditional indicators of crime account for residential population, measures that look at ambient populations may provide a different picture (Andresen 2006 ). Second, as argued by Johnson and Summers ( 2015 ), an unresolved issue in most previous studies of spatial variations is that crime locations are analyzed without regard to who committed the infraction, despite early recognition (Schmid 1960a , b ). Yet, the issue is of primary importance to law enforcement agencies and other organisations if, for example, they hope to offer effective crime prevention programs: there is no point in developing a prevention program that aims at residents of an area if crimes are committed largely by non-residents, and policymakers must have limited expectations with regard to the effect if many non-residents commit crime. Theoretical Perspectives Two prominent theories frequently cited to explain spatial variations of crime in urban settings provide meaningful propositions to explain crime by both residents and outsiders: routine activity (RA) and social disorganization (SD). According to routine activity, crime occurs where criminal opportunities arise, i.e., where likely offenders meet suitable targets in the absence of capable guardianship (Cohen and Felson 1979 ). Routine activity considers residents of an area to be both potential offenders and potential targets and, thus, posits a positive relationship between residential population and crime. The same logic applies to non-resident populations: visitors are potential offenders and targets, and the number of crimes should be positively related to the number of visitors in an area. However, residents and visitors may also act as guardians by their simple presence (Felson and Eckert 2015 ); the size of a population in an area could, therefore, be associated with a decrease in the number of crimes committed by residents and/or visitors. In sum, the number of crimes in an area would, therefore, be positively related to the number of offenders and targets in an area, and negatively related to the number of potential guardians. Any factor that influences the presence of offenders, targets, or guardians is expected to have a corresponding effect on the number of crimes in an area. Social disorganization theory holds that social controls have an important effect on crime rates (Kornhauser 1978 ). Areas where structural conditions are conducive to higher levels of social disorganization—and weaker social controls—should experience higher levels of crime: in other words, any factor that leads to a deterioration in social controls is expected to increase crime. Social disorganization has been measured in various ways, including through indicators of residential mobility: areas where individuals tend to be residents for longer periods (“stable” residential population) have been found to have more effective systems of social organization (Bursik 1988). Thus, areas with a stable residential population are expected to have less crime, while an unstable residential population should arguably increase crime. In social disorganization theory, visitors can be seen as threats to effective collective<|im_end|> <|im_start|>assistant When a city district is said to have a "high crime rate," it's often assumed the criminals are "insiders," people who live in the area. But what if the criminals are actually outsiders, people who live somewhere else? That's what University of Montreal criminology professor Rémi Boivin is trying to figure out. In a new study, published in the Journal of Quantitative Criminology, Boivin takes a novel approach to analyzing violent and property crimes using police and population data. With co-author Marcus Felson of Texas State University, Boivin looked at Montreal police crime data on people charged with or awaiting charge for property or violent crimes in the federal census year 2011. The researchers wanted to see how many were residents of the area where the crime was committed and how many were just visiting. Then, using data from a telephone survey on the transportation habits of 156,000 people in and around the city in 2013, the researchers estimated how many had come for a specific type of activity: recreational (e.g. going to nightclubs and bars), shopping, work or education (going to school). Their conclusion: An increase in visitors not only increases the number of crimes, it also results in more residents in these high-traffic areas getting involved in crimes. In other words, a city's "crime rate" reflects the criminality both of the people who live there and of those who don't. "The novelty of this paper is we focus on visitors," Boivin said. "Criminologists have been studying so-called 'ambient' populations for about a decade, but we try to push that a little further. When it comes to crime, it's always good to know how many people are doing it, but we also need to know who they are." 'Visitors matter' Following up on a previous study Boivin published in 2013 in the Canadian Journal of Criminology and Criminal Justice, he and Felson had an advantage over researchers in the U.S., where precise residency data is almost impossible to come by, and even over researchers in most Canadian cities, where transportation survey data is not collected. "When we look at crime rates, we forget that people move, that people are visitors of other areas all the time," said Boivin, himself an "outsider" to Montreal (he lives on the city's South Shore and commutes to work at the university) and also an "insider" with the city's police force (he worked there as an analyst until 2012 while doing his PhD). "Our new study is unique in two ways," Boivin said. "The first is that we had very detailed data from the police; having the location of crime incidences is not rare, but having the home address of offenders is. The second is we use transportation data, which is something that's not widely available; only four other Canadian cites collect it." What did they learn? "Our main finding, if I had to just sum up in one sentence, is that visitors matter. We need to know more about visitors to better understand crime, and the good news is that we are learning more, from social media and other sources. Visitor data is increasingly available, and our paper is just one of the first on the subject." 'A boom in criminology' One other surprising finding: Not only do parts of the city with high numbers of visitors also have higher crime rates by both visitors and residents, there's also more violent crime in areas that have what Boivin calls "an unstable population," places where there's a high number of recent arrivals, over the last five years or less. Violent crimes include homicide, sexual and non-sexual assault, robbery and kidnapping; property crimes include breaking and entering, various forms of theft, and fraud. Most violent crimes have a high "clearance rate," meaning a suspect is charged or identified; in Montreal, the rate in 2011 was 63 per cent. Property crimes, by contrast are rarely cleared: in Montreal in 2011, the rate was only 12 per cent.Boivin anticipates "there will be a boom in criminology as new data become available," and hopes that more research will buttress his finding that mobility is just as important for property and violent crime as the usual factors related to "social disadvantage" in cities: how many single-parent families live in an area, how many visible minorities, how many recent arrivals, how many low-income households. Twitter data coming next Two further studies are coming this year from Boivin and colleagues at UdeM: The first, co-authored with Patricia Obartel, looks at the relationship between visitor inflows to Montreal and the police's use of force between 2008 and 2011. The paper has been accepted for publication in the CJCCJ.The second involves Twitter. Boivin and criminologist Francis Fortin are looking at where tweets are sent from and how they might relate to crime trends; the scholars plan to submit their findings for publication this summer. The Twitter data, all publicly available, could prove to particularly rich in information. "Transportation survey data is not that specific; we don't really know precisely where people are, just where they say they've been," said Boivin. "Twitter data is something else entirely. They have x/y coordinates, so we can know exactly where people are, as close to five metres away. We can look at the content and see if and how it relates to patterns in crime." <|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 risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14 . We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue–specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives. Main The replicated genome-wide significant T2D association signal at chr7q32.3 maps to a 45-kb recombination interval that extends from 3 kb to 48 kb upstream of KLF14 1 , 2 (Fig. 1a–c ). In previous work based on microarray-derived RNA-expression data, KLF14 , which encodes an imprinted transcription factor, was exposed as the likely cis-effector gene for this locus in subcutaneous adipose tissue 1 and was shown to be a trans regulator of a program of adipose tissue expression 3 . The KLF family of zinc-finger binding proteins has wide-ranging regulatory roles in biological processes such as proliferation, differentiation and growth 4 , 5 . However, little is known about KLF14 , a single-exon gene whose transcription is limited to the maternally inherited chromosome in embryonic, extra-embryonic and adult tissue in humans and mice 6 . Fig. 1: A cell type–specific enhancer in the risk haplotype regulates KLF14 expression. a – c , Association of KLF14 locus variants with T2D ( n = 69,033) (ref. 39 ) ( a ), HDL-C levels ( n = 99,900) (ref. 27 ) ( b ) and KLF14 mRNA abundance in adipose tissue ( n = 766 women; TwinsUK) ( c ). Circles represent genotyped and imputed DNA variants; colors indicate LD r 2 values with the index SNP rs4731702 (key). The red asterisk (below) indicates the position of methylation probe cg02385110. The blue box contains the putative enhancer shown in d . Association between genotype and KLF14 expression was assessed using mixed-effects models, correcting for family structure and relevant covariates ( Methods ). Uncorrected P values are displayed. d , Chromatin-state annotations for the KLF14 locus across 93 reference epigenomes (rows) for cell and tissue types profiled by the Roadmap Epigenomics and ENCODE projects. Colors correspond to chromatin states (yellow, enhancer; red, promoter; as in ref. 43 ). The blue box contains the putative enhancer. Chromosome coordinates correspond to UCSC Genome Browser build hg19. ESC, embryonic stem cell; HSC, hematopoietic stem cell; iPSC, induced pluripotent stem cell. e – i , KLF14 mRNA abundance ( e , f ) and methylation of probe cg02385110 ( g – i ) in concurrently sampled adipose tissue ( n = 720 ( e ) and n = 595 ( g )), skin ( n = 606 ( f ) and n = 414 ( h )) and whole blood ( n = 368 (not shown) and n = 289 ( i )) from participants of the TwinsUK study, based on rs4731702 genotype (CC, risk-allele homozygotes). KLF14 expression was undetectable in whole blood. Box plots display the median, with ‘hinges’ corresponding to the first and third quartiles; whiskers extend from the ‘hinge’ to the largest value no further than 1.5× the inter-quartile range, with values beyond shown as outliers. Associations were assessed by linear regression, with correction for family structure and relevant covariates ( Methods ). Full size image Results Adipose-specific regulation of KLF14 mediates the T2D association Using RNA-based next-generation sequencing (RNA-seq) data from subcutaneous adipose biopsies collected from 766 female twin members of the TwinsUK cohort 7 , we confirmed the cis-expression quantitative trait locus (eQTL) (using the SNP rs4731702 T2D risk allele C as the reference; β = –0.56; P = 1.8 × 10 −36 ) and identified a 38-fold-expanded trans network of 385 genes (false-discovery rate (FDR) < 5%) (Fig. 2 and Supplementary Table 1 ). The cis and trans effects at KLF14 were robust and were replicated in three independent studies of expression in subcutaneous adipose tissue (MGH 8 , METSIM 9 and deCODE 10 ) (Fig. 2c and Supplementary Tables 1 and 2 ). Despite detectable KLF14 expression in a range of tissues, these cis and trans associations were completely adipose specific, with no eQTL signal evident in the following: (i) skin, whole blood or lymphoblastoid cell lines from the same TwinsUK subjects 7 (Figs. 1f and 2d ); (ii) T2D-relevant tissues, such as muscle 11 , liver 8 , 12 or islet 13 ; or (iii) the broader coverage represented in eQTL datasets, such as GTEx 14 (Supplementary Table 3 ). KLF14 is imprinted and, as with its T2D association 1 , the KLF14 cis and trans eQTLs were maternal specific—the paternally inherited allele had no effect on KLF14 expression (Supplementary Fig. 1 and Supplementary Table 4 ). All other genes within 300 kb of the interval are also imprinted but paternally expressed, confirming KLF14 as the likely mediator of the T2D association at this locus. Fig. 2: KLF14 cis-eQTL is an adipose tissue–specific trans-regulator of a large network of genes. a , Genomic location of the 385 trans genes. Line color indicates direction of the trans effect as a positive (blue) or negative (green) association with the T2D risk allele. b , 177 trans genes show enrichment for KLF14 motifs, and 18 trans genes form a sub-network regulated by SREBF1. Gene colors indicate direction of trans effect (as in a ). Solid lines link KLF14 to trans genes", "role": "user" }, { "content": "Scientists at the University of Oxford have identified a gene that in women is linked to the creation and location of new fat cells and in turn contributes to an increased risk of type 2 diabetes. Published in Nature Genetics, the paper examined the effect of a gene called KLF14. The researchers found that genetic variations that control KLF14 have little impact on overall weight but they have a marked impact on where in the body any excess fat is stored. In women, versions of the gene that are result in fat being preferentially deposited around the hips, rather than around the abdomen, provide protection against diabetes. The different variations of KLF14 have an impact on the development of fat cells, and a striking effect on their size. In women carrying the version of the KLF14 gene that is associated with increased risk of diabetes, the individual fat cells are much larger and full of fat. This is likely to because there are fewer such cells in the first place, such that each cell ends up needing to take up more fat. This is known to result in inefficient, unhealthy fat cells that are more likely to contribute to diabetes. The study, which was an international collaboration with King's College London, MRC Harwell, the University of California in Los Angeles, University of Pennsylvania and others, also showed that the effects of these gene variations were specific to females. Not only that, only those versions of the gene inherited from an individual's mother are active. In women who inherited the risk version of the gene from their mothers, the impact is to increase diabetes risk about 30%. The findings provide new insights into some of the mechanisms involved in the development of diabetes, and demonstrates that abnormalities in fat tissue, as well as those in liver and in the insulin-producing cells of the pancreas can contribute. It is anticipated that this understanding may lead to better ways of treating and preventing diabetes in the future. Dr. Kerrin Small, one of the lead authors of the study from the Department of Twin Research and Genetic Epidemiology said: \"These findings provide one of the most complete understandings of a piece of genetic data – we have studied the KLF14 gene to the point that we understand not only where and how it acts in the body but also who it acts in. \"We hope that by building on these findings with further research to try and understand why the gene variant only affects diabetes risk in women that we can contribute towards better treatment plans and prevention and move towards more personalised approaches to medicine.\" Professor Mark McCarthy, another lead author, from the University of Oxford said: \"Being overweight is known to increase the risk of type 2 diabetes, but this study shows that not all fat is equal: where any excess fat is stored in the body has a big impact on disease risk. Here we identify a key gene involved in women in determining whether excess fat is stored around the hips (where it tends to be free of metabolic consequences) or around the waist (where it is particularly likely to increase diabetes risk). \"Rather that assuming that genetic variations exert their effects in the same way in different people, our new work highlights the importance of taking a 'holistic' approach to understanding the causes of disease, interrogating how genes function in different tissues and in different sexes.\" ", "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 risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14 . We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue–specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives. Main The replicated genome-wide significant T2D association signal at chr7q32.3 maps to a 45-kb recombination interval that extends from 3 kb to 48 kb upstream of KLF14 1 , 2 (Fig. 1a–c ). In previous work based on microarray-derived RNA-expression data, KLF14 , which encodes an imprinted transcription factor, was exposed as the likely cis-effector gene for this locus in subcutaneous adipose tissue 1 and was shown to be a trans regulator of a program of adipose tissue expression 3 . The KLF family of zinc-finger binding proteins has wide-ranging regulatory roles in biological processes such as proliferation, differentiation and growth 4 , 5 . However, little is known about KLF14 , a single-exon gene whose transcription is limited to the maternally inherited chromosome in embryonic, extra-embryonic and adult tissue in humans and mice 6 . Fig. 1: A cell type–specific enhancer in the risk haplotype regulates KLF14 expression. a – c , Association of KLF14 locus variants with T2D ( n = 69,033) (ref. 39 ) ( a ), HDL-C levels ( n = 99,900) (ref. 27 ) ( b ) and KLF14 mRNA abundance in adipose tissue ( n = 766 women; TwinsUK) ( c ). Circles represent genotyped and imputed DNA variants; colors indicate LD r 2 values with the index SNP rs4731702 (key). The red asterisk (below) indicates the position of methylation probe cg02385110. The blue box contains the putative enhancer shown in d . Association between genotype and KLF14 expression was assessed using mixed-effects models, correcting for family structure and relevant covariates ( Methods ). Uncorrected P values are displayed. d , Chromatin-state annotations for the KLF14 locus across 93 reference epigenomes (rows) for cell and tissue types profiled by the Roadmap Epigenomics and ENCODE projects. Colors correspond to chromatin states (yellow, enhancer; red, promoter; as in ref. 43 ). The blue box contains the putative enhancer. Chromosome coordinates correspond to UCSC Genome Browser build hg19. ESC, embryonic stem cell; HSC, hematopoietic stem cell; iPSC, induced pluripotent stem cell. e – i , KLF14 mRNA abundance ( e , f ) and methylation of probe cg02385110 ( g – i ) in concurrently sampled adipose tissue ( n = 720 ( e ) and n = 595 ( g )), skin ( n = 606 ( f ) and n = 414 ( h )) and whole blood ( n = 368 (not shown) and n = 289 ( i )) from participants of the TwinsUK study, based on rs4731702 genotype (CC, risk-allele homozygotes). KLF14 expression was undetectable in whole blood. Box plots display the median, with ‘hinges’ corresponding to the first and third quartiles; whiskers extend from the ‘hinge’ to the largest value no further than 1.5× the inter-quartile range, with values beyond shown as outliers. Associations were assessed by linear regression, with correction for family structure and relevant covariates ( Methods ). Full size image Results Adipose-specific regulation of KLF14 mediates the T2D association Using RNA-based next-generation sequencing (RNA-seq) data from subcutaneous adipose biopsies collected from 766 female twin members of the TwinsUK cohort 7 , we confirmed the cis-expression quantitative trait locus (eQTL) (using the SNP rs4731702 T2D risk allele C as the reference; β = –0.56; P = 1.8 × 10 −36 ) and identified a 38-fold-expanded trans network of 385 genes (false-discovery rate (FDR) < 5%) (Fig. 2 and Supplementary Table 1 ). The cis and trans effects at KLF14 were robust and were replicated in three independent studies of expression in subcutaneous adipose tissue (MGH 8 , METSIM 9 and deCODE 10 ) (Fig. 2c and Supplementary Tables 1 and 2 ). Despite detectable KLF14 expression in a range of tissues, these cis and trans associations were completely adipose specific, with no eQTL signal evident in the following: (i) skin, whole blood or lymphoblastoid cell lines from the same TwinsUK subjects 7 (Figs. 1f and 2d ); (ii) T2D-relevant tissues, such as muscle 11 , liver 8 , 12 or islet 13 ; or (iii) the broader coverage represented in eQTL datasets, such as GTEx 14 (Supplementary Table 3 ). KLF14 is imprinted and, as with its T2D association 1 , the KLF14 cis and trans eQTLs were maternal specific—the paternally inherited allele had no effect on KLF14 expression (Supplementary Fig. 1 and Supplementary Table 4 ). All other genes within 300 kb of the interval are also imprinted but paternally expressed, confirming KLF14 as the likely mediator of the T2D association at this locus. Fig. 2: KLF14 cis-eQTL is an adipose tissue–specific trans-regulator of a large network of genes. a , Genomic location of the 385 trans genes. Line color indicates direction of the trans effect as a positive (blue) or negative (green) association with the T2D risk allele. b , 177 trans genes show enrichment for KLF14 motifs, and 18 trans genes form a sub-network regulated by SREBF1. Gene colors indicate direction of trans effect (as in a ). Solid lines link KLF14 to trans genes<|im_end|> <|im_start|>assistant Scientists at the University of Oxford have identified a gene that in women is linked to the creation and location of new fat cells and in turn contributes to an increased risk of type 2 diabetes. Published in Nature Genetics, the paper examined the effect of a gene called KLF14. The researchers found that genetic variations that control KLF14 have little impact on overall weight but they have a marked impact on where in the body any excess fat is stored. In women, versions of the gene that are result in fat being preferentially deposited around the hips, rather than around the abdomen, provide protection against diabetes. The different variations of KLF14 have an impact on the development of fat cells, and a striking effect on their size. In women carrying the version of the KLF14 gene that is associated with increased risk of diabetes, the individual fat cells are much larger and full of fat. This is likely to because there are fewer such cells in the first place, such that each cell ends up needing to take up more fat. This is known to result in inefficient, unhealthy fat cells that are more likely to contribute to diabetes. The study, which was an international collaboration with King's College London, MRC Harwell, the University of California in Los Angeles, University of Pennsylvania and others, also showed that the effects of these gene variations were specific to females. Not only that, only those versions of the gene inherited from an individual's mother are active. In women who inherited the risk version of the gene from their mothers, the impact is to increase diabetes risk about 30%. The findings provide new insights into some of the mechanisms involved in the development of diabetes, and demonstrates that abnormalities in fat tissue, as well as those in liver and in the insulin-producing cells of the pancreas can contribute. It is anticipated that this understanding may lead to better ways of treating and preventing diabetes in the future. Dr. Kerrin Small, one of the lead authors of the study from the Department of Twin Research and Genetic Epidemiology said: "These findings provide one of the most complete understandings of a piece of genetic data – we have studied the KLF14 gene to the point that we understand not only where and how it acts in the body but also who it acts in. "We hope that by building on these findings with further research to try and understand why the gene variant only affects diabetes risk in women that we can contribute towards better treatment plans and prevention and move towards more personalised approaches to medicine." Professor Mark McCarthy, another lead author, from the University of Oxford said: "Being overweight is known to increase the risk of type 2 diabetes, but this study shows that not all fat is equal: where any excess fat is stored in the body has a big impact on disease risk. Here we identify a key gene involved in women in determining whether excess fat is stored around the hips (where it tends to be free of metabolic consequences) or around the waist (where it is particularly likely to increase diabetes risk). "Rather that assuming that genetic variations exert their effects in the same way in different people, our new work highlights the importance of taking a 'holistic' approach to understanding the causes of disease, interrogating how genes function in different tissues and in different sexes." <|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 Silicon is receiving discernable attention as an active material for next generation lithium-ion battery anodes because of its unparalleled gravimetric capacity. However, the large volume change of silicon over charge–discharge cycles weakens its competitiveness in the volumetric energy density and cycle life. Here we report direct graphene growth over silicon nanoparticles without silicon carbide formation. The graphene layers anchored onto the silicon surface accommodate the volume expansion of silicon via a sliding process between adjacent graphene layers. When paired with a commercial lithium cobalt oxide cathode, the silicon carbide-free graphene coating allows the full cell to reach volumetric energy densities of 972 and 700 Wh l −1 at first and 200th cycle, respectively, 1.8 and 1.5 times higher than those of current commercial lithium-ion batteries. This observation suggests that two-dimensional layered structure of graphene and its silicon carbide-free integration with silicon can serve as a prototype in advancing silicon anodes to commercially viable technology. Introduction The theoretical gravimetric capacity of silicon (Si) reaches almost 4,000 mAh g −1 . This unparalleled value has stimulated the battery community to invest considerable research efforts because the high gravimetric capacity enables one to increase the energy densities of lithium-ion batteries (LIBs) significantly, and thus bring future LIB applications, such as electrical vehicles, to a reality 1 , 2 , 3 , 4 , 5 . In the past decade, diverse advanced electrode structures 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 and binder designs 17 , 18 , 19 were developed to resolve chronic capacity fading issues originating from the large volume change of Si, leading to substantially improved cycling performance even over thousands of cycles 11 . In spite of the promising gravimetric value and substantial progress in cycle life, most of Si anodes demonstrated to date have focused primarily on the gravimetric capacity but have not offered a similar promise in their volumetric capacity because existing electrode designs rely on pre-defined void space to accommodate the volume expansion of Si. In many LIB applications including portable electronics, however, the volumetric energy density is a critical parameter in determining battery performance. Together with a relatively inferior cycle life, weak volumetric energy density is presently a major bottleneck in implementing Si anodes in commercial cells. To meet this critical demand, Si anode technology needs to be revisited with different electrode designs that offer stable cycling performance while the electrode volume is minimized. Although a variety of Si morphologies and their composites with other conductive materials are currently available, for an immediate solution to actual manufacturing that requires high-standard quality control, an easy and scalable synthesis of active Si components is crucial. From a practical application standpoint, among a vast number of viable candidates, the use of commercial Si nanoparticles (NPs) with a simple and efficient conductive surface coating would be highly desirable. Various conductive materials including amorphous carbon (AC) have been investigated as coating materials for Si NP anodes 8 , 20 , 21 . However, most of them fail to deliver stable long-term cycling performance because the implemented coating materials are unable to accommodate the volume expansion of Si and consequently fracture over repeated cycles. In an attempt to address the limitation of previous conductive coatings as well as to achieve good cycling performance with a significantly higher volumetric energy density, in this study, we adopt multilayer graphene directly grown on the Si surface as a coating material. The two-dimensional (2D) layered character of graphene provides a unique and efficient operation of Si anodes since multilayered graphene can accommodate Si volume expansion via a sliding process between adjacent layers without the need to provide void space a priori in the as-made electrode. Also, the graphene-coated Si NP pellet exhibits 12.8 S cm −1 at a marginal graphene content of 1 wt% through a high percolation network. To this end, we overcome a challenge of growing graphene directly on Si surfaces without Si carbide (SiC) formation by developing a chemical vapour deposition (CVD) process that involves a mild oxidant. SiC formation is fatal in Si anode operations because SiC is an electrical insulator with poor defect characteristics. Moreover, SiC is inactive in reacting with Li ions and consequently hinders Li ion diffusion into the Si phase. With the assistance of the graphene interlayer sliding process and enhanced conductivity, the graphene-coated Si NPs reach a volumetric capacity of 2,500 mAh cm −3 (versus 550 mAh cm −3 of commercial graphite), the highest value among those reported to date for any LIB anodes while exhibiting excellent cycling and rate performance. Results SiC-free graphene growth on Si The direct growth of high-quality graphene on Si via CVD process has proven challenging 22 because typical graphene synthesis conditions require a reducing atmosphere that tends to strip the native Si oxide layer off the Si surface, and then drives a reaction between Si and decomposed carbon precursors to form SiC 23 . Our initial approach of using methane (CH 4 ) as a carbon precursor mixed with H 2 was indeed unable to achieve a graphene growth on the Si NPs ( Supplementary Fig. 1 ), thereby yielding only β-SiC ( Supplementary Fig. 2 ). To overcome this limitation, we included carbon dioxide (CO 2 ), a mild oxidant, in the CVD process along with CH 4 (refs 24 , 25 ). The inclusion of CO 2 allows one to avoid the formation of SiC and also lower the growth temperature compared with well-known graphene growth on surface 23 . In our experiment, at 900 °C, the graphene growth was incomplete or inhomogeneous ( Supplementary Fig. 3 ), whereas graphene growth at 1,100 °C produced oxide layers on the Si surface that are too thick for efficient Li ion diffusion ( Supplementary Fig. 4 ). At an intermediate temperature of 1,000 °C, 2–10 layers of graphene were formed as shown in transmission electron microscope (TEM) images ( Fig. 1a,b ) clearly displaying the layered", "role": "user" }, { "content": "(Phys.org)—A team of researches affiliated with Samsung's Advanced Institute of Technology, along with colleagues from other institutions in Korea has found a way to greatly extend lithium-ion battery life. In their paper published in the journal Nature Communications, the team describes their new technique and the results they achieved using it. Consumers want their phone batteries to last longer—that is no secret, and battery life has been extended, but mostly due to improved efficiency of the electronics that depend on it. Researchers at phone companies and elsewhere have been working hard to find a way to get more power out of the same size battery but have to date, not made much progress. In this new effort, the researchers looked to silicon and graphene for a better battery. The team started by using silicon as the material for their anode, rather than the traditional graphite—it is denser and therefore can hold more charge—and is something other researchers have tried before. The problem has always been that in order to charge it, lithium must be added, which causes the anode to expand, a deal breaker for small electronic devices. To circumvent that problem, the researches grew carbide-free graphene (to keep it from forming they developed a chemical vapor deposition process which included using a mild oxidant) on its surface creating a protective and restrictive coating. In addition to preventing expansion, the graphene also helped prevent the silicon from breaking down over time (which occurs due to constant expanding and contracting). Testing showed that the arrangement resulted in a battery that had an initial energy density that was 1.8 times that of conventional batteries, and held steady at 1.5 times after repeated use. Translated to the real world that would mean a battery that at least initially, would last nearly twice as long as conventional batteries. That is impressive, of course, but the fly in the ointment is the graphene—despite a lot of time, effort and money invested, scientists still have not figured out a way to manufacture the stuff in bulk, which means, that the new battery design will not be available to consumers until a way can be found to produce the graphene. ", "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 Silicon is receiving discernable attention as an active material for next generation lithium-ion battery anodes because of its unparalleled gravimetric capacity. However, the large volume change of silicon over charge–discharge cycles weakens its competitiveness in the volumetric energy density and cycle life. Here we report direct graphene growth over silicon nanoparticles without silicon carbide formation. The graphene layers anchored onto the silicon surface accommodate the volume expansion of silicon via a sliding process between adjacent graphene layers. When paired with a commercial lithium cobalt oxide cathode, the silicon carbide-free graphene coating allows the full cell to reach volumetric energy densities of 972 and 700 Wh l −1 at first and 200th cycle, respectively, 1.8 and 1.5 times higher than those of current commercial lithium-ion batteries. This observation suggests that two-dimensional layered structure of graphene and its silicon carbide-free integration with silicon can serve as a prototype in advancing silicon anodes to commercially viable technology. Introduction The theoretical gravimetric capacity of silicon (Si) reaches almost 4,000 mAh g −1 . This unparalleled value has stimulated the battery community to invest considerable research efforts because the high gravimetric capacity enables one to increase the energy densities of lithium-ion batteries (LIBs) significantly, and thus bring future LIB applications, such as electrical vehicles, to a reality 1 , 2 , 3 , 4 , 5 . In the past decade, diverse advanced electrode structures 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 and binder designs 17 , 18 , 19 were developed to resolve chronic capacity fading issues originating from the large volume change of Si, leading to substantially improved cycling performance even over thousands of cycles 11 . In spite of the promising gravimetric value and substantial progress in cycle life, most of Si anodes demonstrated to date have focused primarily on the gravimetric capacity but have not offered a similar promise in their volumetric capacity because existing electrode designs rely on pre-defined void space to accommodate the volume expansion of Si. In many LIB applications including portable electronics, however, the volumetric energy density is a critical parameter in determining battery performance. Together with a relatively inferior cycle life, weak volumetric energy density is presently a major bottleneck in implementing Si anodes in commercial cells. To meet this critical demand, Si anode technology needs to be revisited with different electrode designs that offer stable cycling performance while the electrode volume is minimized. Although a variety of Si morphologies and their composites with other conductive materials are currently available, for an immediate solution to actual manufacturing that requires high-standard quality control, an easy and scalable synthesis of active Si components is crucial. From a practical application standpoint, among a vast number of viable candidates, the use of commercial Si nanoparticles (NPs) with a simple and efficient conductive surface coating would be highly desirable. Various conductive materials including amorphous carbon (AC) have been investigated as coating materials for Si NP anodes 8 , 20 , 21 . However, most of them fail to deliver stable long-term cycling performance because the implemented coating materials are unable to accommodate the volume expansion of Si and consequently fracture over repeated cycles. In an attempt to address the limitation of previous conductive coatings as well as to achieve good cycling performance with a significantly higher volumetric energy density, in this study, we adopt multilayer graphene directly grown on the Si surface as a coating material. The two-dimensional (2D) layered character of graphene provides a unique and efficient operation of Si anodes since multilayered graphene can accommodate Si volume expansion via a sliding process between adjacent layers without the need to provide void space a priori in the as-made electrode. Also, the graphene-coated Si NP pellet exhibits 12.8 S cm −1 at a marginal graphene content of 1 wt% through a high percolation network. To this end, we overcome a challenge of growing graphene directly on Si surfaces without Si carbide (SiC) formation by developing a chemical vapour deposition (CVD) process that involves a mild oxidant. SiC formation is fatal in Si anode operations because SiC is an electrical insulator with poor defect characteristics. Moreover, SiC is inactive in reacting with Li ions and consequently hinders Li ion diffusion into the Si phase. With the assistance of the graphene interlayer sliding process and enhanced conductivity, the graphene-coated Si NPs reach a volumetric capacity of 2,500 mAh cm −3 (versus 550 mAh cm −3 of commercial graphite), the highest value among those reported to date for any LIB anodes while exhibiting excellent cycling and rate performance. Results SiC-free graphene growth on Si The direct growth of high-quality graphene on Si via CVD process has proven challenging 22 because typical graphene synthesis conditions require a reducing atmosphere that tends to strip the native Si oxide layer off the Si surface, and then drives a reaction between Si and decomposed carbon precursors to form SiC 23 . Our initial approach of using methane (CH 4 ) as a carbon precursor mixed with H 2 was indeed unable to achieve a graphene growth on the Si NPs ( Supplementary Fig. 1 ), thereby yielding only β-SiC ( Supplementary Fig. 2 ). To overcome this limitation, we included carbon dioxide (CO 2 ), a mild oxidant, in the CVD process along with CH 4 (refs 24 , 25 ). The inclusion of CO 2 allows one to avoid the formation of SiC and also lower the growth temperature compared with well-known graphene growth on surface 23 . In our experiment, at 900 °C, the graphene growth was incomplete or inhomogeneous ( Supplementary Fig. 3 ), whereas graphene growth at 1,100 °C produced oxide layers on the Si surface that are too thick for efficient Li ion diffusion ( Supplementary Fig. 4 ). At an intermediate temperature of 1,000 °C, 2–10 layers of graphene were formed as shown in transmission electron microscope (TEM) images ( Fig. 1a,b ) clearly displaying the layered<|im_end|> <|im_start|>assistant (Phys.org)—A team of researches affiliated with Samsung's Advanced Institute of Technology, along with colleagues from other institutions in Korea has found a way to greatly extend lithium-ion battery life. In their paper published in the journal Nature Communications, the team describes their new technique and the results they achieved using it. Consumers want their phone batteries to last longer—that is no secret, and battery life has been extended, but mostly due to improved efficiency of the electronics that depend on it. Researchers at phone companies and elsewhere have been working hard to find a way to get more power out of the same size battery but have to date, not made much progress. In this new effort, the researchers looked to silicon and graphene for a better battery. The team started by using silicon as the material for their anode, rather than the traditional graphite—it is denser and therefore can hold more charge—and is something other researchers have tried before. The problem has always been that in order to charge it, lithium must be added, which causes the anode to expand, a deal breaker for small electronic devices. To circumvent that problem, the researches grew carbide-free graphene (to keep it from forming they developed a chemical vapor deposition process which included using a mild oxidant) on its surface creating a protective and restrictive coating. In addition to preventing expansion, the graphene also helped prevent the silicon from breaking down over time (which occurs due to constant expanding and contracting). Testing showed that the arrangement resulted in a battery that had an initial energy density that was 1.8 times that of conventional batteries, and held steady at 1.5 times after repeated use. Translated to the real world that would mean a battery that at least initially, would last nearly twice as long as conventional batteries. That is impressive, of course, but the fly in the ointment is the graphene—despite a lot of time, effort and money invested, scientists still have not figured out a way to manufacture the stuff in bulk, which means, that the new battery design will not be available to consumers until a way can be found to produce the graphene. <|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 Hybrid metal nanoparticles, consisting of a nano-crystalline metal core and a protecting shell of organic ligand molecules, have applications in diverse areas such as biolabeling, catalysis, nanomedicine, and solar energy. Despite a rapidly growing database of experimentally determined atom-precise nanoparticle structures and their properties, there has been no successful, systematic way to predict the atomistic structure of the metal-ligand interface. Here, we devise and validate a general method to predict the structure of the metal-ligand interface of ligand-stabilized gold and silver nanoparticles, based on information about local chemical environments of atoms in experimental data. In addition to predicting realistic interface structures, our method is useful for investigations on the steric effects at the metal-ligand interface, as well as for predicting isomers and intermediate structures induced by thermal dynamics or interactions with the environment. Our method is applicable to other hybrid nanomaterials once a suitable set of reference structures is available. Introduction Hybrid metal nanoparticles, consisting of a nano-crystalline metal core and a protecting layer (shell) of organic ligand molecules, are an emerging class of functional nanomaterials that have potential applications in diverse areas such as biolabeling, catalysis, nanomedicine, and solar energy 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . The core-shell framework structure of hybrid nanoparticles offers ample opportunities to tune the physico-chemical properties and functionalities of the particles via controlling the size, shape, elemental composition, and structure of the metal core, together with the chemical composition of the ligand shell. The chemical interactions between the metal atoms and ligand molecules at the core-shell interface are in a crucial role since they dictate the atomic-scale structure, stability, and ensuing properties of the particle. The last decade has witnessed clear advancements in synthesis and experimental structural characterization of very small, atomically precise hybrid nanoparticles with 1–3 nm cores made of metals, stabilized by various organic ligands 3 . These particles are also called monolayer-protected clusters, MPCs, and they represent an interesting subclass of nanoparticles since their structures can be often characterized to atomic precision by using X-ray diffraction method on single MPC crystals. At the moment, more than 150 crystallographically solved structures of MPCs, involving noble metals, main group metals, and various ligand molecules such as thiols, phosphines, and alkynyls, have been reported 3 . This facilitates fundamental studies of the structure-property relationships both experimentally and computationally. In most cases, however, the knowledge of the nanoparticle structures does not reach the atom-level resolution and the ligand-metal interfaces may be ill-defined. Only partial structural knowledge may be available, e.g., by high-resolution electron microscopy where only the heavy atoms (metals) of the core may be visible 9 , 10 . Smallest particles may have low-symmetry or disordered metal cores, and may not be amenable at all to experimental techniques that work well for structural characterization of atomically ordered bulk materials 11 . A practical solution is then to reach conclusions of potential atomic-scale structures by comparing measured properties, such as powder X-ray diffraction data, and various spectroscopic data, to computed properties based on extensive sets of potential candidate structures. A crucial question is then how realistic is the group of the candidate structures, i.e., can the structure corresponding to the true global total energy minimum be included in that group with a high probability. In general, global optimization methods suffer from limitations arising from a prohibitively (exponentially) increasing number of local energy minima in the structural space for system sizes that are larger than just a few metal atoms and ligand molecules. Another time-constraint arises from the fact that most measurable properties must be calculated numerically from the electronic structure using the platform of the density functional theory (DFT), which limits the number of structural candidates that can be examined. It is thus crucial to develop methods that can effectively suggest realistic atomic-scale structures at a very low computational cost. The data on atomically precise structures of MPCs, combined with an ever-growing number measurements of their physico-chemical properties, collectively contains valuable chemical information on the atomic bonding and structure-property relations of these nanomaterials, which could be used for successful structural predictions of yet unknown nanoparticles. Here, we devise and demonstrate a general method for predicting metal-ligand interface structures of an unknown ligand-protected metal nanocluster. Our method is based on a local search algorithm that uses information about the known local atomic environments at the metal-ligand interface of reference nanostructures in the same class of hybrid nanoparticles. The specific example systems discussed in this work comprise gold (Au) and silver (Ag) nanoclusters protected by thiols (SR), phosphines (PR 3 ) and diphosphines (DPPY), and we demonstrate how experimentally verified Au/Ag-thiolate and Ag-phosphine interface structures can be successfully built when the positions of all Au or Ag atoms in the cluster are first defined. However, the method itself is general and can be used for any type of nanoparticle or nanostructure if enough reference structural information is available in the same class of systems. The set of reference structures can be considered as a training set and the whole procedure to refine the candidates for the metal-ligand interfacial structures may be considered as an analogue to applying machine learning methodology to the structure prediction problem 12 . Results Structure prediction algorithm Our procedure to build candidates for the atomic structure of metal-ligand interfaces is summarized below and illustrated in Fig. 1 . Supplementary Note 1 describes the algorithms 1–4 involved. The main algorithm 1 is divided into steps 0–4 as follows (the steps are also numbered the same way in Fig. 1 ). Fig. 1 A schematic visualization of the algorithm. Using a set of reference structures of known Au x (SR) y nanoclusters, several candidates for the structure of the layer of sulfur atoms are built around the gold core of the unknown cluster, with selective ranking of the most probable structures. Au: orange, S: yellow, carbon backbone in ligands: cyan Full size image 0. First, a group of known reference structures (training set) is", "role": "user" }, { "content": "Researchers at the Nanoscience Center and Faculty of Information Technology in the University of Jyväskylä, Finland, have achieved a significant step forward in predicting atomic structures of hybrid nanoparticles. A research article published in Nature Communications on 3 September 2019, demonstrates a new algorithm that learns to predict binding sites of molecules at the metal-molecule interface of hybrid nanoparticles by using already published experimental structural information on nanoparticle reference systems. The algorithm can in principle be applied to any nanometer-size structure consisting of metals and molecules provided that some structural information already exists on the corresponding systems. The research was funded by the AIPSE research program of the Academy of Finland (Novel Applications of Artificial Intelligence in Physical Sciences and Engineering Research). Nanometre-sized hybrid metal nanoparticles have many applications in different processes, including catalysis, nanoelectronics, nanomedicine and biological imaging. Often, it is important to know the detailed atomic structure of the particle in order to understand its functionality. The particles consist of a metal core and a protecting layer of molecules. High-resolution electron microscopes are able to produce 3-D atomic structures of the metal core, but these instruments cannot detect the molecular layer that consists of light atoms such as carbon, nitrogen and oxygen. The new algorithm published by the researchers in Jyväskylä helps to create accurate atomic models of the particles' total structure enabling simulations of the metal-molecule interface as well as of the surface of the molecular layer and its interactions with the environment. The algorithm can also rank the predicted atomic structural models based on how well the models reproduce measured properties of other particles of similar size and type. \"The basic idea behind our algorithm is very simple. Chemical bonds between atoms are always discrete, having well-defined bond angles and bond distances. Therefore, every nanoparticle structure known from experiments, where the positions of all atoms are resolved accurately, tells something essential about the chemistry of the metal-molecule interface. The interesting question regarding applications of artificial intelligence for structural predictions is: how many of these already known structures we need to know so that predictions for new, yet unknown particles become reliable? It looks like we only need a few dozen of known structures, says the lead author of the article, Sami Malola, who works as a University Researcher at the Nanoscience Center of the University of Jyväskylä. \"In the next phase of this work we will build efficient atomic interaction models for hybrid metal nanoparticles by using machine learning methods. These models will allow us to investigate several interesting and important topics such as particle-particle reactions and the nanoparticles' ability to function as delivery vehicles for small drug molecules,\" says Academy Professor Hannu Häkkinen, who led the study. Häkkinen's collaborator, professor Tommi Kärkkäinen from the Faculty of Information Science in the University of Jyväskylä continues: \"This is a significant step forward within the context of new interdisciplinary collaboration in our university. Applying artificial intelligence to challenging topics in nanoscience, such as structural predictions for new nanomaterials, will surely lead to new breakthroughs.\" ", "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 Hybrid metal nanoparticles, consisting of a nano-crystalline metal core and a protecting shell of organic ligand molecules, have applications in diverse areas such as biolabeling, catalysis, nanomedicine, and solar energy. Despite a rapidly growing database of experimentally determined atom-precise nanoparticle structures and their properties, there has been no successful, systematic way to predict the atomistic structure of the metal-ligand interface. Here, we devise and validate a general method to predict the structure of the metal-ligand interface of ligand-stabilized gold and silver nanoparticles, based on information about local chemical environments of atoms in experimental data. In addition to predicting realistic interface structures, our method is useful for investigations on the steric effects at the metal-ligand interface, as well as for predicting isomers and intermediate structures induced by thermal dynamics or interactions with the environment. Our method is applicable to other hybrid nanomaterials once a suitable set of reference structures is available. Introduction Hybrid metal nanoparticles, consisting of a nano-crystalline metal core and a protecting layer (shell) of organic ligand molecules, are an emerging class of functional nanomaterials that have potential applications in diverse areas such as biolabeling, catalysis, nanomedicine, and solar energy 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . The core-shell framework structure of hybrid nanoparticles offers ample opportunities to tune the physico-chemical properties and functionalities of the particles via controlling the size, shape, elemental composition, and structure of the metal core, together with the chemical composition of the ligand shell. The chemical interactions between the metal atoms and ligand molecules at the core-shell interface are in a crucial role since they dictate the atomic-scale structure, stability, and ensuing properties of the particle. The last decade has witnessed clear advancements in synthesis and experimental structural characterization of very small, atomically precise hybrid nanoparticles with 1–3 nm cores made of metals, stabilized by various organic ligands 3 . These particles are also called monolayer-protected clusters, MPCs, and they represent an interesting subclass of nanoparticles since their structures can be often characterized to atomic precision by using X-ray diffraction method on single MPC crystals. At the moment, more than 150 crystallographically solved structures of MPCs, involving noble metals, main group metals, and various ligand molecules such as thiols, phosphines, and alkynyls, have been reported 3 . This facilitates fundamental studies of the structure-property relationships both experimentally and computationally. In most cases, however, the knowledge of the nanoparticle structures does not reach the atom-level resolution and the ligand-metal interfaces may be ill-defined. Only partial structural knowledge may be available, e.g., by high-resolution electron microscopy where only the heavy atoms (metals) of the core may be visible 9 , 10 . Smallest particles may have low-symmetry or disordered metal cores, and may not be amenable at all to experimental techniques that work well for structural characterization of atomically ordered bulk materials 11 . A practical solution is then to reach conclusions of potential atomic-scale structures by comparing measured properties, such as powder X-ray diffraction data, and various spectroscopic data, to computed properties based on extensive sets of potential candidate structures. A crucial question is then how realistic is the group of the candidate structures, i.e., can the structure corresponding to the true global total energy minimum be included in that group with a high probability. In general, global optimization methods suffer from limitations arising from a prohibitively (exponentially) increasing number of local energy minima in the structural space for system sizes that are larger than just a few metal atoms and ligand molecules. Another time-constraint arises from the fact that most measurable properties must be calculated numerically from the electronic structure using the platform of the density functional theory (DFT), which limits the number of structural candidates that can be examined. It is thus crucial to develop methods that can effectively suggest realistic atomic-scale structures at a very low computational cost. The data on atomically precise structures of MPCs, combined with an ever-growing number measurements of their physico-chemical properties, collectively contains valuable chemical information on the atomic bonding and structure-property relations of these nanomaterials, which could be used for successful structural predictions of yet unknown nanoparticles. Here, we devise and demonstrate a general method for predicting metal-ligand interface structures of an unknown ligand-protected metal nanocluster. Our method is based on a local search algorithm that uses information about the known local atomic environments at the metal-ligand interface of reference nanostructures in the same class of hybrid nanoparticles. The specific example systems discussed in this work comprise gold (Au) and silver (Ag) nanoclusters protected by thiols (SR), phosphines (PR 3 ) and diphosphines (DPPY), and we demonstrate how experimentally verified Au/Ag-thiolate and Ag-phosphine interface structures can be successfully built when the positions of all Au or Ag atoms in the cluster are first defined. However, the method itself is general and can be used for any type of nanoparticle or nanostructure if enough reference structural information is available in the same class of systems. The set of reference structures can be considered as a training set and the whole procedure to refine the candidates for the metal-ligand interfacial structures may be considered as an analogue to applying machine learning methodology to the structure prediction problem 12 . Results Structure prediction algorithm Our procedure to build candidates for the atomic structure of metal-ligand interfaces is summarized below and illustrated in Fig. 1 . Supplementary Note 1 describes the algorithms 1–4 involved. The main algorithm 1 is divided into steps 0–4 as follows (the steps are also numbered the same way in Fig. 1 ). Fig. 1 A schematic visualization of the algorithm. Using a set of reference structures of known Au x (SR) y nanoclusters, several candidates for the structure of the layer of sulfur atoms are built around the gold core of the unknown cluster, with selective ranking of the most probable structures. Au: orange, S: yellow, carbon backbone in ligands: cyan Full size image 0. First, a group of known reference structures (training set) is<|im_end|> <|im_start|>assistant Researchers at the Nanoscience Center and Faculty of Information Technology in the University of Jyväskylä, Finland, have achieved a significant step forward in predicting atomic structures of hybrid nanoparticles. A research article published in Nature Communications on 3 September 2019, demonstrates a new algorithm that learns to predict binding sites of molecules at the metal-molecule interface of hybrid nanoparticles by using already published experimental structural information on nanoparticle reference systems. The algorithm can in principle be applied to any nanometer-size structure consisting of metals and molecules provided that some structural information already exists on the corresponding systems. The research was funded by the AIPSE research program of the Academy of Finland (Novel Applications of Artificial Intelligence in Physical Sciences and Engineering Research). Nanometre-sized hybrid metal nanoparticles have many applications in different processes, including catalysis, nanoelectronics, nanomedicine and biological imaging. Often, it is important to know the detailed atomic structure of the particle in order to understand its functionality. The particles consist of a metal core and a protecting layer of molecules. High-resolution electron microscopes are able to produce 3-D atomic structures of the metal core, but these instruments cannot detect the molecular layer that consists of light atoms such as carbon, nitrogen and oxygen. The new algorithm published by the researchers in Jyväskylä helps to create accurate atomic models of the particles' total structure enabling simulations of the metal-molecule interface as well as of the surface of the molecular layer and its interactions with the environment. The algorithm can also rank the predicted atomic structural models based on how well the models reproduce measured properties of other particles of similar size and type. "The basic idea behind our algorithm is very simple. Chemical bonds between atoms are always discrete, having well-defined bond angles and bond distances. Therefore, every nanoparticle structure known from experiments, where the positions of all atoms are resolved accurately, tells something essential about the chemistry of the metal-molecule interface. The interesting question regarding applications of artificial intelligence for structural predictions is: how many of these already known structures we need to know so that predictions for new, yet unknown particles become reliable? It looks like we only need a few dozen of known structures, says the lead author of the article, Sami Malola, who works as a University Researcher at the Nanoscience Center of the University of Jyväskylä. "In the next phase of this work we will build efficient atomic interaction models for hybrid metal nanoparticles by using machine learning methods. These models will allow us to investigate several interesting and important topics such as particle-particle reactions and the nanoparticles' ability to function as delivery vehicles for small drug molecules," says Academy Professor Hannu Häkkinen, who led the study. Häkkinen's collaborator, professor Tommi Kärkkäinen from the Faculty of Information Science in the University of Jyväskylä continues: "This is a significant step forward within the context of new interdisciplinary collaboration in our university. Applying artificial intelligence to challenging topics in nanoscience, such as structural predictions for new nanomaterials, will surely lead to new breakthroughs." <|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 Wheat bran is widely used in the food industry to produce fibre-rich food products with enhanced health benefits. The present study explored the effect of bran size reduction by superfine grinding on the microstructure and quality of bran-enriched dried white noodle (DWN). Coarse ( D 50 = 330.7 μm) and superfine-ground ( D 50 = 50.7 and 27.9 μm) wheat brans were fortified into DWN at levels of 10, 20 and 30%. The physical modifications by bran addition on the microstructure, cooking performance, and textural properties of DWN were determined. Then, the sensory quality of the products was evaluated by the human panel using both the hedonic and “difference-from-control” tests. With the increasing amount of bran added, noodle quality deteriorated in all aspects. DWN fortified with 30% of bran presented a highly obstructed or disrupted microstructure, and their appearance and taste were least favoured by the consumers. Superfine grinding effectively pulverized wheat bran into micro-scale, and DWN fortified with the finest bran ( D 50 = 27.9 μ m) possessed the darkest colour and a compromised cooking yield rate. However, they maintained superior taste and texture that were comparable to the control, with up to 20% of bran addition. The present study demonstrated that superfine grinding not necessarily improves all aspects of noodle processing and cooking but would promote an overall improvement on the sensory quality of bran-fortified noodle. Besides, it was possible to produce fibre-rich DWN with relatively high (10–20%) bran addition levels with acceptable quality. The results may guide future development of bran-enriched products to stimulate consumer’s fibre intake. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction In recent years, consumers are becoming increasingly health-conscious and demand natural, wholesome, and low-calorie food, particularly cereal-based food. As a result, considerable attention has been paid in developing whole-grain food products with enhanced health benefits. Results of several studies have suggested that regular consumption of whole grains provides potential protection against life-style and diet-related disorders such as obesity, diabetes, cardiovascular diseases, and cancers (Kelly et al., 2007 ; Liu et al., 2000 ; Meyer et al., 2000 ; Schatzkin et al., 2007 ). According to Protonotariou et al. ( 2015 ), the majority of the beneficial phytochemicals of whole grains are present in the bran and germ fractions. The bran is the multi-layered outer skin of the grain that is rich in phenolic compounds, vitamins, minerals, and fibre (Jonnalagadda et al., 2011 ). During the refining of whole grains into white flour, the outer bran is largely removed. However, bran has been recognized as a functional natural ingredient for cereal-based foods recently. The effect of wheat bran addition on the quality of bread, cake, biscuit, and spaghetti has been reported in previous studies (Lebesi & Tzia, 2011 ; Leelavathi & Haridas Rao, 1993 ; Mwj et al., 2010 ; Steglich et al., 2015 ), but not as extensively investigated on oriental staples such as steamed bun and various types of Chinese noodles. Noodle is one of the main traditional foods in China and accounts for about 30–35% of the total consumption of wheat flour in China (Chen et al., 2011 ). Colour, shelf-life, cooking performance, textural attributes and sensory quality have been key characteristics affecting the quality of noodle products (Lee et al., 2002 ). While some other factors, such as the nutritional value and glycaemic impact of noodle, are becoming important for novel noodle products to gain consumer acceptance. Barrier against wider use of wheat bran in noodle products is mainly its negative impact on the gluten development of dough and organoleptic qualities of end-product. Bran may alter the microstructure of noodle through interference with dough development and will result in the discontinuity within the gluten matrix, leading to compromised cooking and textural performance (Bruinsma et al., 1978 ; Sharma et al., 2017 ). According to Ritika et al. ( 2016 ), presence of ingredients other than wheat flour could cause discontinuity in the gluten network. Gluten is responsible for the firmness of noodle, and inadequate gluten development may lead to the faster moisture penetration and hence less optimum cooking time of noodles. Additionally, the bran portion may be highly coloured and contain stringent, intensely flavoured compounds, resulting in compromised sensory qualities. Therefore, low levels of bran fortification from 2 to 10% was usually recommended for noodle products by previous studies (Chen et al., 2011 ; Zhao et al., 2008 ). Several approaches have been proposed to improve the quality of bran-fortified noodles, including wheat selection, ingredients addition and bran particle size control (Niu & Hou, 2019 ). The particle size of wheat bran may influence its water binding capacity, water holding capacity, and solubility, which are important properties determining the technological applicability and physical function of bran (Santala et al., 2012 ). According to Steglich et al. ( 2015 ), mean particle size reduction of bran from 440 to 370, 160, and 90 μ m counteracted the destructive effects of bran on the sensory properties of pasta. Another study conducted by Liu et al. ( 2016 ) also has shown that reducing the median particle sizes of bran from 175 mm to 130 mm significantly improved the textural quality of tortilla made from reconstituted whole wheat flour. Other studies found that the negative influence of bran on bread and steamed bread was enhanced when bran particle size was reduced (Noort et al., 2010 ; Xu et al., 2018 ). Research is still ongoing to manipulate the size of bran for desired end-product quality. Due to the soft structure and relatively low density of wheat bran, reduction of the bran size below 40 μ m is often considered difficult using conventional milling. Novel size reduction strategies including microfluidization and jet milling have been studied by several researchers (Mert et al., 2014 ; Protonotariou et al., 2015 ). Superfine grinding is an emerging technology that produces fine powder on a micro-scale (Huang et al., 2017 ). However, limited", "role": "user" }, { "content": "NUS food scientists have demonstrated that finely ground wheat bran can be added to Asian wheat noodles by up to 20% without compromising organoleptic acceptance. This can be an effective approach to promote higher dietary fiber intake. Wheat bran is widely used in the food industry to produce fiber-rich food products with enhanced health benefits. The bran which is the hard outer layer of the wheat kernel is an excellent source of fiber and is rich in various nutrients. However, it is typically removed during processing as its presence in food products makes them less refined in texture and its taste may not appeal to most consumers. A research team led by Prof Zhou Weibiao from the Department of Food Science and Technology, National University of Singapore studied the effect of bran size reduction on the microstructure and performance of bran-enriched dried white noodle (see Figures). The researchers used superfine grinding to produce wheat bran powder at the micro-scale level and used them in making white noodle products. The results show that superfine grinding does not necessarily improve all aspects of noodle processing and cooking, but promote an overall improvement in the sensory quality of bran-enriched noodle. They also found through sensory evaluation that it is possible to produce bran-enriched noodle with relatively high bran levels (up to 20%) that are still deemed acceptable by consumers. Figure 2: Photo showing the colour the starting raw ingredients and resultant noodle samples. The colour of the noodles is an important quality trait because of the visual impact at the point of sale. Legend: RWF = refined wheat flour, CB = coarse bran, SBA = superfine bran A, SBB = superfine bran B (grounded to a finer size compared to SBA). Credit: Food and Bioprocess Technology Superfine grinding is a relatively new food processing technology. There is limited research on the food quality and consumer sensory acceptance of superfine ground wheat bran and its end products. This study assessed the quality of bran-enriched noodles using both analytical instruments and human subjects. The wheat bran was ground into three categories of different granular sizes: coarse bran (diameter ~330.7 μm), superfine bran A (diameter ~50.7 μm) and super fine bran B (diameter ~27.9 μm). These were then added to refined wheat flour in varying quantities (from 10% to 30%) to make the noodles. With more wheat bran added, the dried white noodle quality deteriorated in all aspects. When the amount of bran added reached 30%, the noodles presented a highly obstructed or disrupted microstructure. Their appearance and taste were also least favored by the consumers. Superfine grinding acted as an effective approach to alleviate the negative effect of wheat bran on noodle, particularly for various sensory attributes. Jin Xiaoxuan, a Ph.D. student on the team said, \"The study results contribute to a better understanding of the applicability of superfine grinding in improving the functionality of wheat bran, and will guide future development of bran-enriched products to stimulate consumer's dietary fiber intake.\" Sensory attributes of cooked dried white noodles (DWN) fortified with (a) 10%, (b) 20%, and (c) 30% of wheat brans. All samples were graded on a scale of 1 to 9 against the control (DWN without addition of wheat brans) which is given a score of 5. Higher score means stronger intensity of the attribute/better than control, sample size is 44). Legend: CB, coarse bran; SBA, superfine bran A; SBB, superfine bran B (grounded to a finer size compared to SBA). Credit: Food and Bioprocess Technology Prof Zhou said, \"While the consensus among the scientific community is that dietary fiber intake needs to be significantly boosted to combat a variety of chronic diseases in modern society, the perceived health benefits are insufficient for consumers to sacrifice their taste for \"healthier\" alternatives. Innovative food technologies are needed to make healthier food tasty and for tasty foods to become healthier. Deeper understanding on how healthier foods function when they go through the digestive system is fundamental in achieving this goal.\" Moving on, the research team plans to focus on the effect of wheat bran fortification on the oral processing and glycaemic index (GI) of noodles using both in vitro and in vivo approaches. ", "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 Wheat bran is widely used in the food industry to produce fibre-rich food products with enhanced health benefits. The present study explored the effect of bran size reduction by superfine grinding on the microstructure and quality of bran-enriched dried white noodle (DWN). Coarse ( D 50 = 330.7 μm) and superfine-ground ( D 50 = 50.7 and 27.9 μm) wheat brans were fortified into DWN at levels of 10, 20 and 30%. The physical modifications by bran addition on the microstructure, cooking performance, and textural properties of DWN were determined. Then, the sensory quality of the products was evaluated by the human panel using both the hedonic and “difference-from-control” tests. With the increasing amount of bran added, noodle quality deteriorated in all aspects. DWN fortified with 30% of bran presented a highly obstructed or disrupted microstructure, and their appearance and taste were least favoured by the consumers. Superfine grinding effectively pulverized wheat bran into micro-scale, and DWN fortified with the finest bran ( D 50 = 27.9 μ m) possessed the darkest colour and a compromised cooking yield rate. However, they maintained superior taste and texture that were comparable to the control, with up to 20% of bran addition. The present study demonstrated that superfine grinding not necessarily improves all aspects of noodle processing and cooking but would promote an overall improvement on the sensory quality of bran-fortified noodle. Besides, it was possible to produce fibre-rich DWN with relatively high (10–20%) bran addition levels with acceptable quality. The results may guide future development of bran-enriched products to stimulate consumer’s fibre intake. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction In recent years, consumers are becoming increasingly health-conscious and demand natural, wholesome, and low-calorie food, particularly cereal-based food. As a result, considerable attention has been paid in developing whole-grain food products with enhanced health benefits. Results of several studies have suggested that regular consumption of whole grains provides potential protection against life-style and diet-related disorders such as obesity, diabetes, cardiovascular diseases, and cancers (Kelly et al., 2007 ; Liu et al., 2000 ; Meyer et al., 2000 ; Schatzkin et al., 2007 ). According to Protonotariou et al. ( 2015 ), the majority of the beneficial phytochemicals of whole grains are present in the bran and germ fractions. The bran is the multi-layered outer skin of the grain that is rich in phenolic compounds, vitamins, minerals, and fibre (Jonnalagadda et al., 2011 ). During the refining of whole grains into white flour, the outer bran is largely removed. However, bran has been recognized as a functional natural ingredient for cereal-based foods recently. The effect of wheat bran addition on the quality of bread, cake, biscuit, and spaghetti has been reported in previous studies (Lebesi & Tzia, 2011 ; Leelavathi & Haridas Rao, 1993 ; Mwj et al., 2010 ; Steglich et al., 2015 ), but not as extensively investigated on oriental staples such as steamed bun and various types of Chinese noodles. Noodle is one of the main traditional foods in China and accounts for about 30–35% of the total consumption of wheat flour in China (Chen et al., 2011 ). Colour, shelf-life, cooking performance, textural attributes and sensory quality have been key characteristics affecting the quality of noodle products (Lee et al., 2002 ). While some other factors, such as the nutritional value and glycaemic impact of noodle, are becoming important for novel noodle products to gain consumer acceptance. Barrier against wider use of wheat bran in noodle products is mainly its negative impact on the gluten development of dough and organoleptic qualities of end-product. Bran may alter the microstructure of noodle through interference with dough development and will result in the discontinuity within the gluten matrix, leading to compromised cooking and textural performance (Bruinsma et al., 1978 ; Sharma et al., 2017 ). According to Ritika et al. ( 2016 ), presence of ingredients other than wheat flour could cause discontinuity in the gluten network. Gluten is responsible for the firmness of noodle, and inadequate gluten development may lead to the faster moisture penetration and hence less optimum cooking time of noodles. Additionally, the bran portion may be highly coloured and contain stringent, intensely flavoured compounds, resulting in compromised sensory qualities. Therefore, low levels of bran fortification from 2 to 10% was usually recommended for noodle products by previous studies (Chen et al., 2011 ; Zhao et al., 2008 ). Several approaches have been proposed to improve the quality of bran-fortified noodles, including wheat selection, ingredients addition and bran particle size control (Niu & Hou, 2019 ). The particle size of wheat bran may influence its water binding capacity, water holding capacity, and solubility, which are important properties determining the technological applicability and physical function of bran (Santala et al., 2012 ). According to Steglich et al. ( 2015 ), mean particle size reduction of bran from 440 to 370, 160, and 90 μ m counteracted the destructive effects of bran on the sensory properties of pasta. Another study conducted by Liu et al. ( 2016 ) also has shown that reducing the median particle sizes of bran from 175 mm to 130 mm significantly improved the textural quality of tortilla made from reconstituted whole wheat flour. Other studies found that the negative influence of bran on bread and steamed bread was enhanced when bran particle size was reduced (Noort et al., 2010 ; Xu et al., 2018 ). Research is still ongoing to manipulate the size of bran for desired end-product quality. Due to the soft structure and relatively low density of wheat bran, reduction of the bran size below 40 μ m is often considered difficult using conventional milling. Novel size reduction strategies including microfluidization and jet milling have been studied by several researchers (Mert et al., 2014 ; Protonotariou et al., 2015 ). Superfine grinding is an emerging technology that produces fine powder on a micro-scale (Huang et al., 2017 ). However, limited<|im_end|> <|im_start|>assistant NUS food scientists have demonstrated that finely ground wheat bran can be added to Asian wheat noodles by up to 20% without compromising organoleptic acceptance. This can be an effective approach to promote higher dietary fiber intake. Wheat bran is widely used in the food industry to produce fiber-rich food products with enhanced health benefits. The bran which is the hard outer layer of the wheat kernel is an excellent source of fiber and is rich in various nutrients. However, it is typically removed during processing as its presence in food products makes them less refined in texture and its taste may not appeal to most consumers. A research team led by Prof Zhou Weibiao from the Department of Food Science and Technology, National University of Singapore studied the effect of bran size reduction on the microstructure and performance of bran-enriched dried white noodle (see Figures). The researchers used superfine grinding to produce wheat bran powder at the micro-scale level and used them in making white noodle products. The results show that superfine grinding does not necessarily improve all aspects of noodle processing and cooking, but promote an overall improvement in the sensory quality of bran-enriched noodle. They also found through sensory evaluation that it is possible to produce bran-enriched noodle with relatively high bran levels (up to 20%) that are still deemed acceptable by consumers. Figure 2: Photo showing the colour the starting raw ingredients and resultant noodle samples. The colour of the noodles is an important quality trait because of the visual impact at the point of sale. Legend: RWF = refined wheat flour, CB = coarse bran, SBA = superfine bran A, SBB = superfine bran B (grounded to a finer size compared to SBA). Credit: Food and Bioprocess Technology Superfine grinding is a relatively new food processing technology. There is limited research on the food quality and consumer sensory acceptance of superfine ground wheat bran and its end products. This study assessed the quality of bran-enriched noodles using both analytical instruments and human subjects. The wheat bran was ground into three categories of different granular sizes: coarse bran (diameter ~330.7 μm), superfine bran A (diameter ~50.7 μm) and super fine bran B (diameter ~27.9 μm). These were then added to refined wheat flour in varying quantities (from 10% to 30%) to make the noodles. With more wheat bran added, the dried white noodle quality deteriorated in all aspects. When the amount of bran added reached 30%, the noodles presented a highly obstructed or disrupted microstructure. Their appearance and taste were also least favored by the consumers. Superfine grinding acted as an effective approach to alleviate the negative effect of wheat bran on noodle, particularly for various sensory attributes. Jin Xiaoxuan, a Ph.D. student on the team said, "The study results contribute to a better understanding of the applicability of superfine grinding in improving the functionality of wheat bran, and will guide future development of bran-enriched products to stimulate consumer's dietary fiber intake." Sensory attributes of cooked dried white noodles (DWN) fortified with (a) 10%, (b) 20%, and (c) 30% of wheat brans. All samples were graded on a scale of 1 to 9 against the control (DWN without addition of wheat brans) which is given a score of 5. Higher score means stronger intensity of the attribute/better than control, sample size is 44). Legend: CB, coarse bran; SBA, superfine bran A; SBB, superfine bran B (grounded to a finer size compared to SBA). Credit: Food and Bioprocess Technology Prof Zhou said, "While the consensus among the scientific community is that dietary fiber intake needs to be significantly boosted to combat a variety of chronic diseases in modern society, the perceived health benefits are insufficient for consumers to sacrifice their taste for "healthier" alternatives. Innovative food technologies are needed to make healthier food tasty and for tasty foods to become healthier. Deeper understanding on how healthier foods function when they go through the digestive system is fundamental in achieving this goal." Moving on, the research team plans to focus on the effect of wheat bran fortification on the oral processing and glycaemic index (GI) of noodles using both in vitro and in vivo approaches. <|im_end|>

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21091, 430, 61802, 5015, 34153, 53358, 649, 387, 3779, 311, 14875, 34153, 61260, 555, 709, 311, 220, 508, 4, 2085, 76100, 2942, 1286, 27330, 26586, 13, 1115, 649, 387, 459, 7524, 5603, 311, 12192, 5190, 34625, 24722, 23730, 13, 56738, 53358, 374, 13882, 1511, 304, 279, 3691, 5064, 311, 8356, 24722, 41947, 3691, 3956, 449, 24872, 2890, 7720, 13, 578, 53358, 902, 374, 279, 2653, 16335, 6324, 315, 279, 34153, 10206, 374, 459, 9250, 2592, 315, 24722, 323, 374, 9257, 304, 5370, 37493, 13, 4452, 11, 433, 374, 11383, 7108, 2391, 8863, 439, 1202, 9546, 304, 3691, 3956, 3727, 1124, 2753, 38291, 304, 10651, 323, 1202, 12945, 1253, 539, 14638, 311, 1455, 13723, 13, 362, 3495, 2128, 6197, 555, 8626, 67927, 1226, 581, 23332, 505, 279, 6011, 315, 12369, 10170, 323, 12053, 11, 5165, 3907, 315, 21181, 20041, 279, 2515, 315, 53358, 1404, 14278, 389, 279, 8162, 7993, 323, 5178, 315, 53358, 21430, 14172, 291, 32720, 4251, 46895, 273, 320, 4151, 69356, 570, 578, 12074, 1511, 43117, 483, 17282, 311, 8356, 34153, 53358, 17138, 520, 279, 8162, 13230, 2237, 323, 1511, 1124, 304, 3339, 4251, 46895, 273, 3956, 13, 578, 3135, 1501, 430, 43117, 483, 17282, 1587, 539, 14647, 7417, 682, 13878, 315, 46895, 273, 8863, 323, 17677, 11, 719, 12192, 459, 8244, 16048, 304, 279, 49069, 4367, 315, 53358, 21430, 14172, 291, 46895, 273, 13, 2435, 1101, 1766, 1555, 49069, 16865, 430, 433, 374, 3284, 311, 8356, 53358, 21430, 14172, 291, 46895, 273, 449, 12309, 1579, 53358, 5990, 320, 455, 311, 220, 508, 11587, 430, 527, 2103, 25660, 22281, 555, 13723, 13, 19575, 220, 17, 25, 11064, 9204, 279, 12745, 279, 6041, 7257, 14293, 323, 84913, 46895, 273, 10688, 13, 578, 12745, 315, 279, 61260, 374, 459, 3062, 4367, 18027, 1606, 315, 279, 9302, 5536, 520, 279, 1486, 315, 6412, 13, 28033, 25, 432, 33231, 284, 38291, 34153, 20415, 11, 22024, 284, 50347, 53358, 11, 328, 7209, 284, 43117, 483, 53358, 362, 11, 328, 10306, 284, 43117, 483, 53358, 426, 320, 1993, 291, 311, 264, 73886, 1404, 7863, 311, 328, 7209, 570, 16666, 25, 12369, 323, 12371, 454, 41948, 12053, 7445, 63157, 17282, 374, 264, 12309, 502, 3691, 8863, 5557, 13, 2684, 374, 7347, 3495, 389, 279, 3691, 4367, 323, 11761, 49069, 26586, 315, 43117, 483, 5015, 34153, 53358, 323, 1202, 842, 3956, 13, 1115, 4007, 32448, 279, 4367, 315, 53358, 21430, 14172, 291, 61260, 1701, 2225, 44064, 24198, 323, 3823, 15223, 13, 578, 34153, 53358, 574, 5015, 1139, 2380, 11306, 315, 2204, 16109, 1299, 12562, 25, 50347, 53358, 320, 67, 37144, 4056, 10568, 13, 22, 33983, 76, 705, 43117, 483, 53358, 362, 320, 67, 37144, 4056, 1135, 13, 22, 33983, 76, 8, 323, 2307, 7060, 53358, 426, 320, 67, 37144, 4056, 1544, 13, 24, 33983, 76, 570, 4314, 1051, 1243, 3779, 311, 38291, 34153, 20415, 304, 29865, 33776, 320, 1527, 220, 605, 4, 311, 220, 966, 11587, 311, 1304, 279, 61260, 13, 3161, 810, 34153, 53358, 3779, 11, 279, 32720, 4251, 46895, 273, 4367, 39436, 660, 304, 682, 13878, 13, 3277, 279, 3392, 315, 53358, 3779, 8813, 220, 966, 13689, 279, 61260, 10666, 264, 7701, 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5573, 3445, 16643, 21261, 315, 279, 7180, 3554, 22120, 1109, 2585, 11, 6205, 1404, 374, 220, 2096, 570, 28033, 25, 22024, 11, 50347, 53358, 26, 328, 7209, 11, 43117, 483, 53358, 362, 26, 328, 10306, 11, 43117, 483, 53358, 426, 320, 1993, 291, 311, 264, 73886, 1404, 7863, 311, 328, 7209, 570, 16666, 25, 12369, 323, 12371, 454, 41948, 12053, 8626, 67927, 1071, 11, 330, 8142, 279, 24811, 4315, 279, 12624, 4029, 374, 430, 34625, 24722, 23730, 3966, 311, 387, 12207, 65208, 311, 12896, 264, 8205, 315, 21249, 19338, 304, 6617, 8396, 11, 279, 26617, 2890, 7720, 527, 39413, 369, 13723, 311, 28235, 872, 12945, 369, 330, 12393, 1291, 1, 27548, 13, 98669, 3691, 14645, 527, 4460, 311, 1304, 39345, 3691, 39953, 323, 369, 39953, 15657, 311, 3719, 39345, 13, 1611, 10653, 8830, 389, 1268, 39345, 15657, 734, 994, 814, 733, 1555, 279, 60071, 1887, 374, 16188, 304, 32145, 420, 5915, 1210, 38727, 389, 11, 279, 3495, 2128, 6787, 311, 5357, 389, 279, 2515, 315, 34153, 53358, 12108, 2461, 389, 279, 21308, 8863, 323, 37807, 936, 8274, 1963, 320, 29134, 8, 315, 61260, 1701, 2225, 304, 55004, 323, 304, 41294, 20414, 13, 220, 128257, 198 ]

