ALBERT

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gupta, Sujata -- England -- Nature. 2015 Oct 8;526(7572):S6-7. doi: 10.1038/526S6a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444374" target="_blank"〉PubMed〈/a〉

Description: During fertilization, an egg and a sperm fuse to form a new embryo. Eggs develop from oocytes in a process called meiosis. Meiosis in human oocytes is highly error-prone, and defective eggs are the leading cause of pregnancy loss and several genetic disorders such as Down's syndrome. Which genes safeguard accurate progression through meiosis is largely unclear. Here we develop high-content phenotypic screening methods for the systematic identification of mammalian meiotic genes. We targeted 774 genes by RNA interference within follicle-enclosed mouse oocytes to block protein expression from an early stage of oocyte development onwards. We then analysed the function of several genes simultaneously by high-resolution imaging of chromosomes and microtubules in live oocytes and scored each oocyte quantitatively for 50 phenotypes, generating a comprehensive resource of meiotic gene function. The screen generated an unprecedented annotated data set of meiotic progression in 2,241 mammalian oocytes, which allowed us to analyse systematically which defects are linked to abnormal chromosome segregation during meiosis, identifying progression into anaphase with misaligned chromosomes as well as defects in spindle organization as risk factors. This study demonstrates how high-content screens can be performed in oocytes, and allows systematic studies of meiosis in mammals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538867/" 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/PMC4538867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pfender, Sybille -- Kuznetsov, Vitaliy -- Pasternak, Michal -- Tischer, Thomas -- Santhanam, Balaji -- Schuh, Melina -- 337415/European Research Council/International -- MC_U105185859/Medical Research Council/United Kingdom -- MC_U105192711/Medical Research Council/United Kingdom -- England -- Nature. 2015 Aug 13;524(7564):239-42. doi: 10.1038/nature14568. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147080" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Feb 12;518(7538):145-6. doi: 10.1038/518145a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25673389" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dranovsky, Alex -- Leonardo, E David -- England -- Nature. 2015 Jun 18;522(7556):294-5. doi: 10.1038/522294a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, Division of Integrative Neuroscience, Columbia University, New York, New York 10032, USA, and at the New York State Psychiatric Institute.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085266" target="_blank"〉PubMed〈/a〉

Description: Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adhikari, Avishek -- Lerner, Talia N -- Finkelstein, Joel -- Pak, Sally -- Jennings, Joshua H -- Davidson, Thomas J -- Ferenczi, Emily -- Gunaydin, Lisa A -- Mirzabekov, Julie J -- Ye, Li -- Kim, Sung-Yon -- Lei, Anna -- Deisseroth, Karl -- 1F32MH105053-01/MH/NIMH NIH HHS/ -- K99 MH106649/MH/NIMH NIH HHS/ -- K99MH106649/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):179-85. doi: 10.1038/nature15698. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, Stanford University, Stanford, California 94305, USA. ; CNC Program, Stanford University, Stanford, California 94304, USA. ; Neurosciences Program, Stanford University, Stanford, California 94305, USA. ; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA. ; Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536109" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Picker, Louis J -- Lifson, Jeffrey D -- England -- Nature. 2015 Jan 15;517(7534):281-2. doi: 10.1038/nature14194. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine and Gene Therapy Institute, Oregon Health &Science University, Beaverton, Oregon 97006, USA. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25561174" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gupta, Sujata -- England -- Nature. 2015 Jun 25;522(7557):S57-9. doi: 10.1038/522S57a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26107098" target="_blank"〉PubMed〈/a〉

Description: Nuclear pore complexes are fundamental components of all eukaryotic cells that mediate nucleocytoplasmic exchange. Determining their 110-megadalton structure imposes a formidable challenge and requires in situ structural biology approaches. Of approximately 30 nucleoporins (Nups), 15 are structured and form the Y and inner-ring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold rotationally symmetric structure that fuses the inner and outer nuclear membranes to form a central channel of ~60 nm in diameter. The scaffold is decorated with transport-channel Nups that often contain phenylalanine-repeat sequences and mediate the interaction with cargo complexes. Although the architectural arrangement of parts of the Y complex has been elucidated, it is unclear how exactly it oligomerizes in situ. Here we combine cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modelling to generate, to our knowledge, the most comprehensive architectural model of the human nuclear pore complex to date. Our data suggest previously unknown protein interfaces across Y complexes and to inner-ring complex members. We show that the transport-channel Nup358 (also known as Ranbp2) has a previously unanticipated role in Y-complex oligomerization. Our findings blur the established boundaries between scaffold and transport-channel Nups. We conclude that, similar to coated vesicles, several copies of the same structural building block--although compositionally identical--engage in different local sets of interactions and conformations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von Appen, Alexander -- Kosinski, Jan -- Sparks, Lenore -- Ori, Alessandro -- DiGuilio, Amanda L -- Vollmer, Benjamin -- Mackmull, Marie-Therese -- Banterle, Niccolo -- Parca, Luca -- Kastritis, Panagiotis -- Buczak, Katarzyna -- Mosalaganti, Shyamal -- Hagen, Wim -- Andres-Pons, Amparo -- Lemke, Edward A -- Bork, Peer -- Antonin, Wolfram -- Glavy, Joseph S -- Bui, Khanh Huy -- Beck, Martin -- 1R21AG047433-01/AG/NIA NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):140-3. doi: 10.1038/nature15381. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany. ; Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, 507 River St., Hoboken, New Jersey 07030, USA. ; Friedrich Miescher Laboratory of the Max Planck Society, Spemannstrasse 39, 72076 Tubingen, Germany. ; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416747" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Helen -- England -- Nature. 2015 Jun 25;522(7557):410-2. doi: 10.1038/522410a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26108835" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harris, Isaac S -- Brugge, Joan S -- England -- Nature. 2015 Nov 12;527(7577):170-1. doi: 10.1038/nature15644. Epub 2015 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and the Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503052" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kutschera, U -- England -- Nature. 2015 Jul 2;523(7558):35. doi: 10.1038/523035d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biology, University of Kassel, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135438" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harris, Nicola -- England -- Nature. 2015 Oct 22;526(7574):509-10. doi: 10.1038/526509a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Global Health Institute, School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26490613" target="_blank"〉PubMed〈/a〉

Description: DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report a near-atomic structure of the MCM2-7 double hexamer purified from yeast G1 chromatin. Our structure shows that two single hexamers, arranged in a tilted and twisted fashion through interdigitated amino-terminal domain interactions, form a kinked central channel. Four constricted rings consisting of conserved interior beta-hairpins from the two single hexamers create a narrow passageway that tightly fits duplex DNA. This narrow passageway, reinforced by the offset of the two single hexamers at the double hexamer interface, is flanked by two pairs of gate-forming subunits, MCM2 and MCM5. These unusual features of the twisted and tilted single hexamers suggest a concerted mechanism for the melting of origin DNA that requires structural deformation of the intervening DNA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ningning -- Zhai, Yuanliang -- Zhang, Yixiao -- Li, Wanqiu -- Yang, Maojun -- Lei, Jianlin -- Tye, Bik-Kwoon -- Gao, Ning -- England -- Nature. 2015 Aug 13;524(7564):186-91. doi: 10.1038/nature14685. Epub 2015 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Department of Molecular Biology and Genetics, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26222030" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamilton, Garry -- England -- Nature. 2015 Sep 24;525(7570):444-6. doi: 10.1038/525444a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26399812" 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: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watson, Darach -- Hjorth, Jens -- England -- Nature. 2015 Mar 12;519(7542):158. doi: 10.1038/519158d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Niels Bohr Institute, University of Copenhagen, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762273" target="_blank"〉PubMed〈/a〉

Description: Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G--〉V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486072/" 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/PMC4486072/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asante, Emmanuel A -- Smidak, Michelle -- Grimshaw, Andrew -- Houghton, Richard -- Tomlinson, Andrew -- Jeelani, Asif -- Jakubcova, Tatiana -- Hamdan, Shyma -- Richard-Londt, Angela -- Linehan, Jacqueline M -- Brandner, Sebastian -- Alpers, Michael -- Whitfield, Jerome -- Mead, Simon -- Wadsworth, Jonathan D F -- Collinge, John -- MC_U123160653/Medical Research Council/United Kingdom -- Department of Health/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):478-81. doi: 10.1038/nature14510. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. ; 1] MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK [2] Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061765" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Erez, Neta -- England -- Nature. 2015 Jun 4;522(7554):41-2. doi: 10.1038/nature14529. Epub 2015 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978 Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017311" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sohn, Emily -- England -- Nature. 2015 Nov 19;527(7578):S118-9. doi: 10.1038/527S118a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580162" target="_blank"〉PubMed〈/a〉

Description: The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chassaing, Benoit -- Koren, Omry -- Goodrich, Julia K -- Poole, Angela C -- Srinivasan, Shanthi -- Ley, Ruth E -- Gewirtz, Andrew T -- DK083890/DK/NIDDK NIH HHS/ -- DK099071/DK/NIDDK NIH HHS/ -- R01 DK083890/DK/NIDDK NIH HHS/ -- R01 DK099071/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Mar 5;519(7541):92-6. doi: 10.1038/nature14232. Epub 2015 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30303, USA. ; Faculty of Medicine, Bar Ilan University, Safed, 13115, Israel. ; Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA. ; Digestive Diseases Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25731162" target="_blank"〉PubMed〈/a〉

Description: Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700594/" 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/PMC4700594/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wculek, Stefanie K -- Malanchi, Ilaria -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Dec 17;528(7582):413-7. doi: 10.1038/nature16140. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Francis Crick Institute, Lincolns Inn Fields Laboratories, 44 Lincolns Inn Fields, London WC2A 3LY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649828" target="_blank"〉PubMed〈/a〉

