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The IBEX Imaging Knowledge-Base: A Community Resource Enabling Adoption and development of Immunofluoresence Imaging Methods

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arXiv 2024年

作者： Yaniv, Ziv Anidi, Ifeanyichukwu U. Arakkal, Leanne Arroyo-Mejías, Armando J. Beuschel, Rebecca T. Börner, Katy Chu, Colin J. Clark, Beatrice Clatworthy, Menna R. Colautti, Jake Coscia, Fabian Croteau, Joshua Denha, Saven Dever, Rose Dutra, Walderez O. Fritzsche, Sonja Fullam, Spencer Gerner, Michael Y. Gola, Anita Gollob, Kenneth J. Hernandez, Jonathan M. Hor, Jyh Liang Ichise, Hiroshi Jing, Zhixin Jonigk, Danny Kandov, Evelyn Kastenmüller, Wolfgang Koenig, Joshua F.E. Kothurkar, Aanandita Kortekaas, Rosa K. Kreins, Alexandra Y. Lamborn, Ian T. Lin, Yuri Morais, Katia Luciano Pereira Lunich, Aleksandra Luz, Jean C.S. MacDonald, Ryan B. Makranz, Chen Maltez, Vivien I. McDonough, John E. Moriarty, Ryan V. Ocampo-Godinez, Juan M. Olyntho, Vitoria M. Oxenius, Annette Padhan, Kartika Remmert, Kirsten Richoz, Nathan Schrom, Edward C. Shang, Wanjing Shi, Lihong Shih, Rochelle M. Speranza, Emily Stierli, Salome Teichmann, Sarah A. Veres, Tibor Z. Vierhout, Megan Wachter, Brianna T. Williams, Margaret Zangger, Nathan Germain, Ronald N. Radtke, Andrea J. Bioinformatics and Computational Bioscience Branch National Institute of Allergy and Infectious Diseases National Institutes of Health BethesdaMD United States Critical Care Medicine and Pulmonary Branch National Heart Lung and Blood Institute National Institutes of Health BethesdaMD United States Lymphocyte Biology Section Laboratory of Immune System Biology NIAID NIH BethesdaMD United States Department of Intelligent Systems Engineering Indiana University BloomingtonIN United States UCL Institute of Ophthalmology NIHR Moorfields Biomedical Research Centre London United Kingdom Cambridge Institute for Therapeutic Immunology and Infectious Diseases University of Cambridge Department of Medicine Molecular Immunity Unit Laboratory of Molecular Biology Cambridge United Kingdom McMaster Immunology Research Centre Schroeder Allergy and Immunology Research Institute Department of Medicine Faculty of Health Sciences McMaster University HamiltonON Canada Spatial Proteomics Group Berlin Germany Department of Business Development BioLegend Inc. San DiegoCA United States Functional Immunogenomics Unit National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health BethesdaMD United States Laboratory of Cell-Cell Interactions Department of Morphology Institute of Biological Sciences Universidade Federal de Minas Gerais MG Belo Horizonte Brazil Division of Rheumatology Rush University Medical Center ChicagoIL United States Department of Immunology University of Washington School of Medicine SeattleWA United States Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development The Rockefeller University New YorkNY United States Hospital Israelita Albert Einstein SP Sao Paulo Brazil Surgical Oncology Program National Cancer Institute National Institutes of Health BethesdaMD United States Institute of Pathology Aachen Medical University RWTH Aachen Aachen Germany Hannover Germany Würzburg Institute

The iterative bleaching extends multiplexity (IBEX) Knowledge-Base is a central portal for researchers adopting IBEX and related 2D and 3D immunofluorescence imaging methods. The design of the Knowledge-Base is modeled after efforts in the open-source software community and includes three facets: a development platform (GitHub), static website, and service for data archiving. The Knowledge-Base facilitates the practice of open science throughout the research life cycle by providing validation data for recommended and non-recommended reagents, e.g., primary and secondary antibodies. In addition to reporting negative data, the Knowledge-Base empowers method adoption and evolution by providing a venue for sharing protocols, videos, datasets, software, and publications. A dedicated discussion forum fosters a sense of community among researchers while addressing questions not covered in published manuscripts. Together, scientists from around the world are advancing scientific discovery at a faster pace, reducing wasted time and effort, and instilling greater confidence in the resulting data. © 2024, CC BY.