2,284

[ { "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 Formate can be envisioned at the core of a carbon-neutral bioeconomy, where it is produced from CO 2 by (electro-)chemical means and converted into value-added products by enzymatic cascades or engineered microbes. A key step in expanding synthetic formate assimilation is its thermodynamically challenging reduction to formaldehyde. Here, we develop a two-enzyme route in which formate is activated to formyl phosphate and subsequently reduced to formaldehyde. Exploiting the promiscuity of acetate kinase and N- acetyl-γ-glutamyl phosphate reductase, we demonstrate this phosphate (P i )-based route in vitro and in vivo. We further engineer a formyl phosphate reductase variant with improved formyl phosphate conversion in vivo by suppressing cross-talk with native metabolism and interface the P i route with a recently developed formaldehyde assimilation pathway to enable C2 compound formation from formate as the sole carbon source in Escherichia coli . The P i route therefore offers a potent tool in expanding the landscape of synthetic formate assimilation. Introduction One of the major steps towards establishing a carbon-neutral (or carbon-positive) bio-economy is the valorization of carbon dioxide as a feedstock. While a variety of synthetic CO 2 -fixing cycles and microorganisms have been described recently 1 , 2 , 3 , the direct use of CO 2 in biotechnology still poses several challenges and limitations. An alternative is the chemical conversion of CO 2 into soluble one-carbon (C1) compounds that can be further converted by biological platform organisms. One of the most promising C1-molecules in such chemo-bio hybrid approaches is formate. Formate can be produced electrochemically or by catalytic hydrogenation 4 , 5 , 6 , is fully miscible with water, non - flammable and of little toxicity to the human worker 7 . To develop a formate-based bioeconomy, recent efforts have focused on converting common platform organisms, such as Escherichia coli into synthetic formatotrophs that accept formate as both carbon and energy source 8 , 9 . Formatotrophy naturally relies on the activation of formate to the tetrahydrofolate (T 4 F) cofactor and subsequent reduction to methylene-T 4 F (T 4 F cascade, Fig. 1 ). Methylene-T 4 F can be channeled into central metabolism directly via the serine cycle 10 or the reductive glycine pathway 11 . Alternatively, methylene-T 4 F can spontaneously hydrolyze, releasing formaldehyde, which can enter central carbon metabolism through the ribulose monophosphate pathway (RuMP) 12 , xylulose monophosphate pathway 13 , homoserine cycle 14 , or formolase pathways 15 , 16 , 17 , 18 , 19 , although the spontaneous hydrolysis rate is too slow to fully sustain growth. An alternative to growth-coupled metabolic integration are orthogonal systems for value-added product generation, such as the FORCE pathway 20 . Fig. 1: Design and analysis of different pathways for the reduction of formate to formaldehyde. a Reactions schemes for the different formate reduction routes discussed in this study. The enzymes for each respective route are provided using the following color-coding: T 4 F route (purple), CoA route (light blue), Pi route (dark blue). PTA, which can be used to toggle between CoA and Pi routes, is shown in gray. * indicates (plausible) new-to-nature reactions. ACS acetyl-CoA synthetase, ACR acyl-CoA reductase, PTA phosphate acetyl transferase, ACK acetate kinase, FPR formyl phosphate reductase, FTL formate tetrahydrofolate ligase, MTC methylene tetrahydrofolate cyclohydrolase, MTD methylene tetrahydrofolate dehydrogenase, T 4 F tetrahydrofolate, spon. spontaneous hydrolysis. b MDF calculations for the three routes with either NADPH (solid line) or NADH (dashed line) as reduction equivalent. Energy profiles of individual reactions are given in Supplementary Table 1 . c FBA calculations for the production of 12 relevant metabolic precursors as well as biomass via the three routes and the RuMP pathway in E. coli . g6p glucose 6-phosphate, f6p fructose 6-phosphate, e4p erythrose 4-phosphate, r5p ribose 5-phosphate, g3p glyceraldehyde 3-phosphate, 3pg glycerate 3-phosphate, pep phosphoenolpyruvate, pyr pyruvate, accoa: acetyl-CoA, akg 2-ketoglutarate, succoa: succinyl-CoA, oaa oxaloacetate. Source data are provided as a Source Data file. Full size image To overcome the limitations of the natural methylene-T 4 F route, different synthetic pathways have been proposed and/or developed. One example is the activation of formate to formyl-CoA, followed by the reduction to formaldehyde through the promiscuous activities of acetyl-CoA synthetase (ACS) and acyl-CoA reductase (ACR) 15 , 19 , 21 , 22 . Compared to the natural T 4 F cascade, no spontaneous hydrolysis is required and one less enzyme is needed. However, the CoA-based cascade requires hydrolysis of one additional phosphoanhydride bond for activation (ATP → AMP + PP i , Fig. 1a ). While the CoA-based route has been demonstrated in a proof-of-principle, residual activities of the synthetase with acetate and ACR with the native CoA metabolite pool (e.g., acetyl-CoA) currently limit the application of the CoA-based route in vivo 19 . Another way to activate carboxylic groups prior to reduction is through phosphorylation. Recently, a three-enzyme route was proposed, in which formate is first activated to formyl phosphate (using acetate kinase, ACK), transferred to CoA via phosphate and further reduced by acyl-CoA reductase 20 , 23 , 24 . However, this route still relies on an acyl-CoA reductase and thus faces the same interference with the acetyl-CoA pool. To circumvent this challenge, the direct reduction of formyl phosphate would be a highly attractive alternative. Here, we seek to establish the direct reduction of formyl phosphate into formaldehyde through developing a new-to-nature enzyme, formyl phosphate reductase (FPR). We identify promiscuous FPR activity in four enzyme families and present one homolog of N- acetyl-γ-glutamyl phosphate (NAGP) reductase from Denitrovibrio acetiphilus (DaArgC) that produces relevant levels of formaldehyde. Using a semi-rational enzyme engineering approach, we create a triple substitution variant of the enzyme (DaArgC3) that shows a complete loss of the native enzyme activity (i.e., NAGP reduction), a 300-fold shift in specificity towards formyl phosphate, and a decreased side reactivity with acetyl phosphate. Combining DaArgC3 with ACK allows us to establish a route to formaldehyde that is completely based on phosphate (P i ). This P i -based route outcompetes synthetic CoA-based routes", "role": "user" }, { "content": "New synthetic metabolic pathways for fixation of carbon dioxide could not only help to reduce the carbon dioxide content of the atmosphere, but also replace conventional chemical manufacturing processes for pharmaceuticals and active ingredients with carbon-neutral, biological processes. A new study published in Nature Communications demonstrates a process that can turn carbon dioxide into a valuable material for the biochemical industry via formic acid. In view of rising greenhouse gas emissions, carbon capture, the sequestration of carbon dioxide from large emission sources, is an urgent issue. In nature, carbon dioxide assimilation has been taking place for millions of years, but its capacity is far from sufficient to compensate man-made emissions. Researchers led by Tobias Erb at the Max Planck Institute for Terrestrial Microbiology are using nature's toolbox to develop new ways of carbon dioxide fixation. They have now succeeded in developing an artificial metabolic pathway that produces the highly reactive formaldehyde from formic acid, a possible intermediate product of artificial photosynthesis. Formaldehyde could be fed directly into several metabolic pathways to form other valuable substances without any toxic effects. As in the natural process, two primary components are required: Energy and carbon. The former can be provided not only by direct sunlight but also by electricity—for example from solar modules. Formic acid is a C1 building block Within the added-value chain, the carbon source is variable. carbon dioxide is not the only option here, all monocarbons (C1 building blocks) come into question: carbon monoxide, formic acid, formaldehyde, methanol and methane. However, almost all of these substances are highly toxic—either to living organisms (carbon monoxide, formaldehyde, methanol) or to the planet (methane as a greenhouse gas). Only formic acid, when neutralized to its base formate, is tolerated by many microorganisms in high concentrations. \"Formic acid is a very promising carbon source,\" says Maren Nattermann, first author of the study. \"But converting it to formaldehyde in the test tube is quite energy-intensive.\" This is because the salt of formic acid, formate, cannot be converted easily into formaldehyde. \"There's a serious chemical barrier between the two molecules that we have to bridge with biochemical energy—ATP—before we can perform the actual reaction.\" The researcher's goal was to find a more economical way. After all, the less energy it takes to feed carbon into metabolism, the more energy remains to drive growth or production. But such a path does not exist in nature. \"It takes some creativity to discover so-called promiscuous enzymes with multiple functions,\" says Tobias Erb. \"However, the discovery of candidate enzymes is only the beginning. We're talking about reactions that you can count along with since they're so slow—in some cases, less than one reaction per second per enzyme. Natural reactions can happen a thousand times faster.\" This is where synthetic biochemistry comes in, says Maren Nattermann. \"If you know an enzyme's structure and mechanism, you know where to intervene. Here, we benefit significantly from the preliminary work of our colleagues in basic research.\" High-throughput technology speeds up enzyme optimization The optimization of the enzymes included several approaches: building blocks were specifically exchanged, and random mutations were generated and selected for capability. \"Formate and formaldehyde are both wonderfully suited because they penetrate cell walls. We can put formate into the culture medium of cells that produce our enzymes, and after a few hours convert the formaldehyde produced into a non-toxic yellow dye,\" explains Maren Nattermann. The result would not have been possible in such a short time without the use of high-throughput methods. To achieve this, the researchers cooperated with their industrial partner Festo, based in Esslingen, Germany. \"After about 4,000 variants, we achieved a fourfold improvement in production,\" says Maren Nattermann. \"We have thus created the basis for the model mikrobe Escherichia coli, the microbial workhorse of biotechnology, to grow on formic acid. For now, however, our cells can only produce formaldehyde, not convert it further.\" With collaboration partner Sebastian Wenk at the Max Planck Institute of Molecular Plant Physiology, the researchers are currently developing a strain that can take up the intermediates and introduce them into the central metabolism. In parallel, the team is conducting research with a working group at the Max Planck Institute for Chemical Energy Conversion headed by Walter Leitner on the electrochemical conversion of carbon dioxide to formic acid. The long-term goal is an \"all-in-one platform\"—from carbon dioxide via an electrobiochemical process to products like insulin or biodiesel. ", "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 Formate can be envisioned at the core of a carbon-neutral bioeconomy, where it is produced from CO 2 by (electro-)chemical means and converted into value-added products by enzymatic cascades or engineered microbes. A key step in expanding synthetic formate assimilation is its thermodynamically challenging reduction to formaldehyde. Here, we develop a two-enzyme route in which formate is activated to formyl phosphate and subsequently reduced to formaldehyde. Exploiting the promiscuity of acetate kinase and N- acetyl-γ-glutamyl phosphate reductase, we demonstrate this phosphate (P i )-based route in vitro and in vivo. We further engineer a formyl phosphate reductase variant with improved formyl phosphate conversion in vivo by suppressing cross-talk with native metabolism and interface the P i route with a recently developed formaldehyde assimilation pathway to enable C2 compound formation from formate as the sole carbon source in Escherichia coli . The P i route therefore offers a potent tool in expanding the landscape of synthetic formate assimilation. Introduction One of the major steps towards establishing a carbon-neutral (or carbon-positive) bio-economy is the valorization of carbon dioxide as a feedstock. While a variety of synthetic CO 2 -fixing cycles and microorganisms have been described recently 1 , 2 , 3 , the direct use of CO 2 in biotechnology still poses several challenges and limitations. An alternative is the chemical conversion of CO 2 into soluble one-carbon (C1) compounds that can be further converted by biological platform organisms. One of the most promising C1-molecules in such chemo-bio hybrid approaches is formate. Formate can be produced electrochemically or by catalytic hydrogenation 4 , 5 , 6 , is fully miscible with water, non - flammable and of little toxicity to the human worker 7 . To develop a formate-based bioeconomy, recent efforts have focused on converting common platform organisms, such as Escherichia coli into synthetic formatotrophs that accept formate as both carbon and energy source 8 , 9 . Formatotrophy naturally relies on the activation of formate to the tetrahydrofolate (T 4 F) cofactor and subsequent reduction to methylene-T 4 F (T 4 F cascade, Fig. 1 ). Methylene-T 4 F can be channeled into central metabolism directly via the serine cycle 10 or the reductive glycine pathway 11 . Alternatively, methylene-T 4 F can spontaneously hydrolyze, releasing formaldehyde, which can enter central carbon metabolism through the ribulose monophosphate pathway (RuMP) 12 , xylulose monophosphate pathway 13 , homoserine cycle 14 , or formolase pathways 15 , 16 , 17 , 18 , 19 , although the spontaneous hydrolysis rate is too slow to fully sustain growth. An alternative to growth-coupled metabolic integration are orthogonal systems for value-added product generation, such as the FORCE pathway 20 . Fig. 1: Design and analysis of different pathways for the reduction of formate to formaldehyde. a Reactions schemes for the different formate reduction routes discussed in this study. The enzymes for each respective route are provided using the following color-coding: T 4 F route (purple), CoA route (light blue), Pi route (dark blue). PTA, which can be used to toggle between CoA and Pi routes, is shown in gray. * indicates (plausible) new-to-nature reactions. ACS acetyl-CoA synthetase, ACR acyl-CoA reductase, PTA phosphate acetyl transferase, ACK acetate kinase, FPR formyl phosphate reductase, FTL formate tetrahydrofolate ligase, MTC methylene tetrahydrofolate cyclohydrolase, MTD methylene tetrahydrofolate dehydrogenase, T 4 F tetrahydrofolate, spon. spontaneous hydrolysis. b MDF calculations for the three routes with either NADPH (solid line) or NADH (dashed line) as reduction equivalent. Energy profiles of individual reactions are given in Supplementary Table 1 . c FBA calculations for the production of 12 relevant metabolic precursors as well as biomass via the three routes and the RuMP pathway in E. coli . g6p glucose 6-phosphate, f6p fructose 6-phosphate, e4p erythrose 4-phosphate, r5p ribose 5-phosphate, g3p glyceraldehyde 3-phosphate, 3pg glycerate 3-phosphate, pep phosphoenolpyruvate, pyr pyruvate, accoa: acetyl-CoA, akg 2-ketoglutarate, succoa: succinyl-CoA, oaa oxaloacetate. Source data are provided as a Source Data file. Full size image To overcome the limitations of the natural methylene-T 4 F route, different synthetic pathways have been proposed and/or developed. One example is the activation of formate to formyl-CoA, followed by the reduction to formaldehyde through the promiscuous activities of acetyl-CoA synthetase (ACS) and acyl-CoA reductase (ACR) 15 , 19 , 21 , 22 . Compared to the natural T 4 F cascade, no spontaneous hydrolysis is required and one less enzyme is needed. However, the CoA-based cascade requires hydrolysis of one additional phosphoanhydride bond for activation (ATP → AMP + PP i , Fig. 1a ). While the CoA-based route has been demonstrated in a proof-of-principle, residual activities of the synthetase with acetate and ACR with the native CoA metabolite pool (e.g., acetyl-CoA) currently limit the application of the CoA-based route in vivo 19 . Another way to activate carboxylic groups prior to reduction is through phosphorylation. Recently, a three-enzyme route was proposed, in which formate is first activated to formyl phosphate (using acetate kinase, ACK), transferred to CoA via phosphate and further reduced by acyl-CoA reductase 20 , 23 , 24 . However, this route still relies on an acyl-CoA reductase and thus faces the same interference with the acetyl-CoA pool. To circumvent this challenge, the direct reduction of formyl phosphate would be a highly attractive alternative. Here, we seek to establish the direct reduction of formyl phosphate into formaldehyde through developing a new-to-nature enzyme, formyl phosphate reductase (FPR). We identify promiscuous FPR activity in four enzyme families and present one homolog of N- acetyl-γ-glutamyl phosphate (NAGP) reductase from Denitrovibrio acetiphilus (DaArgC) that produces relevant levels of formaldehyde. Using a semi-rational enzyme engineering approach, we create a triple substitution variant of the enzyme (DaArgC3) that shows a complete loss of the native enzyme activity (i.e., NAGP reduction), a 300-fold shift in specificity towards formyl phosphate, and a decreased side reactivity with acetyl phosphate. Combining DaArgC3 with ACK allows us to establish a route to formaldehyde that is completely based on phosphate (P i ). This P i -based route outcompetes synthetic CoA-based routes<|im_end|> <|im_start|>assistant New synthetic metabolic pathways for fixation of carbon dioxide could not only help to reduce the carbon dioxide content of the atmosphere, but also replace conventional chemical manufacturing processes for pharmaceuticals and active ingredients with carbon-neutral, biological processes. A new study published in Nature Communications demonstrates a process that can turn carbon dioxide into a valuable material for the biochemical industry via formic acid. In view of rising greenhouse gas emissions, carbon capture, the sequestration of carbon dioxide from large emission sources, is an urgent issue. In nature, carbon dioxide assimilation has been taking place for millions of years, but its capacity is far from sufficient to compensate man-made emissions. Researchers led by Tobias Erb at the Max Planck Institute for Terrestrial Microbiology are using nature's toolbox to develop new ways of carbon dioxide fixation. They have now succeeded in developing an artificial metabolic pathway that produces the highly reactive formaldehyde from formic acid, a possible intermediate product of artificial photosynthesis. Formaldehyde could be fed directly into several metabolic pathways to form other valuable substances without any toxic effects. As in the natural process, two primary components are required: Energy and carbon. The former can be provided not only by direct sunlight but also by electricity—for example from solar modules. Formic acid is a C1 building block Within the added-value chain, the carbon source is variable. carbon dioxide is not the only option here, all monocarbons (C1 building blocks) come into question: carbon monoxide, formic acid, formaldehyde, methanol and methane. However, almost all of these substances are highly toxic—either to living organisms (carbon monoxide, formaldehyde, methanol) or to the planet (methane as a greenhouse gas). Only formic acid, when neutralized to its base formate, is tolerated by many microorganisms in high concentrations. "Formic acid is a very promising carbon source," says Maren Nattermann, first author of the study. "But converting it to formaldehyde in the test tube is quite energy-intensive." This is because the salt of formic acid, formate, cannot be converted easily into formaldehyde. "There's a serious chemical barrier between the two molecules that we have to bridge with biochemical energy—ATP—before we can perform the actual reaction." The researcher's goal was to find a more economical way. After all, the less energy it takes to feed carbon into metabolism, the more energy remains to drive growth or production. But such a path does not exist in nature. "It takes some creativity to discover so-called promiscuous enzymes with multiple functions," says Tobias Erb. "However, the discovery of candidate enzymes is only the beginning. We're talking about reactions that you can count along with since they're so slow—in some cases, less than one reaction per second per enzyme. Natural reactions can happen a thousand times faster." This is where synthetic biochemistry comes in, says Maren Nattermann. "If you know an enzyme's structure and mechanism, you know where to intervene. Here, we benefit significantly from the preliminary work of our colleagues in basic research." High-throughput technology speeds up enzyme optimization The optimization of the enzymes included several approaches: building blocks were specifically exchanged, and random mutations were generated and selected for capability. "Formate and formaldehyde are both wonderfully suited because they penetrate cell walls. We can put formate into the culture medium of cells that produce our enzymes, and after a few hours convert the formaldehyde produced into a non-toxic yellow dye," explains Maren Nattermann. The result would not have been possible in such a short time without the use of high-throughput methods. To achieve this, the researchers cooperated with their industrial partner Festo, based in Esslingen, Germany. "After about 4,000 variants, we achieved a fourfold improvement in production," says Maren Nattermann. "We have thus created the basis for the model mikrobe Escherichia coli, the microbial workhorse of biotechnology, to grow on formic acid. For now, however, our cells can only produce formaldehyde, not convert it further." With collaboration partner Sebastian Wenk at the Max Planck Institute of Molecular Plant Physiology, the researchers are currently developing a strain that can take up the intermediates and introduce them into the central metabolism. In parallel, the team is conducting research with a working group at the Max Planck Institute for Chemical Energy Conversion headed by Walter Leitner on the electrochemical conversion of carbon dioxide to formic acid. The long-term goal is an "all-in-one platform"—from carbon dioxide via an electrobiochemical process to products like insulin or biodiesel. <|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 Tropical cyclones (TCs, also known as hurricanes and typhoons) generally form at low latitudes with access to the warm waters of the tropical oceans, but far enough off the equator to allow planetary rotation to cause aggregating convection to spin up into coherent vortices. Yet, current prognostic frameworks for TC latitudes make contradictory predictions for climate change. Simulations of past warm climates, such as the Eocene and Pliocene, show that TCs can form and intensify at higher latitudes than of those during pre-industrial conditions. Observations and model projections for the twenty-first century indicate that TCs may again migrate poleward in response to anthropogenic greenhouse gas emissions, which poses profound risks to the planet’s most populous regions. Previous studies largely neglected the complex processes that occur at temporal and spatial scales of individual storms as these are poorly resolved in numerical models. Here we review this mesoscale physics in the context of responses to climate warming of the Hadley circulation, jet streams and Intertropical Convergence Zone. We conclude that twenty-first century TCs will most probably occupy a broader range of latitudes than those of the past 3 million years as low-latitude genesis will be supplemented with increasing mid-latitude TC favourability, although precise estimates for future migration remain beyond current methodologies. Main Tropical cyclones (TCs) start as O (10 4 ) km 2 clusters of individual thunderstorms weakly rotating around a common axis. The transition from disaggregated convection into a coherent cyclone can occur over hours, days or weeks, as vorticity increases by two orders of magnitude to produce surface winds of over 15 m s –1 (Extended Fig. 1 ) 1 , 2 . Once formed, TCs generally move westward and poleward before they interact with mid-latitude westerlies and weather systems, and in some cases transition into frontal systems in the extratropics (Fig. 1 ). Locally, the physics of evaporation, friction, convection, entrainment, and radiation determine the vortex lifecycle 3 , 4 . Box 1 summarizes these core elements of TC formation, intensification and propagation—the TC lifecycle. How local physics and equator-to-pole TC distribution relate to one another has been discussed for at least a century 5 and yet fundamental disagreement about how TC latitudes depend on climate persists 6 . In this review, we synthesize recent advances and attempt to connect the heuristic view above with a well-defined physical basis for TC latitudinal distribution. Fig. 1: Tropical cyclogenesis in weather and climate. a , Earth’s atmosphere on 22 July 2017 from NASA EOSDIS 154 . This day exhibits the most simultaneously existing TCs in the satellite record. Tropical Storms Roke (peak intensity 18 m s –1 ), Sonca (18 m s –1 ), Kulap (20 m s –1 ) and Typhoon Noru (49 m s –1 ) are seen in the western subtropical North Pacific. In the eastern North Pacific, Hurricane Fernanda (65 m s –1 ), Tropical Storm Greg (27 m s –1 ), Hurricane Hilary (49 m s –1 ) and Hurricane Irwin (40 m s –1 ) are seen at various development stages. b , Schematic of traditional and baroclinically enabled tropical cyclogenesis embedded into the large-scale flow and atmospheric dynamics (see Extended Data Figs. 1 and 2 for examples). The schematic style of the tropical mean circulation follows that of Bony et al. 155 . Full size image One of the central outcomes of this review is to establish the fundamental roles that convective mesoscale processes play in linking the climatological TC occurrence to large-scale atmospheric dynamics in different climates. This emergent view is novel because the lifecycle evolution of TCs, and its intrinsic mesoscale processes, have historically been overlooked in TC climate studies. Instead, the focus has been on whether or not TCs would emerge from a given climatology of wind, temperature and humidity 7 (see ‘Tropical cyclogenesis as a dynamical process’). This well-established framework is underpinned by empirical ‘genesis potential indices’ (GPIs)—best guesses at the functional forms and coefficients for controls on TC formation that are calibrated against the observed TC distribution. Often GPIs are used in tandem with simple TC models that passively propagate cyclones through environmental winds (Box 1 ) neglecting their two-way interactions with the atmospheric environment (known as ‘statistical downscaling’) 8 . These diagnostic methods are adopted, in part, because climate simulations with general circulation models (GCMs) struggle to resolve realistic TCs 9 . A contrasting approach nests higher-resolution models within lower-resolution ones (known as ‘dynamical downscaling’). Both dynamical and statistical downscaling approaches are used to enumerate how past, present and future climates produce TCs (see ‘Past, present and potential latitudinal migrations’). The problem is that these contrasting approaches yield vastly different interpretations of twenty-first century climate projections 10 , 11 , 12 , 13 , which thus establishes the necessity for a prognostic understanding of the relationship between TCs and climate 6 . In this review, we conclude that a joint consideration of the convective mesoscale processes that occur within TCs and the large-scale dynamics of the atmospheric Hadley circulation, Intertropical Convergence Zone (ITCZ) and tropospheric jet streams enables a new framework to understand the relationship of TCs to climate (see ‘Linking mesoscale physics to large-scale climate dynamics’). As discussed later, these links have implications for reducing uncertainty in the projections of twenty-first century TCs. Box 1 Elemental controls Potential intensity PI theory 175 , the only extant analytical framework for TC’s environmental dependences, states that TC strength is regulated by (1) the rate of oceanic heat extraction (mainly through evaporation), (2) frictional dissipation at the ocean surface and (3) thermodynamic efficiency, also called the Carnot efficiency (the normalized difference between ocean surface and TC outflow temperatures) (Methods). The Carnot efficiency concept from classical thermodynamics is modified in the context of TCs to incorporate additional heating due to frictional energy dissipation. An upper bound on TC wind speeds can be inferred from this framework and computed in various ways from gridded climate data. PI theory predicted three decades ago that anthropogenic warming would increase PI in warmer climates", "role": "user" }, { "content": "A new, Yale-led study suggests the 21st century will see an expansion of hurricanes and typhoons into mid-latitude regions, which includes major cities such as New York, Boston, Beijing, and Tokyo. Writing in the journal Nature Geoscience, the study's authors said tropical cyclones—hurricanes and typhoons—could migrate northward and southward in their respective hemispheres, as the planet warms as a result of anthropogenic greenhouse gas emissions. 2020's subtropical storm Alpha, the first tropical cyclone observed making landfall in Portugal, and this year's Hurricane Henri, which made landfall in Connecticut, may be harbingers of such storms. \"This represents an important, under-estimated risk of climate change,\" said first author Joshua Studholme, a physicist in Yale's Department of Earth and Planetary Sciences in the Faculty of Arts and Sciences, and a contributing author on the United Nations' Intergovernmental Panel on Climate Change sixth assessment report published earlier this year. \"This research predicts that the 21st century's tropical cyclones will likely occur over a wider range of latitudes than has been the case on Earth for the last 3 million years,\" Studholme said. Co-authors of the study are Alexey Fedorov, a professor of oceanic and atmospheric sciences at Yale, Sergey Gulev of the Shirshov Institute of Oceanology, Kerry Emanuel of the Massachusetts Institute of Technology, and Kevin Hodges of the University of Reading. While an increase in tropical cyclones is commonly cited as a harbinger of climate change, much remains unclear about how sensitive they are to the planet's average temperature. In the 1980's, study co-author Emanuel used concepts from classical thermodynamics to predict that global warming would result in more intense storms—a prediction that has been validated in the observational record. Yet other aspects of the relationship between tropical cyclones and climate still lack physically based theory. For example, there is no agreement among scientists about whether the total number of storms will increase or decrease as the climate warms, or why the planet experiences roughly 90 such events each year. \"There are large uncertainties in how tropical cyclones will change in the future,\" said Fedorov. \"However, multiple lines of evidence indicate that we could see more tropical cyclones in mid-latitudes, even if the total frequency of tropical cyclones does not increase, which is still actively debated. Compounded by the expected increase in average tropical cyclone intensity, this finding implies higher risks due to tropical cyclones in Earth's warming climate.\" Typically, tropical cyclones form at low latitudes that have access to warm waters from tropical oceans and away from the shearing impact of the jet streams—the west-to-east bands of wind that circle the planet. Earth's rotation causes clusters of thunderstorms to aggregate and spin up to form the vortices that become tropical cyclones. Other mechanisms of hurricane formation also exist. As the climate warms, temperature differences between the Equator and the poles will decrease, the researchers say. In summer months, this may cause weakening or even a split in the jet stream, opening a window in the mid-latitudes for tropical cyclones to form and intensify. For the study, Studholme, Fedorov, and their colleagues analyzed numerical simulations of warm climates from Earth's distant past, recent satellite observations, and a variety of weather and climate projections, as well as the fundamental physics governing atmospheric convection and planetary-scale winds. For example, they noted that simulations of warmer climates during the Eocene (56 to 34 million years ago) and Pliocene (5.3 to 2.6 million years ago) epochs saw tropical cyclones form and intensify at higher latitudes. \"The core problem when making future hurricane predictions is that models used for climate projections do not have sufficient resolution to simulate realistic tropical cyclones,\" said Studholme, who is a postdoctoral fellow at Yale. \"Instead, several different, indirect approaches are typically used. However, those methods seem to distort the underlying physics of how tropical cyclones form and develop. A number of these methods also provide predictions that contradict each other.\" The new study derives its conclusions by examining connections between hurricane physics on scales too small to be represented in current climate models and the better-simulated dynamics of Earth's jet streams and north-south air circulation, known as the Hadley 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 Tropical cyclones (TCs, also known as hurricanes and typhoons) generally form at low latitudes with access to the warm waters of the tropical oceans, but far enough off the equator to allow planetary rotation to cause aggregating convection to spin up into coherent vortices. Yet, current prognostic frameworks for TC latitudes make contradictory predictions for climate change. Simulations of past warm climates, such as the Eocene and Pliocene, show that TCs can form and intensify at higher latitudes than of those during pre-industrial conditions. Observations and model projections for the twenty-first century indicate that TCs may again migrate poleward in response to anthropogenic greenhouse gas emissions, which poses profound risks to the planet’s most populous regions. Previous studies largely neglected the complex processes that occur at temporal and spatial scales of individual storms as these are poorly resolved in numerical models. Here we review this mesoscale physics in the context of responses to climate warming of the Hadley circulation, jet streams and Intertropical Convergence Zone. We conclude that twenty-first century TCs will most probably occupy a broader range of latitudes than those of the past 3 million years as low-latitude genesis will be supplemented with increasing mid-latitude TC favourability, although precise estimates for future migration remain beyond current methodologies. Main Tropical cyclones (TCs) start as O (10 4 ) km 2 clusters of individual thunderstorms weakly rotating around a common axis. The transition from disaggregated convection into a coherent cyclone can occur over hours, days or weeks, as vorticity increases by two orders of magnitude to produce surface winds of over 15 m s –1 (Extended Fig. 1 ) 1 , 2 . Once formed, TCs generally move westward and poleward before they interact with mid-latitude westerlies and weather systems, and in some cases transition into frontal systems in the extratropics (Fig. 1 ). Locally, the physics of evaporation, friction, convection, entrainment, and radiation determine the vortex lifecycle 3 , 4 . Box 1 summarizes these core elements of TC formation, intensification and propagation—the TC lifecycle. How local physics and equator-to-pole TC distribution relate to one another has been discussed for at least a century 5 and yet fundamental disagreement about how TC latitudes depend on climate persists 6 . In this review, we synthesize recent advances and attempt to connect the heuristic view above with a well-defined physical basis for TC latitudinal distribution. Fig. 1: Tropical cyclogenesis in weather and climate. a , Earth’s atmosphere on 22 July 2017 from NASA EOSDIS 154 . This day exhibits the most simultaneously existing TCs in the satellite record. Tropical Storms Roke (peak intensity 18 m s –1 ), Sonca (18 m s –1 ), Kulap (20 m s –1 ) and Typhoon Noru (49 m s –1 ) are seen in the western subtropical North Pacific. In the eastern North Pacific, Hurricane Fernanda (65 m s –1 ), Tropical Storm Greg (27 m s –1 ), Hurricane Hilary (49 m s –1 ) and Hurricane Irwin (40 m s –1 ) are seen at various development stages. b , Schematic of traditional and baroclinically enabled tropical cyclogenesis embedded into the large-scale flow and atmospheric dynamics (see Extended Data Figs. 1 and 2 for examples). The schematic style of the tropical mean circulation follows that of Bony et al. 155 . Full size image One of the central outcomes of this review is to establish the fundamental roles that convective mesoscale processes play in linking the climatological TC occurrence to large-scale atmospheric dynamics in different climates. This emergent view is novel because the lifecycle evolution of TCs, and its intrinsic mesoscale processes, have historically been overlooked in TC climate studies. Instead, the focus has been on whether or not TCs would emerge from a given climatology of wind, temperature and humidity 7 (see ‘Tropical cyclogenesis as a dynamical process’). This well-established framework is underpinned by empirical ‘genesis potential indices’ (GPIs)—best guesses at the functional forms and coefficients for controls on TC formation that are calibrated against the observed TC distribution. Often GPIs are used in tandem with simple TC models that passively propagate cyclones through environmental winds (Box 1 ) neglecting their two-way interactions with the atmospheric environment (known as ‘statistical downscaling’) 8 . These diagnostic methods are adopted, in part, because climate simulations with general circulation models (GCMs) struggle to resolve realistic TCs 9 . A contrasting approach nests higher-resolution models within lower-resolution ones (known as ‘dynamical downscaling’). Both dynamical and statistical downscaling approaches are used to enumerate how past, present and future climates produce TCs (see ‘Past, present and potential latitudinal migrations’). The problem is that these contrasting approaches yield vastly different interpretations of twenty-first century climate projections 10 , 11 , 12 , 13 , which thus establishes the necessity for a prognostic understanding of the relationship between TCs and climate 6 . In this review, we conclude that a joint consideration of the convective mesoscale processes that occur within TCs and the large-scale dynamics of the atmospheric Hadley circulation, Intertropical Convergence Zone (ITCZ) and tropospheric jet streams enables a new framework to understand the relationship of TCs to climate (see ‘Linking mesoscale physics to large-scale climate dynamics’). As discussed later, these links have implications for reducing uncertainty in the projections of twenty-first century TCs. Box 1 Elemental controls Potential intensity PI theory 175 , the only extant analytical framework for TC’s environmental dependences, states that TC strength is regulated by (1) the rate of oceanic heat extraction (mainly through evaporation), (2) frictional dissipation at the ocean surface and (3) thermodynamic efficiency, also called the Carnot efficiency (the normalized difference between ocean surface and TC outflow temperatures) (Methods). The Carnot efficiency concept from classical thermodynamics is modified in the context of TCs to incorporate additional heating due to frictional energy dissipation. An upper bound on TC wind speeds can be inferred from this framework and computed in various ways from gridded climate data. PI theory predicted three decades ago that anthropogenic warming would increase PI in warmer climates<|im_end|> <|im_start|>assistant A new, Yale-led study suggests the 21st century will see an expansion of hurricanes and typhoons into mid-latitude regions, which includes major cities such as New York, Boston, Beijing, and Tokyo. Writing in the journal Nature Geoscience, the study's authors said tropical cyclones—hurricanes and typhoons—could migrate northward and southward in their respective hemispheres, as the planet warms as a result of anthropogenic greenhouse gas emissions. 2020's subtropical storm Alpha, the first tropical cyclone observed making landfall in Portugal, and this year's Hurricane Henri, which made landfall in Connecticut, may be harbingers of such storms. "This represents an important, under-estimated risk of climate change," said first author Joshua Studholme, a physicist in Yale's Department of Earth and Planetary Sciences in the Faculty of Arts and Sciences, and a contributing author on the United Nations' Intergovernmental Panel on Climate Change sixth assessment report published earlier this year. "This research predicts that the 21st century's tropical cyclones will likely occur over a wider range of latitudes than has been the case on Earth for the last 3 million years," Studholme said. Co-authors of the study are Alexey Fedorov, a professor of oceanic and atmospheric sciences at Yale, Sergey Gulev of the Shirshov Institute of Oceanology, Kerry Emanuel of the Massachusetts Institute of Technology, and Kevin Hodges of the University of Reading. While an increase in tropical cyclones is commonly cited as a harbinger of climate change, much remains unclear about how sensitive they are to the planet's average temperature. In the 1980's, study co-author Emanuel used concepts from classical thermodynamics to predict that global warming would result in more intense storms—a prediction that has been validated in the observational record. Yet other aspects of the relationship between tropical cyclones and climate still lack physically based theory. For example, there is no agreement among scientists about whether the total number of storms will increase or decrease as the climate warms, or why the planet experiences roughly 90 such events each year. "There are large uncertainties in how tropical cyclones will change in the future," said Fedorov. "However, multiple lines of evidence indicate that we could see more tropical cyclones in mid-latitudes, even if the total frequency of tropical cyclones does not increase, which is still actively debated. Compounded by the expected increase in average tropical cyclone intensity, this finding implies higher risks due to tropical cyclones in Earth's warming climate." Typically, tropical cyclones form at low latitudes that have access to warm waters from tropical oceans and away from the shearing impact of the jet streams—the west-to-east bands of wind that circle the planet. Earth's rotation causes clusters of thunderstorms to aggregate and spin up to form the vortices that become tropical cyclones. Other mechanisms of hurricane formation also exist. As the climate warms, temperature differences between the Equator and the poles will decrease, the researchers say. In summer months, this may cause weakening or even a split in the jet stream, opening a window in the mid-latitudes for tropical cyclones to form and intensify. For the study, Studholme, Fedorov, and their colleagues analyzed numerical simulations of warm climates from Earth's distant past, recent satellite observations, and a variety of weather and climate projections, as well as the fundamental physics governing atmospheric convection and planetary-scale winds. For example, they noted that simulations of warmer climates during the Eocene (56 to 34 million years ago) and Pliocene (5.3 to 2.6 million years ago) epochs saw tropical cyclones form and intensify at higher latitudes. "The core problem when making future hurricane predictions is that models used for climate projections do not have sufficient resolution to simulate realistic tropical cyclones," said Studholme, who is a postdoctoral fellow at Yale. "Instead, several different, indirect approaches are typically used. However, those methods seem to distort the underlying physics of how tropical cyclones form and develop. A number of these methods also provide predictions that contradict each other." The new study derives its conclusions by examining connections between hurricane physics on scales too small to be represented in current climate models and the better-simulated dynamics of Earth's jet streams and north-south air circulation, known as the Hadley cells. <|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 Hemispheric asymmetry in hand preference for passive cutaneous perception compared to active haptic perception is not well known. A functional near-infrared spectroscopy was used to evaluate the laterality of cortical facilitation when 31 normal right-handed participants were involved in 205 Hz passive vibrotactile cutaneous stimuli on their index fingers of preferred and less-preferred hand. Passive cutaneous perception resulted that preferred (right) hand stimulation was strongly leftward lateralized, whereas less-preferred (left) hand stimulation was less lateralized. This confirms that other manual haptic exploration studies described a higher hemispheric asymmetry in right-handers. Stronger cortical facilitation was found in the right primary somatosensory cortex (S1) and right somatosensory association area (SA) during left-hand stimulation but not right-hand stimulation. This finding suggests that the asymmetric activation in the S1 and SA for less-preferred (left) hand stimulation might contribute to considerably reinforce sensorimotor network just with passive vibrotactile cutaneous stimulation. Introduction Handedness is typically described as preference or performance for use of a hand 1 , 2 , 3 and it is the most evident behavioral asymmetry observed in humans 2 , 3 . It is estimated that around 90% of the world’s population is right-handed 4 . A comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects observed no difference in bilateral cortical surface area in left-handers compared to right-handers and found no significant evidence for associations of handedness with region-specific bilateral surface areas, or their asymmetries, for regions related to language, hand motor control, or visual processing 5 . Nevertheless, hand motor control is functionally lateralized, that is, the right hand is controlled under left sensorimotor cortex and the left hand is controlled under right sensorimotor cortex. This contralateral hand motor control was found in many studies on motor cortex activation between left- and right-handers for action execution or action imagination 6 , 7 , 8 . The hand motor control of objects involves a perception and motor coupling difficult to dissociate 9 . Manual tactile perception is commonly characterized by cutaneous (passive tactile) perception and haptic (active tactile) perception. These two forms of tactile perception can be distinguished by the fact whether the motor system is involved in the manual exploration of objects. In cutaneous perception, because human skin is stimulated in stationary, only the mechanical deformation of part of the skin is coded by cutaneous mechanoreceptors. In haptic perception, the deformations of the muscles, joints, and tendons by proprioceptive receptors resulting from the exploratory movements are added to cutaneous perception. Most studies of motor cortical facilitation for handedness have focused on the haptic perception. The fMRI studies of motor cortical asymmetry for handedness during finger tapping discovered that the more hemispheric asymmetry observed in right-handers who gained more activation in the right hemisphere than in the left hemisphere during contralateral haptic tasks 10 , 11 . A motor evoked potential (MEP) study of haptic perceptual asymmetry related to handedness revealed that right-handers showed greater hemispheric asymmetry in motor facilitation than left-handers and that haptic-relater enhancement in corticospinal excitability were larger when sensing with the left as compared to the right hand. In contrast, left-handers showed no evidence of clear hemispheric asymmetry in relation to the hand used in the task 12 . These results coincided with other transcranial magnetic stimulation (TMS) studies describing a greater degree of hemispheric asymmetry in right-handers, who are typically more strongly lateralized than left-handers 13 , 14 . Our functional near-infrared spectroscopy (fNIRS) study of cortical activation for hand preference of right-handers when performing a chopstick manipulation supported that preferred hand showed stronger cortically lateralized than less-preferred hand 15 . In contrast, there are few studies on hemispheric asymmetry of cutaneous perception compared to those of haptic perception due to experimental difficulties regarding the quantitative and constant tactile cue display. An fMRI study of passive tactile discrimination for right-handers showed a right lateralized asymmetry but passive tactile nondiscrimination tasks mainly activated the contralateral sensorimotor cortex, regardless of the hand used 16 . An fNIRS study of sensorimotor cortex response for right-handers during manual passive touch of fingers observed that contralateral cortical activation was higher than ipsilateral one for all passive tactile stimuli on right- and left-hand 17 . The results only suggested that passive touch could activate the sensorimotor cortex, but didn’t show the hemispheric asymmetry of cutaneous perception for hand preference. From our pilot study of cortical activation observation during vibrotactile stimulation on finger, less-preferred hand showed broader cortical activation than preferred hand and it suggested that cutaneous tactile stimulation by quantitative tactile display could induce different hemispheric facilitation 18 . In this study, a solenoid resonance actuator and stimulation controller were custom-made in order to provide controllable stimulation with its constant amplitude and accurate timing. However, we needed more subjects and more detail analysis to ensure the hemispheric asymmetry of cutaneous tactile perception. Some electrical median nerve stimulation studies were reported to observe the cortical excitation for tactile perception 17 , 20 , 21 . They found that electrical stimuli to the median nerve at the wrist induced the contralateral sensorimotor cortical activation. On the one hand, optimal electrical median nerve stimulation at wrist activated somatosensory cortical and peripheral response 22 . On the other hand, natural cutaneous tactile stimulation was unlike electrical median nerve stimulation at finger from the viewpoint of whole peripheral part of the sensory afferent pathway 23 . Regardless of this controversial, if we are interested in hemispherical specialization in the cutaneous vibrotactile perception, we must direct ourselves towards the study how to naturally evoke peripheral sensory nerve action potentials mediated by Pacinian channel 24 , 25 . Haptic perception accompanies cutaneous perception, that is, sensory information coded by cutaneous and proprioceptive mechanoreceptors is transmitted to the central nervous system by two separate major ascending pathways. On the aforementioned evidences of the hemispheric asymmetry of right-handers in haptic perception 10 , 11 , 12 , 13 , 14 , 15 and the clue of the hemispheric asymmetry of right-handers in cutaneous perception 18", "role": "user" }, { "content": "Have you ever wondered whether the brains of right-handed people work differently from those of left-handers? Is it possible to distinguish between them by observing their brain activity in response to stimuli or tasks? These are important questions from the perspectives of both basic sciences and application-based fields such as brain-computer interfaces, rehabilitation robotics, and augmented reality. Since the past few years, a team of scientists at Daegu Gyeongbuk Institute of Science and Technology (DGIST), Korea, has been actively conducting fundamental research to answer these questions. Led by Principal Scientist Dr. Jinung An, their initial focus was on finding a method to objectively evaluate haptic devices, which provide tactile feedback simulating textures and surfaces, based on user responses at the brain level. In a previous study, they had found that the brains of right-handers responded differently from those of left-handers when performing complicated manipulation tasks. In short, when a right-hander uses their preferred hand, specific areas within the left-brain hemisphere are activated. In contrast, when they use their left hand, a much larger area spanning both brain hemispheres is used. Surprisingly, this asymmetry was significantly more pronounced in right-handers than in left-handers. In their latest study published in Scientific Reports, Dr. An and his colleagues show that this asymmetry in right-handers was also evident during passive tactile stimulation of the fingers. They used a technique called functional near-infrared spectroscopy to noninvasively monitor changes in the oxygenation of red blood cells in the brain, which reflect its local activation patterns. Excited about the results, Dr. An remarks, \"We present the possibility of distinguishing left-handed and right-handed people using passive touch alone, which reveals functional cortical differences. Our outcomes can be immediately used to quantitatively evaluate hand preference and may also be useful for brain-computer interfaces that connect tactile displays to brain signals in augmented reality.\" These findings are also relevant for developing cognitive enhancement treatments for autism and brain-mimicking artificial intelligence. Additionally, this approach could be a turning point in haptics—the study of sensing through touch. \"Although existing haptic research has mainly focused on the peripheral nervous system, I hope that our study will serve as the starting point for a paradigm shift involving central nervous system-oriented research,\" concludes Dr. An. The outcomes of this study may truly have consequences left and right! ", "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 Hemispheric asymmetry in hand preference for passive cutaneous perception compared to active haptic perception is not well known. A functional near-infrared spectroscopy was used to evaluate the laterality of cortical facilitation when 31 normal right-handed participants were involved in 205 Hz passive vibrotactile cutaneous stimuli on their index fingers of preferred and less-preferred hand. Passive cutaneous perception resulted that preferred (right) hand stimulation was strongly leftward lateralized, whereas less-preferred (left) hand stimulation was less lateralized. This confirms that other manual haptic exploration studies described a higher hemispheric asymmetry in right-handers. Stronger cortical facilitation was found in the right primary somatosensory cortex (S1) and right somatosensory association area (SA) during left-hand stimulation but not right-hand stimulation. This finding suggests that the asymmetric activation in the S1 and SA for less-preferred (left) hand stimulation might contribute to considerably reinforce sensorimotor network just with passive vibrotactile cutaneous stimulation. Introduction Handedness is typically described as preference or performance for use of a hand 1 , 2 , 3 and it is the most evident behavioral asymmetry observed in humans 2 , 3 . It is estimated that around 90% of the world’s population is right-handed 4 . A comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects observed no difference in bilateral cortical surface area in left-handers compared to right-handers and found no significant evidence for associations of handedness with region-specific bilateral surface areas, or their asymmetries, for regions related to language, hand motor control, or visual processing 5 . Nevertheless, hand motor control is functionally lateralized, that is, the right hand is controlled under left sensorimotor cortex and the left hand is controlled under right sensorimotor cortex. This contralateral hand motor control was found in many studies on motor cortex activation between left- and right-handers for action execution or action imagination 6 , 7 , 8 . The hand motor control of objects involves a perception and motor coupling difficult to dissociate 9 . Manual tactile perception is commonly characterized by cutaneous (passive tactile) perception and haptic (active tactile) perception. These two forms of tactile perception can be distinguished by the fact whether the motor system is involved in the manual exploration of objects. In cutaneous perception, because human skin is stimulated in stationary, only the mechanical deformation of part of the skin is coded by cutaneous mechanoreceptors. In haptic perception, the deformations of the muscles, joints, and tendons by proprioceptive receptors resulting from the exploratory movements are added to cutaneous perception. Most studies of motor cortical facilitation for handedness have focused on the haptic perception. The fMRI studies of motor cortical asymmetry for handedness during finger tapping discovered that the more hemispheric asymmetry observed in right-handers who gained more activation in the right hemisphere than in the left hemisphere during contralateral haptic tasks 10 , 11 . A motor evoked potential (MEP) study of haptic perceptual asymmetry related to handedness revealed that right-handers showed greater hemispheric asymmetry in motor facilitation than left-handers and that haptic-relater enhancement in corticospinal excitability were larger when sensing with the left as compared to the right hand. In contrast, left-handers showed no evidence of clear hemispheric asymmetry in relation to the hand used in the task 12 . These results coincided with other transcranial magnetic stimulation (TMS) studies describing a greater degree of hemispheric asymmetry in right-handers, who are typically more strongly lateralized than left-handers 13 , 14 . Our functional near-infrared spectroscopy (fNIRS) study of cortical activation for hand preference of right-handers when performing a chopstick manipulation supported that preferred hand showed stronger cortically lateralized than less-preferred hand 15 . In contrast, there are few studies on hemispheric asymmetry of cutaneous perception compared to those of haptic perception due to experimental difficulties regarding the quantitative and constant tactile cue display. An fMRI study of passive tactile discrimination for right-handers showed a right lateralized asymmetry but passive tactile nondiscrimination tasks mainly activated the contralateral sensorimotor cortex, regardless of the hand used 16 . An fNIRS study of sensorimotor cortex response for right-handers during manual passive touch of fingers observed that contralateral cortical activation was higher than ipsilateral one for all passive tactile stimuli on right- and left-hand 17 . The results only suggested that passive touch could activate the sensorimotor cortex, but didn’t show the hemispheric asymmetry of cutaneous perception for hand preference. From our pilot study of cortical activation observation during vibrotactile stimulation on finger, less-preferred hand showed broader cortical activation than preferred hand and it suggested that cutaneous tactile stimulation by quantitative tactile display could induce different hemispheric facilitation 18 . In this study, a solenoid resonance actuator and stimulation controller were custom-made in order to provide controllable stimulation with its constant amplitude and accurate timing. However, we needed more subjects and more detail analysis to ensure the hemispheric asymmetry of cutaneous tactile perception. Some electrical median nerve stimulation studies were reported to observe the cortical excitation for tactile perception 17 , 20 , 21 . They found that electrical stimuli to the median nerve at the wrist induced the contralateral sensorimotor cortical activation. On the one hand, optimal electrical median nerve stimulation at wrist activated somatosensory cortical and peripheral response 22 . On the other hand, natural cutaneous tactile stimulation was unlike electrical median nerve stimulation at finger from the viewpoint of whole peripheral part of the sensory afferent pathway 23 . Regardless of this controversial, if we are interested in hemispherical specialization in the cutaneous vibrotactile perception, we must direct ourselves towards the study how to naturally evoke peripheral sensory nerve action potentials mediated by Pacinian channel 24 , 25 . Haptic perception accompanies cutaneous perception, that is, sensory information coded by cutaneous and proprioceptive mechanoreceptors is transmitted to the central nervous system by two separate major ascending pathways. On the aforementioned evidences of the hemispheric asymmetry of right-handers in haptic perception 10 , 11 , 12 , 13 , 14 , 15 and the clue of the hemispheric asymmetry of right-handers in cutaneous perception 18<|im_end|> <|im_start|>assistant Have you ever wondered whether the brains of right-handed people work differently from those of left-handers? Is it possible to distinguish between them by observing their brain activity in response to stimuli or tasks? These are important questions from the perspectives of both basic sciences and application-based fields such as brain-computer interfaces, rehabilitation robotics, and augmented reality. Since the past few years, a team of scientists at Daegu Gyeongbuk Institute of Science and Technology (DGIST), Korea, has been actively conducting fundamental research to answer these questions. Led by Principal Scientist Dr. Jinung An, their initial focus was on finding a method to objectively evaluate haptic devices, which provide tactile feedback simulating textures and surfaces, based on user responses at the brain level. In a previous study, they had found that the brains of right-handers responded differently from those of left-handers when performing complicated manipulation tasks. In short, when a right-hander uses their preferred hand, specific areas within the left-brain hemisphere are activated. In contrast, when they use their left hand, a much larger area spanning both brain hemispheres is used. Surprisingly, this asymmetry was significantly more pronounced in right-handers than in left-handers. In their latest study published in Scientific Reports, Dr. An and his colleagues show that this asymmetry in right-handers was also evident during passive tactile stimulation of the fingers. They used a technique called functional near-infrared spectroscopy to noninvasively monitor changes in the oxygenation of red blood cells in the brain, which reflect its local activation patterns. Excited about the results, Dr. An remarks, "We present the possibility of distinguishing left-handed and right-handed people using passive touch alone, which reveals functional cortical differences. Our outcomes can be immediately used to quantitatively evaluate hand preference and may also be useful for brain-computer interfaces that connect tactile displays to brain signals in augmented reality." These findings are also relevant for developing cognitive enhancement treatments for autism and brain-mimicking artificial intelligence. Additionally, this approach could be a turning point in haptics—the study of sensing through touch. "Although existing haptic research has mainly focused on the peripheral nervous system, I hope that our study will serve as the starting point for a paradigm shift involving central nervous system-oriented research," concludes Dr. An. The outcomes of this study may truly have consequences left and right! <|im_end|>

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1,875

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Besides purely academic interest, giant field enhancement within subwavelength particles at light scattering of a plane electromagnetic wave is important for numerous applications ranging from telecommunications to medicine and biology. In this paper, we experimentally demonstrate the enhancement of the intensity of the magnetic field in a high-index dielectric cylinder at the proximity of the dipolar Mie resonances by more than two orders of magnitude for both the TE and TM polarizations of the incident wave. We present a complete theoretical explanation of the effect and show that the phenomenon is very general – it should be observed for any high-index particles. The results explain the huge enhancement of nonlinear effects observed recently in optics, suggesting a new landscape for all-dielectric nonlinear nanoscale photonics. Introduction Scattering of electromagnetic waves by subwavelength particles underpins important multidisciplinary research, whose applications in physics and chemistry vary from understanding the colors of sky to characterizing colloidal solutions 1 . Many of such effects can be described by the exact solutions of the Maxwell equations 2 . Study of the scattering of light by metallic nanoparticles has attracted a lot of attention due to the excitation of resonant plasmonic modes, which provide a powerful tool for the manipulation and control of light at the nanoscale 3 . One of the main concepts underpinning the field of nanophotonics is large enhancement of electromagnetic fields in the so-called hot-spots of these nanoparticles 3 . Such an enhancement is important for many applications ranging from medicine 4 , drug and gene delivery 5 , to high-density data recording and storage 6 . However, plasmonic resonances in metal nanoparticles usually are accompanied by large dissipative losses 7 . Therefore, recently a new direction has emerged focused on all-dielectric nanophotonics that makes possible to manipulate optical resonances of dielectric nanoparticles with high refractive index exciting various Mie-type resonant modes selectively 8 , 9 , 10 , 11 , 12 . Their advantages are attributed to relatively high Q -factors of the excited distinct optical resonances and small mode volumes, providing physical grounds for engineering of new optical functionalities and manufacture of novel metadevices with unique properties 13 . The dielectric particles demonstrate low losses and may exhibit huge concentration of the incident electromagnetic field inside the particles, which has been repeatedly discussed in literature (see, e.g., refs 14 , 15 , 16 , 17 , 18 , 19 ). However, most experiments in this subfield are related to near-field measurements outside the particles — direct detection of the field inside a subwavelength particle is a difficult (but appealing!) experimental problem. In the present paper we report a giant enhancement of electromagnetic field in a dielectric cylinder with high refractive index in the proximity of both magnetic and electric dipolar resonances and explain this effect theoretically. The effect is detected experimentally by direct measurements of the field within the cylinder. We observe that the measured intensity of the magnetic field is more than 300 times larger than that of the incident wave, provided the Mie resonant conditions are satisfied. This effect is generic and should be observed for other orders of the Mie-type resonances and other geometries. Methods Experiment We study the Mie scattering by a dielectric cylinder with a high refractive index \$m\\equiv \\sqrt{\\varepsilon }=n+i\\kappa \$ and low losses ( \$0 < {\\rm{Im}}\\,\\varepsilon \\ll {\\rm{Re}}\\,\\varepsilon \$ ), as shown in Fig. 1 . Here ε stands for the complex permittivity of the cylinder. Similar to the recent experimental studies 20 , 21 , we simulate a nanowire scattering of a monochromatic plane linearly polarized wave with the visible range frequency by the macroscopic size cylinder scattering of microwave radiation. To this end we employ a hollow polystyrene cylinder filled with distilled water, known to be an excellent material with large dielectric constant and relatively low losses 22 , 23 , 24 , 25 . Figure 1 Schematic of the experiment. Linearly polarized plane electromagnetic wave with the circular frequency ω and vector k aligning parallel to the y -axis is scattered by a long hollow polystyrene cylinder, whose axis is parallel to the z -axis. The cylinder is filled with distilled water known to possess a high refractive index at the microwave frequencies. Magnetic field is measured by a probe placed inside the cylinder. The field profile and probe orientation are shown for two independent polarizations of the incident wave: ( a ) TE and ( b ) TM, respectively. The red balloons schematically represent surfaces of a constant value of | H | 2 . See the text for details. Full size image The inner radius of the cylinder is 1.8 cm, the wall thickness is 0.2 cm and the hight is 30 cm. The cylinder is blocked from the bottom side with a polystyrene stopper, whereas from the top side it is open to dip a probe into it. The cylinder is situated into an anechoic chamber. A rectangular horn antenna (TRIM 0.75–18 GHz; DR) connected to the first transmitting port of a vector network analyser (VNA) Agilent E8362C is used to approximate a plane wave excitation. The antenna is placed at the 2 m distance from the cylinder. To measure the field distribution inside the cylinder, the well known, conventional near-filed scanning technique is employed 26 , 27 , 28 . The experimental setup is shown in Supplementary Information. To scan the field inside the cylinder, a coaxial cable with the corresponding probe attached to its end is fixed at the arm of the scanner, being connected to the second port of the VNA. During the experiments the probe is placed in the depth of 3 cm below the water level. The field pattern is studied at the frequency f = ω /2 π of the incident wave equal to 1.28 GHz, or 1.3 GHz for the TE (Transverse Electric — vector E of the incident wave is perpendicular to the axis of the cylinder) polarization and 1.25 GHz for the TM (Transverse Magnetic — vector", "role": "user" }, { "content": "Scientists from the Lomonosov Moscow State University, together with their Russian and foreign colleagues, have achieved the first direct measurements of giant electromagnetic fields emerging in dielectric particles with high refractive index at the scattering of electromagnetic waves. The researchers have presented their project results in Scientific Reports. Miniaturization of basic elements in electronics requires new approaches. It has thus become very important to create intensive electromagnetic fields concentrated in the smallest possible volume. Scientists from the Lomonosov Moscow State University in collaboration with an international team conducted the first direct measurements of a giant resonant field excited inside a subwavelength dielectric particle at the scattering of a plane electromagnetic wave and provided the complete quantitatively theoretical explanation of the observed effect. Physicist Michael Tribelsky, the leading author, says, \"In theory, this effect has been known. In this case, the scattering particle acts as a funnel, gathering incident radiation from a large area and concentrating it in a small volume within the particle. However, there are many difficulties on the way to practical realization. Metallic nanoparticles were the first candidates for such 'field concentrators.' Unfortunately, they have deceived the expectations. The point is that metals have high dissipative losses in the most interesting applications area of visible light frequencies of the incident waves. The dissipation leads to significant energy losses, wasted for fruitless (and often harmful) heating of the nanoparticle, and diminishes the resonant enhancement of the electromagnetic field. In such a case, it would be natural to turn to dielectric particles. Unfortunately, it is not so simple to deal with them.\" If a particle does not have a high refractive index, the resonant effects are weak. Regarding the high-index particles, whose size is smaller than the wavelength of the incident radiation, the common belief was that the electromagnetic field hardly penetrated in such a particle. However, it turns out that at some frequencies of the incident radiation, the case is just the opposite. Namely, the field not only penetrates into the particle, but its high concentration may be observed. In a sense, the effect is analogous to the arc of a swing due to weak but well-timed pushes. \"Our main result is that, to the best of our knowledge, we are the first to achieve the direct experimental evidence of the effect and measure the profiles of the excited fields,\" Michael Tribelsky says. The difficulties of the corresponding measurements at optical frequencies are related to the necessity of measuring fields within a nanoparticle, and the spatial resolution of the measurements must be on the order of nanometers. The researchers modeled the scattering of light by a nanoparticle by means of the identical scattering of radio waves by a centimeter-size particle. To be able to move a probe inside the particle, liquid dielectric (usual distilled water held at a certain fixed temperature) poured into a transparent for the incident radio wave container has been employed. The achievement lies on the very frontier of modern studies on subwavelength optics (namely optics dealing with objects whose scales are smaller than the wavelength of the incident radiation). These phenomena have applications including medicine (diagnosis and treatment of diseases, including cancer; targeted drug delivery and others), biology (various sensors and markers), telecommunications (nanoantennas) and systems for information recording and storage and other spheres. It could also be used for the creation of revolutionary new optical computers in which information is transferred not by electric pulses but by light packages. The scientist says, \"In a broad perspective, our project may initiate the creation of a new landscape for design and fabrication of super-miniature nanodevices and metamaterials—namely materials that are artificially formed and structured in a special way to possess unusual electromagnetic properties.\" ", "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 Besides purely academic interest, giant field enhancement within subwavelength particles at light scattering of a plane electromagnetic wave is important for numerous applications ranging from telecommunications to medicine and biology. In this paper, we experimentally demonstrate the enhancement of the intensity of the magnetic field in a high-index dielectric cylinder at the proximity of the dipolar Mie resonances by more than two orders of magnitude for both the TE and TM polarizations of the incident wave. We present a complete theoretical explanation of the effect and show that the phenomenon is very general – it should be observed for any high-index particles. The results explain the huge enhancement of nonlinear effects observed recently in optics, suggesting a new landscape for all-dielectric nonlinear nanoscale photonics. Introduction Scattering of electromagnetic waves by subwavelength particles underpins important multidisciplinary research, whose applications in physics and chemistry vary from understanding the colors of sky to characterizing colloidal solutions 1 . Many of such effects can be described by the exact solutions of the Maxwell equations 2 . Study of the scattering of light by metallic nanoparticles has attracted a lot of attention due to the excitation of resonant plasmonic modes, which provide a powerful tool for the manipulation and control of light at the nanoscale 3 . One of the main concepts underpinning the field of nanophotonics is large enhancement of electromagnetic fields in the so-called hot-spots of these nanoparticles 3 . Such an enhancement is important for many applications ranging from medicine 4 , drug and gene delivery 5 , to high-density data recording and storage 6 . However, plasmonic resonances in metal nanoparticles usually are accompanied by large dissipative losses 7 . Therefore, recently a new direction has emerged focused on all-dielectric nanophotonics that makes possible to manipulate optical resonances of dielectric nanoparticles with high refractive index exciting various Mie-type resonant modes selectively 8 , 9 , 10 , 11 , 12 . Their advantages are attributed to relatively high Q -factors of the excited distinct optical resonances and small mode volumes, providing physical grounds for engineering of new optical functionalities and manufacture of novel metadevices with unique properties 13 . The dielectric particles demonstrate low losses and may exhibit huge concentration of the incident electromagnetic field inside the particles, which has been repeatedly discussed in literature (see, e.g., refs 14 , 15 , 16 , 17 , 18 , 19 ). However, most experiments in this subfield are related to near-field measurements outside the particles — direct detection of the field inside a subwavelength particle is a difficult (but appealing!) experimental problem. In the present paper we report a giant enhancement of electromagnetic field in a dielectric cylinder with high refractive index in the proximity of both magnetic and electric dipolar resonances and explain this effect theoretically. The effect is detected experimentally by direct measurements of the field within the cylinder. We observe that the measured intensity of the magnetic field is more than 300 times larger than that of the incident wave, provided the Mie resonant conditions are satisfied. This effect is generic and should be observed for other orders of the Mie-type resonances and other geometries. Methods Experiment We study the Mie scattering by a dielectric cylinder with a high refractive index $m\equiv \sqrt{\varepsilon }=n+i\kappa $ and low losses ( $0 < {\rm{Im}}\,\varepsilon \ll {\rm{Re}}\,\varepsilon $ ), as shown in Fig. 1 . Here ε stands for the complex permittivity of the cylinder. Similar to the recent experimental studies 20 , 21 , we simulate a nanowire scattering of a monochromatic plane linearly polarized wave with the visible range frequency by the macroscopic size cylinder scattering of microwave radiation. To this end we employ a hollow polystyrene cylinder filled with distilled water, known to be an excellent material with large dielectric constant and relatively low losses 22 , 23 , 24 , 25 . Figure 1 Schematic of the experiment. Linearly polarized plane electromagnetic wave with the circular frequency ω and vector k aligning parallel to the y -axis is scattered by a long hollow polystyrene cylinder, whose axis is parallel to the z -axis. The cylinder is filled with distilled water known to possess a high refractive index at the microwave frequencies. Magnetic field is measured by a probe placed inside the cylinder. The field profile and probe orientation are shown for two independent polarizations of the incident wave: ( a ) TE and ( b ) TM, respectively. The red balloons schematically represent surfaces of a constant value of | H | 2 . See the text for details. Full size image The inner radius of the cylinder is 1.8 cm, the wall thickness is 0.2 cm and the hight is 30 cm. The cylinder is blocked from the bottom side with a polystyrene stopper, whereas from the top side it is open to dip a probe into it. The cylinder is situated into an anechoic chamber. A rectangular horn antenna (TRIM 0.75–18 GHz; DR) connected to the first transmitting port of a vector network analyser (VNA) Agilent E8362C is used to approximate a plane wave excitation. The antenna is placed at the 2 m distance from the cylinder. To measure the field distribution inside the cylinder, the well known, conventional near-filed scanning technique is employed 26 , 27 , 28 . The experimental setup is shown in Supplementary Information. To scan the field inside the cylinder, a coaxial cable with the corresponding probe attached to its end is fixed at the arm of the scanner, being connected to the second port of the VNA. During the experiments the probe is placed in the depth of 3 cm below the water level. The field pattern is studied at the frequency f = ω /2 π of the incident wave equal to 1.28 GHz, or 1.3 GHz for the TE (Transverse Electric — vector E of the incident wave is perpendicular to the axis of the cylinder) polarization and 1.25 GHz for the TM (Transverse Magnetic — vector<|im_end|> <|im_start|>assistant Scientists from the Lomonosov Moscow State University, together with their Russian and foreign colleagues, have achieved the first direct measurements of giant electromagnetic fields emerging in dielectric particles with high refractive index at the scattering of electromagnetic waves. The researchers have presented their project results in Scientific Reports. Miniaturization of basic elements in electronics requires new approaches. It has thus become very important to create intensive electromagnetic fields concentrated in the smallest possible volume. Scientists from the Lomonosov Moscow State University in collaboration with an international team conducted the first direct measurements of a giant resonant field excited inside a subwavelength dielectric particle at the scattering of a plane electromagnetic wave and provided the complete quantitatively theoretical explanation of the observed effect. Physicist Michael Tribelsky, the leading author, says, "In theory, this effect has been known. In this case, the scattering particle acts as a funnel, gathering incident radiation from a large area and concentrating it in a small volume within the particle. However, there are many difficulties on the way to practical realization. Metallic nanoparticles were the first candidates for such 'field concentrators.' Unfortunately, they have deceived the expectations. The point is that metals have high dissipative losses in the most interesting applications area of visible light frequencies of the incident waves. The dissipation leads to significant energy losses, wasted for fruitless (and often harmful) heating of the nanoparticle, and diminishes the resonant enhancement of the electromagnetic field. In such a case, it would be natural to turn to dielectric particles. Unfortunately, it is not so simple to deal with them." If a particle does not have a high refractive index, the resonant effects are weak. Regarding the high-index particles, whose size is smaller than the wavelength of the incident radiation, the common belief was that the electromagnetic field hardly penetrated in such a particle. However, it turns out that at some frequencies of the incident radiation, the case is just the opposite. Namely, the field not only penetrates into the particle, but its high concentration may be observed. In a sense, the effect is analogous to the arc of a swing due to weak but well-timed pushes. "Our main result is that, to the best of our knowledge, we are the first to achieve the direct experimental evidence of the effect and measure the profiles of the excited fields," Michael Tribelsky says. The difficulties of the corresponding measurements at optical frequencies are related to the necessity of measuring fields within a nanoparticle, and the spatial resolution of the measurements must be on the order of nanometers. The researchers modeled the scattering of light by a nanoparticle by means of the identical scattering of radio waves by a centimeter-size particle. To be able to move a probe inside the particle, liquid dielectric (usual distilled water held at a certain fixed temperature) poured into a transparent for the incident radio wave container has been employed. The achievement lies on the very frontier of modern studies on subwavelength optics (namely optics dealing with objects whose scales are smaller than the wavelength of the incident radiation). These phenomena have applications including medicine (diagnosis and treatment of diseases, including cancer; targeted drug delivery and others), biology (various sensors and markers), telecommunications (nanoantennas) and systems for information recording and storage and other spheres. It could also be used for the creation of revolutionary new optical computers in which information is transferred not by electric pulses but by light packages. The scientist says, "In a broad perspective, our project may initiate the creation of a new landscape for design and fabrication of super-miniature nanodevices and metamaterials—namely materials that are artificially formed and structured in a special way to possess unusual electromagnetic properties." <|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 and why does the widespread use of social media affect happiness? The present study examined whether the three components of subjective well-being—positive affect, negative affect, and life satisfaction—were impacted by use of three of the most popular social network sites in the U.S. (Facebook, Twitter, and Instagram), using the experience sampling method. Over 10 days, greater everyday use of social media resulted in lower subjective well-being—specifically, by increasing negative affective states rather than by decreasing positive states or life satisfaction—a pattern evident across all three social network sites. In evaluating why use of social media adversely impacted subjective well-being, social comparison was a strong predictor. Specifically, the more that participants reported comparing themselves to others while using social media, the less subjective well-being they subsequently experienced. In contrast, traditional, offline social interactions exerted the opposite (beneficial) effect on happiness: increasing positive affect and decreasing negative affect. The present study therefore demonstrates that ordinary, day-to-day use of social network sites adversely impacts subjective well-being over time, and further highlights the advantages of employing independent well-being measures and assessing the use of multiple sites. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction Every day, billions of people worldwide interact with social media. Yet the widespread use of social network sites stands in sharp contrast to a comparatively small body of research on how this use impacts people’s happiness, or subjective well-being . Understanding the effects of social media use on happiness is of great interest as achieving high subjective well-being is a major life goal for a majority of people (Diener 2000 ). Not only is the experience of subjective well-being inherently rewarding, it is also related to numerous positive outcomes—such as workplace success, mental health, prosocial behavior, and physical health and longevity (Diener et al. 2017 ). Thus, it is essential that researchers better understand how the ubiquitous use of social network sites impacts people’s happiness. In the present study, we address this theoretical gap by examining how the construct of subjective well-being, defined by high levels of positive affect, low levels of negative affect, and the presence of life satisfaction (Diener 1984 ) is affected by the use of social media. We explore how the use of multiple, widely-used social network sites (Facebook, Twitter, and Instagram) affect subjective well-being and investigate social comparison as an explanation for these effects. While the subjective well-being literature offers few specific predictions about the effects of social media use on happiness, it is possible to derive insight from research on the beneficial impacts of social relationships. Social network sites have the potential to make it easier for people to stay in touch with friends and family members, to share information and updates with acquaintances, and to facilitate social interactions—all of which, at first glance, might be expected to increase subjective well-being. Indeed, rewarding social relationships are among the most robust predictors of greater happiness (Diener and Seligman 2002 ; Diener et al. 2017 ; Rohrer et al. 2018 ). On the other hand, a different prediction might be derived to the extent that social network sites create a context that is fundamentally distinct from traditional, face-to-face social interaction. While high-quality social relationships provide an enduring boost to subjective well-being, social interactions that occur via social network sites may not, for a variety of reasons, resemble traditional, offline relationships. Social network sites, rather than serving as facilitators of face-to-face contact, tend to promote the asynchronous posting and passive consumption of information about others—an environment that encourages upward social comparison (Lee 2014 ; Wise et al. 2010 ). Online personae are subject to impression management, with users overrepresenting positive life events (Walther 2007 ), and exaggerating how positive these events really are (Wang et al. 2017 ). Indeed, positive expressions, such as joy and pride, tend to be perceived as more appropriate than negative expressions, such as sadness, anger, disappointment, and worry, across multiple different social media platforms, including Facebook, Twitter, and Instagram (Waterloo et al. 2018 ). Viewing images and updates that selectively portray others positively may lead social media users to underestimate how much others actually experience negative emotions (Jordan et al. 2011 ) and lead individuals to conclude that their own life—with its mix of positive and negative feelings—is, by comparison, not as good. Supporting this reasoning, comparing oneself to others on Facebook has been linked to negative feelings (Fox and Moreland 2015 ), rumination (Feinstein et al. 2013 ), lower life satisfaction (Frison and Eggermont 2016b ), greater envy (Verduyn et al. 2015 ), and diminished self-esteem (Wang et al. 2017 ). While these findings focus on Facebook, other social network sites afford the opportunity for upward social comparison; for example, greater use of Instagram has also been associated with comparing oneself to others and to increased depressive symptoms (Nesi and Prinstein 2015 ; Lup et al. 2015 ). Given its divergence from traditional interaction and propensity for upward comparison, we hypothesize that social media use has the potential to adversely impact subjective well-being (Wang et al. 2017 ; Wheeler 1966 ). A number of studies are consistent with the possibility that use of social network sites—rather than being a proxy for traditional, direct social interaction—undermines happiness. Use of social network sites is associated with reduced subjective well-being in cross-sectional studies (Chen et al. 2016 ; Shakya and Christakis 2017 ), though such findings are ambiguous with regard to directionality. Nonetheless, brief longitudinal and experimental studies are consistent with the assertion that use of social network sites leads to lower well-being. For instance, participants assigned to use Facebook in a lab setting reported diminished global affect (Verduyn et al. 2015 ), and asking participants to quit Facebook for one week led to increases in life satisfaction and positive affect, relative to those who continued to use Facebook (Tromholt 2016 ). Thus, a recent review concluded that the evidence for the negative effects of social media use on", "role": "user" }, { "content": "New research from UBC Okanagan indicates what's most important for overall happiness is how a person uses social media. Derrick Wirtz, an associate professor of teaching in psychology at the Irving K. Barber Faculty of Arts and Social Sciences, took a close look at how people use three major social platforms—Facebook, Twitter and Instagram—and how that use can impact a person's overall well-being. \"Social network sites are an integral part of everyday life for many people around the world,\" says Wirtz. \"Every day, billions of people interact with social media. Yet the widespread use of social network sites stands in sharp contrast to a comparatively small body of research on how this use impacts a person's happiness.\" Even before COVID-19 and self-isolation became standard practice, Wirtz says social media has transformed how we interact with others. Face-to-face, in-person contact is now matched or exceeded by online social interactions as the primary way people connect. While most people gain happiness from interacting with others face-to-face, Wirtz notes that some come away from using social media with a feeling of negativity—for a variety of different reasons. One issue is social comparison. Participants in Wirtz's study said the more they compared themselves to others while using social media, the less happy they felt. \"Viewing images and updates that selectively portray others positively may lead social media users to underestimate how much others actually experience negative emotions and lead people to conclude that their own life—with its mix of positive and negative feelings—is, by comparison, not as good,\" he says. Wirtz notes that viewing other people's posts and images while not interacting with them lends itself to comparison without the mood-boosting benefits that ordinarily follow social contact, undermining well-being and reducing self-esteem. \"Passive use, scrolling through others' posts and updates, involves little person-to-person reciprocal interaction while providing ample opportunity for upward comparison.\" As part of his research, study participants were asked about four specific functions of Facebook—checking a news feed, messaging, catching up on world news and posting status or picture updates. The most frequently used function was passively checking one's news feed. Participants primarily used Facebook without directly connecting with other users, and the negative effects on subjective well-being were consistent with this form of use. During COVID-19, Wirtz notes people naturally turn to social media to reduce feelings of social isolation. Yet, his research (conducted before the pandemic) found that although people used social media more when they were lonely, time spent on social media only increased feelings of loneliness for participants in the study. \"Today, the necessity of seeing and hearing friends and family only through social media due to COVID-19 might serve as a reminder of missed opportunities to spend time together.\" The more people used any of these three social media sites, the more negative they reported feeling afterwards. \"The three social network sites examined—Facebook, Twitter and Instagram—yielded remarkably convergent findings,\" he says. \"The more respondents had recently used these sites, either in aggregate or individually, the more negative effect they reported when they responded to our randomly-timed surveys over a 10-day period.\" Wirtz's study also included offline interactions with others, either face-to-face or a phone call. Comparing both offline communication with online, he was able to demonstrate that offline social interaction had precisely the opposite effect of using social media, strongly enhancing emotional well-being. But all is not lost, Wirtz says, as this research also reveals how people can use social media positively, something more important than ever during COVID-19. He suggests people avoid passively scrolling and resist comparing themselves to other social media users. He also says people should use social media sites to enable direct interactions and social connectedness—for example, talking online synchronously or arranging time spent with others in-person, when possible and with proper precautions. \"If we all remember to do that, the negative impact of social media use could be reduced—and social networks sites could even have the potential to improve our well-being and happiness,\" he adds. \"In other words, we need to remember how we use social media has the potential to shape the effects on our day-to-day happiness.\" ", "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 and why does the widespread use of social media affect happiness? The present study examined whether the three components of subjective well-being—positive affect, negative affect, and life satisfaction—were impacted by use of three of the most popular social network sites in the U.S. (Facebook, Twitter, and Instagram), using the experience sampling method. Over 10 days, greater everyday use of social media resulted in lower subjective well-being—specifically, by increasing negative affective states rather than by decreasing positive states or life satisfaction—a pattern evident across all three social network sites. In evaluating why use of social media adversely impacted subjective well-being, social comparison was a strong predictor. Specifically, the more that participants reported comparing themselves to others while using social media, the less subjective well-being they subsequently experienced. In contrast, traditional, offline social interactions exerted the opposite (beneficial) effect on happiness: increasing positive affect and decreasing negative affect. The present study therefore demonstrates that ordinary, day-to-day use of social network sites adversely impacts subjective well-being over time, and further highlights the advantages of employing independent well-being measures and assessing the use of multiple sites. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction Every day, billions of people worldwide interact with social media. Yet the widespread use of social network sites stands in sharp contrast to a comparatively small body of research on how this use impacts people’s happiness, or subjective well-being . Understanding the effects of social media use on happiness is of great interest as achieving high subjective well-being is a major life goal for a majority of people (Diener 2000 ). Not only is the experience of subjective well-being inherently rewarding, it is also related to numerous positive outcomes—such as workplace success, mental health, prosocial behavior, and physical health and longevity (Diener et al. 2017 ). Thus, it is essential that researchers better understand how the ubiquitous use of social network sites impacts people’s happiness. In the present study, we address this theoretical gap by examining how the construct of subjective well-being, defined by high levels of positive affect, low levels of negative affect, and the presence of life satisfaction (Diener 1984 ) is affected by the use of social media. We explore how the use of multiple, widely-used social network sites (Facebook, Twitter, and Instagram) affect subjective well-being and investigate social comparison as an explanation for these effects. While the subjective well-being literature offers few specific predictions about the effects of social media use on happiness, it is possible to derive insight from research on the beneficial impacts of social relationships. Social network sites have the potential to make it easier for people to stay in touch with friends and family members, to share information and updates with acquaintances, and to facilitate social interactions—all of which, at first glance, might be expected to increase subjective well-being. Indeed, rewarding social relationships are among the most robust predictors of greater happiness (Diener and Seligman 2002 ; Diener et al. 2017 ; Rohrer et al. 2018 ). On the other hand, a different prediction might be derived to the extent that social network sites create a context that is fundamentally distinct from traditional, face-to-face social interaction. While high-quality social relationships provide an enduring boost to subjective well-being, social interactions that occur via social network sites may not, for a variety of reasons, resemble traditional, offline relationships. Social network sites, rather than serving as facilitators of face-to-face contact, tend to promote the asynchronous posting and passive consumption of information about others—an environment that encourages upward social comparison (Lee 2014 ; Wise et al. 2010 ). Online personae are subject to impression management, with users overrepresenting positive life events (Walther 2007 ), and exaggerating how positive these events really are (Wang et al. 2017 ). Indeed, positive expressions, such as joy and pride, tend to be perceived as more appropriate than negative expressions, such as sadness, anger, disappointment, and worry, across multiple different social media platforms, including Facebook, Twitter, and Instagram (Waterloo et al. 2018 ). Viewing images and updates that selectively portray others positively may lead social media users to underestimate how much others actually experience negative emotions (Jordan et al. 2011 ) and lead individuals to conclude that their own life—with its mix of positive and negative feelings—is, by comparison, not as good. Supporting this reasoning, comparing oneself to others on Facebook has been linked to negative feelings (Fox and Moreland 2015 ), rumination (Feinstein et al. 2013 ), lower life satisfaction (Frison and Eggermont 2016b ), greater envy (Verduyn et al. 2015 ), and diminished self-esteem (Wang et al. 2017 ). While these findings focus on Facebook, other social network sites afford the opportunity for upward social comparison; for example, greater use of Instagram has also been associated with comparing oneself to others and to increased depressive symptoms (Nesi and Prinstein 2015 ; Lup et al. 2015 ). Given its divergence from traditional interaction and propensity for upward comparison, we hypothesize that social media use has the potential to adversely impact subjective well-being (Wang et al. 2017 ; Wheeler 1966 ). A number of studies are consistent with the possibility that use of social network sites—rather than being a proxy for traditional, direct social interaction—undermines happiness. Use of social network sites is associated with reduced subjective well-being in cross-sectional studies (Chen et al. 2016 ; Shakya and Christakis 2017 ), though such findings are ambiguous with regard to directionality. Nonetheless, brief longitudinal and experimental studies are consistent with the assertion that use of social network sites leads to lower well-being. For instance, participants assigned to use Facebook in a lab setting reported diminished global affect (Verduyn et al. 2015 ), and asking participants to quit Facebook for one week led to increases in life satisfaction and positive affect, relative to those who continued to use Facebook (Tromholt 2016 ). Thus, a recent review concluded that the evidence for the negative effects of social media use on<|im_end|> <|im_start|>assistant New research from UBC Okanagan indicates what's most important for overall happiness is how a person uses social media. Derrick Wirtz, an associate professor of teaching in psychology at the Irving K. Barber Faculty of Arts and Social Sciences, took a close look at how people use three major social platforms—Facebook, Twitter and Instagram—and how that use can impact a person's overall well-being. "Social network sites are an integral part of everyday life for many people around the world," says Wirtz. "Every day, billions of people interact with social media. Yet the widespread use of social network sites stands in sharp contrast to a comparatively small body of research on how this use impacts a person's happiness." Even before COVID-19 and self-isolation became standard practice, Wirtz says social media has transformed how we interact with others. Face-to-face, in-person contact is now matched or exceeded by online social interactions as the primary way people connect. While most people gain happiness from interacting with others face-to-face, Wirtz notes that some come away from using social media with a feeling of negativity—for a variety of different reasons. One issue is social comparison. Participants in Wirtz's study said the more they compared themselves to others while using social media, the less happy they felt. "Viewing images and updates that selectively portray others positively may lead social media users to underestimate how much others actually experience negative emotions and lead people to conclude that their own life—with its mix of positive and negative feelings—is, by comparison, not as good," he says. Wirtz notes that viewing other people's posts and images while not interacting with them lends itself to comparison without the mood-boosting benefits that ordinarily follow social contact, undermining well-being and reducing self-esteem. "Passive use, scrolling through others' posts and updates, involves little person-to-person reciprocal interaction while providing ample opportunity for upward comparison." As part of his research, study participants were asked about four specific functions of Facebook—checking a news feed, messaging, catching up on world news and posting status or picture updates. The most frequently used function was passively checking one's news feed. Participants primarily used Facebook without directly connecting with other users, and the negative effects on subjective well-being were consistent with this form of use. During COVID-19, Wirtz notes people naturally turn to social media to reduce feelings of social isolation. Yet, his research (conducted before the pandemic) found that although people used social media more when they were lonely, time spent on social media only increased feelings of loneliness for participants in the study. "Today, the necessity of seeing and hearing friends and family only through social media due to COVID-19 might serve as a reminder of missed opportunities to spend time together." The more people used any of these three social media sites, the more negative they reported feeling afterwards. "The three social network sites examined—Facebook, Twitter and Instagram—yielded remarkably convergent findings," he says. "The more respondents had recently used these sites, either in aggregate or individually, the more negative effect they reported when they responded to our randomly-timed surveys over a 10-day period." Wirtz's study also included offline interactions with others, either face-to-face or a phone call. Comparing both offline communication with online, he was able to demonstrate that offline social interaction had precisely the opposite effect of using social media, strongly enhancing emotional well-being. But all is not lost, Wirtz says, as this research also reveals how people can use social media positively, something more important than ever during COVID-19. He suggests people avoid passively scrolling and resist comparing themselves to other social media users. He also says people should use social media sites to enable direct interactions and social connectedness—for example, talking online synchronously or arranging time spent with others in-person, when possible and with proper precautions. "If we all remember to do that, the negative impact of social media use could be reduced—and social networks sites could even have the potential to improve our well-being and happiness," he adds. "In other words, we need to remember how we use social media has the potential to shape the effects on our day-to-day happiness." <|im_end|>