Description: Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rathert, Philipp -- Roth, Mareike -- Neumann, Tobias -- Muerdter, Felix -- Roe, Jae-Seok -- Muhar, Matthias -- Deswal, Sumit -- Cerny-Reiterer, Sabine -- Peter, Barbara -- Jude, Julian -- Hoffmann, Thomas -- Boryn, Lukasz M -- Axelsson, Elin -- Schweifer, Norbert -- Tontsch-Grunt, Ulrike -- Dow, Lukas E -- Gianni, Davide -- Pearson, Mark -- Valent, Peter -- Stark, Alexander -- Kraut, Norbert -- Vakoc, Christopher R -- Zuber, Johannes -- England -- Nature. 2015 Sep 24;525(7570):543-7. doi: 10.1038/nature14898. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria. ; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria. ; Boehringer Ingelheim - Regional Center Vienna GmbH, 1121 Vienna, Austria. ; Department of Medicine, Hematology &Medical Oncology, Weill Cornell Medical College, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367798" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bakardjiev, Anna -- England -- Nature. 2015 Apr 30;520(7549):627-8. doi: 10.1038/520627a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Benioff Children's Hospital, University of California, San Francisco, San Francisco, California 94143-0654, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25925473" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Le Bot, Nathalie -- England -- Nature. 2015 Mar 26;519(7544):420. doi: 10.1038/519420a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25810200" target="_blank"〉PubMed〈/a〉

Description: Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human gamma-secretase at 3.4 A resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of gamma-secretase function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568306/" 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/PMC4568306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Xiao-chen -- Yan, Chuangye -- Yang, Guanghui -- Lu, Peilong -- Ma, Dan -- Sun, Linfeng -- Zhou, Rui -- Scheres, Sjors H W -- Shi, Yigong -- MC_UP_A025_101/Medical Research Council/United Kingdom -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 10;525(7568):212-7. doi: 10.1038/nature14892. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280335" target="_blank"〉PubMed〈/a〉

Description: micro-Opioid receptors (microORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the muOR in inactive and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of muOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the muOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the beta2-adrenergic receptor. Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sounier, Remy -- Mas, Camille -- Steyaert, Jan -- Laeremans, Toon -- Manglik, Aashish -- Huang, Weijiao -- Kobilka, Brian K -- Demene, Helene -- Granier, Sebastien -- DA036246/DA/NIDA NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):375-8. doi: 10.1038/nature14680. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Centre de Biochimie Structurale, CNRS UMR 5048-INSERM 1054- University of Montpellier, 29 rue de Navacelles, 34090 Montpellier Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245377" target="_blank"〉PubMed〈/a〉

Description: Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders. Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia. The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments, although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus-amygdala-nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ramirez, Steve -- Liu, Xu -- MacDonald, Christopher J -- Moffa, Anthony -- Zhou, Joanne -- Redondo, Roger L -- Tonegawa, Susumu -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 18;522(7556):335-9. doi: 10.1038/nature14514.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085274" target="_blank"〉PubMed〈/a〉

Description: Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs. Because the monounsaturated products of SCD are key precursors of membrane phospholipids, cholesterol esters and triglycerides, SCD is pivotal in fatty acid metabolism. Humans have two SCD homologues (SCD1 and SCD5), while mice have four (SCD1-SCD4). SCD1-deficient mice do not become obese or diabetic when fed a high-fat diet because of improved lipid metabolic profiles and insulin sensitivity. Thus, SCD1 is a pharmacological target in the treatment of obesity, diabetes and other metabolic diseases. SCD1 is an integral membrane protein located in the endoplasmic reticulum, and catalyses the formation of a cis-double bond between the ninth and tenth carbons of stearoyl- or palmitoyl-CoA. The reaction requires molecular oxygen, which is activated by a di-iron centre, and cytochrome b5, which regenerates the di-iron centre. To understand better the structural basis of these characteristics of SCD function, here we crystallize and solve the structure of mouse SCD1 bound to stearoyl-CoA at 2.6 A resolution. The structure shows a novel fold comprising four transmembrane helices capped by a cytosolic domain, and a plausible pathway for lateral substrate access and product egress. The acyl chain of the bound stearoyl-CoA is enclosed in a tunnel buried in the cytosolic domain, and the geometry of the tunnel and the conformation of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal centre is coordinated by a unique spacial arrangement of nine conserved histidine residues that implies a potentially novel mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the di-iron centre.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689147/" 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/PMC4689147/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Yonghong -- McCoy, Jason G -- Levin, Elena J -- Sobrado, Pablo -- Rajashankar, Kanagalaghatta R -- Fox, Brian G -- Zhou, Ming -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41GM103403/GM/NIGMS NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01DK088057/DK/NIDDK NIH HHS/ -- R01GM050853/GM/NIGMS NIH HHS/ -- R01GM098878/GM/NIGMS NIH HHS/ -- R01HL086392/HL/NHLBI NIH HHS/ -- U54 GM094584/GM/NIGMS NIH HHS/ -- U54GM094584/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 13;524(7564):252-6. doi: 10.1038/nature14549. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. ; NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098370" target="_blank"〉PubMed〈/a〉

Description: Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn's disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wertz, Ingrid E -- Newton, Kim -- Seshasayee, Dhaya -- Kusam, Saritha -- Lam, Cynthia -- Zhang, Juan -- Popovych, Nataliya -- Helgason, Elizabeth -- Schoeffler, Allyn -- Jeet, Surinder -- Ramamoorthi, Nandhini -- Kategaya, Lorna -- Newman, Robert J -- Horikawa, Keisuke -- Dugger, Debra -- Sandoval, Wendy -- Mukund, Susmith -- Zindal, Anuradha -- Martin, Flavius -- Quan, Clifford -- Tom, Jeffrey -- Fairbrother, Wayne J -- Townsend, Michael -- Warming, Soren -- DeVoss, Jason -- Liu, Jinfeng -- Dueber, Erin -- Caplazi, Patrick -- Lee, Wyne P -- Goodnow, Christopher C -- Balazs, Mercedesz -- Yu, Kebing -- Kolumam, Ganesh -- Dixit, Vishva M -- England -- Nature. 2015 Dec 17;528(7582):370-5. doi: 10.1038/nature16165. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Discovery Oncology, Genentech, South San Francisco, California 94080, USA. ; Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA. ; Physiological Chemistry, Genentech, South San Francisco, California 94080, USA. ; Immunology, Genentech, South San Francisco, California 94080, USA. ; Molecular Biology, Genentech, South San Francisco, California 94080, USA. ; Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia. ; Protein Chemistry, Genentech, South San Francisco, California 94080, USA. ; Structural Biology, Genentech, South San Francisco, California 94080, USA. ; Bioinformatics, Genentech, South San Francisco, California 94080, USA. ; Pathology, Genentech, South San Francisco, California 94080, USA. ; Immunogenomics Laboratory, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Sydney, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649818" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Check Hayden, Erika -- England -- Nature. 2015 Jul 23;523(7561):393. doi: 10.1038/nature.2015.17951.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26201575" target="_blank"〉PubMed〈/a〉

Description: Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-alpha (ERalpha) function and breast cancer prognosis. Here we show that PR is not merely an ERalpha-induced gene target, but is also an ERalpha-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERalpha to direct ERalpha chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERalpha(+) cell line xenografts and primary ERalpha(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERalpha antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERalpha(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERalpha chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650274/" 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/PMC4650274/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mohammed, Hisham -- Russell, I Alasdair -- Stark, Rory -- Rueda, Oscar M -- Hickey, Theresa E -- Tarulli, Gerard A -- Serandour, Aurelien A -- Birrell, Stephen N -- Bruna, Alejandra -- Saadi, Amel -- Menon, Suraj -- Hadfield, James -- Pugh, Michelle -- Raj, Ganesh V -- Brown, Gordon D -- D'Santos, Clive -- Robinson, Jessica L L -- Silva, Grace -- Launchbury, Rosalind -- Perou, Charles M -- Stingl, John -- Caldas, Carlos -- Tilley, Wayne D -- Carroll, Jason S -- 242664/European Research Council/International -- 5P30CA142543/CA/NCI NIH HHS/ -- A10178/Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jul 16;523(7560):313-7. doi: 10.1038/nature14583. Epub 2015 Jul 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. ; Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide, Adelaide, South Australia 5005, Australia. ; Department of Urology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA. ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, CB7295, Chapel Hill, North Carolina 27599, USA. ; 1] Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK [2] Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK [3] Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26153859" target="_blank"〉PubMed〈/a〉

Description: Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409480/" 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/PMC4409480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉West, A Phillip -- Khoury-Hanold, William -- Staron, Matthew -- Tal, Michal C -- Pineda, Cristiana M -- Lang, Sabine M -- Bestwick, Megan -- Duguay, Brett A -- Raimundo, Nuno -- MacDuff, Donna A -- Kaech, Susan M -- Smiley, James R -- Means, Robert E -- Iwasaki, Akiko -- Shadel, Gerald S -- F31 AG039163/AG/NIA NIH HHS/ -- F32 DK091042/DK/NIDDK NIH HHS/ -- MOP37995/Canadian Institutes of Health Research/Canada -- P01 ES011163/ES/NIEHS NIH HHS/ -- R01 AG047632/AG/NIA NIH HHS/ -- R01 AI054359/AI/NIAID NIH HHS/ -- R01 AI081884/AI/NIAID NIH HHS/ -- T32 AI055403/AI/NIAID NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Apr 23;520(7548):553-7. doi: 10.1038/nature14156. Epub 2015 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. ; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; 1] Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA. ; 1] Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25642965" target="_blank"〉PubMed〈/a〉