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Paddy rice methane emissions across Monsoon Asia

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Remote Sensing of Environment 2023年 284卷

作者： Ouyang, Zutao Jackson, Robert B. McNicol, Gavin Fluet-Chouinard, Etienne Runkle, Benjamin R.K. Papale, Dario Knox, Sara H. Cooley, Sarah Delwiche, Kyle B. Feron, Sarah Irvin, Jeremy Andrew Malhotra, Avni Muddasir, Muhammad Sabbatini, Simone Alberto, Ma. Carmelita R. Cescatti, Alessandro Chen, Chi-Ling Dong, Jinwei Fong, Bryant N. Guo, Haiqiang Hao, Lu Iwata, Hiroki Jia, Qingyu Ju, Weimin Kang, Minseok Li, Hong Kim, Joon Reba, Michele L. Nayak, Amaresh Kumar Roberti, Debora Regina Ryu, Youngryel Swain, Chinmaya Kumar Tsuang, Benjei Xiao, Xiangming Yuan, Wenping Zhang, Geli Zhang, Yongguang Department of Earth System Science Stanford University StanfordCA United States Woods Institute for the Environment Stanford University StanfordCA United States Precourt Institute for Energy Stanford University StanfordCA United States Department of Earth and Environmental Sciences University of Illinois Chicago ChicagoIL United States Department of Biological and Agricultural Engineering University of Arkansas FayettevilleAR United States University of Tuscia Viterbo Italy IAFES division Viterbo Italy Department of Geography The University of British Columbia VancouverBC Canada Department of Geography University of Oregon EugeneOR United States Department of Environmental Science Policy And Management UC Berkeley BerkeleyCA United States Campus Fryslan University of Groningen Groningen Netherlands Department of Computer Science Stanford University StanfordCA United States Department of Geography University of Zurich Zurich Switzerland International Rice Research Institute Laguna Philippines Ispra Italy Taiwan Agricultural Research Institute Taichung Wufeng Taiwan Institute of Geographic Sciences and Natural Resources Research Chinese Academy of Sciences Beijing China USDA ARS Delta Water Management Research Unit JonesboroAR United States Fudan University Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering and Coastal Ecosystems Research Station of the Yangtze River Estuary Shanghai China / Jiangsu Key Laboratory of Agricultural Meteorology Nanjing University of Information Science and Technology Nanjing China Department of Environmental Science Shinshu University Matsumoto Japan China Meteorological Administration Institute of Atmospheric Environment Shenyang China International Institute for Earth System Sciences Jiangsu Center for Collaborative Innovation in Geographical Information Resource Development and Application Nanjing University Jiangsu Nanjing210023 China National Center for AgroM

Although rice cultivation is one of the most important agricultural sources of methane (CH4) and contributes ∼8% of total global anthropogenic emissions, large discrepancies remain among estimates of global CH4 emissions from rice cultivation (ranging from 18 to 115 Tg CH4 yr−1) due to a lack of observational constraints. The spatial distribution of paddy-rice emissions has been assessed at regional-to-global scales by bottom-up inventories and land surface models over coarse spatial resolution (e.g., > 0.5°) or spatial units (e.g., agro-ecological zones). However, high-resolution CH4 flux estimates capable of capturing the effects of local climate and management practices on emissions, as well as replicating in situ data, remain challenging to produce because of the scarcity of high-resolution maps of paddy-rice and insufficient understanding of CH4 predictors. Here, we combine paddy-rice methane-flux data from 23 global eddy covariance sites and MODIS remote sensing data with machine learning to 1) evaluate data-driven model performance and variable importance for predicting rice CH4 fluxes;and 2) produce gridded up-scaling estimates of rice CH4 emissions at 5000-m resolution across Monsoon Asia, where ∼87% of global rice area is cultivated and ∼ 90% of global rice production occurs. Our random-forest model achieved Nash-Sutcliffe Efficiency values of 0.59 and 0.69 for 8-day CH4 fluxes and site mean CH4 fluxes respectively, with land surface temperature, biomass and water-availability-related indices as the most important predictors. We estimate the average annual (winter fallow season excluded) paddy rice CH4 emissions throughout Monsoon Asia to be 20.6 ± 1.1 Tg yr−1 for 2001–2015, which is at the lower range of previous inventory-based estimates (20–32 CH4 Tg yr−1). Our estimates also suggest that CH4 emissions from paddy rice in this region have been declining from 2007 through 2015 following declines in both paddy-rice growing area and emission rates per unit

