ALBERT

Beschreibung: The Gorkha earthquake (magnitude 7.8) on 25 April 2015 and later aftershocks struck South Asia, killing ~9000 people and damaging a large region. Supported by a large campaign of responsive satellite data acquisitions over the earthquake disaster zone, our team undertook a satellite image survey of the earthquakes' induced geohazards in Nepal and China and an assessment of the geomorphic, tectonic, and lithologic controls on quake-induced landslides. Timely analysis and communication aided response and recovery and informed decision-makers. We mapped 4312 coseismic and postseismic landslides. We also surveyed 491 glacier lakes for earthquake damage but found only nine landslide-impacted lakes and no visible satellite evidence of outbursts. Landslide densities correlate with slope, peak ground acceleration, surface downdrop, and specific metamorphic lithologies and large plutonic intrusions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kargel, J S -- Leonard, G J -- Shugar, D H -- Haritashya, U K -- Bevington, A -- Fielding, E J -- Fujita, K -- Geertsema, M -- Miles, E S -- Steiner, J -- Anderson, E -- Bajracharya, S -- Bawden, G W -- Breashears, D F -- Byers, A -- Collins, B -- Dhital, M R -- Donnellan, A -- Evans, T L -- Geai, M L -- Glasscoe, M T -- Green, D -- Gurung, D R -- Heijenk, R -- Hilborn, A -- Hudnut, K -- Huyck, C -- Immerzeel, W W -- Liming, Jiang -- Jibson, R -- Kaab, A -- Khanal, N R -- Kirschbaum, D -- Kraaijenbrink, P D A -- Lamsal, D -- Shiyin, Liu -- Mingyang, Lv -- McKinney, D -- Nahirnick, N K -- Zhuotong, Nan -- Ojha, S -- Olsenholler, J -- Painter, T H -- Pleasants, M -- Pratima, K C -- Yuan, Q I -- Raup, B H -- Regmi, D -- Rounce, D R -- Sakai, A -- Donghui, Shangguan -- Shea, J M -- Shrestha, A B -- Shukla, A -- Stumm, D -- van der Kooij, M -- Voss, K -- Xin, Wang -- Weihs, B -- Wolfe, D -- Lizong, Wu -- Xiaojun, Yao -- Yoder, M R -- Young, N -- New York, N.Y. -- Science. 2016 Jan 8;351(6269):aac8353. doi: 10.1126/science.aac8353. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hydrology and Water Resources, University of Arizona, Tucson, AZ, USA. kargel@hwr.arizona.edu dshugar@uw.edu uharitashya1@udayton.edu. ; Department of Hydrology and Water Resources, University of Arizona, Tucson, AZ, USA. ; School of Interdisciplinary Arts and Sciences, University of Washington Tacoma, Tacoma, WA, USA. kargel@hwr.arizona.edu dshugar@uw.edu uharitashya1@udayton.edu. ; Department of Geology, University of Dayton, Dayton, OH, USA. kargel@hwr.arizona.edu dshugar@uw.edu uharitashya1@udayton.edu. ; Ministry of Forests, Lands and Natural Resource Operations, Prince George, BC, Canada. ; Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA. ; Graduate School of Environmental Studies, Nagoya University, Nagoya, Japan. ; Scott Polar Research Institute, University of Cambridge, Cambridge, UK. ; Institute of Environmental Engineering, Federal Institute of Technology-ETH, Zurich, Switzerland. ; NASA Marshall Space Flight Center, Huntsville, AL, USA. ; International Centre for Integrated Mountain Development, Kathmandu, Nepal. ; NASA Headquarters, Washington, DC, USA. ; GlacierWorks, Marblehead, MA, USA. ; The Mountain Institute, Elkins, WV, USA. ; U.S. Geological Survey, Menlo Park, CA, USA. ; Central Department of Geology, Tribhuvan University, Kirtipur, Kathmandu, Nepal. ; Department of Geography, University of Victoria, Victoria, BC, Canada. ; CVA Engineering, Suresnes, France. ; Earthquake Science Center, U.S. Geological Survey, Pasadena, CA, USA. ; ImageCat, Long Beach, CA, USA. ; Faculty of Geosciences, Utrecht University, Utrecht, Netherlands. ; State Key Laboratory of Geodesy and Earth's Dynamics, Institute of Geodesy and Geophysics, Chinese Academy of Sciences, Wuhan, Hubei Province, China. ; U.S. Geological Survey, Golden, CO, USA. ; Department of Geosciences, University of Oslo, Blindern, Oslo, Norway. ; Hydrological Sciences Laboratory, NASA Goddard Space Flight Center, Greenbelt, MD, USA. ; Cold and Arid Regions of Environmental and Engineering Research Institute, Chinese Academy of Sciences, Lanzhou, China. ; School of Earth Sciences and Engineering, Nanjing University, Nanjing, China. ; Department of Civil, Architectural and Environmental Engineering, University of Texas at Austin, Austin, TX, USA. ; School of Geography Science, Nanjing Normal University, Nanjing, China. ; Department of Geography, Texas A&M University, College Station, TX, USA. ; Department of Geology, University of Dayton, Dayton, OH, USA. ; Arizona Remote Sensing Center, School of Natural Resources and the Environment, University of Arizona, Tucson, AZ, USA. ; National Snow and Ice Data Center, University of Colorado, Boulder, CO, USA. ; Himalayan Research Center, Kathmandu, Nepal. ; Environmental and Water Resources Engineering, University of Texas at Austin, Austin, TX, USA. ; Wadia Institute of Himalayan Geology, Dehradun, India. ; MacDonald Dettwiler and Associates-GSI, Ottawa, Ontario, Canada. ; Department of Geography, University of California, Santa Barbara, Santa Barbara, CA, USA. ; College of Architecture and Urban Planning, Hunan University of Science and Technology, Xiangtan, China. ; Geography Department, Kansas State University, Manhattan, KS, USA. ; Global Land Ice Measurements from Space (GLIMS) Steward, Alaska Region, Anchorage, AK, USA. ; College of Geographical Science and Environment, Northwest Normal University, China. ; Department of Physics, University of California, Davis, Davis, CA, USA. ; Antarctic Climate and Ecosystems Cooperative Research Centre, University of Tasmania, Hobart, TAS, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26676355" target="_blank"〉PubMed〈/a〉