Description: Na(+)-activated K(+) channels are members of the Slo family of large conductance K(+) channels that are widely expressed in the brain, where their opening regulates neuronal excitability. These channels fulfil a number of biological roles and have intriguing biophysical properties, including conductance levels that are ten times those of most other K(+) channels and gating sensitivity to intracellular Na(+). Here we present the structure of a complete Na(+)-activated K(+) channel, chicken Slo2.2, in the Na(+)-free state, determined by cryo-electron microscopy at a nominal resolution of 4.5 angstroms. The channel is composed of a large cytoplasmic gating ring, in which resides the Na(+)-binding site and a transmembrane domain that closely resembles voltage-gated K(+) channels. In the structure, the cytoplasmic domain adopts a closed conformation and the ion conduction pore is also closed. The structure reveals features that can explain the unusually high conductance of Slo channels and how contraction of the cytoplasmic gating ring closes the pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hite, Richard K -- Yuan, Peng -- Li, Zongli -- Hsuing, Yichun -- Walz, Thomas -- MacKinnon, Roderick -- GM43949/GM/NIGMS NIH HHS/ -- R01 GM043949/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):198-203. doi: 10.1038/nature14958. Epub 2015 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA. ; Department of Cell Biology and Howard Hughes Medical Institute, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26436452" target="_blank"〉PubMed〈/a〉

Description: Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca(2+) signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 A) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously approximately 85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca(2+)-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed alpha-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fan, Guizhen -- Baker, Matthew L -- Wang, Zhao -- Baker, Mariah R -- Sinyagovskiy, Pavel A -- Chiu, Wah -- Ludtke, Steven J -- Serysheva, Irina I -- P41 GM103832/GM/NIGMS NIH HHS/ -- P41GM103832/GM/NIGMS NIH HHS/ -- R01 GM072804/GM/NIGMS NIH HHS/ -- R01 GM079429/GM/NIGMS NIH HHS/ -- R01 GM080139/GM/NIGMS NIH HHS/ -- R01GM072804/GM/NIGMS NIH HHS/ -- R01GM079429/GM/NIGMS NIH HHS/ -- R01GM080139/GM/NIGMS NIH HHS/ -- R21 AR063255/AR/NIAMS NIH HHS/ -- R21 GM100229/GM/NIGMS NIH HHS/ -- R21AR063255/AR/NIAMS NIH HHS/ -- R21GM100229/GM/NIGMS NIH HHS/ -- S10 OD016279/OD/NIH HHS/ -- S10OD016279/OD/NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):336-41. doi: 10.1038/nature15249. Epub 2015 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA. ; National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26458101" target="_blank"〉PubMed〈/a〉

Description: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha6beta4 and alpha6beta1 were associated with lung metastasis, while exosomal integrin alphavbeta5 was linked to liver metastasis. Targeting the integrins alpha6beta4 and alphavbeta5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoshino, Ayuko -- Costa-Silva, Bruno -- Shen, Tang-Long -- Rodrigues, Goncalo -- Hashimoto, Ayako -- Tesic Mark, Milica -- Molina, Henrik -- Kohsaka, Shinji -- Di Giannatale, Angela -- Ceder, Sophia -- Singh, Swarnima -- Williams, Caitlin -- Soplop, Nadine -- Uryu, Kunihiro -- Pharmer, Lindsay -- King, Tari -- Bojmar, Linda -- Davies, Alexander E -- Ararso, Yonathan -- Zhang, Tuo -- Zhang, Haiying -- Hernandez, Jonathan -- Weiss, Joshua M -- Dumont-Cole, Vanessa D -- Kramer, Kimberly -- Wexler, Leonard H -- Narendran, Aru -- Schwartz, Gary K -- Healey, John H -- Sandstrom, Per -- Labori, Knut Jorgen -- Kure, Elin H -- Grandgenett, Paul M -- Hollingsworth, Michael A -- de Sousa, Maria -- Kaur, Sukhwinder -- Jain, Maneesh -- Mallya, Kavita -- Batra, Surinder K -- Jarnagin, William R -- Brady, Mary S -- Fodstad, Oystein -- Muller, Volkmar -- Pantel, Klaus -- Minn, Andy J -- Bissell, Mina J -- Garcia, Benjamin A -- Kang, Yibin -- Rajasekhar, Vinagolu K -- Ghajar, Cyrus M -- Matei, Irina -- Peinado, Hector -- Bromberg, Jacqueline -- Lyden, David -- R01 CA169416/CA/NCI NIH HHS/ -- R01-CA169416/CA/NCI NIH HHS/ -- U01 CA169538/CA/NCI NIH HHS/ -- U01-CA169538/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):329-35. doi: 10.1038/nature15756. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan. ; Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal. ; Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. ; Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden. ; Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA. ; Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA. ; Department of Surgery, County Council of Ostergotland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, 58185 Linkoping, Sweden. ; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada. ; Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA. ; Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway. ; Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA. ; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. ; Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524530" target="_blank"〉PubMed〈/a〉

Description: Ubiquinone (also known as coenzyme Q) is a ubiquitous lipid-soluble redox cofactor that is an essential component of electron transfer chains. Eleven genes have been implicated in bacterial ubiquinone biosynthesis, including ubiX and ubiD, which are responsible for decarboxylation of the 3-octaprenyl-4-hydroxybenzoate precursor. Despite structural and biochemical characterization of UbiX as a flavin mononucleotide (FMN)-binding protein, no decarboxylase activity has been detected. Here we report that UbiX produces a novel flavin-derived cofactor required for the decarboxylase activity of UbiD. UbiX acts as a flavin prenyltransferase, linking a dimethylallyl moiety to the flavin N5 and C6 atoms. This adds a fourth non-aromatic ring to the flavin isoalloxazine group. In contrast to other prenyltransferases, UbiX is metal-independent and requires dimethylallyl-monophosphate as substrate. Kinetic crystallography reveals that the prenyltransferase mechanism of UbiX resembles that of the terpene synthases. The active site environment is dominated by pi systems, which assist phosphate-C1' bond breakage following FMN reduction, leading to formation of the N5-C1' bond. UbiX then acts as a chaperone for adduct reorientation, via transient carbocation species, leading ultimately to formation of the dimethylallyl C3'-C6 bond. Our findings establish the mechanism for formation of a new flavin-derived cofactor, extending both flavin and terpenoid biochemical repertoires.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉White, Mark D -- Payne, Karl A P -- Fisher, Karl -- Marshall, Stephen A -- Parker, David -- Rattray, Nicholas J W -- Trivedi, Drupad K -- Goodacre, Royston -- Rigby, Stephen E J -- Scrutton, Nigel S -- Hay, Sam -- Leys, David -- BB/K017802/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/M017702/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):502-6. doi: 10.1038/nature14559. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Synthetic Biology of Fine and Speciality Chemicals, Manchester Institute of Biotechnology, The University of Manchester, Manchester M1 7DN, UK. ; Innovation/Biodomain, Shell International Exploration and Production, Westhollow Technology Center, 3333 Highway 6 South, Houston, Texas 77082-3101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083743" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2015 Nov 5;527(7576):15-6. doi: 10.1038/527015a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536933" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoag, Hannah -- England -- Nature. 2015 Nov 19;527(7578):S114-5. doi: 10.1038/527S114a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580160" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sullivan, Patrick F -- England -- Nature. 2015 Jul 30;523(7562):539-40. doi: 10.1038/nature14635. Epub 2015 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA, and in the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26176922" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2015 Jul 16;523(7560):268-9. doi: 10.1038/523268a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26178945" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fausto-Sterling, Anne -- England -- Nature. 2015 Mar 19;519(7543):291. doi: 10.1038/519291e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Brown University, Providence, Rhode Island, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25788089" target="_blank"〉PubMed〈/a〉

Description: The brain has an extraordinary capacity for memory storage, but how it stores new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca(2+) spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex. These task-related, branch-specific Ca(2+) spikes cause long-lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca(2+) spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca(2+) spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca(2+) spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476301/" 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/PMC4476301/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cichon, Joseph -- Gan, Wen-Biao -- P01 NS074972/NS/NINDS NIH HHS/ -- R01 NS047325/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Apr 9;520(7546):180-5. doi: 10.1038/nature14251. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822789" target="_blank"〉PubMed〈/a〉

Description: Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528969/" 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/PMC4528969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Najm, Fadi J -- Madhavan, Mayur -- Zaremba, Anita -- Shick, Elizabeth -- Karl, Robert T -- Factor, Daniel C -- Miller, Tyler E -- Nevin, Zachary S -- Kantor, Christopher -- Sargent, Alex -- Quick, Kevin L -- Schlatzer, Daniela M -- Tang, Hong -- Papoian, Ruben -- Brimacombe, Kyle R -- Shen, Min -- Boxer, Matthew B -- Jadhav, Ajit -- Robinson, Andrew P -- Podojil, Joseph R -- Miller, Stephen D -- Miller, Robert H -- Tesar, Paul J -- F30 CA183510/CA/NCI NIH HHS/ -- F30CA183510/CA/NCI NIH HHS/ -- NS026543/NS/NINDS NIH HHS/ -- NS030800/NS/NINDS NIH HHS/ -- NS085246/NS/NINDS NIH HHS/ -- P30 CA043703/CA/NCI NIH HHS/ -- P30CA043703/CA/NCI NIH HHS/ -- R01 NS026543/NS/NINDS NIH HHS/ -- R01 NS030800/NS/NINDS NIH HHS/ -- R21 NS085246/NS/NINDS NIH HHS/ -- T32 GM007250/GM/NIGMS NIH HHS/ -- T32 GM008056/GM/NIGMS NIH HHS/ -- T32GM008056/GM/NIGMS NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Jun 11;522(7555):216-20. doi: 10.1038/nature14335. Epub 2015 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; 1] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [2] Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [3] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. ; PerkinElmer, 940 Winter Street, Waltham, Massachusetts 02451, USA. ; Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; Drug Discovery Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237, USA. ; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA. ; Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA. ; 1] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [2] Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25896324" target="_blank"〉PubMed〈/a〉