关键词： Climate change

development and characterization of an innovative Flavobacterium oreochromis antigen-encapsulated hydrogel bead for enhancing oral vaccine delivery in hybrid red tilapia ( Oreochromis spp.)

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Fish & Shellfish Immunology 2025年 165卷 110483页

作者： Patcharapong Thangsunan Pattanapong Thangsunan Thanisorn Mahatnirunkul Wararut Buncharoen Kanokporn Saenphet Supap Saenphet Jitraporn Phaksopa Kim D. Thompson Prapansak Srisapoome Benchawan Kumwan Pakapon Meachasompop Nuttee Suree Anurak Uchuwittayakul Office of Research Administration Chiang Mai University Chiang Mai 50200 Thailand Division of Biochemistry and Biochemical Innovation Department of Chemistry Faculty of Science Chiang Mai University Chiang Mai 50200 Thailand Center of Excellence for Innovation in Chemistry And Research Laboratory on Advanced Materials for Sensor and Biosensor Innovation Material Science Research Center Faculty of Science Chiang Mai University Chiang Mai 50200 Thailand National Nanotechnology Center National Science and Technology Development Agency 111 Thailand Science Park Phahonyothin Road Khlong Luang Pathum Thani 12120 Thailand Department of Biology Faculty of Science Chiang Mai University Chiang Mai 50200 Thailand Department of Marine Science Faculty of Fisheries Kasetsart University Bangkok 10900 Thailand Moredun Research Institute Pentlands Science Park Penicuik EH26 0PZ United Kingdom Special Research Incubator Unit for Development and Application of Vaccine Delivery Systems for Aquatic Animals Department of Aquaculture Faculty of Fisheries Kasetsart University Bangkok 10900 Thailand Laboratory of Aquatic Animal Health Management Department of Aquaculture Faculty of Fisheries Kasetsart University Bangkok 10900 Thailand Center of Excellence in Aquatic Animal Health Management Faculty of Fisheries Kasetsart University Bangkok 10900 Thailand

Traditional oral vaccines often face several challenges, such as antigen degradation and poor immune activation due to harsh gastrointestinal conditions. To address this, an effective oral vaccine was developed using hydrogel beads made of sodium alginate (SA), calcium bentonite (BN), and chitosan (CS) to generate microspheres that can encapsulate F. oreochromis (Fo) cells as an oral vaccine (SA/BN/CS hydrogel Fo -OV) for hybrid red tilapia. This study demonstrates that oral administration of a Fo -encapsulated hydrogel bead vaccine ( Fo- OV hydrogel) can effectively protect the antigen from gastric degradation and release it to fish intestine, as indicated by in vitro studies showing color and structural changes under different pH conditions, allowing the controlled antigen release. This led to significant enhancements in both systemically and predominantly mucosal immune responses in hybrid red tilapia ( Oreochromis spp.) after 14 and 28 days post consecutive 7-day vaccination. The vaccine increased the specific IgM antibody to F. oreochromis in serum and mucosal tissues, and increased the expression of immunoglobulin repertoire genes, IgM , IgT , and IgD in mucosal tissues, indicating activation of the fish immune system. Histological examinations revealed the beneficial changes in the intestinal mucosa by increasing the thickness of lamina propria and causing an increasing number of Goblet cells without any pathological abnormalities in the liver or intestines. Moreover, the Fo -OV hydrogel group showed significantly higher survival rates after the challenge with F. oreochromis than control groups and traditional formalin-killed Fo vaccine. These findings suggest that the hydrogel formulation can protect the antigen from degradation and enhance their uptake by mucosal-associated lymphoid tissues (MALTs), leading to stronger and more specific immune responses. The outcome of this research could be an invaluable tool as the potential application of hydrogel-based