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2,171

[ { "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 Adaptive responses to ecological uncertainty may affect the dynamics of interspecific interactions and shape the course of evolution within symbioses. Obligate avian brood parasites provide a particularly tractable system for understanding how uncertainty, driven by environmental variability and symbiont phenology, influences the evolution of species interactions. Here, we use phylogenetically-informed analyses and a comprehensive dataset on the behaviour and geographic distribution of obligate avian brood parasites and their hosts to demonstrate that increasing uncertainty in thermoregulation and parental investment of parasitic young are positively associated with host richness and diversity. Our findings are consistent with the theoretical expectation that ecological risks and environmental unpredictability should favour the evolution of bet-hedging. Additionally, these highly consistent patterns highlight the important role that ecological uncertainty is likely to play in shaping the evolution of specialisation and generalism in complex interspecific relationships. Introduction Species that derive fitness benefits from symbioses often vary in the number of heterospecifics with which they interact 1 , 2 . Although prior comparative analyses and theory suggest that predators and parasites should rely on a greater number of prey or hosts in more variable and unpredictable environments 3 , this relationship has been challenging to detect empirically because the course and pace of co-adaptation 4 are dictated not only by environmental factors, but also by the responses of all of the species involved 5 , 6 . Understanding how ecological uncertainty influences the degree of specialisation in co-evolving systems is especially important in the current context of global change because climatic patterns are becoming increasingly variable and unpredictable 7 , 8 , 9 , 10 and many parasites, predators, and their symbionts already face significant threats of extinction 11 . Obligate avian brood parasites—species that lay their eggs in the nests of other bird species and do not raise their own young—offer a tractable and well-characterised system 12 , 13 , 14 for understanding the role of ecological uncertainty in shaping species interactions. Obligate brood parasites have evolved independently multiple times across the avian phylogeny (Fig. 1 ) 15 and account for roughly 1% of the more than 10,000 extant bird species. These parasites exhibit wide diversity in their degree of host specialisation 16 , 17 and use nearly 17% of all bird species as hosts (See Supplementary Data 1 ). For example, some brood parasites, like the brown-headed cowbird ( Molothrus ater ), are generalists that can parasitise 300 different known host species, whereas others, like the yellow-throated cuckoo ( Chrysococcyx flavigularis ), parasitise only a single one. Brood parasites and their hosts also show considerable diversity in parasitic virulence, degree of co-adaptation (as measured by endogenous traits including egg mimicry), host breeding strategy, and annual reproductive output 18 , 19 , 20 , 21 , 22 . Evolutionarily, more recently diverged brood parasites typically specialise on fewer host species, suggesting that new parasitic lineages arise through specialised interactions with a single or a few hosts 23 , 24 , 25 . Thus, characterising the factors that determine host diversity in brood parasites may not only improve our understanding of resource use and host–parasite coevolution in avian systems, but also, more generally, of the evolution, maintenance, and coexistence of ecological specialisation in symbioses 26 , 27 . Fig. 1: Stochastic character mapping 15 of obligate brood parasitism (red lineages) in birds. Representative clades for each of the six known altricial and one precocial independent evolutionary origins of obligate brood parasitism in birds include a Indicatoridae, b Anatidae (arrow to character mapping), c Cuculinae, d Neomorphinae, and e Phaenicophaeinae, all within Cuculidae, f Viduidae, and g Icteridae. Silhouettes from N.D. Antonson ( a , d ) and phylopic.org with credit to Sharon Wegner-Larsen ( b ), Ferran Sayol ( c ), Lip Kee Yap ( e ), Maija Karala ( f ), and Matt Wilkins ( g ). The CC BY-SA 3.0 license can be found at and the CC BY 3.0 license at . Information on CC0 1.0 (no copyright) can be found at . Full size image Diversification in reproductive behaviours under environmental uncertainty has been shown across a variety of animal taxa, most notably in insects 28 and non-parasitic (i.e., parental) birds 29 . In parental bird species, including several hosts of brood parasites, behavioural bet-hedging has been proposed as a strategy to maximise fitness in highly unpredictable environments 30 . For example, cooperatively breeding superb starlings ( Lamprotornis superbus ) that live in temporally variable savannas use bet-hedging as a strategy to spread reproductive risk over years and within seasons 31 . In brood parasites, reproductive success is dictated by their hosts’ propensity to accept parasitic eggs and by their ability to raise parasitic chicks successfully 12 , 32 . As such, brood parasitism is a risky endeavour, and the degree of parasite specialisation is therefore likely to be determined by factors related to the availability and quality of parenting behaviours of potential hosts 33 . Specifically, host traits such as migratory behaviour, nesting architecture, breeding phenology, chick-provisioning strategies and resilience to environmental challenges, could drive brood parasites’ host choices by dictating the success of their young. In particular, environmental uncertainty experienced through climatic oscillations could favour the spread of a brood parasite’s reproductive effort across hosts with different behavioural profiles because a wider variety of options is likely to minimise variance in parasitic offspring recruitment across years 34 . If long-term success is obtained at the expense of a lower arithmetic mean fitness, then such a brood parasitic strategy may be considered a form of diversified bet-hedging 35 . Based on the above arguments, we predict that (1) increasing unpredictability in climatic fluctuations should lead to increased phylogenetic diversity and/or number of hosts used by brood parasites; (2) that seasonal migration by hosts and shorter breeding seasons should favour generalisation by increasing the potential for missing out on egg laying in some host species’ nests altogether; (3) that greater reliance on uniparental hosts should favour increased host generalisation by increasing uncertainty in the", "role": "user" }, { "content": "Some birds lay their eggs in the nests of other bird species and let the host parents raise their young. A new study finds that in times of environmental flux, these brood parasites \"diversify their portfolios,\" minimizing the risks of their unorthodox lifestyle by increasing the number and variety of hosts they select as adoptive parents. \"We found that, in unstable environments, brood parasites choose to not put all their eggs in one basket,\" said study lead author Nicholas Antonson, a Ph.D. student at the University of Illinois, Urbana Champaign. \"Our results are consistent with the idea that brood parasites diversify their reproductive risk in areas that are ecologically, behaviorally or environmentally unpredictable.\" Antonson led the study with Mark Hauber, a U. of I. professor of evolution, ecology and behavior; Dustin Rubenstein, a professor of environmental biology at Columbia University; and Carlos Botero, a professor of biology at Washington University in St. Louis. They report their findings in the journal Nature Communications. \"This research begins to answer a longstanding question about how species first interact and then coevolve in environments that are also changing,\" Hauber said. \"Theory suggests that in unpredictable environments, predators and parasites should rely on a greater number and variety of prey hosts. But with so many variables in flux, this is a challenging thing to study.\" Brood parasite success depends on the host's acceptance of the outsider's eggs and its ability to raise the young. Some birds learn to recognize that the foreign eggs are different and eject them or build new nests. Others seem not to notice. They incubate, hatch and care for the parasitic offspring as if they were their own. Several other factors could influence how many hosts and which host species a brood parasite targets. The host must be in egg-laying mode when the interloper comes to call. If only one foster parent is involved in taking care of the young, its nest might not succeed as well as one with two parents present. But having two parents around makes it more difficult for parasites to get into the nest to lay their eggs. \"Similarly, if the host returns from a long migratory trip and begins to nest right away, the parasite might have fewer chances to locate its nest for sneaking in the extra egg,\" Hauber said. \"Variability in temperature and precipitation during the breeding season is another potential influence.\" To account for these factors, the researchers aggregated published and publicly available data on 81 of the nearly 100 species of avian brood parasites, including cowbirds, cuckoos, black-headed ducks, indigobirds and honeyguides. They used records from the Field Museum of Natural History in Chicago to determine the number and diversity of hosts each brood parasite used in different contexts. The team also accounted for the relative abundance of published research on different species, \"as a number of brood parasites closer to the equator remain poorly studied,\" Antonson said. They found that in unpredictable environments, brood parasites target more—and more diverse—hosts. The parasites take advantage of as many host species as possible when opportunity allows. The team found a particularly pronounced relationship between temperature variability and bet-hedging. \"In areas where temperatures are stable, brood parasites tend to specialize on fewer and less diverse host species. Those hosts also tend to build more complex and potentially safer nests,\" Antonson said. \"But as the thermal environment becomes more uncertain, the evolutionary pattern that we see is that they spread around the risk of offspring survival by drawing from a larger and more diverse pool of host species.\" The new findings offer insight into the evolution of specialization and generalization, Hauber said. They also suggest that \"ecological risks and environmental unpredictability favor the evolution of bet-hedging.\" ", "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 Adaptive responses to ecological uncertainty may affect the dynamics of interspecific interactions and shape the course of evolution within symbioses. Obligate avian brood parasites provide a particularly tractable system for understanding how uncertainty, driven by environmental variability and symbiont phenology, influences the evolution of species interactions. Here, we use phylogenetically-informed analyses and a comprehensive dataset on the behaviour and geographic distribution of obligate avian brood parasites and their hosts to demonstrate that increasing uncertainty in thermoregulation and parental investment of parasitic young are positively associated with host richness and diversity. Our findings are consistent with the theoretical expectation that ecological risks and environmental unpredictability should favour the evolution of bet-hedging. Additionally, these highly consistent patterns highlight the important role that ecological uncertainty is likely to play in shaping the evolution of specialisation and generalism in complex interspecific relationships. Introduction Species that derive fitness benefits from symbioses often vary in the number of heterospecifics with which they interact 1 , 2 . Although prior comparative analyses and theory suggest that predators and parasites should rely on a greater number of prey or hosts in more variable and unpredictable environments 3 , this relationship has been challenging to detect empirically because the course and pace of co-adaptation 4 are dictated not only by environmental factors, but also by the responses of all of the species involved 5 , 6 . Understanding how ecological uncertainty influences the degree of specialisation in co-evolving systems is especially important in the current context of global change because climatic patterns are becoming increasingly variable and unpredictable 7 , 8 , 9 , 10 and many parasites, predators, and their symbionts already face significant threats of extinction 11 . Obligate avian brood parasites—species that lay their eggs in the nests of other bird species and do not raise their own young—offer a tractable and well-characterised system 12 , 13 , 14 for understanding the role of ecological uncertainty in shaping species interactions. Obligate brood parasites have evolved independently multiple times across the avian phylogeny (Fig. 1 ) 15 and account for roughly 1% of the more than 10,000 extant bird species. These parasites exhibit wide diversity in their degree of host specialisation 16 , 17 and use nearly 17% of all bird species as hosts (See Supplementary Data 1 ). For example, some brood parasites, like the brown-headed cowbird ( Molothrus ater ), are generalists that can parasitise 300 different known host species, whereas others, like the yellow-throated cuckoo ( Chrysococcyx flavigularis ), parasitise only a single one. Brood parasites and their hosts also show considerable diversity in parasitic virulence, degree of co-adaptation (as measured by endogenous traits including egg mimicry), host breeding strategy, and annual reproductive output 18 , 19 , 20 , 21 , 22 . Evolutionarily, more recently diverged brood parasites typically specialise on fewer host species, suggesting that new parasitic lineages arise through specialised interactions with a single or a few hosts 23 , 24 , 25 . Thus, characterising the factors that determine host diversity in brood parasites may not only improve our understanding of resource use and host–parasite coevolution in avian systems, but also, more generally, of the evolution, maintenance, and coexistence of ecological specialisation in symbioses 26 , 27 . Fig. 1: Stochastic character mapping 15 of obligate brood parasitism (red lineages) in birds. Representative clades for each of the six known altricial and one precocial independent evolutionary origins of obligate brood parasitism in birds include a Indicatoridae, b Anatidae (arrow to character mapping), c Cuculinae, d Neomorphinae, and e Phaenicophaeinae, all within Cuculidae, f Viduidae, and g Icteridae. Silhouettes from N.D. Antonson ( a , d ) and phylopic.org with credit to Sharon Wegner-Larsen ( b ), Ferran Sayol ( c ), Lip Kee Yap ( e ), Maija Karala ( f ), and Matt Wilkins ( g ). The CC BY-SA 3.0 license can be found at and the CC BY 3.0 license at . Information on CC0 1.0 (no copyright) can be found at . Full size image Diversification in reproductive behaviours under environmental uncertainty has been shown across a variety of animal taxa, most notably in insects 28 and non-parasitic (i.e., parental) birds 29 . In parental bird species, including several hosts of brood parasites, behavioural bet-hedging has been proposed as a strategy to maximise fitness in highly unpredictable environments 30 . For example, cooperatively breeding superb starlings ( Lamprotornis superbus ) that live in temporally variable savannas use bet-hedging as a strategy to spread reproductive risk over years and within seasons 31 . In brood parasites, reproductive success is dictated by their hosts’ propensity to accept parasitic eggs and by their ability to raise parasitic chicks successfully 12 , 32 . As such, brood parasitism is a risky endeavour, and the degree of parasite specialisation is therefore likely to be determined by factors related to the availability and quality of parenting behaviours of potential hosts 33 . Specifically, host traits such as migratory behaviour, nesting architecture, breeding phenology, chick-provisioning strategies and resilience to environmental challenges, could drive brood parasites’ host choices by dictating the success of their young. In particular, environmental uncertainty experienced through climatic oscillations could favour the spread of a brood parasite’s reproductive effort across hosts with different behavioural profiles because a wider variety of options is likely to minimise variance in parasitic offspring recruitment across years 34 . If long-term success is obtained at the expense of a lower arithmetic mean fitness, then such a brood parasitic strategy may be considered a form of diversified bet-hedging 35 . Based on the above arguments, we predict that (1) increasing unpredictability in climatic fluctuations should lead to increased phylogenetic diversity and/or number of hosts used by brood parasites; (2) that seasonal migration by hosts and shorter breeding seasons should favour generalisation by increasing the potential for missing out on egg laying in some host species’ nests altogether; (3) that greater reliance on uniparental hosts should favour increased host generalisation by increasing uncertainty in the<|im_end|> <|im_start|>assistant Some birds lay their eggs in the nests of other bird species and let the host parents raise their young. A new study finds that in times of environmental flux, these brood parasites "diversify their portfolios," minimizing the risks of their unorthodox lifestyle by increasing the number and variety of hosts they select as adoptive parents. "We found that, in unstable environments, brood parasites choose to not put all their eggs in one basket," said study lead author Nicholas Antonson, a Ph.D. student at the University of Illinois, Urbana Champaign. "Our results are consistent with the idea that brood parasites diversify their reproductive risk in areas that are ecologically, behaviorally or environmentally unpredictable." Antonson led the study with Mark Hauber, a U. of I. professor of evolution, ecology and behavior; Dustin Rubenstein, a professor of environmental biology at Columbia University; and Carlos Botero, a professor of biology at Washington University in St. Louis. They report their findings in the journal Nature Communications. "This research begins to answer a longstanding question about how species first interact and then coevolve in environments that are also changing," Hauber said. "Theory suggests that in unpredictable environments, predators and parasites should rely on a greater number and variety of prey hosts. But with so many variables in flux, this is a challenging thing to study." Brood parasite success depends on the host's acceptance of the outsider's eggs and its ability to raise the young. Some birds learn to recognize that the foreign eggs are different and eject them or build new nests. Others seem not to notice. They incubate, hatch and care for the parasitic offspring as if they were their own. Several other factors could influence how many hosts and which host species a brood parasite targets. The host must be in egg-laying mode when the interloper comes to call. If only one foster parent is involved in taking care of the young, its nest might not succeed as well as one with two parents present. But having two parents around makes it more difficult for parasites to get into the nest to lay their eggs. "Similarly, if the host returns from a long migratory trip and begins to nest right away, the parasite might have fewer chances to locate its nest for sneaking in the extra egg," Hauber said. "Variability in temperature and precipitation during the breeding season is another potential influence." To account for these factors, the researchers aggregated published and publicly available data on 81 of the nearly 100 species of avian brood parasites, including cowbirds, cuckoos, black-headed ducks, indigobirds and honeyguides. They used records from the Field Museum of Natural History in Chicago to determine the number and diversity of hosts each brood parasite used in different contexts. The team also accounted for the relative abundance of published research on different species, "as a number of brood parasites closer to the equator remain poorly studied," Antonson said. They found that in unpredictable environments, brood parasites target more—and more diverse—hosts. The parasites take advantage of as many host species as possible when opportunity allows. The team found a particularly pronounced relationship between temperature variability and bet-hedging. "In areas where temperatures are stable, brood parasites tend to specialize on fewer and less diverse host species. Those hosts also tend to build more complex and potentially safer nests," Antonson said. "But as the thermal environment becomes more uncertain, the evolutionary pattern that we see is that they spread around the risk of offspring survival by drawing from a larger and more diverse pool of host species." The new findings offer insight into the evolution of specialization and generalization, Hauber said. They also suggest that "ecological risks and environmental unpredictability favor the evolution of bet-hedging." <|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 Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children. Introduction Infectious diarrhea remains a leading cause of death and morbidity among young children in low-middle-income countries where access to clean water and sanitation remains in short supply 1 . Enterotoxigenic E. coli (ETEC), initially discovered as a cause of severe, cholera-like illness 2 , are one of the most common pathogens associated with moderate-severe diarrhea among children under the age of 5 years 3 , 4 , and are perennially the most common cause of diarrhea in travelers 5 to endemic regions where these organisms are thought to account for hundreds of millions of cases of diarrheal illness each year 6 . Importantly, ETEC infections have been linked to non-diarrheal sequelae, including “environmental enteric dysfunction (EED),” a condition characterized by impaired nutrient absorption, impaired growth 7 , 8 , and malnutrition 9 , 10 , adding significantly to the morbidity as well as deaths from diarrhea and other infections 11 . The risk of stunting multiplies with each episode of diarrheal illness in children under the age of two years 12 , a period during which children residing in impoverished areas commonly sustain multiple ETEC infections 8 . However, the molecular pathogenesis underlying the intestinal changes associated with EED, and the contribution of individual pathogens, including ETEC, remain poorly understood. Similarly, toxin-producing E. coli have also been repeatedly identified in patients with tropical sprue 13 , 14 , 15 , a condition classically described in adults residing for extended periods of time in areas where ETEC diarrheal disease is common. Like EED, tropical sprue is associated with changes to the small intestinal villous architecture, including ultrastructural alteration of the epithelial brush border formed by the microvilli 16 , 17 , nutrient malabsorption, and wasting. The basic molecular mechanisms underpinning acute watery diarrhea caused by ETEC are well-established 18 . ETEC produces heat-labile (LT) and/or heat-stable (ST) enterotoxins that activate the production of cAMP and cGMP second messengers, respectively, leading to activation of cellular kinases that in turn modulate the activity of sodium and chloride channels in the apical membrane of intestinal epithelial cells to promote net efflux of salt and water into the intestinal lumen resulting in watery diarrhea. LT and cholera toxin (CT) share ~85% amino acid identity, and both toxins exert their major effects on the cell through the ADP-ribosylation of the alpha subunit of Gs (Gsα), a stimulatory intracellular guanine nucleotide-binding protein. Inhibition of Gsα GTPase activity leads to constitutive activation of adenylate cyclase and increased production of intracellular cAMP 19 . In its central role as a second messenger, cAMP governs a diverse array of cellular processes 20 and modulates the transcription of multiple genes through a number of cAMP-responsive transcriptional activators and repressors 21 . cAMP activates protein kinase A (PKA), a heterotetramer, by liberating its two regulatory subunits from the catalytic subunits, which are then free to phosphorylate a wide variety of cytoplasmic and nuclear protein substrates 22 . PKA largely regulates transcription by phosphorylation of transcription factors, including the cyclic AMP response element binding protein (CREB) and the cAMP-response element modulator (CREM), which bind cAMP-response elements (CRE) in the promoter regions of target genes 21 , 22 , 23 . Notably, cholera toxin (CT), LT, and dibutyryl-cyclic AMP all induce hypersecretion and impact the architecture of gastrointestinal epithelia in rodent small intestine 24 , while small intestinal biopsies of patients with acute cholera exhibit marked changes in the ultrastructure of the intestinal brush border, the major absorptive surface in the small intestine 25 , 26 , including shortening and disruption of the microvilli. Consistent with these observations, studies of young children less than two years of age in Bangladesh have specifically associated LT-producing ETEC with undernutrition 27 , suggesting that heat-labile toxin may exert effects on intestinal mucosa that extend beyond acute diarrheal illness. Here we demonstrate that in addition to the canonical effects of LT on the cellular export of salt and water into the intestinal lumen, this toxin impacts multiple genes involved in the formation of microvilli, resulting in marked alteration of the architecture of the intestinal brush border, the major site of nutrient absorption in the small intestine. These effects are compounded by the alteration of solute transporters within the brush border epithelia, potentially disrupting the absorption of multiple essential nutrients. Results Heat-labile toxin markedly alters the transcriptomes ofintestinal epithelial cells Commensurate with the importance of cAMP as a second messenger, we found that compared to either untreated controls or cells treated with a catalytically inactive (E211K) mutant of LT, wild-type LT holotoxin substantially modulated transcription of many genes in intestinal epithelial cells. In RNA-seq studies of polarized Caco-2 intestinal epithelial cells, we found that 3832 genes were significantly ( p ≤ 10 −5 ) upregulated and 3687 downregulated in response to LT, while the inactive toxin failed", "role": "user" }, { "content": "Diarrhea is no longer the killer it was in the mid-20th century, when an estimated 4.5 million children under age 5 died of it every year. While lifesaving oral rehydration therapy has turned the tide, it doesn't prevent infection. Millions of children in low- and middle-income countries still endure repeated bouts of diarrhea that weaken their bodies and leave them vulnerable to malnutrition and stunted growth, and less able to fight off a wide range of infections. Researchers at Washington University School of Medicine in St. Louis have now determined, in studies of human cells as well as mice, how some types of diarrhea-causing Escherichia coli (E. coli) bacteria damage the intestines to cause malnutrition and stunting. And they've shown that vaccinating against a toxin produced by E. coli protects infant mice from intestinal damage. The findings suggest that a vaccine against this kind of E. coli could boost global efforts to ensure that all children not only make it to age 5, but thrive. The study is available online in Nature Communications. \"Ideally, we'd like to have a vaccine that prevents acute diarrhea, which still kills half a million children a year, and that also protects against long-term effects such as malnutrition, which is perhaps the bigger part of the problem now,\" said senior author James M. Fleckenstein, MD, a professor of medicine and of molecular microbiology. \"When kids become malnourished, their risk of dying from any cause goes up. The World Health Organization is in the process of deciding how to prioritize vaccines for kids in low- and middle-income countries, and I think these data suggest that vaccinating kids against E. coli diarrhea could be hugely beneficial in places that struggle with this.\" Fleckenstein studies a kind of E. coli known as enterotoxigenic E. coli, or ETEC—so named for the two toxins it produces—and its effects on children who live where the bacteria run rampant. E. coli is a common cause of diarrhea worldwide, but the strains found in the U.S. and other high-income countries typically don't carry the same toxins as those in low- and middle-income countries. That may make all the difference. A 2020 study by Fleckenstein and Alaullah Sheikh, Ph.D.—then a postdoctoral researcher in Fleckenstein's lab and now an instructor in medicine—indicated that one of ETEC's two toxins, heat-labile toxin, does more than trigger a case of the runs. The toxin also affects gene expression in the gut, ramping up genes that help the bacteria stick to the gut wall. As part of the latest study, Fleckenstein and Sheikh discovered that the toxin suppresses a whole suite of genes related to the lining of the intestines, where nutrients are absorbed. The so-called brush border of the intestine is composed of microscopic, finger-like projections called microvilli that are tightly packed over the surface of the intestines like bristles on a brush. When Fleckenstein and Sheikh applied the toxin to clusters of human intestinal cells, the brush border disintegrated. \"Instead of being nice and tight and upright with thousands of microvilli per cell, they are short, floppy and sparse, kind of like if you had plucked out most of the bristles, and what was left was kind of raggedy,\" said Sheikh, who led the 2020 and current studies. \"That alone would have a negative impact on the body's ability to absorb nutrients. But on top of that, we found that genes related to absorbing specific vitamins and minerals—notably vitamin B1 and zinc—also were downregulated. That could explain some of the micronutrient deficiencies we see in children repeatedly exposed to these bacteria.\" Children in low- and middle-income countries tend to get diarrhea over and over, and the risk of malnutrition and stunting goes up with each bout. Studying infant mice, the researchers found that a single infection with toxin-producing E. coli was sufficient to damage the brush border, while repeated infections led to extensive intestinal damage and growth lag. Pups infected with a strain of E. coli that lacks the toxin showed no such intestinal damage or stunting. If the toxin is the problem, an immune response neutralizing the toxin may prevent the long-term effects, Fleckenstein and Sheikh reasoned. To find out, they vaccinated nursing mouse mothers with the toxin. Suckling mice are too young to be immunized themselves, but their vaccinated mothers produce antibodies that pass to the pups through breast milk. The researchers found that the intestines of infant mice from vaccinated mothers appeared healthy, suggesting that vaccination can protect against the intestinal damage leading to malnutrition. \"This is an argument for developing a vaccine for this kind of E. coli,\" Fleckenstein said. \"There are lifelong consequences of getting infected over and over in childhood. Vaccination combined with efforts to improve sanitation and access to clean water could protect children from the long-term effects and give them a better shot at long and healthy 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 Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children. Introduction Infectious diarrhea remains a leading cause of death and morbidity among young children in low-middle-income countries where access to clean water and sanitation remains in short supply 1 . Enterotoxigenic E. coli (ETEC), initially discovered as a cause of severe, cholera-like illness 2 , are one of the most common pathogens associated with moderate-severe diarrhea among children under the age of 5 years 3 , 4 , and are perennially the most common cause of diarrhea in travelers 5 to endemic regions where these organisms are thought to account for hundreds of millions of cases of diarrheal illness each year 6 . Importantly, ETEC infections have been linked to non-diarrheal sequelae, including “environmental enteric dysfunction (EED),” a condition characterized by impaired nutrient absorption, impaired growth 7 , 8 , and malnutrition 9 , 10 , adding significantly to the morbidity as well as deaths from diarrhea and other infections 11 . The risk of stunting multiplies with each episode of diarrheal illness in children under the age of two years 12 , a period during which children residing in impoverished areas commonly sustain multiple ETEC infections 8 . However, the molecular pathogenesis underlying the intestinal changes associated with EED, and the contribution of individual pathogens, including ETEC, remain poorly understood. Similarly, toxin-producing E. coli have also been repeatedly identified in patients with tropical sprue 13 , 14 , 15 , a condition classically described in adults residing for extended periods of time in areas where ETEC diarrheal disease is common. Like EED, tropical sprue is associated with changes to the small intestinal villous architecture, including ultrastructural alteration of the epithelial brush border formed by the microvilli 16 , 17 , nutrient malabsorption, and wasting. The basic molecular mechanisms underpinning acute watery diarrhea caused by ETEC are well-established 18 . ETEC produces heat-labile (LT) and/or heat-stable (ST) enterotoxins that activate the production of cAMP and cGMP second messengers, respectively, leading to activation of cellular kinases that in turn modulate the activity of sodium and chloride channels in the apical membrane of intestinal epithelial cells to promote net efflux of salt and water into the intestinal lumen resulting in watery diarrhea. LT and cholera toxin (CT) share ~85% amino acid identity, and both toxins exert their major effects on the cell through the ADP-ribosylation of the alpha subunit of Gs (Gsα), a stimulatory intracellular guanine nucleotide-binding protein. Inhibition of Gsα GTPase activity leads to constitutive activation of adenylate cyclase and increased production of intracellular cAMP 19 . In its central role as a second messenger, cAMP governs a diverse array of cellular processes 20 and modulates the transcription of multiple genes through a number of cAMP-responsive transcriptional activators and repressors 21 . cAMP activates protein kinase A (PKA), a heterotetramer, by liberating its two regulatory subunits from the catalytic subunits, which are then free to phosphorylate a wide variety of cytoplasmic and nuclear protein substrates 22 . PKA largely regulates transcription by phosphorylation of transcription factors, including the cyclic AMP response element binding protein (CREB) and the cAMP-response element modulator (CREM), which bind cAMP-response elements (CRE) in the promoter regions of target genes 21 , 22 , 23 . Notably, cholera toxin (CT), LT, and dibutyryl-cyclic AMP all induce hypersecretion and impact the architecture of gastrointestinal epithelia in rodent small intestine 24 , while small intestinal biopsies of patients with acute cholera exhibit marked changes in the ultrastructure of the intestinal brush border, the major absorptive surface in the small intestine 25 , 26 , including shortening and disruption of the microvilli. Consistent with these observations, studies of young children less than two years of age in Bangladesh have specifically associated LT-producing ETEC with undernutrition 27 , suggesting that heat-labile toxin may exert effects on intestinal mucosa that extend beyond acute diarrheal illness. Here we demonstrate that in addition to the canonical effects of LT on the cellular export of salt and water into the intestinal lumen, this toxin impacts multiple genes involved in the formation of microvilli, resulting in marked alteration of the architecture of the intestinal brush border, the major site of nutrient absorption in the small intestine. These effects are compounded by the alteration of solute transporters within the brush border epithelia, potentially disrupting the absorption of multiple essential nutrients. Results Heat-labile toxin markedly alters the transcriptomes ofintestinal epithelial cells Commensurate with the importance of cAMP as a second messenger, we found that compared to either untreated controls or cells treated with a catalytically inactive (E211K) mutant of LT, wild-type LT holotoxin substantially modulated transcription of many genes in intestinal epithelial cells. In RNA-seq studies of polarized Caco-2 intestinal epithelial cells, we found that 3832 genes were significantly ( p ≤ 10 −5 ) upregulated and 3687 downregulated in response to LT, while the inactive toxin failed<|im_end|> <|im_start|>assistant Diarrhea is no longer the killer it was in the mid-20th century, when an estimated 4.5 million children under age 5 died of it every year. While lifesaving oral rehydration therapy has turned the tide, it doesn't prevent infection. Millions of children in low- and middle-income countries still endure repeated bouts of diarrhea that weaken their bodies and leave them vulnerable to malnutrition and stunted growth, and less able to fight off a wide range of infections. Researchers at Washington University School of Medicine in St. Louis have now determined, in studies of human cells as well as mice, how some types of diarrhea-causing Escherichia coli (E. coli) bacteria damage the intestines to cause malnutrition and stunting. And they've shown that vaccinating against a toxin produced by E. coli protects infant mice from intestinal damage. The findings suggest that a vaccine against this kind of E. coli could boost global efforts to ensure that all children not only make it to age 5, but thrive. The study is available online in Nature Communications. "Ideally, we'd like to have a vaccine that prevents acute diarrhea, which still kills half a million children a year, and that also protects against long-term effects such as malnutrition, which is perhaps the bigger part of the problem now," said senior author James M. Fleckenstein, MD, a professor of medicine and of molecular microbiology. "When kids become malnourished, their risk of dying from any cause goes up. The World Health Organization is in the process of deciding how to prioritize vaccines for kids in low- and middle-income countries, and I think these data suggest that vaccinating kids against E. coli diarrhea could be hugely beneficial in places that struggle with this." Fleckenstein studies a kind of E. coli known as enterotoxigenic E. coli, or ETEC—so named for the two toxins it produces—and its effects on children who live where the bacteria run rampant. E. coli is a common cause of diarrhea worldwide, but the strains found in the U.S. and other high-income countries typically don't carry the same toxins as those in low- and middle-income countries. That may make all the difference. A 2020 study by Fleckenstein and Alaullah Sheikh, Ph.D.—then a postdoctoral researcher in Fleckenstein's lab and now an instructor in medicine—indicated that one of ETEC's two toxins, heat-labile toxin, does more than trigger a case of the runs. The toxin also affects gene expression in the gut, ramping up genes that help the bacteria stick to the gut wall. As part of the latest study, Fleckenstein and Sheikh discovered that the toxin suppresses a whole suite of genes related to the lining of the intestines, where nutrients are absorbed. The so-called brush border of the intestine is composed of microscopic, finger-like projections called microvilli that are tightly packed over the surface of the intestines like bristles on a brush. When Fleckenstein and Sheikh applied the toxin to clusters of human intestinal cells, the brush border disintegrated. "Instead of being nice and tight and upright with thousands of microvilli per cell, they are short, floppy and sparse, kind of like if you had plucked out most of the bristles, and what was left was kind of raggedy," said Sheikh, who led the 2020 and current studies. "That alone would have a negative impact on the body's ability to absorb nutrients. But on top of that, we found that genes related to absorbing specific vitamins and minerals—notably vitamin B1 and zinc—also were downregulated. That could explain some of the micronutrient deficiencies we see in children repeatedly exposed to these bacteria." Children in low- and middle-income countries tend to get diarrhea over and over, and the risk of malnutrition and stunting goes up with each bout. Studying infant mice, the researchers found that a single infection with toxin-producing E. coli was sufficient to damage the brush border, while repeated infections led to extensive intestinal damage and growth lag. Pups infected with a strain of E. coli that lacks the toxin showed no such intestinal damage or stunting. If the toxin is the problem, an immune response neutralizing the toxin may prevent the long-term effects, Fleckenstein and Sheikh reasoned. To find out, they vaccinated nursing mouse mothers with the toxin. Suckling mice are too young to be immunized themselves, but their vaccinated mothers produce antibodies that pass to the pups through breast milk. The researchers found that the intestines of infant mice from vaccinated mothers appeared healthy, suggesting that vaccination can protect against the intestinal damage leading to malnutrition. "This is an argument for developing a vaccine for this kind of E. coli," Fleckenstein said. "There are lifelong consequences of getting infected over and over in childhood. Vaccination combined with efforts to improve sanitation and access to clean water could protect children from the long-term effects and give them a better shot at long and healthy lives." <|im_end|>

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2,482

[ { "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 Precambrian rock record contains numerous examples of microscopic organic filaments and spheres, commonly interpreted as fossil microorganisms. Microfossils are among the oldest traces of life on Earth, making their correct identification crucial to our understanding of early evolution. Yet, spherical and filamentous microscopic objects composed of organic carbon and sulfur can form in the abiogenic reaction of sulfide with organic compounds. Termed organic biomorphs, these objects form under geochemical conditions relevant to the sulfidic environments of early Earth. Furthermore, they adopt a diversity of morphologies that closely mimic a number of microfossil examples from the Precambrian record. Here, we tested the potential for organic biomorphs to be preserved in cherts; i.e., siliceous rocks hosting abundant microbial fossils. We performed experimental silicification of the biomorphs along with the sulfur bacterium Thiothrix . We show that the original morphologies of the biomorphs are well preserved through encrustation by nano-colloidal silica, while the shapes of Thiothrix cells degrade. Sulfur diffuses from the interior of both biomorphs and Thiothrix during silicification, leaving behind empty organic envelopes. Although the organic composition of the biomorphs differs from that of Thiothrix cells, both types of objects present similar nitrogen/carbon ratios after silicification. During silicification, sulfur accumulates along the organic envelopes of the biomorphs, which may promote sulfurization and preservation through diagenesis. Organic biomorphs possessing morphological and chemical characteristics of microfossils may thus be an important component in Precambrian cherts, challenging our understanding of the early life record. INTRODUCTION Reconstructing the early history of life on Earth relies on our ability to identify the remnants of microorganisms in the rock record. Traces of ancient microbial life can be chemical (e.g., biologically derived organic compounds or isotopic signals) or morphological (e.g., microfossils), but their correct identification is rife with challenges ( Schopf et al., 2010 ; Javaux, 2019 ). One of the main issues is the potential for abiotic processes to generate microstructures mimicking prokaryotic cell morphologies, and thus create “false positive” evidence of early life in the geological record. Different types of microstructures emulating microbial cells have been described from laboratory-based ( Fox and Yuyama, 1963 ; Barge et al., 2016 ; McMahon, 2019 ; García-Ruiz et al., 2020 ) and field-based ( Brasier et al., 2002 ; Marshall et al., 2011 ; Wacey et al., 2018 ) studies. Recently, organic microstructures bearing both morphological and chemical resemblance to microbial filamentous and spherical cells were synthesized experimentally ( Cosmidis and Templeton, 2016 ). These objects, called here organic biomorphs, self-assemble when sulfide is oxidized in the presence of organics. They form spontaneously in a wide range of geochemical conditions relevant to modern and ancient sulfidic environments. Furthermore, the organic biomorphs form from diverse organic compounds, including simple prebiotic organics (e.g., glycine) ( Cosmidis et al., 2019 ), and so possibly assembled in Earth's early environments prior to the origin of life. Figure 1 compares the morphologies of laboratory-synthesized organic biomorphs with putative organic microfossils from the Archean and Proterozoic record, namely the 3.5 Ga Dresser Formation ( Baumgartner et al., 2019 ) ( Fig. 1A ), 3.4 Ga Strelley Pool Formation ( Wacey et al., 2011 ) (subset in Fig. 1C ), and 2.4–2.2 Ga Turee Creek Group ( Schopf et al., 2015 ; Barlow and Van Kranendonk, 2018 ) ( Figs. 1C , 1G , 1K , 1M , and 1O ) of Western Australia, and the 1.9 Ga Gunflint Formation ( Wacey et al., 2013 ) ( Figs. 1E and 1I ) in northeastern North America. Organic biomorphs shown for comparison include (1) spheroids, either isolated or clustered ( Fig. 1D ); (2) tubes or filaments, either rigid ( Figs. 1J and 1L ) or flexible ( Figs. 1B and 1N ), in some cases branching ( Fig. 1L ) or forming angles ( Fig. 1H ), isolated ( Fig. 1H ), clustered ( Fig. 1J ), or forming “rivers” ( Fig. 1N ) or tangled networks ( Fig. 1P ); and (3) rosettes of filaments ( Fig. 1F ). These morphological similarities are insufficient for disproving the biogenicity of the putative microfossils exemplified here, which in some cases has been well established (e.g., the Gunflint microfossils; Lepot et al., 2017 ). Yet, this comparison clearly cautions against using morphological criteria for identifying microfossils, especially in rocks marked by sulfide-rich conditions. Euxinic conditions were common in Proterozoic oceans ( Lyons et al., 2009 ), and reduced sulfur species could have been locally concentrated in Archean sedimentary environments despite low global oceanic sulfate (e.g., Marin-Carbonne et al., 2018 ). Precambrian microfossils such as those shown in Figure 1 are commonly closely associated with pyrite (e.g., Wacey et al., 2011 , 2013 ; Baumgartner et al., 2019 ), indicating localized sulfide enrichments and hence conditions expedient for the formation of organic biomorphs. It is currently unknown, however, whether organic biomorphs would be preserved as pseudofossils in the rock record. Chert formations (i.e., silica-rich rocks) host a majority of the Precambrian putative microfossils ( Javaux and Lepot, 2018 ; Javaux, 2019 ). We investigated the preservation potential of organic biomorphs in silica-rich depositional environments through experimental silicification. Freshly collected mats of the sulfur-oxidizing bacterium Thiothrix sp. were used as a microbial control. While most previous experimental silicification studies have focused on the preservation of cyanobacteria (e.g., Benning et al., 2004 ; Lalonde et al., 2005 ), many putative Precambrian microfossils have been interpreted as sulfur-cycling microorganisms ( Wacey et al., 2011 ; Schopf et al., 2015 ; Barlow and Van Kranendonk, 2018 ). Furthermore, Thiothrix forms intracellular sulfur globules ( Larkin and Strohl, 1983 ), making it a good biological analog for the sulfur-encapsulating organic biomorphs. MATERIALS AND METHODS Organic biomorphs were obtained by reacting sulfide in solution with dissolved yeast extract (a complex organic mixture) under sterile conditions. Following earlier experimental silicification protocols ( Toporski et al., 2002 ; Benning et al., 2004 ), the biomorphs were dispensed into a sterile supersaturated sodium-metasilicate solution and stored at room temperature for up to five months. The same", "role": "user" }, { "content": "For most of Earth's history, life was limited to the microscopic realm, with bacteria occupying nearly every possible niche. Life is generally thought to have evolved in some of the most extreme environments, like hydrothermal vents deep in the ocean or hot springs that still simmer in Yellowstone. Much of what we know about the evolution of life comes from the rock record, which preserves rare fossils of bacteria from billions of years ago. But that record is steeped in controversy, with each new discovery (rightfully) critiqued, questioned, and analyzed from every angle. Even then, uncertainty in whether a purported fossil is a trace of life can persist, and the field is plagued by \"false positives\" of early life. To understand evolution on our planet—and to help find signs of life on others—scientists have to be able to tell the difference. New experiments by geobiologists Julie Cosmidis, Christine Nims, and their colleagues, published today in Geology, could help settle arguments over which microfossils are signs of early life and which are not. They have shown that fossilized spheres and filaments—two common bacterial shapes—made of organic carbon (typically associated with life) can form abiotically (in the absence of living organisms) and might even be easier to preserve than bacteria. \"One big problem is that the fossils are a very simple morphology, and there are lots of non-biological processes that can reproduce them,\" Cosmidis says. \"If you find a full skeleton of a dinosaur, it's a very complex structure that's impossible for a chemical process to reproduce.\" It's much harder to have that certainty with fossilized microbes. Their work was spurred by an accidental discovery a few years back, with which both Cosmidis and Nims were involved while working in Alexis Templeton's lab. While mixing organic carbon and sulfide, they noticed that spheres and filaments were forming and assumed they were the result of bacterial activity. But on closer inspection, Cosmidis quickly realized they were formed abiotically. \"Very early, we noticed that these things looked a lot like bacteria, both chemically and morphologically,\" she says. \"They start just looking like a residue at the bottom of the experimental vessel,\" researcher Christine Nims says, \"but under the microscope, you could see these beautiful structures that looked microbial. And they formed in these very sterile conditions, so these stunning features essentially came out of nothing. It was really exciting work.\" \"We thought, 'What if they could form in a natural environment? What if they could be preserved in rocks?'\" Cosmidis says. \"We had to try that, to see if they can be fossilized.\" Nims set about running the new experiments, testing to see if these abiotic structures, which they called biomorphs, could be fossilized, like a bacterium would be. By adding biomorphs to a silica solution, they aimed to recreate the formation of chert, a silica-rich rock that commonly preserves early microfossils. For weeks, she would carefully track the small-scale 'fossilization' progress under a microscope. They found not only that they could be fossilized, but also that these abiotic shapes were much easier to preserve than bacterial remains. The abiotic 'fossils,' structures composed of organic carbon and sulfur, were more resilient and less likely to flatten out than their fragile biological counterparts. \"Microbes don't have bones,\" Cosmidis explains. \"They don't have skins or skeletons. They're just squishy organic matter. So to preserve them, you have to have very specific conditions\"—like low rates of photosynthesis and rapid sediment deposition—\"so it's kind of rare when that happens.\" On one level, their discovery complicates things: knowing that these shapes can be formed without life and preserved more easily than bacteria casts doubt, generally, on our record of early life. But for a while, geobiologists have known better than to rely solely on morphology to analyze potential microfossils. They bring in chemistry, too. The \"organic envelopes\" Nims created in the lab were formed in a high-sulfur environment, replicating conditions on early Earth (and hot springs today). Pyrite, or \"fool's gold,\" is an iron-sulfide mineral that would likely have formed in such conditions, so its presence could be used as a beacon for potentially problematic microfossils. \"If you look at ancient rocks that contain what we think are microfossils, they very often also contain pyrite,\" Cosmidis says. \"For me, that should be a red flag: 'Let's be more careful here.' It's not like we are doomed to never be able to tell what the real microfossils are. We just have to get better at 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 Precambrian rock record contains numerous examples of microscopic organic filaments and spheres, commonly interpreted as fossil microorganisms. Microfossils are among the oldest traces of life on Earth, making their correct identification crucial to our understanding of early evolution. Yet, spherical and filamentous microscopic objects composed of organic carbon and sulfur can form in the abiogenic reaction of sulfide with organic compounds. Termed organic biomorphs, these objects form under geochemical conditions relevant to the sulfidic environments of early Earth. Furthermore, they adopt a diversity of morphologies that closely mimic a number of microfossil examples from the Precambrian record. Here, we tested the potential for organic biomorphs to be preserved in cherts; i.e., siliceous rocks hosting abundant microbial fossils. We performed experimental silicification of the biomorphs along with the sulfur bacterium Thiothrix . We show that the original morphologies of the biomorphs are well preserved through encrustation by nano-colloidal silica, while the shapes of Thiothrix cells degrade. Sulfur diffuses from the interior of both biomorphs and Thiothrix during silicification, leaving behind empty organic envelopes. Although the organic composition of the biomorphs differs from that of Thiothrix cells, both types of objects present similar nitrogen/carbon ratios after silicification. During silicification, sulfur accumulates along the organic envelopes of the biomorphs, which may promote sulfurization and preservation through diagenesis. Organic biomorphs possessing morphological and chemical characteristics of microfossils may thus be an important component in Precambrian cherts, challenging our understanding of the early life record. INTRODUCTION Reconstructing the early history of life on Earth relies on our ability to identify the remnants of microorganisms in the rock record. Traces of ancient microbial life can be chemical (e.g., biologically derived organic compounds or isotopic signals) or morphological (e.g., microfossils), but their correct identification is rife with challenges ( Schopf et al., 2010 ; Javaux, 2019 ). One of the main issues is the potential for abiotic processes to generate microstructures mimicking prokaryotic cell morphologies, and thus create “false positive” evidence of early life in the geological record. Different types of microstructures emulating microbial cells have been described from laboratory-based ( Fox and Yuyama, 1963 ; Barge et al., 2016 ; McMahon, 2019 ; García-Ruiz et al., 2020 ) and field-based ( Brasier et al., 2002 ; Marshall et al., 2011 ; Wacey et al., 2018 ) studies. Recently, organic microstructures bearing both morphological and chemical resemblance to microbial filamentous and spherical cells were synthesized experimentally ( Cosmidis and Templeton, 2016 ). These objects, called here organic biomorphs, self-assemble when sulfide is oxidized in the presence of organics. They form spontaneously in a wide range of geochemical conditions relevant to modern and ancient sulfidic environments. Furthermore, the organic biomorphs form from diverse organic compounds, including simple prebiotic organics (e.g., glycine) ( Cosmidis et al., 2019 ), and so possibly assembled in Earth's early environments prior to the origin of life. Figure 1 compares the morphologies of laboratory-synthesized organic biomorphs with putative organic microfossils from the Archean and Proterozoic record, namely the 3.5 Ga Dresser Formation ( Baumgartner et al., 2019 ) ( Fig. 1A ), 3.4 Ga Strelley Pool Formation ( Wacey et al., 2011 ) (subset in Fig. 1C ), and 2.4–2.2 Ga Turee Creek Group ( Schopf et al., 2015 ; Barlow and Van Kranendonk, 2018 ) ( Figs. 1C , 1G , 1K , 1M , and 1O ) of Western Australia, and the 1.9 Ga Gunflint Formation ( Wacey et al., 2013 ) ( Figs. 1E and 1I ) in northeastern North America. Organic biomorphs shown for comparison include (1) spheroids, either isolated or clustered ( Fig. 1D ); (2) tubes or filaments, either rigid ( Figs. 1J and 1L ) or flexible ( Figs. 1B and 1N ), in some cases branching ( Fig. 1L ) or forming angles ( Fig. 1H ), isolated ( Fig. 1H ), clustered ( Fig. 1J ), or forming “rivers” ( Fig. 1N ) or tangled networks ( Fig. 1P ); and (3) rosettes of filaments ( Fig. 1F ). These morphological similarities are insufficient for disproving the biogenicity of the putative microfossils exemplified here, which in some cases has been well established (e.g., the Gunflint microfossils; Lepot et al., 2017 ). Yet, this comparison clearly cautions against using morphological criteria for identifying microfossils, especially in rocks marked by sulfide-rich conditions. Euxinic conditions were common in Proterozoic oceans ( Lyons et al., 2009 ), and reduced sulfur species could have been locally concentrated in Archean sedimentary environments despite low global oceanic sulfate (e.g., Marin-Carbonne et al., 2018 ). Precambrian microfossils such as those shown in Figure 1 are commonly closely associated with pyrite (e.g., Wacey et al., 2011 , 2013 ; Baumgartner et al., 2019 ), indicating localized sulfide enrichments and hence conditions expedient for the formation of organic biomorphs. It is currently unknown, however, whether organic biomorphs would be preserved as pseudofossils in the rock record. Chert formations (i.e., silica-rich rocks) host a majority of the Precambrian putative microfossils ( Javaux and Lepot, 2018 ; Javaux, 2019 ). We investigated the preservation potential of organic biomorphs in silica-rich depositional environments through experimental silicification. Freshly collected mats of the sulfur-oxidizing bacterium Thiothrix sp. were used as a microbial control. While most previous experimental silicification studies have focused on the preservation of cyanobacteria (e.g., Benning et al., 2004 ; Lalonde et al., 2005 ), many putative Precambrian microfossils have been interpreted as sulfur-cycling microorganisms ( Wacey et al., 2011 ; Schopf et al., 2015 ; Barlow and Van Kranendonk, 2018 ). Furthermore, Thiothrix forms intracellular sulfur globules ( Larkin and Strohl, 1983 ), making it a good biological analog for the sulfur-encapsulating organic biomorphs. MATERIALS AND METHODS Organic biomorphs were obtained by reacting sulfide in solution with dissolved yeast extract (a complex organic mixture) under sterile conditions. Following earlier experimental silicification protocols ( Toporski et al., 2002 ; Benning et al., 2004 ), the biomorphs were dispensed into a sterile supersaturated sodium-metasilicate solution and stored at room temperature for up to five months. The same<|im_end|> <|im_start|>assistant For most of Earth's history, life was limited to the microscopic realm, with bacteria occupying nearly every possible niche. Life is generally thought to have evolved in some of the most extreme environments, like hydrothermal vents deep in the ocean or hot springs that still simmer in Yellowstone. Much of what we know about the evolution of life comes from the rock record, which preserves rare fossils of bacteria from billions of years ago. But that record is steeped in controversy, with each new discovery (rightfully) critiqued, questioned, and analyzed from every angle. Even then, uncertainty in whether a purported fossil is a trace of life can persist, and the field is plagued by "false positives" of early life. To understand evolution on our planet—and to help find signs of life on others—scientists have to be able to tell the difference. New experiments by geobiologists Julie Cosmidis, Christine Nims, and their colleagues, published today in Geology, could help settle arguments over which microfossils are signs of early life and which are not. They have shown that fossilized spheres and filaments—two common bacterial shapes—made of organic carbon (typically associated with life) can form abiotically (in the absence of living organisms) and might even be easier to preserve than bacteria. "One big problem is that the fossils are a very simple morphology, and there are lots of non-biological processes that can reproduce them," Cosmidis says. "If you find a full skeleton of a dinosaur, it's a very complex structure that's impossible for a chemical process to reproduce." It's much harder to have that certainty with fossilized microbes. Their work was spurred by an accidental discovery a few years back, with which both Cosmidis and Nims were involved while working in Alexis Templeton's lab. While mixing organic carbon and sulfide, they noticed that spheres and filaments were forming and assumed they were the result of bacterial activity. But on closer inspection, Cosmidis quickly realized they were formed abiotically. "Very early, we noticed that these things looked a lot like bacteria, both chemically and morphologically," she says. "They start just looking like a residue at the bottom of the experimental vessel," researcher Christine Nims says, "but under the microscope, you could see these beautiful structures that looked microbial. And they formed in these very sterile conditions, so these stunning features essentially came out of nothing. It was really exciting work." "We thought, 'What if they could form in a natural environment? What if they could be preserved in rocks?'" Cosmidis says. "We had to try that, to see if they can be fossilized." Nims set about running the new experiments, testing to see if these abiotic structures, which they called biomorphs, could be fossilized, like a bacterium would be. By adding biomorphs to a silica solution, they aimed to recreate the formation of chert, a silica-rich rock that commonly preserves early microfossils. For weeks, she would carefully track the small-scale 'fossilization' progress under a microscope. They found not only that they could be fossilized, but also that these abiotic shapes were much easier to preserve than bacterial remains. The abiotic 'fossils,' structures composed of organic carbon and sulfur, were more resilient and less likely to flatten out than their fragile biological counterparts. "Microbes don't have bones," Cosmidis explains. "They don't have skins or skeletons. They're just squishy organic matter. So to preserve them, you have to have very specific conditions"—like low rates of photosynthesis and rapid sediment deposition—"so it's kind of rare when that happens." On one level, their discovery complicates things: knowing that these shapes can be formed without life and preserved more easily than bacteria casts doubt, generally, on our record of early life. But for a while, geobiologists have known better than to rely solely on morphology to analyze potential microfossils. They bring in chemistry, too. The "organic envelopes" Nims created in the lab were formed in a high-sulfur environment, replicating conditions on early Earth (and hot springs today). Pyrite, or "fool's gold," is an iron-sulfide mineral that would likely have formed in such conditions, so its presence could be used as a beacon for potentially problematic microfossils. "If you look at ancient rocks that contain what we think are microfossils, they very often also contain pyrite," Cosmidis says. "For me, that should be a red flag: 'Let's be more careful here.' It's not like we are doomed to never be able to tell what the real microfossils are. We just have to get better at 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 Photon pair sources are fundamental building blocks for quantum entanglement and quantum communication. Recent studies in silicon photonics have documented promising characteristics for photon pair sources within the telecommunications band, including sub-milliwatt optical pump power, high spectral brightness and high photon purity. However, most quantum systems suitable for local operations, such as storage and computation, support optical transitions in the visible or short near-infrared bands. In comparison to telecommunications wavelengths, the higher optical attenuation in silica at such wavelengths limits the length scale over which optical-fibre-based quantum communication between such local nodes can take place. One approach to connect such systems over fibre is through a photon pair source that can bridge the visible and telecom bands, but an appropriate source, which should produce narrow-band photon pairs with a high signal-to-noise ratio, has not yet been developed in an integrated platform. Here, we demonstrate a nanophotonic visible–telecom photon pair source, using high quality factor silicon nitride resonators to generate narrow-band photon pairs with unprecedented purity and brightness, with a coincidence-to-accidental ratio up to 3,780 ± 140 and a detected photon pair flux up to (18,400 ± 1,000) pairs s −1 . We further demonstrate visible–telecom time–energy entanglement and its distribution over a 20 km fibre, far exceeding the fibre length over which purely visible wavelength quantum light sources can be efficiently transmitted. Finally, we show how dispersion engineering of the microresonators enables the connections of different species of trapped atoms/ions, defect centres and quantum dots to the telecommunications bands for future quantum communication systems. Main Long-distance quantum communication requires resources for the low-loss storage and transmission of quantum information 1 , 2 . For fibre optic networks, this requirement presents a challenge, in that many systems that are best suited for storage, including trapped ions, neutral atoms and spins in crystals, are connected to photons in the visible or short near-infrared (NIR) bands 3 , where losses in silica fibres are orders of magnitude higher than at telecommunications wavelengths 4 . Although a quantum frequency conversion interface can bridge the spectral gap between the relevant wavelengths 5 , it can be challenging, both in finding appropriate laser sources to connect the input and output wavelengths, and also in limiting added noise photons due to the strong classical pump fields. These challenges are more acute as the local quantum system’s operating wavelength decreases and moves further away from the telecommunications band. A second approach to connecting photonic quantum systems over distance is through suitably engineered entangled photon pair sources. In particular, quantum memories can be remotely entangled via entanglement swapping 6 , 7 , in which photons entangled with the two distant memories propagate towards each other and meet, where they are subjected to a Bell-state measurement. For visible/short-NIR memories, the propagation distance in optical fibre is limited as described above. To overcome this limitation, one can introduce entangled photon pair sources in which one photon is resonant with the memory (that is, at a visible wavelength) and the other is in the telecom band (Fig. 1 ). Successive entanglement swapping operations can then entangle the memories, with their separation now limited by the propagation distance in optical fibre in the telecom band. Such visible–telecom pair sources might also find use in related scenarios—for example, Bell inequality violations using nitrogen–vacancy centre spins in diamond 8 . Fig. 1: Motivation and scheme for a chip-integrated visible–telecom entangled photon pair source. a , Intended application, where photon pairs generated from a silicon nitride nanophotonic chip (centre) connect the visible and telecommunication bands, to enable a link between a nitrogen–vacancy centre in diamond (left) and the telecom fibre network (right), for example. b , Scheme for cavity-enhanced SFWM. The continuous-wave, classical pump field at frequency ω p generates signal and idler photons at ω s and ω i , respectively, dictated by energy conservation 2 ω p = ω s + ω i . The nearest relevant cavity mode frequencies are at \${\\hat{\\omega }}_{\\rm p}\$ , \${\\hat{\\omega }}_{\\rm s}\$ and \${\\hat{\\omega }}_{\\rm i}\$ , respectively. Phase-matching of light generated in these optical modes is equivalent to the condition on the cavity azimuthal mode numbers m that 2 m p = m s + m i . c , Examples of local quantum systems with optical transitions in the visible/short NIR band (left), and classification of the telecommunications wavelength bands (right). Full size image Existing visible–telecom photon pair sources are in platforms such as periodically poled nonlinear crystals 9 , photonic crystal fibres 10 and millimeter-scale crystalline microresonators 11 . The first two platforms generate broadband photons, so that spectral filtering to achieve the narrow linewidths needed for interaction with local quantum systems must be implemented. Filtering after pair generation comes at the price of a decrease in collection efficiency and signal-to-noise ratio, so incorporation of the nonlinear medium into a macroscopic cavity 12 , 13 , 14 has been pursued. The crystalline microresonator platform, although promising, currently exhibits a coincidence-to-accidental ratio (CAR) below 20, which can be a constraint in applications. In general, these platforms all lack the potential for scalable fabrication and integration common to the planar systems used in nanophotonics. A nanophotonic device platform for narrow-linewidth, high-quality visible–telecom photon pairs is the whispering gallery mode microresonator based on silicon photonics 15 . Recent studies have documented promising characteristics for photon pair sources based on spontaneous four-wave mixing (SFWM) in the telecommunications band, including sub-milliwatt optical pump power, high spectral brightness and high photon purity 16 , 17 , 18 , 19 , 20 , 21 , and the potential for large-scale integration 22 . Whereas silicon’s narrow bandgap forbids operation below 1.1 μm, stoichiometric silicon nitride (Si 3 N 4 ) has a much wider bandgap, enabling operation across wavelengths from the near-ultraviolet to the mid-infrared. Such broadband performance has been exploited in octave-spanning optical frequency combs 23 , 24 , 25 , and such microcombs have been operated sub-threshold to generate high-dimensional, frequency-bin entangled photon pairs in the telecom band", "role": "user" }, { "content": "Some of the most advanced communication systems now under development rely on the properties of quantum science to store and transport information. However, researchers designing quantum communication systems that rely on light, rather than electric current, to transmit information face a quandary: The optical components that store and process quantum information typically require visible-light photons (particles of light) to operate. However, only near-infrared photons—with wavelengths about 10 times longer—can transport that information over kilometers of optical fibers. Now, researchers at the National Institute of Standards and Technology (NIST) have developed a novel way to solve this problem. For the first time, the team created quantum-correlated pairs made up of one visible and one near-infrared photon using chip-based optical components that can be mass-produced. These photon pairs combine the best of both worlds: The visible-light partners can interact with trapped atoms, ions, or other systems that serve as quantum versions of computer memory while the near-infrared members of each couple are free to propagate over long distances through the optical fiber. The achievement promises to boost the ability of light-based circuits to securely transmit information to faraway locations. NIST researchers Xiyuan Lu, Kartik Srinivasan and their colleagues at the University of Maryland NanoCenter in College Park, demonstrated the quantum correlation, known as entanglement, using a specific pair of visible-light and near-infrared photons. However, the researchers' design methods can be easily applied to create many other visible-light/near-infrared pairs tailored to match specific systems of interest. Moreover, the miniature optical components that created the entanglements are manufactured in large numbers. Lu, Srinivasan and their colleagues recently described their work in Nature Physics. One of the more counterintuitive properties of quantum mechanics, quantum entanglement occurs when two or more photons or other particles are prepared in a way that makes them so intrinsically connected that they behave as one unit. A measurement that determines the quantum state of one of the entangled particles automatically determines the state of the other, even if the two particles lie on opposite sides of the universe. Entanglement lies at the heart of many quantum information schemes, including quantum computing and encryption. In many situations, the two photons that are entangled have similar wavelengths, or colors. But the NIST researchers deliberately set out to create odd couples—entanglement between photons whose colors are very different. \"We wanted to link together visible-light photons, which are good for storing information in atomic systems, and telecommunication photons, which are in the near-infrared and good at traveling through optical fibers with low signal loss,\" said Srinivasan. To make photons suitable for interacting with most quantum information storage systems, the team also needed the light to be sharply peaked at a particular wavelength rather than having a broader, more diffuse distribution. To create the entangled pairs, the team constructed a specially tailored optical \"whispering gallery\"—a nano-sized silicon nitride resonator that steers light around a tiny racetrack, similar to the way sound waves travel unimpeded around a curved wall such as the dome in St. Paul's Cathedral in London. In such curved structures, known as acoustic whispering galleries, a person standing near one part of the wall easily hears a faint sound originating at any other part of the wall. When a selected wavelength of laser light was directed into the resonator, entangled pairs of visible-light and near-infrared photons emerged. (The specific type of entanglement employed in the experiment, known as time-energy entanglement, links the energy of the photon pairs with the time at which they are generated.) \"We figured out how to engineer these whispering gallery resonators to produce large numbers of the pairs we wanted, with very little background noise and other extraneous light,\" Lu said. The researchers confirmed that entanglement persisted even after the telecommunication photons traveled through several kilometers of optical fiber. In the future, by combining two of the entangled pairs with two quantum memories, the entanglement inherent in the photon pairs can be transferred to the quantum memories. This technique, known as entanglement swapping, allows the memories to be entangled with each other over a much longer distance than would normally be possible. \"Our contribution was to figure out how to make a quantum light source with the right properties that could enable such long-distance entanglement,\" Srinivasan 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 Photon pair sources are fundamental building blocks for quantum entanglement and quantum communication. Recent studies in silicon photonics have documented promising characteristics for photon pair sources within the telecommunications band, including sub-milliwatt optical pump power, high spectral brightness and high photon purity. However, most quantum systems suitable for local operations, such as storage and computation, support optical transitions in the visible or short near-infrared bands. In comparison to telecommunications wavelengths, the higher optical attenuation in silica at such wavelengths limits the length scale over which optical-fibre-based quantum communication between such local nodes can take place. One approach to connect such systems over fibre is through a photon pair source that can bridge the visible and telecom bands, but an appropriate source, which should produce narrow-band photon pairs with a high signal-to-noise ratio, has not yet been developed in an integrated platform. Here, we demonstrate a nanophotonic visible–telecom photon pair source, using high quality factor silicon nitride resonators to generate narrow-band photon pairs with unprecedented purity and brightness, with a coincidence-to-accidental ratio up to 3,780 ± 140 and a detected photon pair flux up to (18,400 ± 1,000) pairs s −1 . We further demonstrate visible–telecom time–energy entanglement and its distribution over a 20 km fibre, far exceeding the fibre length over which purely visible wavelength quantum light sources can be efficiently transmitted. Finally, we show how dispersion engineering of the microresonators enables the connections of different species of trapped atoms/ions, defect centres and quantum dots to the telecommunications bands for future quantum communication systems. Main Long-distance quantum communication requires resources for the low-loss storage and transmission of quantum information 1 , 2 . For fibre optic networks, this requirement presents a challenge, in that many systems that are best suited for storage, including trapped ions, neutral atoms and spins in crystals, are connected to photons in the visible or short near-infrared (NIR) bands 3 , where losses in silica fibres are orders of magnitude higher than at telecommunications wavelengths 4 . Although a quantum frequency conversion interface can bridge the spectral gap between the relevant wavelengths 5 , it can be challenging, both in finding appropriate laser sources to connect the input and output wavelengths, and also in limiting added noise photons due to the strong classical pump fields. These challenges are more acute as the local quantum system’s operating wavelength decreases and moves further away from the telecommunications band. A second approach to connecting photonic quantum systems over distance is through suitably engineered entangled photon pair sources. In particular, quantum memories can be remotely entangled via entanglement swapping 6 , 7 , in which photons entangled with the two distant memories propagate towards each other and meet, where they are subjected to a Bell-state measurement. For visible/short-NIR memories, the propagation distance in optical fibre is limited as described above. To overcome this limitation, one can introduce entangled photon pair sources in which one photon is resonant with the memory (that is, at a visible wavelength) and the other is in the telecom band (Fig. 1 ). Successive entanglement swapping operations can then entangle the memories, with their separation now limited by the propagation distance in optical fibre in the telecom band. Such visible–telecom pair sources might also find use in related scenarios—for example, Bell inequality violations using nitrogen–vacancy centre spins in diamond 8 . Fig. 1: Motivation and scheme for a chip-integrated visible–telecom entangled photon pair source. a , Intended application, where photon pairs generated from a silicon nitride nanophotonic chip (centre) connect the visible and telecommunication bands, to enable a link between a nitrogen–vacancy centre in diamond (left) and the telecom fibre network (right), for example. b , Scheme for cavity-enhanced SFWM. The continuous-wave, classical pump field at frequency ω p generates signal and idler photons at ω s and ω i , respectively, dictated by energy conservation 2 ω p = ω s + ω i . The nearest relevant cavity mode frequencies are at ${\hat{\omega }}_{\rm p}$ , ${\hat{\omega }}_{\rm s}$ and ${\hat{\omega }}_{\rm i}$ , respectively. Phase-matching of light generated in these optical modes is equivalent to the condition on the cavity azimuthal mode numbers m that 2 m p = m s + m i . c , Examples of local quantum systems with optical transitions in the visible/short NIR band (left), and classification of the telecommunications wavelength bands (right). Full size image Existing visible–telecom photon pair sources are in platforms such as periodically poled nonlinear crystals 9 , photonic crystal fibres 10 and millimeter-scale crystalline microresonators 11 . The first two platforms generate broadband photons, so that spectral filtering to achieve the narrow linewidths needed for interaction with local quantum systems must be implemented. Filtering after pair generation comes at the price of a decrease in collection efficiency and signal-to-noise ratio, so incorporation of the nonlinear medium into a macroscopic cavity 12 , 13 , 14 has been pursued. The crystalline microresonator platform, although promising, currently exhibits a coincidence-to-accidental ratio (CAR) below 20, which can be a constraint in applications. In general, these platforms all lack the potential for scalable fabrication and integration common to the planar systems used in nanophotonics. A nanophotonic device platform for narrow-linewidth, high-quality visible–telecom photon pairs is the whispering gallery mode microresonator based on silicon photonics 15 . Recent studies have documented promising characteristics for photon pair sources based on spontaneous four-wave mixing (SFWM) in the telecommunications band, including sub-milliwatt optical pump power, high spectral brightness and high photon purity 16 , 17 , 18 , 19 , 20 , 21 , and the potential for large-scale integration 22 . Whereas silicon’s narrow bandgap forbids operation below 1.1 μm, stoichiometric silicon nitride (Si 3 N 4 ) has a much wider bandgap, enabling operation across wavelengths from the near-ultraviolet to the mid-infrared. Such broadband performance has been exploited in octave-spanning optical frequency combs 23 , 24 , 25 , and such microcombs have been operated sub-threshold to generate high-dimensional, frequency-bin entangled photon pairs in the telecom band<|im_end|> <|im_start|>assistant Some of the most advanced communication systems now under development rely on the properties of quantum science to store and transport information. However, researchers designing quantum communication systems that rely on light, rather than electric current, to transmit information face a quandary: The optical components that store and process quantum information typically require visible-light photons (particles of light) to operate. However, only near-infrared photons—with wavelengths about 10 times longer—can transport that information over kilometers of optical fibers. Now, researchers at the National Institute of Standards and Technology (NIST) have developed a novel way to solve this problem. For the first time, the team created quantum-correlated pairs made up of one visible and one near-infrared photon using chip-based optical components that can be mass-produced. These photon pairs combine the best of both worlds: The visible-light partners can interact with trapped atoms, ions, or other systems that serve as quantum versions of computer memory while the near-infrared members of each couple are free to propagate over long distances through the optical fiber. The achievement promises to boost the ability of light-based circuits to securely transmit information to faraway locations. NIST researchers Xiyuan Lu, Kartik Srinivasan and their colleagues at the University of Maryland NanoCenter in College Park, demonstrated the quantum correlation, known as entanglement, using a specific pair of visible-light and near-infrared photons. However, the researchers' design methods can be easily applied to create many other visible-light/near-infrared pairs tailored to match specific systems of interest. Moreover, the miniature optical components that created the entanglements are manufactured in large numbers. Lu, Srinivasan and their colleagues recently described their work in Nature Physics. One of the more counterintuitive properties of quantum mechanics, quantum entanglement occurs when two or more photons or other particles are prepared in a way that makes them so intrinsically connected that they behave as one unit. A measurement that determines the quantum state of one of the entangled particles automatically determines the state of the other, even if the two particles lie on opposite sides of the universe. Entanglement lies at the heart of many quantum information schemes, including quantum computing and encryption. In many situations, the two photons that are entangled have similar wavelengths, or colors. But the NIST researchers deliberately set out to create odd couples—entanglement between photons whose colors are very different. "We wanted to link together visible-light photons, which are good for storing information in atomic systems, and telecommunication photons, which are in the near-infrared and good at traveling through optical fibers with low signal loss," said Srinivasan. To make photons suitable for interacting with most quantum information storage systems, the team also needed the light to be sharply peaked at a particular wavelength rather than having a broader, more diffuse distribution. To create the entangled pairs, the team constructed a specially tailored optical "whispering gallery"—a nano-sized silicon nitride resonator that steers light around a tiny racetrack, similar to the way sound waves travel unimpeded around a curved wall such as the dome in St. Paul's Cathedral in London. In such curved structures, known as acoustic whispering galleries, a person standing near one part of the wall easily hears a faint sound originating at any other part of the wall. When a selected wavelength of laser light was directed into the resonator, entangled pairs of visible-light and near-infrared photons emerged. (The specific type of entanglement employed in the experiment, known as time-energy entanglement, links the energy of the photon pairs with the time at which they are generated.) "We figured out how to engineer these whispering gallery resonators to produce large numbers of the pairs we wanted, with very little background noise and other extraneous light," Lu said. The researchers confirmed that entanglement persisted even after the telecommunication photons traveled through several kilometers of optical fiber. In the future, by combining two of the entangled pairs with two quantum memories, the entanglement inherent in the photon pairs can be transferred to the quantum memories. This technique, known as entanglement swapping, allows the memories to be entangled with each other over a much longer distance than would normally be possible. "Our contribution was to figure out how to make a quantum light source with the right properties that could enable such long-distance entanglement," Srinivasan 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 Cardiac involvement has been noted in COVID-19 infection. However, the relationship between post-recovery COVID-19 and development of de novo heart failure has not been investigated in a large, nationally representative population. We examined post-recovery outcomes of 587,330 patients hospitalized in the United States (257,075 with COVID-19 and 330,255 without), using data from the National COVID Cohort Collaborative study. Patients hospitalized with COVID-19 were older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). Over a median follow up of 367 days, 10,979 incident heart failure events occurred. After adjustments, COVID-19 hospitalization was associated with a 45% higher hazard of incident heart failure (hazard ratio = 1.45; 95% confidence interval: 1.39–1.51), with more pronounced associations among patients who were younger ( P -interaction = 0.003), White ( P- interaction = 0.005), or who had established cardiovascular disease ( P- interaction = 0.005). In conclusion, COVID-19 hospitalization is associated with increased risk of incident heart failure. Introduction The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in unprecedented morbidity and mortality with several long-term complications, including cardiac and respiratory disorders and an increased risk of premature death, among those who recover 1 , 2 . Despite the absence of significant lung damage in many patients discharged from COVID-19 hospitalization, post-recovery dyspnea and fatigue have been reported, with almost 87% of patients experiencing persistent, post-discharge symptoms 3 . The ‘long-hauler’ phenomenon has been described in patients suffering from chronic symptoms following recovery from COVID-19 infection 4 . However, despite its important clinical implications, there is limited understanding of the pathophysiology and etiology driving these symptoms. Because inflammation is a central pathophysiological mechanism shared by both COVID-19 and heart failure (HF) 5 , an association between COVID-19 and incident HF may exist. In support of this, among 3080 consecutive patients presenting to the emergency department with COVID-19 infection, 60 without prior history of HF were subsequently admitted for acute HF 6 . Further, an analysis from the US Department of Veterans Affairs (VA) national healthcare system showed that military veterans who recovered from COVID-19 were at increased risk of incident cardiovascular diseases, including heart failure 7 . This study demonstrates a significant burden of incident heart failure among COVID-19 survivors; however, the demographic composition, which consisted of veterans who were mostly older males, limits the generalizability of this association to the general population 7 . Herein, we examine the association between COVID-19 recovery and incident HF in a large-scale, population-based, nationally representative study. Results At the time of our analysis, the N3C enclave included electronic health records (EHRs) for inpatient and outpatient encounters for over 12 million unique patients. We limited our study population to patients with a hospitalization occurring during the March 1, 2020–March 31, 2022 interval. A total of 355,673 unique patients with a first-occurring COVID-19 diagnosis date during inpatient hospitalization were identified. Of these, 257,075 survived to discharge and had no prior history of HF. During the same time interval, a total of 2,560,320 unique patients hospitalized without COVID-19 diagnosis were identified. To speed computer processing times, a random sample (15% of the total) was taken, amounting to 384,048 unique patients without COVID-19 infection. Of these, 330,255 survived to discharge and had no prior history of HF. Our total study population included 587,330 unique patients, with the selection flowchart shown in Fig. 1 . Fig. 1: Study population flowchart. The total study population included 587,330 unique patients as in the following selection flowchart. Full size image Patients hospitalized with COVID-19 were generally older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). The prevalence of diabetes was notably higher among patients hospitalized with COVID-19 (24% vs. 16%). History of hypertension (42% vs. 38%) and chronic kidney disease (11% vs. 8%) were also slightly more prevalent; however, the prevalence of obesity, coronary artery disease and chronic lung disease were largely comparable between the two groups (Table 1 ). Patients with COVID-19 hospitalization were similarly likely to be managed by an angiotensin converting enzyme inhibitor (ACEi), angiotensin II receptor blockers (ARBs), or statins, but less likely to be managed by beta blockers (22% vs. 26%). Table 1 Baseline demographic and clinical characteristics of patients hospitalized with and without COVID-19. Full size table Over a median follow up of 367 (25th–75th percentiles: 190–536) days, 10,979 incident HF events and 17,641 deaths occurred. Patients discharged from COVID-19 hospitalizations had a higher cumulative incidence of post-discharge HF (2.3% vs. 1.5%), a higher mortality rate (3.3% vs. 2.6%) and a higher cumulative incidence of composite death or incident HF (5.2% vs. 4.0%) than patients hospitalized without COVID-19 (Table 2 ). The crude incidence rate of HF was also higher for patients discharged from COVID-19 hospitalization (2.55 events per 100 person-years [p.y.] vs. 1.44 events per 100 p.y.). The median follow up to incident HF was shorter for patients discharged from COVID-19 hospitalization (69 vs. 84 days). However, a similar proportion of incident HF cases occurred within 30 days of discharge, when comparing patients with COVID-19 hospitalization (1914/5879, 33%) to those without COVID-19 hospitalization (1506/5100, 30%). Table 2 Summary of post-hospitalization follow up and events among patients with and without COVID-19 hospitalization. Full size table Biomarkers of cardiac injury were not commonly assayed at the index hospitalization. However, a higher percentage of patients with COVID-19 hospitalization had measured natriuretic peptides (23% vs. 6%) or cardiac troponins (21% vs. 8%), compared to patients without COVID-19 hospitalization. Median troponin levels were similar between the two groups, while median levels for natriuretic peptides were slightly higher in patients without COVID-19 hospitalization. Among the cases with subsequent incident HF, elevated natriuretic peptides were noted at the index hospitalization in 19% and 12%, respectively, for patients with and without COVID-19 hospitalization (Table 3 ). Table 3 Cardiac biomarkers assayed at index hospitalization for patients with and without COVID-19 infection. Full size table Without adjustments, post-recovery COVID-19 was associated with", "role": "user" }, { "content": "People hospitalized for COVID-19 were more likely to have heart failure after their discharge than those hospitalized for another reason, a Duke University study published this month found. The study's findings, published in Nature Communications, support a growing body of research that suggests some people infected with COVID-19 go on to develop long-term heart problems. Using health records of more than 580,000 patients admitted to U.S. hospitals, Duke researchers tracked how often those who had COVID went to the hospital for heart issues in the year after their discharge. They found the COVID group was 45% more likely to be diagnosed with heart failure when compared to patients hospitalized with something other than COVID. Duke's study is the first to look at this question in a large, racially diverse population, said Dr. Marat Fudim, a Duke cardiologist and author on the paper. A paper published in February found a similar link between cardiovascular disease, including heart failure, and COVID hospitalization in US Veterans Affairs hospital patients. Fudim said that heart disease might in time be revealed to be a complication for those who had a milder COVID-19 infection. \"I think the next few years, we will uncover the true burden of long COVID,\" he said. \"This article just tells us the worst of the worst.\" An imperfect study Fudim is the first to admit that his study has limitations. He and other researchers used a data set from past hospitalizations and retrospectively ran an analysis. Which means that they can't say that COVID-19 causes heart failure—only that it's associated. Randomized, controlled experiments are the gold standard in scientific research because researchers randomly assign participants to the groups they're comparing, making each group as similar as possible. But randomly assigning a group of people to contract COVID-19 isn't ethical or feasible. Right now, Fudim's study design is the best way scientists have to study the long-term impacts of COVID-19, said Dr. Ziyad Al- Aly, an assistant professor of medicine at Washington University in St. Louis who authored the paper on VA hospitals. \"The truth is there is never, ever going to be a randomized study for COVID,\" he said. Not everyone is convinced the findings point to a severe side effect from COVID. There may be too many other factors that could explain the link between a COVID hospitalization and heart failure, said Dr. Christopher Kelly, UNC cardiologist. For example, people who were hospitalized with COVID-19 likely had pre-existing health conditions that could also explain why they went on to develop heart failure, Kelly said. Those hospitalized for a non-COVID problem don't necessarily have those same chronic health problems if they were in the hospital for a minor procedure like gallbladder surgery, he said. The Duke researchers statistically adjusted for a number of health problems that could go on to cause heart failure like obesity, diabetes, hypertension and kidney disease. Still, Kelly said there's no way to perfectly adjust for the differences between the groups. Al-Aly said the Duke researchers could have made the study design slightly better by comparing the hospitalized COVID-19 patients to those hospitalized for an infection, who are more likely to have a similar set of preexisting health problems. \"There are tons of ways that you can explain the data that don't involve blaming COVID for them developing heart failure later,\" Kelly said. \"There are differences that are unmeasurable and there are differences that you haven't thought about.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cardiac involvement has been noted in COVID-19 infection. However, the relationship between post-recovery COVID-19 and development of de novo heart failure has not been investigated in a large, nationally representative population. We examined post-recovery outcomes of 587,330 patients hospitalized in the United States (257,075 with COVID-19 and 330,255 without), using data from the National COVID Cohort Collaborative study. Patients hospitalized with COVID-19 were older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). Over a median follow up of 367 days, 10,979 incident heart failure events occurred. After adjustments, COVID-19 hospitalization was associated with a 45% higher hazard of incident heart failure (hazard ratio = 1.45; 95% confidence interval: 1.39–1.51), with more pronounced associations among patients who were younger ( P -interaction = 0.003), White ( P- interaction = 0.005), or who had established cardiovascular disease ( P- interaction = 0.005). In conclusion, COVID-19 hospitalization is associated with increased risk of incident heart failure. Introduction The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in unprecedented morbidity and mortality with several long-term complications, including cardiac and respiratory disorders and an increased risk of premature death, among those who recover 1 , 2 . Despite the absence of significant lung damage in many patients discharged from COVID-19 hospitalization, post-recovery dyspnea and fatigue have been reported, with almost 87% of patients experiencing persistent, post-discharge symptoms 3 . The ‘long-hauler’ phenomenon has been described in patients suffering from chronic symptoms following recovery from COVID-19 infection 4 . However, despite its important clinical implications, there is limited understanding of the pathophysiology and etiology driving these symptoms. Because inflammation is a central pathophysiological mechanism shared by both COVID-19 and heart failure (HF) 5 , an association between COVID-19 and incident HF may exist. In support of this, among 3080 consecutive patients presenting to the emergency department with COVID-19 infection, 60 without prior history of HF were subsequently admitted for acute HF 6 . Further, an analysis from the US Department of Veterans Affairs (VA) national healthcare system showed that military veterans who recovered from COVID-19 were at increased risk of incident cardiovascular diseases, including heart failure 7 . This study demonstrates a significant burden of incident heart failure among COVID-19 survivors; however, the demographic composition, which consisted of veterans who were mostly older males, limits the generalizability of this association to the general population 7 . Herein, we examine the association between COVID-19 recovery and incident HF in a large-scale, population-based, nationally representative study. Results At the time of our analysis, the N3C enclave included electronic health records (EHRs) for inpatient and outpatient encounters for over 12 million unique patients. We limited our study population to patients with a hospitalization occurring during the March 1, 2020–March 31, 2022 interval. A total of 355,673 unique patients with a first-occurring COVID-19 diagnosis date during inpatient hospitalization were identified. Of these, 257,075 survived to discharge and had no prior history of HF. During the same time interval, a total of 2,560,320 unique patients hospitalized without COVID-19 diagnosis were identified. To speed computer processing times, a random sample (15% of the total) was taken, amounting to 384,048 unique patients without COVID-19 infection. Of these, 330,255 survived to discharge and had no prior history of HF. Our total study population included 587,330 unique patients, with the selection flowchart shown in Fig. 1 . Fig. 1: Study population flowchart. The total study population included 587,330 unique patients as in the following selection flowchart. Full size image Patients hospitalized with COVID-19 were generally older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). The prevalence of diabetes was notably higher among patients hospitalized with COVID-19 (24% vs. 16%). History of hypertension (42% vs. 38%) and chronic kidney disease (11% vs. 8%) were also slightly more prevalent; however, the prevalence of obesity, coronary artery disease and chronic lung disease were largely comparable between the two groups (Table 1 ). Patients with COVID-19 hospitalization were similarly likely to be managed by an angiotensin converting enzyme inhibitor (ACEi), angiotensin II receptor blockers (ARBs), or statins, but less likely to be managed by beta blockers (22% vs. 26%). Table 1 Baseline demographic and clinical characteristics of patients hospitalized with and without COVID-19. Full size table Over a median follow up of 367 (25th–75th percentiles: 190–536) days, 10,979 incident HF events and 17,641 deaths occurred. Patients discharged from COVID-19 hospitalizations had a higher cumulative incidence of post-discharge HF (2.3% vs. 1.5%), a higher mortality rate (3.3% vs. 2.6%) and a higher cumulative incidence of composite death or incident HF (5.2% vs. 4.0%) than patients hospitalized without COVID-19 (Table 2 ). The crude incidence rate of HF was also higher for patients discharged from COVID-19 hospitalization (2.55 events per 100 person-years [p.y.] vs. 1.44 events per 100 p.y.). The median follow up to incident HF was shorter for patients discharged from COVID-19 hospitalization (69 vs. 84 days). However, a similar proportion of incident HF cases occurred within 30 days of discharge, when comparing patients with COVID-19 hospitalization (1914/5879, 33%) to those without COVID-19 hospitalization (1506/5100, 30%). Table 2 Summary of post-hospitalization follow up and events among patients with and without COVID-19 hospitalization. Full size table Biomarkers of cardiac injury were not commonly assayed at the index hospitalization. However, a higher percentage of patients with COVID-19 hospitalization had measured natriuretic peptides (23% vs. 6%) or cardiac troponins (21% vs. 8%), compared to patients without COVID-19 hospitalization. Median troponin levels were similar between the two groups, while median levels for natriuretic peptides were slightly higher in patients without COVID-19 hospitalization. Among the cases with subsequent incident HF, elevated natriuretic peptides were noted at the index hospitalization in 19% and 12%, respectively, for patients with and without COVID-19 hospitalization (Table 3 ). Table 3 Cardiac biomarkers assayed at index hospitalization for patients with and without COVID-19 infection. Full size table Without adjustments, post-recovery COVID-19 was associated with<|im_end|> <|im_start|>assistant People hospitalized for COVID-19 were more likely to have heart failure after their discharge than those hospitalized for another reason, a Duke University study published this month found. The study's findings, published in Nature Communications, support a growing body of research that suggests some people infected with COVID-19 go on to develop long-term heart problems. Using health records of more than 580,000 patients admitted to U.S. hospitals, Duke researchers tracked how often those who had COVID went to the hospital for heart issues in the year after their discharge. They found the COVID group was 45% more likely to be diagnosed with heart failure when compared to patients hospitalized with something other than COVID. Duke's study is the first to look at this question in a large, racially diverse population, said Dr. Marat Fudim, a Duke cardiologist and author on the paper. A paper published in February found a similar link between cardiovascular disease, including heart failure, and COVID hospitalization in US Veterans Affairs hospital patients. Fudim said that heart disease might in time be revealed to be a complication for those who had a milder COVID-19 infection. "I think the next few years, we will uncover the true burden of long COVID," he said. "This article just tells us the worst of the worst." An imperfect study Fudim is the first to admit that his study has limitations. He and other researchers used a data set from past hospitalizations and retrospectively ran an analysis. Which means that they can't say that COVID-19 causes heart failure—only that it's associated. Randomized, controlled experiments are the gold standard in scientific research because researchers randomly assign participants to the groups they're comparing, making each group as similar as possible. But randomly assigning a group of people to contract COVID-19 isn't ethical or feasible. Right now, Fudim's study design is the best way scientists have to study the long-term impacts of COVID-19, said Dr. Ziyad Al- Aly, an assistant professor of medicine at Washington University in St. Louis who authored the paper on VA hospitals. "The truth is there is never, ever going to be a randomized study for COVID," he said. Not everyone is convinced the findings point to a severe side effect from COVID. There may be too many other factors that could explain the link between a COVID hospitalization and heart failure, said Dr. Christopher Kelly, UNC cardiologist. For example, people who were hospitalized with COVID-19 likely had pre-existing health conditions that could also explain why they went on to develop heart failure, Kelly said. Those hospitalized for a non-COVID problem don't necessarily have those same chronic health problems if they were in the hospital for a minor procedure like gallbladder surgery, he said. The Duke researchers statistically adjusted for a number of health problems that could go on to cause heart failure like obesity, diabetes, hypertension and kidney disease. Still, Kelly said there's no way to perfectly adjust for the differences between the groups. Al-Aly said the Duke researchers could have made the study design slightly better by comparing the hospitalized COVID-19 patients to those hospitalized for an infection, who are more likely to have a similar set of preexisting health problems. "There are tons of ways that you can explain the data that don't involve blaming COVID for them developing heart failure later," Kelly said. "There are differences that are unmeasurable and there are differences that you haven't thought about." <|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 mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown how frequently such contacts occur, how long they last and how they depend on the dynamics of chromosome folding and loop extrusion activity of cohesin. By imaging chromosomal locations at high spatial and temporal resolution in living cells, we show that interactions within topologically associating domains are transient and occur frequently during the course of a cell cycle. Interactions become more frequent and longer in the presence of convergent CTCF sites, resulting in suppression of variability in chromosome folding across time. Supported by physical models of chromosome dynamics, our data suggest that CTCF-anchored loops last around 10 min. Our results show that long-range transcriptional regulation might rely on transient physical proximity, and that cohesin and CTCF stabilize highly dynamic chromosome structures, facilitating selected subsets of chromosomal interactions. Main In mammalian cells, interactions between chromosomal sequences play important roles in fundamental processes such as DNA replication 1 , repair 2 and transcriptional regulation by distal enhancers 3 . Chromosome conformation capture (3C) methods, which measure physical proximity between genomic sequences in fixed cells, revealed that chromosomal contacts are organized into submegabase domains of preferential interactions known as topologically associating domains (TADs) 4 , 5 whose boundaries can functionally insulate regulatory sequences 3 . TADs mainly arise from nested interactions between convergently oriented binding sites of the DNA-binding protein CTCF, which are established as chromatin-bound CTCF arrests the loop extrusion activity of the cohesin complex 6 , 7 , 8 , 9 , 10 . Determining the timing and duration of chromosomal interactions within TADs and their relationship with CTCF and cohesin is key to understanding how enhancers communicate with promoters 11 , 12 . Single-cell analyses of chromosome structure in fixed cells 4 , 13 , 14 , 15 , chromosome tracing experiments 16 , 17 , 18 , 19 , in vitro 9 , 10 , 20 and live-cell 21 measurements of CTCF and cohesin dynamics, and polymer simulations 6 , 15 , 22 , as well as live-cell imaging of chromosomal locations and nascent RNA 23 , 24 , all suggested that TADs and CTCF loops are dynamic structures whose temporal evolution might be governed by the kinetics of loop extrusion 25 . Recent live-cell measurements of a CTCF loop connecting two opposite TAD boundaries in mouse embryonic stem cells (mESCs) provided direct evidence that this is the case, and revealed that cohesin-mediated loops between CTCF sites located 500 kilobases (kb) away last 10–30 min (ref. 26 ). However, it is still unclear if contacts between sequences separated by genomic distances where enhancers and promoters interact within the same TAD occur on the timescale of seconds, minutes or hours. We also have little knowledge on whether and how rates and durations of such contacts are modulated by loop extrusion. We finally do not know if cohesin increases chromosome mobility and thus favors the encounters between genomic sequences by reeling them into loops, or if instead it provides constraints that decrease mobility and prolong the duration of such encounters. Both scenarios have been suggested to be possible theoretically 27 , 28 , but it is unclear which effect dominates in living cells. Here we use live-cell fluorescence microscopy to measure chromosome dynamics and its dependence on cohesin and CTCF in mESCs. By combining two live-cell imaging strategies with polymer simulations, we reveal that loops extruded by cohesin constrain global chromosome motion, while also increasing the temporal frequencies and durations of physical encounters between sequences inside the same TAD. Convergent CTCF sites substantially stabilize contacts through cohesin-mediated CTCF-anchored loops that last around 5–15 min on average. Our results support the notion that chromosome structure within single TADs is highly dynamic during the span of a cell cycle and thus that long-range transcriptional regulation might rely on transient physical proximity between genomic sequences. They also reveal how contact dynamics and the temporal variability in chromosome folding are modulated by cohesin and CTCF in single living cells and provide a quantitative framework for understanding the role of folding dynamics in fundamental biological processes. Results Cohesin decreases chromosome mobility independently of CTCF To study how cohesin and CTCF influence the global dynamics of the chromatin fiber independently of local chromatin state and structural differences, we examined the dynamic properties of large numbers of random genomic locations in living cells. We generated clonal mESC lines carrying multiple random integrations of an array of ~140 repeats of the bacterial Tet operator sequence (TetO) using piggyBac transposition 29 . These can be visualized upon binding of Tet repressor (TetR) fused to the red fluorescent protein tdTomato. To compare the motion of genomic locations that either block or allow the loop extrusion activity of cohesin, the TetO array was adjacent to three CTCF motifs (3 × CTCF) that could be removed by Cre-assisted recombination (Fig. 1a ). Motifs were selected based on high CTCF enrichment in chromatin immunoprecipitation followed by sequencing (ChIP–seq) and each was confirmed to be bound by CTCF in nearly 100% of alleles at any time in mESCs using dual-enzyme single-molecule footprinting 30 (R. Grand and D. Schübeler, personal communication), thus providing a close experimental representative of an ‘impermeable’ loop extrusion barrier. Fig. 1: Cohesin slows down chromosome dynamics in living cells. a , Clonal mESC lines containing random TetO arrays flanked by 3 × CTCF motifs and expressing TetR-tdTomato. Constructs were integrated using piggyBac transposition in mESCs allowing auxin-inducible degradation of GFP-tagged RAD21, WAPL or CTCF. ITR, inverted terminal repeats. b , Representative images of RAD21-AID-eGFP cells containing 3 × CTCF-TetO imaged before or after 90 min of auxin treatment (exposure time eGFP and tdTomato: 50 ms, deconvolved, maximum intensity projection, bicubic interpolation, n = 3 replicates). c , Left, time series of TetR-tdTomato signal over 30 min (maximum intensity projection, time interval dt = 10 s, color-coded for intensity changes over time). Right, magnification with overlay of TetR-tdTomato signal with", "role": "user" }, { "content": "New work by Friedrich Miescher Institute researchers shows that key proteins help to stabilize the interaction between otherwise highly dynamic DNA structures. The findings shed light onto how the complex folds that help to fit nearly two meters of DNA into the cell's nucleus influence important biological processes. The genome is organized into 3D structures that can control gene expression by bringing genes together with their regulatory elements. However, it is unknown if contacts between DNA sequences are rare and stable or if they are frequent and transient. Researchers in the group of Luca Giorgetti tagged sequences within self-interacting DNA regions with fluorescent proteins. Then, they watched how the sequences interacted with each other in living cells over several hours. The researchers found that the DNA sequences frequently came into close proximity, but they stayed next to each other only for a few minutes. The contacts became longer and more frequent in the presence of the cohesin protein complex and of DNA snippets that are typically bound by a protein called CTCF. In the cell, CTCF and cohesin help to shape the DNA molecule into loops of various sizes. The team also developed physical models of chromosome dynamics, which suggest that DNA loops that are pinched together by CTCF can last up to 15 minutes. The paper is published in the journal Nature Genetics. The findings shed light onto how these complex folds influence key processes such as the regulation of gene expression. Credit: Friedrich Miescher Institute for Biomedical Research ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown how frequently such contacts occur, how long they last and how they depend on the dynamics of chromosome folding and loop extrusion activity of cohesin. By imaging chromosomal locations at high spatial and temporal resolution in living cells, we show that interactions within topologically associating domains are transient and occur frequently during the course of a cell cycle. Interactions become more frequent and longer in the presence of convergent CTCF sites, resulting in suppression of variability in chromosome folding across time. Supported by physical models of chromosome dynamics, our data suggest that CTCF-anchored loops last around 10 min. Our results show that long-range transcriptional regulation might rely on transient physical proximity, and that cohesin and CTCF stabilize highly dynamic chromosome structures, facilitating selected subsets of chromosomal interactions. Main In mammalian cells, interactions between chromosomal sequences play important roles in fundamental processes such as DNA replication 1 , repair 2 and transcriptional regulation by distal enhancers 3 . Chromosome conformation capture (3C) methods, which measure physical proximity between genomic sequences in fixed cells, revealed that chromosomal contacts are organized into submegabase domains of preferential interactions known as topologically associating domains (TADs) 4 , 5 whose boundaries can functionally insulate regulatory sequences 3 . TADs mainly arise from nested interactions between convergently oriented binding sites of the DNA-binding protein CTCF, which are established as chromatin-bound CTCF arrests the loop extrusion activity of the cohesin complex 6 , 7 , 8 , 9 , 10 . Determining the timing and duration of chromosomal interactions within TADs and their relationship with CTCF and cohesin is key to understanding how enhancers communicate with promoters 11 , 12 . Single-cell analyses of chromosome structure in fixed cells 4 , 13 , 14 , 15 , chromosome tracing experiments 16 , 17 , 18 , 19 , in vitro 9 , 10 , 20 and live-cell 21 measurements of CTCF and cohesin dynamics, and polymer simulations 6 , 15 , 22 , as well as live-cell imaging of chromosomal locations and nascent RNA 23 , 24 , all suggested that TADs and CTCF loops are dynamic structures whose temporal evolution might be governed by the kinetics of loop extrusion 25 . Recent live-cell measurements of a CTCF loop connecting two opposite TAD boundaries in mouse embryonic stem cells (mESCs) provided direct evidence that this is the case, and revealed that cohesin-mediated loops between CTCF sites located 500 kilobases (kb) away last 10–30 min (ref. 26 ). However, it is still unclear if contacts between sequences separated by genomic distances where enhancers and promoters interact within the same TAD occur on the timescale of seconds, minutes or hours. We also have little knowledge on whether and how rates and durations of such contacts are modulated by loop extrusion. We finally do not know if cohesin increases chromosome mobility and thus favors the encounters between genomic sequences by reeling them into loops, or if instead it provides constraints that decrease mobility and prolong the duration of such encounters. Both scenarios have been suggested to be possible theoretically 27 , 28 , but it is unclear which effect dominates in living cells. Here we use live-cell fluorescence microscopy to measure chromosome dynamics and its dependence on cohesin and CTCF in mESCs. By combining two live-cell imaging strategies with polymer simulations, we reveal that loops extruded by cohesin constrain global chromosome motion, while also increasing the temporal frequencies and durations of physical encounters between sequences inside the same TAD. Convergent CTCF sites substantially stabilize contacts through cohesin-mediated CTCF-anchored loops that last around 5–15 min on average. Our results support the notion that chromosome structure within single TADs is highly dynamic during the span of a cell cycle and thus that long-range transcriptional regulation might rely on transient physical proximity between genomic sequences. They also reveal how contact dynamics and the temporal variability in chromosome folding are modulated by cohesin and CTCF in single living cells and provide a quantitative framework for understanding the role of folding dynamics in fundamental biological processes. Results Cohesin decreases chromosome mobility independently of CTCF To study how cohesin and CTCF influence the global dynamics of the chromatin fiber independently of local chromatin state and structural differences, we examined the dynamic properties of large numbers of random genomic locations in living cells. We generated clonal mESC lines carrying multiple random integrations of an array of ~140 repeats of the bacterial Tet operator sequence (TetO) using piggyBac transposition 29 . These can be visualized upon binding of Tet repressor (TetR) fused to the red fluorescent protein tdTomato. To compare the motion of genomic locations that either block or allow the loop extrusion activity of cohesin, the TetO array was adjacent to three CTCF motifs (3 × CTCF) that could be removed by Cre-assisted recombination (Fig. 1a ). Motifs were selected based on high CTCF enrichment in chromatin immunoprecipitation followed by sequencing (ChIP–seq) and each was confirmed to be bound by CTCF in nearly 100% of alleles at any time in mESCs using dual-enzyme single-molecule footprinting 30 (R. Grand and D. Schübeler, personal communication), thus providing a close experimental representative of an ‘impermeable’ loop extrusion barrier. Fig. 1: Cohesin slows down chromosome dynamics in living cells. a , Clonal mESC lines containing random TetO arrays flanked by 3 × CTCF motifs and expressing TetR-tdTomato. Constructs were integrated using piggyBac transposition in mESCs allowing auxin-inducible degradation of GFP-tagged RAD21, WAPL or CTCF. ITR, inverted terminal repeats. b , Representative images of RAD21-AID-eGFP cells containing 3 × CTCF-TetO imaged before or after 90 min of auxin treatment (exposure time eGFP and tdTomato: 50 ms, deconvolved, maximum intensity projection, bicubic interpolation, n = 3 replicates). c , Left, time series of TetR-tdTomato signal over 30 min (maximum intensity projection, time interval dt = 10 s, color-coded for intensity changes over time). Right, magnification with overlay of TetR-tdTomato signal with<|im_end|> <|im_start|>assistant New work by Friedrich Miescher Institute researchers shows that key proteins help to stabilize the interaction between otherwise highly dynamic DNA structures. The findings shed light onto how the complex folds that help to fit nearly two meters of DNA into the cell's nucleus influence important biological processes. The genome is organized into 3D structures that can control gene expression by bringing genes together with their regulatory elements. However, it is unknown if contacts between DNA sequences are rare and stable or if they are frequent and transient. Researchers in the group of Luca Giorgetti tagged sequences within self-interacting DNA regions with fluorescent proteins. Then, they watched how the sequences interacted with each other in living cells over several hours. The researchers found that the DNA sequences frequently came into close proximity, but they stayed next to each other only for a few minutes. The contacts became longer and more frequent in the presence of the cohesin protein complex and of DNA snippets that are typically bound by a protein called CTCF. In the cell, CTCF and cohesin help to shape the DNA molecule into loops of various sizes. The team also developed physical models of chromosome dynamics, which suggest that DNA loops that are pinched together by CTCF can last up to 15 minutes. The paper is published in the journal Nature Genetics. The findings shed light onto how these complex folds influence key processes such as the regulation of gene expression. Credit: Friedrich Miescher Institute for Biomedical Research <|im_end|>