Description: MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hsu, Tiffany Y-T -- Simon, Lukas M -- Neill, Nicholas J -- Marcotte, Richard -- Sayad, Azin -- Bland, Christopher S -- Echeverria, Gloria V -- Sun, Tingting -- Kurley, Sarah J -- Tyagi, Siddhartha -- Karlin, Kristen L -- Dominguez-Vidana, Rocio -- Hartman, Jessica D -- Renwick, Alexander -- Scorsone, Kathleen -- Bernardi, Ronald J -- Skinner, Samuel O -- Jain, Antrix -- Orellana, Mayra -- Lagisetti, Chandraiah -- Golding, Ido -- Jung, Sung Y -- Neilson, Joel R -- Zhang, Xiang H-F -- Cooper, Thomas A -- Webb, Thomas R -- Neel, Benjamin G -- Shaw, Chad A -- Westbrook, Thomas F -- 1F30CA180447/CA/NCI NIH HHS/ -- 1R01CA178039-01/CA/NCI NIH HHS/ -- P30 AI036211/AI/NIAID NIH HHS/ -- P30CA125123/CA/NCI NIH HHS/ -- R01 AR045653/AR/NIAMS NIH HHS/ -- R01 AR060733/AR/NIAMS NIH HHS/ -- R01 CA140474/CA/NCI NIH HHS/ -- R01 HL045565/HL/NHLBI NIH HHS/ -- S10 RR024574/RR/NCRR NIH HHS/ -- U54-CA149196/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 17;525(7569):384-8. doi: 10.1038/nature14985. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA. ; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada. ; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Physics, University of Illinois, Urbana, Illinois 61801, USA. ; Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA. ; The Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Medical Biophysics, University of Toronto, Toronto M5S 2J7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331541" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Behar, Samuel M -- Baehrecke, Eric H -- R01 AI098637/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):482-3. doi: 10.1038/nature16324. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Physiological Systems, and Eric H. Baehrecke is in the Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649822" target="_blank"〉PubMed〈/a〉

Description: In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681099/" 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/PMC4681099/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Forslund, Kristoffer -- Hildebrand, Falk -- Nielsen, Trine -- Falony, Gwen -- Le Chatelier, Emmanuelle -- Sunagawa, Shinichi -- Prifti, Edi -- Vieira-Silva, Sara -- Gudmundsdottir, Valborg -- Krogh Pedersen, Helle -- Arumugam, Manimozhiyan -- Kristiansen, Karsten -- Voigt, Anita Yvonne -- Vestergaard, Henrik -- Hercog, Rajna -- Igor Costea, Paul -- Kultima, Jens Roat -- Li, Junhua -- Jorgensen, Torben -- Levenez, Florence -- Dore, Joel -- MetaHIT consortium -- Nielsen, H Bjorn -- Brunak, Soren -- Raes, Jeroen -- Hansen, Torben -- Wang, Jun -- Ehrlich, S Dusko -- Bork, Peer -- Pedersen, Oluf -- England -- Nature. 2015 Dec 10;528(7581):262-6. doi: 10.1038/nature15766. Epub 2015 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany. ; VIB Center for the Biology of Disease, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. ; Department of Bioscience Engineering, Vrije Universiteit Brussel, 1040 Brussels, Belgium. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. ; Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. ; MICALIS, Institut National de la Recherche Agronomique, 78352 Jouy en Josas, France. ; Metagenopolis, Institut National de la Recherche Agronomique, 78352 Jouy en Josas, France. ; Institute of Cardiometabolism and Nutrition, 75013 Paris, France. ; Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. ; Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark. ; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany. ; Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany. ; Bejing Genomics Institute (BGI)-Shenzhen, 518083 Shenzhen, China. ; Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark. ; Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, 2600 Copenhagen, Denmark. ; Faculty of Medicine, University of Aalborg, 9100 Aalborg, Denmark. ; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. ; Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark. ; Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, 80205 Jeddah, Saudi Arabia. ; Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China. ; Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong. ; Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy's Hospital, King's College London, London SE1 9RT , UK. ; Max Delbruck Centre for Molecular Medicine, 13125 Berlin, Germany. ; Department of Bioinformatics, University of Wuerzburg, 97074 Wurzburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26633628" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fox, Bennett W -- Tibbetts, Randal S -- T32 GM008505/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 3;525(7567):36-7. doi: 10.1038/nature15208. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308896" target="_blank"〉PubMed〈/a〉

Description: To contend with hazards posed by environmental fluoride, microorganisms export this anion through F(-)-specific ion channels of the Fluc family. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F(-) over Cl(-) and dual-topology dimeric assembly. To understand the chemical basis for F(-) permeation and how the antiparallel subunits convene to form a F(-)-selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F(-) present, to a maximum resolution of 2.1 A. The structures reveal a surprising 'double-barrelled' channel architecture in which two F(-) ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na(+). F(-) selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stockbridge, Randy B -- Kolmakova-Partensky, Ludmila -- Shane, Tania -- Koide, Akiko -- Koide, Shohei -- Miller, Christopher -- Newstead, Simon -- 102890/Z/13/Z/Wellcome Trust/United Kingdom -- K99 GM111767/GM/NIGMS NIH HHS/ -- K99-GM-111767/GM/NIGMS NIH HHS/ -- R01 GM107023/GM/NIGMS NIH HHS/ -- R01-GM107023/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 24;525(7570):548-51. doi: 10.1038/nature14981. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA. ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA. ; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QU, UK. ; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344196" target="_blank"〉PubMed〈/a〉

Description: T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs. Here we explore in mice whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Yongqiang -- van der Veeken, Joris -- Shugay, Mikhail -- Putintseva, Ekaterina V -- Osmanbeyoglu, Hatice U -- Dikiy, Stanislav -- Hoyos, Beatrice E -- Moltedo, Bruno -- Hemmers, Saskia -- Treuting, Piper -- Leslie, Christina S -- Chudakov, Dmitriy M -- Rudensky, Alexander Y -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI034206/AI/NIAID NIH HHS/ -- R37 AI034206/AI/NIAID NIH HHS/ -- U01 HG007893/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 3;528(7580):132-6. doi: 10.1038/nature16141. Epub 2015 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya 16/10, Moscow 117997, Russia. ; Pirogov Russian National Research Medical University, Ostrovityanova 1, Moscow 117997, Russia. ; Central European Institute of Technology, Masaryk University, Kamenice 753/5, Brno 62500, Czech Republic. ; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605529" target="_blank"〉PubMed〈/a〉

Description: DNA methylation is an important epigenetic modification. Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 A and 1.97 A resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure, and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Lulu -- Lu, Junyan -- Cheng, Jingdong -- Rao, Qinhui -- Li, Ze -- Hou, Haifeng -- Lou, Zhiyong -- Zhang, Lei -- Li, Wei -- Gong, Wei -- Liu, Mengjie -- Sun, Chang -- Yin, Xiaotong -- Li, Jie -- Tan, Xiangshi -- Wang, Pengcheng -- Wang, Yinsheng -- Fang, Dong -- Cui, Qiang -- Yang, Pengyuan -- He, Chuan -- Jiang, Hualiang -- Luo, Cheng -- Xu, Yanhui -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 5;527(7576):118-22. doi: 10.1038/nature15713. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China. ; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China. ; MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China. ; Department of Chemistry, University of California-Riverside, Riverside, California 92521-0403, USA. ; Theoretical Chemistry Institute, Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA. ; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524525" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2015 Feb 26;518(7540):474-6. doi: 10.1038/518474a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719648" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mosquera, Juan-Miguel -- Varma, Sonal -- Pauli, Chantal -- MacDonald, Theresa Y -- Yashinskie, Jossie J -- Varga, Zsuzsanna -- Sboner, Andrea -- Moch, Holger -- Rubin, Mark A -- Shin, Sandra J -- England -- Nature. 2015 Apr 16;520(7547):E11-2. doi: 10.1038/nature14265.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] Institute for Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York 10021, USA. ; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA. ; 1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] Institute for Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York 10021, USA [3] Institute for Surgical Pathology, University Hospital Zurich 8091, Switzerland. ; Institute for Surgical Pathology, University Hospital Zurich 8091, Switzerland. ; 1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] Institute for Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York 10021, USA [3] Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25877206" target="_blank"〉PubMed〈/a〉