关键词： F. oreochromis Hybrid red tilapia Hydrogel vaccine Mucosal immune responses Oral vaccines

The IBEX Knowledge-Base: Achieving more together with open science

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arXiv 2024年

作者： Radtke, Andrea J. Anidi, Ifeanyichukwu Arakkal, Leanne Arroyo-Mejias, Armando Beuschel, Rebecca T. Börner, Katy Chu, Colin J. Clark, Beatrice Clatworthy, Menna R. Colautti, Jake Croteau, Joshua Denha, Saven Dever, Rose Dutra, Walderez O. Fritzsche, Sonja Fullam, Spencer Gerner, Michael Y. Gola, Anita Gollob, Kenneth J. Hernandez, Jonathan M. Hor, Jyh Liang Ichise, Hiroshi Jing, Zhixin Jonigk, Danny Kandov, Evelyn Kastenmüller, Wolfgang Koenig, Joshua F.E. Kothurkar, Aanandita Kreins, Alexandra Y. Lamborn, Ian Lin, Yuri Morais, Katia Luciano Pereira Lunich, Aleksandra Luz, Jean C.S. MacDonald, Ryan B. Makranz, Chen Maltez, Vivien I. Moriaty, Ryan V. Ocampo-Godinez, Juan M. Olyntho, Vitoria M. Padhan, Kartika Remmert, Kirsten Richoz, Nathan Schrom, Edward C. Shang, Wanjing Shi, Lihong Shih, Rochelle M. Speranza, Emily Stierli, Salome Teichmann, Sarah A. Veres, Tibor Z. Vierhout, Megan Wachter, Brianna T. Wade-Vallance, Adam K. Williams, Margaret Zangger, Nathan Germain, Ronald N. Yaniv, Ziv Lymphocyte Biology Section Center for Advanced Tissue Imaging Laboratory of Immune System Biology National Institute of Allergy and Infectious Diseases National Institutes of Health BethesdaMD United States Critical Care Medicine and Pulmonary Branch National Heart Lung and Blood Institute National Institutes of Health BethesdaMD United States Lymphocyte Biology Section Laboratory of Immune System Biology National Institute of Allergy and Infectious Diseases National Institutes of Health BethesdaMD United States Department of Intelligent Systems Engineering Indiana University BloomingtonIN United States UCL Institute of Ophthalmology NIHR Moorfields Biomedical Research Centre London United Kingdom Cambridge Institute for Therapeutic Immunology and Infectious Diseases University of Cambridge Department of Medicine Molecular Immunity Unit Laboratory of Molecular Biology Cambridge United Kingdom McMaster Immunology Research Centre Schroeder Allergy and Immunology Research Institute Department of Medicine Faculty of Health Sciences McMaster University HamiltonON Canada Department of Business Development BioLegend Inc. San DiegoCA United States Functional Immunogenomics Unit National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health BethesdaMD United States Laboratory of Cell-Cell Interactions Department of Morphology Institute of Biological Sciences Universidade Federal de Minas Gerais MG Belo Horizonte Brazil Spatial Proteomics Group Berlin Germany Division of Rheumatology Rush University Medical Center ChicagoIL United States Department of Immunology University of Washington School of Medicine SeattleWA United States Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development The Rockefeller University New YorkNY United States Hospital Israelita Albert Einstein SP Sao Paulo Brazil Surgical Oncology Program National Cancer Institute National Institutes of Health BethesdaMD United St

Iterative Bleaching Extends multipleXity (IBEX) is a versatile method for highly multiplexed imaging of diverse tissues. Based on open science principles, we created the IBEX Knowledge-Base, a resource for reagents, p... 详细信息

