ALBERT

Description: Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001806/" 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/PMC4001806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roy, Michelle G -- Livraghi-Butrico, Alessandra -- Fletcher, Ashley A -- McElwee, Melissa M -- Evans, Scott E -- Boerner, Ryan M -- Alexander, Samantha N -- Bellinghausen, Lindsey K -- Song, Alfred S -- Petrova, Youlia M -- Tuvim, Michael J -- Adachi, Roberto -- Romo, Irlanda -- Bordt, Andrea S -- Bowden, M Gabriela -- Sisson, Joseph H -- Woodruff, Prescott G -- Thornton, David J -- Rousseau, Karine -- De la Garza, Maria M -- Moghaddam, Seyed J -- Karmouty-Quintana, Harry -- Blackburn, Michael R -- Drouin, Scott M -- Davis, C William -- Terrell, Kristy A -- Grubb, Barbara R -- O'Neal, Wanda K -- Flores, Sonia C -- Cota-Gomez, Adela -- Lozupone, Catherine A -- Donnelly, Jody M -- Watson, Alan M -- Hennessy, Corinne E -- Keith, Rebecca C -- Yang, Ivana V -- Barthel, Lea -- Henson, Peter M -- Janssen, William J -- Schwartz, David A -- Boucher, Richard C -- Dickey, Burton F -- Evans, Christopher M -- CA016086/CA/NCI NIH HHS/ -- CA016672/CA/NCI NIH HHS/ -- CA046934/CA/NCI NIH HHS/ -- G1000450/Medical Research Council/United Kingdom -- K01 DK090285/DK/NIDDK NIH HHS/ -- P01 HL108808/HL/NHLBI NIH HHS/ -- P01 HL110873/HL/NHLBI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- P30 DK065988/DK/NIDDK NIH HHS/ -- P30DK065988/DK/NIDDK NIH HHS/ -- P50 HL107168/HL/NHLBI NIH HHS/ -- R01 AA008769/AA/NIAAA NIH HHS/ -- R01 HL080396/HL/NHLBI NIH HHS/ -- R01 HL097000/HL/NHLBI NIH HHS/ -- R01 HL109517/HL/NHLBI NIH HHS/ -- R01 HL114381/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Jan 16;505(7483):412-6. doi: 10.1038/nature12807. Epub 2013 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2]. ; 1] University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA [2]. ; 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2]. ; University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; University of Texas Health Science Center-Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA. ; 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Instituto Tecnologico y de Estudios Superiores de Monterrey, Avenida Eugenio Garza Sada 2501 Sur Colonia Tecnologico, Monterrey, Nuevo Leon 64849, Mexico. ; Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA [2] University of Houston-Downtown, 1 Main Street, Houston, Texas 77002, USA. ; University of Nebraska Medical Center, 985910 Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 27599, USA. ; University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK. ; University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA. ; University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA. ; 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2] National Jewish Health, Denver, Colorado 80206, USA. ; 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24317696" target="_blank"〉PubMed〈/a〉

Description: Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653134/" 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/PMC4653134/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barouch, Dan H -- Alter, Galit -- Broge, Thomas -- Linde, Caitlyn -- Ackerman, Margaret E -- Brown, Eric P -- Borducchi, Erica N -- Smith, Kaitlin M -- Nkolola, Joseph P -- Liu, Jinyan -- Shields, Jennifer -- Parenteau, Lily -- Whitney, James B -- Abbink, Peter -- Ng'ang'a, David M -- Seaman, Michael S -- Lavine, Christy L -- Perry, James R -- Li, Wenjun -- Colantonio, Arnaud D -- Lewis, Mark G -- Chen, Bing -- Wenschuh, Holger -- Reimer, Ulf -- Piatak, Michael -- Lifson, Jeffrey D -- Handley, Scott A -- Virgin, Herbert W -- Koutsoukos, Marguerite -- Lorin, Clarisse -- Voss, Gerald -- Weijtens, Mo -- Pau, Maria G -- Schuitemaker, Hanneke -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI080289/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI102660/AI/NIAID NIH HHS/ -- AI102691/AI/NIAID NIH HHS/ -- OD011170/OD/NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- R01 AI080289/AI/NIAID NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R01 AI102660/AI/NIAID NIH HHS/ -- R01 AI102691/AI/NIAID NIH HHS/ -- R01 OD011170/OD/NIH HHS/ -- R37 AI080289/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):320-4. doi: 10.1126/science.aab3886. Epub 2015 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA. dbarouch@bidmc.harvard.edu. ; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA. ; Thayer School of Engineering at Dartmouth, Hanover, NH 03755, USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. ; University of Massachusetts Medical School, Worcester, MA 01605, USA. ; New England Primate Research Center, Southborough, MA 01772, USA. ; Bioqual, Rockville, MD 20852, USA. ; Children's Hospital, Boston, MA 02115, USA. ; JPT Peptide Technologies GmbH, 12489 Berlin, Germany. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA. ; Washington University School of Medicine, St. Louis, MO 63110, USA. ; GSK Vaccines, 1330 Rixensart, Belgium. ; Janssen Infectious Diseases and Vaccines (formerly Crucell), 2301 Leiden, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26138104" target="_blank"〉PubMed〈/a〉