Description: T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORgammat, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORgammat partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORgammat and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORgammat interaction and RORgammat target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORgammat complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762670/" 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/PMC4762670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Wendy -- Thomas, Benjamin -- Flynn, Ryan A -- Gavzy, Samuel J -- Wu, Lin -- Kim, Sangwon V -- Hall, Jason A -- Miraldi, Emily R -- Ng, Charles P -- Rigo, Frank W -- Meadows, Sarah -- Montoya, Nina R -- Herrera, Natalia G -- Domingos, Ana I -- Rastinejad, Fraydoon -- Myers, Richard M -- Fuller-Pace, Frances V -- Bonneau, Richard -- Chang, Howard Y -- Acuto, Oreste -- Littman, Dan R -- 1F30CA189514-01/CA/NCI NIH HHS/ -- F30 CA189514/CA/NCI NIH HHS/ -- P50 HG007735/HG/NHGRI NIH HHS/ -- P50-HG007735/HG/NHGRI NIH HHS/ -- R01 AI080885/AI/NIAID NIH HHS/ -- R01 AI121436/AI/NIAID NIH HHS/ -- R01 DK103358/DK/NIDDK NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01AI080885/AI/NIAID NIH HHS/ -- R01DK103358/DK/NIDDK NIH HHS/ -- R01HG004361/HG/NHGRI NIH HHS/ -- T32 AI100853/AI/NIAID NIH HHS/ -- T32 CA009161/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 24;528(7583):517-22. doi: 10.1038/nature16193. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA. ; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. ; Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA. ; Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA. ; Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10012, USA. ; Simons Center for Data Analysis, Simons Foundation, New York, New York 10010, USA. ; Isis Pharmaceuticals, Carlsbad, California 92010, USA. ; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA. ; Instituto Gulbenkian de Ciencia, Oeiras 2780-156, Portugal. ; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA. ; Division of Cancer Research, University of Dundee, Dundee DD1 9SY, UK. ; Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675721" target="_blank"〉PubMed〈/a〉

Description: The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631399/" 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/PMC4631399/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Freibaum, Brian D -- Lu, Yubing -- Lopez-Gonzalez, Rodrigo -- Kim, Nam Chul -- Almeida, Sandra -- Lee, Kyung-Ha -- Badders, Nisha -- Valentine, Marc -- Miller, Bruce L -- Wong, Philip C -- Petrucelli, Leonard -- Kim, Hong Joo -- Gao, Fen-Biao -- Taylor, J Paul -- AG019724/AG/NIA NIH HHS/ -- N079725/PHS HHS/ -- NS079725/NS/NINDS NIH HHS/ -- P01 AG019724/AG/NIA NIH HHS/ -- R01 NS057553/NS/NINDS NIH HHS/ -- R01 NS079725/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):129-33. doi: 10.1038/nature14974. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California 94158, USA. ; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA. ; Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308899" target="_blank"〉PubMed〈/a〉

Description: Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) by the PPAR-alpha agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-alpha agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-alpha alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-alpha co-occupies many chromatin sites with GR; when activated by PPAR-alpha agonists, additional PPAR-alpha is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-alpha agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-alpha agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498266/" 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/PMC4498266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Hsiang-Ying -- Gao, Xiaofei -- Barrasa, M Inmaculada -- Li, Hu -- Elmes, Russell R -- Peters, Luanne L -- Lodish, Harvey F -- 2 P01 HL032262-25/HL/NHLBI NIH HHS/ -- DK100692/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- R01 DK100692/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Jun 25;522(7557):474-7. doi: 10.1038/nature14326. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA. ; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970251" target="_blank"〉PubMed〈/a〉

Description: At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Xi-Ping -- Karpiak, Joel -- Kroeze, Wesley K -- Zhu, Hu -- Chen, Xin -- Moy, Sheryl S -- Saddoris, Kara A -- Nikolova, Viktoriya D -- Farrell, Martilias S -- Wang, Sheng -- Mangano, Thomas J -- Deshpande, Deepak A -- Jiang, Alice -- Penn, Raymond B -- Jin, Jian -- Koller, Beverly H -- Kenakin, Terry -- Shoichet, Brian K -- Roth, Bryan L -- GM59957/GM/NIGMS NIH HHS/ -- GM71896/GM/NIGMS NIH HHS/ -- P01 HL114471/HL/NHLBI NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U01 MH104974/MH/NIMH NIH HHS/ -- U19MH082441/MH/NIMH NIH HHS/ -- U54 HD079124/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):477-83. doi: 10.1038/nature15699. Epub 2015 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA. ; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA. ; Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, 1700 4th Street, San Francisco, California 94158-2550, USA. ; Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7363, USA. ; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA. ; Department of Psychiatry and Carolina Institute for Developmental Disabilities (CIDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7146, USA. ; Center for Translational Medicine and Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26550826" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chi, Kelly Rae -- England -- Nature. 2015 Oct 8;526(7572):S12-3. doi: 10.1038/526S12a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444368" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Seung-Jae -- Masliah, Eliezer -- England -- Nature. 2015 Jun 18;522(7556):296-7. doi: 10.1038/nature14526. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Department of Pathology and Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061764" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hejtmancik, J Fielding -- England -- Nature. 2015 Jul 30;523(7562):540-1. doi: 10.1038/nature14629. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ophthalmic Molecular Genetics Section, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, Maryland 20892-9402, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200338" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mezey, Eva -- Palkovits, Miklos -- England -- Nature. 2015 Aug 27;524(7566):415. doi: 10.1038/524415b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA. ; Semmelweis University, Budapest, Hungary.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26310754" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sohn, Emily -- England -- Nature. 2015 Sep 24;525(7570):S12-3. doi: 10.1038/525S12a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26398732" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hendrix, Mary J C -- England -- Nature. 2015 Apr 16;520(7547):300-2. doi: 10.1038/nature14382. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stanley Manne Children's Research Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611-2605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855292" target="_blank"〉PubMed〈/a〉

Description: Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA-dependent RNA polymerases that can both transcribe and replicate the viral RNA genome. In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching. Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5' and 3' termini of viral genome segments), showing FluPol in transcription pre-initiation states. Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 A, revealing a new 'closed' conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols. The endonuclease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hengrung, Narin -- El Omari, Kamel -- Serna Martin, Itziar -- Vreede, Frank T -- Cusack, Stephen -- Rambo, Robert P -- Vonrhein, Clemens -- Bricogne, Gerard -- Stuart, David I -- Grimes, Jonathan M -- Fodor, Ervin -- 075491/Z/04/Wellcome Trust/United Kingdom -- 092931/Z/10/Z/Wellcome Trust/United Kingdom -- G1000099/Medical Research Council/United Kingdom -- G1100138/Medical Research Council/United Kingdom -- MR/K000241/1/Medical Research Council/United Kingdom -- England -- Nature. 2015 Nov 5;527(7576):114-7. doi: 10.1038/nature15525. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. ; Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, UK. ; European Molecular Biology Laboratory, Grenoble Outstation and University Grenoble Alpes-Centre National de la Recherche Scientifique-EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France. ; Diamond Light Source Ltd, Harwell Science &Innovation Campus, Didcot OX11 0DE, UK. ; Global Phasing Ltd, Sheraton House, Castle Park, Cambridge CB3 0AX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503046" target="_blank"〉PubMed〈/a〉

Description: After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510871/" 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/PMC4510871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitchell, Duane A -- Batich, Kristen A -- Gunn, Michael D -- Huang, Min-Nung -- Sanchez-Perez, Luis -- Nair, Smita K -- Congdon, Kendra L -- Reap, Elizabeth A -- Archer, Gary E -- Desjardins, Annick -- Friedman, Allan H -- Friedman, Henry S -- Herndon, James E 2nd -- Coan, April -- McLendon, Roger E -- Reardon, David A -- Vredenburgh, James J -- Bigner, Darell D -- Sampson, John H -- 1UL2 RR024128-01/RR/NCRR NIH HHS/ -- P01 CA154291/CA/NCI NIH HHS/ -- P01-CA154291-01A1/CA/NCI NIH HHS/ -- P50 CA108786/CA/NCI NIH HHS/ -- P50 NS020023/NS/NINDS NIH HHS/ -- P50-CA108786/CA/NCI NIH HHS/ -- P50-NS20023/NS/NINDS NIH HHS/ -- R01 CA134844/CA/NCI NIH HHS/ -- R01 CA177476/CA/NCI NIH HHS/ -- R01 NS067037/NS/NINDS NIH HHS/ -- R01-CA134844/CA/NCI NIH HHS/ -- R01-CA177476-01/CA/NCI NIH HHS/ -- R01-NS067037/NS/NINDS NIH HHS/ -- T32 AI052077/AI/NIAID NIH HHS/ -- T32 GM007171/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Mar 19;519(7543):366-9. doi: 10.1038/nature14320. Epub 2015 Mar 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA [4] Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA [5] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762141" target="_blank"〉PubMed〈/a〉

Description: Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N(6)-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376618/" 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/PMC4376618/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spitale, Robert C -- Flynn, Ryan A -- Zhang, Qiangfeng Cliff -- Crisalli, Pete -- Lee, Byron -- Jung, Jong-Wha -- Kuchelmeister, Hannes Y -- Batista, Pedro J -- Torre, Eduardo A -- Kool, Eric T -- Chang, Howard Y -- F30 CA189514/CA/NCI NIH HHS/ -- F30CA189514/CA/NCI NIH HHS/ -- P50 HG007735/HG/NHGRI NIH HHS/ -- P50HG007735/HG/NHGRI NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01HG004361/HG/NHGRI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- T32AR007422/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 26;519(7544):486-90. doi: 10.1038/nature14263. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Chemistry, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799993" target="_blank"〉PubMed〈/a〉