Beschreibung: Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537935/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537935/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rivas, Manuel A -- Pirinen, Matti -- Conrad, Donald F -- Lek, Monkol -- Tsang, Emily K -- Karczewski, Konrad J -- Maller, Julian B -- Kukurba, Kimberly R -- DeLuca, David S -- Fromer, Menachem -- Ferreira, Pedro G -- Smith, Kevin S -- Zhang, Rui -- Zhao, Fengmei -- Banks, Eric -- Poplin, Ryan -- Ruderfer, Douglas M -- Purcell, Shaun M -- Tukiainen, Taru -- Minikel, Eric V -- Stenson, Peter D -- Cooper, David N -- Huang, Katharine H -- Sullivan, Timothy J -- Nedzel, Jared -- GTEx Consortium -- Geuvadis Consortium -- Bustamante, Carlos D -- Li, Jin Billy -- Daly, Mark J -- Guigo, Roderic -- Donnelly, Peter -- Ardlie, Kristin -- Sammeth, Michael -- Dermitzakis, Emmanouil T -- McCarthy, Mark I -- Montgomery, Stephen B -- Lappalainen, Tuuli -- MacArthur, Daniel G -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095552/Wellcome Trust/United Kingdom -- 095552/Z/11/Z/Wellcome Trust/United Kingdom -- 098381/Wellcome Trust/United Kingdom -- DA006227/DA/NIDA NIH HHS/ -- HHSN261200800001E/CA/NCI NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- HHSN268201000029C/HL/NHLBI NIH HHS/ -- HHSN268201000029C/PHS HHS/ -- MH090936/MH/NIMH NIH HHS/ -- MH090937/MH/NIMH NIH HHS/ -- MH090941/MH/NIMH NIH HHS/ -- MH090948/MH/NIMH NIH HHS/ -- MH090951/MH/NIMH NIH HHS/ -- P30 DK020595/DK/NIDDK NIH HHS/ -- R01 GM104371/GM/NIGMS NIH HHS/ -- R01 MH090941/MH/NIMH NIH HHS/ -- R01 MH101810/MH/NIMH NIH HHS/ -- R01 MH101814/MH/NIMH NIH HHS/ -- R01 MH101820/MH/NIMH NIH HHS/ -- R01GM104371/GM/NIGMS NIH HHS/ -- R01MH090941/MH/NIMH NIH HHS/ -- R01MH101810/MH/NIMH NIH HHS/ -- R01MH101814/MH/NIMH NIH HHS/ -- U01 HG007593/HG/NHGRI NIH HHS/ -- U01HG007593/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 May 8;348(6235):666-9. doi: 10.1126/science.1261877.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu. ; FInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. ; Washington University in St. Louis, St. Louis, MO, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. ; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA. Biomedical Informatics Program, Stanford University, Stanford, CA, USA. ; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA. ; Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. ; Department of Genetics, Stanford University, Stanford, CA, USA. ; Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA. ; Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. ; Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. ; Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Department of Statistics, University of Oxford, Oxford, UK. ; Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil. ; Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Oxford Center for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK. ; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25954003" target="_blank"〉PubMed〈/a〉

Beschreibung: Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-gamma (IFN-gamma) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORgamma and RORgammaT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORgamma- and RORgammaT-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gammadelta T cells and CD4(+)CCR6(+)CXCR3(+) alphabeta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORgamma, RORgammaT, or both.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668938/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668938/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada, Satoshi -- Markle, Janet G -- Deenick, Elissa K -- Mele, Federico -- Averbuch, Dina -- Lagos, Macarena -- Alzahrani, Mohammed -- Al-Muhsen, Saleh -- Halwani, Rabih -- Ma, Cindy S -- Wong, Natalie -- Soudais, Claire -- Henderson, Lauren A -- Marzouqa, Hiyam -- Shamma, Jamal -- Gonzalez, Marcela -- Martinez-Barricarte, Ruben -- Okada, Chizuru -- Avery, Danielle T -- Latorre, Daniela -- Deswarte, Caroline -- Jabot-Hanin, Fabienne -- Torrado, Egidio -- Fountain, Jeffrey -- Belkadi, Aziz -- Itan, Yuval -- Boisson, Bertrand -- Migaud, Melanie -- Arlehamn, Cecilia S Lindestam -- Sette, Alessandro -- Breton, Sylvain -- McCluskey, James -- Rossjohn, Jamie -- de Villartay, Jean-Pierre -- Moshous, Despina -- Hambleton, Sophie -- Latour, Sylvain -- Arkwright, Peter D -- Picard, Capucine -- Lantz, Olivier -- Engelhard, Dan -- Kobayashi, Masao -- Abel, Laurent -- Cooper, Andrea M -- Notarangelo, Luigi D -- Boisson-Dupuis, Stephanie -- Puel, Anne -- Sallusto, Federica -- Bustamante, Jacinta -- Tangye, Stuart G -- Casanova, Jean-Laurent -- 8UL1TR000043/TR/NCATS NIH HHS/ -- HHSN272200900044C/AI/NIAID NIH HHS/ -- HHSN272200900044C/PHS HHS/ -- R37 AI095983/AI/NIAID NIH HHS/ -- R37AI095983/AI/NIAID NIH HHS/ -- T32 AI007512/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):606-13. doi: 10.1126/science.aaa4282. Epub 2015 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. jmarkle@rockefeller.edu jean-laurent.casanova@rockefeller.edu. ; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia. ; Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. ; Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel. ; Department of Immunology, School of Medicine, Universidad de Valparaiso, Santiago, Chile. Department of Pediatrics, Padre Hurtado Hospital and Clinica Alemana, Santiago, Chile. ; Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. ; Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia. ; Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia. ; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. ; Institut Curie, INSERM U932, Paris, France. ; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA. ; Caritas Baby Hospital, Post Office Box 11535, Jerusalem, Israel. ; Department of Immunology, School of Medicine, Universidad de Valparaiso, Santiago, Chile. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. ; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. ; Trudeau Institute, Saranac Lake, NY 12983, USA. ; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. ; Department of Radiology, Assistance Publique-Hopitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France. ; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. ; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK. ; Laboratoire Dynamique du Genome et Systeme Immunitaire, INSERM UMR 1163, Universite Paris Descartes-Sorbonne Paris Cite, Imagine Institute, Paris, France. ; Laboratoire Dynamique du Genome et Systeme Immunitaire, INSERM UMR 1163, Universite Paris Descartes-Sorbonne Paris Cite, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. ; Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne NE4 6BE, UK. ; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Universite Paris Descartes-Sorbonne Paris Cite, Imagine Institute, Paris, France. ; Department of Paediatric Allergy Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. ; Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. ; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA. Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA. ; Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. Center of Medical Immunology, Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. Howard Hughes Medical Institute, New York, NY 10065, USA. jmarkle@rockefeller.edu jean-laurent.casanova@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160376" target="_blank"〉PubMed〈/a〉