Description: Reciprocal gene activation and restriction during cell type differentiation from a common lineage is a hallmark of mammalian organogenesis. A key question, then, is whether a critical transcriptional activator of cell type-specific gene targets can also restrict expression of the same genes in other cell types. Here, we show that whereas the pituitary-specific POU domain factor Pit-1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from a second cell type, the lactotrope. This distinction depends on a two-base pair spacing in accommodation of the bipartite POU domains on a conserved growth hormone promoter site. The allosteric effect on Pit-1, in combination with other DNA binding factors, results in the recruitment of a corepressor complex, including nuclear receptor corepressor N-CoR, which, unexpectedly, is required for active long-term repression of the growth hormone gene in lactotropes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scully, K M -- Jacobson, E M -- Jepsen, K -- Lunyak, V -- Viadiu, H -- Carriere, C -- Rose, D W -- Hooshmand, F -- Aggarwal, A K -- Rosenfeld, M G -- R01 DK18477/DK/NIDDK NIH HHS/ -- R01 DK54802/DK/NIDDK NIH HHS/ -- R01 GM49327/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2000 Nov 10;290(5494):1127-31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11073444" target="_blank"〉PubMed〈/a〉

Description: The identification of pathways mediated by the kinase Cdk5 and the ligand reelin has provided a conceptual framework for exploring the molecular mechanisms underlying proper lamination of the developing mammalian cerebral cortex. In this report, we identify a component of the regulation of Cdk5-mediated cortical lamination by genetic analysis of the roles of the class III POU domain transcription factors, Brn-1 and Brn-2, expressed during the development of the forebrain and coexpressed in most layer II-V cortical neurons. Brn-1 and Brn-2 appear to critically control the initiation of radial migration, redundantly regulating the cell-autonomous expression of the p35 and p39 regulatory subunits of Cdk5 in migrating cortical neurons, with Brn-1(-/-)/Brn-2(-/-) mice exhibiting cortical inversion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McEvilly, Robert J -- de Diaz, Marcela Ortiz -- Schonemann, Marcus D -- Hooshmand, Farideh -- Rosenfeld, Michael G -- New York, N.Y. -- Science. 2002 Feb 22;295(5559):1528-32.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92037-0648, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11859196" target="_blank"〉PubMed〈/a〉

Description: Natural killer (NK) cells are lymphocytes that can be distinguished from T and B cells through their involvement in innate immunity and their lack of rearranged antigen receptors. Although NK cells and their receptors were initially characterized in terms of tumor killing in vitro, we have determined that the NK cell activation receptor, Ly-49H, is critically involved in resistance to murine cytomegalovirus in vivo. Ly-49H requires an immunoreceptor tyrosine-based activation motif (ITAM)-containing transmembrane molecule for expression and signal transduction. Thus, NK cells use receptors functionally resembling ITAM-coupled T and B cell antigen receptors to provide vital innate host defense.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brown, M G -- Dokun, A O -- Heusel, J W -- Smith, H R -- Beckman, D L -- Blattenberger, E A -- Dubbelde, C E -- Stone, L R -- Scalzo, A A -- Yokoyama, W M -- New York, N.Y. -- Science. 2001 May 4;292(5518):934-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Rheumatology Division, Washington University School of Medicine, St. Louis, MO 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11340207" target="_blank"〉PubMed〈/a〉

Description: The lymphatic system plays a key role in tissue fluid regulation and tumour metastasis, and lymphatic defects underlie many pathological states including lymphoedema, lymphangiectasia, lymphangioma and lymphatic dysplasia. However, the origins of the lymphatic system in the embryo, and the mechanisms that direct growth of the network of lymphatic vessels, remain unclear. Lymphatic vessels are thought to arise from endothelial precursor cells budding from the cardinal vein under the influence of the lymphatic hallmark gene Prox1 (prospero homeobox 1; ref. 4). Defects in the transcription factor gene SOX18 (SRY (sex determining region Y) box 18) cause lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia, suggesting that Sox18 may also play a role in lymphatic development or function. Here we use molecular, cellular and genetic assays in mice to show that Sox18 acts as a molecular switch to induce differentiation of lymphatic endothelial cells. Sox18 is expressed in a subset of cardinal vein cells that later co-express Prox1 and migrate to form lymphatic vessels. Sox18 directly activates Prox1 transcription by binding to its proximal promoter. Overexpression of Sox18 in blood vascular endothelial cells induces them to express Prox1 and other lymphatic endothelial markers, while Sox18-null embryos show a complete blockade of lymphatic endothelial cell differentiation from the cardinal vein. Our findings demonstrate a critical role for Sox18 in developmental lymphangiogenesis, and suggest new avenues to investigate for therapeutic management of human lymphangiopathies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Francois, Mathias -- Caprini, Andrea -- Hosking, Brett -- Orsenigo, Fabrizio -- Wilhelm, Dagmar -- Browne, Catherine -- Paavonen, Karri -- Karnezis, Tara -- Shayan, Ramin -- Downes, Meredith -- Davidson, Tara -- Tutt, Desmond -- Cheah, Kathryn S E -- Stacker, Steven A -- Muscat, George E O -- Achen, Marc G -- Dejana, Elisabetta -- Koopman, Peter -- England -- Nature. 2008 Dec 4;456(7222):643-7. doi: 10.1038/nature07391. Epub 2008 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18931657" target="_blank"〉PubMed〈/a〉