Description: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393366/" 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/PMC4393366/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hibar, Derrek P -- Stein, Jason L -- Renteria, Miguel E -- Arias-Vasquez, Alejandro -- Desrivieres, Sylvane -- Jahanshad, Neda -- Toro, Roberto -- Wittfeld, Katharina -- Abramovic, Lucija -- Andersson, Micael -- Aribisala, Benjamin S -- Armstrong, Nicola J -- Bernard, Manon -- Bohlken, Marc M -- Boks, Marco P -- Bralten, Janita -- Brown, Andrew A -- Chakravarty, M Mallar -- Chen, Qiang -- Ching, Christopher R K -- Cuellar-Partida, Gabriel -- den Braber, Anouk -- Giddaluru, Sudheer -- Goldman, Aaron L -- Grimm, Oliver -- Guadalupe, Tulio -- Hass, Johanna -- Woldehawariat, Girma -- Holmes, Avram J -- Hoogman, Martine -- Janowitz, Deborah -- Jia, Tianye -- Kim, Sungeun -- Klein, Marieke -- Kraemer, Bernd -- Lee, Phil H -- Olde Loohuis, Loes M -- Luciano, Michelle -- Macare, Christine -- Mather, Karen A -- Mattheisen, Manuel -- Milaneschi, Yuri -- Nho, Kwangsik -- Papmeyer, Martina -- Ramasamy, Adaikalavan -- Risacher, Shannon L -- Roiz-Santianez, Roberto -- Rose, Emma J -- Salami, Alireza -- Samann, Philipp G -- Schmaal, Lianne -- Schork, Andrew J -- Shin, Jean -- Strike, Lachlan T -- Teumer, Alexander -- van Donkelaar, Marjolein M J -- van Eijk, Kristel R -- Walters, Raymond K -- Westlye, Lars T -- Whelan, Christopher D -- Winkler, Anderson M -- Zwiers, Marcel P -- Alhusaini, Saud -- Athanasiu, Lavinia -- Ehrlich, Stefan -- Hakobjan, Marina M H -- Hartberg, Cecilie B -- Haukvik, Unn K -- Heister, Angelien J G A M -- Hoehn, David -- Kasperaviciute, Dalia -- Liewald, David C M -- Lopez, Lorna M -- Makkinje, Remco R R -- Matarin, Mar -- Naber, Marlies A M -- McKay, D Reese -- Needham, Margaret -- Nugent, Allison C -- Putz, Benno -- Royle, Natalie A -- Shen, Li -- Sprooten, Emma -- Trabzuni, Daniah -- van der Marel, Saskia S L -- van Hulzen, Kimm J E -- Walton, Esther -- Wolf, Christiane -- Almasy, Laura -- Ames, David -- Arepalli, Sampath -- Assareh, Amelia A -- Bastin, Mark E -- Brodaty, Henry -- Bulayeva, Kazima B -- Carless, Melanie A -- Cichon, Sven -- Corvin, Aiden -- Curran, Joanne E -- Czisch, Michael -- de Zubicaray, Greig I -- Dillman, Allissa -- Duggirala, Ravi -- Dyer, Thomas D -- Erk, Susanne -- Fedko, Iryna O -- Ferrucci, Luigi -- Foroud, Tatiana M -- Fox, Peter T -- Fukunaga, Masaki -- Gibbs, J Raphael -- Goring, Harald H H -- Green, Robert C -- Guelfi, Sebastian -- Hansell, Narelle K -- Hartman, Catharina A -- Hegenscheid, Katrin -- Heinz, Andreas -- Hernandez, Dena G -- Heslenfeld, Dirk J -- Hoekstra, Pieter J -- Holsboer, Florian -- Homuth, Georg -- Hottenga, Jouke-Jan -- Ikeda, Masashi -- Jack, Clifford R Jr -- Jenkinson, Mark -- Johnson, Robert -- Kanai, Ryota -- Keil, Maria -- Kent, Jack W Jr -- Kochunov, Peter -- Kwok, John B -- Lawrie, Stephen M -- Liu, Xinmin -- Longo, Dan L -- McMahon, Katie L -- Meisenzahl, Eva -- Melle, Ingrid -- Mohnke, Sebastian -- Montgomery, Grant W -- Mostert, Jeanette C -- Muhleisen, Thomas W -- Nalls, Michael A -- Nichols, Thomas E -- Nilsson, Lars G -- Nothen, Markus M -- Ohi, Kazutaka -- Olvera, Rene L -- Perez-Iglesias, Rocio -- Pike, G Bruce -- Potkin, Steven G -- Reinvang, Ivar -- Reppermund, Simone -- Rietschel, Marcella -- Romanczuk-Seiferth, Nina -- Rosen, Glenn D -- Rujescu, Dan -- Schnell, Knut -- Schofield, Peter R -- Smith, Colin -- Steen, Vidar M -- Sussmann, Jessika E -- Thalamuthu, Anbupalam -- Toga, Arthur W -- Traynor, Bryan J -- Troncoso, Juan -- Turner, Jessica A -- Valdes Hernandez, Maria C -- van 't Ent, Dennis -- van der Brug, Marcel -- van der Wee, Nic J A -- van Tol, Marie-Jose -- Veltman, Dick J -- Wassink, Thomas H -- Westman, Eric -- Zielke, Ronald H -- Zonderman, Alan B -- Ashbrook, David G -- Hager, Reinmar -- Lu, Lu -- McMahon, Francis J -- Morris, Derek W -- Williams, Robert W -- Brunner, Han G -- Buckner, Randy L -- Buitelaar, Jan K -- Cahn, Wiepke -- Calhoun, Vince D -- Cavalleri, Gianpiero L -- Crespo-Facorro, Benedicto -- Dale, Anders M -- Davies, Gareth E -- Delanty, Norman -- Depondt, Chantal -- Djurovic, Srdjan -- Drevets, Wayne C -- Espeseth, Thomas -- Gollub, Randy L -- Ho, Beng-Choon -- Hoffmann, Wolfgang -- Hosten, Norbert -- Kahn, Rene S -- Le Hellard, Stephanie -- Meyer-Lindenberg, Andreas -- Muller-Myhsok, Bertram -- Nauck, Matthias -- Nyberg, Lars -- Pandolfo, Massimo -- Penninx, Brenda W J H -- Roffman, Joshua L -- Sisodiya, Sanjay M -- Smoller, Jordan W -- van Bokhoven, Hans -- van Haren, Neeltje E M -- Volzke, Henry -- Walter, Henrik -- Weiner, Michael W -- Wen, Wei -- White, Tonya -- Agartz, Ingrid -- Andreassen, Ole A -- Blangero, John -- Boomsma, Dorret I -- Brouwer, Rachel M -- Cannon, Dara M -- Cookson, Mark R -- de Geus, Eco J C -- Deary, Ian J -- Donohoe, Gary -- Fernandez, Guillen -- Fisher, Simon E -- Francks, Clyde -- Glahn, David C -- Grabe, Hans J -- Gruber, Oliver -- Hardy, John -- Hashimoto, Ryota -- Hulshoff Pol, Hilleke E -- Jonsson, Erik G -- Kloszewska, Iwona -- Lovestone, Simon -- Mattay, Venkata S -- Mecocci, Patrizia -- McDonald, Colm -- McIntosh, Andrew M -- Ophoff, Roel A -- Paus, Tomas -- Pausova, Zdenka -- Ryten, Mina -- Sachdev, Perminder S -- Saykin, Andrew J -- Simmons, Andy -- Singleton, Andrew -- Soininen, Hilkka -- Wardlaw, Joanna M -- Weale, Michael E -- Weinberger, Daniel R -- Adams, Hieab H H -- Launer, Lenore J -- Seiler, Stephan -- Schmidt, Reinhold -- Chauhan, Ganesh -- Satizabal, Claudia L -- Becker, James T -- Yanek, Lisa -- van der Lee, Sven J -- Ebling, 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AG005134/AG/NIA NIH HHS/ -- P50 AG005146/AG/NIA NIH HHS/ -- R00 LM011384/LM/NLM NIH HHS/ -- R01 AG040060/AG/NIA NIH HHS/ -- R01 EB015611/EB/NIBIB NIH HHS/ -- RF1 AG041915/AG/NIA NIH HHS/ -- U01 AG049505/AG/NIA NIH HHS/ -- U24 AG021886/AG/NIA NIH HHS/ -- U54 EB020403/EB/NIBIB NIH HHS/ -- UL1 TR001108/TR/NCATS NIH HHS/ -- UL1 TR001120/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Apr 9;520(7546):224-9. doi: 10.1038/nature14101. Epub 2015 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA. ; 1] Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA. [2] Neurogenetics Program, Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095, USA. ; QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. ; 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [3] Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [4] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. ; MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK. ; 1] Laboratory of Human Genetics and Cognitive Functions, Institut Pasteur, Paris 75015, France. [2] Centre Nationale de Recherche Scientifique (CNRS) Unite de Recherche Associee (URA) 2182 Genes, Synapses and Cognition, Institut Pasteur, Paris 75015, France. [3] Universite Paris Diderot, Sorbonne Paris Cite, Paris 75015, France. ; 1] German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany. [2] Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany. ; Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands. ; Umea Centre for Functional Brain Imaging (UFBI), Umea University, Umea 901 87, Sweden. ; 1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. [2] Department of Computer Science, Lagos State University, Lagos, Nigeria. [3] Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK. ; 1] Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia. [2] School of Mathematics and Statistics, University of Sydney, Sydney 2006, Australia. ; The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada. ; 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [3] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. ; 1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway. [2] NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway. ; 1] Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal H4H 1R3, Canada. [2] Department of Psychiatry and Biomedical Engineering, McGill University, Montreal H3A 2B4, Canada. ; Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA. ; 1] Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA. [2] Interdepartmental Neuroscience Graduate Program, UCLA School of Medicine, Los Angeles, California 90095, USA. ; Biological Psychology, Neuroscience Campus Amsterdam &EMGO Institute for Health and Care Research, VU University &VU Medical Center, Amsterdam 1081 BT, The Netherlands. ; 1] NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway. [2] Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway. ; Central Institute of Mental Health, Medical Faculty Mannheim, University Heidelberg, Mannheim 68159, Germany. ; 1] Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands. [2] International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands. ; Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Dresden 01307 Germany. ; Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA. ; 1] Department of Psychology, Yale University, New Haven, Connecticut 06511, USA. [2] Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. ; 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. ; Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany. ; 1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [3] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany. ; 1] Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts 02141, USA. [4] Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA. ; Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. ; Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia. ; 1] Department of Biomedicine, Aarhus University, Aarhus DK-8000, Denmark. [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen DK-8000, Denmark. [3] Center for integrated Sequencing, iSEQ, Aarhus University, Aarhus DK-8000, Denmark. ; Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands. ; Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK. ; 1] Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK. [2] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. ; 1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; 1] Department of Psychiatry, University Hospital Marques de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander 39008, Spain. [2] Cibersam (Centro Investigacion Biomedica en Red Salud Mental), Madrid 28029, Spain. ; 1] Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland. [2] Center for Translational Research on Adversity, Neurodevelopment and Substance Abuse (C-TRANS), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21045, USA. ; 1] Umea Centre for Functional Brain Imaging (UFBI), Umea University, Umea 901 87, Sweden. [2] Aging Research Center, Karolinska Institutet and Stockholm University, 11330 Stockholm, Sweden. ; Max Planck Institute of Psychiatry, Munich 80804, Germany. ; 1] Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, California 92093, USA. [2] Department of Cognitive Sciences, University of California, San Diego, California 92161, USA. ; 1] QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. [2] School of Psychology, University of Queensland, Brisbane 4072, Australia. [3] Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia. ; Institute for Community Medicine, University Medicine Greifswald, Greifswald D-17475, Germany. ; 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [2] Medical and Population Genetics Program, Broad Institute of Harvard and MIT, Boston, Massachusetts 02142, USA. ; 1] NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway. [2] Department of Psychology, University of Oslo, Oslo 0373, Norway. ; 1] The Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK. [2] Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut 06511, USA. ; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. ; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada. ; 1] Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Dresden 01307 Germany. [2] Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [3] The Athinoula A.Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway. [2] Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway. ; NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway. ; 1] UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK. [2] Department of Medicine, Imperial College London, London W12 0NN, UK. ; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, UK. ; 1] Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut 06511, USA. [2] Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA. ; Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland. ; 1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. [3] Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK. ; 1] Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK. [2] Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut 06511, USA. [3] Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA. ; 1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. [2] Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. ; 1] Texas Biomedical Research Institute, San Antonio, Texas 78245, USA. [2] University of Texas Health Science Center, San Antonio, Texas 78229, USA. ; 1] National Ageing Research Institute, Royal Melbourne Hospital, Melbourne 3052, Australia. [2] Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia. ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. [2] Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK. [3] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. [4] Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK. ; N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia. ; Texas Biomedical Research Institute, San Antonio, Texas 78245, USA. ; 1] Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel 4055, Switzerland. [2] Institute of Human Genetics, University of Bonn, Bonn, D-53127, Germany. [3] Institute of Neuroscience and Medicine (INM-1), Research Centre Julich, Julich, D-52425, Germany. [4] Department of Genomics, Life &Brain Center, University of Bonn, Bonn D-53127, Germany. ; School of Psychology, University of Queensland, Brisbane 4072, Australia. ; Department of Psychiatry and Psychotherapy, Charite Universitatsmedizin Berlin, CCM, Berlin 10117, Germany. ; Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 20892, USA. ; 1] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; 1] University of Texas Health Science Center, San Antonio, Texas 78229, USA. [2] South Texas Veterans Health Care System, San Antonio, Texas 78229, USA. ; Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. ; 1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. [2] Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia. ; 1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. ; Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands. ; Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany. ; Department of Genomics, Life &Brain Center, University of Bonn, Bonn D-53127, Germany. ; Departments of Cognitive and Clinical Neuropsychology, VU University Amsterdam, 1081 BT Amsterdam, The Netherlands. ; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17489, Germany. ; Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan. ; Radiology, Mayo Clinic, Rochester, Minnesota 55905, USA. ; FMRIB Centre, University of Oxford, Oxford OX3 9DU, UK. ; NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA. ; 1] School of Psychology, University of Sussex, Brighton BN1 9QH, UK. [2] Institute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK. ; Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21201, USA. ; 1] Neuroscience Research Australia, Sydney 2031, Australia. [2] School of Medical Sciences, UNSW, Sydney 2052, Australia. ; 1] Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA. [2] Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA. ; Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. ; Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia. ; Department of Psychiatry, Ludwig-Maximilians-Universitat, Munich 80336, Germany. ; 1] Institute of Human Genetics, University of Bonn, Bonn, D-53127, Germany. [2] Institute of Neuroscience and Medicine (INM-1), Research Centre Julich, Julich, D-52425, Germany. [3] Department of Genomics, Life &Brain Center, University of Bonn, Bonn D-53127, Germany. ; 1] FMRIB Centre, University of Oxford, Oxford OX3 9DU, UK. [2] Department of Statistics &WMG, University of Warwick, Coventry CV4 7AL, UK. ; 1] Institute of Human Genetics, University of Bonn, Bonn, D-53127, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn D-53127, Germany. ; Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; 1] Cibersam (Centro Investigacion Biomedica en Red Salud Mental), Madrid 28029, Spain. [2] Institute of Psychiatry, King's College London, London SE5 8AF, UK. ; 1] Department of Neurology, University of Calgary, Calgary T2N 2T9, Canada. [2] Department of Clinical Neuroscience, University of Calgary, Calgary T2N 2T9, Canada. ; Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA. ; Department of Psychology, University of Oslo, Oslo 0373, Norway. ; 1] Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of General Psychiatry, Heidelberg University Hospital, Heidelberg 69115, Germany. ; Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Edinburgh EH8 9AG, UK. ; Laboratory of Neuro Imaging, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA. ; Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21287, USA. ; Psychology Department and Neuroscience Institute, Georgia State University, Atlanta, Georgia 30302, USA. ; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Genentech, South San Francisco, California 94080, USA. ; Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. ; Neuroimaging Centre, University of Groningen, University Medical Center Groningen, Groningen 9713 AW, The Netherlands. ; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. ; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm SE-141 83, Sweden. ; Behavioral Epidemiology Section, National Institute on Aging Intramural Research Program, Baltimore, Maryland 20892, USA. ; Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. ; 1] Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. [2] Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. [3] Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong 226001, China. ; 1] Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland. [2] Cognitive Genetics and Therapy Group, School of Psychology &Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland. ; 1] Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. [2] Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. ; 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. [3] Department of Clinical Genetics, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands. ; 1] Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [2] Department of Psychology, Center for Brain Science, Harvard University, Boston, Massachusetts 02138, USA. ; 1] Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. [3] Karakter Child and Adolescent Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. ; 1] The Mind Research Network &LBERI, Albuquerque, New Mexico 87106, USA. [2] Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA. ; 1] Center for Translational Imaging and Personalized Medicine, University of California, San Diego, California 92093, USA. [2] Departments of Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of California, San Diego, California 92093, USA. ; Avera Institute for Human Genetics, Sioux Falls, South Dakota, 57108, USA. ; 1] Molecular and Cellular Therapeutics, The Royal College of Surgeons, Dublin 2, Ireland. [2] Neurology Division, Beaumont Hospital, Dublin 9, Ireland. ; Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels 1070, Belgium. ; 1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway. [2] Department of Medical Genetics, Oslo University Hospital, Oslo 0450, Norway. ; 1] Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA. [2] Janssen Research &Development, Johnson &Johnson, Titusville, New Jersey 08560, USA. ; 1] Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [2] The Athinoula A.Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. [3] Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA. ; 1] German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany. [2] Institute for Community Medicine, University Medicine Greifswald, Greifswald D-17475, Germany. ; 1] Max Planck Institute of Psychiatry, Munich 80804, Germany. [2] Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany. [3] University of Liverpool, Institute of Translational Medicine, Liverpool L69 3BX, UK. ; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany. ; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. ; UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK. ; 1] Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [2] Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02115, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts 02141, USA. [4] Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Imaging of Neurodegenerative Disease, San Francisco VA Medical Center, University of California, San Francisco, California 94121, USA. ; 1] Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000 CB, The Netherlands. [2] Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands. ; 1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway. [2] Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway. [3] Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm SE-171 76, Sweden. ; 1] Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA. [2] Clinical Neuroimaging Laboratory, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland. ; 1] Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. ; 1] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. [2] Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands. ; 1] Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany. [2] Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund 18435, Germany. ; 1] Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany. [2] Max Planck Institute of Psychiatry, Munich 80804, Germany. ; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan. ; 1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway. [2] Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm SE-171 76, Sweden. ; Medical University of Lodz, Lodz 90-419, Poland. ; 1] Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK. [2] NIHR Dementia Biomedical Research Unit, King's College London, London SE5 8AF, UK. ; 1] Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia 06156, Italy. ; Clinical Neuroimaging Laboratory, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland. ; 1] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. [2] Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK. ; 1] Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands. [2] Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA. ; 1] Rotman Research Institute, University of Toronto, Toronto M6A 2E1, Canada. [2] Departments of Psychology and Psychiatry, University of Toronto, Toronto M5T 1R8, Canada. ; 1] The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada. [2] Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto M5S 3E2, Canada. ; 1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. [2] Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK. ; 1] Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia. [2] Neuropsychiatric Institute, Prince of Wales Hospital, Sydney 2031, Australia. ; 1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [3] Department of Psychiatry and Psychotherapy, Charite Universitatsmedizin Berlin, CCM, Berlin 10117, Germany. ; 1] Department of Neuroimaging, Institute of Psychiatry, King's College London, London SE5 8AF, UK. [2] Biomedical Research Centre for Mental Health, King's College London, London SE5 8AF, UK. [3] Biomedical Research Unit for Dementia, King's College London, London SE5 8AF, UK. ; 1] Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio FI-70211, Finland. [2] Neurocentre Neurology, Kuopio University Hospital, Kuopio FI-70211, Finland. ; Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK. ; 1] Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA. [2] Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands. [2] Department of Epidemiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands. ; Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, Maryland 20892, USA. ; Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz 8010, Austria. ; INSERM U897, University of Bordeaux, Bordeaux 33076, France. ; 1] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [2] Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; 1] Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. [2] Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. [3] Department of Psychology, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. ; General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Epidemiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands. ; 1] The Athinoula A.Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] The Athinoula A.Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. [3] Computer Science and AI Lab, Massachusetts Institute of Technology, Boston, Massachusetts 02141, USA. ; Department of Neurology University of Washington, Seattle, Washington 98195, USA. ; Institute of Molecular Biology and Biochemistry, Medical University Graz, 8010 Graz, Austria. ; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Groupe d'Imagerie Neurofonctionnelle, UMR5296 CNRS, CEA and University of Bordeaux, Bordeaux 33076, France. ; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98101, USA. ; Icelandic Heart Association, University of Iceland, Faculty of Medicine, Reykjavik 101, Iceland. ; 1] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [2] Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. ; 1] QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. [2] School of Psychology, University of Queensland, Brisbane 4072, Australia. ; 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [3] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25607358" target="_blank"〉PubMed〈/a〉