关键词： Cleaning

The 2022 report of the Lancet Countdown on health and climate change: health at the mercy of fossil fuels (vol 400, pg 1619, 2022)

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LANCET 2022年第10365期400卷 1766-1766页

作者： Romanello, M. Di Napoli, C. Drummond, P. Institute for Global Health University College London London UK School of Agriculture Policy and Development University of Reading Reading UK Institute for Sustainable Resources University College London London UK Department of Global Health Centre for Health and the Global Environment University of Washington Seattle WA USA UCL Energy Institute University College London London UK Department of Health Sciences University of York York UK Department of Meteorology University of Reading Reading UK Institute for Risk and Disaster Reduction University College London London UK School of Earth and Environment University of Leeds Leeds UK Centre on Climate Change and Planetary Health London School of Hygiene & Tropical Medicine London UK School of Population Health University of Melbourne Melbourne VIC Australia Department of Earth System Science Tsinghua University Beijing China Mercator Research Institute on Global Commons and Climate Change Berlin Germany Department of Environment Climate Change and Health World Health Organization Geneva Switzerland Institute of Environmental Sciences University of Geneva Geneva Switzerland Cardiovascular Epidemiology Unit Department of Public Health & Primary Care University of Cambridge Cambridge UK School of Government University of Birmingham Birmingham UK Economic Analysis of Climate Impacts and Policy Division Centro Euro-Mediterraneo sui Cambiamenti Climatici Venice Italy Institute for Environmental Design and Engineering University College London London UK Natural Resources Institute University of Greenwich London UK Department of Environmental Health Sciences and Yale Center on Climate Change and Health Yale University New Haven CT USA Department of Civil and Environmental Engineering Northeastern University Boston MA USA Department of Fish and Wildlife Conservation Virginia Polytechnic Institute and State University Blacksburg VA USA Department of Geography University College London London UK NU

With advancements in the science of detection and attribution studies, the influence of climate change over many events has now been quantified. Because of the rapidly increasing temperatures, vulnerable populations (adults older than 65 years, and children younger than one year of age) were exposed to 3·7 billion more heatwave days in 2021 than annually in 1986–2005 (indicator 1.1.2), and heat-related deaths increased by 68% between 2000–04 and 2017–21 (indicator 1.1.5), a death toll that was significantly exacerbated by the confluence of the COVID-19 pandemic. Despite the local cooling and overall health benefits of urban greenspaces, only 277 (27%) of 1038 global urban centres were at least moderately green in 2021 (indicator 2.2.3), and the number of households with air conditioning increased by 66% from 2000 to 2020, a maladaptive response that worsens the energy crisis and further increases urban heat, air pollution, and greenhouse gas emissions. [...]millions of people do not have access to the energy needed to keep their homes at healthy temperatures, preserve food and medication, and meet the seventh Sustainable development Goal (to ensure access to affordable, reliable, sustainable, and modern energy for all). Aggravating this situation even further, governments continue to incentivise fossil fuel production and consumption: 69 (80%) of 86 countries reviewed had net-negative carbon prices (ie, provided a net subsidy to fossil fuels) for a net total of US$400 billion

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Synergy of Binary Substitutions for Improving the Cycle Performance in LiNiO2 Revealed by Ab Initio Materials Informatics

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arXiv 2020年

作者： Yoshida, Tomohiro Maezono, Ryo Hongo, Kenta Department of Computer-Aided Engineering and Development Sumitomo Metal Mining Co. Ltd. 3-5 Sobiraki-cho NiihamaEhime792-0001 Japan School of Information Science JAIST Asahidai 1-1 IshikawaNomi923-1292 Japan Computational Engineering Applications Unit RIKEN 2-1 Hirosawa SaitamaWako351-0198 Japan Research Center for Advanced Computing Infrastructure JAIST Asahidai 1-1 NomiIshikawa923-1292 Japan Center for Materials Research by Information Integration Research and Services Division of Materials Data and Integrated System National Institute for Materials Science 1-2-1 Sengen TsukubaIbaraki305-0047 Japan PRESTO Japan Science and Technology Agency 4-1-8 Honcho SaitamaKawaguchi-shi322-0012 Japan