Beschreibung: How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733658/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733658/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raghavan, Maanasa -- Steinrucken, Matthias -- Harris, Kelley -- Schiffels, Stephan -- Rasmussen, Simon -- DeGiorgio, Michael -- Albrechtsen, Anders -- Valdiosera, Cristina -- Avila-Arcos, Maria C -- Malaspinas, Anna-Sapfo -- Eriksson, Anders -- Moltke, Ida -- Metspalu, Mait -- Homburger, Julian R -- Wall, Jeff -- Cornejo, Omar E -- Moreno-Mayar, J Victor -- Korneliussen, Thorfinn S -- Pierre, Tracey -- Rasmussen, Morten -- Campos, Paula F -- Damgaard, Peter de Barros -- Allentoft, Morten E -- Lindo, John -- Metspalu, Ene -- Rodriguez-Varela, Ricardo -- Mansilla, Josefina -- Henrickson, Celeste -- Seguin-Orlando, Andaine -- Malmstrom, Helena -- Stafford, Thomas Jr -- Shringarpure, Suyash S -- Moreno-Estrada, Andres -- Karmin, Monika -- Tambets, Kristiina -- Bergstrom, Anders -- Xue, Yali -- Warmuth, Vera -- Friend, Andrew D -- Singarayer, Joy -- Valdes, Paul -- Balloux, Francois -- Leboreiro, Ilan -- Vera, Jose Luis -- Rangel-Villalobos, Hector -- Pettener, Davide -- Luiselli, Donata -- Davis, Loren G -- Heyer, Evelyne -- Zollikofer, Christoph P E -- Ponce de Leon, Marcia S -- Smith, Colin I -- Grimes, Vaughan -- Pike, Kelly-Anne -- Deal, Michael -- Fuller, Benjamin T -- Arriaza, Bernardo -- Standen, Vivien -- Luz, Maria F -- Ricaut, Francois -- Guidon, Niede -- Osipova, Ludmila -- Voevoda, Mikhail I -- Posukh, Olga L -- Balanovsky, Oleg -- Lavryashina, Maria -- Bogunov, Yuri -- Khusnutdinova, Elza -- Gubina, Marina -- Balanovska, Elena -- Fedorova, Sardana -- Litvinov, Sergey -- Malyarchuk, Boris -- Derenko, Miroslava -- Mosher, M J -- Archer, David -- Cybulski, Jerome -- Petzelt, Barbara -- Mitchell, Joycelynn -- Worl, Rosita -- Norman, Paul J -- Parham, Peter -- Kemp, Brian M -- Kivisild, Toomas -- Tyler-Smith, Chris -- Sandhu, Manjinder S -- Crawford, Michael -- Villems, Richard -- Smith, David Glenn -- Waters, Michael R -- Goebel, Ted -- Johnson, John R -- Malhi, Ripan S -- Jakobsson, Mattias -- Meltzer, David J -- Manica, Andrea -- Durbin, Richard -- Bustamante, Carlos D -- Song, Yun S -- Nielsen, Rasmus -- Willerslev, Eske -- 098051/Wellcome Trust/United Kingdom -- 261213/European Research Council/International -- 2R01HG003229-09/HG/NHGRI NIH HHS/ -- BB/H005854/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- R01-AI17892/AI/NIAID NIH HHS/ -- R01-GM094402/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):aab3884. doi: 10.1126/science.aab3884. Epub 2015 Jul 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. ; Computer Science Division, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA 01003, USA. ; Department of Mathematics, University of California, Berkeley, Berkeley, CA 94720, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. ; Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, Building 208, 2800 Kongens Lyngby, Denmark. ; Departments of Biology and Statistics, Pennsylvania State University, 502 Wartik Laboratory, University Park, PA 16802, USA. ; The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. Department of Archaeology and History, La Trobe University, Melbourne, Victoria 3086, Australia. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. Department of Genetics, School of Medicine, Stanford University, 300 Pasteur Drive, Lane Building, Room L331, Stanford, CA 94305, USA. ; Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. Integrative Systems Biology Laboratory, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Kingdom of Saudi Arabia. ; Estonian Biocentre, Evolutionary Biology Group, Tartu 51010, Estonia. Department of Evolutionary Biology, University of Tartu, Tartu 51010, Estonia. ; Department of Genetics, School of Medicine, Stanford University, 300 Pasteur Drive, Lane Building, Room L331, Stanford, CA 94305, USA. ; Institute for Human Genetics, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. ; School of Biological Sciences, Washington State University, Post Office Box 644236, Heald 429, Pullman, WA 99164, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. Centro de Investigacion en Ciencias del Mar y Limnologia/Centro Interdisciplinar de Investigacao Marinha e Ambiental, Centro Interdisciplinar de Investigacao Marinha e Ambiental, Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal. ; Department of Anthropology, University of Illinois at Urbana-Champaign, 607 S. Mathews Avenue, Urbana, IL 61801, USA. ; Centro Mixto, Universidad Complutense de Madrid-Instituto de Salud Carlos III de Evolucion y Comportamiento Humano, Madrid, Spain. ; Instituto Nacional de Antropologia e Historia, Moneda 13, Centro, Cuauhtemoc, 06060 Mexico City, Mexico. ; University of Utah, Department of Anthropology, 270 S 1400 E, Salt Lake City, UT 84112, USA. ; Department of Evolutionary Biology and Science for Life Laboratory, Uppsala University, Norbyvagen 18D, SE-752 36 Uppsala, Sweden. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. Acceleration Mass Spectrometry 14C Dating Centre, Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, 8000 Aarhus, Denmark. ; Department of Genetics, School of Medicine, Stanford University, 300 Pasteur Drive, Lane Building, Room L331, Stanford, CA 94305, USA. Laboratorio Nacional de Genomica para la Biodiversidad (LANGEBIO), Centro de Investigacion y de Estudios Avanzados, Irapuato, Guanajuato 36821, Mexico. ; Estonian Biocentre, Evolutionary Biology Group, Tartu 51010, Estonia. ; Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK. Evolutionsbiologiskt Centrum, Norbyvagen 18D, 75236 Uppsala, Sweden. ; Department of Geography, University of Cambridge, Downing Place, Cambridge CB2 3EN, UK. ; Centre for Past Climate Change and Department of Meteorology, University of Reading, Earley Gate, Post Office Box 243, Reading, UK. ; School of Geographical Sciences, University Road, Clifton, Bristol BS8 