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1,736

[ { "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 An epigenome-wide association study (EWAS) was performed on buccal cells from monozygotic-twins (MZ) reared together as children, but who live apart as adults. Cohorts of twin pairs were used to investigate associations between neighborhood walkability and objectively measured physical activity (PA) levels. Due to dramatic cellular epigenetic sex differences, male and female MZ twin pairs were analyzed separately to identify differential DNA methylation regions (DMRs). A priori comparisons were made on MZ twin pairs discordant on body mass index (BMI), PA levels, and neighborhood walkability. In addition to direct comparative analysis to identify specific DMRs, a weighted genome coexpression network analysis (WGCNA) was performed to identify DNA methylation sites associated with the physiological traits of interest. The pairs discordant in PA levels had epigenetic alterations that correlated with reduced metabolic parameters (i.e., BMI and waist circumference). The DNA methylation sites are associated with over fifty genes previously found to be specific to vigorous PA, metabolic risk factors, and sex. Combined observations demonstrate that behavioral factors, such as physical activity, appear to promote systemic epigenetic alterations that impact metabolic risk factors. The epigenetic DNA methylation sites and associated genes identified provide insight into PA impacts on metabolic parameters and the etiology of obesity. Introduction Regular physical activity (PA) and proper nutrition are the foundations of chronic disease prevention and treatment efforts. However, we have failed to motivate adoption and maintenance of these critical health behaviors at the population level. Strategies to increase levels of PA in the population are a critical public health goal 1 , 2 , 3 , 4 . The role of the “built” environment in supporting health behaviors has received increased attention over the last decade because of the failure of individual-level approaches (i.e., behavior change) to impact this population-level problem (i.e., obesity and associated metabolic syndrome). “Healthy” or “walkable” built environments provide opportunities for PA and better choices for food. These environments potentially lead to lower obesity and associated diseases 5 . Detrimental built environments include sprawling suburbs where automobiles are the only transportation option and fast-food restaurants and strip malls are numerous. This “obesogenic” environment minimizes energy expenditure and maximizes energy intake to promote obesity. While it is known that exposure to an obesogenic built environment negatively influences PA and eating behaviors, it is not clear whether exposure to an obesogenic built environment can affect on a molecular level gene activity 6 . These “molecular signatures” of obesity can be investigated through epigenetics. Our previous work documents “quasi-causal” associations between the built environment and health behaviors in a community-based sample of identical adult twins (monozygotic, MZ) who were reared together as children, but now reside apart 7 , 8 . This unique sample group permits us to address environmental self-selection by accounting for genetic and shared environmental factors that would otherwise introduce selection biases confounding statistical associations. Because MZ twins have the same genetic background and are matched on numerous childhood exposures, they are an ideal sample to study epigenetics and environmental influences on health behaviors and associated health outcomes. Genetic mutation and gene expression correlations in with twin studies have demonstrated that most genome-wide association studies (GWAS) have identified genes with a very low frequency correlation often in less than 1% of the patient population examined 9 . Although twin studies help reduce the variation of the GWAS analysis, negligible correlations or associations with genetic mutations have been observed 10 . Therefore, neither PA nor metabolic parameters (e.g., BMI and waist circumference) have been shown to have a high frequency association with genetic mutations 11 . Gene expression analysis has been more useful to correlate PA and metabolic parameters, which supports the hypothesis that gene expression is involved 12 . However, the molecular control of this gene expression and how PA may impact metabolism is unclear. Observations support a lack of genetic DNA sequence alterations in PA and metabolic pathways. An additional molecular mechanism not involving DNA sequence alterations is epigenetics. Limited associations between PA and metabolic disease have been made using a systems epigenome-wide approach. Since the primary molecular control of gene expression involves epigenetics, environmental factors such as PA may alter epigenetic regulation of gene expression to promote the physiology observed 13 . Classic genetics and genetic mutations do not have the capacity to be environmentally responsive and promote gene expression alterations and physiologies without the inclusion of epigenetics in the process. Therefore, the current study takes a novel systems approach to examine in a genome-wide manner the impacts of PA and metabolic syndrome (e.g., obesity) measures in twin studies with controlled genetics. Epigenetics is defined as “molecular factors and processes around DNA that regulate genome activity, independent of DNA sequence, and are mitotically stable” 14 . Epigenetic factors include DNA methylation, histone modifications, chromatin structure and non-coding RNAs 14 . Epigenetics in part evolved to provide a molecular mechanism to be responsive to the environment and impact biology. Examples of environmental and behavioral factors that can regulate epigenetics to impact physiology include environmental toxicants, nutrition, and stress 14 , 15 . The current study extends these observations to examine the impact of PA 16 on epigenetics and allow associations with metabolic parameters (e.g., BMI and waist circumference) 17 , 18 measures using identical twins (monozygotic, MZ) to control for genetic background variation. The initial analysis used is a standard paired comparison between two groups to identify differential DNA methylated regions (DMRs), as previously described 15 . This is ideal when the specific groups to compare are known, but not as useful with unknown potential correlations. Therefore, an additional analysis was performed involving weighted genome coexpression network analysis (WGCNA) 19 . The ability to use a WGCNA protocol was established for genetic and physiological parameter correlations 20 with the use of primarily gene expression data 21 . The potential of WGCNA to be used for an epigenetic analysis has also been established 22 , 23 . The current study uses WGCNA with epigenetic DNA methylation data to correlate PA and measures", "role": "user" }, { "content": "One might expect identical twins to have the same health outcomes. But it's not just genetics that makes a notable difference in their weight and in how their genes behave, according to a new study. Exercise can alter genetic markers of metabolic disease—any of the diseases or disorders that disrupt normal metabolism. The study could help explain exercise's key role in health. \"The findings provide a molecular mechanism for the link between physical activity and metabolic disease,\" explained study co-author Michael Skinner, a biologist at Washington State University, in Pullman. Scientists have previously found that a majority of identical twins develop different diseases as they get older, even though they have the same genes. Epigenetics—the study of how your behaviors and environment affect the day-to-day function of genes—may explain that, Skinner said. \"Physical exercise is known to reduce the susceptibility to obesity, but now it looks like exercise through epigenetics is affecting a lot of cell types, many of them involved in metabolic disease,\" he noted in a university news release. For this study, the researchers swabbed the cheeks of 70 pairs of identical twins, who also participated in an exercise study through the Washington State Twin Registry. The team, led by registry director Glen Duncan, collected data on the twins at several different points between 2012 and 2019. The researchers used fitness trackers to gauge the twins' activity, measured their waistlines and assessed their body mass indexes (or BMI, an estimate of body fat based on height and weight). Participants also answered questions about their lifestyle and neighborhoods. In many of the twin pairs, the individuals differed in levels of exercise, neighborhood walkability and BMI. The more physically active siblings had lower signs of metabolic disease, measured by waist size and BMI, the findings showed. This correlated with differences in their epigenomes, the molecular processes that influence gene expression. More active twins had epigenetic markers that were linked to lowered metabolic syndrome, a condition that can lead to heart disease, stroke and type 2 diabetes. For those with different behavior, the lab also found epigenetic differences. The twin with a high level of physical activity, defined as more than 150 minutes of exercise a week, had epigenetic changes that correlated with reduced BMI and waist size. The genetic regions where these changes are found are associated with more than 50 genes specific to vigorous physical activity and metabolic risk factors, the researchers reported. Epigenetics may explain why most identical twins develop different diseases as they age, Skinner said. \"If genetics and DNA sequence were the only driver for biology, then essentially twins should have the same diseases. But they don't,\" said Skinner. \"So that means there has to be an environmental impact on the twins that is driving the development of disease.\" The findings were recently published online 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 An epigenome-wide association study (EWAS) was performed on buccal cells from monozygotic-twins (MZ) reared together as children, but who live apart as adults. Cohorts of twin pairs were used to investigate associations between neighborhood walkability and objectively measured physical activity (PA) levels. Due to dramatic cellular epigenetic sex differences, male and female MZ twin pairs were analyzed separately to identify differential DNA methylation regions (DMRs). A priori comparisons were made on MZ twin pairs discordant on body mass index (BMI), PA levels, and neighborhood walkability. In addition to direct comparative analysis to identify specific DMRs, a weighted genome coexpression network analysis (WGCNA) was performed to identify DNA methylation sites associated with the physiological traits of interest. The pairs discordant in PA levels had epigenetic alterations that correlated with reduced metabolic parameters (i.e., BMI and waist circumference). The DNA methylation sites are associated with over fifty genes previously found to be specific to vigorous PA, metabolic risk factors, and sex. Combined observations demonstrate that behavioral factors, such as physical activity, appear to promote systemic epigenetic alterations that impact metabolic risk factors. The epigenetic DNA methylation sites and associated genes identified provide insight into PA impacts on metabolic parameters and the etiology of obesity. Introduction Regular physical activity (PA) and proper nutrition are the foundations of chronic disease prevention and treatment efforts. However, we have failed to motivate adoption and maintenance of these critical health behaviors at the population level. Strategies to increase levels of PA in the population are a critical public health goal 1 , 2 , 3 , 4 . The role of the “built” environment in supporting health behaviors has received increased attention over the last decade because of the failure of individual-level approaches (i.e., behavior change) to impact this population-level problem (i.e., obesity and associated metabolic syndrome). “Healthy” or “walkable” built environments provide opportunities for PA and better choices for food. These environments potentially lead to lower obesity and associated diseases 5 . Detrimental built environments include sprawling suburbs where automobiles are the only transportation option and fast-food restaurants and strip malls are numerous. This “obesogenic” environment minimizes energy expenditure and maximizes energy intake to promote obesity. While it is known that exposure to an obesogenic built environment negatively influences PA and eating behaviors, it is not clear whether exposure to an obesogenic built environment can affect on a molecular level gene activity 6 . These “molecular signatures” of obesity can be investigated through epigenetics. Our previous work documents “quasi-causal” associations between the built environment and health behaviors in a community-based sample of identical adult twins (monozygotic, MZ) who were reared together as children, but now reside apart 7 , 8 . This unique sample group permits us to address environmental self-selection by accounting for genetic and shared environmental factors that would otherwise introduce selection biases confounding statistical associations. Because MZ twins have the same genetic background and are matched on numerous childhood exposures, they are an ideal sample to study epigenetics and environmental influences on health behaviors and associated health outcomes. Genetic mutation and gene expression correlations in with twin studies have demonstrated that most genome-wide association studies (GWAS) have identified genes with a very low frequency correlation often in less than 1% of the patient population examined 9 . Although twin studies help reduce the variation of the GWAS analysis, negligible correlations or associations with genetic mutations have been observed 10 . Therefore, neither PA nor metabolic parameters (e.g., BMI and waist circumference) have been shown to have a high frequency association with genetic mutations 11 . Gene expression analysis has been more useful to correlate PA and metabolic parameters, which supports the hypothesis that gene expression is involved 12 . However, the molecular control of this gene expression and how PA may impact metabolism is unclear. Observations support a lack of genetic DNA sequence alterations in PA and metabolic pathways. An additional molecular mechanism not involving DNA sequence alterations is epigenetics. Limited associations between PA and metabolic disease have been made using a systems epigenome-wide approach. Since the primary molecular control of gene expression involves epigenetics, environmental factors such as PA may alter epigenetic regulation of gene expression to promote the physiology observed 13 . Classic genetics and genetic mutations do not have the capacity to be environmentally responsive and promote gene expression alterations and physiologies without the inclusion of epigenetics in the process. Therefore, the current study takes a novel systems approach to examine in a genome-wide manner the impacts of PA and metabolic syndrome (e.g., obesity) measures in twin studies with controlled genetics. Epigenetics is defined as “molecular factors and processes around DNA that regulate genome activity, independent of DNA sequence, and are mitotically stable” 14 . Epigenetic factors include DNA methylation, histone modifications, chromatin structure and non-coding RNAs 14 . Epigenetics in part evolved to provide a molecular mechanism to be responsive to the environment and impact biology. Examples of environmental and behavioral factors that can regulate epigenetics to impact physiology include environmental toxicants, nutrition, and stress 14 , 15 . The current study extends these observations to examine the impact of PA 16 on epigenetics and allow associations with metabolic parameters (e.g., BMI and waist circumference) 17 , 18 measures using identical twins (monozygotic, MZ) to control for genetic background variation. The initial analysis used is a standard paired comparison between two groups to identify differential DNA methylated regions (DMRs), as previously described 15 . This is ideal when the specific groups to compare are known, but not as useful with unknown potential correlations. Therefore, an additional analysis was performed involving weighted genome coexpression network analysis (WGCNA) 19 . The ability to use a WGCNA protocol was established for genetic and physiological parameter correlations 20 with the use of primarily gene expression data 21 . The potential of WGCNA to be used for an epigenetic analysis has also been established 22 , 23 . The current study uses WGCNA with epigenetic DNA methylation data to correlate PA and measures<|im_end|> <|im_start|>assistant One might expect identical twins to have the same health outcomes. But it's not just genetics that makes a notable difference in their weight and in how their genes behave, according to a new study. Exercise can alter genetic markers of metabolic disease—any of the diseases or disorders that disrupt normal metabolism. The study could help explain exercise's key role in health. "The findings provide a molecular mechanism for the link between physical activity and metabolic disease," explained study co-author Michael Skinner, a biologist at Washington State University, in Pullman. Scientists have previously found that a majority of identical twins develop different diseases as they get older, even though they have the same genes. Epigenetics—the study of how your behaviors and environment affect the day-to-day function of genes—may explain that, Skinner said. "Physical exercise is known to reduce the susceptibility to obesity, but now it looks like exercise through epigenetics is affecting a lot of cell types, many of them involved in metabolic disease," he noted in a university news release. For this study, the researchers swabbed the cheeks of 70 pairs of identical twins, who also participated in an exercise study through the Washington State Twin Registry. The team, led by registry director Glen Duncan, collected data on the twins at several different points between 2012 and 2019. The researchers used fitness trackers to gauge the twins' activity, measured their waistlines and assessed their body mass indexes (or BMI, an estimate of body fat based on height and weight). Participants also answered questions about their lifestyle and neighborhoods. In many of the twin pairs, the individuals differed in levels of exercise, neighborhood walkability and BMI. The more physically active siblings had lower signs of metabolic disease, measured by waist size and BMI, the findings showed. This correlated with differences in their epigenomes, the molecular processes that influence gene expression. More active twins had epigenetic markers that were linked to lowered metabolic syndrome, a condition that can lead to heart disease, stroke and type 2 diabetes. For those with different behavior, the lab also found epigenetic differences. The twin with a high level of physical activity, defined as more than 150 minutes of exercise a week, had epigenetic changes that correlated with reduced BMI and waist size. The genetic regions where these changes are found are associated with more than 50 genes specific to vigorous physical activity and metabolic risk factors, the researchers reported. Epigenetics may explain why most identical twins develop different diseases as they age, Skinner said. "If genetics and DNA sequence were the only driver for biology, then essentially twins should have the same diseases. But they don't," said Skinner. "So that means there has to be an environmental impact on the twins that is driving the development of disease." The findings were recently published online 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 A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico evaluation, but few have yet demonstrated real benefit to patient care. Early-stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use and pave the way to further large-scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multi-stakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two-round, modified Delphi process to collect and analyze expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 pre-defined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. In total, 123 experts participated in the first round of Delphi, 138 in the second round, 16 in the consensus meeting and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI-specific reporting items (made of 28 subitems) and ten generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we developed a guideline comprising key items that should be reported in early-stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings. Main The prospect of improved clinical outcomes and more efficient health systems has fueled a rapid rise in the development and evaluation of AI systems over the last decade. Because most AI systems within healthcare are complex interventions designed as clinical decision support systems, rather than autonomous agents, the interactions among the AI systems, their users and the implementation environments are defining components of the AI interventions’ overall potential effectiveness. Therefore, bringing AI systems from mathematical performance to clinical utility needs an adapted, stepwise implementation and evaluation pathway, addressing the complexity of this collaboration between two independent forms of intelligence, beyond measures of effectiveness alone 1 . Despite indications that some AI-based algorithms now match the accuracy of human experts within preclinical in silico studies 2 , there is little high-quality evidence for improved clinician performance or patient outcomes in clinical studies 3 , 4 . Reasons proposed for this so-called AI chasm 5 are lack of necessary expertise needed for translating a tool into practice, lack of funding available for translation, a general underappreciation of clinical research as a translation mechanism 6 and, more specifically, a disregard for the potential value of the early stages of clinical evaluation and the analysis of human factors 7 . The challenges of early-stage clinical AI evaluation (Box 1 ) are similar to those of complex interventions, as reported by the Medical Research Council dedicated guidance 1 , and surgical innovation, as described by the IDEAL Framework 8 , 9 . For example, in all three cases, the evaluation needs to consider the potential for iterative modification of the interventions and the characteristics of the operators (or users) performing them. In this regard, the IDEAL framework offers readily implementable and stage-specific recommendations for the evaluation of surgical innovations under development. IDEAL stages 2a and 2b, for example, are described as development and exploratory stages, during which the intervention is refined, operators’ learning curves are analyzed and the influence of patient and operator variability on effectiveness are explored prospectively, before large-scale efficacy testing. Early-stage clinical evaluation of AI systems should also place a strong emphasis on validation of performance and safety, in a similar manner to phase 1 and phase 2 pharmaceutical trials, before efficacy evaluation at scale in phase 3. For example, small changes in the distribution of the underlying data between the algorithm training and clinical evaluation populations (so-called dataset shift) can lead to substantial variation in clinical performance and expose patients to potential unexpected harm 10 , 11 . Human factors (or ergonomics) evaluations are commonly conducted in safety-critical fields such as aviation, military and energy sectors 12 , 13 , 14 . Their assessments evaluate the effect of a device or procedure on their users’ physical and cognitive performance and vice-versa. Human factors, such as usability evaluation, are an integral part of the regulatory process for new medical devices 15 , 16 , and their application to AI-specific challenges is attracting growing attention in the medical literature 17 , 18 , 19 , 20 . However, few clinical AI studies have reported on the evaluation of human factors 3 , and usability evaluation of related digital health technology is often performed with inconstant methodology and reporting 21 . Other areas of suboptimal reporting of clinical AI studies have also recently been highlighted 3 , 22 , such as implementation environment, user characteristics and selection process, training provided, underlying algorithm identification and disclosure of funding sources. Transparent reporting is necessary for informed study appraisal and to facilitate reproducibility of study results. In a relatively new and dynamic field such as clinical AI, comprehensive reporting is also key to construct a common and comparable knowledge base to build upon. Guidelines already exist, or are under development, for the reporting of preclinical, in silico studies of AI systems, their offline validation and their evaluation in large comparative studies 23 , 24 , 25 , 26 ; but there is an important stage of research between these, namely studies focusing on the initial clinical use of AI systems, for which no such guidance currently exists (Fig. 1 and Table 1 ). This early clinical evaluation provides a crucial scoping evaluation of clinical utility, safety and human factors challenges in live clinical settings. By investigating the potential obstacles to clinical evaluation at scale and informing protocol design, these studies are also important stepping stones", "role": "user" }, { "content": "New reporting guidelines, jointly published in Nature Medicine and the BMJ by Oxford researchers, will ensure that early studies on using Artificial Intelligence (AI) to treat real patients will give researchers the information needed to develop AI systems safely and effectively. Artificial Intelligence in medicine has shown promising results in numerous simulation studies, but very few AI systems have yet been used in patient care. But as a growing number of AI-driven clinical decision-support systems are progressing from development to implementation, better guidance on the reporting of human factors and early-stage clinical evaluation is needed. Researchers from Oxford have led the development of a new guideline, DECIDE-AI, which aims to improve the reporting of research on AI systems when they are used for the first time in real clinical settings by doctors treating actual patients. It was developed based on opinions and feedback from over 150 experts across 18 countries, including computer scientists, clinicians, ethicists, patient representatives, and entrepreneurs. Baptiste Vasey of Oxford University's Nuffield Department of Surgical Sciences said: \"While AI has shown promising results for clinical application in simulations, very few AI systems have had any significant effect on patient care so far. A major problem has been a lack of robust scientific evidence to back widespread use in clinical practice. \"This study is the first to clearly define the minimum reporting standards for the early stage evaluation of AI-based decision support systems in clinical settings.\" Professor Peter McCulloch, the senior author, also based at the Nuffield Department, said: \"These guidelines take the principles developed for evaluating new surgical operations by the Oxford-based IDEAL Collaboration, and apply them to an important new field where guidance is lacking. The idea that innovation and evaluation should proceed in tandem at every stage in the development of new treatments applies just as much to AI as it does to surgery. Ben Hornsby, Project Coordinator for the IDEAL Collaboration at Oxford's Nuffield Department of Medicine, said: \"DECIDE-AI is only the second reporting guideline dedicated to AI systems research, and the first ever to focus on the development stage of this technology. \"We chose to focus on early-stage evaluation results to emphasize the need for researchers to report transparently about four key aspects of AI research, to build confidence in the technology and highlight the practical benefits and improved efficiencies the technology can bring to health care.\" The factors DECIDE-AI evaluates are: proof of clinical value in a live care environmentthe AI system's safety profile and potential risks for patientshuman factors around the use of the system, such as how the AI system is integrated into the existing care pathway and how it influences clinicians' behaviorthe steps needed to develop the larger-scale trials which will be needed to provide conclusive evidence necessary for an AI system to be accepted into routine patient care. \"Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI,\" is published in Nature Medicine and the BMJ. ", "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 growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico evaluation, but few have yet demonstrated real benefit to patient care. Early-stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use and pave the way to further large-scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multi-stakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two-round, modified Delphi process to collect and analyze expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 pre-defined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. In total, 123 experts participated in the first round of Delphi, 138 in the second round, 16 in the consensus meeting and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI-specific reporting items (made of 28 subitems) and ten generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we developed a guideline comprising key items that should be reported in early-stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings. Main The prospect of improved clinical outcomes and more efficient health systems has fueled a rapid rise in the development and evaluation of AI systems over the last decade. Because most AI systems within healthcare are complex interventions designed as clinical decision support systems, rather than autonomous agents, the interactions among the AI systems, their users and the implementation environments are defining components of the AI interventions’ overall potential effectiveness. Therefore, bringing AI systems from mathematical performance to clinical utility needs an adapted, stepwise implementation and evaluation pathway, addressing the complexity of this collaboration between two independent forms of intelligence, beyond measures of effectiveness alone 1 . Despite indications that some AI-based algorithms now match the accuracy of human experts within preclinical in silico studies 2 , there is little high-quality evidence for improved clinician performance or patient outcomes in clinical studies 3 , 4 . Reasons proposed for this so-called AI chasm 5 are lack of necessary expertise needed for translating a tool into practice, lack of funding available for translation, a general underappreciation of clinical research as a translation mechanism 6 and, more specifically, a disregard for the potential value of the early stages of clinical evaluation and the analysis of human factors 7 . The challenges of early-stage clinical AI evaluation (Box 1 ) are similar to those of complex interventions, as reported by the Medical Research Council dedicated guidance 1 , and surgical innovation, as described by the IDEAL Framework 8 , 9 . For example, in all three cases, the evaluation needs to consider the potential for iterative modification of the interventions and the characteristics of the operators (or users) performing them. In this regard, the IDEAL framework offers readily implementable and stage-specific recommendations for the evaluation of surgical innovations under development. IDEAL stages 2a and 2b, for example, are described as development and exploratory stages, during which the intervention is refined, operators’ learning curves are analyzed and the influence of patient and operator variability on effectiveness are explored prospectively, before large-scale efficacy testing. Early-stage clinical evaluation of AI systems should also place a strong emphasis on validation of performance and safety, in a similar manner to phase 1 and phase 2 pharmaceutical trials, before efficacy evaluation at scale in phase 3. For example, small changes in the distribution of the underlying data between the algorithm training and clinical evaluation populations (so-called dataset shift) can lead to substantial variation in clinical performance and expose patients to potential unexpected harm 10 , 11 . Human factors (or ergonomics) evaluations are commonly conducted in safety-critical fields such as aviation, military and energy sectors 12 , 13 , 14 . Their assessments evaluate the effect of a device or procedure on their users’ physical and cognitive performance and vice-versa. Human factors, such as usability evaluation, are an integral part of the regulatory process for new medical devices 15 , 16 , and their application to AI-specific challenges is attracting growing attention in the medical literature 17 , 18 , 19 , 20 . However, few clinical AI studies have reported on the evaluation of human factors 3 , and usability evaluation of related digital health technology is often performed with inconstant methodology and reporting 21 . Other areas of suboptimal reporting of clinical AI studies have also recently been highlighted 3 , 22 , such as implementation environment, user characteristics and selection process, training provided, underlying algorithm identification and disclosure of funding sources. Transparent reporting is necessary for informed study appraisal and to facilitate reproducibility of study results. In a relatively new and dynamic field such as clinical AI, comprehensive reporting is also key to construct a common and comparable knowledge base to build upon. Guidelines already exist, or are under development, for the reporting of preclinical, in silico studies of AI systems, their offline validation and their evaluation in large comparative studies 23 , 24 , 25 , 26 ; but there is an important stage of research between these, namely studies focusing on the initial clinical use of AI systems, for which no such guidance currently exists (Fig. 1 and Table 1 ). This early clinical evaluation provides a crucial scoping evaluation of clinical utility, safety and human factors challenges in live clinical settings. By investigating the potential obstacles to clinical evaluation at scale and informing protocol design, these studies are also important stepping stones<|im_end|> <|im_start|>assistant New reporting guidelines, jointly published in Nature Medicine and the BMJ by Oxford researchers, will ensure that early studies on using Artificial Intelligence (AI) to treat real patients will give researchers the information needed to develop AI systems safely and effectively. Artificial Intelligence in medicine has shown promising results in numerous simulation studies, but very few AI systems have yet been used in patient care. But as a growing number of AI-driven clinical decision-support systems are progressing from development to implementation, better guidance on the reporting of human factors and early-stage clinical evaluation is needed. Researchers from Oxford have led the development of a new guideline, DECIDE-AI, which aims to improve the reporting of research on AI systems when they are used for the first time in real clinical settings by doctors treating actual patients. It was developed based on opinions and feedback from over 150 experts across 18 countries, including computer scientists, clinicians, ethicists, patient representatives, and entrepreneurs. Baptiste Vasey of Oxford University's Nuffield Department of Surgical Sciences said: "While AI has shown promising results for clinical application in simulations, very few AI systems have had any significant effect on patient care so far. A major problem has been a lack of robust scientific evidence to back widespread use in clinical practice. "This study is the first to clearly define the minimum reporting standards for the early stage evaluation of AI-based decision support systems in clinical settings." Professor Peter McCulloch, the senior author, also based at the Nuffield Department, said: "These guidelines take the principles developed for evaluating new surgical operations by the Oxford-based IDEAL Collaboration, and apply them to an important new field where guidance is lacking. The idea that innovation and evaluation should proceed in tandem at every stage in the development of new treatments applies just as much to AI as it does to surgery. Ben Hornsby, Project Coordinator for the IDEAL Collaboration at Oxford's Nuffield Department of Medicine, said: "DECIDE-AI is only the second reporting guideline dedicated to AI systems research, and the first ever to focus on the development stage of this technology. "We chose to focus on early-stage evaluation results to emphasize the need for researchers to report transparently about four key aspects of AI research, to build confidence in the technology and highlight the practical benefits and improved efficiencies the technology can bring to health care." The factors DECIDE-AI evaluates are: proof of clinical value in a live care environmentthe AI system's safety profile and potential risks for patientshuman factors around the use of the system, such as how the AI system is integrated into the existing care pathway and how it influences clinicians' behaviorthe steps needed to develop the larger-scale trials which will be needed to provide conclusive evidence necessary for an AI system to be accepted into routine patient care. "Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI," is published in Nature Medicine and the BMJ. <|im_end|>

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1,847

[ { "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 invasive aquatic fern Azolla filiculoides has been present in Great Britain (GB) since the end of the nineteenth century, while its specialist natural enemy, the weevil Stenopelmus rufinasus was first recorded nearly four decades later, in 1921. The purpose of this study was to estimate the economic value of management cost savings resulting from the presence of S. rufinasus as a biocontrol agent of A. filiculoides in GB, including the value of additional augmentative releases of the weevil made since the mid-2000s, compared with the expected costs of control in the absence of S. rufinasus . Methods Estimated economic costs (based on the length/area of affected waterbodies, their infestation rates, and the proportion targeted for management) were calculated for three scenarios in which A. filiculoides occurs in GB: (1) without weevils; (2) with naturalised weevil populations; and (3) with naturalised weevil populations plus augmentative weevil releases. Results In the absence of biocontrol, the expected average annual costs of A. filiculoides management were estimated to range from £8.4 to 16.9 million (US$9.4 to 18.9 million) (£1 = US$1.12). The impacts of naturalised S. rufinasus populations on A. filiculoides were expected to reduce management costs to £0.8 to 1.6 million (US$0.9 to 1.8 million) per year. With additional augmentative releases of the weevil, A. filiculoides management costs were estimated to be lower still, ranging from £31.5 to 45.8 thousand (US$35.3 to 51.3 thousand) per year, giving an estimated benefit to cost ratio of augmentative S. rufinasus releases of 43.7:1 to 88.4:1. Conclusions The unintentional introduction of the weevil S. rufinasus to GB is estimated to have resulted in millions of pounds of savings annually in management costs for A. filiculoides . Additional augmentative releases of the weevil provide further net cost savings, tackling A. filiculoides outbreaks and bolstering naturalised populations. The use of herbicides in the aquatic environment is likely greatly reduced due to A. filiculoides biocontrol. Although somewhat climate-limited at present in GB, climate change may result in even more effective biocontrol of A. filiculoides by S. rufinasus as has been observed in warmer regions such as South Africa, where the plant is no longer considered a threat since the introduction of the weevil. Background Azolla filiculoides Lamarck (Azollaceae), a small aquatic free-floating fern native to the Americas has been introduced to Europe, North and sub-Saharan Africa, China, Japan, New Zealand, Australia, the Caribbean and Hawaii (Lumpkin and Plucknett 1980 ). In Europe, A. filiculoides is reported as an invasive alien species in numerous countries with its main occurrence in Atlantic-Mediterranean regions (Hussner 2012 ; Espinar et al. 2015 ; EPPO Global Database 2022 ). In Great Britain (GB) in 1883, Azolla caroliniana was reported from a pond in Middlesex, however it is now thought that A. filiculoides is the only Azolla species in the UK and as such there is a high likelihood that this was actually the first record of A. filiculoides , although herbarium specimens for confirmation are lacking (Odell 1883 in Reeder et al. 2018 ). Since its introduction, A. filiculoides has become naturalised and spread throughout lowland regions of southern and central GB in ponds, lakes, canals, ditches and other slow-moving fresh water (Preston and Croft 1997 ; Stace 2010 ), increasingly also infesting northerly sites in England and into Scotland (CABI data unpublished; NBN Atlas 2021a , b ) (see Fig. 1 ). The main route for introduction was likely via the aquatic pond plant trade for ornamental use and in aquaria where A. filiculoides was previously sold or inadvertently carried on other water plants. The ornamental trade is considered a major pathway for the introduction of invasive alien plants globally (Hussner 2012 ; Kay and Hoyle 2001 ). However, A. filiculoides now spreads readily throughout water networks, is transferred by water birds and other animals and is carried on boats and equipment used in freshwater systems. Azolla filiculoides is listed under Schedule 9 to the Wildlife and Countryside Act (1981) making it an offence to plant or otherwise cause this species to grow in the wild in England and Wales, and was banned from sale in England in 2014 (legislation.gov.uk 2014 , 2022 ). Fig. 1 © Crown copyright and database right 2021) Azolla filiculoides occurrence records for the UK (NBN Atlas 2021a ) with watercourse layer (OS Open Rivers—Contains OS data Full size image Azolla filiculoides’ preference for eutrophic water systems and its rapid growth rate allow it to outcompete indigenous vegetation. Under ideal conditions the fern can double in area in 4–5 days via rapid vegetative reproduction (Hill 1998 ; Lumpkin and Plucknett 1980 ). Dense mats form quickly across water bodies resulting in reduced light penetration into the water column (Janes et al. 1996 ), as is observed with other invasive floating water weeds such as Salvinia molesta (Motitsoe et al. 2020 ) and Pistia stratiotes (Coetzee et al. 2020 ). Thick mats of A. filiculoides in conjunction with decaying submerged root and leaf matter, create anaerobic conditions and reduced water quality (GB Non-Native Species Secretariat, 2015 ; Janes et al. 1996 ) with the potential to reduce dissolved oxygen by more than half (Gratwicke and Marshall 2001 ; Janes et al. 1996 ) and to lower pH levels (Pinero-Rodríguez et al. 2021 ). The presence of A. filiculoides at high density reduces water temperatures and prevents air-breathing organisms reaching the surface (GB Non-Native Species Secretariat 2015 ). In addition to outcompeting native plants, the presence of spreading A. filiculoides mats results in the disappearance of most submerged plants, reduces macrophyte abundance, richness and biomass, causes changes in zooplankton composition, negative impacts on invertebrate communities and reduced survival and body condition of tadpoles (Janes et al. 1996 ; Gratwicke and Marshall 2001 ; Pinero-Rodríguez et al. 2021 ). The weed also detrimentally affects recreational use of water bodies, water transportation/navigation, impacts water flow and blocks irrigation pumps (Hill 1998 ). Management of A. filiculoides using traditional approaches, namely manual/mechanical removal or chemical treatment has limited efficacy. The impacts", "role": "user" }, { "content": "A new CABI-led study suggests that a tiny weevil (Stenopelmus rufinasus) has huge benefits in saving Great Britain up to £16.8m in annual management costs of the invasive aquatic fern Azolla filiculoides. The research, published in the journal CABI Agriculture and Bioscience, estimates that without any biocontrol the expected yearly costs of managing A. filiculoides would range from £8.4m to £16.9m. The scientists say that the impacts of naturalized S. rufinasus populations on A. filiculoides alone could be expected to reduce management costs to £800,000 to £1.6m a year. However, they estimate A. filiculoides management costs to be lower still due to additional augmentative releases of the weevil that take place each summer, resulting in annual management costs of £31,500 to £45,800. Azolla filiculoides, a type of floating water fern, was introduced to Great Britain at the end of the 19th century for ornamental use in ponds and aquaria. But its introduction into the wild has meant it has spread rapidly throughout England and Wales and to a lesser degree, Scotland. The invasive aquatic fern outcompetes native species by forming a dense covering on the surface of the water. It blocks out light and can also deoxygenate water. A. filiculoides can also block canals, drains and overflows and may lead to an increased risk of flooding. It can affect irrigation systems—both by blocking their water supply and by reducing water quality. It has been banned from sale in England and Wales since April 2014. Its specialist natural enemy, S. rufinasus, was first recorded in 1921. It is suspected to have been introduced from America as a stowaway on A. filiculoides. Stenopelmus rufinasus is also reported to be present in numerous additional European countries where A. filiculoides is present. The study sought to estimate the management cost savings resulting from the presence of S. rufinasus as a biocontrol agent in Great Britain. This includes the value of additional augmentative releases of the weevil made since the mid-2000s, compared with the expected costs of control in the absence of S. rufinasus. Corin Pratt, lead author and Invasive Species Management Researcher at CABI, said, \"The unintentional introduction of the weevil S. rufinasus to Great Britain is estimated to have resulted in millions of pounds of savings annually in management costs for A. filiculoides. \"Additional augmentative releases of the weevil provide further net cost savings, tackling A. filiculoides outbreaks and bolstering naturalized populations. \"The use of herbicides in the aquatic environment is likely greatly reduced due to A. filiculoides biocontrol. Although somewhat climate-limited at present in Great Britain, climate change may result in even more effective biocontrol of A. filiculoides by S. rufinasus. \"This has been observed in warmer regions such as South Africa, where the plant is no longer considered a threat since the introduction of S. rufinasus.\" The scientists conclude by arguing that in the absence of the specialist weevil S. rufinasus, A. filiculoides could be expected to be the dominant aquatic macrophyte in Great Britain. This would require extensive, costly management and likely widespread use of herbicides in the aquatic environment. They state that the estimated benefit to cost ratio of augmentative S. rufinasus releases to be of 43.7:1 to 88.4:1. ", "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 invasive aquatic fern Azolla filiculoides has been present in Great Britain (GB) since the end of the nineteenth century, while its specialist natural enemy, the weevil Stenopelmus rufinasus was first recorded nearly four decades later, in 1921. The purpose of this study was to estimate the economic value of management cost savings resulting from the presence of S. rufinasus as a biocontrol agent of A. filiculoides in GB, including the value of additional augmentative releases of the weevil made since the mid-2000s, compared with the expected costs of control in the absence of S. rufinasus . Methods Estimated economic costs (based on the length/area of affected waterbodies, their infestation rates, and the proportion targeted for management) were calculated for three scenarios in which A. filiculoides occurs in GB: (1) without weevils; (2) with naturalised weevil populations; and (3) with naturalised weevil populations plus augmentative weevil releases. Results In the absence of biocontrol, the expected average annual costs of A. filiculoides management were estimated to range from £8.4 to 16.9 million (US$9.4 to 18.9 million) (£1 = US$1.12). The impacts of naturalised S. rufinasus populations on A. filiculoides were expected to reduce management costs to £0.8 to 1.6 million (US$0.9 to 1.8 million) per year. With additional augmentative releases of the weevil, A. filiculoides management costs were estimated to be lower still, ranging from £31.5 to 45.8 thousand (US$35.3 to 51.3 thousand) per year, giving an estimated benefit to cost ratio of augmentative S. rufinasus releases of 43.7:1 to 88.4:1. Conclusions The unintentional introduction of the weevil S. rufinasus to GB is estimated to have resulted in millions of pounds of savings annually in management costs for A. filiculoides . Additional augmentative releases of the weevil provide further net cost savings, tackling A. filiculoides outbreaks and bolstering naturalised populations. The use of herbicides in the aquatic environment is likely greatly reduced due to A. filiculoides biocontrol. Although somewhat climate-limited at present in GB, climate change may result in even more effective biocontrol of A. filiculoides by S. rufinasus as has been observed in warmer regions such as South Africa, where the plant is no longer considered a threat since the introduction of the weevil. Background Azolla filiculoides Lamarck (Azollaceae), a small aquatic free-floating fern native to the Americas has been introduced to Europe, North and sub-Saharan Africa, China, Japan, New Zealand, Australia, the Caribbean and Hawaii (Lumpkin and Plucknett 1980 ). In Europe, A. filiculoides is reported as an invasive alien species in numerous countries with its main occurrence in Atlantic-Mediterranean regions (Hussner 2012 ; Espinar et al. 2015 ; EPPO Global Database 2022 ). In Great Britain (GB) in 1883, Azolla caroliniana was reported from a pond in Middlesex, however it is now thought that A. filiculoides is the only Azolla species in the UK and as such there is a high likelihood that this was actually the first record of A. filiculoides , although herbarium specimens for confirmation are lacking (Odell 1883 in Reeder et al. 2018 ). Since its introduction, A. filiculoides has become naturalised and spread throughout lowland regions of southern and central GB in ponds, lakes, canals, ditches and other slow-moving fresh water (Preston and Croft 1997 ; Stace 2010 ), increasingly also infesting northerly sites in England and into Scotland (CABI data unpublished; NBN Atlas 2021a , b ) (see Fig. 1 ). The main route for introduction was likely via the aquatic pond plant trade for ornamental use and in aquaria where A. filiculoides was previously sold or inadvertently carried on other water plants. The ornamental trade is considered a major pathway for the introduction of invasive alien plants globally (Hussner 2012 ; Kay and Hoyle 2001 ). However, A. filiculoides now spreads readily throughout water networks, is transferred by water birds and other animals and is carried on boats and equipment used in freshwater systems. Azolla filiculoides is listed under Schedule 9 to the Wildlife and Countryside Act (1981) making it an offence to plant or otherwise cause this species to grow in the wild in England and Wales, and was banned from sale in England in 2014 (legislation.gov.uk 2014 , 2022 ). Fig. 1 © Crown copyright and database right 2021) Azolla filiculoides occurrence records for the UK (NBN Atlas 2021a ) with watercourse layer (OS Open Rivers—Contains OS data Full size image Azolla filiculoides’ preference for eutrophic water systems and its rapid growth rate allow it to outcompete indigenous vegetation. Under ideal conditions the fern can double in area in 4–5 days via rapid vegetative reproduction (Hill 1998 ; Lumpkin and Plucknett 1980 ). Dense mats form quickly across water bodies resulting in reduced light penetration into the water column (Janes et al. 1996 ), as is observed with other invasive floating water weeds such as Salvinia molesta (Motitsoe et al. 2020 ) and Pistia stratiotes (Coetzee et al. 2020 ). Thick mats of A. filiculoides in conjunction with decaying submerged root and leaf matter, create anaerobic conditions and reduced water quality (GB Non-Native Species Secretariat, 2015 ; Janes et al. 1996 ) with the potential to reduce dissolved oxygen by more than half (Gratwicke and Marshall 2001 ; Janes et al. 1996 ) and to lower pH levels (Pinero-Rodríguez et al. 2021 ). The presence of A. filiculoides at high density reduces water temperatures and prevents air-breathing organisms reaching the surface (GB Non-Native Species Secretariat 2015 ). In addition to outcompeting native plants, the presence of spreading A. filiculoides mats results in the disappearance of most submerged plants, reduces macrophyte abundance, richness and biomass, causes changes in zooplankton composition, negative impacts on invertebrate communities and reduced survival and body condition of tadpoles (Janes et al. 1996 ; Gratwicke and Marshall 2001 ; Pinero-Rodríguez et al. 2021 ). The weed also detrimentally affects recreational use of water bodies, water transportation/navigation, impacts water flow and blocks irrigation pumps (Hill 1998 ). Management of A. filiculoides using traditional approaches, namely manual/mechanical removal or chemical treatment has limited efficacy. The impacts<|im_end|> <|im_start|>assistant A new CABI-led study suggests that a tiny weevil (Stenopelmus rufinasus) has huge benefits in saving Great Britain up to £16.8m in annual management costs of the invasive aquatic fern Azolla filiculoides. The research, published in the journal CABI Agriculture and Bioscience, estimates that without any biocontrol the expected yearly costs of managing A. filiculoides would range from £8.4m to £16.9m. The scientists say that the impacts of naturalized S. rufinasus populations on A. filiculoides alone could be expected to reduce management costs to £800,000 to £1.6m a year. However, they estimate A. filiculoides management costs to be lower still due to additional augmentative releases of the weevil that take place each summer, resulting in annual management costs of £31,500 to £45,800. Azolla filiculoides, a type of floating water fern, was introduced to Great Britain at the end of the 19th century for ornamental use in ponds and aquaria. But its introduction into the wild has meant it has spread rapidly throughout England and Wales and to a lesser degree, Scotland. The invasive aquatic fern outcompetes native species by forming a dense covering on the surface of the water. It blocks out light and can also deoxygenate water. A. filiculoides can also block canals, drains and overflows and may lead to an increased risk of flooding. It can affect irrigation systems—both by blocking their water supply and by reducing water quality. It has been banned from sale in England and Wales since April 2014. Its specialist natural enemy, S. rufinasus, was first recorded in 1921. It is suspected to have been introduced from America as a stowaway on A. filiculoides. Stenopelmus rufinasus is also reported to be present in numerous additional European countries where A. filiculoides is present. The study sought to estimate the management cost savings resulting from the presence of S. rufinasus as a biocontrol agent in Great Britain. This includes the value of additional augmentative releases of the weevil made since the mid-2000s, compared with the expected costs of control in the absence of S. rufinasus. Corin Pratt, lead author and Invasive Species Management Researcher at CABI, said, "The unintentional introduction of the weevil S. rufinasus to Great Britain is estimated to have resulted in millions of pounds of savings annually in management costs for A. filiculoides. "Additional augmentative releases of the weevil provide further net cost savings, tackling A. filiculoides outbreaks and bolstering naturalized populations. "The use of herbicides in the aquatic environment is likely greatly reduced due to A. filiculoides biocontrol. Although somewhat climate-limited at present in Great Britain, climate change may result in even more effective biocontrol of A. filiculoides by S. rufinasus. "This has been observed in warmer regions such as South Africa, where the plant is no longer considered a threat since the introduction of S. rufinasus." The scientists conclude by arguing that in the absence of the specialist weevil S. rufinasus, A. filiculoides could be expected to be the dominant aquatic macrophyte in Great Britain. This would require extensive, costly management and likely widespread use of herbicides in the aquatic environment. They state that the estimated benefit to cost ratio of augmentative S. rufinasus releases to be of 43.7:1 to 88.4:1. <|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 Religious beliefs, an important element of culture, influence adaptation to climate change. Less understood is how changing beliefs shape the adaptive capacity of communities responding to climate change. In the last century sub-Saharan Africa has experienced a transformation in beliefs. Since 1900 Christians have increased 70-fold while in rural areas Traditional Beliefs and associated Traditional Ecological Knowledge (TEK) continue to influence the lived practices of vulnerable rural communities. Using two case studies of rural communities in Malawi (Bolero) and Zambia (Monze) we explore how Christianity and Traditional beliefs (and associated TEK) co-exist and assess if, and how, holding multiple belief systems affects climate-sensitive livelihood practices of food production. In Bolero we observed a lack of tensions between belief systems with Traditional leaders and elders noting the flexibility of adhering to both belief systems. In Monze however, basing livelihood decisions on the practice of rain-rituals resulted in strong tensions. In both communities elders noted their concern of how changing beliefs affect adherence to TEK management practices. We find that culture and beliefs play an important role in adaptive capacity but are not static. In the context of changing beliefs, adaptive capacity will be influenced by how different belief systems co-exist and how epistemological and intergenerational frictions are negotiated. As climate services become the focus of research and government interventions in vulnerable regions, avoiding culturally and economically expensive mal-adaptation will require giving attention to the complexity and dynamism of changing religious landscapes. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes 1 Introduction Successful adaptation to climate change will require understanding processes of social and biophysical change and their interactions within socio-ecological systems. In such systems, culture is often conceptualised as a slowly changing variable that creates domains of stability within which adaptive capacity emerges (Berkes 2012 ; Armitage et al. 2008 ). Culture is the medium through which people transform mundane material phenomena into significant symbols through which meaning and value is attached (Cosgrove and Jackson 1987 ), through which social order and norms are communicated, reproduced, experienced and explored (Williams 1982 ) and through which social groups develop distinct patterns of life (Jackson 1989 ). It is symbolic, yet active, subject to change and riven with relations of power. Culture is socially constructed, mediated and causative in that it can explain actions, behaviour, resistance or social formations (Mitchell 1995 ). Culture, therefore, shapes societal-environmental relationships and mediates responses to environmental change (Adger et al. 2009 ; Hulme 2010 ; Adger et al. 2013 ; Hackmann et al. 2014 ) within complex power dynamics (Santos 2008 ). Olsson et al. ( 2004 ) define adaptive capacity as an attribute that permits coping with disturbance and change while retaining critical system function, structure and feedback mechanisms. In socio-ecological systems Folke et al. ( 2003 ) identify four key aspects of adaptive capacity as i). learning to live with uncertainty through allowing and encouraging small scale disturbances in avoiding large scale collapse, ii). supporting diversity (biological and institutional) in facilitating reorganisation and renewal following crisis, iii). combining different types of knowledge for learning and iv). creating opportunities for self-organisation. Armitage ( 2005 ) and Armitage et al. ( 2008 ) also highlights the importance of collective action, maintenance of collective experiences, the transfer of knowledge and social capital in the form of trust, reciprocity and cohesion in influencing adaptive capacity (Armitage et al. 2008 ). Of increasing interest is how religion, an important (even inseparable) element of culture, influences adaptation and the role of religion in understanding and responding to climate change (Adger et al. 2013 ; Haluza-DeLay 2014 ). In broad terms we take religion to refer to beliefs and practices upheld by individuals and wider groups based on spirituality, mysticism, and faith in divinity, enshrined in formal institutions in organised religions, in informal institutions in traditional belief systems and expressed in devolved form through superstitions, mythology and folktales (Schipper 2010 ). Therefore, while beliefs refer to underlying spiritual philosophies and worldviews of individuals and communities, practices refer to the real and tangible lived expressions of those beliefs, particularly through rituals and actions taken at individual and broader scales. Social and individual values and worldviews, often determined by religion or spirituality, influence decisions about whether and how to adapt (Adger et al. 2013 ), while religion has been positively associated with adaptive capacity by enhancing social capital (Schipper 2010 ; Gomez-Baggethun et al. 2012 ). Less understood, however, is how changing religious beliefs and practices shape adaptive capacity in responding to climate change. On a global scale vulnerability to climate change tends to be greatest in parts of the world where religion is most important in daily life (Fig. 1 a). This is certainly the case in sub-Saharan Africa where countries, characterised as predominantly Christian, rank highest in terms of vulnerability and importance of religion (Fig. 1 b). However, religious beliefs are not static. The 20th century witnessed a rapid transformation of religious beliefs throughout much of the Global South. In sub-Saharan Africa the number of Christians increased 70-fold, Muslims 20 fold, whilst adherence to traditional belief systems have declined dramatically (PEW 2010 ). While this transformation has been impressive in scale, the umbrella of ‘Christian’ hides a multitude of variants. Early in the 20th century this transformation was dominated by the role of mainstream (western) mission churches associated with colonialism. A second wave is characterised by the Africanisation of mainstream Christian beliefs and the emergence of African Independent Churches, while more recently (especially since the 1990s) religious change in much of sub-Saharan Africa has been marked by the explosion of Pentecostal Charismatic Churches, often preaching a prosperity gospel (Meyer 2004 ). However, Traditional belief systems continue to play an important role in the lives of vulnerable rural communities, with many individuals affiliating themselves with both Christian and Traditional belief systems (PEW 2010 ). Fig. 1 a Correspondence between vulnerability to climate change and importance of religion in everyday life. Top, ND-GAIN 2012 vulnerability score", "role": "user" }, { "content": "Experts should take note of local knowledge and beliefs when making plans about how to help people in vulnerable regions cope with the impacts of climate change. This will ensure that such interventions are money well spent, and are not culturally insensitive, advises Conor Murphy of Ireland's Maynooth University. Together with an interdisciplinary research team from universities in Malawi, Zambia and Ireland he interviewed community members in rural Malawi and Zambia to assess how well they are able to adapt to the way they produce food within the context of shifting belief systems and climate change. The findings are published in Springer's journal Climatic Change. On a global scale, vulnerability to climate change tends to be greatest in parts of the world where religion is most important in daily life. In a vulnerable area such as sub-Saharan Africa, for instance, Christians have increased 70-fold and Muslims 20-fold over the past century. Traditional beliefs and traditional ecological knowledge (TEK) rooted within an ancestral spirit-world however continue to influence the day-to-day lives especially of rural communities. Religious beliefs are an important element of culture, but are not always static. Such shifting belief systems influence how people respond and adapt to important issues such as the challenges relating to climate change. The research team interviewed members of two rural communities in Africa: Bolero in Malawi and Monze in Zambia. Christianity and traditional beliefs co-exist within these communities. The researchers assessed how holding multiple belief systems influences the ability of these communities to produce food and adapt to the impact of changing climates. In Bolero, a smooth co-existence and integration was observed between traditional and Christian beliefs and practices. Faith-based organizations have helped community members to better understand what causes climate variability in their area. Previously, this was associated with punishment from ancestral spirits. In Monze, by contrast, tensions were experienced when livelihood decisions were made based on the practice of rain rituals. Traditional practices and worshipping of ancestral spirits were seen as evil by Christian religions. Elders blamed recent failures of rainfall on a lack of adherence to traditional beliefs by younger generations. In both communities, elders were concerned that changing beliefs are affecting the way people use traditional ecological knowledge management practices. \"Culture, when approached through the lens of religious beliefs and practices, plays an important role in adaptive capacity, but is not static,\" reminds Prof. Olusegun Yerokun of Mulungushi University, co-author of the paper. \"The manner by which communities holding multiple belief systems are able to adapt is largely determined by the manner in which belief systems co-exist, and how different knowledge forms are valued, accepted and integrated.\" \"As climate services become the focus of research and government interventions in vulnerable regions, avoiding culturally and economically expensive mal-adaptation will require giving attention to the complexity and dynamism of such changing religious landscapes,\" Murphy advises. ", "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 Religious beliefs, an important element of culture, influence adaptation to climate change. Less understood is how changing beliefs shape the adaptive capacity of communities responding to climate change. In the last century sub-Saharan Africa has experienced a transformation in beliefs. Since 1900 Christians have increased 70-fold while in rural areas Traditional Beliefs and associated Traditional Ecological Knowledge (TEK) continue to influence the lived practices of vulnerable rural communities. Using two case studies of rural communities in Malawi (Bolero) and Zambia (Monze) we explore how Christianity and Traditional beliefs (and associated TEK) co-exist and assess if, and how, holding multiple belief systems affects climate-sensitive livelihood practices of food production. In Bolero we observed a lack of tensions between belief systems with Traditional leaders and elders noting the flexibility of adhering to both belief systems. In Monze however, basing livelihood decisions on the practice of rain-rituals resulted in strong tensions. In both communities elders noted their concern of how changing beliefs affect adherence to TEK management practices. We find that culture and beliefs play an important role in adaptive capacity but are not static. In the context of changing beliefs, adaptive capacity will be influenced by how different belief systems co-exist and how epistemological and intergenerational frictions are negotiated. As climate services become the focus of research and government interventions in vulnerable regions, avoiding culturally and economically expensive mal-adaptation will require giving attention to the complexity and dynamism of changing religious landscapes. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes 1 Introduction Successful adaptation to climate change will require understanding processes of social and biophysical change and their interactions within socio-ecological systems. In such systems, culture is often conceptualised as a slowly changing variable that creates domains of stability within which adaptive capacity emerges (Berkes 2012 ; Armitage et al. 2008 ). Culture is the medium through which people transform mundane material phenomena into significant symbols through which meaning and value is attached (Cosgrove and Jackson 1987 ), through which social order and norms are communicated, reproduced, experienced and explored (Williams 1982 ) and through which social groups develop distinct patterns of life (Jackson 1989 ). It is symbolic, yet active, subject to change and riven with relations of power. Culture is socially constructed, mediated and causative in that it can explain actions, behaviour, resistance or social formations (Mitchell 1995 ). Culture, therefore, shapes societal-environmental relationships and mediates responses to environmental change (Adger et al. 2009 ; Hulme 2010 ; Adger et al. 2013 ; Hackmann et al. 2014 ) within complex power dynamics (Santos 2008 ). Olsson et al. ( 2004 ) define adaptive capacity as an attribute that permits coping with disturbance and change while retaining critical system function, structure and feedback mechanisms. In socio-ecological systems Folke et al. ( 2003 ) identify four key aspects of adaptive capacity as i). learning to live with uncertainty through allowing and encouraging small scale disturbances in avoiding large scale collapse, ii). supporting diversity (biological and institutional) in facilitating reorganisation and renewal following crisis, iii). combining different types of knowledge for learning and iv). creating opportunities for self-organisation. Armitage ( 2005 ) and Armitage et al. ( 2008 ) also highlights the importance of collective action, maintenance of collective experiences, the transfer of knowledge and social capital in the form of trust, reciprocity and cohesion in influencing adaptive capacity (Armitage et al. 2008 ). Of increasing interest is how religion, an important (even inseparable) element of culture, influences adaptation and the role of religion in understanding and responding to climate change (Adger et al. 2013 ; Haluza-DeLay 2014 ). In broad terms we take religion to refer to beliefs and practices upheld by individuals and wider groups based on spirituality, mysticism, and faith in divinity, enshrined in formal institutions in organised religions, in informal institutions in traditional belief systems and expressed in devolved form through superstitions, mythology and folktales (Schipper 2010 ). Therefore, while beliefs refer to underlying spiritual philosophies and worldviews of individuals and communities, practices refer to the real and tangible lived expressions of those beliefs, particularly through rituals and actions taken at individual and broader scales. Social and individual values and worldviews, often determined by religion or spirituality, influence decisions about whether and how to adapt (Adger et al. 2013 ), while religion has been positively associated with adaptive capacity by enhancing social capital (Schipper 2010 ; Gomez-Baggethun et al. 2012 ). Less understood, however, is how changing religious beliefs and practices shape adaptive capacity in responding to climate change. On a global scale vulnerability to climate change tends to be greatest in parts of the world where religion is most important in daily life (Fig. 1 a). This is certainly the case in sub-Saharan Africa where countries, characterised as predominantly Christian, rank highest in terms of vulnerability and importance of religion (Fig. 1 b). However, religious beliefs are not static. The 20th century witnessed a rapid transformation of religious beliefs throughout much of the Global South. In sub-Saharan Africa the number of Christians increased 70-fold, Muslims 20 fold, whilst adherence to traditional belief systems have declined dramatically (PEW 2010 ). While this transformation has been impressive in scale, the umbrella of ‘Christian’ hides a multitude of variants. Early in the 20th century this transformation was dominated by the role of mainstream (western) mission churches associated with colonialism. A second wave is characterised by the Africanisation of mainstream Christian beliefs and the emergence of African Independent Churches, while more recently (especially since the 1990s) religious change in much of sub-Saharan Africa has been marked by the explosion of Pentecostal Charismatic Churches, often preaching a prosperity gospel (Meyer 2004 ). However, Traditional belief systems continue to play an important role in the lives of vulnerable rural communities, with many individuals affiliating themselves with both Christian and Traditional belief systems (PEW 2010 ). Fig. 1 a Correspondence between vulnerability to climate change and importance of religion in everyday life. Top, ND-GAIN 2012 vulnerability score<|im_end|> <|im_start|>assistant Experts should take note of local knowledge and beliefs when making plans about how to help people in vulnerable regions cope with the impacts of climate change. This will ensure that such interventions are money well spent, and are not culturally insensitive, advises Conor Murphy of Ireland's Maynooth University. Together with an interdisciplinary research team from universities in Malawi, Zambia and Ireland he interviewed community members in rural Malawi and Zambia to assess how well they are able to adapt to the way they produce food within the context of shifting belief systems and climate change. The findings are published in Springer's journal Climatic Change. On a global scale, vulnerability to climate change tends to be greatest in parts of the world where religion is most important in daily life. In a vulnerable area such as sub-Saharan Africa, for instance, Christians have increased 70-fold and Muslims 20-fold over the past century. Traditional beliefs and traditional ecological knowledge (TEK) rooted within an ancestral spirit-world however continue to influence the day-to-day lives especially of rural communities. Religious beliefs are an important element of culture, but are not always static. Such shifting belief systems influence how people respond and adapt to important issues such as the challenges relating to climate change. The research team interviewed members of two rural communities in Africa: Bolero in Malawi and Monze in Zambia. Christianity and traditional beliefs co-exist within these communities. The researchers assessed how holding multiple belief systems influences the ability of these communities to produce food and adapt to the impact of changing climates. In Bolero, a smooth co-existence and integration was observed between traditional and Christian beliefs and practices. Faith-based organizations have helped community members to better understand what causes climate variability in their area. Previously, this was associated with punishment from ancestral spirits. In Monze, by contrast, tensions were experienced when livelihood decisions were made based on the practice of rain rituals. Traditional practices and worshipping of ancestral spirits were seen as evil by Christian religions. Elders blamed recent failures of rainfall on a lack of adherence to traditional beliefs by younger generations. In both communities, elders were concerned that changing beliefs are affecting the way people use traditional ecological knowledge management practices. "Culture, when approached through the lens of religious beliefs and practices, plays an important role in adaptive capacity, but is not static," reminds Prof. Olusegun Yerokun of Mulungushi University, co-author of the paper. "The manner by which communities holding multiple belief systems are able to adapt is largely determined by the manner in which belief systems co-exist, and how different knowledge forms are valued, accepted and integrated." "As climate services become the focus of research and government interventions in vulnerable regions, avoiding culturally and economically expensive mal-adaptation will require giving attention to the complexity and dynamism of such changing religious landscapes," Murphy advises. <|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 Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state 1 , 2 , 3 . It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing 4 , 5 , 6 , 7 , 8 . We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung. Main Melanoma cells implanted in the skin of aged mice result in lung metastases at greater rates than those implanted in younger mice 4 . Whether this is due to increased dissemination from the primary site, or because the aged microenvironment at metastatic sites promotes outgrowth, remains unclear. To investigate this question, we intradermally implanted Yumm1.7 (mCherry) melanoma cells into young (8 weeks) and aged (more than 52 weeks) C57BL6 mice. The primary tumour grew faster in young mice, as shown previously 4 (Fig. 1a ). We examined distal lung metastases at weeks 1, 3 and 5 using an immunohistochemistry (IHC) analysis of mCherry-positive cells in the lung. At week 1, we did not detect melanoma cells. At week 3, we found that melanoma cells seeded the lung in equal numbers in young and aged mice as single cells (Fig. 1b, c , Extended Data Fig. 1a ). At week 5, larger metastatic colonies formed (more than 10 cells clustered together) in the aged lung, but single cells persisted in the young lungs (Fig. 1b, c ). Single mCherry-positive melanoma cells in young mice stained negative for the proliferative marker Ki-67, whereas colonies in aged mice stained positive (Fig. 1d ), suggesting that the aged lung promotes proliferation and melanoma outgrowth, compared to the young (which was growth-restrictive). Of note, although the number of cells seeded in young versus aged lungs was similar at three weeks, the metastatic efficiency (number of cells disseminating per mm 3 of tumour volume) was far higher in aged mice. To determine whether the differences in lung outgrowth at week 5 were due to an overall increase in dissemination from aged primary tumours, we surgically removed the primary tumours from aged mice after three weeks to prevent further dissemination compared to mice containing primary tumours. This did not affect the rate of metastatic outgrowth and proliferation in aged mice lungs (Extended Data Fig. 1c–e ). To further determine whether the aged lung was more growth-permissive for melanoma cells, we performed a tail vein colonization assay with our Yumm1.7 mCherry melanoma cells (Fig. 1e, f ). We intravenously injected 1 × 10 5 Yumm1.7 cells into young and aged mice. Mice were euthanized once both groups showed clinical signs of metastasis, which occurred at day 35. We analysed the area of visible lung metastases relative to the total lung area and found that the aged mice had more metastases: 9 out of10 aged mice had a relative area of 50% or higher metastatic burden, and 6 out of10 reached levels of 62–75% (Fig. 1e, f ). None of the 10 younger mice reached a metastatic burden of higher than 50%. We next analysed the ratio of Ki-67-positive nuclei to total nuclei in larger lung metastatic tumour samples, and found that younger mice had fewer Ki-67-positive melanoma cells than did aged mice (Fig. 1g, h ). Overall, these data provide strong evidence that the aged lung microenvironment promotes efficient melanoma outgrowth, whereas the young lung is growth-restrictive and may promote a dormant melanoma phenotype. Fig. 1: The aged lung microenvironment promotes efficient lung metastasis through aged fibroblasts. a , Six young (8 weeks) and six aged (more than 52 weeks) C57BL6 mice were intradermally injected with 2.5 × 10 5 Yumm1.7 mCherry mouse melanoma cells, and tumours were measured over 36 days. Data are mean ± s.e.m. for each time point ( P values day 30 and 36; two-way ANOVA with a post hoc Holm–Sidak’s multiple comparisons test for each time point; ** P < 0.0049, **** P < 0.0001). b , c , IHC analysis of lungs from five young and five aged mice to quantify the number of mCherry + colonies (more than 10 mCherry + cells per lesion) per section at weeks 3 and 5 ( b ). Data are mean ± s.e.m. (Student’s two-sided two-sided t -test; P = 0.0007). Representative images of mCherry staining of lungs are displayed ( c ). Scale bars, 100 μm. d , Lung sections from young and aged mice at week 5, stained for mCherry and Ki-67 to assess colocalization. Scale bars, 100 μm. e , f , Ten young and ten aged mice were injected intravenously via the tail vein with 1 × 10 5 Yumm1.7 mCherry melanoma cells and analysed until visible clinical signs of metastasis (weight loss and hunched posture). Whole sections of H&E-stained lungs were scanned at 40× (Aperio Slide Scanner) and analysed for total lung tissue area versus area of metastatic tissue using Concentriq software ( e ). Data are mean ± s.e.m. (Student’s two-sided two-sided t", "role": "user" }, { "content": "Spreading cancer cells that escape a primary tumor site can seed in tissues distant from the tumor, but may take several years or decades to grow into full metastatic cancers. Understanding of tumor dormancy, the process by which this happens, was incomplete. Now, new laboratory research directed by investigators at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health finds that secreted age-induced changes in distant sites such as the lung can effectively reactivate dormant cells and cause them to grow. The researchers found that age-related changes in the secreted factors from the lung fibroblasts, normal noncancer cells in the vicinity of the tumor, facilitated a pathway for growth of dormant melanoma cells. Age-related changes in the skin microenvironment suppressed the growth of melanoma cells but drove their dissemination, seeding the deadly spread of cancer to distant organs. The results of this multicenter study were published in the June 1 issue of Nature. Aging can play a role in the development of cancer metastases, says senior study author Ashani Weeraratna, Ph.D., the E.V. McCollum Professor and chair of the Department of Biochemistry and Molecular Biology at the Bloomberg School of Public Health, a Bloomberg Distinguished Professor (cancer biology), a professor of oncology and co-leader of the cancer invasion and metastasis program at the Kimmel Cancer Center. The study found that when melanoma cells were injected into the skin of young (8 weeks old, equivalent to young adult human) and older mice (18 months old, equivalent to humans age 55 to 65), they traveled to the lungs at similar rates initially, but in the aged lung, they grew rapidly and formed bigger tumors, whereas in the younger lung, they tended to remain as small, single-cell or double-cell colonies. The researchers grew melanoma cells together with human skin or lung fibroblasts—common cells that help maintain the structure of tissue and repair injury—from young (under age 35) or older (above age 55) healthy donors. Melanoma cells in the aged lung fibroblast environment dramatically increased in proliferation compared to those in a young lung fibroblast environment. Conversely, melanoma cells in an aged skin fibroblast microenvironment proliferated more slowly when compared with young skin fibroblasts. Laboratory studies of melanoma cells suggested that changes in factors secreted by the fibroblasts were key to promoting these differences. Next, the study team performed proteomic analysis (a study of proteins) on factors secreted by healthy human young and aged lung fibroblasts. The team identified changes in the WNT signaling pathway, specifically in secreted frizzled related proteins (SFRPs) that regulated WNT5A, a protein involved in various processes including melanoma metastasis. The researchers found WNT5A to be a master regulator in activating melanoma cell dormancy in the lung, enabling efficient dissemination, seeding and survival of melanoma cells in metastatic niches, but suppressing their outgrowth. \"These changes were very consistent with a phenomenon in melanoma we call phenotype switching, in which melanoma exists either in a state of growing or invading,\" Weeraratna says. \"What our data showed is that these cells use different arms of the WNT pathway to switch back and forth between these two states,\" she adds. \"When the WNT5A signaling pathway is activated, the cells are highly invasive but not very proliferative and don't grow fast. By contrast, when the WNT5A signaling pathway is suppressed, the cells grow much faster.\" Age-induced re-programming of the lung fibroblasts increases the secretion of the protein sFRP1, which inhibits WNT5A and enables metastatic outgrowth. The team also identified the tyrosine kinase receptors AXL and MER—which play a role in normal cell proliferation—as helpers promoting the process from dormancy to reactivation. \"Our data revealed an unexpected complexity in the role of WNT signaling and other downstream pathways in melanoma cell dormancy and metastasis initiation that is regulated by aging,\" says lead study author Mitchell Fane, Ph.D., a postdoctoral fellow in Weeraratna's laboratory. \"WNT5A promotes the initial dissemination of the tumor cells but then acts to maintain them in a dormant state to allow survival and adaptation in the lungs. This state is maintained until age-related changes in the distal site induce an emergence from tumor dormancy. Then, sFRP1 is secreted at higher levels by aged lung fibroblasts and decreases WNT5A expression to allow the reactivation from dormancy in the aged lung. We also defined an axis where AXL-MER converge downstream of WNT5A that helps reactivate the dormant cells.\" Much research is still needed to better understand the microenvironment at distant sites, including the brain, where melanoma also can metastasize, says Weeraratna. ", "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 Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state 1 , 2 , 3 . It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing 4 , 5 , 6 , 7 , 8 . We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung. Main Melanoma cells implanted in the skin of aged mice result in lung metastases at greater rates than those implanted in younger mice 4 . Whether this is due to increased dissemination from the primary site, or because the aged microenvironment at metastatic sites promotes outgrowth, remains unclear. To investigate this question, we intradermally implanted Yumm1.7 (mCherry) melanoma cells into young (8 weeks) and aged (more than 52 weeks) C57BL6 mice. The primary tumour grew faster in young mice, as shown previously 4 (Fig. 1a ). We examined distal lung metastases at weeks 1, 3 and 5 using an immunohistochemistry (IHC) analysis of mCherry-positive cells in the lung. At week 1, we did not detect melanoma cells. At week 3, we found that melanoma cells seeded the lung in equal numbers in young and aged mice as single cells (Fig. 1b, c , Extended Data Fig. 1a ). At week 5, larger metastatic colonies formed (more than 10 cells clustered together) in the aged lung, but single cells persisted in the young lungs (Fig. 1b, c ). Single mCherry-positive melanoma cells in young mice stained negative for the proliferative marker Ki-67, whereas colonies in aged mice stained positive (Fig. 1d ), suggesting that the aged lung promotes proliferation and melanoma outgrowth, compared to the young (which was growth-restrictive). Of note, although the number of cells seeded in young versus aged lungs was similar at three weeks, the metastatic efficiency (number of cells disseminating per mm 3 of tumour volume) was far higher in aged mice. To determine whether the differences in lung outgrowth at week 5 were due to an overall increase in dissemination from aged primary tumours, we surgically removed the primary tumours from aged mice after three weeks to prevent further dissemination compared to mice containing primary tumours. This did not affect the rate of metastatic outgrowth and proliferation in aged mice lungs (Extended Data Fig. 1c–e ). To further determine whether the aged lung was more growth-permissive for melanoma cells, we performed a tail vein colonization assay with our Yumm1.7 mCherry melanoma cells (Fig. 1e, f ). We intravenously injected 1 × 10 5 Yumm1.7 cells into young and aged mice. Mice were euthanized once both groups showed clinical signs of metastasis, which occurred at day 35. We analysed the area of visible lung metastases relative to the total lung area and found that the aged mice had more metastases: 9 out of10 aged mice had a relative area of 50% or higher metastatic burden, and 6 out of10 reached levels of 62–75% (Fig. 1e, f ). None of the 10 younger mice reached a metastatic burden of higher than 50%. We next analysed the ratio of Ki-67-positive nuclei to total nuclei in larger lung metastatic tumour samples, and found that younger mice had fewer Ki-67-positive melanoma cells than did aged mice (Fig. 1g, h ). Overall, these data provide strong evidence that the aged lung microenvironment promotes efficient melanoma outgrowth, whereas the young lung is growth-restrictive and may promote a dormant melanoma phenotype. Fig. 1: The aged lung microenvironment promotes efficient lung metastasis through aged fibroblasts. a , Six young (8 weeks) and six aged (more than 52 weeks) C57BL6 mice were intradermally injected with 2.5 × 10 5 Yumm1.7 mCherry mouse melanoma cells, and tumours were measured over 36 days. Data are mean ± s.e.m. for each time point ( P values day 30 and 36; two-way ANOVA with a post hoc Holm–Sidak’s multiple comparisons test for each time point; ** P < 0.0049, **** P < 0.0001). b , c , IHC analysis of lungs from five young and five aged mice to quantify the number of mCherry + colonies (more than 10 mCherry + cells per lesion) per section at weeks 3 and 5 ( b ). Data are mean ± s.e.m. (Student’s two-sided two-sided t -test; P = 0.0007). Representative images of mCherry staining of lungs are displayed ( c ). Scale bars, 100 μm. d , Lung sections from young and aged mice at week 5, stained for mCherry and Ki-67 to assess colocalization. Scale bars, 100 μm. e , f , Ten young and ten aged mice were injected intravenously via the tail vein with 1 × 10 5 Yumm1.7 mCherry melanoma cells and analysed until visible clinical signs of metastasis (weight loss and hunched posture). Whole sections of H&E-stained lungs were scanned at 40× (Aperio Slide Scanner) and analysed for total lung tissue area versus area of metastatic tissue using Concentriq software ( e ). Data are mean ± s.e.m. (Student’s two-sided two-sided t<|im_end|> <|im_start|>assistant Spreading cancer cells that escape a primary tumor site can seed in tissues distant from the tumor, but may take several years or decades to grow into full metastatic cancers. Understanding of tumor dormancy, the process by which this happens, was incomplete. Now, new laboratory research directed by investigators at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health finds that secreted age-induced changes in distant sites such as the lung can effectively reactivate dormant cells and cause them to grow. The researchers found that age-related changes in the secreted factors from the lung fibroblasts, normal noncancer cells in the vicinity of the tumor, facilitated a pathway for growth of dormant melanoma cells. Age-related changes in the skin microenvironment suppressed the growth of melanoma cells but drove their dissemination, seeding the deadly spread of cancer to distant organs. The results of this multicenter study were published in the June 1 issue of Nature. Aging can play a role in the development of cancer metastases, says senior study author Ashani Weeraratna, Ph.D., the E.V. McCollum Professor and chair of the Department of Biochemistry and Molecular Biology at the Bloomberg School of Public Health, a Bloomberg Distinguished Professor (cancer biology), a professor of oncology and co-leader of the cancer invasion and metastasis program at the Kimmel Cancer Center. The study found that when melanoma cells were injected into the skin of young (8 weeks old, equivalent to young adult human) and older mice (18 months old, equivalent to humans age 55 to 65), they traveled to the lungs at similar rates initially, but in the aged lung, they grew rapidly and formed bigger tumors, whereas in the younger lung, they tended to remain as small, single-cell or double-cell colonies. The researchers grew melanoma cells together with human skin or lung fibroblasts—common cells that help maintain the structure of tissue and repair injury—from young (under age 35) or older (above age 55) healthy donors. Melanoma cells in the aged lung fibroblast environment dramatically increased in proliferation compared to those in a young lung fibroblast environment. Conversely, melanoma cells in an aged skin fibroblast microenvironment proliferated more slowly when compared with young skin fibroblasts. Laboratory studies of melanoma cells suggested that changes in factors secreted by the fibroblasts were key to promoting these differences. Next, the study team performed proteomic analysis (a study of proteins) on factors secreted by healthy human young and aged lung fibroblasts. The team identified changes in the WNT signaling pathway, specifically in secreted frizzled related proteins (SFRPs) that regulated WNT5A, a protein involved in various processes including melanoma metastasis. The researchers found WNT5A to be a master regulator in activating melanoma cell dormancy in the lung, enabling efficient dissemination, seeding and survival of melanoma cells in metastatic niches, but suppressing their outgrowth. "These changes were very consistent with a phenomenon in melanoma we call phenotype switching, in which melanoma exists either in a state of growing or invading," Weeraratna says. "What our data showed is that these cells use different arms of the WNT pathway to switch back and forth between these two states," she adds. "When the WNT5A signaling pathway is activated, the cells are highly invasive but not very proliferative and don't grow fast. By contrast, when the WNT5A signaling pathway is suppressed, the cells grow much faster." Age-induced re-programming of the lung fibroblasts increases the secretion of the protein sFRP1, which inhibits WNT5A and enables metastatic outgrowth. The team also identified the tyrosine kinase receptors AXL and MER—which play a role in normal cell proliferation—as helpers promoting the process from dormancy to reactivation. "Our data revealed an unexpected complexity in the role of WNT signaling and other downstream pathways in melanoma cell dormancy and metastasis initiation that is regulated by aging," says lead study author Mitchell Fane, Ph.D., a postdoctoral fellow in Weeraratna's laboratory. "WNT5A promotes the initial dissemination of the tumor cells but then acts to maintain them in a dormant state to allow survival and adaptation in the lungs. This state is maintained until age-related changes in the distal site induce an emergence from tumor dormancy. Then, sFRP1 is secreted at higher levels by aged lung fibroblasts and decreases WNT5A expression to allow the reactivation from dormancy in the aged lung. We also defined an axis where AXL-MER converge downstream of WNT5A that helps reactivate the dormant cells." Much research is still needed to better understand the microenvironment at distant sites, including the brain, where melanoma also can metastasize, says Weeraratna. <|im_end|>