Description: Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533874/" 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/PMC4533874/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Dohoon -- Fiske, Brian P -- Birsoy, Kivanc -- Freinkman, Elizaveta -- Kami, Kenjiro -- Possemato, Richard L -- Chudnovsky, Yakov -- Pacold, Michael E -- Chen, Walter W -- Cantor, Jason R -- Shelton, Laura M -- Gui, Dan Y -- Kwon, Manjae -- Ramkissoon, Shakti H -- Ligon, Keith L -- Kang, Seong Woo -- Snuderl, Matija -- Vander Heiden, Matthew G -- Sabatini, David M -- 5P30CA14051/CA/NCI NIH HHS/ -- AI07389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- K08 NS087118/NS/NINDS NIH HHS/ -- K08-NS087118/NS/NINDS NIH HHS/ -- K99 CA168940/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA168653/CA/NCI NIH HHS/ -- R01CA168653/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 16;520(7547):363-7. doi: 10.1038/nature14363. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Human Metabolome Technologies, Inc., Tsuruoka 997-0052, Japan. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [6] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Human Metabolome Technologies America, Inc., Boston, Massachusetts 02134, USA. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Pathology, NYU Langone Medical Center and Medical School, New York, New York 10016, USA. ; 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855294" target="_blank"〉PubMed〈/a〉

Description: The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Lan -- Oliver, Eduardo -- Maratou, Klio -- Atanur, Santosh S -- Dubois, Olivier D -- Cotroneo, Emanuele -- Chen, Chien-Nien -- Wang, Lei -- Arce, Cristina -- Chabosseau, Pauline L -- Ponsa-Cobas, Joan -- Frid, Maria G -- Moyon, Benjamin -- Webster, Zoe -- Aldashev, Almaz -- Ferrer, Jorge -- Rutter, Guy A -- Stenmark, Kurt R -- Aitman, Timothy J -- Wilkins, Martin R -- 098424/Wellcome Trust/United Kingdom -- 101033/Wellcome Trust/United Kingdom -- MR/J0003042/1/Medical Research Council/United Kingdom -- P01 HL014985/HL/NHLBI NIH HHS/ -- PG/04/035/16912/British Heart Foundation/United Kingdom -- PG/10/59/28478/British Heart Foundation/United Kingdom -- PG/12/61/29818/British Heart Foundation/United Kingdom -- PG/2000137/British Heart Foundation/United Kingdom -- PG/95170/British Heart Foundation/United Kingdom -- PG/98018/British Heart Foundation/United Kingdom -- RG/10/16/28575/British Heart Foundation/United Kingdom -- WT098424AIA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):356-60. doi: 10.1038/nature14620. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA. ; Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan. ; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258299" target="_blank"〉PubMed〈/a〉

Description: Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P 〈 1 x 10(-300), 2.1 x 10(-6), 2.5 x 10(-10) and 1.8 x 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141/" 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/PMC4516141/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joshi, Peter K -- Esko, Tonu -- Mattsson, Hannele -- Eklund, Niina -- Gandin, Ilaria -- Nutile, Teresa -- Jackson, Anne U -- Schurmann, Claudia -- Smith, Albert V -- Zhang, Weihua -- Okada, Yukinori -- Stancakova, Alena -- Faul, Jessica D -- Zhao, Wei -- Bartz, Traci M -- Concas, Maria Pina -- Franceschini, Nora -- Enroth, Stefan -- Vitart, Veronique -- Trompet, Stella -- Guo, Xiuqing -- Chasman, Daniel I -- O'Connel, Jeffrey R -- Corre, Tanguy -- Nongmaithem, Suraj S -- Chen, Yuning -- Mangino, Massimo -- Ruggiero, Daniela -- Traglia, Michela -- Farmaki, Aliki-Eleni -- Kacprowski, Tim -- Bjonnes, Andrew -- van der Spek, Ashley -- Wu, Ying -- Giri, Anil K -- Yanek, Lisa R -- Wang, Lihua -- Hofer, Edith -- Rietveld, Cornelius A -- McLeod, Olga -- Cornelis, Marilyn C -- Pattaro, Cristian -- Verweij, Niek -- Baumbach, Clemens -- Abdellaoui, Abdel -- Warren, Helen R -- Vuckovic, Dragana -- Mei, Hao -- Bouchard, Claude -- Perry, John R B -- Cappellani, Stefania -- Mirza, Saira S -- Benton, Miles C -- Broeckel, Ulrich -- Medland, Sarah E -- Lind, Penelope A -- Malerba, Giovanni -- Drong, Alexander -- Yengo, Loic -- Bielak, Lawrence F -- Zhi, Degui -- van der Most, Peter J -- Shriner, Daniel -- Magi, Reedik -- Hemani, Gibran -- Karaderi, Tugce -- Wang, Zhaoming -- Liu, Tian -- Demuth, Ilja -- Zhao, Jing Hua -- Meng, Weihua -- Lataniotis, Lazaros -- van der Laan, Sander W -- Bradfield, Jonathan P -- Wood, Andrew R -- Bonnefond, Amelie -- Ahluwalia, Tarunveer S -- Hall, Leanne M -- Salvi, Erika -- Yazar, Seyhan -- Carstensen, Lisbeth -- de Haan, Hugoline G -- Abney, Mark -- Afzal, Uzma -- Allison, Matthew A -- Amin, Najaf -- Asselbergs, Folkert W -- Bakker, Stephan J L -- Barr, R Graham -- Baumeister, Sebastian E -- Benjamin, Daniel J -- Bergmann, Sven -- Boerwinkle, Eric -- Bottinger, Erwin P -- Campbell, Archie -- Chakravarti, Aravinda -- Chan, Yingleong -- Chanock, Stephen J -- Chen, Constance -- Chen, Y-D Ida -- Collins, Francis S -- Connell, John -- Correa, Adolfo -- Cupples, L Adrienne -- Smith, George Davey -- Davies, Gail -- Dorr, Marcus -- Ehret, Georg -- Ellis, Stephen B -- Feenstra, Bjarke -- Feitosa, Mary F -- Ford, Ian -- Fox, Caroline S -- Frayling, Timothy M -- Friedrich, Nele -- Geller, Frank -- Scotland, Generation -- Gillham-Nasenya, Irina -- Gottesman, Omri -- Graff, Misa -- Grodstein, Francine -- Gu, Charles -- Haley, Chris -- Hammond, Christopher J -- Harris, Sarah E -- Harris, Tamara B -- Hastie, Nicholas D -- Heard-Costa, Nancy L -- Heikkila, Kauko -- Hocking, Lynne J -- Homuth, Georg -- Hottenga, Jouke-Jan -- Huang, Jinyan -- Huffman, Jennifer E -- Hysi, Pirro G -- Ikram, M Arfan -- Ingelsson, Erik -- Joensuu, Anni -- Johansson, Asa -- Jousilahti, Pekka -- Jukema, J Wouter -- Kahonen, Mika -- Kamatani, Yoichiro -- Kanoni, Stavroula -- Kerr, Shona M -- Khan, Nazir M -- Koellinger, Philipp -- Koistinen, Heikki A -- Kooner, Manraj K -- Kubo, Michiaki -- Kuusisto, Johanna -- Lahti, Jari -- Launer, Lenore J -- Lea, Rodney A -- Lehne, Benjamin -- Lehtimaki, Terho -- Liewald, David C M -- Lind, Lars -- Loh, Marie -- Lokki, Marja-Liisa -- London, Stephanie J -- Loomis, Stephanie J -- Loukola, Anu -- Lu, Yingchang -- Lumley, Thomas -- Lundqvist, Annamari -- Mannisto, Satu -- Marques-Vidal, Pedro -- Masciullo, Corrado -- Matchan, Angela -- Mathias, Rasika A -- Matsuda, Koichi -- Meigs, James B -- Meisinger, Christa -- Meitinger, Thomas -- Menni, Cristina -- Mentch, Frank D -- Mihailov, Evelin -- Milani, Lili -- Montasser, May E -- Montgomery, Grant W -- Morrison, Alanna -- Myers, Richard H -- Nadukuru, Rajiv -- Navarro, Pau -- Nelis, Mari -- Nieminen, Markku S -- Nolte, Ilja M -- O'Connor, George T -- Ogunniyi, Adesola -- Padmanabhan, Sandosh -- Palmas, Walter R -- Pankow, James S -- Patarcic, Inga -- Pavani, Francesca -- Peyser, Patricia A -- Pietilainen, Kirsi -- Poulter, Neil -- Prokopenko, Inga -- Ralhan, Sarju -- Redmond, Paul -- Rich, Stephen S -- Rissanen, Harri -- Robino, Antonietta -- Rose, Lynda M -- Rose, Richard -- Sala, Cinzia -- Salako, Babatunde -- Salomaa, Veikko -- Sarin, Antti-Pekka -- Saxena, Richa -- Schmidt, Helena -- Scott, Laura J -- Scott, William R -- Sennblad, Bengt -- Seshadri, Sudha -- Sever, Peter -- Shrestha, Smeeta -- Smith, Blair H -- Smith, Jennifer A -- Soranzo, Nicole -- Sotoodehnia, Nona -- Southam, Lorraine -- Stanton, Alice V -- Stathopoulou, Maria G -- Strauch, Konstantin -- Strawbridge, Rona J -- Suderman, Matthew J -- Tandon, Nikhil -- Tang, Sian-Tsun -- Taylor, Kent D -- Tayo, Bamidele O -- Toglhofer, Anna Maria -- Tomaszewski, Maciej -- Tsernikova, Natalia -- Tuomilehto, Jaakko -- Uitterlinden, Andre G -- Vaidya, Dhananjay -- van Hylckama Vlieg, Astrid -- van Setten, Jessica -- Vasankari, Tuula -- Vedantam, Sailaja -- Vlachopoulou, Efthymia -- Vozzi, Diego -- Vuoksimaa, Eero -- Waldenberger, Melanie -- Ware, Erin B -- Wentworth-Shields, William -- Whitfield, John B -- Wild, Sarah -- Willemsen, Gonneke -- Yajnik, Chittaranjan S -- Yao, Jie -- Zaza, Gianluigi -- Zhu, Xiaofeng -- BioBank Japan Project -- Salem, Rany M -- Melbye, Mads -- Bisgaard, Hans -- Samani, Nilesh J -- Cusi, Daniele -- Mackey, David A -- Cooper, Richard S -- Froguel, Philippe -- Pasterkamp, Gerard -- Grant, Struan F A -- Hakonarson, Hakon -- Ferrucci, Luigi -- Scott, Robert A -- Morris, Andrew D -- Palmer, Colin N A -- Dedoussis, George -- Deloukas, Panos -- Bertram, Lars -- Lindenberger, Ulman -- Berndt, Sonja I -- Lindgren, Cecilia M -- Timpson, Nicholas J -- Tonjes, Anke -- Munroe, Patricia B -- Sorensen, Thorkild I A -- Rotimi, Charles N -- Arnett, Donna K -- Oldehinkel, Albertine J -- Kardia, Sharon L R -- Balkau, Beverley -- Gambaro, Giovanni -- Morris, Andrew P -- Eriksson, Johan G -- Wright, Margie J -- Martin, Nicholas G -- Hunt, Steven C -- Starr, John M -- Deary, Ian J -- Griffiths, Lyn R -- Tiemeier, Henning -- Pirastu, Nicola -- Kaprio, Jaakko -- Wareham, Nicholas J -- Perusse, Louis -- Wilson, James G -- Girotto, Giorgia -- Caulfield, Mark J -- Raitakari, Olli -- Boomsma, Dorret I -- Gieger, Christian -- van der Harst, Pim -- Hicks, Andrew A -- Kraft, Peter -- Sinisalo, Juha -- Knekt, Paul -- Johannesson, Magnus -- Magnusson, Patrik K E -- Hamsten, Anders -- Schmidt, Reinhold -- Borecki, Ingrid B -- Vartiainen, Erkki -- Becker, Diane M -- Bharadwaj, Dwaipayan -- Mohlke, Karen L -- Boehnke, Michael -- van Duijn, Cornelia M -- Sanghera, Dharambir K -- Teumer, Alexander -- Zeggini, Eleftheria -- Metspalu, Andres -- Gasparini, Paolo -- Ulivi, Sheila -- Ober, Carole -- Toniolo, Daniela -- Rudan, Igor -- Porteous, David J -- Ciullo, Marina -- Spector, Tim D -- Hayward, Caroline -- Dupuis, Josee -- Loos, Ruth J F -- Wright, Alan F -- Chandak, Giriraj R -- Vollenweider, Peter -- Shuldiner, Alan R -- Ridker, Paul M -- Rotter, Jerome I -- Sattar, Naveed -- Gyllensten, Ulf -- North, Kari E -- Pirastu, Mario -- Psaty, Bruce M -- Weir, David R -- Laakso, Markku -- Gudnason, Vilmundur -- Takahashi, Atsushi -- Chambers, John C -- Kooner, Jaspal S -- Strachan, David P -- Campbell, Harry -- Hirschhorn, Joel N -- Perola, Markus -- Polasek, Ozren -- Wilson, James F -- 068545/Wellcome Trust/United Kingdom -- 072856/Wellcome Trust/United Kingdom -- 072960/Wellcome Trust/United Kingdom -- 079771/Wellcome Trust/United Kingdom -- 084723/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 099194/Wellcome Trust/United Kingdom -- 105022/Wellcome Trust/United Kingdom -- 250157/European Research Council/International -- 280559/European Research Council/International -- 323195/European Research Council/International -- BARCVBRU-2012-1/Department of Health/United Kingdom -- BB/F019394/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- CZB/4/276/Chief Scientist Office/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- CZD/16/6/Chief Scientist Office/United Kingdom -- CZD/16/6/2/Chief Scientist Office/United Kingdom -- CZD/16/6/3/Chief Scientist Office/United Kingdom -- CZD/16/6/4/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- MC_UU_12013/3/Medical Research Council/United Kingdom -- MC_UU_12015/1/Medical