1SS, UK. ; Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK. ; Escuela Nacional de AntropologIa e Historia, Periferico Sur y Zapote s/n Colonia Isidro Fabela, Tlalpan, Isidro Fabela, 14030 Mexico City, Mexico. ; Instituto de Investigacion en Genetica Molecular, Universidad de Guadalajara, Ocotlan, Mexico. ; Dipartimento di Scienze Biologiche, Geologiche e Ambientali (BiGeA), Universita di Bologna, Via Selmi 3, 40126 Bologna, Italy. ; Department of Anthropology, Oregon State University, 238 Waldo Hall, Corvallis, OR 97331 USA. ; Museum National d'Histoire Naturelle, CNRS, Universite Paris 7 Diderot, Sorbonne Paris Cite, Sorbonne Universites, Unite Eco-Anthropologie et Ethnobiologie (UMR7206), Paris, France. ; Anthropological Institute and Museum, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. ; Department of Archaeology and History, La Trobe University, Melbourne, Victoria 3086, Australia. ; Department of Archaeology, Memorial University, Queen's College, 210 Prince Philip Drive, St. John's, Newfoundland A1C 5S7, Canada. Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig 04103, Germany. ; Department of Archaeology, Memorial University, Queen's College, 210 Prince Philip Drive, St. John's, Newfoundland A1C 5S7, Canada. ; Department of Earth System Science, University of California, Irvine, Keck Carbon Cycle Accelerator Mass Spectrometry Group, B321 Croul Hall, Irvine, CA 92697, USA. ; Instituto de Alta Investigacion, Universidad de Tarapaca, 18 de Septiembre 2222, Carsilla 6-D Arica, Chile. ; Departamento de Antropologia, Universidad de Tarapaca, 18 de Septiembre 2222, Carsilla 6-D Arica, Chile. ; Fundacao Museu do Homem Americano, Centro Cultural Sergio Motta, Campestre, 64770-000 Sao Raimundo Nonato, Brazil. ; Laboratoire d'Anthropologie Moleculaire et Imagerie de Synthese UMR-5288, CNRS, Universite de Toulouse, 31073 Toulouse, France. ; Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia. Novosibirsk State University, 2 Pirogova Street, 630090 Novosibirsk, Russia. ; Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia. Institute of Internal Medicine, Siberian Branch of RAS, 175/1 ul. B. Bogatkova, Novosibirsk 630089, Russia. Novosibirsk State University, Laboratory of Molecular Epidemiology and Bioinformatics, 630090 Novosibirsk, Russia. ; Vavilov Institute of General Genetics, Gubkina 3, 119333 Moscow, Russia. Research Centre for Medical Genetics, Moskvorechie 1, 115478 Moscow, Russia. ; Kemerovo State University, Krasnaya 3, 650000 Kemerovo, Russia. ; Vavilov Institute of General Genetics, Gubkina 3, 119333 Moscow, Russia. ; Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Prospekt Oktyabrya 71, 450054 Ufa, Russia. Department of Genetics and Fundamental Medicine, Bashkir State University, Zaki Validi 32, 450076 Ufa, Russia. ; Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia. ; Research Centre for Medical Genetics, Moskvorechie 1, 115478 Moscow, Russia. ; Department of Molecular Genetics, Yakut Scientific Centre of Complex Medical Problems, Sergelyahskoe Shosse 4, 677010 Yakutsk, Russia. Laboratory of Molecular Biology, Institute of Natural Sciences, M. K. Ammosov North-Eastern Federal University, 677000 Yakutsk, Russia. ; Estonian Biocentre, Evolutionary Biology Group, Tartu 51010, Estonia. Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Prospekt Oktyabrya 71, 450054 Ufa, Russia. ; Institute of Biological Problems of the North, Russian Academy of Sciences, Portovaya Street 18, Magadan 685000, Russia. ; Department of Anthropology, Western Washington University, Bellingham, WA 98225, USA. ; Department of Anthropology, Northwest Community College, 353 Fifth Street, Prince Rupert, British Columbia V8J 3L6, Canada. ; Canadian Museum of History, 100 Rue Laurier, Gatineau, Quebec K1A 0M8, Canada. University of Western Ontario, London, Ontario N6A 3K7, Canada. Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. ; Metlakatla Treaty Office, Post Office Box 224, Prince Rupert, BC V8J 3P6, Canada. ; Sealaska Heritage Institute, 105 S. Seward Street, Juneau, AK 99801, USA. ; Department of Structural Biology, Stanford University School of Medicine, D100 Fairchild Science Building, Stanford, CA 94305-5126, USA. ; School of Biological Sciences, Washington State University, Post Office Box 644236, Heald 429, Pullman, WA 99164, USA. Department of Anthropology, Washington State University, Pullman, WA 99163, USA. ; Estonian Biocentre, Evolutionary Biology Group, Tartu 51010, Estonia. Division of Biological Anthropology, University of Cambridge, Henry Wellcome Building, Fitzwilliam Street, Cambridge CB2 1QH, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. Department of Medicine, University of Cambridge, Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Laboratory of Biological Anthropology, University of Kansas, 1415 Jayhawk Boulevard, 622 Fraser Hall, Lawrence, KS 66045, USA. ; Molecular Anthropology Laboratory, 209 Young Hall, Department of Anthropology, University of California, One Shields Avenue, Davis, CA 95616, USA. ; Center for the Study of the First Americans, Texas A&M University, College Station, TX 77843-4352, USA. Department of Anthropology, Texas A&M University, College Station, TX 77843-4352, USA. Department of Geography, Texas A&M University, College Station, TX 77843-4352, USA. ; Center for the Study of the First Americans, Texas A&M University, College Station, TX 77843-4352, USA. ; Santa Barbara Museum of Natural History, 2559 Puesta del Sol, Santa Barbara, CA 93105, USA. ; Department of Anthropology, University of Illinois at Urbana-Champaign, 607 S. Mathews Avenue, Urbana, IL 61801, USA. Carle R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. Department of Anthropology, Southern Methodist University, Dallas, TX 75275, USA. ; Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. ; Computer Science Division, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Integrative Biology, University of California, 3060 Valley Life Sciences Building 3140, Berkeley, CA 94720, USA. ewillierslev@snm.ku.dk rasmus_nielsen@berkeley.edu yss@berkeley.edu. ; Department of Integrative Biology, University of California, 3060 Valley Life Sciences Building 3140, Berkeley, CA 94720, USA. ewillierslev@snm.ku.dk rasmus_nielsen@berkeley.edu yss@berkeley.edu. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen, Denmark. ewillierslev@snm.ku.dk rasmus_nielsen@berkeley.edu yss@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26198033" target="_blank"〉PubMed〈/a〉