Description: No large group of recently extinct placental mammals remains as evolutionarily cryptic as the approximately 280 genera grouped as 'South American native ungulates'. To Charles Darwin, who first collected their remains, they included perhaps the 'strangest animal[s] ever discovered'. Today, much like 180 years ago, it is no clearer whether they had one origin or several, arose before or after the Cretaceous/Palaeogene transition 66.2 million years ago, or are more likely to belong with the elephants and sirenians of superorder Afrotheria than with the euungulates (cattle, horses, and allies) of superorder Laurasiatheria. Morphology-based analyses have proved unconvincing because convergences are pervasive among unrelated ungulate-like placentals. Approaches using ancient DNA have also been unsuccessful, probably because of rapid DNA degradation in semitropical and temperate deposits. Here we apply proteomic analysis to screen bone samples of the Late Quaternary South American native ungulate taxa Toxodon (Notoungulata) and Macrauchenia (Litopterna) for phylogenetically informative protein sequences. For each ungulate, we obtain approximately 90% direct sequence coverage of type I collagen alpha1- and alpha2-chains, representing approximately 900 of 1,140 amino-acid residues for each subunit. A phylogeny is estimated from an alignment of these fossil sequences with collagen (I) gene transcripts from available mammalian genomes or mass spectrometrically derived sequence data obtained for this study. The resulting consensus tree agrees well with recent higher-level mammalian phylogenies. Toxodon and Macrauchenia form a monophyletic group whose sister taxon is not Afrotheria or any of its constituent clades as recently claimed, but instead crown Perissodactyla (horses, tapirs, and rhinoceroses). These results are consistent with the origin of at least some South American native ungulates from 'condylarths', a paraphyletic assembly of archaic placentals. With ongoing improvements in instrumentation and analytical procedures, proteomics may produce a revolution in systematics such as that achieved by genomics, but with the possibility of reaching much further back in time.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Welker, Frido -- Collins, Matthew J -- Thomas, Jessica A -- Wadsley, Marc -- Brace, Selina -- Cappellini, Enrico -- Turvey, Samuel T -- Reguero, Marcelo -- Gelfo, Javier N -- Kramarz, Alejandro -- Burger, Joachim -- Thomas-Oates, Jane -- Ashford, David A -- Ashton, Peter D -- Rowsell, Keri -- Porter, Duncan M -- Kessler, Benedikt -- Fischer, Roman -- Baessmann, Carsten -- Kaspar, Stephanie -- Olsen, Jesper V -- Kiley, Patrick -- Elliott, James A -- Kelstrup, Christian D -- Mullin, Victoria -- Hofreiter, Michael -- Willerslev, Eske -- Hublin, Jean-Jacques -- Orlando, Ludovic -- Barnes, Ian -- MacPhee, Ross D E -- England -- Nature. 2015 Jun 4;522(7554):81-4. doi: 10.1038/nature14249. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] BioArCh, University of York, York YO10 5DD, UK [2] Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany. ; BioArCh, University of York, York YO10 5DD, UK. ; Department of Earth Sciences, Natural History Museum, London SW7 5BD, UK. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, 1350 Copenhagen K, Denmark. ; Institute of Zoology, Zoological Society of London, London NW1 4RY, UK. ; CONICET- Division Paleontologia de Vertebrados, Museo de La Plata. Facultad de Ciencias Naturales y Museo de La Plata, Universidad Nacional de La Plata. Paseo del Bosque s/n, B1900FWA, La Plata, Argentina. ; Seccion Paleontologia de Vertebrados. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia", 470 Angel Gallardo Av., C1405DJR, Buenos Aires, Argentina. ; Institute of Anthropology, Johannes Gutenberg-University, Anselm-Franz-von-Bentzel-Weg 7, D-55128 Mainz, Germany. ; Department of Chemistry, University of York, York YO10 5DD, UK. ; Bioscience Technology Facility, Department of Biology, University of York, York YO10 5DD, UK. ; Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. ; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK. ; Applications Development, Bruker Daltonik GmbH, 28359 Bremen, Germany. ; Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark. ; Department of Materials Science and Metallurgy, University of Cambridge, Cambridge CB3 0FS, UK. ; Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. ; 1] BioArCh, University of York, York YO10 5DD, UK [2] Institute for Biochemistry and Biology, Karl-Liebknecht-Strasse 24-25, 14476 Potsdam OT Golm, Germany. ; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany. ; Department of Mammalogy, American Museum of Natural History, New York, New York 10024, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799987" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moberg, Carol L -- England -- Nature. 2015 Feb 19;518(7539):303. doi: 10.1038/518303a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Rockefeller University, New York, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693555" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rawlins, Emma L -- England -- Nature. 2015 Jan 29;517(7536):556-7. doi: 10.1038/517556a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust/Cancer Research UK Gurdon Institute, the Wellcome Trust/MRC Stem Cell Institute and in the Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25631438" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hilton, Douglas -- England -- Nature. 2015 Jul 2;523(7558):7. doi: 10.1038/523007a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135413" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Sep 24;525(7570):425-6. doi: 10.1038/525425b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26399789" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2015 Nov 12;527(7577):146-7. doi: 10.1038/nature.2015.18737.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560278" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hitz, Marc-Phillip -- Andelfinger, Gregor -- England -- Nature. 2015 Apr 9;520(7546):160-1. doi: 10.1038/nature14379. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK, and at the University Hospital Schleswig-Holstein and the Christian-Albrechts University, Kiel, Germany. ; Department of Pediatrics, CHU Sainte Justine Research Center, Universite de Montreal, Montreal H3T 1C5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830886" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bauer, Gordon -- Vukelich, Sarah -- England -- Nature. 2015 Aug 13;524(7564):161. doi: 10.1038/524161e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Oslo, Norway. ; Williams College, Williamstown, Massachusetts, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26268184" target="_blank"〉PubMed〈/a〉