Research Council/United Kingdom -- MR/K026992/1/Medical Research Council/United Kingdom -- P20 MD006899/MD/NIMHD NIH HHS/ -- P30 DK020572/DK/NIDDK NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R03 DC013373/DC/NIDCD NIH HHS/ -- RG/2001004/12869/British Heart Foundation/United Kingdom -- RP-PG-0407-10371/Department of Health/United Kingdom -- SAG09977/Biotechnology and Biological Sciences Research Council/United Kingdom -- UL1 TR000124/TR/NCATS NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Jul 23;523(7561):459-62. doi: 10.1038/nature14618. Epub 2015 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141 Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [4] Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; 1] Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. ; Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. ; Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, 34149 Trieste, Italy. ; Institute of Genetics and Biophysics "A. Buzzati-Traverso" CNR, via Pietro Castellino, 111, 80131 Naples, Italy. ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; 1] Icelandic Heart Association, Holtasmari 1, 201, Kopavogur, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. ; 1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland. ; Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, Michigan 48104, USA. ; Department of Epidemiology, University of Michigan, 1415 Washington Heights, Ann Arbor, Michigan 48109, USA. ; Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; Institute of Population Genetics, National Research Council, Trav. La Crucca n. 3 - Reg. Baldinca, 07100 Sassari, Italy. ; Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, Chapel Hill, North Carolina 27599, USA. ; Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden. ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; 1] Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, California 90502, USA. [2] Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90502, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, East, Harvard Medical School, Boston, Boston, Massachusetts 02215, USA. ; Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. ; 1] Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, Lausanne, 1005, Switzerland. [2] Swiss Institute of Bioinformatics, Quartier Sorge - batiment genopode, Lausanne, 1015, Switzerland. ; Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India. ; Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA. ; 1] Department of Twin Research &Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK. [2] NIHR Biomedical Research Centre, Guy's and St. Thomas' Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy. ; Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens 17671, Greece. ; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, Greifswald 17475, Germany. ; Center for Human Genetic Research, 55 Fruit Street, Massachusetts General Hospital, Massachusetts 02114, USA. ; Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ; Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mathura Road, New Delhi, 110025, India. ; The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ; Department of Genetics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, Missouri 63108, USA. ; 1] Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria. [2] Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz2, Graz, A-8036, Austria. ; Erasmus School of Economics, Erasmus University Rotterdam, Burgemeester Oudlaan 50, Rotterdam, 3000 DR, The Netherlands. ; Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden. ; 1] Channing Division of Network Medicine, Brigham &Women's Hospital, 181 Longwood, Boston, Massachusetts 02115, USA. [2] Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, Massachusetts 02215, USA. ; Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), 39100 Bolzano, Italy (affiliated Institute of the University of Lubeck, D-23562 Lubeck, Germany). ; University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [3] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Amsterdam, 1081 BT, The Netherlands. ; 1] Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. [2] NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ; Department of Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, Mississippi 39216, USA. ; Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, Louisiana 70808, USA. ; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. ; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. ; Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, GPO Box 2434, Brisbane Queensland 4001, Australia. ; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, Wisconsin 53226, USA. ; Quantitative Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane Queensland 4006, Australia. ; Dipartimento di Scienze della Vita e della Riproduzione, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000 Lille, France. ; Department of Biostatistics, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, Alabama 35294, USA. ; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, P.O. box 30.001, 9700 RB, Groningen, The Netherlands. ; Center for Research on Genomics and Global Health, National Human Genome Research Institute, Building 12A/Room 4047, 12 South Dr., Bethesda, Maryland 20892, USA. ; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. ; MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. ; 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, Maryland 20850, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin 14195, Germany. [2] Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195 Germany. ; 1] Charite Research Group on Geriatrics, Charite - Universitatsmedizin Berlin, Reinickendorferstr. 