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2,495

[ { "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 blind cave eel, Ophisternon candidum (Mees in J R Soc West Aust 45: 24–32,1962), is a rare groundwater inhabitant found in geographically isolated populations of north-west Australia. The species is listed as vulnerable under Commonwealth legislation and is a priority consideration when environmental disturbance by resource companies is proposed. Detection of this species for Environmental Impact Assessment (EIA) and monitoring is difficult because individuals are naturally rare or traditional sampling techniques are ineffective. To properly manage the species, information on population distribution and connectivity is critical. We sought to examine whether environmental DNA (eDNA) of O. candidum could be detected and whether positive detection was correlated with previous locations where the species had been physically caught. We developed new eDNA species-specific PCR assays to screen groundwater sampling points and we detected O. candidum DNA in three boreholes where the species has previously been collected and five additional groundwater sampling points. Our results demonstrated that the newly designed assays were effective for detecting this rare and vulnerable subterranean species. This work sets a benchmark for the application of eDNA species-specific PCR assays for EIA and monitoring, and has potential for these assays to be expanded more broadly to high-throughput eDNA metabarcoding for subterranean groundwater communities in the future. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Rare species are taxa that are uncommon, scarce, or infrequently encountered with small population sizes (Drury, 1974 ). These species usually occupy narrow endemic ranges, fragmented or degraded habitat and are vulnerable to ecological perturbations (Mouillot et al., 2013 ), especially if evolutionary processes have led to physiological adaptation to unique environmental conditions (Prendergast et al., 1993 ; Burgman & Lindenmayer, 1998 ). For truly rare taxa, sampling issues can compound difficulties of detection for their monitoring and conservation. Sampling rare taxa can be further complicated if they are cryptic or are able to avoid capture (McDonald, 2004 ). In this respect, alternative approaches to improve survey methodology, especially those that are non-destructive, will ultimately enhance conservation management. Groundwater has origins in regions of high rainfall and is stored in fissures and spaces in soil, sediment and rock. As the largest source of unfrozen freshwater on Earth, it is retained underground in aquifers, often for millions of years, providing water to ecosystems, agriculture, potable water for human communities, and the sustainment of aquatic and terrestrial ecosystem function. However, even though individual groundwater resources can be very large (e.g. Australia’s Great Artesian Basin covers one-third of the continent) their ecosystems can be extremely vulnerable due to overexploitation and depletion (Devitt et al., 2019 ; Saccò et al., 2019 ). Far from being a sterile habitat, groundwater is home to a wide variety of subterranean life including microbes, worms, arthropods and some vertebrates (i.e. fish and salamanders). Obligate subterranean groundwater organisms (stygobionts) are poorly known in Australia, as elsewhere, even though their role in ecosystem services are thought to be substantial (Simon et al., 2003 ; Hancock et al., 2005 ; Hose & Stumpp, 2019 ). Stygobionts can occur up to a kilometre below the surface and only in the last three decades has the diversity of subterranean communities in Australia been fully appreciated (e.g. Humphreys, 2008 ; Guzik et al., 2011 ). The isolated nature of many subterranean habitats occupied by stygobionts has resulted in narrow distribution ranges and increased short-range endemism (Asmyhr & Cooper, 2012 ). In the state of Western Australia, consideration of subterranean biodiversity is required, both within and around major resource development projects, as part of the Environmental Impact Assessment (EIA) process. Consequently, with improved knowledge of the unique nature of these subterranean communities, biodiversity assessment and monitoring have increased in importance. Sampling and identification of stygobionts for monitoring and conservation management is logistically difficult (Hancock & Boulton, 2009 ). Access to these habitats is sparce and is almost exclusively limited to pre-drilled, remote boreholes that target specific geologies of economic importance or difficult to access cave systems. Traditional monitoring techniques that are able to access these habitats (e.g. haul net surveys and traps) and subsequent processing (sorting, counting, morphological identification and molecular verification) are time-consuming and expensive. In addition, these methods are biased towards the most common and easily sampled species (i.e. invertebrates) making them impractical for sampling rare or difficult to sample species (e.g. active dispersers). All biota leave a trail of DNA in the environment through excretion, secretions, decay and other metabolic processes. Environmental DNA (eDNA) can be captured and sequenced using metabarcoding and thus provides a lens into species’ assemblages that recently inhabited a particular location (Taberlet et al., 2012 ; Port et al., 2016 ; Stat et al., 2017 ). Of current and particular interest, is refining metabarcoding methodologies (e.g. PCR assays and databases) for holistic audits of total biodiversity (Stat et al., 2017 ). Only a few studies have presented data for detection of stygobionts using eDNA from groundwater (Gorički et al., 2017 ; Korbel et al., 2017 ; Niemiller et al., 2018 ). Accordingly, there is much research still needed to explore the applicability of eDNA metabarcoding in subterranean environments including, but not limited to, improved understanding of DNA turnover, transport, sampling methods, reference databases, type I + II errors (Ficetola et al., 2016 ) and PCR assays. The blind cave eel Ophisternon candidum (Mees) (Mees, 1962 ) (Synbranchidae) is the largest of three cavefish species known from Australia (average length, 34.0 cm) (Fig. 1 ). The species exists entirely in subterranean water systems of the northern Carnarvon Basin (Cape Range and Barrow Island) and the Robe River catchment in the Pilbara region, north-western Australia, and has the traits characteristic of subterranean animals, e.g. lacking eyes and with unpigmented skin (Fig. 1 ). With limited information on its reproductive biology and ecology, O. candidum is thought to feed on stygobiontic crustaceans and opportunistically on aquatic larvae and arthropods that have sunk to bottom of the water column (Moore et al., 2018", "role": "user" }, { "content": "New species-specific tests that can detect endangered and hard-to-find aquatic animals through the DNA they shed in the water has been created by researchers at the University of Adelaide and Curtin University. The tests, which are developed by sequencing the mitochondrial genome of an individual species and rely on environmental DNA in the water (termed eDNA), were used to detect the Blind Cave Eel (Ophisternon candidum) in the Pilbara, Western Australia, at eight separate locations; three sites where it has previously been physically detected and, more significantly, at five sites from which the species has never been recorded. The Blind Cave Eel is the largest of three cavefish species known from Australia, growing up to 40cm long. It exists entirely in subterranean groundwater systems of the northern Carnarvon Basin and the Robe River catchment in north-western Australia. It lacks eyes, has unpigmented skin and is notoriously difficult to locate during environmental surveys. It is listed as a vulnerable species. Researcher Dr. Michelle Guzik, from the University of Adelaide's School of Biological Sciences and Environment Institute, said the eel could avoid capture using traditional sampling methods, which can bias the results from field surveys. \"There is a real need to develop non-invasive methods and knowledge that will increase the speed and scientific rigor of biological surveys for Environmental Protection Authority (EPA) approvals when assessing the potential for environmental disturbance,\" she said. \"We aim to broaden our eDNA approach and methodology for future inclusion into EPA guidelines.\" Dr. Nicole White, from the Trace and Environmental DNA (TrEnD) Laboratory at Curtin University's School of Molecular and Life Sciences, said the new species-specific test meant the Blind Cave Eel could be detected without the need to physically catch the animal. \"Detection of rare or cryptic species in their environment can be challenging at the best of times and our results show eDNA can offer conservation agencies an additional monitoring tool to augment existing approaches.\" ", "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 blind cave eel, Ophisternon candidum (Mees in J R Soc West Aust 45: 24–32,1962), is a rare groundwater inhabitant found in geographically isolated populations of north-west Australia. The species is listed as vulnerable under Commonwealth legislation and is a priority consideration when environmental disturbance by resource companies is proposed. Detection of this species for Environmental Impact Assessment (EIA) and monitoring is difficult because individuals are naturally rare or traditional sampling techniques are ineffective. To properly manage the species, information on population distribution and connectivity is critical. We sought to examine whether environmental DNA (eDNA) of O. candidum could be detected and whether positive detection was correlated with previous locations where the species had been physically caught. We developed new eDNA species-specific PCR assays to screen groundwater sampling points and we detected O. candidum DNA in three boreholes where the species has previously been collected and five additional groundwater sampling points. Our results demonstrated that the newly designed assays were effective for detecting this rare and vulnerable subterranean species. This work sets a benchmark for the application of eDNA species-specific PCR assays for EIA and monitoring, and has potential for these assays to be expanded more broadly to high-throughput eDNA metabarcoding for subterranean groundwater communities in the future. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Rare species are taxa that are uncommon, scarce, or infrequently encountered with small population sizes (Drury, 1974 ). These species usually occupy narrow endemic ranges, fragmented or degraded habitat and are vulnerable to ecological perturbations (Mouillot et al., 2013 ), especially if evolutionary processes have led to physiological adaptation to unique environmental conditions (Prendergast et al., 1993 ; Burgman & Lindenmayer, 1998 ). For truly rare taxa, sampling issues can compound difficulties of detection for their monitoring and conservation. Sampling rare taxa can be further complicated if they are cryptic or are able to avoid capture (McDonald, 2004 ). In this respect, alternative approaches to improve survey methodology, especially those that are non-destructive, will ultimately enhance conservation management. Groundwater has origins in regions of high rainfall and is stored in fissures and spaces in soil, sediment and rock. As the largest source of unfrozen freshwater on Earth, it is retained underground in aquifers, often for millions of years, providing water to ecosystems, agriculture, potable water for human communities, and the sustainment of aquatic and terrestrial ecosystem function. However, even though individual groundwater resources can be very large (e.g. Australia’s Great Artesian Basin covers one-third of the continent) their ecosystems can be extremely vulnerable due to overexploitation and depletion (Devitt et al., 2019 ; Saccò et al., 2019 ). Far from being a sterile habitat, groundwater is home to a wide variety of subterranean life including microbes, worms, arthropods and some vertebrates (i.e. fish and salamanders). Obligate subterranean groundwater organisms (stygobionts) are poorly known in Australia, as elsewhere, even though their role in ecosystem services are thought to be substantial (Simon et al., 2003 ; Hancock et al., 2005 ; Hose & Stumpp, 2019 ). Stygobionts can occur up to a kilometre below the surface and only in the last three decades has the diversity of subterranean communities in Australia been fully appreciated (e.g. Humphreys, 2008 ; Guzik et al., 2011 ). The isolated nature of many subterranean habitats occupied by stygobionts has resulted in narrow distribution ranges and increased short-range endemism (Asmyhr & Cooper, 2012 ). In the state of Western Australia, consideration of subterranean biodiversity is required, both within and around major resource development projects, as part of the Environmental Impact Assessment (EIA) process. Consequently, with improved knowledge of the unique nature of these subterranean communities, biodiversity assessment and monitoring have increased in importance. Sampling and identification of stygobionts for monitoring and conservation management is logistically difficult (Hancock & Boulton, 2009 ). Access to these habitats is sparce and is almost exclusively limited to pre-drilled, remote boreholes that target specific geologies of economic importance or difficult to access cave systems. Traditional monitoring techniques that are able to access these habitats (e.g. haul net surveys and traps) and subsequent processing (sorting, counting, morphological identification and molecular verification) are time-consuming and expensive. In addition, these methods are biased towards the most common and easily sampled species (i.e. invertebrates) making them impractical for sampling rare or difficult to sample species (e.g. active dispersers). All biota leave a trail of DNA in the environment through excretion, secretions, decay and other metabolic processes. Environmental DNA (eDNA) can be captured and sequenced using metabarcoding and thus provides a lens into species’ assemblages that recently inhabited a particular location (Taberlet et al., 2012 ; Port et al., 2016 ; Stat et al., 2017 ). Of current and particular interest, is refining metabarcoding methodologies (e.g. PCR assays and databases) for holistic audits of total biodiversity (Stat et al., 2017 ). Only a few studies have presented data for detection of stygobionts using eDNA from groundwater (Gorički et al., 2017 ; Korbel et al., 2017 ; Niemiller et al., 2018 ). Accordingly, there is much research still needed to explore the applicability of eDNA metabarcoding in subterranean environments including, but not limited to, improved understanding of DNA turnover, transport, sampling methods, reference databases, type I + II errors (Ficetola et al., 2016 ) and PCR assays. The blind cave eel Ophisternon candidum (Mees) (Mees, 1962 ) (Synbranchidae) is the largest of three cavefish species known from Australia (average length, 34.0 cm) (Fig. 1 ). The species exists entirely in subterranean water systems of the northern Carnarvon Basin (Cape Range and Barrow Island) and the Robe River catchment in the Pilbara region, north-western Australia, and has the traits characteristic of subterranean animals, e.g. lacking eyes and with unpigmented skin (Fig. 1 ). With limited information on its reproductive biology and ecology, O. candidum is thought to feed on stygobiontic crustaceans and opportunistically on aquatic larvae and arthropods that have sunk to bottom of the water column (Moore et al., 2018<|im_end|> <|im_start|>assistant New species-specific tests that can detect endangered and hard-to-find aquatic animals through the DNA they shed in the water has been created by researchers at the University of Adelaide and Curtin University. The tests, which are developed by sequencing the mitochondrial genome of an individual species and rely on environmental DNA in the water (termed eDNA), were used to detect the Blind Cave Eel (Ophisternon candidum) in the Pilbara, Western Australia, at eight separate locations; three sites where it has previously been physically detected and, more significantly, at five sites from which the species has never been recorded. The Blind Cave Eel is the largest of three cavefish species known from Australia, growing up to 40cm long. It exists entirely in subterranean groundwater systems of the northern Carnarvon Basin and the Robe River catchment in north-western Australia. It lacks eyes, has unpigmented skin and is notoriously difficult to locate during environmental surveys. It is listed as a vulnerable species. Researcher Dr. Michelle Guzik, from the University of Adelaide's School of Biological Sciences and Environment Institute, said the eel could avoid capture using traditional sampling methods, which can bias the results from field surveys. "There is a real need to develop non-invasive methods and knowledge that will increase the speed and scientific rigor of biological surveys for Environmental Protection Authority (EPA) approvals when assessing the potential for environmental disturbance," she said. "We aim to broaden our eDNA approach and methodology for future inclusion into EPA guidelines." Dr. Nicole White, from the Trace and Environmental DNA (TrEnD) Laboratory at Curtin University's School of Molecular and Life Sciences, said the new species-specific test meant the Blind Cave Eel could be detected without the need to physically catch the animal. "Detection of rare or cryptic species in their environment can be challenging at the best of times and our results show eDNA can offer conservation agencies an additional monitoring tool to augment existing approaches." <|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 Heterochromatin mostly comprises repeated sequences prone to harmful ectopic recombination during double-strand break (DSB) repair. In Drosophila cells, ‘safe’ homologous recombination (HR) repair of heterochromatic breaks relies on a specialized pathway that relocalizes damaged sequences away from the heterochromatin domain before strand invasion. Here we show that heterochromatic DSBs move to the nuclear periphery to continue HR repair. Relocalization depends on nuclear pores and inner nuclear membrane proteins (INMPs) that anchor repair sites to the nuclear periphery through the Smc5/6-interacting proteins STUbL/RENi. Both the initial block to HR progression inside the heterochromatin domain, and the targeting of repair sites to the nuclear periphery, rely on SUMO and SUMO E3 ligases. This study reveals a critical role for SUMOylation in the spatial and temporal regulation of HR repair in heterochromatin, and identifies the nuclear periphery as a specialized site for heterochromatin repair in a multicellular eukaryote. Main Nuclear architecture contributes to HR repair of certain types of DSB in budding yeast. Specifically, most DSBs exhibit Brownian motion and remain in the nucleoplasm during HR (refs 1 , 2 , 3 , 4 ), but persistent DSBs are shunted to the nuclear periphery after resection 1 , 2 , 5 , 6 . This relocalization has been observed in conditions where HR repair is effectively stalled, such as in the absence of a donor sequence for repair 1 , 2 , 5 , 6 or after fork collapse 1 , 7 . Whether relocalization is a physiological response to DSBs is still controversial, and the existence of similar roles for the nuclear periphery in multicellular eukaryotes has not been addressed. Pericentromeric heterochromatin occupies about 30% of fly and human genomes 8 and is characterized by large contiguous stretches of repeated sequences (transposons and ‘satellite’ repeats 9 , 10 , 11 ), and the ‘silent’ epigenetic marks H3K9me2/3 and Heterochromatin Protein 1 (HP1a in Drosophila ) 12 . Although pericentromeric heterochromatin is absent in budding yeast, it represents a major threat to genome stability in multicellular eukaryotes 13 , 14 . Thousands to millions of identical repeated sequences on different chromosomes can engage in ectopic recombination and generate chromosome rearrangements (for example, acentric and dicentric chromosomes) during DSB repair 13 , 14 . We previously identified a mechanism that promotes HR repair while preventing aberrant recombination in Drosophila 14 , 15 . Early HR steps (resection and ATRIP/TopBP1 recruitment) occur quickly within the heterochromatin domain 15 , but later steps (Rad51 recruitment) occur only after repair sites have relocalized to outside the domain 15 , 16 . Relocalization of heterochromatic DSBs also occurs in mouse cells, suggesting that this mechanism is conserved 14 , 17 . We proposed that relocalization prevents aberrant recombination by separating damaged DNA from similar repeats on non-homologous chromosomes, while promoting ‘safe’ exchanges with the sister chromatid or homologous chromosome 14 , 15 . Removing heterochromatic proteins (for example, Smc5/6) results in relocalization defects, abnormal recruitment of Rad51 inside the heterochromatin domain, and massive aberrant recombination between heterochromatic sequences 15 , revealing the importance of this pathway to genome stability. Whether heterochromatic DSBs relocalize to a specific subnuclear compartment was unclear, and the mechanisms responsible for relocalization and the regulation of HR progression were unknown. RESULTS SUMOylation blocks HR progression in heterochromatin and promotes DSB relocalization In Saccharomyces cerevisiae , SUMOylation mediates the relocalization of DSBs in ribosomal DNA (rDNA) to outside the nucleolus 18 and the movement of persistent DSBs to the nuclear periphery 6 . The Smc5/6 complex is required for relocalizing heterochromatic DSBs in Drosophila 15 and contains the SUMO E3 ligase Nse2 (refs 19 , 20 , 21 ), leading us to investigate the role of SUMOylation and SUMO ligases in heterochromatin repair. First, we determined that SUMO ligases are present at heterochromatic DSBs by monitoring the recruitment of these proteins to repair foci induced by exposure to ionizing radiation. Nse2 is broadly enriched in the heterochromatin domain in the absence of ionizing radiation exposure 15 ( Fig. 1a ). However, shortly after exposure to ionizing radiation and similar to other early repair components (for example, TopBP1/ATRIP (ref. 15 )), Nse2 is recruited to foci inside the heterochromatin domain that co-localize with the DSB markers γH2Av and TopBP1 ( Fig. 1a, b and Supplementary Fig. 1a ). Other Smc5/6 subunits form foci with similar kinetics ( Supplementary Fig. 1b ), and Nse2 focus formation depends on the core subunits Smc5 and Smc6 ( Supplementary Fig. 1c ), suggesting that Nse2 is recruited to heterochromatic DSBs as part of the Smc5/6 complex. Yeast Nse2/Mms21 shares numerous targets with the SUMO E3 ligases Siz1 and Siz2 (refs 22 , 23 , 24 , 25 ), homologues of Drosophila dPIAS (ref. 26 ). dPIAS is also recruited to heterochromatic repair foci with kinetics similar to ATRIP/TopBP1 ( Fig. 1c and ref. 15 ). Bright dPIAS foci frequently overlap with dim γH2Av foci, and vice versa ( Fig. 1c ), and the peak of dPIAS focus intensity temporally precedes that of γH2Av ( Supplementary Fig. 1d ), suggesting that dPIAS recruitment to DSBs precedes γH2Av spreading. These data suggest an early function of Nse2 and dPIAS SUMO ligases at heterochromatic DSBs. Figure 1: SUMOylation blocks HR progression in heterochromatin and promotes DSB relocalization. ( a ) Live imaging (left) and quantification (right) show GFP–Nse2 relative to mCh–HP1a (heterochromatin marker 15 ) before (Unt, 0) and after exposure to ionizing radiation. Nse2 focus relocalization results in reduction of focus number inside the heterochromatin domain (IN) between 10 and 30 min after exposure to ionizing radiation (error bars: s.e.m., P = 0.0001 for 10 versus 30 min, two-tailed Mann–Whitney test, n = 9 cells from one experiment), concurrently with focus increase at the periphery of the heterochromatin domain (periphery in/out), and in the euchromatic space (OUT; ref. 15 ). ( b ) Live imaging shows GFP–Nse2 and mCh–TopBP1 foci 15 min after exposure to ionizing radiation. ( c ) Immunofluorescence (left) and quantification (right) show the number of γH2Av foci", "role": "user" }, { "content": "Scientists have found a new function of the nuclear membrane, the envelope that encases and protects DNA in the nucleus of a cell - it fixes potentially fatal breaks in DNA strands. Previously, the nuclear membrane was thought to be mostly just a protective bubble around the nuclear material, with pores acting as channels to transport molecules in and out. But in a study published on October 26 in Nature Cell Biology, a research team led by Irene Chiolo documents how broken strands of a portion of DNA known as heterochromatin are dragged to the nuclear membrane for repair. DNA exists inside of a cell's nucleus in two forms: euchromatin and heterochromatin. Euchromatin gets all of the attention because it encodes most of the genome, while heterochromatin, which is mostly composed of repeated DNA sequences, has long been ignored as \"junk DNA.\" \"Scientists are now starting to pay a lot of attention to this mysterious component of the genome,\" said Chiolo, assistant professor at the USC Dornsife College of Letters, Arts and Sciences. \"Heterochromatin is not only essential for chromosome maintenance during cell division; it also poses specific threats to genome stability. Heterochromatin is potentially one of the most powerful driving forces for cancer formation, but it is the 'dark matter' of the genome. We are just beginning to unravel how repair works here.\" The reason why we don't experience thousands of cancers every day in our body is because we have incredibly efficient molecular mechanisms that repair the frequent damages occurring in our DNA. But those that work in heterochromatin are quite extraordinary. \"Repeated sequences tend to recombine with each other during DNA repair,\" said Taehyun Ryu, USC graduate student and first author on this study. \"This would lead to chromosome aberrations as frequently observed in cancer cells. What prevents these outcomes in normal cells was unclear.\" \"We knew that nuclear membrane dysfunctions are common in cancer cells,\" Chiolo said. \"Our studies now suggest how these dysfunctions can affect heterochromatin repair and have a causative role in cancer progression.\" Working with the fruit fly Drosophila melanogaster, the team observed that breaks in heterochromatin are repaired after damaged sequences move away from the rest of the chromosome to the inner wall of the nuclear membrane. There, a trio of proteins mends the break in a safe environment, where it cannot accidentally get tangled up with incorrect chromosomes. This study may help reveal how and why organisms become more predisposed to cancer as they age - the nuclear membrane progressively deteriorates as an organism ages, removing this bulwark against genome instability. Next, Chiolo, Ryu and their colleagues will explore how the movement of broken sequences is accomplished and regulated, and what happens in cells and organisms when this membrane-based repair mechanism fails. Their ultimate goal is to understand how this mechanism functions in human cells and identify new strategies to prevent their catastrophic failure and cancer formation. ", "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 Heterochromatin mostly comprises repeated sequences prone to harmful ectopic recombination during double-strand break (DSB) repair. In Drosophila cells, ‘safe’ homologous recombination (HR) repair of heterochromatic breaks relies on a specialized pathway that relocalizes damaged sequences away from the heterochromatin domain before strand invasion. Here we show that heterochromatic DSBs move to the nuclear periphery to continue HR repair. Relocalization depends on nuclear pores and inner nuclear membrane proteins (INMPs) that anchor repair sites to the nuclear periphery through the Smc5/6-interacting proteins STUbL/RENi. Both the initial block to HR progression inside the heterochromatin domain, and the targeting of repair sites to the nuclear periphery, rely on SUMO and SUMO E3 ligases. This study reveals a critical role for SUMOylation in the spatial and temporal regulation of HR repair in heterochromatin, and identifies the nuclear periphery as a specialized site for heterochromatin repair in a multicellular eukaryote. Main Nuclear architecture contributes to HR repair of certain types of DSB in budding yeast. Specifically, most DSBs exhibit Brownian motion and remain in the nucleoplasm during HR (refs 1 , 2 , 3 , 4 ), but persistent DSBs are shunted to the nuclear periphery after resection 1 , 2 , 5 , 6 . This relocalization has been observed in conditions where HR repair is effectively stalled, such as in the absence of a donor sequence for repair 1 , 2 , 5 , 6 or after fork collapse 1 , 7 . Whether relocalization is a physiological response to DSBs is still controversial, and the existence of similar roles for the nuclear periphery in multicellular eukaryotes has not been addressed. Pericentromeric heterochromatin occupies about 30% of fly and human genomes 8 and is characterized by large contiguous stretches of repeated sequences (transposons and ‘satellite’ repeats 9 , 10 , 11 ), and the ‘silent’ epigenetic marks H3K9me2/3 and Heterochromatin Protein 1 (HP1a in Drosophila ) 12 . Although pericentromeric heterochromatin is absent in budding yeast, it represents a major threat to genome stability in multicellular eukaryotes 13 , 14 . Thousands to millions of identical repeated sequences on different chromosomes can engage in ectopic recombination and generate chromosome rearrangements (for example, acentric and dicentric chromosomes) during DSB repair 13 , 14 . We previously identified a mechanism that promotes HR repair while preventing aberrant recombination in Drosophila 14 , 15 . Early HR steps (resection and ATRIP/TopBP1 recruitment) occur quickly within the heterochromatin domain 15 , but later steps (Rad51 recruitment) occur only after repair sites have relocalized to outside the domain 15 , 16 . Relocalization of heterochromatic DSBs also occurs in mouse cells, suggesting that this mechanism is conserved 14 , 17 . We proposed that relocalization prevents aberrant recombination by separating damaged DNA from similar repeats on non-homologous chromosomes, while promoting ‘safe’ exchanges with the sister chromatid or homologous chromosome 14 , 15 . Removing heterochromatic proteins (for example, Smc5/6) results in relocalization defects, abnormal recruitment of Rad51 inside the heterochromatin domain, and massive aberrant recombination between heterochromatic sequences 15 , revealing the importance of this pathway to genome stability. Whether heterochromatic DSBs relocalize to a specific subnuclear compartment was unclear, and the mechanisms responsible for relocalization and the regulation of HR progression were unknown. RESULTS SUMOylation blocks HR progression in heterochromatin and promotes DSB relocalization In Saccharomyces cerevisiae , SUMOylation mediates the relocalization of DSBs in ribosomal DNA (rDNA) to outside the nucleolus 18 and the movement of persistent DSBs to the nuclear periphery 6 . The Smc5/6 complex is required for relocalizing heterochromatic DSBs in Drosophila 15 and contains the SUMO E3 ligase Nse2 (refs 19 , 20 , 21 ), leading us to investigate the role of SUMOylation and SUMO ligases in heterochromatin repair. First, we determined that SUMO ligases are present at heterochromatic DSBs by monitoring the recruitment of these proteins to repair foci induced by exposure to ionizing radiation. Nse2 is broadly enriched in the heterochromatin domain in the absence of ionizing radiation exposure 15 ( Fig. 1a ). However, shortly after exposure to ionizing radiation and similar to other early repair components (for example, TopBP1/ATRIP (ref. 15 )), Nse2 is recruited to foci inside the heterochromatin domain that co-localize with the DSB markers γH2Av and TopBP1 ( Fig. 1a, b and Supplementary Fig. 1a ). Other Smc5/6 subunits form foci with similar kinetics ( Supplementary Fig. 1b ), and Nse2 focus formation depends on the core subunits Smc5 and Smc6 ( Supplementary Fig. 1c ), suggesting that Nse2 is recruited to heterochromatic DSBs as part of the Smc5/6 complex. Yeast Nse2/Mms21 shares numerous targets with the SUMO E3 ligases Siz1 and Siz2 (refs 22 , 23 , 24 , 25 ), homologues of Drosophila dPIAS (ref. 26 ). dPIAS is also recruited to heterochromatic repair foci with kinetics similar to ATRIP/TopBP1 ( Fig. 1c and ref. 15 ). Bright dPIAS foci frequently overlap with dim γH2Av foci, and vice versa ( Fig. 1c ), and the peak of dPIAS focus intensity temporally precedes that of γH2Av ( Supplementary Fig. 1d ), suggesting that dPIAS recruitment to DSBs precedes γH2Av spreading. These data suggest an early function of Nse2 and dPIAS SUMO ligases at heterochromatic DSBs. Figure 1: SUMOylation blocks HR progression in heterochromatin and promotes DSB relocalization. ( a ) Live imaging (left) and quantification (right) show GFP–Nse2 relative to mCh–HP1a (heterochromatin marker 15 ) before (Unt, 0) and after exposure to ionizing radiation. Nse2 focus relocalization results in reduction of focus number inside the heterochromatin domain (IN) between 10 and 30 min after exposure to ionizing radiation (error bars: s.e.m., P = 0.0001 for 10 versus 30 min, two-tailed Mann–Whitney test, n = 9 cells from one experiment), concurrently with focus increase at the periphery of the heterochromatin domain (periphery in/out), and in the euchromatic space (OUT; ref. 15 ). ( b ) Live imaging shows GFP–Nse2 and mCh–TopBP1 foci 15 min after exposure to ionizing radiation. ( c ) Immunofluorescence (left) and quantification (right) show the number of γH2Av foci<|im_end|> <|im_start|>assistant Scientists have found a new function of the nuclear membrane, the envelope that encases and protects DNA in the nucleus of a cell - it fixes potentially fatal breaks in DNA strands. Previously, the nuclear membrane was thought to be mostly just a protective bubble around the nuclear material, with pores acting as channels to transport molecules in and out. But in a study published on October 26 in Nature Cell Biology, a research team led by Irene Chiolo documents how broken strands of a portion of DNA known as heterochromatin are dragged to the nuclear membrane for repair. DNA exists inside of a cell's nucleus in two forms: euchromatin and heterochromatin. Euchromatin gets all of the attention because it encodes most of the genome, while heterochromatin, which is mostly composed of repeated DNA sequences, has long been ignored as "junk DNA." "Scientists are now starting to pay a lot of attention to this mysterious component of the genome," said Chiolo, assistant professor at the USC Dornsife College of Letters, Arts and Sciences. "Heterochromatin is not only essential for chromosome maintenance during cell division; it also poses specific threats to genome stability. Heterochromatin is potentially one of the most powerful driving forces for cancer formation, but it is the 'dark matter' of the genome. We are just beginning to unravel how repair works here." The reason why we don't experience thousands of cancers every day in our body is because we have incredibly efficient molecular mechanisms that repair the frequent damages occurring in our DNA. But those that work in heterochromatin are quite extraordinary. "Repeated sequences tend to recombine with each other during DNA repair," said Taehyun Ryu, USC graduate student and first author on this study. "This would lead to chromosome aberrations as frequently observed in cancer cells. What prevents these outcomes in normal cells was unclear." "We knew that nuclear membrane dysfunctions are common in cancer cells," Chiolo said. "Our studies now suggest how these dysfunctions can affect heterochromatin repair and have a causative role in cancer progression." Working with the fruit fly Drosophila melanogaster, the team observed that breaks in heterochromatin are repaired after damaged sequences move away from the rest of the chromosome to the inner wall of the nuclear membrane. There, a trio of proteins mends the break in a safe environment, where it cannot accidentally get tangled up with incorrect chromosomes. This study may help reveal how and why organisms become more predisposed to cancer as they age - the nuclear membrane progressively deteriorates as an organism ages, removing this bulwark against genome instability. Next, Chiolo, Ryu and their colleagues will explore how the movement of broken sequences is accomplished and regulated, and what happens in cells and organisms when this membrane-based repair mechanism fails. Their ultimate goal is to understand how this mechanism functions in human cells and identify new strategies to prevent their catastrophic failure and cancer formation. <|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 fate of coastal ecosystems depends on their ability to keep pace with sea-level rise—yet projections of accretion widely ignore effects of engineering fauna. Here, we quantify effects of the mussel , Geukensia demissa , on southeastern US saltmarsh accretion. Multi-season and -tidal stage surveys, in combination with field experiments, reveal that deposition is 2.8-10.7-times greater on mussel aggregations than any other marsh location. Our Delft-3D-BIVALVES model further predicts that mussels drive substantial changes to both the magnitude (±<0.1 cm·yr −1 ) and spatial patterning of accretion at marsh domain scales. We explore the validity of model predictions with a multi-year creekshed mussel manipulation of >200,000 mussels and find that this faunal engineer drives far greater changes to relative marsh accretion rates than predicted (±>0.4 cm·yr −1 ). Thus, we highlight an urgent need for empirical, experimental, and modeling work to resolve the importance of faunal engineers in directly and indirectly modifying the persistence of coastal ecosystems globally. Introduction As rates of sea-level rise accelerate globally, the fate of vegetated coastal ecosystems, such as salt marshes, mangroves, and seagrasses is uncertain 1 , 2 , 3 , 4 , 5 , 6 . Since these systems often occupy a narrow elevational range, relatively small changes in sea level may lead to substantial ‘drowning’, or conversion of vegetated, intertidal habitat to open water 7 , 8 , 9 . Given the valuable shoreline stabilization, wave attenuation, nutrient filtration, habitat provisioning, and carbon sequestration services provided by these ecosystems 10 , 11 , significant effort and resources have been invested in quantifying their past and current rates of vertical and horizontal accretion and erosion, and using both field data and modeling to forecast their size, stability, and spatial distribution under different sea-level rise scenarios 3 , 6 , 12 , 13 , 14 . Historically, modeling efforts primarily focused on the relationships between physical factors including sediment supply, elevation, and tidal range 15 . More recent models also account for the effects of vegetation, such as the trapping of sediment by aboveground stems and leaves, the accumulation of organic matter via root and rhizome production belowground 16 , and the feedbacks between vegetation and physical forcing factors 17 , in influencing vegetated coastal ecosystem dynamics and stability. Despite the flourishing sophistication of such models, they do not yet consider the role of fauna in altering vertical and horizontal accretion and erosion processes 18 , 19 . This lack of consideration of faunal influence is potentially problematic given the significant body of literature demonstrating that animals can modify sedimentation processes and vegetation coverage, density, and other above- and belowground traits (e.g., 20 ). Formed in temperate, low energy coastlines around the world 21 , salt marshes are among the most well-studied vegetated coastal ecosystems. These intertidal grasslands respond dynamically to tidal oscillations and sea level changes, as periodic flooding and draining of tidewaters control sediment delivery to marsh platforms, as well as plant zonation, productivity, and allocation to above- and belowground tissues 17 . Zero-, one-, and two-dimensional models have been developed to assess marsh accretion and erosion processes under various environmental scenarios at a single point, along a transect, or across a marsh platform, respectively 17 , 19 , 22 , 23 , 24 , 25 , 26 . More sophisticated ecogeomorphic models of marsh accretion have also been developed to incorporate the direct and indirect feedbacks between salt marsh vegetation and physical processes ( 17 , 18 , 19 , 22 , 23 , 24 , 25 , 26 , 27 ; Fig. S1 ). In these ecogeomorphic models, progressive flocculation and settling of suspended particles as flooding tides breach marsh platforms drives sediment deposition on marsh edges — a process that leads to the formation of levees, or elevated bands of sediment, along the margins of marsh channels and tidal creeks. As tidewaters flood from channels and creeks onto marsh platforms, flow velocities decrease and suspended sediments settle out of the water column, resulting in a sedimentation gradient whereby sediment deposition is highest along marsh margins and decreases with distance onto marsh platforms 28 . This mechanistic understanding of spatial gradients in sediment deposition that contribute to salt marsh vertical accretion is widely supported by empirical data and numerical modeling (e.g., 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ). While salt marshes and other vegetated coastal systems are built and structurally defined by habitat-forming plants, ecosystem engineering infauna and epifauna often play powerful roles in modulating their structure and stability 35 , 36 , 37 , 38 , 39 , 40 . Ecosystem engineering fauna, hereafter ‘faunal engineers’, can modify sediment deposition and accretion processes through a variety of direct and indirect mechanisms (e.g., 41 ). Suspension- and filter-feeding organisms, such as bivalves and sponges, actively contribute to sediment deposition, while bioturbating organisms, such as burrowing crabs and worms, resuspend sediment into the water column 41 , 42 . Both activity types can directly alter rates of inorganic and organic sediment import and export from coastal systems ( 36 , 43 , 44 see 45 for biota-mediated blue carbon cycling). Simultaneously, through deposition of nutrient-rich material, oxygenation of soil, and commensurate enhancement of above- and below-ground marsh plant growth, faunal engineers have the potential to indirectly enhance sediment capture by plant leaves or soil accumulation via root production. Further, herbivorous crabs, fungal-farming snails, and other consumers can decrease above and belowground plant biomass directly through their grazing activities, and/or indirectly through the spread of disease 46 , 47 , 48 . Likewise, larger-bodied herbivores (e.g., hogs, sheep, cows, and horses) often trample, graze, and compact marsh vegetation and landforms, thereby altering the spatial patterns in sediment accumulation and accretion or subsidence 49 , 50 , 51 . Most likely because such fauna exhibit significant temporal and spatial variability in their distribution and engineering impacts and are generally perceived to be far", "role": "user" }, { "content": "Faunal organisms such as the humble mussel often play an underappreciated yet important role in protecting and building coastal ecosystems, according to a new study led by the Carbon Containment Lab at the Yale School of the Environment. \"As sea levels rise, coastal ecosystems have to adapt and evolve to changing conditions,\" says Sinéad Crotty, associate director of science at the CC Lab and lead author of the study. \"This study shows that small and innocuous animals that live within an ecosystem can play a critical role in helping coastal systems persist in the face of climate change.\" Mussels (Geukensia demissa) serve as \"ecosystem engineers\"—organisms that directly or indirectly drive habitat construction and control the availability of resources to other organisms, according to the study's findings. Mussels are considered indicators of water quality, helping to keep streams and rivers clean by absorbing heavy metals and filtering harmful silt and particulates as they feed and breathe in aquatic ecosystems. Their shells also provide habitat and nesting sites for insects, small fish, and plants. In addition to these valuable characteristics, mussels also deposit large volumes of material on marsh surfaces through their feeding process. This contribution of sediment helps marshes grow through a process called accretion, which is the natural action of sand, soil or silt washing up to the land from the seashore or river. The study focused on 750,000 acres of expansive salt marsh systems in the U.S. along the coastal area known as the South Atlantic Bight, a region stretching over 150 miles from Cape Fear, North Carolina to Cape Canaveral, Florida and examined research on a variety of fauna including crabs, lugworms, and ghost shrimp. Field research for the study, which was recently published in Nature Communications, included surveys of mussel cover across the South Atlantic Bight. More detailed field measurements were taken on Sapelo Island, a barrier island off the coast of central Georgia. In addition to measurements taken across seasons and tidal phases, the researchers deployed three experiments designed to test mussels' impact on accretion from small, local scales to whole landscape scales. The largest experiment involved moving over 200,000 mussels by hand from one landscape to another and measuring changes to the marsh elevation over three years. \"We found that, in reality, the effects of mussels are far greater than predicted by the models, and occur at large, landscape scales,\" Crotty says. Similar trends are likely to occur with other fauna engineers, such as bioturbating crabs or worms, the authors note. Including ecosystem engineers in future modeling and ecosystem management will be important as sea levels continue to rise, the study's authors say. \"This study can help us think through how we prioritize certain marsh areas for protection,\" Crotty says. \"Given that mussels are disproportionately important in driving accretion and other ecosystem functions, we should prioritize their protection, or outplanting, as a means to promoting all of their associated benefits.\" The study's co-authors include researchers from the Department of Civil and Coastal Engineering at the University of Florida School for Sustainable Infrastructure and Environment, and the Royal Netherlands Institute of Sea Research, and Department of Physical Geography, Utrecht University. Co-author Tjeerd J. Bouma, senior scientist at the Royal Netherlands Institute for Sea Research, says the study provides important data on salt marches and climate change. \"The present study provides new insight into the mechanisms by which coastal ecosystems that are highly valuable for flood defense, such as salt marshes, can cope with sea-level rise,\" 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 The fate of coastal ecosystems depends on their ability to keep pace with sea-level rise—yet projections of accretion widely ignore effects of engineering fauna. Here, we quantify effects of the mussel , Geukensia demissa , on southeastern US saltmarsh accretion. Multi-season and -tidal stage surveys, in combination with field experiments, reveal that deposition is 2.8-10.7-times greater on mussel aggregations than any other marsh location. Our Delft-3D-BIVALVES model further predicts that mussels drive substantial changes to both the magnitude (±<0.1 cm·yr −1 ) and spatial patterning of accretion at marsh domain scales. We explore the validity of model predictions with a multi-year creekshed mussel manipulation of >200,000 mussels and find that this faunal engineer drives far greater changes to relative marsh accretion rates than predicted (±>0.4 cm·yr −1 ). Thus, we highlight an urgent need for empirical, experimental, and modeling work to resolve the importance of faunal engineers in directly and indirectly modifying the persistence of coastal ecosystems globally. Introduction As rates of sea-level rise accelerate globally, the fate of vegetated coastal ecosystems, such as salt marshes, mangroves, and seagrasses is uncertain 1 , 2 , 3 , 4 , 5 , 6 . Since these systems often occupy a narrow elevational range, relatively small changes in sea level may lead to substantial ‘drowning’, or conversion of vegetated, intertidal habitat to open water 7 , 8 , 9 . Given the valuable shoreline stabilization, wave attenuation, nutrient filtration, habitat provisioning, and carbon sequestration services provided by these ecosystems 10 , 11 , significant effort and resources have been invested in quantifying their past and current rates of vertical and horizontal accretion and erosion, and using both field data and modeling to forecast their size, stability, and spatial distribution under different sea-level rise scenarios 3 , 6 , 12 , 13 , 14 . Historically, modeling efforts primarily focused on the relationships between physical factors including sediment supply, elevation, and tidal range 15 . More recent models also account for the effects of vegetation, such as the trapping of sediment by aboveground stems and leaves, the accumulation of organic matter via root and rhizome production belowground 16 , and the feedbacks between vegetation and physical forcing factors 17 , in influencing vegetated coastal ecosystem dynamics and stability. Despite the flourishing sophistication of such models, they do not yet consider the role of fauna in altering vertical and horizontal accretion and erosion processes 18 , 19 . This lack of consideration of faunal influence is potentially problematic given the significant body of literature demonstrating that animals can modify sedimentation processes and vegetation coverage, density, and other above- and belowground traits (e.g., 20 ). Formed in temperate, low energy coastlines around the world 21 , salt marshes are among the most well-studied vegetated coastal ecosystems. These intertidal grasslands respond dynamically to tidal oscillations and sea level changes, as periodic flooding and draining of tidewaters control sediment delivery to marsh platforms, as well as plant zonation, productivity, and allocation to above- and belowground tissues 17 . Zero-, one-, and two-dimensional models have been developed to assess marsh accretion and erosion processes under various environmental scenarios at a single point, along a transect, or across a marsh platform, respectively 17 , 19 , 22 , 23 , 24 , 25 , 26 . More sophisticated ecogeomorphic models of marsh accretion have also been developed to incorporate the direct and indirect feedbacks between salt marsh vegetation and physical processes ( 17 , 18 , 19 , 22 , 23 , 24 , 25 , 26 , 27 ; Fig. S1 ). In these ecogeomorphic models, progressive flocculation and settling of suspended particles as flooding tides breach marsh platforms drives sediment deposition on marsh edges — a process that leads to the formation of levees, or elevated bands of sediment, along the margins of marsh channels and tidal creeks. As tidewaters flood from channels and creeks onto marsh platforms, flow velocities decrease and suspended sediments settle out of the water column, resulting in a sedimentation gradient whereby sediment deposition is highest along marsh margins and decreases with distance onto marsh platforms 28 . This mechanistic understanding of spatial gradients in sediment deposition that contribute to salt marsh vertical accretion is widely supported by empirical data and numerical modeling (e.g., 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ). While salt marshes and other vegetated coastal systems are built and structurally defined by habitat-forming plants, ecosystem engineering infauna and epifauna often play powerful roles in modulating their structure and stability 35 , 36 , 37 , 38 , 39 , 40 . Ecosystem engineering fauna, hereafter ‘faunal engineers’, can modify sediment deposition and accretion processes through a variety of direct and indirect mechanisms (e.g., 41 ). Suspension- and filter-feeding organisms, such as bivalves and sponges, actively contribute to sediment deposition, while bioturbating organisms, such as burrowing crabs and worms, resuspend sediment into the water column 41 , 42 . Both activity types can directly alter rates of inorganic and organic sediment import and export from coastal systems ( 36 , 43 , 44 see 45 for biota-mediated blue carbon cycling). Simultaneously, through deposition of nutrient-rich material, oxygenation of soil, and commensurate enhancement of above- and below-ground marsh plant growth, faunal engineers have the potential to indirectly enhance sediment capture by plant leaves or soil accumulation via root production. Further, herbivorous crabs, fungal-farming snails, and other consumers can decrease above and belowground plant biomass directly through their grazing activities, and/or indirectly through the spread of disease 46 , 47 , 48 . Likewise, larger-bodied herbivores (e.g., hogs, sheep, cows, and horses) often trample, graze, and compact marsh vegetation and landforms, thereby altering the spatial patterns in sediment accumulation and accretion or subsidence 49 , 50 , 51 . Most likely because such fauna exhibit significant temporal and spatial variability in their distribution and engineering impacts and are generally perceived to be far<|im_end|> <|im_start|>assistant Faunal organisms such as the humble mussel often play an underappreciated yet important role in protecting and building coastal ecosystems, according to a new study led by the Carbon Containment Lab at the Yale School of the Environment. "As sea levels rise, coastal ecosystems have to adapt and evolve to changing conditions," says Sinéad Crotty, associate director of science at the CC Lab and lead author of the study. "This study shows that small and innocuous animals that live within an ecosystem can play a critical role in helping coastal systems persist in the face of climate change." Mussels (Geukensia demissa) serve as "ecosystem engineers"—organisms that directly or indirectly drive habitat construction and control the availability of resources to other organisms, according to the study's findings. Mussels are considered indicators of water quality, helping to keep streams and rivers clean by absorbing heavy metals and filtering harmful silt and particulates as they feed and breathe in aquatic ecosystems. Their shells also provide habitat and nesting sites for insects, small fish, and plants. In addition to these valuable characteristics, mussels also deposit large volumes of material on marsh surfaces through their feeding process. This contribution of sediment helps marshes grow through a process called accretion, which is the natural action of sand, soil or silt washing up to the land from the seashore or river. The study focused on 750,000 acres of expansive salt marsh systems in the U.S. along the coastal area known as the South Atlantic Bight, a region stretching over 150 miles from Cape Fear, North Carolina to Cape Canaveral, Florida and examined research on a variety of fauna including crabs, lugworms, and ghost shrimp. Field research for the study, which was recently published in Nature Communications, included surveys of mussel cover across the South Atlantic Bight. More detailed field measurements were taken on Sapelo Island, a barrier island off the coast of central Georgia. In addition to measurements taken across seasons and tidal phases, the researchers deployed three experiments designed to test mussels' impact on accretion from small, local scales to whole landscape scales. The largest experiment involved moving over 200,000 mussels by hand from one landscape to another and measuring changes to the marsh elevation over three years. "We found that, in reality, the effects of mussels are far greater than predicted by the models, and occur at large, landscape scales," Crotty says. Similar trends are likely to occur with other fauna engineers, such as bioturbating crabs or worms, the authors note. Including ecosystem engineers in future modeling and ecosystem management will be important as sea levels continue to rise, the study's authors say. "This study can help us think through how we prioritize certain marsh areas for protection," Crotty says. "Given that mussels are disproportionately important in driving accretion and other ecosystem functions, we should prioritize their protection, or outplanting, as a means to promoting all of their associated benefits." The study's co-authors include researchers from the Department of Civil and Coastal Engineering at the University of Florida School for Sustainable Infrastructure and Environment, and the Royal Netherlands Institute of Sea Research, and Department of Physical Geography, Utrecht University. Co-author Tjeerd J. Bouma, senior scientist at the Royal Netherlands Institute for Sea Research, says the study provides important data on salt marches and climate change. "The present study provides new insight into the mechanisms by which coastal ecosystems that are highly valuable for flood defense, such as salt marshes, can cope with sea-level rise," he says. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae ( N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain ( N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone. Introduction The placenta, the first organ to form in mammals, is critically involved in early stages of development, establishing a maternal-embryo/fetal interface that supplies the bioenergetic needs of the conceptus. In addition to providing nutrients and oxygen support, the placenta disposes waste products, prevents perilous immune responses, and protects the embryo/fetus from infections 1 . All of these functions are essential for the development of the brain 2 . Indeed, conditions associated with a disruption of such functions are also associated with an increased risk for neuropsychiatric disorders, such as schizophrenia 2 , 3 . Schizophrenia is a complex disorder, affecting approximately 1% of the world’s population 4 , with a higher incidence in male individuals, compared with females 5 . While the onset is usually dated to late adolescence or early adulthood, the trajectories of risk start early in life, consistent with the neurodevelopmental origins of the disorder 6 . Such trajectories are likely affected by genetic susceptibility 7 . The heritability of the disorder is estimated between 50 and 80% 8 , and recent Genome Wide Association Studies (GWAS) 9 , 10 have identified hundreds of genetic loci associated with the disease, allowing for the calculation of aggregate metrics of genomic risk 11 , 12 , which account for around 7.3% of the liability to the disorder 10 . However, we still do not adequately understand the mechanisms that link genomic risk to illness and, although genetic studies of the disorder have been around for more than half a century, no incisive prevention or treatment strategy has been developed based on the knowledge derived by them. The commonly shared view on schizophrenia etiopathogenesis is that genetic variants associated with risk play a role directly in the brain, by inducing changes in the expression of genes (e.g., schizophrenia risk-associated genes) that might disrupt brain development and function. This view is supported by experimental evidence from animal models 13 , 14 , 15 and in vitro studies 16 , 17 , 18 , and from research in humans 15 , 19 , 20 , showing the effect of these genes on selected brain phenotypes. Recently, the integration of GWAS with expression mapping studies has led to the development of computational approaches 21 , 22 , 23 , 24 , 25 , 26 that allow prediction of gene expression in specific tissues for each individual in GWAS case-control samples. In this way, statistical associations can be estimated between predicted gene expression and a trait, in samples much larger than those usually available in transcriptomic studies. These approaches include Transcriptome Wide Association Studies (TWAS) 22 , 26 , which have the advantage of aggregating the effects of multiple SNPs onto specific genes, reducing multiple comparisons, and increasing power for association testing 21 , 22 , and Summary data based Mendelian Randomization (SMR), a complementary method for causative gene inference that helps to distinguish linkage from pleiotropy 25 , 26 . These approaches have allowed the identification and prioritization of candidate causal genes for schizophrenia, in brain areas whose development is thought to be altered in the disorder, such as cerebral cortex 26 , 27 , 28 , hippocampus 27 , and caudate 29 . While most of these studies are based on datasets from adult individuals, recent transcriptomic and epigenetic studies also indicate that some of the putative schizophrenia risk genes are dynamically regulated in brain in early development 30 , 31 , 32 . Indeed, some candidate causal genes for schizophrenia have also been highlighted by TWAS and SMR studies performed in fetal brain 10 , 33 . Because complications during prenatal and perinatal life (Early Life Complications, ELCs), represent the most common environmental risk factor associated with schizophrenia in offspring 3 , 34 , we have previously investigated the possibility of a convergence between ELCs and genomic risk for schizophrenia 35 , 36 . We found that genomic risk for schizophrenia interacts with ELCs so the liability for the disorder associated with genomic risk is up to five times higher in the presence of ELCs, compared to when ELCs are absent 35 . We also found that genes in schizophrenia risk loci are highly expressed in placenta and, specifically, in placentae from complicated pregnancies; moreover, they are more highly expressed in placentae from male compared with female offspring 35 . By computing an index of placental genomic risk for schizophrenia based on gene expression in placenta, we found that placental gene expression appears to mediate the interaction between genomic risk and ELCs on case-control status 35 . The same index of placental genomic risk was associated with early neurodevelopmental trajectories of risk, as shown by its association with neonatal brain volume, and developmental scores at one year of age, particularly in male individuals 36 . One subsequent study 37 that used a less detailed inventory for the assessment of ELCs and that did not survey many of the ELCs associated with schizophrenia 38 , 39 did not observe a statistical", "role": "user" }, { "content": "More than 100 genes linked to the risk of schizophrenia seem to cause illness because of their role in the placenta rather than in the developing brain, according to a new study led by the Lieber Institute for Brain Development. Scientists had generally assumed for over a century that genes for schizophrenia risk were principally, if not exclusively, about the brain. But the latest research, just published in Nature Communications, found that the placenta plays a much more significant role in developing illness than previously known. \"The secret of the genetics of schizophrenia has been hiding in plain sight—the placenta, the critical organ in supporting prenatal development, launches the developmental trajectory of risk,\" says Daniel Weinberger, M.D., senior author of the paper and Director and CEO of the Lieber Institute for Brain Development, located on the Johns Hopkins medical campus in Baltimore. \"The commonly shared view on the causes of schizophrenia is that genetic and environmental risk factors play a role directly and only in the brain, but these latest results show that placenta health is also critical.\" The researchers found that schizophrenia genes influence a critical function of the placenta to sense nutrients in the mother's bloodstream, including oxygen, and exchange nutrients based on what it finds. The schizophrenia risk genes are more lowly expressed in the cells of the placenta that form the core of this maternal-fetal nutrient exchange, called trophoblasts, negatively affecting the placenta's role in nurturing the developing fetus. The paper also identifies several genes in the placenta that are causative factors for diabetes, bipolar disorder, depression, autism and attention deficit hyperactivity disorder, or ADHD. The scientists, however, found far more genetic associations with genes for schizophrenia than for any of these other disorders. The researchers also discovered that the risk genes for schizophrenia found in the placenta may have a relatively greater effect on heritability, the likelihood of illness inherited from ancestors, than risk genes found in the brain. \"Targeting placenta biology is a crucial new potential approach to prevention, which is the holy grail of public health,\" says Gianluca Ursini, M.D., Ph.D., the lead author on the paper and an investigator at the Lieber Institute. \"Scientists could detect changes in placental risk genes decades before the possible onset of a disorder, possibly even in the mother's bloodstream during pregnancy. If doctors knew which children were most at risk of developmental disorders, they could implement early interventions to keep them healthy.\" The scientists also found interesting sex-based differences in the placenta risk genes. Different genes were associated with schizophrenia risk based on whether the placenta came from a male or female child. In pregnancies with male children, inflammatory processes in the placenta seem to play a central role. Previous research has shown males are more vulnerable than females to prenatal stress. Generally speaking, developmental disorders such as schizophrenia occur more frequently in men and boys. The researchers also uncovered concerning results about COVID-19 pregnancies. The scientists studied a small sample of placentas from mothers who had COVID-19 during pregnancy and found the schizophrenia genes for placenta risk were dramatically activated in these placentas. The finding indicates that COVID-19 infection during pregnancy may be a risk factor for schizophrenia because of how infection affects the placenta. Lieber Institute scientists are pursuing this possibility with research examining COVID-19 placentas to learn more. The Lieber Institute researchers hope their ongoing study of the genes of the placenta will one day lead to new treatment and diagnostic tools, perhaps revolutionizing the field of prenatal medicine. \"In the modern era of molecular and genetic medicine, the standard treatment for a complicated pregnancy is still primarily bedrest,\" says Dr. Weinberger. \"These new molecular insights into how genes related to disorders of the brain and other organs play out in the placenta offer new opportunities for improving prenatal health and preventing complications later in life.\" ", "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 Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae ( N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain ( N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone. Introduction The placenta, the first organ to form in mammals, is critically involved in early stages of development, establishing a maternal-embryo/fetal interface that supplies the bioenergetic needs of the conceptus. In addition to providing nutrients and oxygen support, the placenta disposes waste products, prevents perilous immune responses, and protects the embryo/fetus from infections 1 . All of these functions are essential for the development of the brain 2 . Indeed, conditions associated with a disruption of such functions are also associated with an increased risk for neuropsychiatric disorders, such as schizophrenia 2 , 3 . Schizophrenia is a complex disorder, affecting approximately 1% of the world’s population 4 , with a higher incidence in male individuals, compared with females 5 . While the onset is usually dated to late adolescence or early adulthood, the trajectories of risk start early in life, consistent with the neurodevelopmental origins of the disorder 6 . Such trajectories are likely affected by genetic susceptibility 7 . The heritability of the disorder is estimated between 50 and 80% 8 , and recent Genome Wide Association Studies (GWAS) 9 , 10 have identified hundreds of genetic loci associated with the disease, allowing for the calculation of aggregate metrics of genomic risk 11 , 12 , which account for around 7.3% of the liability to the disorder 10 . However, we still do not adequately understand the mechanisms that link genomic risk to illness and, although genetic studies of the disorder have been around for more than half a century, no incisive prevention or treatment strategy has been developed based on the knowledge derived by them. The commonly shared view on schizophrenia etiopathogenesis is that genetic variants associated with risk play a role directly in the brain, by inducing changes in the expression of genes (e.g., schizophrenia risk-associated genes) that might disrupt brain development and function. This view is supported by experimental evidence from animal models 13 , 14 , 15 and in vitro studies 16 , 17 , 18 , and from research in humans 15 , 19 , 20 , showing the effect of these genes on selected brain phenotypes. Recently, the integration of GWAS with expression mapping studies has led to the development of computational approaches 21 , 22 , 23 , 24 , 25 , 26 that allow prediction of gene expression in specific tissues for each individual in GWAS case-control samples. In this way, statistical associations can be estimated between predicted gene expression and a trait, in samples much larger than those usually available in transcriptomic studies. These approaches include Transcriptome Wide Association Studies (TWAS) 22 , 26 , which have the advantage of aggregating the effects of multiple SNPs onto specific genes, reducing multiple comparisons, and increasing power for association testing 21 , 22 , and Summary data based Mendelian Randomization (SMR), a complementary method for causative gene inference that helps to distinguish linkage from pleiotropy 25 , 26 . These approaches have allowed the identification and prioritization of candidate causal genes for schizophrenia, in brain areas whose development is thought to be altered in the disorder, such as cerebral cortex 26 , 27 , 28 , hippocampus 27 , and caudate 29 . While most of these studies are based on datasets from adult individuals, recent transcriptomic and epigenetic studies also indicate that some of the putative schizophrenia risk genes are dynamically regulated in brain in early development 30 , 31 , 32 . Indeed, some candidate causal genes for schizophrenia have also been highlighted by TWAS and SMR studies performed in fetal brain 10 , 33 . Because complications during prenatal and perinatal life (Early Life Complications, ELCs), represent the most common environmental risk factor associated with schizophrenia in offspring 3 , 34 , we have previously investigated the possibility of a convergence between ELCs and genomic risk for schizophrenia 35 , 36 . We found that genomic risk for schizophrenia interacts with ELCs so the liability for the disorder associated with genomic risk is up to five times higher in the presence of ELCs, compared to when ELCs are absent 35 . We also found that genes in schizophrenia risk loci are highly expressed in placenta and, specifically, in placentae from complicated pregnancies; moreover, they are more highly expressed in placentae from male compared with female offspring 35 . By computing an index of placental genomic risk for schizophrenia based on gene expression in placenta, we found that placental gene expression appears to mediate the interaction between genomic risk and ELCs on case-control status 35 . The same index of placental genomic risk was associated with early neurodevelopmental trajectories of risk, as shown by its association with neonatal brain volume, and developmental scores at one year of age, particularly in male individuals 36 . One subsequent study 37 that used a less detailed inventory for the assessment of ELCs and that did not survey many of the ELCs associated with schizophrenia 38 , 39 did not observe a statistical<|im_end|> <|im_start|>assistant More than 100 genes linked to the risk of schizophrenia seem to cause illness because of their role in the placenta rather than in the developing brain, according to a new study led by the Lieber Institute for Brain Development. Scientists had generally assumed for over a century that genes for schizophrenia risk were principally, if not exclusively, about the brain. But the latest research, just published in Nature Communications, found that the placenta plays a much more significant role in developing illness than previously known. "The secret of the genetics of schizophrenia has been hiding in plain sight—the placenta, the critical organ in supporting prenatal development, launches the developmental trajectory of risk," says Daniel Weinberger, M.D., senior author of the paper and Director and CEO of the Lieber Institute for Brain Development, located on the Johns Hopkins medical campus in Baltimore. "The commonly shared view on the causes of schizophrenia is that genetic and environmental risk factors play a role directly and only in the brain, but these latest results show that placenta health is also critical." The researchers found that schizophrenia genes influence a critical function of the placenta to sense nutrients in the mother's bloodstream, including oxygen, and exchange nutrients based on what it finds. The schizophrenia risk genes are more lowly expressed in the cells of the placenta that form the core of this maternal-fetal nutrient exchange, called trophoblasts, negatively affecting the placenta's role in nurturing the developing fetus. The paper also identifies several genes in the placenta that are causative factors for diabetes, bipolar disorder, depression, autism and attention deficit hyperactivity disorder, or ADHD. The scientists, however, found far more genetic associations with genes for schizophrenia than for any of these other disorders. The researchers also discovered that the risk genes for schizophrenia found in the placenta may have a relatively greater effect on heritability, the likelihood of illness inherited from ancestors, than risk genes found in the brain. "Targeting placenta biology is a crucial new potential approach to prevention, which is the holy grail of public health," says Gianluca Ursini, M.D., Ph.D., the lead author on the paper and an investigator at the Lieber Institute. "Scientists could detect changes in placental risk genes decades before the possible onset of a disorder, possibly even in the mother's bloodstream during pregnancy. If doctors knew which children were most at risk of developmental disorders, they could implement early interventions to keep them healthy." The scientists also found interesting sex-based differences in the placenta risk genes. Different genes were associated with schizophrenia risk based on whether the placenta came from a male or female child. In pregnancies with male children, inflammatory processes in the placenta seem to play a central role. Previous research has shown males are more vulnerable than females to prenatal stress. Generally speaking, developmental disorders such as schizophrenia occur more frequently in men and boys. The researchers also uncovered concerning results about COVID-19 pregnancies. The scientists studied a small sample of placentas from mothers who had COVID-19 during pregnancy and found the schizophrenia genes for placenta risk were dramatically activated in these placentas. The finding indicates that COVID-19 infection during pregnancy may be a risk factor for schizophrenia because of how infection affects the placenta. Lieber Institute scientists are pursuing this possibility with research examining COVID-19 placentas to learn more. The Lieber Institute researchers hope their ongoing study of the genes of the placenta will one day lead to new treatment and diagnostic tools, perhaps revolutionizing the field of prenatal medicine. "In the modern era of molecular and genetic medicine, the standard treatment for a complicated pregnancy is still primarily bedrest," says Dr. Weinberger. "These new molecular insights into how genes related to disorders of the brain and other organs play out in the placenta offer new opportunities for improving prenatal health and preventing complications later in life." <|im_end|>