Beschreibung: Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanoni, Paolo -- Khetarpal, Sumeet A -- Larach, Daniel B -- Hancock-Cerutti, William F -- Millar, John S -- Cuchel, Marina -- DerOhannessian, Stephanie -- Kontush, Anatol -- Surendran, Praveen -- Saleheen, Danish -- Trompet, Stella -- Jukema, J Wouter -- De Craen, Anton -- Deloukas, Panos -- Sattar, Naveed -- Ford, Ian -- Packard, Chris -- Majumder, Abdullah al Shafi -- Alam, Dewan S -- Di Angelantonio, Emanuele -- Abecasis, Goncalo -- Chowdhury, Rajiv -- Erdmann, Jeanette -- Nordestgaard, Borge G -- Nielsen, Sune F -- Tybjaerg-Hansen, Anne -- Schmidt, Ruth Frikke -- Kuulasmaa, Kari -- Liu, Dajiang J -- Perola, Markus -- Blankenberg, Stefan -- Salomaa, Veikko -- Mannisto, Satu -- Amouyel, Philippe -- Arveiler, Dominique -- Ferrieres, Jean -- Muller-Nurasyid, Martina -- Ferrario, Marco -- Kee, Frank -- Willer, Cristen J -- Samani, Nilesh -- Schunkert, Heribert -- Butterworth, Adam S -- Howson, Joanna M M -- Peloso, Gina M -- Stitziel, Nathan O -- Danesh, John -- Kathiresan, Sekar -- Rader, Daniel J -- CHD Exome+ Consortium -- CARDIoGRAM Exome Consortium -- Global Lipids Genetics Consortium -- R01 DK089256/DK/NIDDK NIH HHS/ -- R01 HL117078/HL/NHLBI NIH HHS/ -- TL1 RR024133/RR/NCRR NIH HHS/ -- TL1R000138/PHS HHS/ -- TL1RR024133/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1166-71. doi: 10.1126/science.aad3517.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. INSERM UMR 1166 ICAN, Universite Pierre et Marie Curie Paris 6, Hopital de la Pitie, Paris, France. ; INSERM UMR 1166 ICAN, Universite Pierre et Marie Curie Paris 6, Hopital de la Pitie, Paris, France. ; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Centre for Non-Communicable Diseases, Karachi, Pakistan. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. ; Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. The Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. ; Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. ; Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. ; Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. ; Glasgow Clinical Research Facility, Western Infirmary, Glasgow, UK. ; National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh. ; International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh. ; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA. ; Institute for Integrative and Experimental Genomics, University of Lubeck, Lubeck 23562, Germany. ; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. ; Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark. ; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. ; Department of Health, National Institute for Health and Welfare, Helsinki, Finland. ; Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA. ; Department of Health, National Institute for Health and Welfare, Helsinki, Finland. Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland. ; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ; Department of Epidemiology and Public Health, Institut Pasteur de Lille, Lille, France. ; Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France. ; Department of Epidemiology, Toulouse University-CHU Toulouse, Toulouse, France. ; Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Neuherberg, Germany. Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany. ; Research Centre in Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy. ; UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Northern Ireland. ; Department of Computational Medicine and Bioinformatics, Department of Human Genetics, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. ; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hotel, Leicester, UK. ; Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Munich, Germany. ; Broad Institute and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. ; Department of Medicine, Division of Cardiology, Department of Genetics, and the McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. ; Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. rader@mail.med.upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965621" target="_blank"〉PubMed〈/a〉

Beschreibung: Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miyamoto, David T -- Zheng, Yu -- Wittner, Ben S -- Lee, Richard J -- Zhu, Huili -- Broderick, Katherine T -- Desai, Rushil -- Fox, Douglas B -- Brannigan, Brian W -- Trautwein, Julie -- Arora, Kshitij S -- Desai, Niyati -- Dahl, Douglas M -- Sequist, Lecia V -- Smith, Matthew R -- Kapur, Ravi -- Wu, Chin-Lee -- Shioda, Toshi -- Ramaswamy, Sridhar -- Ting, David T -- Toner, Mehmet -- Maheswaran, Shyamala -- Haber, Daniel A -- 2R01CA129933/CA/NCI NIH HHS/ -- EB008047/EB/NIBIB NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1351-6. doi: 10.1126/science.aab0917.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383955" target="_blank"〉PubMed〈/a〉

Beschreibung: Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380271/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380271/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neafsey, Daniel E -- Waterhouse, Robert M -- Abai, Mohammad R -- Aganezov, Sergey S -- Alekseyev, Max A -- Allen, James E -- Amon, James -- Arca, Bruno -- Arensburger, Peter -- Artemov, Gleb -- Assour, Lauren A -- Basseri, Hamidreza -- Berlin, Aaron -- Birren, Bruce W -- Blandin, Stephanie A -- Brockman, Andrew I -- Burkot, Thomas R -- Burt, Austin -- Chan, Clara S -- Chauve, Cedric -- Chiu, Joanna C -- Christensen, Mikkel -- Costantini, Carlo -- Davidson, Victoria L M -- Deligianni, Elena -- Dottorini, Tania -- Dritsou, Vicky -- Gabriel, Stacey B -- Guelbeogo, Wamdaogo M -- Hall, Andrew B -- Han, Mira V -- Hlaing, Thaung -- Hughes, Daniel S T -- Jenkins, Adam M -- Jiang, Xiaofang -- Jungreis, Irwin -- Kakani, Evdoxia G -- Kamali, Maryam -- Kemppainen, Petri -- Kennedy, Ryan C -- Kirmitzoglou, Ioannis K -- Koekemoer, Lizette L -- Laban, Njoroge -- Langridge, Nicholas -- Lawniczak, Mara K N -- Lirakis, Manolis -- Lobo, Neil F -- Lowy, Ernesto -- MacCallum, Robert M -- Mao, Chunhong -- Maslen, Gareth -- Mbogo, Charles -- McCarthy, Jenny -- Michel, Kristin -- Mitchell, Sara N -- Moore, Wendy -- Murphy, Katherine A -- Naumenko, Anastasia N -- Nolan, Tony -- Novoa, Eva M -- O'Loughlin, Samantha -- Oringanje, Chioma -- Oshaghi, Mohammad A -- Pakpour, Nazzy -- Papathanos, Philippos A -- Peery, Ashley N -- Povelones, Michael -- Prakash, Anil -- Price, David P -- Rajaraman, Ashok -- Reimer, Lisa J -- Rinker, David C -- Rokas, Antonis -- Russell, Tanya L -- Sagnon, N'Fale -- Sharakhova, Maria V -- Shea, Terrance -- Simao, Felipe A -- Simard, Frederic -- Slotman, Michel A -- Somboon, Pradya -- Stegniy, Vladimir -- Struchiner, Claudio J -- Thomas, Gregg W C -- Tojo, Marta -- Topalis, Pantelis -- Tubio, Jose M C -- Unger, Maria F -- Vontas, John -- Walton, Catherine -- Wilding, Craig S -- Willis, Judith H -- Wu, Yi-Chieh -- Yan, Guiyun -- Zdobnov, Evgeny M -- Zhou, Xiaofan -- Catteruccia, Flaminia -- Christophides, George K -- Collins, Frank H -- Cornman, Robert S -- Crisanti, Andrea -- Donnelly, Martin J -- Emrich, Scott J -- Fontaine, Michael C -- Gelbart, William -- Hahn, Matthew W -- Hansen, Immo A -- Howell, Paul I -- Kafatos, Fotis C -- Kellis, Manolis -- Lawson, Daniel -- Louis, Christos -- Luckhart, Shirley -- Muskavitch, Marc A T -- Ribeiro, Jose M -- Riehle, Michael A -- Sharakhov, Igor V -- Tu, Zhijian -- Zwiebel, Laurence J -- Besansky, Nora J -- 092654/Wellcome Trust/United Kingdom -- R01 AI050243/AI/NIAID NIH HHS/ -- R01 AI063508/AI/NIAID NIH HHS/ -- R01 AI073745/AI/NIAID NIH HHS/ -- R01 AI076584/AI/NIAID NIH HHS/ -- R01 AI080799/AI/NIAID NIH HHS/ -- R01 AI104956/AI/NIAID NIH HHS/ -- R21 AI101459/AI/NIAID NIH HHS/ -- R56 AI107263/AI/NIAID NIH HHS/ -- SC1 AI109055/AI/NIAID NIH HHS/ -- U19 AI089686/AI/NIAID NIH HHS/ -- U19 AI110818/AI/NIAID NIH HHS/ -- U41 HG007234/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):1258522. doi: 10.1126/science.1258522. Epub 2014 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Sequencing and Analysis Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. neafsey@broadinstitute.org nbesansk@nd.edu. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA. The Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Department of Genetic Medicine and Development, University of Geneva Medical School, Rue Michel-Servet 1, 1211 Geneva, Switzerland. Swiss Institute of Bioinformatics, Rue Michel-Servet 1, 1211 Geneva, Switzerland. ; Department of Medical Entomology and Vector Control, School of Public Health and Institute of Health Researches, Tehran University of Medical Sciences, Tehran, Iran. ; George Washington University, Department of Mathematics and Computational Biology Institute, 45085 University Drive, Ashburn, VA 20147, USA. ; European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; National Vector Borne Disease Control Programme, Ministry of Health, Tafea Province, Vanuatu. ; Department of Public Health and Infectious Diseases, Division of Parasitology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy. ; Department of Biological Sciences, California State Polytechnic-Pomona, 3801 West Temple Avenue, Pomona, CA 91768, USA. ; Tomsk State University, 36 Lenina Avenue, Tomsk, Russia. ; Department of Computer Science and Engineering, Eck Institute for Global Health, 211B Cushing Hall, University of Notre Dame, Notre Dame, IN 46556, USA. ; Genome Sequencing and Analysis Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. ; Inserm, U963, F-67084 Strasbourg, France. CNRS, UPR9022, IBMC, F-67084 Strasbourg, France. ; Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. ; Faculty of Medicine, Health and Molecular Science, Australian Institute of Tropical Health Medicine, James Cook University, Cairns 4870, Australia. ; Department of Life Sciences, Imperial College London, Silwood Park Campus, Ascot SL5 7PY, UK. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA. The Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA. ; Department of Mathematics, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada. ; Department of Entomology and Nematology, One Shields Avenue, University of California-Davis, Davis, CA 95616, USA. ; Institut de Recherche pour le Developpement, Unites Mixtes de Recherche Maladies Infectieuses et Vecteurs Ecologie, Genetique, Evolution et Controle, 911, Avenue Agropolis, BP 64501 Montpellier, France. ; Division of Biology, Kansas State University, 271 Chalmers Hall, Manhattan, KS 66506, USA. ; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Nikolaou Plastira 100 GR-70013, Heraklion, Crete, Greece. ; Centre of Functional Genomics, University of Perugia, Perugia, Italy. ; Genomics Platform, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. ; Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou 01 BP 2208, Burkina Faso. ; Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; School of Life Sciences, University of Nevada, Las Vegas, NV 89154, USA. ; Department of Medical Research, No. 5 Ziwaka Road, Dagon Township, Yangon 11191, Myanmar. ; European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA. ; Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA. ; Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Harvard School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA 02115, USA. Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Universita degli Studi di Perugia, Perugia, Italy. ; Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Computational Evolutionary Biology Group, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. ; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA. ; Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. Bioinformatics Research Laboratory, Department of Biological Sciences, New Campus, University of Cyprus, CY 1678 Nicosia, Cyprus. ; Wits Research Institute for Malaria, Faculty of Health Sciences, and Vector Control Reference Unit, National Institute for Communicable Diseases of the National Health Laboratory Service, Sandringham 2131, Johannesburg, South Africa. ; National Museums of Kenya, P.O. Box 40658-00100, Nairobi, Kenya. ; Department of Biology, University of Crete, 700 13 Heraklion, Greece. ; Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA. ; Virginia Bioinformatics Institute, 1015 Life Science Circle, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Kenya Medical Research Institute-Wellcome Trust Research Programme, Centre for Geographic Medicine Research - Coast, P.O. Box 230-80108, Kilifi, Kenya. ; Harvard School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA 02115, USA. ; Department of Entomology, 1140 East South Campus Drive, Forbes 410, University of Arizona, Tucson, AZ 85721, USA. ; Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA. ; Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. Centre of Functional Genomics, University of Perugia, Perugia, Italy. ; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA. ; Regional Medical Research Centre NE, Indian Council of Medical Research, P.O. Box 105, Dibrugarh-786 001, Assam, India. ; Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA. Molecular Biology Program, New Mexico State University, Las Cruces, NM 88003, USA. ; Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. ; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37235, USA. ; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37235, USA. Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA. ; Department of Genetic Medicine and Development, University of Geneva Medical School, Rue Michel-Servet 1, 1211 Geneva, Switzerland. Swiss Institute of Bioinformatics, Rue Michel-Servet 1, 1211 Geneva, Switzerland. ; Department of Entomology, Texas A&M University, College Station, TX 77807, USA. ; Department of Parasitology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. ; Fundacao Oswaldo Cruz, Avenida Brasil 4365, RJ Brazil. Instituto de Medicina Social, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. ; School of Informatics and Computing, Indiana University, Bloomington, IN 47405, USA. ; Department of Physiology, School of Medicine, Center for Research in Molecular Medicine and Chronic Diseases, Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, Santiago de Compostela, A Coruna, Spain. ; Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK. ; School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool L3 3AF, UK. ; Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA. The Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Department of Computer Science, Harvey Mudd College, Claremont, CA 91711, USA. ; Program in Public Health, College of Health Sciences, University of California, Irvine, Hewitt Hall, Irvine, CA 92697, USA. ; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA. ; Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SJ, UK. ; Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA. Centre of Evolutionary and Ecological Studies (Marine Evolution and Conservation group), University of Groningen, Nijenborgh 7, NL-9747 AG Groningen, Netherlands. ; Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA. ; Department of Biology, Indiana University, Bloomington, IN 47405, USA. School of Informatics and Computing, Indiana University, Bloomington, IN 47405, USA. ; Centers for Disease Control and Prevention, 1600 Clifton Road NE MSG49, Atlanta, GA 30329, USA. ; Department of Biology, University of Crete, 700 13 Heraklion, Greece. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Nikolaou Plastira 100 GR-70013, Heraklion, Crete, Greece. Centre of Functional Genomics, University of Perugia, Perugia, Italy. ; Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA. Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. ; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, 12735 Twinbrook Parkway, Rockville, MD 20852, USA. ; Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ; Departments of Biological Sciences and Pharmacology, Institutes for Chemical Biology, Genetics and Global Health, Vanderbilt University and Medical Center, Nashville, TN 37235, USA. ; Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA. neafsey@broadinstitute.org nbesansk@nd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554792" target="_blank"〉PubMed〈/a〉

Beschreibung: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437632/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437632/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cirulli, Elizabeth T -- Lasseigne, Brittany N -- Petrovski, Slave -- Sapp, Peter C -- Dion, Patrick A -- Leblond, Claire S -- Couthouis, Julien -- Lu, Yi-Fan -- Wang, Quanli -- Krueger, Brian J -- Ren, Zhong -- Keebler, Jonathan -- Han, Yujun -- Levy, Shawn E -- Boone, Braden E -- Wimbish, Jack R -- Waite, Lindsay L -- Jones, Angela L -- Carulli, John P -- Day-Williams, Aaron G -- Staropoli, John F -- Xin, Winnie W -- Chesi, Alessandra -- Raphael, Alya R -- McKenna-Yasek, Diane -- Cady, Janet -- Vianney de Jong, J M B -- Kenna, Kevin P -- Smith, Bradley N -- Topp, Simon -- Miller, Jack -- Gkazi, Athina -- FALS Sequencing Consortium -- Al-Chalabi, Ammar -- van den Berg, Leonard H -- Veldink, Jan -- Silani, Vincenzo -- Ticozzi, Nicola -- Shaw, Christopher E -- Baloh, Robert H -- Appel, Stanley -- Simpson, Ericka -- Lagier-Tourenne, Clotilde -- Pulst, Stefan M -- Gibson, Summer -- Trojanowski, John Q -- Elman, Lauren -- McCluskey, Leo -- Grossman, Murray -- Shneider, Neil A -- Chung, Wendy K -- Ravits, John M -- Glass, Jonathan D -- Sims, Katherine B -- Van Deerlin, Vivianna M -- Maniatis, Tom -- Hayes, Sebastian D -- Ordureau, Alban -- Swarup, Sharan -- Landers, John -- Baas, Frank -- Allen, Andrew S -- Bedlack, Richard S -- Harper, J Wade -- Gitler, Aaron D -- Rouleau, Guy A -- Brown, Robert -- Harms, Matthew B -- Cooper, Gregory M -- Harris, Tim -- Myers, Richard M -- Goldstein, David B -- 089701/Wellcome Trust/United Kingdom -- K08 NS075094/NS/NINDS NIH HHS/ -- P01 AG017586/AG/NIA NIH HHS/ -- P01 AG032953/AG/NIA NIH HHS/ -- P50 AG025688/AG/NIA NIH HHS/ -- R37 NS033123/NS/NINDS NIH HHS/ -- R37 NS083524/NS/NINDS NIH HHS/ -- T32 GM007754/GM/NIGMS NIH HHS/ -- TL1 TR001066/TR/NCATS NIH HHS/ -- UL1 TR001067/TR/NCATS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 27;347(6229):1436-41. doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC 27708, USA. ; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. ; Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA. ; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA. ; Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada. ; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Duke University School of Medicine, Durham, NC 27708, USA. ; Biogen Idec, Cambridge, MA 02142, USA. ; Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA. ; Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, Netherlands. ; Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland. ; Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK. ; Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, 3508 GA Utrecht, Netherlands. ; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy, and Department of Pathophysiology and Transplantation, Dino Ferrari Center, Universita degli Studi di Milano, Milan 20122, Italy. ; Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. ; Houston Methodist Hospital, Houston, TX 77030, USA, and Weill Cornell Medical College of Cornell University, New York, NY 10065, USA. ; Ludwig Institute for Cancer Research and Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Neurology, Penn ALS Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA. ; Department of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA. ; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Neurology, Emory University, Atlanta, GA 30322, USA. ; Department of Biochemistry & Molecular Biophysics, Columbia University, New York, NY 10027, USA. ; Biogen Idec, Cambridge, MA 02142, USA. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. ; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27708, USA. ; Duke ALS Clinic and Durham VA Medical Center, Durham, NC 27708, USA. ; Biogen Idec, Cambridge, MA 02142, USA. tim.harris@biogenidec.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700176" target="_blank"〉PubMed〈/a〉

Beschreibung: Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neandertals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neandertal variants to over 1000 electronic health record (EHR)-derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neandertal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neandertal alleles together explained a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neandertal alleles were significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neandertal haplotypes, and demonstrate the utility of EHR data in evolutionary analyses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simonti, Corinne N -- Vernot, Benjamin -- Bastarache, Lisa -- Bottinger, Erwin -- Carrell, David S -- Chisholm, Rex L -- Crosslin, David R -- Hebbring, Scott J -- Jarvik, Gail P -- Kullo, Iftikhar J -- Li, Rongling -- Pathak, Jyotishman -- Ritchie, Marylyn D -- Roden, Dan M -- Verma, Shefali S -- Tromp, Gerard -- Prato, Jeffrey D -- Bush, William S -- Akey, Joshua M -- Denny, Joshua C -- Capra, John A -- 1K22LM011938/LM/NLM NIH HHS/ -- 1R01GM114128/GM/NIGMS NIH HHS/ -- 5T32EY021453/EY/NEI NIH HHS/ -- R01GM110068/GM/NIGMS NIH HHS/ -- R01LM010685/LM/NLM NIH HHS/ -- U01HG004438/HG/NHGRI NIH HHS/ -- U01HG004608/HG/NHGRI NIH HHS/ -- U01HG004609/HG/NHGRI NIH HHS/ -- U01HG004610/HG/NHGRI NIH HHS/ -- U01HG006378/HG/NHGRI NIH HHS/ -- U01HG006379/HG/NHGRI NIH HHS/ -- U01HG006380/HG/NHGRI NIH HHS/ -- U01HG006382/HG/NHGRI NIH HHS/ -- U01HG006385/HG/NHGRI NIH HHS/ -- U01HG006388/HG/NHGRI NIH HHS/ -- U01HG006389/HG/NHGRI NIH HHS/ -- U01HG008657/HG/NHGRI NIH HHS/ -- U01HG04599/HG/NHGRI NIH HHS/ -- U01HG04603/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):737-41. doi: 10.1126/science.aad2149.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA, USA. ; Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. ; Mount Sinai School of Medicine, New York, NY, USA. ; Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA. ; Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA. ; Center for Human Genetics, Marshfield Clinic, Marshfield, WI, USA. ; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. ; Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. ; Division of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. ; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA. Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA. ; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Medicine, Vanderbilt University, Nashville, TN, USA. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA. ; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA. ; Weis Center for Research, Geisinger Health System, Danville, PA, USA. Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Health Science, Stellenbosch University, Tygerberg, South Africa. ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. ; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Medicine, Vanderbilt University, Nashville, TN, USA. ; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA. Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912863" target="_blank"〉PubMed〈/a〉

Beschreibung: Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chan, Pamela Y -- Carrera Silva, Eugenio A -- De Kouchkovsky, Dimitri -- Joannas, Leonel D -- Hao, Liming -- Hu, Donglei -- Huntsman, Scott -- Eng, Celeste -- Licona-Limon, Paula -- Weinstein, Jason S -- Herbert, De'Broski R -- Craft, Joseph E -- Flavell, Richard A -- Repetto, Silvia -- Correale, Jorge -- Burchard, Esteban G -- Torgerson, Dara G -- Ghosh, Sourav -- Rothlin, Carla V -- HL004464/HL/NHLBI NIH HHS/ -- HL078885/HL/NHLBI NIH HHS/ -- HL088133/HL/NHLBI NIH HHS/ -- HL104608/HL/NHLBI NIH HHS/ -- HL117004/HL/NHLBI NIH HHS/ -- MD006902/MD/NIMHD NIH HHS/ -- R01 AI089824/AI/NIAID NIH HHS/ -- T32 AI007019/AI/NIAID NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):99-103. doi: 10.1126/science.aaf1358.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Laboratorio de Trombosis Experimental, Instituto de Medicina Experimental, Academia Nacional de Medicina-CONICET, Buenos Aires, 1425, Argentina. ; Department of Pathology, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Medicine, University of California San Francisco, CA 94158, USA. ; Department of Experimental Medicine, University of California San Francisco, CA 94158, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Department of Internal Medicine (Rheumatology), School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Instituto de Investigaciones en Microbiologia y Parasitologia Medica, University of Buenos Aires-CONICET, Buenos Aires, 1121, Argentina. Hospital de Clinicas Jose de San Martin, University of Buenos Aires, 1120, Argentina. ; Center for Research on Neuroimmunological Diseases, Raul Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina. ; Department of Medicine, University of California San Francisco, CA 94158, USA. Department of Bioengineering, School of Pharmacy, University of California San Francisco, CA 94158, USA. ; Department of Neurology, School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. carla.rothlin@yale.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27034374" target="_blank"〉PubMed〈/a〉