We explore LiNiO2-based cathode materials with two-element substitutions by an ab initio simulation based materials informatics (AIMI) approach. According to our previous study, a higher cycle performance strongly correlates with less structural change during charge–discharge cycles;the latter can be used for evaluating the former. However, if we target the full substitution space, full simulations are infeasible even for all binary combinations. To circumvent such an exhaustive search, we rely on Bayesian optimization. Actually, by searching only 4% of all the combinations, our AIMI approach discovered two promising combinations, Cr-Mg and Cr-Re, whereas each atom itself never improved the performance. We conclude that the synergy never emerges from a common strategy restricted to combinations of "good" elements that individually improve the performance. In addition, we propose a guideline for the binary substitutions by elucidating the mechanism of crystal structure change. Copyright © 2020, The Authors. All rights reserved.

关键词： Binary alloys

Model predictive controller with average emissions constraints for diesel airpath

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arXiv 2018年

作者： Sankar, Gokul S. Shekhar, Rohan C. Manzie, Chris Sano, Takeshi Nakada, Hayato Department of Mechanical Engineering University of Melbourne VIC3010 Australia Department of Electrical and Electronic Engineering University of Melbourne VIC3010 Australia Advanced Unit Management System Development Division Toyota Motor Corporation Higashi-Fuji Technical Center 1200 Mishuku Susono-city Shizuoka410-1193 Japan

Diesel airpath controllers are required to deliver good tracking performance whilst satisfying operational constraints and physical limitations of the actuators. Due to explicit constraint handling capabilities, model predictive controllers (MPC) have been successfully deployed in diesel airpath applications. Previous MPC implementations have considered instantaneous constraints on engine-out emissions in order to meet legislated emissions regulations. However, the emissions standards are specified over a drive cycle, and hence, can be satisfied on average rather than just instantaneously, potentially allowing the controller to exploit the trade-off between emissions and fuel economy. In this work, an MPC is formulated to maximise the fuel efficiency whilst tracking boost pressure and exhaust gas recirculation (EGR) rate references, and in the face of uncertainties, adhering to the input, safety constraints and constraints on emissions averaged over some finite time period. The tracking performance and satisfaction of average emissions constraints using the proposed controller are demonstrated through an experimental study considering the new European drive cycle. Copyright © 2018, The Authors. All rights reserved.

关键词： Model predictive control

Fast calibration of a robust model predictive controller for diesel engine airpath

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arXiv 2018年

作者： Sankar, Gokul S. Shekhar, Rohan C. Manzie, Chris Sano, Takeshi Nakada, Hayato Department of Mechanical Engineering University of Melbourne Victoria3010 Australia Department of Electrical and Electronic Engineering University of Melbourne Victoria3010 Australia Advanced Unit Management System Development Division Toyota Motor Corporation Higashi-Fuji Technical Center 1200 Mishuku Susono-city Shizuoka410-1193 Japan

A significant challenge in the development of control systems for diesel airpath applications is to tune the controller parameters to achieve satisfactory output performance, especially whilst adhering to input and safety constraints in the presence of unknown system disturbances. Model-based control techniques, such as model predictive control (MPC), have been successfully applied to multivariable and highly nonlinear systems, such as diesel engines, while considering operational constraints. However, efficient calibration of typical implementations of MPC is hindered by the high number of tuning parameters and their non-intuitive correlation with the output response. In this paper, the number of effective tuning parameters is reduced through suitable structural modifications to the controller formulation and an appropriate redesign of the MPC cost function to aid rapid calibration. Furthermore, a constraint tightening-like approach is augmented to the control architecture to provide robustness guarantees in the face of uncertainties. A switched linear time-invariant MPC strategy with recursive feasibility guarantees during controller switching is proposed to handle transient operation of the engine. The robust controller is first implemented on a high fidelity simulation environment, with a comprehensive investigation of its calibration to achieve desired transient response under step changes in the fuelling rate. An experimental study then validates and highlights the performance of the proposed controller architecture for selected tunings of the calibration parameters for fuelling steps and over drive cycles. Copyright © 2018, The Authors. All rights reserved.