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2,091

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding how species’ thermal limits have evolved across the tree of life is central to predicting species’ responses to climate change. Here, using experimentally-derived estimates of thermal tolerance limits for over 2000 terrestrial and aquatic species, we show that most of the variation in thermal tolerance can be attributed to a combination of adaptation to current climatic extremes, and the existence of evolutionary ‘attractors’ that reflect either boundaries or optima in thermal tolerance limits. Our results also reveal deep-time climate legacies in ectotherms, whereby orders that originated in cold paleoclimates have presently lower cold tolerance limits than those with warm thermal ancestry. Conversely, heat tolerance appears unrelated to climate ancestry. Cold tolerance has evolved more quickly than heat tolerance in endotherms and ectotherms. If the past tempo of evolution for upper thermal limits continues, adaptive responses in thermal limits will have limited potential to rescue the large majority of species given the unprecedented rate of contemporary climate change. Introduction Understanding the geographic distribution of life on Earth is a core ecological research goal 1 . Across aquatic and terrestrial realms, connections between species’ geographic range boundaries and their physiological thermal limits can help project the consequences of climate change on biodiversity 2 , 3 . For example, the tendency of species to retain their ancestral climatic affinities through evolutionary time is thought to constrain their ability to occupy climatic niches that differ from those occupied by their ancestors 4 , 5 , 6 , limiting their potential to adapt to rapid warming. The ability of organisms to tolerate cold temperatures is highly variable across species 7 , clades 8 and geographic locations 9 , while tolerance to heat is strikingly invariant across latitudes 10 , 11 , elevation 12 and phylogeny 13 . This pattern is counter-intuitive when considering thermal fitness/performance curves, which are generally left-skewed: i.e. body temperature increases at higher temperatures have a much greater effect on fitness than the equivalent temperature decreases at lower temperatures. At the global scale, what causes upper thermal limits to be less variable across the entire tree of life than lower thermal limits 10 , 14 remains untested but could be elucidated by three distinctive but not mutually exclusive mechanisms 13 . First, ‘deep-time climate legacies’ would be detectable in thermal limits if species had a tendency to retain their ancestral climatic affinities under niche conservatism 4 , 6 , 15 and given the Earth’s climate history. On a palaeoclimatic scale, Earth has been predominantly warm with intermittent glaciations 16 , 17 , thus most clades may have originated during warm periods and may have had limited opportunities to evolve beyond the warm environmental conditions in which they arose 18 . If a ʻdeep-time climate legacyʼ is primarily responsible for the differential evolution of upper and lower tolerance limits, we expect both cold and heat thermal limits to be lower in cold-originating clades compared to warm-originating clades. By contrast, upper and lower thermal limits are expected to be higher in warm-originating clades. Second, ‘physiological boundaries’ could limit physiological adaptation beyond certain temperatures. Lower thermal limits have been documented to exhibit more variation than upper thermal limits in both animals and plants 13 , with a few exceptions emerging when considering intraspecific variation 19 . The inability of organisms to counter the destabilizing effects of high temperatures on membranes and proteins could constrain variation of heat tolerance beyond certain limits 13 , 20 . If so, this suggests the existence of a physiological boundary for heat (not necessarily for cold) tolerance. If as other physiological traits, such a boundary was evolutionary constrained, then it should be detectable using phylogenetic analyses that evaluate the tempo and mode of evolution of thermal limits. Specifically, if a boundary exists we would expect thermal physiological limits across clades to accumulate through time consistent with an Orstein–Uhlenbeck (OU) model of evolution which indicates a stabilising selection on species thermal tolerance traits towards a fitness optimum 21 . Conversely, if neither a physiological boundary nor fitness optimum exist, the evolution of thermal limits may better fit a random model of evolution such as Brownian Motion, where a trait evolves in a random walk process, or white noise, where the trait value varies independently around the global mean 22 . While slower rates of evolution are expected for heat tolerance, because it is less variable than cold tolerance 13 , we still lack a phylogenetically informed multi-taxon test for this hypothesis. If a physiological boundary or optimum is the primary driver of invariance in upper thermal limits, we would expect the mode of evolution to show aggregation around an upper limit value, consistent with an evolutionary constraint for tolerance to heat. A lack of such aggregation would be expected for lower thermal limits. Third, ‘adaptation to current climatic extremes’ is expected to exert selective pressure on thermal limits. However, we expect current climatic extremes to exert greater selection on lower compared to upper thermal limits for two reasons. On the one hand, maximum environmental temperatures tend to be less variable across contemporary biogeographic gradients (i.e. latitude) compared to minimum temperatures 9 , 23 , 24 . On the other hand, behavioural buffering is more likely to reduce selective pressure on heat tolerance relative to cold tolerance 15 , because while organisms are able to use behaviour to evade heat stress, there tends to be fewer opportunities to behaviourally evade cold stress 5 , 15 . If ʻadaptation to current climatic extremesʼ is the main determinant of species’ thermal tolerance limits, we would expect a close match between experienced and tolerated temperature extremes 9 and similar rates of evolution in upper and lower thermal limits, with no global optimum or boundary. Here, using the largest existing dataset for thermal limits 25 , we conduct a series of comprehensive analyses to disentangle the relative role of the above-mentioned mechanisms that may have contributed to shape the global variation in thermal physiological limits. We stress again that these mechanisms are not mutually", "role": "user" }, { "content": "Many species might be left vulnerable in the face of climate change, unable to adapt their physiologies to respond to rapid global warming. According to a team of international researchers, species evolve heat tolerance more slowly than cold tolerance, and the level of heat they can adapt to has limits. In a study published in the Nature Communications, McGill professor Jennifer Sunday and her co-authors wanted to understand how species' thermal limits have evolved. To examine variation across the tree of life, the researchers developed the largest available database compiling thermal tolerances for all types of organisms (GlobTherm database). The researchers found that first and foremost, a species' thermal tolerance is linked to the current climate where they live. \"It's logical that thermal limits mostly match a species' present-day climate but tracing the evolutionary history of thermal limits can reveal how species got to be where they are today,\" says Sunday, an Assistant Professor in the Department of Biology. The researchers also found that tolerance to cold has evolved much faster than tolerance to heat, particularly in endotherms as compared to ectotherms and plants. Endothermic animals are those that generate metabolic heat to regulate their own body temperature—for example, mammals and birds—while ectothermic animals are those that regulate their body temperature using external heat sources, like reptiles, fishes and invertebrates. One cause of this disparity could be that heat tolerance has reached an evolutionary barrier, called an 'attractor,' beyond which further evolution is constrained or selected against. \"This is very concerning because it suggests that the vast majority of species will not be able to adapt fast enough to survive the unprecedented rate of contemporary climate change,\" says co-author Joanne Bennett of Leipzig University and University of Canberra. The results of this study are particularly relevant to conservation management, say the researchers. Protecting and creating areas that provide refuges for biodiversity from upper temperature extremes is a key strategy for conservation managers. ", "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 how species’ thermal limits have evolved across the tree of life is central to predicting species’ responses to climate change. Here, using experimentally-derived estimates of thermal tolerance limits for over 2000 terrestrial and aquatic species, we show that most of the variation in thermal tolerance can be attributed to a combination of adaptation to current climatic extremes, and the existence of evolutionary ‘attractors’ that reflect either boundaries or optima in thermal tolerance limits. Our results also reveal deep-time climate legacies in ectotherms, whereby orders that originated in cold paleoclimates have presently lower cold tolerance limits than those with warm thermal ancestry. Conversely, heat tolerance appears unrelated to climate ancestry. Cold tolerance has evolved more quickly than heat tolerance in endotherms and ectotherms. If the past tempo of evolution for upper thermal limits continues, adaptive responses in thermal limits will have limited potential to rescue the large majority of species given the unprecedented rate of contemporary climate change. Introduction Understanding the geographic distribution of life on Earth is a core ecological research goal 1 . Across aquatic and terrestrial realms, connections between species’ geographic range boundaries and their physiological thermal limits can help project the consequences of climate change on biodiversity 2 , 3 . For example, the tendency of species to retain their ancestral climatic affinities through evolutionary time is thought to constrain their ability to occupy climatic niches that differ from those occupied by their ancestors 4 , 5 , 6 , limiting their potential to adapt to rapid warming. The ability of organisms to tolerate cold temperatures is highly variable across species 7 , clades 8 and geographic locations 9 , while tolerance to heat is strikingly invariant across latitudes 10 , 11 , elevation 12 and phylogeny 13 . This pattern is counter-intuitive when considering thermal fitness/performance curves, which are generally left-skewed: i.e. body temperature increases at higher temperatures have a much greater effect on fitness than the equivalent temperature decreases at lower temperatures. At the global scale, what causes upper thermal limits to be less variable across the entire tree of life than lower thermal limits 10 , 14 remains untested but could be elucidated by three distinctive but not mutually exclusive mechanisms 13 . First, ‘deep-time climate legacies’ would be detectable in thermal limits if species had a tendency to retain their ancestral climatic affinities under niche conservatism 4 , 6 , 15 and given the Earth’s climate history. On a palaeoclimatic scale, Earth has been predominantly warm with intermittent glaciations 16 , 17 , thus most clades may have originated during warm periods and may have had limited opportunities to evolve beyond the warm environmental conditions in which they arose 18 . If a ʻdeep-time climate legacyʼ is primarily responsible for the differential evolution of upper and lower tolerance limits, we expect both cold and heat thermal limits to be lower in cold-originating clades compared to warm-originating clades. By contrast, upper and lower thermal limits are expected to be higher in warm-originating clades. Second, ‘physiological boundaries’ could limit physiological adaptation beyond certain temperatures. Lower thermal limits have been documented to exhibit more variation than upper thermal limits in both animals and plants 13 , with a few exceptions emerging when considering intraspecific variation 19 . The inability of organisms to counter the destabilizing effects of high temperatures on membranes and proteins could constrain variation of heat tolerance beyond certain limits 13 , 20 . If so, this suggests the existence of a physiological boundary for heat (not necessarily for cold) tolerance. If as other physiological traits, such a boundary was evolutionary constrained, then it should be detectable using phylogenetic analyses that evaluate the tempo and mode of evolution of thermal limits. Specifically, if a boundary exists we would expect thermal physiological limits across clades to accumulate through time consistent with an Orstein–Uhlenbeck (OU) model of evolution which indicates a stabilising selection on species thermal tolerance traits towards a fitness optimum 21 . Conversely, if neither a physiological boundary nor fitness optimum exist, the evolution of thermal limits may better fit a random model of evolution such as Brownian Motion, where a trait evolves in a random walk process, or white noise, where the trait value varies independently around the global mean 22 . While slower rates of evolution are expected for heat tolerance, because it is less variable than cold tolerance 13 , we still lack a phylogenetically informed multi-taxon test for this hypothesis. If a physiological boundary or optimum is the primary driver of invariance in upper thermal limits, we would expect the mode of evolution to show aggregation around an upper limit value, consistent with an evolutionary constraint for tolerance to heat. A lack of such aggregation would be expected for lower thermal limits. Third, ‘adaptation to current climatic extremes’ is expected to exert selective pressure on thermal limits. However, we expect current climatic extremes to exert greater selection on lower compared to upper thermal limits for two reasons. On the one hand, maximum environmental temperatures tend to be less variable across contemporary biogeographic gradients (i.e. latitude) compared to minimum temperatures 9 , 23 , 24 . On the other hand, behavioural buffering is more likely to reduce selective pressure on heat tolerance relative to cold tolerance 15 , because while organisms are able to use behaviour to evade heat stress, there tends to be fewer opportunities to behaviourally evade cold stress 5 , 15 . If ʻadaptation to current climatic extremesʼ is the main determinant of species’ thermal tolerance limits, we would expect a close match between experienced and tolerated temperature extremes 9 and similar rates of evolution in upper and lower thermal limits, with no global optimum or boundary. Here, using the largest existing dataset for thermal limits 25 , we conduct a series of comprehensive analyses to disentangle the relative role of the above-mentioned mechanisms that may have contributed to shape the global variation in thermal physiological limits. We stress again that these mechanisms are not mutually<|im_end|> <|im_start|>assistant Many species might be left vulnerable in the face of climate change, unable to adapt their physiologies to respond to rapid global warming. According to a team of international researchers, species evolve heat tolerance more slowly than cold tolerance, and the level of heat they can adapt to has limits. In a study published in the Nature Communications, McGill professor Jennifer Sunday and her co-authors wanted to understand how species' thermal limits have evolved. To examine variation across the tree of life, the researchers developed the largest available database compiling thermal tolerances for all types of organisms (GlobTherm database). The researchers found that first and foremost, a species' thermal tolerance is linked to the current climate where they live. "It's logical that thermal limits mostly match a species' present-day climate but tracing the evolutionary history of thermal limits can reveal how species got to be where they are today," says Sunday, an Assistant Professor in the Department of Biology. The researchers also found that tolerance to cold has evolved much faster than tolerance to heat, particularly in endotherms as compared to ectotherms and plants. Endothermic animals are those that generate metabolic heat to regulate their own body temperature—for example, mammals and birds—while ectothermic animals are those that regulate their body temperature using external heat sources, like reptiles, fishes and invertebrates. One cause of this disparity could be that heat tolerance has reached an evolutionary barrier, called an 'attractor,' beyond which further evolution is constrained or selected against. "This is very concerning because it suggests that the vast majority of species will not be able to adapt fast enough to survive the unprecedented rate of contemporary climate change," says co-author Joanne Bennett of Leipzig University and University of Canberra. The results of this study are particularly relevant to conservation management, say the researchers. Protecting and creating areas that provide refuges for biodiversity from upper temperature extremes is a key strategy for conservation managers. <|im_end|>

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13693, 304, 2225, 10099, 323, 11012, 220, 1032, 1174, 449, 264, 2478, 20157, 24084, 994, 13126, 10805, 300, 15934, 23851, 220, 777, 662, 578, 38550, 315, 44304, 311, 5663, 279, 72257, 4954, 6372, 315, 1579, 20472, 389, 79348, 323, 28896, 1436, 80799, 23851, 315, 8798, 25065, 7953, 3738, 13693, 220, 1032, 1174, 220, 508, 662, 1442, 779, 11, 420, 13533, 279, 14209, 315, 264, 53194, 19254, 369, 8798, 320, 1962, 14647, 369, 9439, 8, 25065, 13, 1442, 439, 1023, 53194, 25022, 11, 1778, 264, 19254, 574, 41993, 54852, 11, 1243, 433, 1288, 387, 11388, 481, 1701, 37555, 86945, 5411, 29060, 430, 15806, 279, 24108, 323, 3941, 315, 15740, 315, 29487, 13693, 13, 45863, 11, 422, 264, 19254, 6866, 584, 1053, 1755, 29487, 53194, 13693, 4028, 1206, 3536, 311, 47376, 1555, 892, 13263, 449, 459, 2582, 12711, 4235, 52, 71767, 55177, 320, 12188, 8, 1646, 315, 15740, 902, 15151, 264, 27276, 3876, 6727, 389, 9606, 29487, 25065, 25022, 7119, 264, 17479, 54767, 220, 1691, 662, 82671, 11, 422, 14188, 264, 53194, 19254, 6463, 17479, 54767, 3073, 11, 279, 15740, 315, 29487, 13693, 1253, 2731, 5052, 264, 4288, 1646, 315, 15740, 1778, 439, 10690, 1122, 27660, 11, 1405, 264, 18027, 93054, 304, 264, 4288, 4321, 1920, 11, 477, 4251, 12248, 11, 1405, 279, 18027, 907, 35327, 29235, 2212, 279, 3728, 3152, 220, 1313, 662, 6104, 29493, 7969, 315, 15740, 527, 3685, 369, 8798, 25065, 11, 1606, 433, 374, 2753, 3977, 1109, 9439, 25065, 220, 1032, 1174, 584, 2103, 6996, 264, 37555, 86945, 37774, 16369, 7447, 2442, 52936, 1296, 369, 420, 31178, 13, 1442, 264, 53194, 19254, 477, 54767, 374, 279, 6156, 5696, 315, 304, 959, 5397, 304, 8582, 29487, 13693, 11, 584, 1053, 1755, 279, 3941, 315, 15740, 311, 1501, 52729, 2212, 459, 8582, 4017, 907, 11, 13263, 449, 459, 41993, 22295, 369, 25065, 311, 8798, 13, 362, 6996, 315, 1778, 52729, 1053, 387, 3685, 369, 4827, 29487, 13693, 13, 21530, 11, 3451, 89171, 367, 311, 1510, 11323, 780, 69971, 529, 374, 3685, 311, 43844, 44010, 7410, 389, 29487, 13693, 13, 4452, 11, 584, 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7928, 6484, 10550, 369, 29487, 13693, 220, 914, 1174, 584, 6929, 264, 4101, 315, 16195, 29060, 311, 834, 306, 4134, 279, 8844, 3560, 315, 279, 3485, 12, 37691, 24717, 430, 1253, 617, 20162, 311, 6211, 279, 3728, 23851, 304, 29487, 53194, 13693, 13, 1226, 8631, 1578, 430, 1521, 24717, 527, 539, 53579, 128257, 198, 128256, 78191, 198, 8607, 9606, 2643, 387, 2163, 20134, 304, 279, 3663, 315, 10182, 2349, 11, 12153, 311, 10737, 872, 4571, 72, 9268, 311, 6013, 311, 11295, 3728, 24808, 13, 10771, 311, 264, 2128, 315, 6625, 12074, 11, 9606, 38680, 8798, 25065, 810, 14297, 1109, 9439, 25065, 11, 323, 279, 2237, 315, 8798, 814, 649, 10737, 311, 706, 13693, 13, 763, 264, 4007, 4756, 304, 279, 22037, 26545, 11, 94076, 14561, 30750, 7418, 323, 1077, 1080, 34603, 1105, 4934, 311, 3619, 1268, 9606, 6, 29487, 13693, 617, 28995, 13, 2057, 21635, 23851, 4028, 279, 5021, 315, 2324, 11, 279, 12074, 8040, 279, 7928, 2561, 4729, 55320, 29487, 15230, 3095, 369, 682, 4595, 315, 44304, 320, 38, 1718, 1016, 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1,646

[ { "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 Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer. Main Inheritance, variation and selection are foundational principles of Darwinian organismal evolution that have been used to explain how cancers emerge, progress and adapt 1 , 2 , 3 , 4 . The concept of genetic identity by descent is central to the application of evolutionary theory to cancer, suggesting a physical basis for identity through chromosomal inheritance during cell division, thereby explaining the clonal trajectories commonly seen in tumors 5 , 6 , 7 . However, several issues challenge current models of tumor clonal evolution. First, some aggressive forms of cancer maintain high levels of intratumoral copy number heterogeneity instead of undergoing selective sweeps, as would be predicted 8 . This is especially true for amplified oncogenes, whose cell-to-cell variability is high, despite the fitness advantage conferred 9 , 10 , 11 , 12 . Consequently, the mechanisms maintaining heterogeneous oncogene amplification events have been difficult to establish. Second, the ability of some cancers to rapidly adapt to changing conditions, including treatment, by changing their genomes, especially changing the copy number of amplified oncogenes, is not well explained by current models of genetic inheritance 9 . Third, the lag time to resistance predicted by the selection for drug resistance-conferring mutations arising in a single cell, or a small number of cells, is not seen in some cancers, raising questions about whether tumors are undergoing a genetic bottleneck 9 , 13 . The presence of ecDNA amplification may explain some of these paradoxical features. Extrachromosomal oncogene amplification on circular particles that lack centromeres is now recognized as a common event in human cancer that is linked to poor outcome and treatment resistance in patients 14 , 15 . It has been suggested that ecDNAs, because they lack centromeres, are unequally segregated to daughter cells during cell division 16 , 17 , 18 . However, the impact of nonchromosomal oncogene inheritance in cancer—random identity by descent—on intratumoral genetic heterogeneity, accelerated tumor evolution, enhanced ability to withstand environmental stresses and rapid genome change on therapeutic resistance, is not well understood. In this study, we integrated computer simulations, mathematical modeling, evolutionary theory, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C to generate ecDNA, as well as longitudinal analyses of patients’ tumors (Extended Data Fig. 1a ), to better understand ecDNA inheritance and its functional consequences. Random segregation of ecDNA in human cancer cells First, we tested if different ecDNA-amplified oncogenes segregate randomly after cell division or if we can observe oncogene-specific differences. Chromosomal segregation during mitotic cell division ensures that each daughter cell has the same DNA content (Fig. 1a , red line), although in cancer, dysregulation of chromosomal segregation can also contribute to segregation errors 19 . If ecDNA segregation is completely random with equal probabilities between daughter cells to inherit ecDNA, then we predict an approximate Gaussian distribution in the per-cell content of ecDNA after mitosis (Fig. 1a and Supplementary Information 1.1 ). Therefore, we developed a FISH-based method combined with unbiased image analysis to quantify ecDNA in daughter cells after cell division, using FISH probes to detect the amplified oncogenes residing on those ecDNAs, and Aurora B kinase immunostaining to identify the daughter cells in late mitosis 20 (Fig. 1b ). In cancer cell lines of different histological types, including prostate, gastric, colon, neuroblastoma and glioblastoma, carrying different oncogenes on ecDNA, and including cancer cell lines with multiple species of oncogene-containing ecDNAs, we quantified the ecDNA distribution of approximately 100 pairs of postmitotic daughter cells per-cell line, which permits sufficient resolution (Extended Data Fig. 2a and Supplementary Information 2.3 ). These experiments revealed a wide approximate Gaussian distribution that was independent of cancer cell type or the oncogene contained on the ecDNA (Fig. 1b,c and Extended Data Fig. 2c ). The fraction of segregated ecDNA per daughter cell (histograms) was highly concordant with the theoretical prediction of random segregation (dashed line) (Kolmogorov–Smirnov test P > 0.05, Extended Data Fig. 2c ) (Fig. 1c and Methods ). Fig. 1: ecDNA is randomly segregated to daughter cells. a , Schematic of ecDNA segregation and predicted distribution of ecDNA fractions. b , Representative images of ecDNA distribution to daughter cells, identified by Aurora B midbody staining, in multiple cancer cell lines in late mitosis. c , Frequency histograms of ecDNA fractions in cancer cell lines analyzed in b , showing agreement between simulated random segregations (dotted distributions) and observation (colored distributions) (Kolmogorov–Smirnov test P > 0.05). d , Schematic of the CRISPR-based genetic approach used for live-cell imaging of ecDNA in prostate cancer cells. HA, homology arms. e , Live-cell time-lapse imaging revealed unequal distribution of ecDNA between daughter cells. Time stamps, hh:mm. Scale bars, 5 μm. Source data Full size image To confirm these correlative observations, we designed a live-cell imaging system to visualize ecDNA dynamics during cell division. We used CRISPR–Cas9 (ref. 21 ) to insert a TetO array into the intergenic region between MYC and PVT1 of the ecDNA in PC3 prostate cancer cells (Fig. 1d ). Insertion of this array was confirmed by PCR, Sanger sequencing and TetO-MYC", "role": "user" }, { "content": "New research, co-led by Dr. Benjamin Werner from Barts Cancer Institute at Queen Mary University of London, indicates that the circular DNA structures present in around a third of cancers lead to extensive genetic diversity within tumors, giving them the ability to adapt rapidly to environmental stress and resist targeted cancer treatment. The findings of the proof-of-principle study, published in Nature Genetics, add to the understanding of how cancer's circular genomes, known as extrachromosomal DNA or ecDNA, contribute to poor outcomes in patients with some of the hardest-to-treat cancer types, and suggest that treating such cancers may require targeting the unique characteristics of ecDNAs in the future. Defying the rules of segregation Unlike the majority of a cell's DNA that is packed into structures called chromosomes within the cell's nucleus, ecDNAs are pieces of chromosomal DNA that have broken off and formed rings that float freely within the nucleus. Cancer cells can carry none, one or many ecDNAs and represent an extra source of genetic variation within tumors. Just like chromosomal DNA, ecDNA can carry mutated genes that drive cancer, called oncogenes. In healthy cells, chromosomal DNA is usually split equally between two daughter cells when the cell divides. However, ecDNAs do not follow the normal rules of segregation, as they lack the machinery that controls this even split. As a result, when a cancer cell containing ecDNAs divides, the circular DNA particles are split randomly between the two daughter cells. As cell division continues, populations of cells with different numbers of ecDNAs build up, driving genetic variation within the tumor. In this study, the team used a combination of mathematical and computational modeling, experimental approaches and clinical data to study how the numbers of ecDNA molecules vary from cell to cell within a population of cancer cells, and how this variation affects cancer's ability to respond to challenges. Using fluorescent labeling and live-cell imaging, the researchers observed that oncogene-carrying ecDNAs are randomly inherited in cell lines of prostate cancer, gastric cancer, colon cancer, neuroblastoma and glioblastoma. They then used computer and mathematical modeling to simulate what happens when a single cell containing ecDNAs expands to generate a population of 1 million cells. The simulations predicted that as the number of cells grew, the number of ecDNAs in each cell varied extremely, with many cells predicted to carry a few ecDNA copies and a few cells estimated to carry hundreds of ecDNA copies. The team expanded their analyses to look at six tumor cell lines of different cancer types known to carry oncogenes on ecDNA, and clinical samples taken from six patients with glioblastoma and four patients with neuroblastoma. In the cell lines and clinical samples, ecDNA copy number showed extreme cell-to-cell variation that matched the distributions predicted by the team's simulations. ecDNAs give cancer cells the ability to adapt faster Tumor evolution driven by genetic variation is a major obstacle in the treatment of cancer. The greater the genetic variation (or heterogeneity) within a tumor, the more likely it will be able to adapt to changes in its environment. Using a cell line pair derived from a patient with glioblastoma, the team investigated whether the presence of ecDNAs allowed the cells to adapt faster to survive challenges in their environment, including exposure to a targeted cancer drug. Both cell lines carried a common oncogene (a mutation in the EGFR gene) that allows cancer cells to grow faster, but one cell line carried this oncogene on ecDNAs, which varied in copy number from cell to cell, and the other carried the oncogene on chromosomal DNA. After treating both cell lines with a drug that specifically targets the EGFR mutation, the cell line with ecDNAs was able to adapt much faster to resist the effects of the drug by changing its composition to contain cells that carried fewer copies of ecDNA. With less of the drug target present in the population, the cells developed resistance to the drug in just two weeks, while the other cell line remained sensitive to the treatment. The team saw similar effects in cell lines and samples of other cancer types carrying different oncogenes treated with other drugs, indicating that ecDNA generates high levels of heterogeneity, which enables increased initial resistance to environmental or therapeutic challenges. Dr. Benjamin Werner, reader in somatic evolution at Barts Cancer Institute, says that \"ecDNA has sporadically been recognized for many years, but only more recently has it been observed to drive tumor aggressiveness and poor outcomes in patients. In order to give us the best chance at finding effective ways to treat ecDNA-carrying cancers, and to make it possible to predict disease course and outcome, it is essential to understand the behavior of these circular DNA structures.\" \"Our proof-of-principal study provides important insights into ecDNA's unique properties of segregation and evolution, which are essential to helping us find ways to turn this apparent selective advantage into a disadvantage for cancer 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 Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer. Main Inheritance, variation and selection are foundational principles of Darwinian organismal evolution that have been used to explain how cancers emerge, progress and adapt 1 , 2 , 3 , 4 . The concept of genetic identity by descent is central to the application of evolutionary theory to cancer, suggesting a physical basis for identity through chromosomal inheritance during cell division, thereby explaining the clonal trajectories commonly seen in tumors 5 , 6 , 7 . However, several issues challenge current models of tumor clonal evolution. First, some aggressive forms of cancer maintain high levels of intratumoral copy number heterogeneity instead of undergoing selective sweeps, as would be predicted 8 . This is especially true for amplified oncogenes, whose cell-to-cell variability is high, despite the fitness advantage conferred 9 , 10 , 11 , 12 . Consequently, the mechanisms maintaining heterogeneous oncogene amplification events have been difficult to establish. Second, the ability of some cancers to rapidly adapt to changing conditions, including treatment, by changing their genomes, especially changing the copy number of amplified oncogenes, is not well explained by current models of genetic inheritance 9 . Third, the lag time to resistance predicted by the selection for drug resistance-conferring mutations arising in a single cell, or a small number of cells, is not seen in some cancers, raising questions about whether tumors are undergoing a genetic bottleneck 9 , 13 . The presence of ecDNA amplification may explain some of these paradoxical features. Extrachromosomal oncogene amplification on circular particles that lack centromeres is now recognized as a common event in human cancer that is linked to poor outcome and treatment resistance in patients 14 , 15 . It has been suggested that ecDNAs, because they lack centromeres, are unequally segregated to daughter cells during cell division 16 , 17 , 18 . However, the impact of nonchromosomal oncogene inheritance in cancer—random identity by descent—on intratumoral genetic heterogeneity, accelerated tumor evolution, enhanced ability to withstand environmental stresses and rapid genome change on therapeutic resistance, is not well understood. In this study, we integrated computer simulations, mathematical modeling, evolutionary theory, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C to generate ecDNA, as well as longitudinal analyses of patients’ tumors (Extended Data Fig. 1a ), to better understand ecDNA inheritance and its functional consequences. Random segregation of ecDNA in human cancer cells First, we tested if different ecDNA-amplified oncogenes segregate randomly after cell division or if we can observe oncogene-specific differences. Chromosomal segregation during mitotic cell division ensures that each daughter cell has the same DNA content (Fig. 1a , red line), although in cancer, dysregulation of chromosomal segregation can also contribute to segregation errors 19 . If ecDNA segregation is completely random with equal probabilities between daughter cells to inherit ecDNA, then we predict an approximate Gaussian distribution in the per-cell content of ecDNA after mitosis (Fig. 1a and Supplementary Information 1.1 ). Therefore, we developed a FISH-based method combined with unbiased image analysis to quantify ecDNA in daughter cells after cell division, using FISH probes to detect the amplified oncogenes residing on those ecDNAs, and Aurora B kinase immunostaining to identify the daughter cells in late mitosis 20 (Fig. 1b ). In cancer cell lines of different histological types, including prostate, gastric, colon, neuroblastoma and glioblastoma, carrying different oncogenes on ecDNA, and including cancer cell lines with multiple species of oncogene-containing ecDNAs, we quantified the ecDNA distribution of approximately 100 pairs of postmitotic daughter cells per-cell line, which permits sufficient resolution (Extended Data Fig. 2a and Supplementary Information 2.3 ). These experiments revealed a wide approximate Gaussian distribution that was independent of cancer cell type or the oncogene contained on the ecDNA (Fig. 1b,c and Extended Data Fig. 2c ). The fraction of segregated ecDNA per daughter cell (histograms) was highly concordant with the theoretical prediction of random segregation (dashed line) (Kolmogorov–Smirnov test P > 0.05, Extended Data Fig. 2c ) (Fig. 1c and Methods ). Fig. 1: ecDNA is randomly segregated to daughter cells. a , Schematic of ecDNA segregation and predicted distribution of ecDNA fractions. b , Representative images of ecDNA distribution to daughter cells, identified by Aurora B midbody staining, in multiple cancer cell lines in late mitosis. c , Frequency histograms of ecDNA fractions in cancer cell lines analyzed in b , showing agreement between simulated random segregations (dotted distributions) and observation (colored distributions) (Kolmogorov–Smirnov test P > 0.05). d , Schematic of the CRISPR-based genetic approach used for live-cell imaging of ecDNA in prostate cancer cells. HA, homology arms. e , Live-cell time-lapse imaging revealed unequal distribution of ecDNA between daughter cells. Time stamps, hh:mm. Scale bars, 5 μm. Source data Full size image To confirm these correlative observations, we designed a live-cell imaging system to visualize ecDNA dynamics during cell division. We used CRISPR–Cas9 (ref. 21 ) to insert a TetO array into the intergenic region between MYC and PVT1 of the ecDNA in PC3 prostate cancer cells (Fig. 1d ). Insertion of this array was confirmed by PCR, Sanger sequencing and TetO-MYC<|im_end|> <|im_start|>assistant New research, co-led by Dr. Benjamin Werner from Barts Cancer Institute at Queen Mary University of London, indicates that the circular DNA structures present in around a third of cancers lead to extensive genetic diversity within tumors, giving them the ability to adapt rapidly to environmental stress and resist targeted cancer treatment. The findings of the proof-of-principle study, published in Nature Genetics, add to the understanding of how cancer's circular genomes, known as extrachromosomal DNA or ecDNA, contribute to poor outcomes in patients with some of the hardest-to-treat cancer types, and suggest that treating such cancers may require targeting the unique characteristics of ecDNAs in the future. Defying the rules of segregation Unlike the majority of a cell's DNA that is packed into structures called chromosomes within the cell's nucleus, ecDNAs are pieces of chromosomal DNA that have broken off and formed rings that float freely within the nucleus. Cancer cells can carry none, one or many ecDNAs and represent an extra source of genetic variation within tumors. Just like chromosomal DNA, ecDNA can carry mutated genes that drive cancer, called oncogenes. In healthy cells, chromosomal DNA is usually split equally between two daughter cells when the cell divides. However, ecDNAs do not follow the normal rules of segregation, as they lack the machinery that controls this even split. As a result, when a cancer cell containing ecDNAs divides, the circular DNA particles are split randomly between the two daughter cells. As cell division continues, populations of cells with different numbers of ecDNAs build up, driving genetic variation within the tumor. In this study, the team used a combination of mathematical and computational modeling, experimental approaches and clinical data to study how the numbers of ecDNA molecules vary from cell to cell within a population of cancer cells, and how this variation affects cancer's ability to respond to challenges. Using fluorescent labeling and live-cell imaging, the researchers observed that oncogene-carrying ecDNAs are randomly inherited in cell lines of prostate cancer, gastric cancer, colon cancer, neuroblastoma and glioblastoma. They then used computer and mathematical modeling to simulate what happens when a single cell containing ecDNAs expands to generate a population of 1 million cells. The simulations predicted that as the number of cells grew, the number of ecDNAs in each cell varied extremely, with many cells predicted to carry a few ecDNA copies and a few cells estimated to carry hundreds of ecDNA copies. The team expanded their analyses to look at six tumor cell lines of different cancer types known to carry oncogenes on ecDNA, and clinical samples taken from six patients with glioblastoma and four patients with neuroblastoma. In the cell lines and clinical samples, ecDNA copy number showed extreme cell-to-cell variation that matched the distributions predicted by the team's simulations. ecDNAs give cancer cells the ability to adapt faster Tumor evolution driven by genetic variation is a major obstacle in the treatment of cancer. The greater the genetic variation (or heterogeneity) within a tumor, the more likely it will be able to adapt to changes in its environment. Using a cell line pair derived from a patient with glioblastoma, the team investigated whether the presence of ecDNAs allowed the cells to adapt faster to survive challenges in their environment, including exposure to a targeted cancer drug. Both cell lines carried a common oncogene (a mutation in the EGFR gene) that allows cancer cells to grow faster, but one cell line carried this oncogene on ecDNAs, which varied in copy number from cell to cell, and the other carried the oncogene on chromosomal DNA. After treating both cell lines with a drug that specifically targets the EGFR mutation, the cell line with ecDNAs was able to adapt much faster to resist the effects of the drug by changing its composition to contain cells that carried fewer copies of ecDNA. With less of the drug target present in the population, the cells developed resistance to the drug in just two weeks, while the other cell line remained sensitive to the treatment. The team saw similar effects in cell lines and samples of other cancer types carrying different oncogenes treated with other drugs, indicating that ecDNA generates high levels of heterogeneity, which enables increased initial resistance to environmental or therapeutic challenges. Dr. Benjamin Werner, reader in somatic evolution at Barts Cancer Institute, says that "ecDNA has sporadically been recognized for many years, but only more recently has it been observed to drive tumor aggressiveness and poor outcomes in patients. In order to give us the best chance at finding effective ways to treat ecDNA-carrying cancers, and to make it possible to predict disease course and outcome, it is essential to understand the behavior of these circular DNA structures." "Our proof-of-principal study provides important insights into ecDNA's unique properties of segregation and evolution, which are essential to helping us find ways to turn this apparent selective advantage into a disadvantage for cancer cells." <|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 demand for renewable and sustainable fuel has prompted the rapid development of advanced nanotechnologies to effectively harness solar power. The construction of photosynthetic biohybrid systems (PBSs) aims to link preassembled biosynthetic pathways with inorganic light absorbers. This strategy inherits both the high light-harvesting efficiency of solid-state semiconductors and the superior catalytic performance of whole-cell microorganisms. Here, we introduce an intracellular, biocompatible light absorber, in the form of gold nanoclusters (AuNCs), to circumvent the sluggish kinetics of electron transfer for existing PBSs. Translocation of these AuNCs into non-photosynthetic bacteria enables photosynthesis of acetic acid from CO 2 . The AuNCs also serve as inhibitors of reactive oxygen species (ROS) to maintain high bacterium viability. With the dual advantages of light absorption and biocompatibility, this new generation of PBS can efficiently harvest sunlight and transfer photogenerated electrons to cellular metabolism, realizing CO 2 fixation continuously over several days. Main Although the conversion efficiencies of inorganic semiconductor devices from solar to different energy forms can easily surpass 20%, the transduction of solar energy into specific organics remains a bottleneck for abiotic catalysts 1 , 2 . The construction of PBSs enables solar-to-chemical energy conversion with high specificity and low cost 3 . Among several well-documented prototypes of hybrid inorganic–biological systems for photosynthetic CO 2 fixation 4 , 5 , 6 , the whole-cell strategy is favoured because of the involvement of a complete biological CO 2 reduction cycle and the ability to self-replicate and self-repair 7 (Fig. 1 ). Non-photosynthetic organisms, especially those developed in modern synthetic biology, possess more desirable metabolic pathways than their photosynthetic counterparts, offering a tunable CO 2 metabolism for diverse products 8 . Our proof-of-concept whole-cell hybrid system was realized by interfacing the non-photosynthetic electrotrophic bacterium Sporomusa ovata with a photoelectrochemical silicon nanowire array 4 . Sporomusa ovata can directly use electrons from the silicon photoelectrode through the bio-inorganic interface assisted by numerous active enzymes and functional proteins on their membranes 9 . Recently, we demonstrated that the acetogenic bacterium Moorella thermoacetica (ATCC 39073) can self-precipitate cadmium sulfide (CdS) nanoparticles on its membrane 7 . The photo-excited electrons from CdS nanoparticles are captured by membrane proteins to produce reducing equivalents that are ultimately transported into the cytoplasm to drive the Wood–Ljungdahl pathway for CO 2 fixation. In both examples, intimate bio–inorganic interfaces are formed between the inorganic semiconductors and the bacteria. Nevertheless, as most biocatalytic CO 2 fixation cycles are carried out in the cytoplasm, mass transport of redox shuttle molecules across the membrane into the cytoplasm would consume extra energy and be bottlenecked by transmembrane diffusion 10 . Therefore, simultaneous generation of photo-excited electrons and reducing equivalents inside the bacteria should improve the efficiency of energy transduction. An essential prerequisite for the light absorber is the ability to be taken up by living microorganisms without losing its chemical integrity. Fig. 1: Schematic diagram of the M. thermoacetica /AuNC hybrid system. a , The Au 22 (SG) 18 nanoclusters were delivered into bare M. thermoacetica (grey) during the culture process, forming M. thermoacetica /AuNCs with red emission. The simulated chemical structure of Au 22 (SG) 18 nanoclusters is shown in the inset 18 . Light yellow spheres, Au atoms in the core; dark yellow, Au atoms in the staple motifs; red, S atoms in the shell. All other atoms (carbon, hydrogen) have been omitted from this structure for clarity. Also shown are space-filling models of acetic acid and CO 2 (orange, oxygen; grey, carbon; white, hydrogen). b , Schematic of bacterium. The electrons generated from intracellular AuNCs under illumination are used by enzymatic mediators inside the cytoplasm and are finally passed on to the Wood–Ljungdahl pathway. Hypothesized electron transfer pathways are presented in Supplementary Fig. 1. Full size image Here we introduce ultra-small AuNCs as the biocompatible intracellular photosensitizer for non-photosynthetic bacteria. AuNCs possess chromophore-like discrete energy states and unique geometric structures 11 . The tunability of the core size and surface ligands of the AuNCs allows us to manipulate their biochemical/biophysical properties such as cell uptake, cytotoxicity, biocompatibility and molecular electronic structures 12 , 13 , 14 . In particular, strides have been made in the use of AuNCs in solar light harvesting as a visible-light absorber in the form of a type II junction 15 . Proof-of-concept studies have demonstrated that AuNCs can be delivered into mammalian cells either in vivo or in vitro to achieve cell imaging with high biocompatibility 16 , 17 . Incorporation of Au nanoclusters into M. thermoacetica Water-soluble AuNCs (majority Au 22 (SG) 18 , where SG is glutathione) were synthesized following a procedure reported previously, with slight modification (Au 22 (SG) 18 content ~92%) 18 , 19 . Moorella thermoacetica bacteria were inoculated and cultured in heterotrophic medium for 2 days before the Au 22 (SG) 18 solution was injected (see Methods for details). In the following 2 days, the bacteria underwent exponential growth in the presence of AuNCs. They were then centrifuged, separated from the supernatant and redispersed in autotrophic medium. In Supplementary Fig. 2 , the redispersed solution shows almost the same colour as before the centrifugation, whereas the supernatant is clear, suggesting that AuNCs were preferentially taken up by M. thermoacetica with a 95.37% uptake efficiency (see Supplementary Information ). Furthermore, the ultraviolet–visible (UV–vis) absorption spectrum of the redispersed M. thermoacetica /AuNC solution displays the same characteristic peaks as the bare AuNC solution, in contrast to the featureless absorption curve of the bare M. thermoacetica solution (Supplementary Fig. 3 ), indicating that the AuNCs remain intact during the integration process. Structure illumination microscopy (SIM) was further used to clarify the location of AuNCs in the hybrid biosystem by collecting the emissive fluorescence from AuNCs under excitation at 540 nm (Fig. 2a ) 20 . Figure 2b displays the image of several AuNC-treated M. thermoacetica on different focal planes with a step increment of 86 nm along the z direction. This shows the emission intensity profile from the bottom through the top cross-sections of the bacteria.", "role": "user" }, { "content": "A bacterium named Moorella thermoacetica won't work for free. But UC Berkeley researchers have figured out it has an appetite for gold. And in exchange for this special treat, the bacterium has revealed a more efficient path to producing solar fuels through artificial photosynthesis. M. thermoacetica first made its debut as the first non-photosensitive bacterium to carry out artificial photosynthesis in a study led by Peidong Yang, a professor in UC Berkeley's College of Chemistry. By attaching light-absorbing nanoparticles made of cadmium sulfide (CdS) to the bacterial membrane exterior, the researchers turned M. thermoacetica into a tiny photosynthesis machine, converting sunlight and carbon dioxide into useful chemicals. Now Yang and his team of researchers have found a better way to entice this CO2-hungry bacterium into being even more productive. By placing light-absorbing gold nanoclusters inside the bacterium, they have created a biohybrid system that produces a higher yield of chemical products than previously demonstrated. The research, funded by the National Institutes of Health, was published on Oct. 1 in Nature Nanotechnology. For the first hybrid model, M. thermoacetica-CdS, the researchers chose cadmium sulfide as the semiconductor for its ability to absorb visible light. But because cadmium sulfide is toxic to bacteria, the nanoparticles had to be attached to the cell membrane \"extracellularly,\" or outside the M. thermoacetica-CdS system. Sunlight excites each cadmium-sulfide nanoparticle into generating a charged particle known as an electron. As these light-generated electrons travel through the bacterium, they interact with multiple enzymes in a process known as \"CO2 reduction,\" triggering a cascade of reactions that eventually turns CO2 into acetate, a valuable chemical for making solar fuels. But within the extracellular model, the electrons end up interacting with other chemicals that have no part in turning CO2 into acetate. And as a result, some electrons are lost and never reach the enzymes. So to improve what's known as \"quantum efficiency,\" or the bacterium's ability to produce acetate each time it gains an electron, the researchers found another semiconductor: nanoclusters made of 22 gold atoms (Au22), a material that M. thermoacetica took a surprising shine to. When fed gold nanoclusters, the bacterium Moorella thermoacetica is transformed into a hybrid artificial photosynthesis system that converts sunlight and carbon dioxide into useful chemicals for solar fuels. Credit: Peidong Yang, UC Berkeley \"We selected Au22 because it's ideal for absorbing visible light and has the potential for driving the CO2 reduction process, but we weren't sure whether it would be compatible with the bacteria,\" Yang said. \"When we inspected them under the microscope, we discovered that the bacteria were loaded with these Au22 clusters—and were still happily alive.\" Imaging of the M. thermoacetica-Au22 system was done at UC Berkeley's Molecular Imaging Center. The researchers also selected Au22 ¬- dubbed by the researchers as \"magic\" gold nanoclusters—for its ultrasmall size: A single Au22 nanocluster is only 1 nanometer in diameter, allowing each nanocluster to easily slip through the bacterial cell wall. \"By feeding bacteria with Au22 nanoclusters, we've effectively streamlined the electron transfer process for the CO2 reduction pathway inside the bacteria, as evidenced by a 2.86 percent quantum efficiency—or 33 percent more acetate produced within the M. thermoacetica-Au22 system than the CdS model,\" Yang said. The magic gold nanocluster is the latest discovery coming out of Yang's lab, which for the past six years has focused on using biohybrid nanostructures to convert CO2 into useful chemicals as part of an ongoing effort to find affordable, abundant resources for renewable fuels, and potential solutions to thwart the effects of climate change. \"Next, we'd like to find a way to reduce costs, improve the lifetimes for these biohybrid systems, and improve quantum efficiency,\" Yang said. \"By continuing to look at the fundamental aspect of how gold nanoclusters are being photoactivated, and by following the electron transfer process within the CO2 reduction pathway, we hope to find even better solutions.\" ", "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 demand for renewable and sustainable fuel has prompted the rapid development of advanced nanotechnologies to effectively harness solar power. The construction of photosynthetic biohybrid systems (PBSs) aims to link preassembled biosynthetic pathways with inorganic light absorbers. This strategy inherits both the high light-harvesting efficiency of solid-state semiconductors and the superior catalytic performance of whole-cell microorganisms. Here, we introduce an intracellular, biocompatible light absorber, in the form of gold nanoclusters (AuNCs), to circumvent the sluggish kinetics of electron transfer for existing PBSs. Translocation of these AuNCs into non-photosynthetic bacteria enables photosynthesis of acetic acid from CO 2 . The AuNCs also serve as inhibitors of reactive oxygen species (ROS) to maintain high bacterium viability. With the dual advantages of light absorption and biocompatibility, this new generation of PBS can efficiently harvest sunlight and transfer photogenerated electrons to cellular metabolism, realizing CO 2 fixation continuously over several days. Main Although the conversion efficiencies of inorganic semiconductor devices from solar to different energy forms can easily surpass 20%, the transduction of solar energy into specific organics remains a bottleneck for abiotic catalysts 1 , 2 . The construction of PBSs enables solar-to-chemical energy conversion with high specificity and low cost 3 . Among several well-documented prototypes of hybrid inorganic–biological systems for photosynthetic CO 2 fixation 4 , 5 , 6 , the whole-cell strategy is favoured because of the involvement of a complete biological CO 2 reduction cycle and the ability to self-replicate and self-repair 7 (Fig. 1 ). Non-photosynthetic organisms, especially those developed in modern synthetic biology, possess more desirable metabolic pathways than their photosynthetic counterparts, offering a tunable CO 2 metabolism for diverse products 8 . Our proof-of-concept whole-cell hybrid system was realized by interfacing the non-photosynthetic electrotrophic bacterium Sporomusa ovata with a photoelectrochemical silicon nanowire array 4 . Sporomusa ovata can directly use electrons from the silicon photoelectrode through the bio-inorganic interface assisted by numerous active enzymes and functional proteins on their membranes 9 . Recently, we demonstrated that the acetogenic bacterium Moorella thermoacetica (ATCC 39073) can self-precipitate cadmium sulfide (CdS) nanoparticles on its membrane 7 . The photo-excited electrons from CdS nanoparticles are captured by membrane proteins to produce reducing equivalents that are ultimately transported into the cytoplasm to drive the Wood–Ljungdahl pathway for CO 2 fixation. In both examples, intimate bio–inorganic interfaces are formed between the inorganic semiconductors and the bacteria. Nevertheless, as most biocatalytic CO 2 fixation cycles are carried out in the cytoplasm, mass transport of redox shuttle molecules across the membrane into the cytoplasm would consume extra energy and be bottlenecked by transmembrane diffusion 10 . Therefore, simultaneous generation of photo-excited electrons and reducing equivalents inside the bacteria should improve the efficiency of energy transduction. An essential prerequisite for the light absorber is the ability to be taken up by living microorganisms without losing its chemical integrity. Fig. 1: Schematic diagram of the M. thermoacetica /AuNC hybrid system. a , The Au 22 (SG) 18 nanoclusters were delivered into bare M. thermoacetica (grey) during the culture process, forming M. thermoacetica /AuNCs with red emission. The simulated chemical structure of Au 22 (SG) 18 nanoclusters is shown in the inset 18 . Light yellow spheres, Au atoms in the core; dark yellow, Au atoms in the staple motifs; red, S atoms in the shell. All other atoms (carbon, hydrogen) have been omitted from this structure for clarity. Also shown are space-filling models of acetic acid and CO 2 (orange, oxygen; grey, carbon; white, hydrogen). b , Schematic of bacterium. The electrons generated from intracellular AuNCs under illumination are used by enzymatic mediators inside the cytoplasm and are finally passed on to the Wood–Ljungdahl pathway. Hypothesized electron transfer pathways are presented in Supplementary Fig. 1. Full size image Here we introduce ultra-small AuNCs as the biocompatible intracellular photosensitizer for non-photosynthetic bacteria. AuNCs possess chromophore-like discrete energy states and unique geometric structures 11 . The tunability of the core size and surface ligands of the AuNCs allows us to manipulate their biochemical/biophysical properties such as cell uptake, cytotoxicity, biocompatibility and molecular electronic structures 12 , 13 , 14 . In particular, strides have been made in the use of AuNCs in solar light harvesting as a visible-light absorber in the form of a type II junction 15 . Proof-of-concept studies have demonstrated that AuNCs can be delivered into mammalian cells either in vivo or in vitro to achieve cell imaging with high biocompatibility 16 , 17 . Incorporation of Au nanoclusters into M. thermoacetica Water-soluble AuNCs (majority Au 22 (SG) 18 , where SG is glutathione) were synthesized following a procedure reported previously, with slight modification (Au 22 (SG) 18 content ~92%) 18 , 19 . Moorella thermoacetica bacteria were inoculated and cultured in heterotrophic medium for 2 days before the Au 22 (SG) 18 solution was injected (see Methods for details). In the following 2 days, the bacteria underwent exponential growth in the presence of AuNCs. They were then centrifuged, separated from the supernatant and redispersed in autotrophic medium. In Supplementary Fig. 2 , the redispersed solution shows almost the same colour as before the centrifugation, whereas the supernatant is clear, suggesting that AuNCs were preferentially taken up by M. thermoacetica with a 95.37% uptake efficiency (see Supplementary Information ). Furthermore, the ultraviolet–visible (UV–vis) absorption spectrum of the redispersed M. thermoacetica /AuNC solution displays the same characteristic peaks as the bare AuNC solution, in contrast to the featureless absorption curve of the bare M. thermoacetica solution (Supplementary Fig. 3 ), indicating that the AuNCs remain intact during the integration process. Structure illumination microscopy (SIM) was further used to clarify the location of AuNCs in the hybrid biosystem by collecting the emissive fluorescence from AuNCs under excitation at 540 nm (Fig. 2a ) 20 . Figure 2b displays the image of several AuNC-treated M. thermoacetica on different focal planes with a step increment of 86 nm along the z direction. This shows the emission intensity profile from the bottom through the top cross-sections of the bacteria.<|im_end|> <|im_start|>assistant A bacterium named Moorella thermoacetica won't work for free. But UC Berkeley researchers have figured out it has an appetite for gold. And in exchange for this special treat, the bacterium has revealed a more efficient path to producing solar fuels through artificial photosynthesis. M. thermoacetica first made its debut as the first non-photosensitive bacterium to carry out artificial photosynthesis in a study led by Peidong Yang, a professor in UC Berkeley's College of Chemistry. By attaching light-absorbing nanoparticles made of cadmium sulfide (CdS) to the bacterial membrane exterior, the researchers turned M. thermoacetica into a tiny photosynthesis machine, converting sunlight and carbon dioxide into useful chemicals. Now Yang and his team of researchers have found a better way to entice this CO2-hungry bacterium into being even more productive. By placing light-absorbing gold nanoclusters inside the bacterium, they have created a biohybrid system that produces a higher yield of chemical products than previously demonstrated. The research, funded by the National Institutes of Health, was published on Oct. 1 in Nature Nanotechnology. For the first hybrid model, M. thermoacetica-CdS, the researchers chose cadmium sulfide as the semiconductor for its ability to absorb visible light. But because cadmium sulfide is toxic to bacteria, the nanoparticles had to be attached to the cell membrane "extracellularly," or outside the M. thermoacetica-CdS system. Sunlight excites each cadmium-sulfide nanoparticle into generating a charged particle known as an electron. As these light-generated electrons travel through the bacterium, they interact with multiple enzymes in a process known as "CO2 reduction," triggering a cascade of reactions that eventually turns CO2 into acetate, a valuable chemical for making solar fuels. But within the extracellular model, the electrons end up interacting with other chemicals that have no part in turning CO2 into acetate. And as a result, some electrons are lost and never reach the enzymes. So to improve what's known as "quantum efficiency," or the bacterium's ability to produce acetate each time it gains an electron, the researchers found another semiconductor: nanoclusters made of 22 gold atoms (Au22), a material that M. thermoacetica took a surprising shine to. When fed gold nanoclusters, the bacterium Moorella thermoacetica is transformed into a hybrid artificial photosynthesis system that converts sunlight and carbon dioxide into useful chemicals for solar fuels. Credit: Peidong Yang, UC Berkeley "We selected Au22 because it's ideal for absorbing visible light and has the potential for driving the CO2 reduction process, but we weren't sure whether it would be compatible with the bacteria," Yang said. "When we inspected them under the microscope, we discovered that the bacteria were loaded with these Au22 clusters—and were still happily alive." Imaging of the M. thermoacetica-Au22 system was done at UC Berkeley's Molecular Imaging Center. The researchers also selected Au22 ¬- dubbed by the researchers as "magic" gold nanoclusters—for its ultrasmall size: A single Au22 nanocluster is only 1 nanometer in diameter, allowing each nanocluster to easily slip through the bacterial cell wall. "By feeding bacteria with Au22 nanoclusters, we've effectively streamlined the electron transfer process for the CO2 reduction pathway inside the bacteria, as evidenced by a 2.86 percent quantum efficiency—or 33 percent more acetate produced within the M. thermoacetica-Au22 system than the CdS model," Yang said. The magic gold nanocluster is the latest discovery coming out of Yang's lab, which for the past six years has focused on using biohybrid nanostructures to convert CO2 into useful chemicals as part of an ongoing effort to find affordable, abundant resources for renewable fuels, and potential solutions to thwart the effects of climate change. "Next, we'd like to find a way to reduce costs, improve the lifetimes for these biohybrid systems, and improve quantum efficiency," Yang said. "By continuing to look at the fundamental aspect of how gold nanoclusters are being photoactivated, and by following the electron transfer process within the CO2 reduction pathway, we hope to find even better solutions." <|im_end|>

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279, 4668, 1752, 44225, 16029, 315, 279, 12743, 386, 13, 97247, 68323, 3074, 6425, 320, 10254, 67082, 23966, 13, 220, 18, 7026, 19392, 430, 279, 33150, 10153, 82, 7293, 35539, 2391, 279, 18052, 1920, 13, 29696, 77052, 92914, 320, 47716, 8, 574, 4726, 1511, 311, 38263, 279, 3813, 315, 33150, 10153, 82, 304, 279, 26038, 49554, 615, 555, 26984, 279, 99763, 535, 97332, 505, 33150, 10153, 82, 1234, 3521, 7709, 520, 220, 17048, 26807, 320, 30035, 13, 220, 17, 64, 883, 220, 508, 662, 19575, 220, 17, 65, 19207, 279, 2217, 315, 3892, 33150, 10153, 88186, 386, 13, 97247, 68323, 3074, 389, 2204, 42199, 25761, 449, 264, 3094, 16650, 315, 220, 4218, 26807, 3235, 279, 1167, 5216, 13, 1115, 5039, 279, 41353, 21261, 5643, 505, 279, 5740, 1555, 279, 1948, 5425, 22327, 82, 315, 279, 24032, 13, 128257, 198, 128256, 78191, 198, 32, 17854, 2411, 7086, 20832, 36882, 97247, 68323, 3074, 2834, 956, 990, 369, 1949, 13, 2030, 31613, 33108, 12074, 617, 25720, 704, 433, 706, 459, 38575, 369, 6761, 13, 1628, 304, 9473, 369, 420, 3361, 4322, 11, 279, 17854, 2411, 706, 10675, 264, 810, 11297, 1853, 311, 17843, 13238, 40373, 1555, 21075, 7397, 74767, 13, 386, 13, 97247, 68323, 3074, 1176, 1903, 1202, 17755, 439, 279, 1176, 2536, 12, 25625, 19245, 17854, 2411, 311, 6920, 704, 21075, 7397, 74767, 304, 264, 4007, 6197, 555, 5250, 307, 647, 25482, 11, 264, 14561, 304, 31613, 33108, 596, 9304, 315, 42846, 13, 3296, 72908, 3177, 97510, 269, 7278, 94753, 1903, 315, 19973, 51318, 40769, 579, 320, 91300, 50, 8, 311, 279, 45964, 39654, 28362, 11, 279, 12074, 6656, 386, 13, 97247, 68323, 3074, 1139, 264, 13987, 7397, 74767, 5780, 11, 34537, 40120, 323, 12782, 40589, 1139, 5505, 26333, 13, 4800, 25482, 323, 813, 2128, 315, 12074, 617, 1766, 264, 2731, 1648, 311, 1218, 560, 420, 7432, 17, 2902, 2234, 894, 17854, 2411, 1139, 1694, 1524, 810, 27331, 13, 3296, 25012, 3177, 97510, 269, 7278, 6761, 20622, 62868, 14947, 4871, 279, 17854, 2411, 11, 814, 617, 3549, 264, 17332, 8671, 16621, 1887, 430, 19159, 264, 5190, 7692, 315, 11742, 3956, 1109, 8767, 21091, 13, 578, 3495, 11, 24853, 555, 279, 5165, 73828, 315, 6401, 11, 574, 4756, 389, 5020, 13, 220, 16, 304, 22037, 33242, 52536, 13, 1789, 279, 1176, 26038, 1646, 11, 386, 13, 97247, 68323, 3074, 7813, 67, 50, 11, 279, 12074, 14896, 19973, 51318, 40769, 579, 439, 279, 87836, 369, 1202, 5845, 311, 35406, 9621, 3177, 13, 2030, 1606, 19973, 51318, 40769, 579, 374, 21503, 311, 24032, 11, 279, 94753, 1047, 311, 387, 12673, 311, 279, 2849, 39654, 330, 39749, 65441, 398, 1359, 477, 4994, 279, 386, 13, 97247, 68323, 3074, 7813, 67, 50, 1887, 13, 8219, 4238, 3521, 3695, 1855, 19973, 51318, 1355, 14643, 579, 76307, 7203, 1139, 24038, 264, 11684, 19320, 3967, 439, 459, 17130, 13, 1666, 1521, 3177, 16581, 57678, 5944, 1555, 279, 17854, 2411, 11, 814, 16681, 449, 5361, 56067, 304, 264, 1920, 3967, 439, 330, 8445, 17, 14278, 1359, 52605, 264, 43118, 315, 25481, 430, 9778, 10800, 7432, 17, 1139, 65802, 349, 11, 264, 15525, 11742, 369, 3339, 13238, 40373, 13, 2030, 2949, 279, 11741, 65441, 1646, 11, 279, 57678, 842, 709, 45830, 449, 1023, 26333, 430, 617, 912, 961, 304, 13353, 7432, 17, 1139, 65802, 349, 13, 1628, 439, 264, 1121, 11, 1063, 57678, 527, 5675, 323, 2646, 5662, 279, 56067, 13, 2100, 311, 7417, 1148, 596, 3967, 439, 330, 31548, 372, 15374, 1359, 477, 279, 17854, 2411, 596, 5845, 311, 8356, 65802, 349, 1855, 892, 433, 20192, 459, 17130, 11, 279, 12074, 1766, 2500, 87836, 25, 20622, 62868, 14947, 1903, 315, 220, 1313, 6761, 33299, 320, 66432, 1313, 705, 264, 3769, 430, 386, 13, 97247, 68323, 3074, 3952, 264, 15206, 33505, 311, 13, 3277, 23114, 6761, 20622, 62868, 14947, 11, 279, 17854, 2411, 20832, 36882, 97247, 68323, 3074, 374, 24411, 1139, 264, 26038, 21075, 7397, 74767, 1887, 430, 33822, 40120, 323, 12782, 40589, 1139, 5505, 26333, 369, 13238, 40373, 13, 16666, 25, 5250, 307, 647, 25482, 11, 31613, 33108, 330, 1687, 4183, 33150, 1313, 1606, 433, 596, 10728, 369, 70275, 9621, 3177, 323, 706, 279, 4754, 369, 10043, 279, 7432, 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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 subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs. Introduction SRC-3 functions as a transcriptional coactivator for steroid hormone receptors including the estrogen, progesterone and numerous other nuclear receptors, but also functions as a primary coactivator for many other DNA-binding transcription factors including E2F, NFκB, and members of the ETS family 1 , 2 , 3 , 4 . SRC-3 can be extensively modified by post-translational modifications (PTMs), including phosphorylation, methylation, acetylation, and ubiquitination that regulate its function and affinity for transcription factors and coactivator protein complexes 5 , 6 . These combinatorial PTMs are reflective of the environment of hormones, cytokines, and environment to which cells are exposed and the state of their respective signaling pathways. Since SRC-3 can assimilate diverse cellular cues in this way, it is thought to function as a nutrient sensor and signaling integrator to drive diverse gene expression patterns that reflect the needs of the cell. It is well established that breast cancer is a heterogeneous disease, both in terms of tumor subtypes present in patient populations and the milieu of cell types present within individual tumors. An important component of the tumor microenvironment is infiltrating immune cells that can serve various roles in controlling tumor growth or providing local immune suppression, effectively protecting the tumor from destruction by the immune system. Various suppressive immune cell types from myeloid or lymphoid origins are known to block anti-tumor immunity, including myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and regulatory T cells (Tregs). The latter cell type is of particular interest since Treg infiltration has been experimentally proven in breast tumor biopsies and correlates with poor prognosis and reduced breast cancer patient survival 7 , 8 . Tregs are critical to prevent autoimmunity in peripheral tissues where they can suppress local immunity and contribute to self-tolerance. A hallmark of Tregs is their intracellular expression of the forkhead box transcription factor 3 (Foxp3), which is critical for Treg suppressive immune function. Mice with mutations or deletions of FOXP3 develop lethal autoimmunity and humans with mutations in FOXP3 develop a rare disease called immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. Autoimmunity, thrombocytopenia, alopecia, erythematous plaques and general dermatitis characterize these diseases. In severe cases, neonates fail to thrive and require bone marrow transplantation. Conversely, Treg function can be hijacked by tumors or viruses to evade immune clearance. Regulation of the FOXP3 gene is thus a critical determinant for immune self-tolerance, and factors controlling FOXP3 transcription may be attractive targets to modulate Treg activity. Results The role of SRC-3 in the immune system is not well understood at present, despite publications showing high SRC-3 expression in leukocytes. We have found that knockout of the Src-3 gene in mice results in phenotypes that include broad lymphoproliferation and hypersensitivity to acute inflammation 9 , 10 . Our aged Src-3 null mice develop B-cell lymphomas and display elevated numbers of B cells and T cells in lymph nodes, spleen, and bone marrow 9 . Additionally, Src-3 knockout mice challenged with LPS experience endotoxic shock and are unable to defend body temperature or dampen inflammatory cytokines including TNFα, IL-6, and IL-1β 10 . To confirm that these immune phenotypes have not drifted from our previous reports, we performed comprehensive immune phenotyping of spleens from our Src-3 knockout mice and age-matched littermates. We used an antibody panel established by the Cell Cytometry and Sorting Core at Baylor College of Medicine in collaboration with the International Mouse Phenotyping Consortium (See Supplementary Fig. 1 A online). Metadata for mouse age, weight, body temperature, blood glucose, tibia length, splenocytes number and viability, and the number of FACS events were collected (See Supplementary Fig. 1 B online). No overt inguinal lymphomas were observed by gross inspection in any of the knockout or wild-type mice. Additionally, and consistent with general dwarfism observed in the Src-3 knockout mice 11 , 12 spleens were not enlarged relative to littermates (data not shown). We observe broad lymphoproliferation of T cells and B cells (See Supplementary Fig. 1 C and Supplementary File 1 online), while natural killer (NK) cells and myeloid lineages were unchanged or slightly decreased (See Supplementary Fig. 1 D and Supplementary File 1 online). Collectively, these results corroborate previous reports and suggest that loss of SRC-3 conveys a stable immune phenotype that is sensitive to lymphocyte-mediated inflammatory stress. We noted high expression of SRC-3 protein in the thymus of healthy C57BL6/J mice (Fig. 1 A, inset) and took an explorative bioinformatics approach to identify the SRC-3 immune compartment. Query of microarray data in the BioGPS web portal shows that the Src-3 transcript is highly expressed in T cells and B cells, and enriched in regulatory T cells (Tregs) (Fig. 1 A). Similarly, microarray and more recent RNA sequencing data available through the Immune Genome project (ImmGen) 13 , 14 , 15 indicates that the Src-3 transcript is highly expressed in regulatory T cells (See Supplementary Fig. 1 E online). Next, we sought to use an orthogonal approach and assembled a curated list of 297 transcriptional coregulators from the Nuclear Receptor Signaling Atlas (NURSA) 16 . This coregulator gene list was parsed against Foxp3 transcript expression using the gene set enrichment analysis (GSEA) function in", "role": "user" }, { "content": "A study led by researchers at Baylor College of Medicine reveals a novel role of the steroid receptor coactivator 3 (SRC-3/NCOA3), a protein crucial for steroid hormone function and a prognostic marker for aggressive human breast and other cancers. The team discovered that SRC-3 also regulates human immune T regulatory cells (Tregs), which contribute to the regulation of the body's immunological activity by suppressing the function of other immune cells, including those involved in fighting cancer. The study, which appears in the journal Scientific Reports, shows that Tregs whose SRC-3 function was eliminated failed to suppress the activity of other immune cells in the lab. The authors anticipate that their findings may help in the fight against cancer in the future by leading to new approaches to inhibit Tregs activity which consequently would release immune attack in tumors. \"Tregs play an important role by suppressing immune activity that can potentially harm the body,\" said co-corresponding author, Dr. Bert O'Malley, chancellor and professor of molecular and cellular biology at Baylor. \"For instance, Tregs are critical to prevent autoimmunity, an immune response directed against normal tissues of a person, which can lead to severe disease.\" In addition, breast cancer and other types of tumors include infiltrating immune cells that can contribute to the control of tumor growth or, on the other hand, provide local immune suppression that would favor tumor growth. Treg infiltration has been experimentally proven in breast tumor biopsies and correlates with poor prognosis and reduced patient survival. \"Dr. O'Malley's lab is the leader in SRC-3 research,\" said co-first author Dr. Bryan Nikolai, adjunct assistant professor molecular and cellular biology at Baylor and senior scientist at CooperGenomics. \"SRC-3 is well-known for its role in cancer formation and proliferation, but we wondered what role it would play in immune T cells. A review of bioinformatics data revealed that SRC-3 is highly expressed in Tregs and this encouraged us to pursue this study.\" \"We experimentally show that SRC-3 is significantly enriched in both murine and human Tregs,\" said co-first author Dr. Prashi Jain, instructor of molecular and cellular biology at Baylor. \"Working with human Tregs, we used our small molecule inhibitor SI-2 to effectively inhibit SRC-3 in Tregs. As a result, Tregs greatly reduced their ability to inhibit the activation of other immune cells that help in maintaining antitumor immunity.\" The O'Malley lab had previously shown that SI-2 eliminates SRC-3 in breast cancer cells and, consequently, inhibits tumor growth in a mouse model of breast cancer. \"Now that we know that SRC-3 also plays a key role in the immune system, I am excited to see whether our SRC-3 small molecule inhibitors might provide a dual benefit, eliminating cancer cells directly and also blocking the suppressive activity of Tregs, like killing two birds with one stone,\" said co-author Dr. David Lonard, associate professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. \"There is a great deal of interest in finding ways to inhibit Tregs that suppress the immune system,\" said O'Malley, a member of Baylor's Dan L Duncan Comprehensive Cancer Center. \"We are excited about the possibility that our approach with small molecule inhibitors might lead to promising therapies in the future. If we can remove the suppressive effect Tregs have in anticancer immune response with our small molecule inhibitors, the immune system then would be free to go after the tumor.\" ", "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 subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs. Introduction SRC-3 functions as a transcriptional coactivator for steroid hormone receptors including the estrogen, progesterone and numerous other nuclear receptors, but also functions as a primary coactivator for many other DNA-binding transcription factors including E2F, NFκB, and members of the ETS family 1 , 2 , 3 , 4 . SRC-3 can be extensively modified by post-translational modifications (PTMs), including phosphorylation, methylation, acetylation, and ubiquitination that regulate its function and affinity for transcription factors and coactivator protein complexes 5 , 6 . These combinatorial PTMs are reflective of the environment of hormones, cytokines, and environment to which cells are exposed and the state of their respective signaling pathways. Since SRC-3 can assimilate diverse cellular cues in this way, it is thought to function as a nutrient sensor and signaling integrator to drive diverse gene expression patterns that reflect the needs of the cell. It is well established that breast cancer is a heterogeneous disease, both in terms of tumor subtypes present in patient populations and the milieu of cell types present within individual tumors. An important component of the tumor microenvironment is infiltrating immune cells that can serve various roles in controlling tumor growth or providing local immune suppression, effectively protecting the tumor from destruction by the immune system. Various suppressive immune cell types from myeloid or lymphoid origins are known to block anti-tumor immunity, including myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and regulatory T cells (Tregs). The latter cell type is of particular interest since Treg infiltration has been experimentally proven in breast tumor biopsies and correlates with poor prognosis and reduced breast cancer patient survival 7 , 8 . Tregs are critical to prevent autoimmunity in peripheral tissues where they can suppress local immunity and contribute to self-tolerance. A hallmark of Tregs is their intracellular expression of the forkhead box transcription factor 3 (Foxp3), which is critical for Treg suppressive immune function. Mice with mutations or deletions of FOXP3 develop lethal autoimmunity and humans with mutations in FOXP3 develop a rare disease called immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. Autoimmunity, thrombocytopenia, alopecia, erythematous plaques and general dermatitis characterize these diseases. In severe cases, neonates fail to thrive and require bone marrow transplantation. Conversely, Treg function can be hijacked by tumors or viruses to evade immune clearance. Regulation of the FOXP3 gene is thus a critical determinant for immune self-tolerance, and factors controlling FOXP3 transcription may be attractive targets to modulate Treg activity. Results The role of SRC-3 in the immune system is not well understood at present, despite publications showing high SRC-3 expression in leukocytes. We have found that knockout of the Src-3 gene in mice results in phenotypes that include broad lymphoproliferation and hypersensitivity to acute inflammation 9 , 10 . Our aged Src-3 null mice develop B-cell lymphomas and display elevated numbers of B cells and T cells in lymph nodes, spleen, and bone marrow 9 . Additionally, Src-3 knockout mice challenged with LPS experience endotoxic shock and are unable to defend body temperature or dampen inflammatory cytokines including TNFα, IL-6, and IL-1β 10 . To confirm that these immune phenotypes have not drifted from our previous reports, we performed comprehensive immune phenotyping of spleens from our Src-3 knockout mice and age-matched littermates. We used an antibody panel established by the Cell Cytometry and Sorting Core at Baylor College of Medicine in collaboration with the International Mouse Phenotyping Consortium (See Supplementary Fig. 1 A online). Metadata for mouse age, weight, body temperature, blood glucose, tibia length, splenocytes number and viability, and the number of FACS events were collected (See Supplementary Fig. 1 B online). No overt inguinal lymphomas were observed by gross inspection in any of the knockout or wild-type mice. Additionally, and consistent with general dwarfism observed in the Src-3 knockout mice 11 , 12 spleens were not enlarged relative to littermates (data not shown). We observe broad lymphoproliferation of T cells and B cells (See Supplementary Fig. 1 C and Supplementary File 1 online), while natural killer (NK) cells and myeloid lineages were unchanged or slightly decreased (See Supplementary Fig. 1 D and Supplementary File 1 online). Collectively, these results corroborate previous reports and suggest that loss of SRC-3 conveys a stable immune phenotype that is sensitive to lymphocyte-mediated inflammatory stress. We noted high expression of SRC-3 protein in the thymus of healthy C57BL6/J mice (Fig. 1 A, inset) and took an explorative bioinformatics approach to identify the SRC-3 immune compartment. Query of microarray data in the BioGPS web portal shows that the Src-3 transcript is highly expressed in T cells and B cells, and enriched in regulatory T cells (Tregs) (Fig. 1 A). Similarly, microarray and more recent RNA sequencing data available through the Immune Genome project (ImmGen) 13 , 14 , 15 indicates that the Src-3 transcript is highly expressed in regulatory T cells (See Supplementary Fig. 1 E online). Next, we sought to use an orthogonal approach and assembled a curated list of 297 transcriptional coregulators from the Nuclear Receptor Signaling Atlas (NURSA) 16 . This coregulator gene list was parsed against Foxp3 transcript expression using the gene set enrichment analysis (GSEA) function in<|im_end|> <|im_start|>assistant A study led by researchers at Baylor College of Medicine reveals a novel role of the steroid receptor coactivator 3 (SRC-3/NCOA3), a protein crucial for steroid hormone function and a prognostic marker for aggressive human breast and other cancers. The team discovered that SRC-3 also regulates human immune T regulatory cells (Tregs), which contribute to the regulation of the body's immunological activity by suppressing the function of other immune cells, including those involved in fighting cancer. The study, which appears in the journal Scientific Reports, shows that Tregs whose SRC-3 function was eliminated failed to suppress the activity of other immune cells in the lab. The authors anticipate that their findings may help in the fight against cancer in the future by leading to new approaches to inhibit Tregs activity which consequently would release immune attack in tumors. "Tregs play an important role by suppressing immune activity that can potentially harm the body," said co-corresponding author, Dr. Bert O'Malley, chancellor and professor of molecular and cellular biology at Baylor. "For instance, Tregs are critical to prevent autoimmunity, an immune response directed against normal tissues of a person, which can lead to severe disease." In addition, breast cancer and other types of tumors include infiltrating immune cells that can contribute to the control of tumor growth or, on the other hand, provide local immune suppression that would favor tumor growth. Treg infiltration has been experimentally proven in breast tumor biopsies and correlates with poor prognosis and reduced patient survival. "Dr. O'Malley's lab is the leader in SRC-3 research," said co-first author Dr. Bryan Nikolai, adjunct assistant professor molecular and cellular biology at Baylor and senior scientist at CooperGenomics. "SRC-3 is well-known for its role in cancer formation and proliferation, but we wondered what role it would play in immune T cells. A review of bioinformatics data revealed that SRC-3 is highly expressed in Tregs and this encouraged us to pursue this study." "We experimentally show that SRC-3 is significantly enriched in both murine and human Tregs," said co-first author Dr. Prashi Jain, instructor of molecular and cellular biology at Baylor. "Working with human Tregs, we used our small molecule inhibitor SI-2 to effectively inhibit SRC-3 in Tregs. As a result, Tregs greatly reduced their ability to inhibit the activation of other immune cells that help in maintaining antitumor immunity." The O'Malley lab had previously shown that SI-2 eliminates SRC-3 in breast cancer cells and, consequently, inhibits tumor growth in a mouse model of breast cancer. "Now that we know that SRC-3 also plays a key role in the immune system, I am excited to see whether our SRC-3 small molecule inhibitors might provide a dual benefit, eliminating cancer cells directly and also blocking the suppressive activity of Tregs, like killing two birds with one stone," said co-author Dr. David Lonard, associate professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "There is a great deal of interest in finding ways to inhibit Tregs that suppress the immune system," said O'Malley, a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "We are excited about the possibility that our approach with small molecule inhibitors might lead to promising therapies in the future. If we can remove the suppressive effect Tregs have in anticancer immune response with our small molecule inhibitors, the immune system then would be free to go after the tumor." <|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 Oligodendrocyte dysfunction underlies many neurological disorders, but rapid assessment of mutation-specific effects in these cells has been impractical. To enable functional genetics in oligodendrocytes, here we report a highly efficient method for generating oligodendrocytes and their progenitors from mouse embryonic and induced pluripotent stem cells, independent of mouse strain or mutational status. We demonstrate that this approach, when combined with genome engineering, provides a powerful platform for the expeditious study of genotype–phenotype relationships in oligodendrocytes. Introduction Oligodendrocytes generate myelin, a multilaminar structure that allows saltatory propagation of action potentials in the central nervous system (CNS). The functional importance of oligodendrocytes is underscored by numerous neurological diseases characterized by myelin loss or dysfunction, including multiple sclerosis (MS), neuromyelitis optica, leukodystrophies (e.g., Pelizaeus–Merzbacher disease), and mental health disorders such as schizophrenia 1 , 2 . A myriad of genes, regulatory elements, and single-nucleotide polymorphisms have been associated with oligodendrocyte dysfunction, but reverse genetics has not kept pace due to the cost and time of generating mutant mice and the lack of technology required to genetically manipulate primary oligodendrocytes 3 . To facilitate more rapid studies into the molecular mechanisms that underlie oligodendrocyte function and myelin disease, we report a new method for generating pure and highly scalable populations of myelinogenic oligodendrocytes and their progenitor cells (oligodendrocyte progenitor cells (OPCs)) from pluripotent cell sources including mouse embryonic stem cells (mESCs) and induced pluripotent stem cells (iPSCs). Our previous method of generating OPCs from pluripotent mouse epiblast stem cells relied on a starting cell type that is challenging to grow, less accessible, and difficult to genetically manipulate 4 . In contrast, our new method is highly efficient and universally reproducible across pluripotent stem cell lines from any wild-type or mutant genetic background, as well as from lines purposefully edited with CRISPR-Cas9 nuclease or other methods of genome engineering. Given the widespread accessibility of mESCs and iPSCs, this new protocol can be combined with existent methodologies such as CRISPR-Cas9 technology to enable in vitro molecular and cellular phenotyping of OPCs and oligodendrocytes with defined genotypes in <3 weeks. Results Generation of myelinogenic OPCs from patterned mESCs We initially selected four previously isolated germline-competent male mESC lines derived from independent mouse strains 129P2/Ola, C57BL/6, PO, and CBA/Ca 5 . Prior to beginning the current studies, ES cell cultures were karyotyped (see Methods) and confirmed to express canonical markers of pluripotency, Oct4 and Nanog (Supplementary Figs. 1a, b and 2a ). All four mESC lines were then differentiated to OPCs and oligodendrocytes using stage-specific small molecules and growth factors that mimic signaling events known to specify oligodendrocyte fate during development (see Fig. 1a for overview and Methods for the detailed protocol) 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Fig. 1 Reproducible generation of OPCs and oligodendrocytes from mESCs. a Graphical overview of the differentiation time course for generating OPCs and stage-specific oligodendrocytes from mESCs. b Quantification of immunocytochemistry for stage-specific markers demarcating the transition from pluripotency (Oct4) to neuroectoderm (Pax6) to ventral neural tube (Olig2) over 9 days. n = 4 independent biological replicates (mESC lines) with >25 colonies scored per cell line. Data are represented as means ± SEM. c Representative immunofluorescent images of starting mESCs (Oct4 and Nanog) and day 5 neuroectoderm (Pax6 and Sox1). Scale bar, 50 µm. d Quantification of OPC-defining transcription factors Olig2, Nkx2.2, and Sox10 at passages 1 and 3 of the differentiation protocol. n = 4 independent mESC lines; >114,500 cells scored per cell line. Data are represented as means ± SEM. *** P value <0.001; unpaired t test. e Immunofluorescent image of passage 1 cultures stained for Sox10, an OPC marker, and βIII-Tubulin, a marker of neurons. Scale bar, 50 µm. f Representative phase contrast image of mESC-derived OPCs exhibiting a canonical bipolar morphology. Scale bar, 50 µm. g Immunostained image of passage 3 mESC-derived OPCs co-expressing Olig2, Nkx2.2, and Sox10, canonical OPC transcription factors. Scale bar, 50 µm. h Cell surface immunostaining of the immature oligodendrocyte marker O4, after treatment with T3. Scale bar, 50 µm. i Representative images of differentiated OPCs immunostained for mature oligodendrocyte markers MBP and PLP1, 72 h post treatment with T3. Scale bar, 50 µm. j Representative images of OPC/DRG co-cultures stained for MBP and neurofilament (NF) at day 10. Scale bar, 50 µm. Unless otherwise noted, images presented in Fig. 1 are derived from the CBA/Ca mESC line, and are representative of results obtained with C57BL/6, PO, and 129P2/Ola lines, which are shown separately in Supplementary Fig. 2 Full size image First, naive mESCs were transitioned to primed epiblast-like cells by culturing in suspension as spheres in the presence of a small-molecule inhibitor of the Janus kinase (JAK)/signal transducers and activators of transcription pathway 6 . Cells were then specified to the neuroectodermal lineage using small molecules and recombinant proteins to inhibit both Activin/Nodal and bone morphogenetic protein signaling pathways 15 . By day 5 of differentiation, cells robustly downregulated the pluripotency marker Oct4 and upregulated the early neuroectodermal lineage marker Pax6 (Fig. 1b, c and Supplementary Fig. 2b ). Subsequent treatment with retinoic acid and sonic hedgehog (SHH) stimulated downregulation of Pax6 and emergence of Olig2 expression, a domain marker of the ventral developing neural tube from which OPCs are first specified in vivo (Fig. 1b–g ) 16 . To facilitate outgrowth, expansion, and maturation of OPCs, day 9 ventralized spheres were seeded on polyornithine and laminin-coated culture plates (termed passage 0). Neuronal axons rapidly extended from the attached spheres followed by migratory and proliferative early OPCs expressing Olig2 and Sox10 (Fig. 1d, e, g and Supplementary Fig. 2c ). Passaging of these cultures in the presence of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and SHH enabled selective enrichment and continued maturation of OPCs co-expressing Olig2, Sox10, and Nkx2.2. At passage 1, 49 ± 4.32% of cells co-expressed all three of these OPC-defining transcription factors and adopted a bipolar morphology typical of bona fide OPCs", "role": "user" }, { "content": "In two newly published papers, a scientific team at Case Western Reserve University School of Medicine reports on the discovery and implementation of a new, more efficient method for generating an important brain stem cell in the laboratory. The findings pave the way for greater understanding of the underlying mechanisms of neurological disorders of myelin and ultimately, possible new treatment and prevention options. The studies were published in the September issues of Nature Communications and Stem Cell Reports. \"Making these specialized brain stem cells on a large scale at high purity from pluripotent stem cells gives us a powerful tool to study previously inaccessible normal and diseased tissues in the central nervous system,\" said the senior author of the two papers, Paul Tesar, Ph.D., the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine. \"We applied our technology to genetic models of myelin disease, which resulted in the discovery of a chemical compound that helps diseased myelin-producing cells to survive.\" Myelin, a fatty substance produced by cells called oligodendrocytes, coats nerve fibers and enables electrical signaling in the brain and facilitates normal neurological function. Induced pluripotent stem cells are master cells that can potentially produce any cell the body needs. They are generated directly from existing adult cells. Embryonic stem cells are also pluripotent. As reported in Nature Communications, first author Angela Lager, Ph.D., and colleagues developed a new methodology to generate large quantities of oligodendrocytes and their progenitor cells— known as oligodendrocyte progenitor cells or OPCs—from mouse embryonic stem cells and induced pluripotent stem cells. Many genes and cellular processes have been associated with oligodendrocyte dysfunction, but scientists have typically needed to make mutant mice to investigate these processes, often involving expensive, multi-year studies to examine a single aspect of this biology. To address this problem, the Case Western Reserve team developed a rapid and highly efficient method for generating OPCs and oligodendrocytes from pluripotent stem cells from any genetic background—providing new access to these relatively inaccessible brain cells in healthy and diseased states. In Stem Cell Reports, first author Matthew Elitt, Ph.D., and colleagues leveraged this OPC generation technology to provide new insights and therapeutic strategies for a fatal genetic disorder of myelin, Pelizaeus Merzbacher disease (PMD). The team found that there was an unexpectedly early critical phase in PMD-affected cells characterized by endoplasmic reticulum stress and cell death as OPCs exit their progenitor state. The endoplasmic reticulum is the part of the cell involved in the processing of protein. In PMD, which almost exclusively affects male children, oligodendrocytes are lost and myelin is not properly formed in the brain and spinal cord. Due to their diseased myelin, children with PMD exhibit often-debilitating problems of coordination, motor skills, verbal expression, and learning. Due to the disease's severity, patients typically die before adulthood. To overcome this early cell death in PMD cells, the team screened thousands of drug-like compounds and found that one, known as Ro 25-6981, was especially successful in rescuing the survival of PMD oligodendrocytes in mouse and human cells in the laboratory and in PMD mice. \"Our work is an important first step of a multi-phase process,\" said Tesar. \"We have achieved survival of oligodendrocytes which normally die in the disease. The next step is to figure out how to coax these cells to efficiently myelinate and restore function to patients.\" The Case Western Reserve team's findings have implications beyond PMD. Numerous neurological and psychiatric diseases are characterized by myelin loss or dysfunction, including multiple sclerosis, spinal cord injury, and schizophrenia. Measures to regenerate or restore myelin could offer patients hope in these and numerous other disorders affecting the brain and spinal cord. ", "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 Oligodendrocyte dysfunction underlies many neurological disorders, but rapid assessment of mutation-specific effects in these cells has been impractical. To enable functional genetics in oligodendrocytes, here we report a highly efficient method for generating oligodendrocytes and their progenitors from mouse embryonic and induced pluripotent stem cells, independent of mouse strain or mutational status. We demonstrate that this approach, when combined with genome engineering, provides a powerful platform for the expeditious study of genotype–phenotype relationships in oligodendrocytes. Introduction Oligodendrocytes generate myelin, a multilaminar structure that allows saltatory propagation of action potentials in the central nervous system (CNS). The functional importance of oligodendrocytes is underscored by numerous neurological diseases characterized by myelin loss or dysfunction, including multiple sclerosis (MS), neuromyelitis optica, leukodystrophies (e.g., Pelizaeus–Merzbacher disease), and mental health disorders such as schizophrenia 1 , 2 . A myriad of genes, regulatory elements, and single-nucleotide polymorphisms have been associated with oligodendrocyte dysfunction, but reverse genetics has not kept pace due to the cost and time of generating mutant mice and the lack of technology required to genetically manipulate primary oligodendrocytes 3 . To facilitate more rapid studies into the molecular mechanisms that underlie oligodendrocyte function and myelin disease, we report a new method for generating pure and highly scalable populations of myelinogenic oligodendrocytes and their progenitor cells (oligodendrocyte progenitor cells (OPCs)) from pluripotent cell sources including mouse embryonic stem cells (mESCs) and induced pluripotent stem cells (iPSCs). Our previous method of generating OPCs from pluripotent mouse epiblast stem cells relied on a starting cell type that is challenging to grow, less accessible, and difficult to genetically manipulate 4 . In contrast, our new method is highly efficient and universally reproducible across pluripotent stem cell lines from any wild-type or mutant genetic background, as well as from lines purposefully edited with CRISPR-Cas9 nuclease or other methods of genome engineering. Given the widespread accessibility of mESCs and iPSCs, this new protocol can be combined with existent methodologies such as CRISPR-Cas9 technology to enable in vitro molecular and cellular phenotyping of OPCs and oligodendrocytes with defined genotypes in <3 weeks. Results Generation of myelinogenic OPCs from patterned mESCs We initially selected four previously isolated germline-competent male mESC lines derived from independent mouse strains 129P2/Ola, C57BL/6, PO, and CBA/Ca 5 . Prior to beginning the current studies, ES cell cultures were karyotyped (see Methods) and confirmed to express canonical markers of pluripotency, Oct4 and Nanog (Supplementary Figs. 1a, b and 2a ). All four mESC lines were then differentiated to OPCs and oligodendrocytes using stage-specific small molecules and growth factors that mimic signaling events known to specify oligodendrocyte fate during development (see Fig. 1a for overview and Methods for the detailed protocol) 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Fig. 1 Reproducible generation of OPCs and oligodendrocytes from mESCs. a Graphical overview of the differentiation time course for generating OPCs and stage-specific oligodendrocytes from mESCs. b Quantification of immunocytochemistry for stage-specific markers demarcating the transition from pluripotency (Oct4) to neuroectoderm (Pax6) to ventral neural tube (Olig2) over 9 days. n = 4 independent biological replicates (mESC lines) with >25 colonies scored per cell line. Data are represented as means ± SEM. c Representative immunofluorescent images of starting mESCs (Oct4 and Nanog) and day 5 neuroectoderm (Pax6 and Sox1). Scale bar, 50 µm. d Quantification of OPC-defining transcription factors Olig2, Nkx2.2, and Sox10 at passages 1 and 3 of the differentiation protocol. n = 4 independent mESC lines; >114,500 cells scored per cell line. Data are represented as means ± SEM. *** P value <0.001; unpaired t test. e Immunofluorescent image of passage 1 cultures stained for Sox10, an OPC marker, and βIII-Tubulin, a marker of neurons. Scale bar, 50 µm. f Representative phase contrast image of mESC-derived OPCs exhibiting a canonical bipolar morphology. Scale bar, 50 µm. g Immunostained image of passage 3 mESC-derived OPCs co-expressing Olig2, Nkx2.2, and Sox10, canonical OPC transcription factors. Scale bar, 50 µm. h Cell surface immunostaining of the immature oligodendrocyte marker O4, after treatment with T3. Scale bar, 50 µm. i Representative images of differentiated OPCs immunostained for mature oligodendrocyte markers MBP and PLP1, 72 h post treatment with T3. Scale bar, 50 µm. j Representative images of OPC/DRG co-cultures stained for MBP and neurofilament (NF) at day 10. Scale bar, 50 µm. Unless otherwise noted, images presented in Fig. 1 are derived from the CBA/Ca mESC line, and are representative of results obtained with C57BL/6, PO, and 129P2/Ola lines, which are shown separately in Supplementary Fig. 2 Full size image First, naive mESCs were transitioned to primed epiblast-like cells by culturing in suspension as spheres in the presence of a small-molecule inhibitor of the Janus kinase (JAK)/signal transducers and activators of transcription pathway 6 . Cells were then specified to the neuroectodermal lineage using small molecules and recombinant proteins to inhibit both Activin/Nodal and bone morphogenetic protein signaling pathways 15 . By day 5 of differentiation, cells robustly downregulated the pluripotency marker Oct4 and upregulated the early neuroectodermal lineage marker Pax6 (Fig. 1b, c and Supplementary Fig. 2b ). Subsequent treatment with retinoic acid and sonic hedgehog (SHH) stimulated downregulation of Pax6 and emergence of Olig2 expression, a domain marker of the ventral developing neural tube from which OPCs are first specified in vivo (Fig. 1b–g ) 16 . To facilitate outgrowth, expansion, and maturation of OPCs, day 9 ventralized spheres were seeded on polyornithine and laminin-coated culture plates (termed passage 0). Neuronal axons rapidly extended from the attached spheres followed by migratory and proliferative early OPCs expressing Olig2 and Sox10 (Fig. 1d, e, g and Supplementary Fig. 2c ). Passaging of these cultures in the presence of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and SHH enabled selective enrichment and continued maturation of OPCs co-expressing Olig2, Sox10, and Nkx2.2. At passage 1, 49 ± 4.32% of cells co-expressed all three of these OPC-defining transcription factors and adopted a bipolar morphology typical of bona fide OPCs<|im_end|> <|im_start|>assistant In two newly published papers, a scientific team at Case Western Reserve University School of Medicine reports on the discovery and implementation of a new, more efficient method for generating an important brain stem cell in the laboratory. The findings pave the way for greater understanding of the underlying mechanisms of neurological disorders of myelin and ultimately, possible new treatment and prevention options. The studies were published in the September issues of Nature Communications and Stem Cell Reports. "Making these specialized brain stem cells on a large scale at high purity from pluripotent stem cells gives us a powerful tool to study previously inaccessible normal and diseased tissues in the central nervous system," said the senior author of the two papers, Paul Tesar, Ph.D., the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine. "We applied our technology to genetic models of myelin disease, which resulted in the discovery of a chemical compound that helps diseased myelin-producing cells to survive." Myelin, a fatty substance produced by cells called oligodendrocytes, coats nerve fibers and enables electrical signaling in the brain and facilitates normal neurological function. Induced pluripotent stem cells are master cells that can potentially produce any cell the body needs. They are generated directly from existing adult cells. Embryonic stem cells are also pluripotent. As reported in Nature Communications, first author Angela Lager, Ph.D., and colleagues developed a new methodology to generate large quantities of oligodendrocytes and their progenitor cells— known as oligodendrocyte progenitor cells or OPCs—from mouse embryonic stem cells and induced pluripotent stem cells. Many genes and cellular processes have been associated with oligodendrocyte dysfunction, but scientists have typically needed to make mutant mice to investigate these processes, often involving expensive, multi-year studies to examine a single aspect of this biology. To address this problem, the Case Western Reserve team developed a rapid and highly efficient method for generating OPCs and oligodendrocytes from pluripotent stem cells from any genetic background—providing new access to these relatively inaccessible brain cells in healthy and diseased states. In Stem Cell Reports, first author Matthew Elitt, Ph.D., and colleagues leveraged this OPC generation technology to provide new insights and therapeutic strategies for a fatal genetic disorder of myelin, Pelizaeus Merzbacher disease (PMD). The team found that there was an unexpectedly early critical phase in PMD-affected cells characterized by endoplasmic reticulum stress and cell death as OPCs exit their progenitor state. The endoplasmic reticulum is the part of the cell involved in the processing of protein. In PMD, which almost exclusively affects male children, oligodendrocytes are lost and myelin is not properly formed in the brain and spinal cord. Due to their diseased myelin, children with PMD exhibit often-debilitating problems of coordination, motor skills, verbal expression, and learning. Due to the disease's severity, patients typically die before adulthood. To overcome this early cell death in PMD cells, the team screened thousands of drug-like compounds and found that one, known as Ro 25-6981, was especially successful in rescuing the survival of PMD oligodendrocytes in mouse and human cells in the laboratory and in PMD mice. "Our work is an important first step of a multi-phase process," said Tesar. "We have achieved survival of oligodendrocytes which normally die in the disease. The next step is to figure out how to coax these cells to efficiently myelinate and restore function to patients." The Case Western Reserve team's findings have implications beyond PMD. Numerous neurological and psychiatric diseases are characterized by myelin loss or dysfunction, including multiple sclerosis, spinal cord injury, and schizophrenia. Measures to regenerate or restore myelin could offer patients hope in these and numerous other disorders affecting the brain and spinal cord. <|im_end|>