61, 13347 Berlin, Germany. [2] Institute of Medical and Human Genetics, Charite - Universitatsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany. ; Division of Population Health Sciences, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee DD2 4BF, UK. ; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. ; Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. ; Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. ; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK. ; 1] COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Copenhagen, Denmark. [2] Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark. [3] Steno Diabetes Centre, Niels Steensens Vej 2, Gentofte, 2820, Denmark. ; Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. ; Department of Health Sciences, University of Milan, via A. di Rudini 8, 20142 Milan, Italy. ; Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, 2 Verdun Street, Perth, Western Australia 6009, Australia. ; Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark. ; Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, Illinois 60637, USA. ; Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; 1] Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands. [3] Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, Gower Street, London WC1E 6BT, UK. ; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; Department of Medicine, Columbia University, 622 W. 168th Street, New York, New York 10032, USA. ; Institute for Community Medicine, University Medicine Greifswald, W.-Rathenau-Str. 48, Greifswald 17475, Germany. ; 1] Department of Economics, Cornell University, 480 Uris Hall, Ithaca, New York 14853, USA. [2] Department of Economics and Center for Economic and Social Research, University of Southern California, 314C Dauterive Hall, 635 Downey Way, Los Angeles, California 90089, USA. ; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler Street, Suite 453E, Houston, Texas 77030, USA. ; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141 Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [3] Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, Maryland 20850, USA. ; Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, 665 Huntington Ave, Boston, Massachusetts 02115, USA. ; Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, College Office, Level 10, Dundee DD1 9SY, UK. ; 1] Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA. [2] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. ; 1] Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department of Internal Medicine B, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, Greifswald 17475, Germany. ; 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Cardiology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, 4, Geneve 14, 1211, Switzerland. ; Robertson Centre, University of Glasgow, Boyd Orr Building, Glasgow G12 8QQ, Scotland. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, Massachusetts 02115, USA. ; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, 17475 Greifswald, Germany. ; Department of Twin Research &Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK. ; Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, Massachusetts 02215, USA. ; Division of Biostatistics, Washington University, 660 S Euclid, St Louis, Missouri 63110, USA. ; 1] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK. [2] Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK. ; 1] Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; National Institutes on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Department of Neurology, Boston University School of Medicine, 72 E Concord St, Boston, Massachusetts 02118, USA. ; Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland. ; Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. ; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Radiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [2] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, SE-17121, Sweden. ; 1] Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden. [2] Uppsala Clinical Research Center, Uppsala University, Uppsala, SE-75237, Sweden. ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. ; Department of Cardiology C5-P, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; Department of Clinical Physiology, University of Tampere and Tampere University Hospital, P.O. Box 2000, Tampere, FI-33521, Finland. ; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; 1] Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland. [3] Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki, FI-00290, Finland. ; Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. ; Laboratory for Genotyping Development RCfIMS, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, FI-70210, Finland. ; 1] Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, University of Helsinki, Helsinki, FI-00014, Finland. [2] Folkhalsan Reasearch Centre, PB 63, Helsinki, FI-00014 University of Helsinki, Finland. ; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. ; Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, FI-33520, Finland. ; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department of Medical Sciences, University Hospital, Uppsala, 75185, Sweden. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, 138648, Singapore. ; Transplantation laboratory, Haartman Institute, University of Helsinki, P.O. Box 21, Helsinki, FI-00014, Finland. ; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA. ; Ophthalmology, Massachusetts Eye and Ear, 243 Charles Street, Boston, Massachusetts 02114, USA. ; Department of Statistics, University of Auckland, 303.325 Science Centre, Private Bag 92019, Auckland, 1142, New Zealand. ; Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. ; Department of Internal Medicine, University Hospital, Rue du Bugnon 44, Lausanne, 1011, Switzerland. ; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. ; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. ; Division of General Internal Medicine, Massachusetts General Hospital, 50 Staniford St, Boston, Massachusetts 02114, USA. ; Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; 1] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Human Genetics, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Str. 22, Munchen 81675, Germany. ; Molecular Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, Massachusetts 02118, USA. ; HUCH Heart and Lung center, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FI-00029, Finland. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Pulmonary Center and Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, Massachusetts 02118, USA. ; Department of Medicine, University of Ibadan, Ibadan, Nigeria. ; ICAMS, University of Glasgow, 126 University Way, Glasgow G12 8TA, UK. ; Division of Epidemiology and Community Health, University of Minnesota, 1300 S 2nd Street, Minneapolis, Minnesota 55454, USA. ; Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. [2] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland. [3] Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, P.O.Box 63, Haartmaninkatu 8, FI-00014, Helsinki, Finland. ; International Centre for Circulatory Health, Imperial College London, London W2 1LA, UK. ; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK. ; Department of Cardiology and Cardio thoracic Surgery Hero DMC Heart Institute, Civil Lines, 141001, Ludhiana, India. ; Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department Public Health Sciences, University of Virginia School of Medicine, 3232 West Complex, Charlottesville, Virginia 22908, USA. ; Department of Psychological &Brain Sciences, Indiana University Bloomington, 1101 E. 10th Street, Bloomington, Indiana 47405, USA. ; Institute of Molecular Biology and Biochemistry, Medical University Graz, Harrachgasse 21, Graz, A-8010, Austria. ; 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden. [2] Science for Life Laboratory, Karolinska Institutet, Stockholm, SE-17121, Sweden. ; University of Dundee, Kirsty Semple Way, Dundee DD2 4DB, UK. ; Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [2] Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland. ; UMR INSERM U1122; IGE-PCV "Interactions Gene-Environnement en Physiopathologie Cardio-Vasculaire", INSERM, University of Lorraine, 30 Rue Lionnois, 54000 Nancy, France. ; 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, Munich 81377, Germany. ; Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, 110029, India. ; National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK. ; Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA. ; 1] Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. [2] NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Institute of Molecular and Cell Biology, University of Tartu, Riia 23, Tartu, 51010, Estonia. ; 1] Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria. [3] Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; Finnish Lung Health Association, Sibeliuksenkatu 11 A 1, Helsinki, FI-00250, Finland. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Centre for Population Health Sciences, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; Diabetes Unit, KEM Hospital and Research Centre, Rasta Peth, Pune, 411011, India. ; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, California 90502, USA. ; Renal Unit, Department of Medicine, University of Verona, Piazzale A. Stefani 1, 37124 Verona, Italy. ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA. ; 1] Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark. [2] Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA. ; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Copenhagen, Denmark. ; 1] CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000 Lille, France. [2] Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK. ; 1] Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. [2] Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. ; Translational Gerontology Branch, National institute on Aging, Baltimore, Maryland 21225, USA. ; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, No. 9 Edinburgh Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, UK. ; Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee DD1 9SY, UK. ; 1] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK [2] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia. ; 1] Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195 Germany. [2] Faculty of Medicine, Imperial College London, Charing Cross Campus, St Dunstan's Road, London W6 8RP, UK. [3] Institutes for Neurogenetics and Integrative &Experimental Genomics, University of Lubeck, Lubeck 23562, Germany. ; Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin 14195, Germany. ; 1] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; Department of Medicine, University of Leipzig, Leipzig 04103, Germany. ; 1] MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. [2] Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark. [3] Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, 2000, Denmark. ; Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294, USA. ; Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, Groningen, 9700 RB, The Netherlands. ; Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Inserm, CESP Center for Research in Epidemiology and Population Health U1018, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif, France. ; Dipartimento di Scienze Mediche, Catholic University of the Sacred Heart, Via G. Moscati 31/34, 00168 Roma, Italy. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [3] Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Stree, Liverpool L69 3GA, UK. ; 1] Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. [2] Department of General Practice and Primary Health Care, University of Helsinki, P.O. Box 20, University of Helsinki, Helsinki, FI-00014, Finland. [3] Vasa Central Hospital, Sandviksgatan 2-4, Vasa, FI-65130, Finland. [4] Folkhalsan Reasearch Centre, PB 63, University of Helsinki, Helsinki, FI-00014, Finland. [5] Unit of General Practice, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, FI-00290, Finland. ; Neuro-Imaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Cardiovascular Genetics Division, University of Utah, 420 Chipeta Way, Room 1160, Salt Lake City, Utah 84117, USA. ; 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. [2] Alzheimer Scotland Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Psychiatry, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, 34149 Trieste, Italy. [2] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. [2] Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland. [3] National Institute for Health and Welfare (THL), P.O.Box 30, Mannerheimintie 166, Helsinki, FI-00271, Finland. ; Department of Kinesiology, Laval University, 2300 rue de la Terrasse, Quebec G1V 0A6, Canada. ; Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, Mississippi 39216, USA. ; 1] Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, FI-20521, Finland. [2] Research Center of Applied and Preventive Cardiovascular medicine, University of Turku, Turku, FI-20521, Finland. ; 1] University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands. [3] University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; Department of Economics, Stockholm School of Economics, Box 6501, Stockholm, SE-113 83, Sweden. ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, SE-171 77, Sweden. ; Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria. ; Department of Genetics and Biostatistics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, Missouri 63108, USA. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; 1] Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mathura Road, New Delhi, 110025, India. [2] School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. ; 1] Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 Stanton Young Boulevard, Oklahoma City, Oklahoma 73104, USA. [2] Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. ; 1] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. [2] Sidra Medical and Research Centre, Doha, Qatar. ; 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [3] The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; 1] Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India. [2] Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore. ; 1] Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. [2] Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. [3] Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, 685 W Baltimore MSTF, Baltimore, Maryland 21201, USA. ; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. ; 1] Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, 137 E. Franklin Street, Suite 306, Chapel Hill, North Carolina 27599, USA. ; 1] Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. [2] Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. [3] Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London W2 1NY, UK. ; 1] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. [2] National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK. [3] Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London W2 1NY, UK. ; Population Health Research Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. ; 1] Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia. ; 1] Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26131930" target="_blank"〉PubMed〈/a〉

Description: The study of the human pathogen papillomaviruses (HPVs) has been hampered by the inability to propagate the virus in tissue culture. The addition of 12-O-tetradecanoyl phorbol-13-acetate to the media of organotypic (raft) cultures increased expression of physiological markers of keratinocyte differentiation and concomitantly induced production of virions. Capsid production was detected in differentiated suprabasal cells. Virions approximately 54 nanometers in size were observed by electron microscopy in raft tissue cross sections in the suprabasal layers. Virions purified through isopycnic gradients were found to contain type 31b DNA and exhibited an icosahedral shape similar to that of papillomaviruses found in clinical samples.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meyers, C -- Frattini, M G -- Hudson, J B -- Laimins, L A -- New York, N.Y. -- Science. 1992 Aug 14;257(5072):971-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, University of Chicago, IL 60637.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1323879" target="_blank"〉PubMed〈/a〉