关键词： Controllers

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

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Nature 2024年第8003期627卷 347-357页

作者： Ken Suzuki Konstantinos Hatzikotoulas Lorraine Southam Henry J Taylor Xianyong Yin Kim M Lorenz Ravi Mandla Alicia Huerta-Chagoya Giorgio E M Melloni Stavroula Kanoni Nigel W Rayner Ozvan Bocher Ana Luiza Arruda Kyuto Sonehara Shinichi Namba Simon S K Lee Michael H Preuss Lauren E Petty Philip Schroeder Brett Vanderwerff Mart Kals Fiona Bragg Kuang Lin Xiuqing Guo Weihua Zhang Jie Yao Young Jin Kim Mariaelisa Graff Fumihiko Takeuchi Jana Nano Amel Lamri Masahiro Nakatochi Sanghoon Moon Robert A Scott James P Cook Jung-Jin Lee Ian Pan Daniel Taliun Esteban J Parra Jin-Fang Chai Lawrence F Bielak Yasuharu Tabara Yang Hai Gudmar Thorleifsson Niels Grarup Tamar Sofer Matthias Wuttke Chloé Sarnowski Christian Gieger Darryl Nousome Stella Trompet Soo-Heon Kwak Jirong Long Meng Sun Lin Tong Wei-Min Chen Suraj S Nongmaithem Raymond Noordam Victor J Y Lim Claudia H T Tam Yoonjung Yoonie Joo Chien-Hsiun Chen Laura M Raffield Bram Peter Prins Aude Nicolas Lisa R Yanek Guanjie Chen Jennifer A Brody Edmond Kabagambe Ping An Anny H Xiang Hyeok Sun Choi Brian E Cade Jingyi Tan K Alaine Broadaway Alice Williamson Zoha Kamali Jinrui Cui Manonanthini Thangam Linda S Adair Adebowale Adeyemo Carlos A Aguilar-Salinas Tarunveer S Ahluwalia Sonia S Anand Alain Bertoni Jette Bork-Jensen Ivan Brandslund Thomas A Buchanan Charles F Burant Adam S Butterworth Mickaël Canouil Juliana C N Chan Li-Ching Chang Miao-Li Chee Ji Chen Shyh-Huei Chen Yuan-Tsong Chen Zhengming Chen Lee-Ming Chuang Mary Cushman John Danesh Swapan K Das H Janaka de Silva George Dedoussis Latchezar Dimitrov Ayo P Doumatey Shufa Du Qing Duan Kai-Uwe Eckardt Leslie S Emery Daniel S Evans Michele K Evans Krista Fischer James S Floyd Ian Ford Oscar H Franco Timothy M Frayling Barry I Freedman Pauline Genter Hertzel C Gerstein Vilmantas Giedraitis Clicerio González-Villalpando Maria Elena González-Villalpando Penny Gordon-Larsen Myron Gross Lindsay A Guare Sophie Hackinger Liisa Hakaste Sohee Han Andrew T Hattersley Christian Herder Momoko Horikoshi Annie-Green Howard Willa Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research Division of Musculoskeletal and Dermatological Sciences University of Manchester Manchester UK. Department of Diabetes and Metabolic Diseases Graduate School of Medicine University of Tokyo Tokyo Japan. Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Japan. Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany. konstantinos.hatzikotoulas@helmholtz-munich.de. Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany. Center for Precision Health Research National Human Genome Research Institute National Institutes of Health Bethesda MD USA. British Heart Foundation Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Cambridge UK. Heart and Lung Research Institute University of Cambridge Cambridge UK. Department of Epidemiology School of Public Health Nanjing Medical University Nanjing China. Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor MI USA. Corporal Michael J. Crescenz VA Medical Center Philadelphia PA USA. Department of Systems Pharmacology and Translational Therapeutics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA. Department of Genetics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA. Programs in Metabolism and Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA. Diabetes Unit and Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA. William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London L

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

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