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2,518

[ { "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 Quantum key distribution (QKD) 1 , 2 , 3 is a theoretically secure way of sharing secret keys between remote users. It has been demonstrated in a laboratory over a coiled optical fibre up to 404 kilometres long 4 , 5 , 6 , 7 . In the field, point-to-point QKD has been achieved from a satellite to a ground station up to 1,200 kilometres away 8 , 9 , 10 . However, real-world QKD-based cryptography targets physically separated users on the Earth, for which the maximum distance has been about 100 kilometres 11 , 12 . The use of trusted relays can extend these distances from across a typical metropolitan area 13 , 14 , 15 , 16 to intercity 17 and even intercontinental distances 18 . However, relays pose security risks, which can be avoided by using entanglement-based QKD, which has inherent source-independent security 19 , 20 . Long-distance entanglement distribution can be realized using quantum repeaters 21 , but the related technology is still immature for practical implementations 22 . The obvious alternative for extending the range of quantum communication without compromising its security is satellite-based QKD, but so far satellite-based entanglement distribution has not been efficient 23 enough to support QKD. Here we demonstrate entanglement-based QKD between two ground stations separated by 1,120 kilometres at a finite secret-key rate of 0.12 bits per second, without the need for trusted relays. Entangled photon pairs were distributed via two bidirectional downlinks from the Micius satellite to two ground observatories in Delingha and Nanshan in China. The development of a high-efficiency telescope and follow-up optics crucially improved the link efficiency. The generated keys are secure for realistic devices, because our ground receivers were carefully designed to guarantee fair sampling and immunity to all known side channels 24 , 25 . Our method not only increases the secure distance on the ground tenfold but also increases the practical security of QKD to an unprecedented level. Main Our experimental arrangement is shown in Fig. 1 . The two receiving ground stations are located at Delingha (37°22′ 44.43′′ N, 97°43′ 37.01′′ E; altitude 3,153 m) in Qinghai province, and Nanshan (43°28′ 31.66′′ N, 87°10′ 36.07′′ E; altitude 2,028 m) in Xinjiang province, China. The physical distance between Delingha and Nanshan is 1,120 km. To optimize the receiving efficiencies, both the two ground telescopes are newly built with a diameter of 1.2 m, specifically designed for the entanglement distribution experiments. All the optical elements, such as mirrors, in the telescopes maintain polarization. Fig. 1: Overview of the experimental set-up of entanglement based quantum key distribution. a , An illustration of the Micius satellite and the two ground stations. Image credit: Fengyun-3C/Visible and Infrared Radiometer, with permission (2020). The satellite flies in a Sun-synchronous orbit at an altitude of 500 km. The physical distance between Nanshan and Delingha ground station is 1,120 km. b , The spaceborne entangled-photon source. A free space isolator is used to minimize back reflection to the 405-nm pump laser. A pair of off-axis concave mirrors is used to focus the pump laser and collimate the down-converted photon pairs. PBS, polarization beam splitter; DM, dichroic mirror; LP, long-pass edge filter; PI, piezo steering mirror; HWP, half-wave plate; QWP, quarter-wave plate; PPKTP, periodically poled KTiOPO 4 . c , The follow-up optic at the optical ground station. The tracking and synchronization laser is separated from the signal photon by DM3 and detected by the single photon detector (SPD5). The spatial filter (SF), broad-bandwidth filter (BF) and interference filter (IF) are used to filter out the input light in frequency and spatial domains. BS, beam splitter; BE, beam expander; FSM, fast steering mirror. Full size image The satellite is equipped with a compact spaceborne entangled photon source with a weight of 23.8 kg. A periodically poled KTiOPO 4 crystal inside a Sagnac interferometer is pumped in both the clockwise and anticlockwise directions simultaneously by a continuous-wave laser with a wavelength centred at 405 nm and a linewidth of 160 MHz, and generates down-converted polarization-entangled photon pairs at 810 nm close to the form of \$|\\varPsi {\\rangle }_{12}=(|H{\\rangle }_{1}|V{\\rangle }_{2}+|V{\\rangle }_{1}|H{\\rangle }_{2})/\\sqrt{2}\$ , where | H ⟩ and | V ⟩ denote the horizontal and vertical polarization states, respectively, and the subscripts 1 and 2 denote the two output spatial modes. The entangled photon pairs are then collected and guided by two single-mode fibres to two independent transmitters equipped in the satellite. Both transmitters have a near-diffraction-limited far-field divergence of about 10 μrad. Under a pump power of 30 mW, the source distributes up to 5.9 × 10 6 entangled photon pairs per second. The photons are collected by the telescopes on two optical ground stations. For each one, the follow-up optics is installed on one of the rotating arms and rotates along with the telescope. As shown in Fig. 1c , a beam splitter, a half-wave plate and two polarized beam splitters are combined to analyse the polarization of the entangled photons randomly in the bases of Z ∈ {| H ⟩ , | V ⟩ } and X ∈ {|+ ⟩ , |− ⟩ }, where \$| \\pm \\rangle =(| H\\rangle \\pm | V\\rangle )/\\sqrt{2}\$ . After being transmitted or reflected by the beam splitter and polarized beam splitters, the photons are collected by four multimode fibres with the core diameter of 105 µm and detected by four single photon detectors (SPDs) respectively. We carefully selected the four SPDs to ensure that the detector efficiency is better than 53%, the efficiency consistency is better than 98.5% and the dark counts are less than 100 counts per second (see Extended Data Table 1 for details). A motorized half-wave plate (HWP1) is used to compensate the relative rotation between the transmitter and the receiver, where the correction angle offsets are calculated in advance. The entangled photons are filtered in both the frequency and spatial domains to satisfy the fair sampling assumption and to guarantee practical security. In particular, an extra field diaphragm,", "role": "user" }, { "content": "The exchange of a secret key for encrypting and decrypting messages over a distance of 1,120 kilometers is reported in Nature this week. This achievement is made using entanglement-based quantum key distribution, a theoretically secure communication technique. Previous attempts to directly distribute quantum keys between two ground users under real-world conditions have reached distances of only around 100 kilometers. Quantum communication uses photons to securely distribute a \"secret key\" to allow the exchange of encrypted messages. Previous work has demonstrated quantum key distribution along up to 404 kilometers of coiled optical fiber in a laboratory, or from a satellite to a ground station up to 1,200 kilometers away. However, real-world application between two users has been limited to around 100 kilometers. This is due to photon losses, which increase rapidly with distance. Trusted relays or \"repeaters\" offer a way to extend the distance and avoid photon loss, but the relay stations introduce security risks. Jian-Wei Pan and colleagues circumvented the need for repeaters by using a satellite to establish a secure link between two ground stations on Earth, using entangled photons. Entangled photons are linked in such a way that, even when separated by long distances, outcomes of measurements of their quantum properties are perfectly correlated. Two telescopes, designed to receive such quantum signals, were built 1,120 kilometers apart in Delingha and Nanshan in China. Entangled photons produced by the Micius satellite are transmitted to the ground as the satellite passes over the stations. Although satellite-based entanglement distribution has been reported before, the authors have now increased their transmission efficiency and reduced error rates enough to use entanglement to transmit quantum keys. They show that the system produces a secure channel that is resistant to attacks. The results represent a path toward entanglement-based global quantum networks, the authors conclude. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Quantum key distribution (QKD) 1 , 2 , 3 is a theoretically secure way of sharing secret keys between remote users. It has been demonstrated in a laboratory over a coiled optical fibre up to 404 kilometres long 4 , 5 , 6 , 7 . In the field, point-to-point QKD has been achieved from a satellite to a ground station up to 1,200 kilometres away 8 , 9 , 10 . However, real-world QKD-based cryptography targets physically separated users on the Earth, for which the maximum distance has been about 100 kilometres 11 , 12 . The use of trusted relays can extend these distances from across a typical metropolitan area 13 , 14 , 15 , 16 to intercity 17 and even intercontinental distances 18 . However, relays pose security risks, which can be avoided by using entanglement-based QKD, which has inherent source-independent security 19 , 20 . Long-distance entanglement distribution can be realized using quantum repeaters 21 , but the related technology is still immature for practical implementations 22 . The obvious alternative for extending the range of quantum communication without compromising its security is satellite-based QKD, but so far satellite-based entanglement distribution has not been efficient 23 enough to support QKD. Here we demonstrate entanglement-based QKD between two ground stations separated by 1,120 kilometres at a finite secret-key rate of 0.12 bits per second, without the need for trusted relays. Entangled photon pairs were distributed via two bidirectional downlinks from the Micius satellite to two ground observatories in Delingha and Nanshan in China. The development of a high-efficiency telescope and follow-up optics crucially improved the link efficiency. The generated keys are secure for realistic devices, because our ground receivers were carefully designed to guarantee fair sampling and immunity to all known side channels 24 , 25 . Our method not only increases the secure distance on the ground tenfold but also increases the practical security of QKD to an unprecedented level. Main Our experimental arrangement is shown in Fig. 1 . The two receiving ground stations are located at Delingha (37°22′ 44.43′′ N, 97°43′ 37.01′′ E; altitude 3,153 m) in Qinghai province, and Nanshan (43°28′ 31.66′′ N, 87°10′ 36.07′′ E; altitude 2,028 m) in Xinjiang province, China. The physical distance between Delingha and Nanshan is 1,120 km. To optimize the receiving efficiencies, both the two ground telescopes are newly built with a diameter of 1.2 m, specifically designed for the entanglement distribution experiments. All the optical elements, such as mirrors, in the telescopes maintain polarization. Fig. 1: Overview of the experimental set-up of entanglement based quantum key distribution. a , An illustration of the Micius satellite and the two ground stations. Image credit: Fengyun-3C/Visible and Infrared Radiometer, with permission (2020). The satellite flies in a Sun-synchronous orbit at an altitude of 500 km. The physical distance between Nanshan and Delingha ground station is 1,120 km. b , The spaceborne entangled-photon source. A free space isolator is used to minimize back reflection to the 405-nm pump laser. A pair of off-axis concave mirrors is used to focus the pump laser and collimate the down-converted photon pairs. PBS, polarization beam splitter; DM, dichroic mirror; LP, long-pass edge filter; PI, piezo steering mirror; HWP, half-wave plate; QWP, quarter-wave plate; PPKTP, periodically poled KTiOPO 4 . c , The follow-up optic at the optical ground station. The tracking and synchronization laser is separated from the signal photon by DM3 and detected by the single photon detector (SPD5). The spatial filter (SF), broad-bandwidth filter (BF) and interference filter (IF) are used to filter out the input light in frequency and spatial domains. BS, beam splitter; BE, beam expander; FSM, fast steering mirror. Full size image The satellite is equipped with a compact spaceborne entangled photon source with a weight of 23.8 kg. A periodically poled KTiOPO 4 crystal inside a Sagnac interferometer is pumped in both the clockwise and anticlockwise directions simultaneously by a continuous-wave laser with a wavelength centred at 405 nm and a linewidth of 160 MHz, and generates down-converted polarization-entangled photon pairs at 810 nm close to the form of $|\varPsi {\rangle }_{12}=(|H{\rangle }_{1}|V{\rangle }_{2}+|V{\rangle }_{1}|H{\rangle }_{2})/\sqrt{2}$ , where | H ⟩ and | V ⟩ denote the horizontal and vertical polarization states, respectively, and the subscripts 1 and 2 denote the two output spatial modes. The entangled photon pairs are then collected and guided by two single-mode fibres to two independent transmitters equipped in the satellite. Both transmitters have a near-diffraction-limited far-field divergence of about 10 μrad. Under a pump power of 30 mW, the source distributes up to 5.9 × 10 6 entangled photon pairs per second. The photons are collected by the telescopes on two optical ground stations. For each one, the follow-up optics is installed on one of the rotating arms and rotates along with the telescope. As shown in Fig. 1c , a beam splitter, a half-wave plate and two polarized beam splitters are combined to analyse the polarization of the entangled photons randomly in the bases of Z ∈ {| H ⟩ , | V ⟩ } and X ∈ {|+ ⟩ , |− ⟩ }, where $| \pm \rangle =(| H\rangle \pm | V\rangle )/\sqrt{2}$ . After being transmitted or reflected by the beam splitter and polarized beam splitters, the photons are collected by four multimode fibres with the core diameter of 105 µm and detected by four single photon detectors (SPDs) respectively. We carefully selected the four SPDs to ensure that the detector efficiency is better than 53%, the efficiency consistency is better than 98.5% and the dark counts are less than 100 counts per second (see Extended Data Table 1 for details). A motorized half-wave plate (HWP1) is used to compensate the relative rotation between the transmitter and the receiver, where the correction angle offsets are calculated in advance. The entangled photons are filtered in both the frequency and spatial domains to satisfy the fair sampling assumption and to guarantee practical security. In particular, an extra field diaphragm,<|im_end|> <|im_start|>assistant The exchange of a secret key for encrypting and decrypting messages over a distance of 1,120 kilometers is reported in Nature this week. This achievement is made using entanglement-based quantum key distribution, a theoretically secure communication technique. Previous attempts to directly distribute quantum keys between two ground users under real-world conditions have reached distances of only around 100 kilometers. Quantum communication uses photons to securely distribute a "secret key" to allow the exchange of encrypted messages. Previous work has demonstrated quantum key distribution along up to 404 kilometers of coiled optical fiber in a laboratory, or from a satellite to a ground station up to 1,200 kilometers away. However, real-world application between two users has been limited to around 100 kilometers. This is due to photon losses, which increase rapidly with distance. Trusted relays or "repeaters" offer a way to extend the distance and avoid photon loss, but the relay stations introduce security risks. Jian-Wei Pan and colleagues circumvented the need for repeaters by using a satellite to establish a secure link between two ground stations on Earth, using entangled photons. Entangled photons are linked in such a way that, even when separated by long distances, outcomes of measurements of their quantum properties are perfectly correlated. Two telescopes, designed to receive such quantum signals, were built 1,120 kilometers apart in Delingha and Nanshan in China. Entangled photons produced by the Micius satellite are transmitted to the ground as the satellite passes over the stations. Although satellite-based entanglement distribution has been reported before, the authors have now increased their transmission efficiency and reduced error rates enough to use entanglement to transmit quantum keys. They show that the system produces a secure channel that is resistant to attacks. The results represent a path toward entanglement-based global quantum networks, the authors conclude. <|im_end|>

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1,870

[ { "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 Beef production represents a complex global sustainability challenge including reducing poverty and hunger and the need for climate action. Understanding the trade-offs between these goals at a global scale and at resolutions to inform land use is critical for a global transition towards sustainable beef. Here we optimize global beef production at fine spatial resolution and identify trade-offs between economic and environmental objectives interpretable to global sustainability ambitions. We reveal that shifting production areas, compositions of current feeds and informed land restoration enable large emissions reductions of 34–85% annually (612–1,506 MtCO 2 e yr −1 ) without increasing costs. Even further reductions are possible but come at a trade-off with costs of production. Critically our approach can help to identify such trade-offs among multiple sustainability goals, produces fine-resolution mapping to inform required land-use change and does so at the scale necessary to shift towards a globally sustainable industry for beef and to sectors beyond. Main Beef production and consumption has a large environmental footprint, including substantial greenhouse gas (GHG) emissions 1 , mainly through enteric fermentation 2 and land-use change 1 , representing ~40% of all livestock emissions 3 . To reduce negative environmental impacts, many studies have called for beef consumption reductions 4 , 5 . However, despite the clear importance of diet shifts, a strategy focused solely on demand reduction is unlikely to produce rapid sustainability outcomes due to slow behaviour change 6 , coupled with rising overall meat demand 7 spurred by population growth in many low- and middle-income countries. Beef is an economically important agricultural commodity, representing ~19% of total global livestock production value at a return of >US$245 billion globally in 2020 8 . In addition, livestock farming supports the livelihoods of nearly 600 million smallholder farmers in the developing world 9 . This is particularly important in the context of the Sustainable Development Goals (SDGs) 10 and global commitments towards reducing inequalities, responsible consumption and production and combatting climate change. The complexity of this challenge requires a multipronged approach, including promoting dietary change to reduce demand but also reaching the current and future demand with more sustainable beef production. Improving ‘sustainability’ across the global beef supply chain is a complex balance of multiple objectives including reducing emissions, reducing the impact on natural ecosystems and maintaining or increasing incomes. The choice of where and how we produce beef to reach a level of demand involves trade-offs between these objectives. For instance, minimizing economic costs can entail producing beef in marginal land, such as rangelands and forested areas, with low land value and low production costs. However, lower forage yield and quality in extensive grazing systems lead to higher emission intensity and low production efficiency that can result in land clearing for pasture or cropland expansion 11 . Conversely, shifts to grain-based diets and pasture intensification tend to lower emission intensity of meat production, resulting from higher forage quality 12 , 13 but may also substantially increase production costs. In addition to lower emission intensity of non-CO 2 emissions from enteric fermentation and manure management, intensification of production allows for land sparing and carbon sequestration strategies, for instance, reforestation 14 . Sustainability shifts are driven at multiple scales by the choices of suppliers, national regulatory agencies and consumers and thus require mechanisms to assess the impacts of changes to livestock production across different objectives, at scales and resolutions that adequately support these choices. While there are reasonable farm-scale analyses of cattle production systems against multiple objectives 15 , 16 , these lack scale that could drive the sustainable transition of an industry. There are also global analyses of livestock that simulate the food system to examine trade-offs between environmental and economic outcomes 17 , 18 under specific market conditions. However, these often provide outcomes at continental or broad regional geographic areas and thus lack the spatial granularity to inform actors across the beef sector on the land-use management needed to minimize trade-offs in economic and environmental goals. Here, we fill these gaps by taking a multidimensional lens to assess sustainable beef supply and spatially optimize where and how beef could be produced to meet global demand while minimizing production costs and GHG emissions at 5 arcmin (~9.26 km at the equator) resolution across the globe. To estimate economic costs of production, we consider land-use transition, opportunity, feed production and transport costs. GHG emissions include: non-CO 2 emissions from enteric fermentation, manure management and fertilizer application; CO 2 emissions from the change in belowground and aboveground biomass; and postfarm emissions resulting from transport, export, processing and packaging. We also consider the ‘carbon opportunity cost’ 19 —the carbon sequestration potential through active or passive forest restoration if the current beef production ceases. We include the cost of restoration in total production costs and the aboveground and belowground biomass change resulting from reforestation in total GHG emissions. For each grid cell, a weighted sum of production costs and GHG emissions is calculated and minimized for each feed mix, given the attribution of a weight on the two objectives. The grid cells with the lowest weighted sum are selected for beef production until beef demand is reached. Beef production, costs and emissions for these selected grid cells are then aggregated globally to generate a single Pareto-efficient solution. By changing the weights on production cost and GHG emissions, we trace out a set of efficient solutions (Pareto frontier 20 ; Methods ). Each solution along the frontier corresponds to an optimal spatial arrangement of feed compositions and locations that minimize a given weighted sum of production costs and GHG emissions. The steepness of the Pareto frontier indicates the gain of one objective at the loss of another, for instance, GHG reduction (gain) per dollar spent (loss). We examine five solutions along the frontier in more detail where (1) only economic costs are minimized, (2) costs are minimized and the solution constrained to not increase GHG emissions, (3) GHG emissions are minimized and constrained to not increase production costs, (4) only", "role": "user" }, { "content": "A research team led by the University of Queensland has developed a tool to help the global beef industry simultaneously reduce costs and greenhouse gas emissions while meeting demand for meat. The team assessed the economic and emissions impacts of different cattle feeds at different locations around the globe to formulate a framework to guide and inform industry sustainability efforts. Postdoctoral Research Fellow Adam C. Castonguay from UQ's School of Veterinary Science said the study showed that as much as 85 percent of emissions could be cut without an overall economic hit to the beef sector. \"This can be achieved by opting for more efficient feeds and locations, and restoring forests in inefficient areas, without increasing global costs of production or reducing demand for beef,\" Mr. Castonguay said. \"We have mapped out the most efficient locations around the world to produce beef and the maps change when factors are altered, such as how much society values reducing emissions over reducing production costs. \"This has given us an unprecedented insight into the 'what, where, and why' of beef production at a global level and decisions about the future of the industry can be informed by inputting trade-offs and opportunities.\" The research group says the tool could be used by governments and industry to develop policy and strategy. \"There will be continued global demand for beef and there are a huge number of livelihoods associated with it, so this research aims to find an appropriate balance to maintain the bottom line of the sector,\" Mr. Castonguay said. \"Further economic modelling and fine-tuning the data for specific locations would reveal the implications of any changes, including on beef prices for consumers.\" Mr. Castonguay said the optimization method developed by the team using mapping technology overcame historic roadblocks to finding an environmental-economic balance. \"There are many innovations in cattle feed to increase productivity or reduce emissions which have not been analyzed as a trade-off with other values and goals,\" he said. \"Our results highlight the massive potential for improvements in the way we produce beef, to help us to meet global sustainability goals. \"The extent to which we reduce emissions and production costs depends on our values or preferences as a society.\" This research has been published in Nature Sustainability. ", "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 Beef production represents a complex global sustainability challenge including reducing poverty and hunger and the need for climate action. Understanding the trade-offs between these goals at a global scale and at resolutions to inform land use is critical for a global transition towards sustainable beef. Here we optimize global beef production at fine spatial resolution and identify trade-offs between economic and environmental objectives interpretable to global sustainability ambitions. We reveal that shifting production areas, compositions of current feeds and informed land restoration enable large emissions reductions of 34–85% annually (612–1,506 MtCO 2 e yr −1 ) without increasing costs. Even further reductions are possible but come at a trade-off with costs of production. Critically our approach can help to identify such trade-offs among multiple sustainability goals, produces fine-resolution mapping to inform required land-use change and does so at the scale necessary to shift towards a globally sustainable industry for beef and to sectors beyond. Main Beef production and consumption has a large environmental footprint, including substantial greenhouse gas (GHG) emissions 1 , mainly through enteric fermentation 2 and land-use change 1 , representing ~40% of all livestock emissions 3 . To reduce negative environmental impacts, many studies have called for beef consumption reductions 4 , 5 . However, despite the clear importance of diet shifts, a strategy focused solely on demand reduction is unlikely to produce rapid sustainability outcomes due to slow behaviour change 6 , coupled with rising overall meat demand 7 spurred by population growth in many low- and middle-income countries. Beef is an economically important agricultural commodity, representing ~19% of total global livestock production value at a return of >US$245 billion globally in 2020 8 . In addition, livestock farming supports the livelihoods of nearly 600 million smallholder farmers in the developing world 9 . This is particularly important in the context of the Sustainable Development Goals (SDGs) 10 and global commitments towards reducing inequalities, responsible consumption and production and combatting climate change. The complexity of this challenge requires a multipronged approach, including promoting dietary change to reduce demand but also reaching the current and future demand with more sustainable beef production. Improving ‘sustainability’ across the global beef supply chain is a complex balance of multiple objectives including reducing emissions, reducing the impact on natural ecosystems and maintaining or increasing incomes. The choice of where and how we produce beef to reach a level of demand involves trade-offs between these objectives. For instance, minimizing economic costs can entail producing beef in marginal land, such as rangelands and forested areas, with low land value and low production costs. However, lower forage yield and quality in extensive grazing systems lead to higher emission intensity and low production efficiency that can result in land clearing for pasture or cropland expansion 11 . Conversely, shifts to grain-based diets and pasture intensification tend to lower emission intensity of meat production, resulting from higher forage quality 12 , 13 but may also substantially increase production costs. In addition to lower emission intensity of non-CO 2 emissions from enteric fermentation and manure management, intensification of production allows for land sparing and carbon sequestration strategies, for instance, reforestation 14 . Sustainability shifts are driven at multiple scales by the choices of suppliers, national regulatory agencies and consumers and thus require mechanisms to assess the impacts of changes to livestock production across different objectives, at scales and resolutions that adequately support these choices. While there are reasonable farm-scale analyses of cattle production systems against multiple objectives 15 , 16 , these lack scale that could drive the sustainable transition of an industry. There are also global analyses of livestock that simulate the food system to examine trade-offs between environmental and economic outcomes 17 , 18 under specific market conditions. However, these often provide outcomes at continental or broad regional geographic areas and thus lack the spatial granularity to inform actors across the beef sector on the land-use management needed to minimize trade-offs in economic and environmental goals. Here, we fill these gaps by taking a multidimensional lens to assess sustainable beef supply and spatially optimize where and how beef could be produced to meet global demand while minimizing production costs and GHG emissions at 5 arcmin (~9.26 km at the equator) resolution across the globe. To estimate economic costs of production, we consider land-use transition, opportunity, feed production and transport costs. GHG emissions include: non-CO 2 emissions from enteric fermentation, manure management and fertilizer application; CO 2 emissions from the change in belowground and aboveground biomass; and postfarm emissions resulting from transport, export, processing and packaging. We also consider the ‘carbon opportunity cost’ 19 —the carbon sequestration potential through active or passive forest restoration if the current beef production ceases. We include the cost of restoration in total production costs and the aboveground and belowground biomass change resulting from reforestation in total GHG emissions. For each grid cell, a weighted sum of production costs and GHG emissions is calculated and minimized for each feed mix, given the attribution of a weight on the two objectives. The grid cells with the lowest weighted sum are selected for beef production until beef demand is reached. Beef production, costs and emissions for these selected grid cells are then aggregated globally to generate a single Pareto-efficient solution. By changing the weights on production cost and GHG emissions, we trace out a set of efficient solutions (Pareto frontier 20 ; Methods ). Each solution along the frontier corresponds to an optimal spatial arrangement of feed compositions and locations that minimize a given weighted sum of production costs and GHG emissions. The steepness of the Pareto frontier indicates the gain of one objective at the loss of another, for instance, GHG reduction (gain) per dollar spent (loss). We examine five solutions along the frontier in more detail where (1) only economic costs are minimized, (2) costs are minimized and the solution constrained to not increase GHG emissions, (3) GHG emissions are minimized and constrained to not increase production costs, (4) only<|im_end|> <|im_start|>assistant A research team led by the University of Queensland has developed a tool to help the global beef industry simultaneously reduce costs and greenhouse gas emissions while meeting demand for meat. The team assessed the economic and emissions impacts of different cattle feeds at different locations around the globe to formulate a framework to guide and inform industry sustainability efforts. Postdoctoral Research Fellow Adam C. Castonguay from UQ's School of Veterinary Science said the study showed that as much as 85 percent of emissions could be cut without an overall economic hit to the beef sector. "This can be achieved by opting for more efficient feeds and locations, and restoring forests in inefficient areas, without increasing global costs of production or reducing demand for beef," Mr. Castonguay said. "We have mapped out the most efficient locations around the world to produce beef and the maps change when factors are altered, such as how much society values reducing emissions over reducing production costs. "This has given us an unprecedented insight into the 'what, where, and why' of beef production at a global level and decisions about the future of the industry can be informed by inputting trade-offs and opportunities." The research group says the tool could be used by governments and industry to develop policy and strategy. "There will be continued global demand for beef and there are a huge number of livelihoods associated with it, so this research aims to find an appropriate balance to maintain the bottom line of the sector," Mr. Castonguay said. "Further economic modelling and fine-tuning the data for specific locations would reveal the implications of any changes, including on beef prices for consumers." Mr. Castonguay said the optimization method developed by the team using mapping technology overcame historic roadblocks to finding an environmental-economic balance. "There are many innovations in cattle feed to increase productivity or reduce emissions which have not been analyzed as a trade-off with other values and goals," he said. "Our results highlight the massive potential for improvements in the way we produce beef, to help us to meet global sustainability goals. "The extent to which we reduce emissions and production costs depends on our values or preferences as a society." This research has been published in Nature Sustainability. <|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: recent applications of wastewater-based epidemiology (WBE) have demonstrated its ability to track the spread and dynamics of COVID-19 at the community level. Despite the growing body of research, quantitative synthesis of SARS-CoV-2 RNA levels in wastewater generated from studies across space and time using diverse methods has not been performed. Objective: the objective of this study is to examine the correlations between SARS-CoV-2 RNA levels in wastewater and epidemiological indicators across studies, stratified by key covariates in study methodologies. In addition, we examined the association of proportions of positive detections in wastewater samples and methodological covariates. Methods: we systematically searched the Web of Science for studies published by February 16th, 2021, performed a reproducible screening, and employed mixed-effects models to estimate the levels of SARS-CoV-2 viral RNA quantities in wastewater samples and their correlations to the case prevalence, the sampling mode (grab or composite sampling), and the wastewater fraction analyzed ( i.e. , solids, solid–supernatant mixtures, or supernatants/filtrates). Results: a hundred and one studies were found; twenty studies (671 biosamples and 1751 observations) were retained following a reproducible screening. The mean positivity across all studies was 0.68 (95%-CI, [0.52; 0.85]). The mean viral RNA abundance was 5244 marker copies per mL (95%-CI, [0; 16 432]). The Pearson correlation coefficients between the viral RNA levels and case prevalence were 0.28 (95%-CI, [0.01; 0.51]) for daily new cases or 0.29 (95%-CI, [−0.15; 0.73]) for cumulative cases. The fraction analyzed accounted for 12.4% of the variability in the percentage of positive detections, followed by the case prevalence (9.3% by daily new cases and 5.9% by cumulative cases) and sampling mode (0.6%). Among observations with positive detections, the fraction analyzed accounted for 56.0% of the variability in viral RNA levels, followed by the sampling mode (6.9%) and case prevalence (0.9% by daily new cases and 0.8% by cumulative cases). While the sampling mode and fraction analyzed both significantly correlated with the SARS-CoV-2 viral RNA levels, the magnitude of the increase in positive detection associated with the fraction analyzed was larger. The mixed-effects model treating studies as random effects and case prevalence as fixed effects accounted for over 90% of the variability in SARS-CoV-2 positive detections and viral RNA levels. Interpretations: positive pooled means and confidence intervals in the Pearson correlation coefficients between the SARS-CoV-2 viral RNA levels and case prevalence indicators provide quantitative evidence that reinforces the value of wastewater-based monitoring of COVID-19. Large heterogeneities among studies in proportions of positive detections, viral RNA levels, and Pearson correlation coefficients suggest a strong demand for methods to generate data accounting for cross-study heterogeneities and more detailed metadata reporting. Large variance was explained by the fraction analyzed, suggesting sample pre-processing and fractionation as a direction that needs to be prioritized in method standardization. Mixed-effects models accounting for study level variations provide a new perspective to synthesize data from multiple studies. This article is part of the themed collections: Emerging Investigator Series , Best Papers of 2022 from RSC’s Environmental Science journals , Recent Open Access Articles , Environmental Science: Water Research & Technology Recent HOT Articles , Best Papers 2022 – Environmental Science: Water Research & Technology and Environmental Science – coronavirus research Water impact Recent applications of wastewater-based epidemiology (WBE) have demonstrated its ability to track the spread and dynamics of COVID-19 at the community level. Despite the growing body of research, quantitative synthesis of SARS-CoV-2 viral RNA levels in wastewater generated from studies across space and time using diverse methods has not been performed. The meta-analysis methodology treats individual studies as members of a population of studies that all provide information on a given effect instead of drawing conclusions on exemplary studies that have shown strong positive effects. Leveraging a large sample size, meta-analysis can help move the narrative beyond statistical significance and draw attention to the magnitude, direction, and variance in effects. This study employed a meta-analysis methodology to quantitatively synthesize results among WBE studies in the first year of the COVID-19 pandemic. Positive pooled means and confidence intervals in the Pearson correlation coefficients between the SARS-CoV-2 viral RNA levels and case prevalence indicators provide quantitative evidence reinforcing the value of wastewater-based monitoring of COVID-19. Large heterogeneities among studies suggest a strong demand for experimental and computational methods to address cross-study heterogeneities. Mixed-effects models accounting for study level variations provide a new perspective to synthesize data from multiple WBE studies. 1. Introduction Wastewater-based virus monitoring has been shown as a promising tool for tracking disease dynamics in a large population during the ongoing COVID-19 pandemic. 1 It has been reported that 39 to 65% of infected individuals may excrete viral particles through urine and feces, 2–4 thus allowing wastewater-based detection. The current epidemiological approaches to estimate the COVID-19 disease prevalence rely on individualized patient testing ( i.e. , detection of SARS-CoV-2 in nasopharyngeal specimens). Individual testing is invasive, resource-intensive, and mostly restricted to symptomatic individuals with access to healthcare. 5 Wastewater-based epidemiology (WBE) has the potential to circumvent biases caused by the varied access to individual-based testing, the presence of asymptomatic cases, and social stigma. 6 Moreover, WBE has been applied in the environmental monitoring of poliovirus, effectively detecting new variants and preventing disease resurgence. 7 The poliovirus experience suggests the long-term benefits of developing and refining WBE as a public health monitoring technology. As the number of WBE studies continues to grow, study-to-study variations are often encountered; thus, the growing body of data demands attention to generalizable relationships across studies. Although WBE studies focusing on the SARS-CoV-2 virus have been all conducted during the pandemic, not all tested wastewater samples provided a measurable detection when known cases were present in the associated area, thus presenting false negatives in the detection. 8–20 In addition, while positive correlations between SARS-CoV-2 wastewater-based measurements and COVID-19 cases have been described, 8,9,11,21–23 the strength of the correlations may vary among studies. To better describe the advantages and limitations of WBE and make evidence-based recommendations, research synthesis efforts are needed to quantify the detection rates of", "role": "user" }, { "content": "Before a community hospital is stretched thin with COVID-19-patients, even before antigen tests—no matter how rapid—return results, there is one place that may be able to capture the number of COVID-19 infections in a community. A new research paper from the lab of Fangqiong Ling, assistant professor of energy, environmental and chemical engineering at Washington University in St. Louis' McKelvey School of Engineering, has shown the viability of wastewater as an accurate tool when it comes to describing COVID-19 outbreaks in a community. Beyond proving the usefulness of COVID-19 detection, the breadth of the paper's analysis also makes it a resource for other researchers in the fast-growing field of wastewater epidemiology. The research was published as the cover story of the July 22 issue of the journal Environmental Science, Water Research & Technology. Since the beginning of the COVID-19 pandemic, researchers across the world have begun or ramped up existing water monitoring programs. Working collaboratively with the Washington University School of Medicine and researchers from two other universities, Ling and David Mantilla-Calderon, a postdoctoral associate in her lab, took advantage of the data to determine what, if any, relationship they could find between the number of COVID-19 cases reported in an area and the amount of genetic material from SARS-CoV-2 in municipal wastewater. Starting with 101 studies of wastewater from around the globe, Ling and her team decided on a set of common variables and other inclusion criteria that had to be met to accurately combine data for a kind of \"study of studies\" known as a meta-analysis systematic review. This kind of study allows researchers to investigate a question using much more data than they could have collected themselves; ultimately, they were able to use 20 of the 101 studies. \"In general, we found a positive correlation,\" Mantilla-Calderon said. As recorded cases went up, they found more viral material in the wastewater. \"But it's not a one-to-one correlation—the strength of the correlation changes with each system.\" That's because every wastewater system is unique. Mantilla-Calderon knows this better than most because he has a background in wastewater monitoring and is familiar with the ways these systems can vary. Wastewater systems can be built from different materials and use different processes or chemicals at different parts of the system. They often are built in different configurations and serve vastly different-sized populations. Adding to the study's complexity, among the 20 papers that shared enough variables to be included in the study, different researchers used different RNA extraction methods. It's these quirks of individual wastewater systems and of researchers' methods and preferences that have led to a field full of data without enough context to make it generalizable. With this paper, however, Ling's lab has made a significant contribution toward defining that context. \"The study provides general statistical guidance,\" Mantilla-Calderon said. In the future, researchers will be able to use it to help them better understand how to interpret their data, given the kinds of samples they have and the systems they are working with. It also begins to bridge any gaps between medical researchers and engineers. \"We use the same kind of meta-analysis systematic review method that's typically used in clinical research,\" Ling said. \"This creates a kind of common language for medical researchers and engineering researchers.\" This may facilitate the exchange of data and results, leading to a more robust understanding of the relationships between viruses moving through the engineered world and diseases spreading through populations. Why wastewater? \"Our premise is that wastewater, unbiased way to collect information,\" Mantilla-Calderon said. It has the potential to be a more representative sample of infection than, for instance, cases reported by a hospital for several reasons, including: Asymptomatic people don't get tested as often.Some people don't have easy access to tests.Many people with mild symptoms use home tests, and those results aren't shared with hospitals.Not everyone sheds the virus through feces—studies suggest about 40% to 65% of people do. But of that group, about 50% are asymptomatic and likely would not have been tested. \"The public wastewater infrastructure is perhaps the piece of social infrastructure that's most equitable toward people,\" Ling 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: recent applications of wastewater-based epidemiology (WBE) have demonstrated its ability to track the spread and dynamics of COVID-19 at the community level. Despite the growing body of research, quantitative synthesis of SARS-CoV-2 RNA levels in wastewater generated from studies across space and time using diverse methods has not been performed. Objective: the objective of this study is to examine the correlations between SARS-CoV-2 RNA levels in wastewater and epidemiological indicators across studies, stratified by key covariates in study methodologies. In addition, we examined the association of proportions of positive detections in wastewater samples and methodological covariates. Methods: we systematically searched the Web of Science for studies published by February 16th, 2021, performed a reproducible screening, and employed mixed-effects models to estimate the levels of SARS-CoV-2 viral RNA quantities in wastewater samples and their correlations to the case prevalence, the sampling mode (grab or composite sampling), and the wastewater fraction analyzed ( i.e. , solids, solid–supernatant mixtures, or supernatants/filtrates). Results: a hundred and one studies were found; twenty studies (671 biosamples and 1751 observations) were retained following a reproducible screening. The mean positivity across all studies was 0.68 (95%-CI, [0.52; 0.85]). The mean viral RNA abundance was 5244 marker copies per mL (95%-CI, [0; 16 432]). The Pearson correlation coefficients between the viral RNA levels and case prevalence were 0.28 (95%-CI, [0.01; 0.51]) for daily new cases or 0.29 (95%-CI, [−0.15; 0.73]) for cumulative cases. The fraction analyzed accounted for 12.4% of the variability in the percentage of positive detections, followed by the case prevalence (9.3% by daily new cases and 5.9% by cumulative cases) and sampling mode (0.6%). Among observations with positive detections, the fraction analyzed accounted for 56.0% of the variability in viral RNA levels, followed by the sampling mode (6.9%) and case prevalence (0.9% by daily new cases and 0.8% by cumulative cases). While the sampling mode and fraction analyzed both significantly correlated with the SARS-CoV-2 viral RNA levels, the magnitude of the increase in positive detection associated with the fraction analyzed was larger. The mixed-effects model treating studies as random effects and case prevalence as fixed effects accounted for over 90% of the variability in SARS-CoV-2 positive detections and viral RNA levels. Interpretations: positive pooled means and confidence intervals in the Pearson correlation coefficients between the SARS-CoV-2 viral RNA levels and case prevalence indicators provide quantitative evidence that reinforces the value of wastewater-based monitoring of COVID-19. Large heterogeneities among studies in proportions of positive detections, viral RNA levels, and Pearson correlation coefficients suggest a strong demand for methods to generate data accounting for cross-study heterogeneities and more detailed metadata reporting. Large variance was explained by the fraction analyzed, suggesting sample pre-processing and fractionation as a direction that needs to be prioritized in method standardization. Mixed-effects models accounting for study level variations provide a new perspective to synthesize data from multiple studies. This article is part of the themed collections: Emerging Investigator Series , Best Papers of 2022 from RSC’s Environmental Science journals , Recent Open Access Articles , Environmental Science: Water Research & Technology Recent HOT Articles , Best Papers 2022 – Environmental Science: Water Research & Technology and Environmental Science – coronavirus research Water impact Recent applications of wastewater-based epidemiology (WBE) have demonstrated its ability to track the spread and dynamics of COVID-19 at the community level. Despite the growing body of research, quantitative synthesis of SARS-CoV-2 viral RNA levels in wastewater generated from studies across space and time using diverse methods has not been performed. The meta-analysis methodology treats individual studies as members of a population of studies that all provide information on a given effect instead of drawing conclusions on exemplary studies that have shown strong positive effects. Leveraging a large sample size, meta-analysis can help move the narrative beyond statistical significance and draw attention to the magnitude, direction, and variance in effects. This study employed a meta-analysis methodology to quantitatively synthesize results among WBE studies in the first year of the COVID-19 pandemic. Positive pooled means and confidence intervals in the Pearson correlation coefficients between the SARS-CoV-2 viral RNA levels and case prevalence indicators provide quantitative evidence reinforcing the value of wastewater-based monitoring of COVID-19. Large heterogeneities among studies suggest a strong demand for experimental and computational methods to address cross-study heterogeneities. Mixed-effects models accounting for study level variations provide a new perspective to synthesize data from multiple WBE studies. 1. Introduction Wastewater-based virus monitoring has been shown as a promising tool for tracking disease dynamics in a large population during the ongoing COVID-19 pandemic. 1 It has been reported that 39 to 65% of infected individuals may excrete viral particles through urine and feces, 2–4 thus allowing wastewater-based detection. The current epidemiological approaches to estimate the COVID-19 disease prevalence rely on individualized patient testing ( i.e. , detection of SARS-CoV-2 in nasopharyngeal specimens). Individual testing is invasive, resource-intensive, and mostly restricted to symptomatic individuals with access to healthcare. 5 Wastewater-based epidemiology (WBE) has the potential to circumvent biases caused by the varied access to individual-based testing, the presence of asymptomatic cases, and social stigma. 6 Moreover, WBE has been applied in the environmental monitoring of poliovirus, effectively detecting new variants and preventing disease resurgence. 7 The poliovirus experience suggests the long-term benefits of developing and refining WBE as a public health monitoring technology. As the number of WBE studies continues to grow, study-to-study variations are often encountered; thus, the growing body of data demands attention to generalizable relationships across studies. Although WBE studies focusing on the SARS-CoV-2 virus have been all conducted during the pandemic, not all tested wastewater samples provided a measurable detection when known cases were present in the associated area, thus presenting false negatives in the detection. 8–20 In addition, while positive correlations between SARS-CoV-2 wastewater-based measurements and COVID-19 cases have been described, 8,9,11,21–23 the strength of the correlations may vary among studies. To better describe the advantages and limitations of WBE and make evidence-based recommendations, research synthesis efforts are needed to quantify the detection rates of<|im_end|> <|im_start|>assistant Before a community hospital is stretched thin with COVID-19-patients, even before antigen tests—no matter how rapid—return results, there is one place that may be able to capture the number of COVID-19 infections in a community. A new research paper from the lab of Fangqiong Ling, assistant professor of energy, environmental and chemical engineering at Washington University in St. Louis' McKelvey School of Engineering, has shown the viability of wastewater as an accurate tool when it comes to describing COVID-19 outbreaks in a community. Beyond proving the usefulness of COVID-19 detection, the breadth of the paper's analysis also makes it a resource for other researchers in the fast-growing field of wastewater epidemiology. The research was published as the cover story of the July 22 issue of the journal Environmental Science, Water Research & Technology. Since the beginning of the COVID-19 pandemic, researchers across the world have begun or ramped up existing water monitoring programs. Working collaboratively with the Washington University School of Medicine and researchers from two other universities, Ling and David Mantilla-Calderon, a postdoctoral associate in her lab, took advantage of the data to determine what, if any, relationship they could find between the number of COVID-19 cases reported in an area and the amount of genetic material from SARS-CoV-2 in municipal wastewater. Starting with 101 studies of wastewater from around the globe, Ling and her team decided on a set of common variables and other inclusion criteria that had to be met to accurately combine data for a kind of "study of studies" known as a meta-analysis systematic review. This kind of study allows researchers to investigate a question using much more data than they could have collected themselves; ultimately, they were able to use 20 of the 101 studies. "In general, we found a positive correlation," Mantilla-Calderon said. As recorded cases went up, they found more viral material in the wastewater. "But it's not a one-to-one correlation—the strength of the correlation changes with each system." That's because every wastewater system is unique. Mantilla-Calderon knows this better than most because he has a background in wastewater monitoring and is familiar with the ways these systems can vary. Wastewater systems can be built from different materials and use different processes or chemicals at different parts of the system. They often are built in different configurations and serve vastly different-sized populations. Adding to the study's complexity, among the 20 papers that shared enough variables to be included in the study, different researchers used different RNA extraction methods. It's these quirks of individual wastewater systems and of researchers' methods and preferences that have led to a field full of data without enough context to make it generalizable. With this paper, however, Ling's lab has made a significant contribution toward defining that context. "The study provides general statistical guidance," Mantilla-Calderon said. In the future, researchers will be able to use it to help them better understand how to interpret their data, given the kinds of samples they have and the systems they are working with. It also begins to bridge any gaps between medical researchers and engineers. "We use the same kind of meta-analysis systematic review method that's typically used in clinical research," Ling said. "This creates a kind of common language for medical researchers and engineering researchers." This may facilitate the exchange of data and results, leading to a more robust understanding of the relationships between viruses moving through the engineered world and diseases spreading through populations. Why wastewater? "Our premise is that wastewater, unbiased way to collect information," Mantilla-Calderon said. It has the potential to be a more representative sample of infection than, for instance, cases reported by a hospital for several reasons, including: Asymptomatic people don't get tested as often.Some people don't have easy access to tests.Many people with mild symptoms use home tests, and those results aren't shared with hospitals.Not everyone sheds the virus through feces—studies suggest about 40% to 65% of people do. But of that group, about 50% are asymptomatic and likely would not have been tested. "The public wastewater infrastructure is perhaps the piece of social infrastructure that's most equitable toward people," Ling 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 Every spring and summer melt ponds form at the surface of polar sea ice and become habitats where biological production may take place. Previous studies report a large variability in the productivity, but the causes are unknown. We investigated if nutrients limit the productivity in these first-year ice melt ponds by adding nutrients to three enclosures ([1] PO 4 3− , [2] NO 3 − , and [3] PO 4 3− and NO 3 − ) and one natural melt pond (PO 4 3− and NO 3 − ), while one enclosure and one natural melt pond acted as controls. After 7–13 days, Chl a concentrations and cumulative primary production were between two- and tenfold higher in the enclosures and natural melt ponds with nutrient addition compared with their respective controls, with the largest increase occurring in the enclosures. Separate additions of PO 4 3− and NO 3 − in the enclosures led to intermediate increases in productivity, suggesting co-limitation of nutrients. Bacterial production and the biovolume of ciliates, which were the dominant grazers, were positively correlated with primary production, showing a tight coupling between primary production and both microbial activity and ciliate grazing. To our knowledge, this study is the first to ascertain nutrient limitation in melt ponds. We also document that the addition of nutrients, although at relative high concentrations, can stimulate biological productivity at several trophic levels. Given the projected increase in first-year ice, increased melt pond coverage during the Arctic spring and potential additional nutrient supply from, e.g. terrestrial sources imply that biological activity of melt ponds may become increasingly important for the sympagic carbon cycling in the future Arctic. Working on a manuscript? Avoid the common mistakes Introduction Rising temperatures have reduced the extent and thickness of sea ice in the Arctic region (e.g. Serreze et al. 2000 ; Haas et al. 2008 ), leading to the replacement of most of the multiyear ice with first-year ice (Maslanik et al. 2007 ; Comiso 2012 ). These changes have increased the total areal coverage of melt ponds during the Arctic summer (Nicolaus et al. 2012 ; Rösel and Kaleschke 2013 ). The temporal evolution in melt pond coverage is mainly determined by the increasing atmospheric temperature during spring and summer, facilitating snow melting (Bursa 1963 ). Typically, the relative areal melt pond coverage increases at an exponential rate, peaking at 20–50% (Eicken et al. 2002 ), thereby strongly reducing the overall sea ice albedo (Polashenski et al. 2012 ; Perovich and Polashenski 2012 ). Hence, melt ponds enhance light availability within and below the sea ice (Nicolaus et al. 2012 ), which stimulates the light-limited biological productivity and can lead to early nutrient depletion in surface waters before ice brake-up (Arrigo et al. 2014 ). The ponds in themselves also represent a microbial habitat (Bursa 1963 ), but the results of the so far few available studies reflect a wide range of productivity in these melt ponds, from almost insignificant production (Mundy et al. 2011 ; Fernández-Méndez et al. 2015 ) to highly productive ponds covered by microbial mats and aggregates (Lee et al. 2011 ; Fernández-Méndez et al. 2014 ). It has been speculated that this large range in production may be associated with differences in nutrient availability (Mundy et al. 2011 ; Fernández-Méndez et al. 2015 ) and with incident UV-radiation as an additional moderator of the biological productivity (Marcoval et al. 2007 ; Wängberg et al. 2008 ). Nutrient availability is typically correlated with salinity (e.g. Mundy et al. 2011 ), suggesting that a substantial snow cover would reduce nutrient availability in the melt ponds as the melting of the snow progresses. In contrast, inflow, spraying, and flooding from surface sea water could likely increase nutrient availability and thus stimulate productivity. The algal community in the melt ponds can consist of fresh water species, such as Chlamydomonas nivalis and Meringosphaera mediterranea (Melnikov et al. 2002 ), as well as marine species, which are mainly dominated by diatom genera such as Navicula sp., Nitzchia sp., Thalassiosira sp., Chaetoceros sp. and Melosira arctica (Bursa 1963 ; Melnikov et al. 2002 ; Fernández-Méndez et al. 2014 ). The presence of diatom species is consistent with the algal community found within the interior of sea ice (e.g. Mundy et al. 2011 ) or right below the ice, suggesting that the melt pond community structure is mainly determined by the community occurring within the sea ice (e.g. Bursa 1963 ). Along with the bacterial community, these primary producers represent the foundation of ice-associated food webs, and therefore, regulate potential colonization by higher trophic levels (Bursa 1963 ; Lee et al. 2011 ; Fernández-Méndez et al. 2014 ). Hence, to understand the present-day Arctic sympagic carbon cycling and how the predicted increase in melt pond coverage might alter this, it is important to determine the limiting factor for primary production in melt ponds. The aim of the present study was, therefore, to experimentally determine if nutrients limit total biological production in ice melt ponds of Arctic sea ice. Materials and methods Study site and melt pond setup The study was carried out during June 2014 in Young Sound (NE Greenland) (Fig. 1 a), ~2 km from the coastline just outside Daneborg (Fig. 1 b). At the study site, sea ice normally forms in October and gradually grows to a maximum thickness of ~150 cm in May. Hereafter the sea ice thickness declines rapidly, transitioning into a free-floating ice cover that is exported from the fjord in early July (Rysgaard et al. 1999 ). Melt pond formation typically starts towards the end of May, with the melt pond coverage increasing at an exponential rate towards the sea ice break-up (e.g. Rysgaard et al. 1999 ; Rysgaard and Glud 2007 ). During the 2014 sea ice melting season, the increasing melt pond coverage was estimated from daily photos of the sea ice taken from the shore, adjusting the perspective in each photo and estimating the fraction of the melt ponds", "role": "user" }, { "content": "When spring arrives in the Arctic, both snow and sea ice melt, forming melt ponds on the surface of the sea ice. Every year, as global warming increases, there are more and larger melt ponds. Melt ponds provide more light and heat for the ice and the underlying water, but now it turns out that they may also have a more direct and potentially important influence on life in the Arctic waters. Mats of algae and bacteria can evolve in the melt ponds, which can provide food for marine creatures. This is the conclusion of researchers in the periodical, Polar Biology. Own little ecosystems \"The melt ponds can form their own little ecosystem. When all the sea ice melts during the summer, algae and other organisms from melt ponds are released into the surrounding seawater. Some of this food is immediately ingested by creatures living high up in the water column. Other food sinks to the bottom and gets eaten by seabed dwellers,\" explains Heidi Louise Sørensen, who is the principal author of the scientific article, continuing: \"Given that larger and larger areas of melt ponds are being formed in the Arctic, we can expect the release of more and more food for creatures in the polar sea.\" Heidi Louise Sørensen studied the phenomenon in a number of melt ponds in North-Eastern Greenland as part of her PhD thesis at University of Southern Denmark (SDU). Bo Thamdrup and Ronnie Glud of SDU, and Erik Jeppesen and Søren Rysgaard of Aarhus University also contributed to the work. Food for seals and sea cucumbers In the upper part of the water column it is mainly krill and copepods that benefit from the nutrient-rich algae and bacteria from melt ponds. These creatures are eaten by various larger animals, ranging from amphipods to fish, seals and whales. Deeper down, it is seabed dwellers such as sea cucumbers and brittle stars that benefit from the algae that sink down. For some time now, researchers have been aware that simple biological organisms can evolve in melt ponds – they may even support very diverse communities. But so far it has been unclear why sometimes there are many organisms in the ponds, and on other occasions virtually none. According to the new study, 'nutrients' is the keyword. When nutrients such as phosphorus and nitrogen find their way into a melt pond, entire communities of algae and micro-organisms can flourish. From the Siberian tundra Nutrients can find their way into a melt pond in a variety of ways, For example, they can be washed in with waves of sea water; they can be transported by dust storms from the mainland (for example, from the Siberian tundra); or they can be washed with earth from the coast out on the ice, when it rains. Finally, migratory birds or other larger animals resting on the ice can leave behind sources of nutrient. \"Climate change is accompanies by more storms and more precipitation, and we must expect that more nutrients will be released from the surroundings into the melt ponds. These conditions, plus the fact that the distribution of areas of melt ponds is increasing, can contribute to increased productivity in plant and animal life in the Arctic seas,\" says Professor Ronnie N. Glud of the Department of Biology at SDU. Warmer and more windy There are further factors that may potentially contribute to increased productivity in the Arctic seas: When the sea ice disappears, light can penetrate down into the water.When the sea ice disappears, wind and storms can stir the water up, bringing nutrients up to the surface from deep water. When it gets warmer on the mainland, this creates more melt water, which can flow out into the sea, carrying nutrients in its wake. ", "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 Every spring and summer melt ponds form at the surface of polar sea ice and become habitats where biological production may take place. Previous studies report a large variability in the productivity, but the causes are unknown. We investigated if nutrients limit the productivity in these first-year ice melt ponds by adding nutrients to three enclosures ([1] PO 4 3− , [2] NO 3 − , and [3] PO 4 3− and NO 3 − ) and one natural melt pond (PO 4 3− and NO 3 − ), while one enclosure and one natural melt pond acted as controls. After 7–13 days, Chl a concentrations and cumulative primary production were between two- and tenfold higher in the enclosures and natural melt ponds with nutrient addition compared with their respective controls, with the largest increase occurring in the enclosures. Separate additions of PO 4 3− and NO 3 − in the enclosures led to intermediate increases in productivity, suggesting co-limitation of nutrients. Bacterial production and the biovolume of ciliates, which were the dominant grazers, were positively correlated with primary production, showing a tight coupling between primary production and both microbial activity and ciliate grazing. To our knowledge, this study is the first to ascertain nutrient limitation in melt ponds. We also document that the addition of nutrients, although at relative high concentrations, can stimulate biological productivity at several trophic levels. Given the projected increase in first-year ice, increased melt pond coverage during the Arctic spring and potential additional nutrient supply from, e.g. terrestrial sources imply that biological activity of melt ponds may become increasingly important for the sympagic carbon cycling in the future Arctic. Working on a manuscript? Avoid the common mistakes Introduction Rising temperatures have reduced the extent and thickness of sea ice in the Arctic region (e.g. Serreze et al. 2000 ; Haas et al. 2008 ), leading to the replacement of most of the multiyear ice with first-year ice (Maslanik et al. 2007 ; Comiso 2012 ). These changes have increased the total areal coverage of melt ponds during the Arctic summer (Nicolaus et al. 2012 ; Rösel and Kaleschke 2013 ). The temporal evolution in melt pond coverage is mainly determined by the increasing atmospheric temperature during spring and summer, facilitating snow melting (Bursa 1963 ). Typically, the relative areal melt pond coverage increases at an exponential rate, peaking at 20–50% (Eicken et al. 2002 ), thereby strongly reducing the overall sea ice albedo (Polashenski et al. 2012 ; Perovich and Polashenski 2012 ). Hence, melt ponds enhance light availability within and below the sea ice (Nicolaus et al. 2012 ), which stimulates the light-limited biological productivity and can lead to early nutrient depletion in surface waters before ice brake-up (Arrigo et al. 2014 ). The ponds in themselves also represent a microbial habitat (Bursa 1963 ), but the results of the so far few available studies reflect a wide range of productivity in these melt ponds, from almost insignificant production (Mundy et al. 2011 ; Fernández-Méndez et al. 2015 ) to highly productive ponds covered by microbial mats and aggregates (Lee et al. 2011 ; Fernández-Méndez et al. 2014 ). It has been speculated that this large range in production may be associated with differences in nutrient availability (Mundy et al. 2011 ; Fernández-Méndez et al. 2015 ) and with incident UV-radiation as an additional moderator of the biological productivity (Marcoval et al. 2007 ; Wängberg et al. 2008 ). Nutrient availability is typically correlated with salinity (e.g. Mundy et al. 2011 ), suggesting that a substantial snow cover would reduce nutrient availability in the melt ponds as the melting of the snow progresses. In contrast, inflow, spraying, and flooding from surface sea water could likely increase nutrient availability and thus stimulate productivity. The algal community in the melt ponds can consist of fresh water species, such as Chlamydomonas nivalis and Meringosphaera mediterranea (Melnikov et al. 2002 ), as well as marine species, which are mainly dominated by diatom genera such as Navicula sp., Nitzchia sp., Thalassiosira sp., Chaetoceros sp. and Melosira arctica (Bursa 1963 ; Melnikov et al. 2002 ; Fernández-Méndez et al. 2014 ). The presence of diatom species is consistent with the algal community found within the interior of sea ice (e.g. Mundy et al. 2011 ) or right below the ice, suggesting that the melt pond community structure is mainly determined by the community occurring within the sea ice (e.g. Bursa 1963 ). Along with the bacterial community, these primary producers represent the foundation of ice-associated food webs, and therefore, regulate potential colonization by higher trophic levels (Bursa 1963 ; Lee et al. 2011 ; Fernández-Méndez et al. 2014 ). Hence, to understand the present-day Arctic sympagic carbon cycling and how the predicted increase in melt pond coverage might alter this, it is important to determine the limiting factor for primary production in melt ponds. The aim of the present study was, therefore, to experimentally determine if nutrients limit total biological production in ice melt ponds of Arctic sea ice. Materials and methods Study site and melt pond setup The study was carried out during June 2014 in Young Sound (NE Greenland) (Fig. 1 a), ~2 km from the coastline just outside Daneborg (Fig. 1 b). At the study site, sea ice normally forms in October and gradually grows to a maximum thickness of ~150 cm in May. Hereafter the sea ice thickness declines rapidly, transitioning into a free-floating ice cover that is exported from the fjord in early July (Rysgaard et al. 1999 ). Melt pond formation typically starts towards the end of May, with the melt pond coverage increasing at an exponential rate towards the sea ice break-up (e.g. Rysgaard et al. 1999 ; Rysgaard and Glud 2007 ). During the 2014 sea ice melting season, the increasing melt pond coverage was estimated from daily photos of the sea ice taken from the shore, adjusting the perspective in each photo and estimating the fraction of the melt ponds<|im_end|> <|im_start|>assistant When spring arrives in the Arctic, both snow and sea ice melt, forming melt ponds on the surface of the sea ice. Every year, as global warming increases, there are more and larger melt ponds. Melt ponds provide more light and heat for the ice and the underlying water, but now it turns out that they may also have a more direct and potentially important influence on life in the Arctic waters. Mats of algae and bacteria can evolve in the melt ponds, which can provide food for marine creatures. This is the conclusion of researchers in the periodical, Polar Biology. Own little ecosystems "The melt ponds can form their own little ecosystem. When all the sea ice melts during the summer, algae and other organisms from melt ponds are released into the surrounding seawater. Some of this food is immediately ingested by creatures living high up in the water column. Other food sinks to the bottom and gets eaten by seabed dwellers," explains Heidi Louise Sørensen, who is the principal author of the scientific article, continuing: "Given that larger and larger areas of melt ponds are being formed in the Arctic, we can expect the release of more and more food for creatures in the polar sea." Heidi Louise Sørensen studied the phenomenon in a number of melt ponds in North-Eastern Greenland as part of her PhD thesis at University of Southern Denmark (SDU). Bo Thamdrup and Ronnie Glud of SDU, and Erik Jeppesen and Søren Rysgaard of Aarhus University also contributed to the work. Food for seals and sea cucumbers In the upper part of the water column it is mainly krill and copepods that benefit from the nutrient-rich algae and bacteria from melt ponds. These creatures are eaten by various larger animals, ranging from amphipods to fish, seals and whales. Deeper down, it is seabed dwellers such as sea cucumbers and brittle stars that benefit from the algae that sink down. For some time now, researchers have been aware that simple biological organisms can evolve in melt ponds – they may even support very diverse communities. But so far it has been unclear why sometimes there are many organisms in the ponds, and on other occasions virtually none. According to the new study, 'nutrients' is the keyword. When nutrients such as phosphorus and nitrogen find their way into a melt pond, entire communities of algae and micro-organisms can flourish. From the Siberian tundra Nutrients can find their way into a melt pond in a variety of ways, For example, they can be washed in with waves of sea water; they can be transported by dust storms from the mainland (for example, from the Siberian tundra); or they can be washed with earth from the coast out on the ice, when it rains. Finally, migratory birds or other larger animals resting on the ice can leave behind sources of nutrient. "Climate change is accompanies by more storms and more precipitation, and we must expect that more nutrients will be released from the surroundings into the melt ponds. These conditions, plus the fact that the distribution of areas of melt ponds is increasing, can contribute to increased productivity in plant and animal life in the Arctic seas," says Professor Ronnie N. Glud of the Department of Biology at SDU. Warmer and more windy There are further factors that may potentially contribute to increased productivity in the Arctic seas: When the sea ice disappears, light can penetrate down into the water.When the sea ice disappears, wind and storms can stir the water up, bringing nutrients up to the surface from deep water. When it gets warmer on the mainland, this creates more melt water, which can flow out into the sea, carrying nutrients in its wake. <|im_end|>

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2,173

[ { "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 Macroscopic quantum phenomena, such as observed in superfluids and superconductors, have led to promising technological advancements and some of the most important tests of fundamental physics. At present, quantum detection of light is mostly relegated to the microscale, where avalanche photodiodes are very sensitive to distinguishing single-photon events from vacuum but cannot differentiate between larger photon-number events. Beyond this, the ability to perform measurements to resolve photon numbers is highly desirable for a variety of quantum information applications, including computation, sensing and cryptography. True photon-number resolving detectors do exist, but they are currently limited to the ability to resolve on the order of 10 photons, which is too small for several quantum-state generation methods based on heralded detection. Here we extend photon measurement into the mesoscopic regime by implementing a detection scheme based on multiplexing highly quantum-efficient transition-edge sensors to accurately resolve photon numbers between 0 and 100. We then demonstrate the use of our system by implementing a quantum random-number generator with no inherent bias. This method is based on sampling a coherent state in the photon-number basis and is robust against environmental noise, phase and amplitude fluctuations in the laser, loss and detector inefficiency as well as eavesdropping. Beyond true random-number generation, our detection scheme serves as a means to implement quantum measurement and engineering techniques valuable for photonic quantum information processing. Main The nature of quantum mechanics dictates a fundamental wave–particle duality for physical systems, which was first recognized by Einstein through the understanding that light is composed of individual energy quanta known as photons 1 . The ability to accurately measure photons has led to checking the validity of the notion of ‘spooky action at a distance’ 2 and tremendous technological advancement in quantum communication 3 , quantum metrology 4 , 5 , 6 and quantum computation 7 , 8 . Much of this progress relies on the ability to measure single photons, such as through the use of avalanche photodiodes 9 ; however, the ability to resolve arbitrary numbers of photons beyond simply distinguishing vacuum from non-vacuum is highly desirable for many quantum information applications 8 , 10 , 11 , 12 . The process of projecting a subset of modes of an entangled state onto the Fock basis can allow for engineering non-Gaussian quantum states with negative Wigner functions 13 , 14 , 15 —a requirement for any quantum speed-up in continuous-variable quantum information 16 . Recent claims of quantum supremacy with Gaussian boson sampling devices 7 can be challenged with substantially greater ease when threshold detectors are used in place of photon-number-resolving detectors (PNRDs) 17 . Finally, sampling the photon number of a wave-like superposition such as a coherent state reveals fundamentally random outcomes that can be used to generate true random numbers 18 , 19 , 20 . The transition-edge sensor (TES), which is based on a calorimeter formed from a superconducting wafer held just below the critical temperature, has arisen as a viable PNRD with quantum efficiency approaching unity and entirely negligible dark counts 21 , 22 , 23 . Previous results with TES systems show the ability to measure non-classical systems with high mean photon numbers 24 , 25 ; however, these experiments were based on methods requiring extensive post-processing that give generally good estimates of photon-number measurements but relatively low distinguishability between individual photon counts above 10 photons 26 . For demanding applications requiring photon-number resolution, even a single-photon discrepancy destroys quantum correlations. Current methods demonstrate the potential to accurately count photons in the low double digits (~16) 27 , but certain proposals necessitate considerably higher detection events for conditional-state preparation. One particularly salient example is the preparation of a cubic-phase state to complete a universal gate set for continuous-variable quantum computation 28 . For the numerical approximations used in this formalism to hold, one must detect a large number of photons—simulations suggest 50 or more 29 . The detection scheme we demonstrate here now easily surpasses this previously unreachable milestone. In this Article, we extend the resolving capabilities of individual TES detectors to a maximum of 37 photons per detection channel with on-the-fly signal processing. We then multiplex three detectors into a system capable of resolving 0–100 photons with detector quantum efficiencies above 90%. Furthermore, we illustrate the utility of our scheme towards quantum cryptography applications by creating a quantum random-number generator (QRNG). The need for random numbers arises in many applications including cryptography, simulation and games of chance. Pseudo-random-number generators are not truly random and can, for example, lead to erroneous results in Monte Carlo simulations 30 . The stochastic nature of quantum mechanics leads to true randomness, but many current implementations sample random events from a non-uniform distribution, which can lead to bias that must be corrected classically 31 , 32 . Our method to implement a QRNG is based on sampling the photon statistics of a coherent state and is fundamentally unbiased, robust to experimental and environmental noise, and invulnerable to eavesdropping. The detection system used here is constructed by splitting a laser pulse equally across three paths and sending each to a TES as shown in Fig. 1a . Each TES is a PNRD that makes use of the extremely temperature-dependent resistance of a superconductor near the phase transition. Our TESs are composed of superconducting tungsten wafers that operate with a critical temperature near 100 mK. When light is incident on a chip, the thermal energy of an absorbed photon acts to locally break the superconducting state and induce a spot of non-zero resistance, which increases nearly linearly with absorbed energy 21 . This change in resistance is detected by a series of highly sensitive superconducting quantum interference devices (SQUIDs) and is then amplified and converted to an output voltage that is sent to an external field-programmable gate array (FPGA) to extract key signal parameters on the fly (system details in Methods ). The detectors used were optimized to be highly absorptive at the desired wavelength, and while our detectors achieve above 90%", "role": "user" }, { "content": "Experts in nuclear physics and quantum information have demonstrated the application of a photon-number-resolving system to accurately resolve more than 100 photons. The feat is a major step forward in capability for quantum computing development efforts. It also may enable quantum generation of truly random numbers, a long-sought goal for developing unbreakable encryption techniques for applications in—for instance—military communications and financial transactions. The detector was recently reported in Nature Photonics. Physicists around the world are hotly pursuing the promise of reliable and robust quantum computing. Not only would harnessing quantum computing herald a giant leap for science, but it would also elevate the economy and enhance national security. But getting there has so far eluded the best brains on the planet. A pair of engineers at the U.S. Department of Energy's Thomas Jefferson National Accelerator Facility has designed a crucial piece of a photon detection system that has brought physicists a step closer to fully operational photonics-based quantum computing—that is, a quantum computer built entirely with light. The engineers are part of an interdisciplinary team of federal and academic researchers led by Jefferson Lab who are working on advancing quantum computing in nuclear physics. There are many different ways to try to make a fully functioning quantum computer. For photonics-based computing, quantum detection of light particles, or photons, is vital. Currently, individual detectors can resolve up to about 10 photons, but that number is too small for many quantum-state generation methods. No one had yet demonstrated detection of more than 16 photons, but simulations suggest that quantum computing will require detecting large numbers of photons—50 or more. Crossing that 50-photon threshold means being able to implement a \"cubic gate\"—a milestone toward building a complete gate set for universal quantum computing, explained Amr Hossameldin, team member and graduate research assistant in quantum computing and quantum optics at the University of Virginia. The team blew past the record of 16 photons and demonstrated a photon count of about 35 per single detector and reached 100 photons with a three-detector system. \"They could predict that they were resolving 100 of these photons that were impacting upon the detectors with this extremely accurate resolution,\" said Robert Edwards, senior staff scientist and deputy associate director for theoretical and computational physics at Jefferson Lab. \"It's super accurate—and that has never been achieved.\" \"The lack of detection has been a major limitation to this approach of quantum computing. The new photon number resolution is the necessary step to implementing a universal instruction set,\" he continued. The new detection system also has another highly valuable secondary benefit: quantum generation of truly random numbers—a boon to unbreakable secret codes or encryptions in such areas as military communications and financial transactions. So-called random numbers generated by classical computer algorithms aren't truly random. The algorithm they are generated from can be compromised with some effort by playing a numbers game—looking for which numbers pop up more often than others. True random-number generation using quantum physics has no such flaw or bias. \"There is an intrinsic randomness in quantum mechanics, where you can have a physical system that's in two states at once,\" explained Olivier Pfister, a physics professor at UVa who specializes in quantum fields and quantum information and served as external team leader for the project. \"And when you want to know which it is, it's random. \"Einstein got bugged by this. He called it 'the Old One playing dice with the universe.' And we don't know any better than Einstein.\" Pfister and Hossameldin are co-authors of the paper presenting the team's research. Other authors are Chris Cuevas and Hai Dong from Jefferson Lab, Richard Birrittella and Paul Alsing from the Air Force Research Laboratory in New York, Miller Eaton from UVa, and Christopher C. Gerry from the City University of New York. Signals not seen before The team effort was inspired by an announcement in 2019 by the DOE Office of Science offering funding opportunities for quantum information science research for nuclear physics under the Quantum Horizons program. Edwards secured a small grant to fund a lecture series bringing in experts in quantum computing. Pfister was the first lecturer in March 2020. A week later, the COVID-19 pandemic shut down the lab, but the seed for joint research into photonics-based quantum computing had been planted. A large team of physicists, engineers and postdocs was assembled. The collaboration began with the goal to use quantum photonics for calculations relevant to the Jefferson Lab science program. UVa already had a photon-based system for making quantum calculations using a pulsed laser, but lacked the means to detect with great speed and accuracy the number of photons impacting on its detector before the signal decayed. Meanwhile, detecting particles with speed and accuracy is Jefferson Lab's forte. Its Continuous Electron Beam Accelerator Facility, or CEBAF, has been used for decades in experiments that rely on ultra-sensitive detectors to measure the cascade of fleeting subatomic particles created when a particle beam slams into targets at nearly the speed of light. CEBAF is a DOE Office of Science user facility that is accessed by more than 1,850 nuclear physicists for their research. In a team experiment at Pfister's Quantum Optics Lab at UVa, Hossameldin linked up three superconducting transition-edge sensor (TES) devices to make one detector, with each TES device capable of seeing 35 photons, and set them in front of the laser and turned on the beam. A high-speed digitizer designed and developed by Dong at Jefferson Lab was a key piece of the detector electronics. \"The TES original digitizers did not have the high-speed capabilities that are included with our design,\" said Cuevas. \"Our digitizer has a 12-bit accuracy with a 4ns sampling time, so this allowed us to capture signals from the TES that were not seen before.\" Research for quantum computing is evolving at an exponential pace, and Cuevas predicts new technology will replace their system soon. But the larger collaboration to build a light-based quantum computer continues. \"The project is a very good example where designs can be reused and applied to a completely different scientific application,\" Cuevas said. \"Sharing technology is a core foundation for the scientific communities, and as electronics engineers, it is exciting to know our designs can further important discoveries.\" ", "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 Macroscopic quantum phenomena, such as observed in superfluids and superconductors, have led to promising technological advancements and some of the most important tests of fundamental physics. At present, quantum detection of light is mostly relegated to the microscale, where avalanche photodiodes are very sensitive to distinguishing single-photon events from vacuum but cannot differentiate between larger photon-number events. Beyond this, the ability to perform measurements to resolve photon numbers is highly desirable for a variety of quantum information applications, including computation, sensing and cryptography. True photon-number resolving detectors do exist, but they are currently limited to the ability to resolve on the order of 10 photons, which is too small for several quantum-state generation methods based on heralded detection. Here we extend photon measurement into the mesoscopic regime by implementing a detection scheme based on multiplexing highly quantum-efficient transition-edge sensors to accurately resolve photon numbers between 0 and 100. We then demonstrate the use of our system by implementing a quantum random-number generator with no inherent bias. This method is based on sampling a coherent state in the photon-number basis and is robust against environmental noise, phase and amplitude fluctuations in the laser, loss and detector inefficiency as well as eavesdropping. Beyond true random-number generation, our detection scheme serves as a means to implement quantum measurement and engineering techniques valuable for photonic quantum information processing. Main The nature of quantum mechanics dictates a fundamental wave–particle duality for physical systems, which was first recognized by Einstein through the understanding that light is composed of individual energy quanta known as photons 1 . The ability to accurately measure photons has led to checking the validity of the notion of ‘spooky action at a distance’ 2 and tremendous technological advancement in quantum communication 3 , quantum metrology 4 , 5 , 6 and quantum computation 7 , 8 . Much of this progress relies on the ability to measure single photons, such as through the use of avalanche photodiodes 9 ; however, the ability to resolve arbitrary numbers of photons beyond simply distinguishing vacuum from non-vacuum is highly desirable for many quantum information applications 8 , 10 , 11 , 12 . The process of projecting a subset of modes of an entangled state onto the Fock basis can allow for engineering non-Gaussian quantum states with negative Wigner functions 13 , 14 , 15 —a requirement for any quantum speed-up in continuous-variable quantum information 16 . Recent claims of quantum supremacy with Gaussian boson sampling devices 7 can be challenged with substantially greater ease when threshold detectors are used in place of photon-number-resolving detectors (PNRDs) 17 . Finally, sampling the photon number of a wave-like superposition such as a coherent state reveals fundamentally random outcomes that can be used to generate true random numbers 18 , 19 , 20 . The transition-edge sensor (TES), which is based on a calorimeter formed from a superconducting wafer held just below the critical temperature, has arisen as a viable PNRD with quantum efficiency approaching unity and entirely negligible dark counts 21 , 22 , 23 . Previous results with TES systems show the ability to measure non-classical systems with high mean photon numbers 24 , 25 ; however, these experiments were based on methods requiring extensive post-processing that give generally good estimates of photon-number measurements but relatively low distinguishability between individual photon counts above 10 photons 26 . For demanding applications requiring photon-number resolution, even a single-photon discrepancy destroys quantum correlations. Current methods demonstrate the potential to accurately count photons in the low double digits (~16) 27 , but certain proposals necessitate considerably higher detection events for conditional-state preparation. One particularly salient example is the preparation of a cubic-phase state to complete a universal gate set for continuous-variable quantum computation 28 . For the numerical approximations used in this formalism to hold, one must detect a large number of photons—simulations suggest 50 or more 29 . The detection scheme we demonstrate here now easily surpasses this previously unreachable milestone. In this Article, we extend the resolving capabilities of individual TES detectors to a maximum of 37 photons per detection channel with on-the-fly signal processing. We then multiplex three detectors into a system capable of resolving 0–100 photons with detector quantum efficiencies above 90%. Furthermore, we illustrate the utility of our scheme towards quantum cryptography applications by creating a quantum random-number generator (QRNG). The need for random numbers arises in many applications including cryptography, simulation and games of chance. Pseudo-random-number generators are not truly random and can, for example, lead to erroneous results in Monte Carlo simulations 30 . The stochastic nature of quantum mechanics leads to true randomness, but many current implementations sample random events from a non-uniform distribution, which can lead to bias that must be corrected classically 31 , 32 . Our method to implement a QRNG is based on sampling the photon statistics of a coherent state and is fundamentally unbiased, robust to experimental and environmental noise, and invulnerable to eavesdropping. The detection system used here is constructed by splitting a laser pulse equally across three paths and sending each to a TES as shown in Fig. 1a . Each TES is a PNRD that makes use of the extremely temperature-dependent resistance of a superconductor near the phase transition. Our TESs are composed of superconducting tungsten wafers that operate with a critical temperature near 100 mK. When light is incident on a chip, the thermal energy of an absorbed photon acts to locally break the superconducting state and induce a spot of non-zero resistance, which increases nearly linearly with absorbed energy 21 . This change in resistance is detected by a series of highly sensitive superconducting quantum interference devices (SQUIDs) and is then amplified and converted to an output voltage that is sent to an external field-programmable gate array (FPGA) to extract key signal parameters on the fly (system details in Methods ). The detectors used were optimized to be highly absorptive at the desired wavelength, and while our detectors achieve above 90%<|im_end|> <|im_start|>assistant Experts in nuclear physics and quantum information have demonstrated the application of a photon-number-resolving system to accurately resolve more than 100 photons. The feat is a major step forward in capability for quantum computing development efforts. It also may enable quantum generation of truly random numbers, a long-sought goal for developing unbreakable encryption techniques for applications in—for instance—military communications and financial transactions. The detector was recently reported in Nature Photonics. Physicists around the world are hotly pursuing the promise of reliable and robust quantum computing. Not only would harnessing quantum computing herald a giant leap for science, but it would also elevate the economy and enhance national security. But getting there has so far eluded the best brains on the planet. A pair of engineers at the U.S. Department of Energy's Thomas Jefferson National Accelerator Facility has designed a crucial piece of a photon detection system that has brought physicists a step closer to fully operational photonics-based quantum computing—that is, a quantum computer built entirely with light. The engineers are part of an interdisciplinary team of federal and academic researchers led by Jefferson Lab who are working on advancing quantum computing in nuclear physics. There are many different ways to try to make a fully functioning quantum computer. For photonics-based computing, quantum detection of light particles, or photons, is vital. Currently, individual detectors can resolve up to about 10 photons, but that number is too small for many quantum-state generation methods. No one had yet demonstrated detection of more than 16 photons, but simulations suggest that quantum computing will require detecting large numbers of photons—50 or more. Crossing that 50-photon threshold means being able to implement a "cubic gate"—a milestone toward building a complete gate set for universal quantum computing, explained Amr Hossameldin, team member and graduate research assistant in quantum computing and quantum optics at the University of Virginia. The team blew past the record of 16 photons and demonstrated a photon count of about 35 per single detector and reached 100 photons with a three-detector system. "They could predict that they were resolving 100 of these photons that were impacting upon the detectors with this extremely accurate resolution," said Robert Edwards, senior staff scientist and deputy associate director for theoretical and computational physics at Jefferson Lab. "It's super accurate—and that has never been achieved." "The lack of detection has been a major limitation to this approach of quantum computing. The new photon number resolution is the necessary step to implementing a universal instruction set," he continued. The new detection system also has another highly valuable secondary benefit: quantum generation of truly random numbers—a boon to unbreakable secret codes or encryptions in such areas as military communications and financial transactions. So-called random numbers generated by classical computer algorithms aren't truly random. The algorithm they are generated from can be compromised with some effort by playing a numbers game—looking for which numbers pop up more often than others. True random-number generation using quantum physics has no such flaw or bias. "There is an intrinsic randomness in quantum mechanics, where you can have a physical system that's in two states at once," explained Olivier Pfister, a physics professor at UVa who specializes in quantum fields and quantum information and served as external team leader for the project. "And when you want to know which it is, it's random. "Einstein got bugged by this. He called it 'the Old One playing dice with the universe.' And we don't know any better than Einstein." Pfister and Hossameldin are co-authors of the paper presenting the team's research. Other authors are Chris Cuevas and Hai Dong from Jefferson Lab, Richard Birrittella and Paul Alsing from the Air Force Research Laboratory in New York, Miller Eaton from UVa, and Christopher C. Gerry from the City University of New York. Signals not seen before The team effort was inspired by an announcement in 2019 by the DOE Office of Science offering funding opportunities for quantum information science research for nuclear physics under the Quantum Horizons program. Edwards secured a small grant to fund a lecture series bringing in experts in quantum computing. Pfister was the first lecturer in March 2020. A week later, the COVID-19 pandemic shut down the lab, but the seed for joint research into photonics-based quantum computing had been planted. A large team of physicists, engineers and postdocs was assembled. The collaboration began with the goal to use quantum photonics for calculations relevant to the Jefferson Lab science program. UVa already had a photon-based system for making quantum calculations using a pulsed laser, but lacked the means to detect with great speed and accuracy the number of photons impacting on its detector before the signal decayed. Meanwhile, detecting particles with speed and accuracy is Jefferson Lab's forte. Its Continuous Electron Beam Accelerator Facility, or CEBAF, has been used for decades in experiments that rely on ultra-sensitive detectors to measure the cascade of fleeting subatomic particles created when a particle beam slams into targets at nearly the speed of light. CEBAF is a DOE Office of Science user facility that is accessed by more than 1,850 nuclear physicists for their research. In a team experiment at Pfister's Quantum Optics Lab at UVa, Hossameldin linked up three superconducting transition-edge sensor (TES) devices to make one detector, with each TES device capable of seeing 35 photons, and set them in front of the laser and turned on the beam. A high-speed digitizer designed and developed by Dong at Jefferson Lab was a key piece of the detector electronics. "The TES original digitizers did not have the high-speed capabilities that are included with our design," said Cuevas. "Our digitizer has a 12-bit accuracy with a 4ns sampling time, so this allowed us to capture signals from the TES that were not seen before." Research for quantum computing is evolving at an exponential pace, and Cuevas predicts new technology will replace their system soon. But the larger collaboration to build a light-based quantum computer continues. "The project is a very good example where designs can be reused and applied to a completely different scientific application," Cuevas said. "Sharing technology is a core foundation for the scientific communities, and as electronics engineers, it is exciting to know our designs can further important discoveries." <|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 Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells 1 . By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis 1 . Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8 + T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T reg ) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T reg cells is dependent on T reg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T reg cell function in the presence of glucose. Main Cellular energy metabolism reprogramming is a crucial hallmark of cancer 2 . High glucose consumption and lactate production by tumour cells restrict nutrient availability in the tumour microenvironment for effector T cells, which also rely on glycolysis to proliferate and function 3 , 4 , 5 . We corroborated the negative effect of tumour glucose metabolism on T cell function using the highly glycolytic mouse mammary carcinoma 4T1 6 , 7 , 8 . We found that 4T1 cells, cultured either alone or with activated T cells, consume more glucose and produce more lactate than activated T cell monocultures (Extended Data Fig. 1a ). In the presence of 4T1 cells, or similar non-toxic concentrations of exogenous lactate (Extended Data Fig. 1b ), T cells were significantly less activated and viable (Extended Data Fig. 1c, d ), which indicates the negative effect of tumour glycolysis on T cell function and potentially response to immunotherapy. To explore the role of tumour glycolysis in response to immunotherapy, we correlated tumour immune infiltration and glycolysis before and after CTLA-4 blockade using RNA sequencing (RNA-seq) data from patients with advanced melanoma receiving ipilimumab treatment 9 , 10 . At baseline, the expression of glucose catabolism genes was frequently negatively correlated with the infiltration of major immune cell subsets (Fig. 1a , left, Extended Data Fig. 1e ), in agreement with previous observations 11 , 12 , 13 , which suggests that tumour glycolysis may contribute to a non-inflamed tumour phenotype. After treatment with ipilimumab, these negative correlations were alleviated, with some glycolysis-related genes becoming positively correlated with most immune cell subsets (Fig. 1a , right, Extended Data Fig. 1f ). However, key glycolytic genes—such as Ldha , which encodes the crucial enzyme subunit for lactate production, and Slc16a1 , which encodes the lactate transporter MCT1, remained inversely correlated with immune infiltrates after ipilimumab treatment (Fig. 1a , right)—which suggests that anti-CTLA-4 alone may not be sufficient to potentiate immune cell fitness in highly glycolytic tumours that overexpress these genes. We investigated these effects in a more controlled setting, by using a glycolysis-defective 4T1 variant generated with short hairpin RNA (shRNA) targeting Ldha (4T1-KD) in comparison with the scramble-shRNA-transfected 4T1 control (4T1-Sc) (Extended Data Fig. 2a ). 4T1-KD resulted in decreased glycolytic capacity and slightly but significantly delayed tumour growth compared to 4T1-Sc in immunocompetent mice (Extended Data Fig. 2b, c ), pointing to increased immune sensitivity. CTLA-4 blockade did not alter the growth of these tumours, and by resecting 4T1-Sc and 4T1-KD lesions three days apart, we could equalize their size for downstream analyses (Extended Data Fig. 2d ). In this setting, positive correlations between glycolysis-related genes and immune cell subsets became particularly apparent in glycolysis-defective 4T1-KD tumours after CTLA-4 blockade (Fig. 1b, c ). In these tumours, in which LDHA is selectively downregulated in tumour cells (Extended Data Fig. 2a, e ), we observed positive correlations between Ldha expression and the immune infiltrate, which were eventually amplified by CTLA-4 blockade, pointing to activation of glycolysis in immune cells (Fig. 1c , right). This suggested that glycolysis-low tumours may be more responsive to CTLA-4 blockade, whereas the treatment of glycolysis-high tumours may require dampening tumour glycolysis together with anti-CTLA-4. Fig. 1: Correlation between tumour glycolysis and immune cell infiltration after CTLA-4 blockade. a – c , Heat maps with identical colour mapping setting showing indexes of Pearson correlation analyses between the indicated glycolysis-related genes and immune cell signatures by CIBERSORT in RNA-seq datasets from human melanoma samples at baseline (left) and after treatment with ipilimumab (right) ( a ), and from 4T1-Sc ( b ) and 4T1-KD ( c ) tumours treated with anti-CTLA-4 (right) or the IgG isotype control (left). Pre-ipilimumab, n = 7; post-ipilimumab, n = 15 ( a ). 4T1-Sc IgG, n = 4; 4T1-Sc anti-CTLA-4, n = 5 ( b ). 4T1-KD IgG and anti-CTLA-4, n = 5 per treatment ( c ). SLC16A1 and LDHA are highlighted in blue. aDC, activated dendritic cell; DC, dendritic cell; NK, natural killer. Full size image LDHA-KD tumours respond better to anti-CTLA-4 We next investigated the effect of slowing tumour glycolysis on the efficacy of CTLA-4 blockade and the underlying mechanisms. To simulate the clinical management of breast cancer, we treated mice orthotopically implanted with 4T1-KD or 4T1-Sc cells with anti-CTLA-4 before surgical tumour resection. Again, we resected 4T1-KD and 4T1-Sc tumours three days apart to equalize tumour size on the day of surgery (Fig. 2a , Extended Data Fig. 2d ). Notably, lactate dehydrogenase (LDH) activity remained potently downregulated in 4T1-KD tumours compared with control 4T1-Sc tumours up to the day of surgery (Extended Data Fig.", "role": "user" }, { "content": "Cancer cells and immune cells share something in common: They both love sugar. Sugar is an important nutrient. All cells use sugar as a vital source of energy and building blocks. For immune cells, gobbling up sugar is a good thing, since it means getting enough nutrients to grow and divide for stronger immune responses. But cancer cells use sugar for more nefarious ends. So, what happens when tumor cells and immune cells battle for access to the same supply of sugar? That's the central question that Memorial Sloan Kettering researchers Taha Merghoub, Jedd Wolchok, and Roberta Zappasodi explore in a new study published February 15 in the journal Nature. Using mouse models and data from human patients, the researchers found a direct relationship between the amount of sugar—specifically glucose—that a tumor consumes and the effectiveness of immunotherapy: The more sugar the tumor consumed, the less effective the immunotherapy. The findings suggest that blocking cancer cells' use of sugar could tip the scales in favor of immune cells, especially when they are activated by immunotherapy drugs. \"If we reduce a tumor's use of glucose, then we free up more of it for immune cells to use, which benefits the immune response,\" says Dr. Merghoub, who co-led the research effort. \"What we think we've identified is a new means to improve checkpoint blockade immunotherapy,\" adds Dr. Wolchok. Immune checkpoint inhibitors release the brakes on immune cells and can provide lasting benefits for people with cancer, but they do not work for everyone. The new research may provide a way to boost their effectiveness. Dr. Wolchok, Chief of the Immuno-Oncology Service in the Human Oncology and Pathogenesis Program at MSK, also directs the Parker Institute for Cancer Immunotherapy at MSK and co-directs the Ludwig Center for Cancer Immunotherapy at MSK. Vying for Resources To examine the relationship between tumor cells' use of glucose and response to immunotherapy, the researchers turned to a mouse model of breast cancer that is highly glycolytic—meaning it uses a lot of sugar to grow. In the first set of tumors, the researchers genetically knocked down a key enzyme cells require to rapidly consume glucose in a process called glycolysis. In the second set, the enzyme was left alone. Each set of tumors was grown in mice and then the mice were treated with checkpoint inhibitors targeting CTLA-4 before having surgery to remove the tumor. The results: The mice whose tumors consumed less sugar survived longer and had a far lower rate of metastasis (when the cancer spreads) than the mice with tumors that used more glucose. This indicated an improved response to immunotherapy in mice whose tumors consumed less glucose. Moreover, the improved immune response exhibited memory. When researchers re-implanted tumors in the mice exposed to the less-glycolytic tumors, tumor growth remained suppressed. By contrast, mice exposed to the more-glycolytic tumors were not able to control the growth of re-implanted tumors. The team also looked at human data. When they measured glucose use by tumors and compared that to the number of immune cells present in a tumor, they found that the two measures were inversely correlated: The higher the glucose use by tumors, the fewer immune cells present. Releasing Multiple Brakes When it comes to immune checkpoint blockade, two types of T cells are crucially important—effector T cells and regulatory T cells (Tregs). Effector T cells are the ones that actually attack cancer cells and kill them, whereas Tregs serve as a kind of brake on the effector T cells. It turns out that glucose affects these two T cell types differently. More available glucose boosts the effector T cells' killing ability. With Tregs, more glucose means they lose their ability to apply the brakes. That means that freeing up glucose for use by immune cells is doubly beneficial at giving a boost to immunotherapy drugs. \"It was surprising and exciting to see that CTLA-4 blockade induces Tregs to use glucose and that this in turn reduces the suppression activity of these cells,\" says Dr. Zappasodi, a former Parker Institute Bridge Scholar in the Merghoub-Wolchok lab and now a faculty member at Weill Cornell Medicine. \"The implication is that for tumors that are highly glycolytic and don't respond to immune checkpoint blockade, one way of overcoming this resistance is to target tumor glycolysis with drugs,\" Dr. Merghoub adds. The feasibility of using sugar to boost immune responses depends on being able to preferentially limit glucose use by tumors—and that's where it gets tricky. Existing drugs that block sugar use by cancer cells will also block sugar use by immune cells, which would defeat the purpose. What is needed are drugs that can prevent tumor cells from using glucose while allowing immune cells to use it freely. The team has a few leads and is exploring them 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 Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells 1 . By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis 1 . Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8 + T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T reg ) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T reg cells is dependent on T reg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T reg cell function in the presence of glucose. Main Cellular energy metabolism reprogramming is a crucial hallmark of cancer 2 . High glucose consumption and lactate production by tumour cells restrict nutrient availability in the tumour microenvironment for effector T cells, which also rely on glycolysis to proliferate and function 3 , 4 , 5 . We corroborated the negative effect of tumour glucose metabolism on T cell function using the highly glycolytic mouse mammary carcinoma 4T1 6 , 7 , 8 . We found that 4T1 cells, cultured either alone or with activated T cells, consume more glucose and produce more lactate than activated T cell monocultures (Extended Data Fig. 1a ). In the presence of 4T1 cells, or similar non-toxic concentrations of exogenous lactate (Extended Data Fig. 1b ), T cells were significantly less activated and viable (Extended Data Fig. 1c, d ), which indicates the negative effect of tumour glycolysis on T cell function and potentially response to immunotherapy. To explore the role of tumour glycolysis in response to immunotherapy, we correlated tumour immune infiltration and glycolysis before and after CTLA-4 blockade using RNA sequencing (RNA-seq) data from patients with advanced melanoma receiving ipilimumab treatment 9 , 10 . At baseline, the expression of glucose catabolism genes was frequently negatively correlated with the infiltration of major immune cell subsets (Fig. 1a , left, Extended Data Fig. 1e ), in agreement with previous observations 11 , 12 , 13 , which suggests that tumour glycolysis may contribute to a non-inflamed tumour phenotype. After treatment with ipilimumab, these negative correlations were alleviated, with some glycolysis-related genes becoming positively correlated with most immune cell subsets (Fig. 1a , right, Extended Data Fig. 1f ). However, key glycolytic genes—such as Ldha , which encodes the crucial enzyme subunit for lactate production, and Slc16a1 , which encodes the lactate transporter MCT1, remained inversely correlated with immune infiltrates after ipilimumab treatment (Fig. 1a , right)—which suggests that anti-CTLA-4 alone may not be sufficient to potentiate immune cell fitness in highly glycolytic tumours that overexpress these genes. We investigated these effects in a more controlled setting, by using a glycolysis-defective 4T1 variant generated with short hairpin RNA (shRNA) targeting Ldha (4T1-KD) in comparison with the scramble-shRNA-transfected 4T1 control (4T1-Sc) (Extended Data Fig. 2a ). 4T1-KD resulted in decreased glycolytic capacity and slightly but significantly delayed tumour growth compared to 4T1-Sc in immunocompetent mice (Extended Data Fig. 2b, c ), pointing to increased immune sensitivity. CTLA-4 blockade did not alter the growth of these tumours, and by resecting 4T1-Sc and 4T1-KD lesions three days apart, we could equalize their size for downstream analyses (Extended Data Fig. 2d ). In this setting, positive correlations between glycolysis-related genes and immune cell subsets became particularly apparent in glycolysis-defective 4T1-KD tumours after CTLA-4 blockade (Fig. 1b, c ). In these tumours, in which LDHA is selectively downregulated in tumour cells (Extended Data Fig. 2a, e ), we observed positive correlations between Ldha expression and the immune infiltrate, which were eventually amplified by CTLA-4 blockade, pointing to activation of glycolysis in immune cells (Fig. 1c , right). This suggested that glycolysis-low tumours may be more responsive to CTLA-4 blockade, whereas the treatment of glycolysis-high tumours may require dampening tumour glycolysis together with anti-CTLA-4. Fig. 1: Correlation between tumour glycolysis and immune cell infiltration after CTLA-4 blockade. a – c , Heat maps with identical colour mapping setting showing indexes of Pearson correlation analyses between the indicated glycolysis-related genes and immune cell signatures by CIBERSORT in RNA-seq datasets from human melanoma samples at baseline (left) and after treatment with ipilimumab (right) ( a ), and from 4T1-Sc ( b ) and 4T1-KD ( c ) tumours treated with anti-CTLA-4 (right) or the IgG isotype control (left). Pre-ipilimumab, n = 7; post-ipilimumab, n = 15 ( a ). 4T1-Sc IgG, n = 4; 4T1-Sc anti-CTLA-4, n = 5 ( b ). 4T1-KD IgG and anti-CTLA-4, n = 5 per treatment ( c ). SLC16A1 and LDHA are highlighted in blue. aDC, activated dendritic cell; DC, dendritic cell; NK, natural killer. Full size image LDHA-KD tumours respond better to anti-CTLA-4 We next investigated the effect of slowing tumour glycolysis on the efficacy of CTLA-4 blockade and the underlying mechanisms. To simulate the clinical management of breast cancer, we treated mice orthotopically implanted with 4T1-KD or 4T1-Sc cells with anti-CTLA-4 before surgical tumour resection. Again, we resected 4T1-KD and 4T1-Sc tumours three days apart to equalize tumour size on the day of surgery (Fig. 2a , Extended Data Fig. 2d ). Notably, lactate dehydrogenase (LDH) activity remained potently downregulated in 4T1-KD tumours compared with control 4T1-Sc tumours up to the day of surgery (Extended Data Fig.<|im_end|> <|im_start|>assistant Cancer cells and immune cells share something in common: They both love sugar. Sugar is an important nutrient. All cells use sugar as a vital source of energy and building blocks. For immune cells, gobbling up sugar is a good thing, since it means getting enough nutrients to grow and divide for stronger immune responses. But cancer cells use sugar for more nefarious ends. So, what happens when tumor cells and immune cells battle for access to the same supply of sugar? That's the central question that Memorial Sloan Kettering researchers Taha Merghoub, Jedd Wolchok, and Roberta Zappasodi explore in a new study published February 15 in the journal Nature. Using mouse models and data from human patients, the researchers found a direct relationship between the amount of sugar—specifically glucose—that a tumor consumes and the effectiveness of immunotherapy: The more sugar the tumor consumed, the less effective the immunotherapy. The findings suggest that blocking cancer cells' use of sugar could tip the scales in favor of immune cells, especially when they are activated by immunotherapy drugs. "If we reduce a tumor's use of glucose, then we free up more of it for immune cells to use, which benefits the immune response," says Dr. Merghoub, who co-led the research effort. "What we think we've identified is a new means to improve checkpoint blockade immunotherapy," adds Dr. Wolchok. Immune checkpoint inhibitors release the brakes on immune cells and can provide lasting benefits for people with cancer, but they do not work for everyone. The new research may provide a way to boost their effectiveness. Dr. Wolchok, Chief of the Immuno-Oncology Service in the Human Oncology and Pathogenesis Program at MSK, also directs the Parker Institute for Cancer Immunotherapy at MSK and co-directs the Ludwig Center for Cancer Immunotherapy at MSK. Vying for Resources To examine the relationship between tumor cells' use of glucose and response to immunotherapy, the researchers turned to a mouse model of breast cancer that is highly glycolytic—meaning it uses a lot of sugar to grow. In the first set of tumors, the researchers genetically knocked down a key enzyme cells require to rapidly consume glucose in a process called glycolysis. In the second set, the enzyme was left alone. Each set of tumors was grown in mice and then the mice were treated with checkpoint inhibitors targeting CTLA-4 before having surgery to remove the tumor. The results: The mice whose tumors consumed less sugar survived longer and had a far lower rate of metastasis (when the cancer spreads) than the mice with tumors that used more glucose. This indicated an improved response to immunotherapy in mice whose tumors consumed less glucose. Moreover, the improved immune response exhibited memory. When researchers re-implanted tumors in the mice exposed to the less-glycolytic tumors, tumor growth remained suppressed. By contrast, mice exposed to the more-glycolytic tumors were not able to control the growth of re-implanted tumors. The team also looked at human data. When they measured glucose use by tumors and compared that to the number of immune cells present in a tumor, they found that the two measures were inversely correlated: The higher the glucose use by tumors, the fewer immune cells present. Releasing Multiple Brakes When it comes to immune checkpoint blockade, two types of T cells are crucially important—effector T cells and regulatory T cells (Tregs). Effector T cells are the ones that actually attack cancer cells and kill them, whereas Tregs serve as a kind of brake on the effector T cells. It turns out that glucose affects these two T cell types differently. More available glucose boosts the effector T cells' killing ability. With Tregs, more glucose means they lose their ability to apply the brakes. That means that freeing up glucose for use by immune cells is doubly beneficial at giving a boost to immunotherapy drugs. "It was surprising and exciting to see that CTLA-4 blockade induces Tregs to use glucose and that this in turn reduces the suppression activity of these cells," says Dr. Zappasodi, a former Parker Institute Bridge Scholar in the Merghoub-Wolchok lab and now a faculty member at Weill Cornell Medicine. "The implication is that for tumors that are highly glycolytic and don't respond to immune checkpoint blockade, one way of overcoming this resistance is to target tumor glycolysis with drugs," Dr. Merghoub adds. The feasibility of using sugar to boost immune responses depends on being able to preferentially limit glucose use by tumors—and that's where it gets tricky. Existing drugs that block sugar use by cancer cells will also block sugar use by immune cells, which would defeat the purpose. What is needed are drugs that can prevent tumor cells from using glucose while allowing immune cells to use it freely. The team has a few leads and is exploring them now. <|im_end|>

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2,659

[ { "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 cellular components of mammalian neocortical circuits are diverse, and capturing this diversity in computational models is challenging. Here we report an approach for generating biophysically detailed models of 170 individual neurons in the Allen Cell Types Database to link the systematic experimental characterization of cell types to the construction of cortical models. We build models from 3D morphologies and somatic electrophysiological responses measured in the same cells. Densities of active somatic conductances and additional parameters are optimized with a genetic algorithm to match electrophysiological features. We evaluate the models by applying additional stimuli and comparing model responses to experimental data. Applying this technique across a diverse set of neurons from adult mouse primary visual cortex, we verify that models preserve the distinctiveness of intrinsic properties between subsets of cells observed in experiments. The optimized models are accessible online alongside the experimental data. Code for optimization and simulation is also openly distributed. Introduction Diverse neuronal types assemble into circuits in the mammalian neocortex. This cell type diversity has been characterized across a number of different dimensions: intrinsic physiology, morphology, connectivity, and genetic identity 1 , 2 , 3 , 4 , 5 , 6 . Specific subpopulations of cortical cells can be linked to particular genetic markers, and genetic tools that take advantage of these markers can provide access to these populations across a variety of experimental paradigms 7 . With this rich and expanding body of cell-type characterization, detailed computational models of neocortical circuits could serve as a framework for synthesizing a broad set of experimental data and generate hypotheses about cell-type-specific roles in the context of an active network. However, relatively few models attempt to incorporate the diversity of cellular properties observed experimentally. The largest-scale studies of this type 8 have taken the approach of generating a canonical model for each analytically defined cell type, then applying those parameters to a wide variety of morphologies to generate variations in intrinsic properties. An alternative to this approach would be to fit many individual cells that have each been characterized experimentally, then populate a network model by drawing from this large model library, without necessarily defining cell types in advance. One challenge in creating a large library of individual cell models is that the characterization of different cell types is frequently done by different laboratories under different conditions. It is difficult for modelers to gather a set of data across many cells that facilitates the generation of models in a consistent way. Since the balance of active conductances that governs a neuron’s intrinsic electrophysiological behavior is finely tuned, it is difficult and time-consuming to optimize the combination of model parameters that accurately reproduces the target neuron’s activity. To address this challenge, several studies have described automated parameter fitting approaches with multicompartment conductance-based models 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . These approaches include several different (though sometimes overlapping) optimization methods (e.g., genetic algorithms, simulated annealing, downhill simplex) and target objective functions (e.g., direct fitting of voltage traces, feature-based comparisons, phase plane comparisons). In addition, many of the more recent studies have released open-source code so that others may use similar methods. However, these studies typically demonstrate their methods on a limited number of experimental examples, which often represent a relatively specific cell type, such as cortical layer 5 pyramidal neurons. Therefore, it is not clear how easily the methods can be transferred to novel cell types. In addition, while the parameter fitting is automated with these methods, setting up the methods to apply them to many cells can require additional manually executed steps. Here we present an approach for automatic optimization of biophysically detailed neuronal models and a set of 170 models generated from a high-throughput experimental data pipeline (the Allen Cell Types Database 18 ). These models are systematically generated for a wide variety of cell types based on experimental data collected via a highly standardized protocol from the primary visual cortex of the adult mouse. The models are based on individual recorded cells that in most cases were labeled by a specific transgenic driver line, and the locations of the recorded cells in the brain were mapped to a standard three-dimensional (3D) reference space (the Allen Mouse Common Coordinate Framework 19 ). We show that this optimization procedure generates models that reproduce essential features of the electrophysiological properties of the original cells and generalize across a range of stimulus types that were applied in experiments. This flexible analysis and optimization approach is publicly available as open-source code, which has the advantages of being relatively concise, extendable, and based upon open-source, well-supported libraries. Additionally, we use classification methods to demonstrate that the model set largely preserves the distinctiveness across cell types found in the original data. Together, this model set provides the fundamental components for larger models of neocortical networks. Results Model fitting procedure We developed an automated analysis and optimization procedure to allow for the systematic generation of models from a high-throughput experimental pipeline (Fig. 1 ). We implemented our methods in Python via a code base that drew on open-source projects for improved ease of use and better maintenance. These software projects include the Allen Software Development Kit (Allen SDK) 20 for electrophysiological feature analysis and simulation control and the Distributed Evolutionary Algorithms in Python (DEAP) library 21 for flexible optimization via genetic algorithm. The integration with these packages enabled the flexible use of different analytic and optimization routines. In addition, different styles of fit (e.g., different combinations of conductances, different feature sets) could be quickly implemented via configuration files using the widespread JavaScript Object Notation file format. Sample code illustrating the use of these libraries is shown in Fig. 1b , and the code implementing these procedures is publicly available. Fig. 1 Overview of model fitting procedure and resources. a Schematic showing the steps involved in using the standardized data from individual neurons in the Allen Cell Types Database to generate optimized models that", "role": "user" }, { "content": "The Allen Institute for Brain Science has produced the first comprehensive, publicly available database of predictive neuron models, along with their corresponding data. The generalized leaky integrate-and-fire (GLIF) and biophysically detailed models are described in two articles published in the journal Nature Communications. \"The publication of these mathematical-physical models of the individual components making up neural networks is an important landmark in our ten-year quest to understand the brain\" said Christof Koch, Ph.D., President and Chief Scientist at the Allen Institute for Brain Science. \"We now seek to understand how vast assemblies of these elements give rise to behavior, perception and the feeling of life itself - consciousness.\" The GLIF and biophysical models were built from extensive data in the Allen Cell Types Database: a massive publicly available repository of cortical neurons in both the mouse and human brain. Launched in 2015, this database contains electrophysiological, morphological, and transcriptomic properties gathered from individual cells, and models simulating cell activity, all building toward a \"periodic table\" of cell types. \"This project is a testament to the Allen Institute's interdisciplinary collaboration and teamwork,\" said Nathan Gouwens, Ph.D., an Allen Institute scientist. \"Five years ago, we all began working together to build the pipeline for the Allen Cell Types Database. Now we have a parallel pipeline for generating models for each cell in the database.\" GLIF models reproduce the spike times of neurons and capture the abstract transformations taking place inside of neurons. These models have the benefit of requiring a relatively low level of computer power to simulate, meaning that it's feasible to model the millions and millions of neurons making up the brain of a mouse. The biophysical models are more detailed. As such, they accurately represent the mechanisms reproducing the actual voltage waveform of action potentials (nerve pulses) and other forms of electrical activity across the dendritic tree and the cell body of neurons. Biophysical models take considerably more computational power than GLIF models to execute. \"We have generated a large library of cell models - ranging from simple to complex - which can be put together like building blocks to construct higher-level circuit models, providing a valuable resource for the neuroscience community,\" said Anton Arkhipov, Ph.D., an Allen Institute scientist. \"The models can be used as building blocks for larger simulations, but also to understand how some cell types differ from the other. Researchers can classify cell types by only looking at model parameters,\" said Stefan Mihalas, an Allen Institute scientist. Perhaps in the future, detailed models of multiple cell types can be used in larger simulations to model neurological or psychiatric disorders, such as epilepsy, autism or Alzheimer's, and applying virtual perturbations to cells or networks of cells may allow us to see how the brain might respond to specific therapies. \"These studies make great use of the Allen's unique single-cell physiology data base by putting all recorded responses into a single model framework,\" said Adrienne Fairhall, Ph.D., co-director of the Computational Neuroscience program at the University of Washington. \"This can play a huge role in allowing researchers to compare and potentially differentiate the computations of different cell types.\" \"Our models represent a large step in enabling scientists around the world to use standardized data, methods and models for exploring network behavior in the brain,\" said Corinne Teeter, Ph.D., the lead scientist for the GLIF modeling effort at the Allen Institute. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The cellular components of mammalian neocortical circuits are diverse, and capturing this diversity in computational models is challenging. Here we report an approach for generating biophysically detailed models of 170 individual neurons in the Allen Cell Types Database to link the systematic experimental characterization of cell types to the construction of cortical models. We build models from 3D morphologies and somatic electrophysiological responses measured in the same cells. Densities of active somatic conductances and additional parameters are optimized with a genetic algorithm to match electrophysiological features. We evaluate the models by applying additional stimuli and comparing model responses to experimental data. Applying this technique across a diverse set of neurons from adult mouse primary visual cortex, we verify that models preserve the distinctiveness of intrinsic properties between subsets of cells observed in experiments. The optimized models are accessible online alongside the experimental data. Code for optimization and simulation is also openly distributed. Introduction Diverse neuronal types assemble into circuits in the mammalian neocortex. This cell type diversity has been characterized across a number of different dimensions: intrinsic physiology, morphology, connectivity, and genetic identity 1 , 2 , 3 , 4 , 5 , 6 . Specific subpopulations of cortical cells can be linked to particular genetic markers, and genetic tools that take advantage of these markers can provide access to these populations across a variety of experimental paradigms 7 . With this rich and expanding body of cell-type characterization, detailed computational models of neocortical circuits could serve as a framework for synthesizing a broad set of experimental data and generate hypotheses about cell-type-specific roles in the context of an active network. However, relatively few models attempt to incorporate the diversity of cellular properties observed experimentally. The largest-scale studies of this type 8 have taken the approach of generating a canonical model for each analytically defined cell type, then applying those parameters to a wide variety of morphologies to generate variations in intrinsic properties. An alternative to this approach would be to fit many individual cells that have each been characterized experimentally, then populate a network model by drawing from this large model library, without necessarily defining cell types in advance. One challenge in creating a large library of individual cell models is that the characterization of different cell types is frequently done by different laboratories under different conditions. It is difficult for modelers to gather a set of data across many cells that facilitates the generation of models in a consistent way. Since the balance of active conductances that governs a neuron’s intrinsic electrophysiological behavior is finely tuned, it is difficult and time-consuming to optimize the combination of model parameters that accurately reproduces the target neuron’s activity. To address this challenge, several studies have described automated parameter fitting approaches with multicompartment conductance-based models 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . These approaches include several different (though sometimes overlapping) optimization methods (e.g., genetic algorithms, simulated annealing, downhill simplex) and target objective functions (e.g., direct fitting of voltage traces, feature-based comparisons, phase plane comparisons). In addition, many of the more recent studies have released open-source code so that others may use similar methods. However, these studies typically demonstrate their methods on a limited number of experimental examples, which often represent a relatively specific cell type, such as cortical layer 5 pyramidal neurons. Therefore, it is not clear how easily the methods can be transferred to novel cell types. In addition, while the parameter fitting is automated with these methods, setting up the methods to apply them to many cells can require additional manually executed steps. Here we present an approach for automatic optimization of biophysically detailed neuronal models and a set of 170 models generated from a high-throughput experimental data pipeline (the Allen Cell Types Database 18 ). These models are systematically generated for a wide variety of cell types based on experimental data collected via a highly standardized protocol from the primary visual cortex of the adult mouse. The models are based on individual recorded cells that in most cases were labeled by a specific transgenic driver line, and the locations of the recorded cells in the brain were mapped to a standard three-dimensional (3D) reference space (the Allen Mouse Common Coordinate Framework 19 ). We show that this optimization procedure generates models that reproduce essential features of the electrophysiological properties of the original cells and generalize across a range of stimulus types that were applied in experiments. This flexible analysis and optimization approach is publicly available as open-source code, which has the advantages of being relatively concise, extendable, and based upon open-source, well-supported libraries. Additionally, we use classification methods to demonstrate that the model set largely preserves the distinctiveness across cell types found in the original data. Together, this model set provides the fundamental components for larger models of neocortical networks. Results Model fitting procedure We developed an automated analysis and optimization procedure to allow for the systematic generation of models from a high-throughput experimental pipeline (Fig. 1 ). We implemented our methods in Python via a code base that drew on open-source projects for improved ease of use and better maintenance. These software projects include the Allen Software Development Kit (Allen SDK) 20 for electrophysiological feature analysis and simulation control and the Distributed Evolutionary Algorithms in Python (DEAP) library 21 for flexible optimization via genetic algorithm. The integration with these packages enabled the flexible use of different analytic and optimization routines. In addition, different styles of fit (e.g., different combinations of conductances, different feature sets) could be quickly implemented via configuration files using the widespread JavaScript Object Notation file format. Sample code illustrating the use of these libraries is shown in Fig. 1b , and the code implementing these procedures is publicly available. Fig. 1 Overview of model fitting procedure and resources. a Schematic showing the steps involved in using the standardized data from individual neurons in the Allen Cell Types Database to generate optimized models that<|im_end|> <|im_start|>assistant The Allen Institute for Brain Science has produced the first comprehensive, publicly available database of predictive neuron models, along with their corresponding data. The generalized leaky integrate-and-fire (GLIF) and biophysically detailed models are described in two articles published in the journal Nature Communications. "The publication of these mathematical-physical models of the individual components making up neural networks is an important landmark in our ten-year quest to understand the brain" said Christof Koch, Ph.D., President and Chief Scientist at the Allen Institute for Brain Science. "We now seek to understand how vast assemblies of these elements give rise to behavior, perception and the feeling of life itself - consciousness." The GLIF and biophysical models were built from extensive data in the Allen Cell Types Database: a massive publicly available repository of cortical neurons in both the mouse and human brain. Launched in 2015, this database contains electrophysiological, morphological, and transcriptomic properties gathered from individual cells, and models simulating cell activity, all building toward a "periodic table" of cell types. "This project is a testament to the Allen Institute's interdisciplinary collaboration and teamwork," said Nathan Gouwens, Ph.D., an Allen Institute scientist. "Five years ago, we all began working together to build the pipeline for the Allen Cell Types Database. Now we have a parallel pipeline for generating models for each cell in the database." GLIF models reproduce the spike times of neurons and capture the abstract transformations taking place inside of neurons. These models have the benefit of requiring a relatively low level of computer power to simulate, meaning that it's feasible to model the millions and millions of neurons making up the brain of a mouse. The biophysical models are more detailed. As such, they accurately represent the mechanisms reproducing the actual voltage waveform of action potentials (nerve pulses) and other forms of electrical activity across the dendritic tree and the cell body of neurons. Biophysical models take considerably more computational power than GLIF models to execute. "We have generated a large library of cell models - ranging from simple to complex - which can be put together like building blocks to construct higher-level circuit models, providing a valuable resource for the neuroscience community," said Anton Arkhipov, Ph.D., an Allen Institute scientist. "The models can be used as building blocks for larger simulations, but also to understand how some cell types differ from the other. Researchers can classify cell types by only looking at model parameters," said Stefan Mihalas, an Allen Institute scientist. Perhaps in the future, detailed models of multiple cell types can be used in larger simulations to model neurological or psychiatric disorders, such as epilepsy, autism or Alzheimer's, and applying virtual perturbations to cells or networks of cells may allow us to see how the brain might respond to specific therapies. "These studies make great use of the Allen's unique single-cell physiology data base by putting all recorded responses into a single model framework," said Adrienne Fairhall, Ph.D., co-director of the Computational Neuroscience program at the University of Washington. "This can play a huge role in allowing researchers to compare and potentially differentiate the computations of different cell types." "Our models represent a large step in enabling scientists around the world to use standardized data, methods and models for exploring network behavior in the brain," said Corinne Teeter, Ph.D., the lead scientist for the GLIF modeling effort at the Allen Institute. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As global temperatures rise, large amounts of carbon sequestered in permafrost are becoming available for microbial degradation. Accurate prediction of carbon gas emissions from thawing permafrost is limited by our understanding of these microbial communities. Here we use metagenomic sequencing of 214 samples from a permafrost thaw gradient to recover 1,529 metagenome-assembled genomes, including many from phyla with poor genomic representation. These genomes reflect the diversity of this complex ecosystem, with genus-level representatives for more than sixty per cent of the community. Meta-omic analysis revealed key populations involved in the degradation of organic matter, including bacteria whose genomes encode a previously undescribed fungal pathway for xylose degradation. Microbial and geochemical data highlight lineages that correlate with the production of greenhouse gases and indicate novel syntrophic relationships. Our findings link changing biogeochemistry to specific microbial lineages involved in carbon processing, and provide key information for predicting the effects of climate change on permafrost systems. Main Permafrost thaw induced by climate change is predicted to make up to 174 Pg of near-surface carbon (less than 3 m below the surface) available for microbial degradation by 2100 1 . Prediction of the magnitude of carbon loss as carbon dioxide (CO 2 ) or methane (CH 4 ) is hampered by our limited knowledge of microbial metabolism of organic matter in these environments. Genome-centric metagenomic analysis of microbial communities provides the necessary information to examine how specific lineages transform organic matter during permafrost thaw. However, these methods are challenged by the inherent complexity and spatial heterogeneity of near-surface soil communities that support diverse functional processes 2 , 3 , 4 . Previous metagenomic studies in permafrost-associated soils from Alaskan tundra 5 , 6 and a mineral soil permafrost 7 recovered a small number (14–33) of metagenome-assembled genomes (MAGs), which represent only a fraction of the species present in these systems. However, the ability to recover MAGs from complex microbial communities is continually improving in parallel with advances in sequencing technology and bioinformatic techniques 8 , 9 . Recovery and distribution of MAGs The discontinuous permafrost at Stordalen Mire in northern Sweden is a model Arctic peatland ecosystem for studying thaw progression 10 . To gain an understanding of the microbial communities at this site and their associated carbon metabolism, soil samples were collected from the active layer (seasonally thawed) of three sites across a thaw gradient: an intact palsa (thawed to approximately 30 cm), a partially thawed bog (approximately 60 cm), and a fully thawed fen. Although bogs and fens exist in diverse landscapes, thaw-associated shifts in hydrology cause them to be a common feature of thawing northern peatland permafrost systems (see Methods ). Triplicate soil cores and biogeochemical measurements were taken at each site from four active layer depths (near surface, mid, deep and extra-deep; 1–51 cm; Fig. 1 , Supplementary Data 1 ) over three growing seasons. In total, 1.7 Tb of metagenomic sequence data were generated from 214 samples (2–165 Gb per sample), with supporting metatranscriptomic and metaproteomic data from a subset of these samples (Supplementary Data 1 , 2 ). Metagenome assembly and differential coverage binning yielded 1,529 medium- to high-quality MAGs (more than 70% complete and less than 10% contaminated) from a diverse range of bacterial (1,434 genomes) and archaeal phyla (95 genomes; Extended Data Fig. 1a , Supplementary Data 3 ). The Stordalen Mire MAGs expand the number of genomes recovered from permafrost-associated soils by two orders of magnitude. Fig. 1: Genome-resolved view of the microbial communities at Stordalen Mire. a , Schematic of the permafrost thaw gradient. Permafrost is light brown, active layer is blue (saturated peat) and dark brown (non-saturated peat). b , Community profile derived from MAG abundances (rows) across the active layer metagenomes (columns) from palsa (brown), bog (green) and fen (blue) samples. Black lines divide sites and depth (E, extra-deep). Red lines separate samples taken above (left) and below (right) the water table. Numbers in parentheses show total MAGs recovered and phylogenetic gain of Stordalen MAGs compared to publicly available genomes for each phylum. Red text indicates previously poorly represented phyla. c , Shannon diversity of each sample (filled circles) or averages for the sample’s thaw stage and depth (open circles). Full size image To resolve the taxonomic distribution of the Stordalen Mire MAGs, phylogenetic trees were inferred from concatenated sets of single-copy marker genes (120 bacterial or 122 archaeal genes). The recovered MAGs spanned 30 phyla, including Bacteria belonging to Actinobacteria (385 genomes), Acidobacteria (364), Proteobacteria (205) and Chloroflexi (66), and Archaea from the Euryarchaeota (85). The Stordalen genomes substantially expand representation of several common soil-dwelling lineages (Extended Data Fig. 1 ), such as the ubiquitous Acidobacteria, for which genomic representation was increased threefold. MAGs were also recovered from many poorly characterized phyla, including 47 genomes from the bacterial candidate phylum Dormibacteraeota (AD3), 53 from Eremiobacteraeota (WPS-2), six from FCPU426 and eight archaea from the Bathyarchaeota (Extended Data Fig. 1 , Supplementary Data 10 , 11 ). The Stordalen genomes broadly represent the major groups present in the system (Extended Data Fig. 2a, b ) as well as many lineages previously detected in other permafrost-associated environments 6 , 11 . On the basis of the diversity of ribosomal protein sequences detected in the metagenomes, we conservatively estimate that more than 24,000 strains inhabit Stordalen Mire (Supplementary Note 1 ). The Stordalen MAGs represent about 60% of microorganisms in the mire at the genus level (Supplementary Note 2 ), making this, to our knowledge, the most comprehensive recovery of genomes from a complex, natural soil environment to date. Stordalen genomes were explicitly linked to the changing habitats by mapping their abundances across the thaw gradient (Fig. 1 , Supplementary Data 4 ). Communities shifted substantially between sites (Extended Data Fig. 2c ), with MAGs belonging to the Acidobacteria, Actinobacteria, Eremiobacteraeota, Alphaproteobacteria and Gammaproteobacteria predominant in the palsa and bog (5–41% of the community), whereas Deltaproteobacteria, Bacteroidetes, Chloroflexi and Ignavibacteriae were almost exclusively observed in the fen (8–14%; Extended Data Fig. 2e, f", "role": "user" }, { "content": "A University of Queensland-led international study could lead to more accurate predictions or the rate of global warming from greenhouse gas emissions produced by thawing permafrost in the next 100 years. The study of the microorganisms involved in permafrost carbon degradation links changing microbial communities and biogeochemistry to the rise of greenhouse gas emissions. It was led by Australian Centre for Ecogenomics researchers in the UQ School of Chemistry and Molecular Biosciences Dr. Ben Woodcroft, Ph.D. student Caitlin Singleton, Professor Gene Tyson and international colleagues. \"As global temperatures rise, large amounts of carbon sequestered in perennially frozen permafrost are becoming available for microbial degradation,\" Dr. Woodcroft said. \"Until now, accurate prediction of greenhouse gas emissions produced from thawing permafrost has been limited by our understanding of permafrost microbial communities and their carbon metabolisms.\" Using sequencing techniques pioneered by Professor Tyson, over 200 samples from intact, thawing and thawed permafrost sites in northern Sweden were examined. DNA sequences of more than 1500 microbial genomes all new to science and involved in complex biochemical networks were recovered. Lapporten (The Gate to Lapland) valley, situated near the study site. Credit: Caitlin Singleton The research, which included new metagenomics software run on UQ supercomputers, also implicated a number of these entirely new lineages in the production of greenhouse gases. Ms Singleton said permafrost stores around 50 per cent of the total global soil carbon (or 1580 billion tonnes). \"The Intergovernmental Panel on Climate Change report estimated that between 30 and 99 per cent of near-surface permafrost could disappear by 2100,\" she said. \"Northern permafrost wetlands contribute a significant portion of global methane emissions, particularly as collapsing permafrost can create the perfect anaerobic conditions for methane-producing microorganisms (methanogens), and their metabolic partners, to thrive. \"This is important as methane is a potent greenhouse gas—25 times more efficient at trapping the sun's radiation in our atmosphere than carbon dioxide.\" Frozen Lake Torneträsk, located next to the study site. Credit: Caitlin Singleton She said that as permafrost thaws, methane emissions increase, causing a positive feedback loop where increased atmospheric warming caused more thawing. The study is published in Nature and co-authored by researchers at The Ohio State University, Rochester Institute of Technology, Florida State University, Pacific Northwest National Laboratory, University of New Hampshire, Stockholm University, and the University of Arizona. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract As global temperatures rise, large amounts of carbon sequestered in permafrost are becoming available for microbial degradation. Accurate prediction of carbon gas emissions from thawing permafrost is limited by our understanding of these microbial communities. Here we use metagenomic sequencing of 214 samples from a permafrost thaw gradient to recover 1,529 metagenome-assembled genomes, including many from phyla with poor genomic representation. These genomes reflect the diversity of this complex ecosystem, with genus-level representatives for more than sixty per cent of the community. Meta-omic analysis revealed key populations involved in the degradation of organic matter, including bacteria whose genomes encode a previously undescribed fungal pathway for xylose degradation. Microbial and geochemical data highlight lineages that correlate with the production of greenhouse gases and indicate novel syntrophic relationships. Our findings link changing biogeochemistry to specific microbial lineages involved in carbon processing, and provide key information for predicting the effects of climate change on permafrost systems. Main Permafrost thaw induced by climate change is predicted to make up to 174 Pg of near-surface carbon (less than 3 m below the surface) available for microbial degradation by 2100 1 . Prediction of the magnitude of carbon loss as carbon dioxide (CO 2 ) or methane (CH 4 ) is hampered by our limited knowledge of microbial metabolism of organic matter in these environments. Genome-centric metagenomic analysis of microbial communities provides the necessary information to examine how specific lineages transform organic matter during permafrost thaw. However, these methods are challenged by the inherent complexity and spatial heterogeneity of near-surface soil communities that support diverse functional processes 2 , 3 , 4 . Previous metagenomic studies in permafrost-associated soils from Alaskan tundra 5 , 6 and a mineral soil permafrost 7 recovered a small number (14–33) of metagenome-assembled genomes (MAGs), which represent only a fraction of the species present in these systems. However, the ability to recover MAGs from complex microbial communities is continually improving in parallel with advances in sequencing technology and bioinformatic techniques 8 , 9 . Recovery and distribution of MAGs The discontinuous permafrost at Stordalen Mire in northern Sweden is a model Arctic peatland ecosystem for studying thaw progression 10 . To gain an understanding of the microbial communities at this site and their associated carbon metabolism, soil samples were collected from the active layer (seasonally thawed) of three sites across a thaw gradient: an intact palsa (thawed to approximately 30 cm), a partially thawed bog (approximately 60 cm), and a fully thawed fen. Although bogs and fens exist in diverse landscapes, thaw-associated shifts in hydrology cause them to be a common feature of thawing northern peatland permafrost systems (see Methods ). Triplicate soil cores and biogeochemical measurements were taken at each site from four active layer depths (near surface, mid, deep and extra-deep; 1–51 cm; Fig. 1 , Supplementary Data 1 ) over three growing seasons. In total, 1.7 Tb of metagenomic sequence data were generated from 214 samples (2–165 Gb per sample), with supporting metatranscriptomic and metaproteomic data from a subset of these samples (Supplementary Data 1 , 2 ). Metagenome assembly and differential coverage binning yielded 1,529 medium- to high-quality MAGs (more than 70% complete and less than 10% contaminated) from a diverse range of bacterial (1,434 genomes) and archaeal phyla (95 genomes; Extended Data Fig. 1a , Supplementary Data 3 ). The Stordalen Mire MAGs expand the number of genomes recovered from permafrost-associated soils by two orders of magnitude. Fig. 1: Genome-resolved view of the microbial communities at Stordalen Mire. a , Schematic of the permafrost thaw gradient. Permafrost is light brown, active layer is blue (saturated peat) and dark brown (non-saturated peat). b , Community profile derived from MAG abundances (rows) across the active layer metagenomes (columns) from palsa (brown), bog (green) and fen (blue) samples. Black lines divide sites and depth (E, extra-deep). Red lines separate samples taken above (left) and below (right) the water table. Numbers in parentheses show total MAGs recovered and phylogenetic gain of Stordalen MAGs compared to publicly available genomes for each phylum. Red text indicates previously poorly represented phyla. c , Shannon diversity of each sample (filled circles) or averages for the sample’s thaw stage and depth (open circles). Full size image To resolve the taxonomic distribution of the Stordalen Mire MAGs, phylogenetic trees were inferred from concatenated sets of single-copy marker genes (120 bacterial or 122 archaeal genes). The recovered MAGs spanned 30 phyla, including Bacteria belonging to Actinobacteria (385 genomes), Acidobacteria (364), Proteobacteria (205) and Chloroflexi (66), and Archaea from the Euryarchaeota (85). The Stordalen genomes substantially expand representation of several common soil-dwelling lineages (Extended Data Fig. 1 ), such as the ubiquitous Acidobacteria, for which genomic representation was increased threefold. MAGs were also recovered from many poorly characterized phyla, including 47 genomes from the bacterial candidate phylum Dormibacteraeota (AD3), 53 from Eremiobacteraeota (WPS-2), six from FCPU426 and eight archaea from the Bathyarchaeota (Extended Data Fig. 1 , Supplementary Data 10 , 11 ). The Stordalen genomes broadly represent the major groups present in the system (Extended Data Fig. 2a, b ) as well as many lineages previously detected in other permafrost-associated environments 6 , 11 . On the basis of the diversity of ribosomal protein sequences detected in the metagenomes, we conservatively estimate that more than 24,000 strains inhabit Stordalen Mire (Supplementary Note 1 ). The Stordalen MAGs represent about 60% of microorganisms in the mire at the genus level (Supplementary Note 2 ), making this, to our knowledge, the most comprehensive recovery of genomes from a complex, natural soil environment to date. Stordalen genomes were explicitly linked to the changing habitats by mapping their abundances across the thaw gradient (Fig. 1 , Supplementary Data 4 ). Communities shifted substantially between sites (Extended Data Fig. 2c ), with MAGs belonging to the Acidobacteria, Actinobacteria, Eremiobacteraeota, Alphaproteobacteria and Gammaproteobacteria predominant in the palsa and bog (5–41% of the community), whereas Deltaproteobacteria, Bacteroidetes, Chloroflexi and Ignavibacteriae were almost exclusively observed in the fen (8–14%; Extended Data Fig. 2e, f<|im_end|> <|im_start|>assistant A University of Queensland-led international study could lead to more accurate predictions or the rate of global warming from greenhouse gas emissions produced by thawing permafrost in the next 100 years. The study of the microorganisms involved in permafrost carbon degradation links changing microbial communities and biogeochemistry to the rise of greenhouse gas emissions. It was led by Australian Centre for Ecogenomics researchers in the UQ School of Chemistry and Molecular Biosciences Dr. Ben Woodcroft, Ph.D. student Caitlin Singleton, Professor Gene Tyson and international colleagues. "As global temperatures rise, large amounts of carbon sequestered in perennially frozen permafrost are becoming available for microbial degradation," Dr. Woodcroft said. "Until now, accurate prediction of greenhouse gas emissions produced from thawing permafrost has been limited by our understanding of permafrost microbial communities and their carbon metabolisms." Using sequencing techniques pioneered by Professor Tyson, over 200 samples from intact, thawing and thawed permafrost sites in northern Sweden were examined. DNA sequences of more than 1500 microbial genomes all new to science and involved in complex biochemical networks were recovered. Lapporten (The Gate to Lapland) valley, situated near the study site. Credit: Caitlin Singleton The research, which included new metagenomics software run on UQ supercomputers, also implicated a number of these entirely new lineages in the production of greenhouse gases. Ms Singleton said permafrost stores around 50 per cent of the total global soil carbon (or 1580 billion tonnes). "The Intergovernmental Panel on Climate Change report estimated that between 30 and 99 per cent of near-surface permafrost could disappear by 2100," she said. "Northern permafrost wetlands contribute a significant portion of global methane emissions, particularly as collapsing permafrost can create the perfect anaerobic conditions for methane-producing microorganisms (methanogens), and their metabolic partners, to thrive. "This is important as methane is a potent greenhouse gas—25 times more efficient at trapping the sun's radiation in our atmosphere than carbon dioxide." Frozen Lake Torneträsk, located next to the study site. Credit: Caitlin Singleton She said that as permafrost thaws, methane emissions increase, causing a positive feedback loop where increased atmospheric warming caused more thawing. The study is published in Nature and co-authored by researchers at The Ohio State University, Rochester Institute of Technology, Florida State University, Pacific Northwest National Laboratory, University of New Hampshire, Stockholm University, and the University of Arizona. <|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 Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer–promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type–specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS. Introduction Williams syndrome (WS), also known as Williams-Beuren syndrome, is a rare genetic multi-systemic neurodevelopmental disorder caused by a pathological micro-deletion of 26–28 genes in the 7q11.23 region, also referred to as the WS critical region (WSCR) [ 1 , 2 , 3 ]. WS is characterized by social abnormalities, such as hyper-sociability, striking social fearlessness, distinct over-friendliness, and excessive empathy, along with poor social judgment ability [ 1 , 4 ]. WS is also associated with distinctive facial features [ 5 ], cardiovascular abnormalities [ 6 , 7 , 8 ], endocrine imbalances [ 9 , 10 ], severe visuospatial construction weakness [ 11 , 12 , 13 ] and intellectual disability [ 13 , 14 , 15 , 16 , 17 ]. The WSCR can undergo deletion, duplication, or inversion, with such aberrations having been associated with other disorders, such as autism [ 18 , 19 ] and schizophrenia [ 19 , 20 ]. Consistent with these phenotypes, previous studies revealed genome-wide transcriptional disruption in various cell types and organs of individuals with WS [ 21 , 22 , 23 ]. Specifically, we previously showed reduction in myelin-related gene transcript levels, OL numbers, neuronal myelination [ 21 ] and white matter properties [ 24 , 25 ] in individuals with WS, as compared to TD controls. Although the molecular basis for the neurological phenotypes seen in WS has been intensively studied, the potential effect of WSCR deletion on epigenetic modifications remains poorly understood. To date, WS has been largely studied as a monogenic disease using mouse models in which the roles of individual genes were considered. While this approach is important for our understanding of each of these genes, multigenic mechanisms that modulate relevant gene expression and the subsequent effects on brain development are still largely unknown. Such multigenic effects could be regulated by epigenetic modifications which affect transcription without altering the underlying DNA sequences. Such modifications could involve several processes, including DNA methylation, mRNA degradation via non-coding RNAs, and/or post-translational modifications of histones, DNA-associated chromosomal proteins [ 26 , 27 ]. Although reversible, epigenetic changes are typically stable, presenting patterns that vary across cell types and throughout development [ 28 ]. It is now evident that errors in the epigenetic code, such as modifying the wrong gene or failure to add an epigenetic modification, can lead to abnormal gene activity, and thus could contribute to alterations in phenotype or to pathologies [ 29 ]. Interestingly, deletions of several genes in the WSCR locus were linked to epigenetic regulation [ 22 , 23 ]. For example, WBSCR22 , BAZ1B , and BCL7B , corresponding to WSCR genes, encode proteins involved in chromatin remodeling [ 30 , 31 , 32 , 33 ], while the product of NSUN5 has been shown to act as an RNA methyltransferase [ 34 ]. Moreover, two additional WSCR genes, GTF2I and GTF2IRD1 , encode proteins that have been shown to functionally interact with several regulatory complexes [ 35 , 36 , 37 , 38 , 39 ], chromatin and DNA modifiers [ 40 , 41 ]. These include histone deacetylases (HDAC1-3) [ 42 ], lysine-specific demethylase 1 (LSD1), components of the repressive poly-comb complex [ 43 , 44 ], and DNA-methyltransferase 3-like protein (DNMT3L) [ 45 ]. DNA methylation is one of the better-known epigenetic modifications and has been widely studied in the context of numerous biological and brain functions, including embryonic development [ 46 , 47 , 48 , 49 ], cell differentiation [ 50 , 51 , 52 ], neurodevelopment [ 53 , 54 , 55 ], myelination [ 50 , 52 , 56 , 57 , 58 , 59 , 60 ], neurogenesis and cell identity [ 46 , 47 , 61 , 62 ]. Methylation of mammalian genomes occurs predominantly at cytosines adjacent to guanines (‘CpG’ sites) [ 61 , 63 ]. As a result, the accessibility of the transcriptional machinery to a particular gene or given regulatory element (RE) may be altered. While de novo DNA methylation is predominantly regulated by DNA methyltransferase (DNMT) family members, active de-methylation is regulated by members of the ten-eleven translocase (TET) family of enzymes. Aberrant DNA methylation has been implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) [ 64 ] and schizophrenia [ 65 ]. Previous work by Strong et al . examined DNA methylation patterns from blood samples taken", "role": "user" }, { "content": "A new study by the Tel Aviv and Hebrew Universities found that abnormal processes lead to disruption in the expression of genes essential for brain development in people suffering from Williams syndrome—a rare, multisystem genetic syndrome that causes disorders in brain development. According to the researchers, \"Our findings may contribute to the future development of targeted treatments that will enable normal expression of the affected genes we identified in the research.\" The research was led by Dr. Boaz Barak from the School of Psychological Sciences and the Sagol School of Neuroscience at Tel Aviv University and Dr. Asaf Marco from the Faculty of Agriculture, Food and Environment of the Hebrew University. Also participating in the research were Dr. Sari Trangle, Mr. Gilad Levy and Ms. Ela Bar from Dr. Barak's laboratory, and Dr. Tali Rosenberg and Ms. Hadar Parnas from Dr. Marco's laboratory. The research findings were published in Molecular Psychiatry. Dr. Barak says, \"Williams syndrome is a rare, multisystem genetic syndrome that includes disorders in brain development that lead to heightened social interactions, mental retardation, and other characteristic features. Past research has revealed that 25 genes are missing from the DNA on chromosome number seven of people with Williams syndrome, and the study of the syndrome to date has mainly focused on those missing genes and their functions.\" \"We wanted to examine whether the syndrome is also characterized by defects in the genomes contained in brain cells which prevent the proper expression of essential genes. Specifically, we asked: Is it possible that certain genes are not expressed properly in the brains of people with Williams syndrome due to the phenomenon of methylation—when a molecule known as a methyl group is located on a certain gene that is present in the genome, preventing it from expressing itself properly?\" To illustrate the phenomenon, Dr. Barak took for example an instruction book in which some of its pages were torn out (as a parallel to the missing genes), and as a result of the lack of these pages, anyone following the instructions would make mistakes. Similarly, hiding some of the letters in the pages left in the book with a black marker would result in instructions being corrupted, just like methylation on an existing gene disrupts its expression. The researchers emphasize that methylation is in many cases a normal mechanism in the cells of the body, as its role is to prevent expression of certain genes when appropriate. However, when there are disruptions in the correct application of methylation, the abnormal expression of the genes may lead to impairments in cell function, and subsequently to damage to various organs, including damage to normal brain development, as found in the current study. As part of the study, the researchers examined human brain tissues taken from adults with and without Williams syndrome who died of causes unrelated to the syndrome and donated their brains to science. Dr. Barak explains, \"We focused on samples from the frontal lobe, the area of the brain that is responsible for brain functions such as cognition and decision-making. In a previous study, we located in this area damage to the characteristics of the nerve cells and the cells that support nerve cell activity in people with Williams syndrome.\" \"In this study, we examined all the genes in all the cells of the frontal lobe to determine whether there are genes in people with Williams syndrome that have undergone abnormal methylation processes, i.e., increased or decreased gene silencing compared to a brain with typical development.\" The researchers found that indeed in people with Williams syndrome abnormal methylation does exist in this area of the brain, resulting in disruption of the normal expression of many genes related to the normal development of the brain's neural functions, such as regulation of social behavior (people with Williams syndrome are known to be overly friendly), cognition, plasticity of the brain, and cell survival. Dr. Marco says, \"We uncovered significant information about the defective expression of genes in people with Williams syndrome, even though these genes are fully present in the genome of the brain cells—until now it was not known that these abnormally-regulated genes are involved in the syndrome. In addition, one of our main findings is that the disruptions in methylation do not have to appear near the gene whose function is impaired, and sometimes the disruptions are located at a great distance from it.\" \"This information is critical because it allows us to better understand the spatial organization of DNA and its effect on gene control. Moreover, since we know of enzymes that are able to remove or add methyl molecules, the next challenge will be to precisely direct those enzymes to the disrupted sites identified in our research, with the aim of allowing the genes to be properly expressed.\" Dr. Barak concludes, \"Our research revealed new factors related to the disabilities that characterize Williams syndrome. Instead of focusing on the effects of the missing gene, as has been done until now, we shed light on many more genes that are expressed in a defective manner. Building on our findings, it will be possible to focus future efforts on the development of targeted treatments that will reach the disrupted sites that we identified in the study in order to 'correct' the defective expressions.\" ", "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 Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer–promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type–specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS. Introduction Williams syndrome (WS), also known as Williams-Beuren syndrome, is a rare genetic multi-systemic neurodevelopmental disorder caused by a pathological micro-deletion of 26–28 genes in the 7q11.23 region, also referred to as the WS critical region (WSCR) [ 1 , 2 , 3 ]. WS is characterized by social abnormalities, such as hyper-sociability, striking social fearlessness, distinct over-friendliness, and excessive empathy, along with poor social judgment ability [ 1 , 4 ]. WS is also associated with distinctive facial features [ 5 ], cardiovascular abnormalities [ 6 , 7 , 8 ], endocrine imbalances [ 9 , 10 ], severe visuospatial construction weakness [ 11 , 12 , 13 ] and intellectual disability [ 13 , 14 , 15 , 16 , 17 ]. The WSCR can undergo deletion, duplication, or inversion, with such aberrations having been associated with other disorders, such as autism [ 18 , 19 ] and schizophrenia [ 19 , 20 ]. Consistent with these phenotypes, previous studies revealed genome-wide transcriptional disruption in various cell types and organs of individuals with WS [ 21 , 22 , 23 ]. Specifically, we previously showed reduction in myelin-related gene transcript levels, OL numbers, neuronal myelination [ 21 ] and white matter properties [ 24 , 25 ] in individuals with WS, as compared to TD controls. Although the molecular basis for the neurological phenotypes seen in WS has been intensively studied, the potential effect of WSCR deletion on epigenetic modifications remains poorly understood. To date, WS has been largely studied as a monogenic disease using mouse models in which the roles of individual genes were considered. While this approach is important for our understanding of each of these genes, multigenic mechanisms that modulate relevant gene expression and the subsequent effects on brain development are still largely unknown. Such multigenic effects could be regulated by epigenetic modifications which affect transcription without altering the underlying DNA sequences. Such modifications could involve several processes, including DNA methylation, mRNA degradation via non-coding RNAs, and/or post-translational modifications of histones, DNA-associated chromosomal proteins [ 26 , 27 ]. Although reversible, epigenetic changes are typically stable, presenting patterns that vary across cell types and throughout development [ 28 ]. It is now evident that errors in the epigenetic code, such as modifying the wrong gene or failure to add an epigenetic modification, can lead to abnormal gene activity, and thus could contribute to alterations in phenotype or to pathologies [ 29 ]. Interestingly, deletions of several genes in the WSCR locus were linked to epigenetic regulation [ 22 , 23 ]. For example, WBSCR22 , BAZ1B , and BCL7B , corresponding to WSCR genes, encode proteins involved in chromatin remodeling [ 30 , 31 , 32 , 33 ], while the product of NSUN5 has been shown to act as an RNA methyltransferase [ 34 ]. Moreover, two additional WSCR genes, GTF2I and GTF2IRD1 , encode proteins that have been shown to functionally interact with several regulatory complexes [ 35 , 36 , 37 , 38 , 39 ], chromatin and DNA modifiers [ 40 , 41 ]. These include histone deacetylases (HDAC1-3) [ 42 ], lysine-specific demethylase 1 (LSD1), components of the repressive poly-comb complex [ 43 , 44 ], and DNA-methyltransferase 3-like protein (DNMT3L) [ 45 ]. DNA methylation is one of the better-known epigenetic modifications and has been widely studied in the context of numerous biological and brain functions, including embryonic development [ 46 , 47 , 48 , 49 ], cell differentiation [ 50 , 51 , 52 ], neurodevelopment [ 53 , 54 , 55 ], myelination [ 50 , 52 , 56 , 57 , 58 , 59 , 60 ], neurogenesis and cell identity [ 46 , 47 , 61 , 62 ]. Methylation of mammalian genomes occurs predominantly at cytosines adjacent to guanines (‘CpG’ sites) [ 61 , 63 ]. As a result, the accessibility of the transcriptional machinery to a particular gene or given regulatory element (RE) may be altered. While de novo DNA methylation is predominantly regulated by DNA methyltransferase (DNMT) family members, active de-methylation is regulated by members of the ten-eleven translocase (TET) family of enzymes. Aberrant DNA methylation has been implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) [ 64 ] and schizophrenia [ 65 ]. Previous work by Strong et al . examined DNA methylation patterns from blood samples taken<|im_end|> <|im_start|>assistant A new study by the Tel Aviv and Hebrew Universities found that abnormal processes lead to disruption in the expression of genes essential for brain development in people suffering from Williams syndrome—a rare, multisystem genetic syndrome that causes disorders in brain development. According to the researchers, "Our findings may contribute to the future development of targeted treatments that will enable normal expression of the affected genes we identified in the research." The research was led by Dr. Boaz Barak from the School of Psychological Sciences and the Sagol School of Neuroscience at Tel Aviv University and Dr. Asaf Marco from the Faculty of Agriculture, Food and Environment of the Hebrew University. Also participating in the research were Dr. Sari Trangle, Mr. Gilad Levy and Ms. Ela Bar from Dr. Barak's laboratory, and Dr. Tali Rosenberg and Ms. Hadar Parnas from Dr. Marco's laboratory. The research findings were published in Molecular Psychiatry. Dr. Barak says, "Williams syndrome is a rare, multisystem genetic syndrome that includes disorders in brain development that lead to heightened social interactions, mental retardation, and other characteristic features. Past research has revealed that 25 genes are missing from the DNA on chromosome number seven of people with Williams syndrome, and the study of the syndrome to date has mainly focused on those missing genes and their functions." "We wanted to examine whether the syndrome is also characterized by defects in the genomes contained in brain cells which prevent the proper expression of essential genes. Specifically, we asked: Is it possible that certain genes are not expressed properly in the brains of people with Williams syndrome due to the phenomenon of methylation—when a molecule known as a methyl group is located on a certain gene that is present in the genome, preventing it from expressing itself properly?" To illustrate the phenomenon, Dr. Barak took for example an instruction book in which some of its pages were torn out (as a parallel to the missing genes), and as a result of the lack of these pages, anyone following the instructions would make mistakes. Similarly, hiding some of the letters in the pages left in the book with a black marker would result in instructions being corrupted, just like methylation on an existing gene disrupts its expression. The researchers emphasize that methylation is in many cases a normal mechanism in the cells of the body, as its role is to prevent expression of certain genes when appropriate. However, when there are disruptions in the correct application of methylation, the abnormal expression of the genes may lead to impairments in cell function, and subsequently to damage to various organs, including damage to normal brain development, as found in the current study. As part of the study, the researchers examined human brain tissues taken from adults with and without Williams syndrome who died of causes unrelated to the syndrome and donated their brains to science. Dr. Barak explains, "We focused on samples from the frontal lobe, the area of the brain that is responsible for brain functions such as cognition and decision-making. In a previous study, we located in this area damage to the characteristics of the nerve cells and the cells that support nerve cell activity in people with Williams syndrome." "In this study, we examined all the genes in all the cells of the frontal lobe to determine whether there are genes in people with Williams syndrome that have undergone abnormal methylation processes, i.e., increased or decreased gene silencing compared to a brain with typical development." The researchers found that indeed in people with Williams syndrome abnormal methylation does exist in this area of the brain, resulting in disruption of the normal expression of many genes related to the normal development of the brain's neural functions, such as regulation of social behavior (people with Williams syndrome are known to be overly friendly), cognition, plasticity of the brain, and cell survival. Dr. Marco says, "We uncovered significant information about the defective expression of genes in people with Williams syndrome, even though these genes are fully present in the genome of the brain cells—until now it was not known that these abnormally-regulated genes are involved in the syndrome. In addition, one of our main findings is that the disruptions in methylation do not have to appear near the gene whose function is impaired, and sometimes the disruptions are located at a great distance from it." "This information is critical because it allows us to better understand the spatial organization of DNA and its effect on gene control. Moreover, since we know of enzymes that are able to remove or add methyl molecules, the next challenge will be to precisely direct those enzymes to the disrupted sites identified in our research, with the aim of allowing the genes to be properly expressed." Dr. Barak concludes, "Our research revealed new factors related to the disabilities that characterize Williams syndrome. Instead of focusing on the effects of the missing gene, as has been done until now, we shed light on many more genes that are expressed in a defective manner. Building on our findings, it will be possible to focus future efforts on the development of targeted treatments that will reach the disrupted sites that we identified in the study in order to 'correct' the defective expressions." <|im_end|>

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