Description: The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes. Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane. Previous studies have described the architecture of dynamin dimers, but the molecular determinants for dynamin assembly and its regulation have remained unclear. Here we present the crystal structure of the human dynamin tetramer in the nucleotide-free state. Combining structural data with mutational studies, oligomerization measurements and Markov state models of molecular dynamics simulations, we suggest a mechanism by which oligomerization of dynamin is linked to the release of intramolecular autoinhibitory interactions. We elucidate how mutations that interfere with tetramer formation and autoinhibition can lead to the congenital muscle disorders Charcot-Marie-Tooth neuropathy and centronuclear myopathy, respectively. Notably, the bent shape of the tetramer explains how dynamin assembles into a right-handed helical oligomer of defined diameter, which has direct implications for its function in membrane constriction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reubold, Thomas F -- Faelber, Katja -- Plattner, Nuria -- Posor, York -- Ketel, Katharina -- Curth, Ute -- Schlegel, Jeanette -- Anand, Roopsee -- Manstein, Dietmar J -- Noe, Frank -- Haucke, Volker -- Daumke, Oliver -- Eschenburg, Susanne -- England -- Nature. 2015 Sep 17;525(7569):404-8. doi: 10.1038/nature14880. Epub 2015 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. ; Max-Delbruck-Centrum fur Molekulare Medizin, Kristallographie, Robert-Rossle-Strasse 10, 13125 Berlin, Germany. ; Institut fur Mathematik, Freie Universitat Berlin, Arnimallee 6, 14195 Berlin, Germany. ; Leibniz-Institut fur Molekulare Pharmakologie, Robert-Rossle-Strasse 10, 13125 Berlin, Germany. ; Forschungseinrichtung Strukturanalyse, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. ; Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 6, 14195 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26302298" target="_blank"〉PubMed〈/a〉

Description: It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by 〉1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Jin-Hua -- O'Boyle, Donald R 2nd -- Fridell, Robert A -- Langley, David R -- Wang, Chunfu -- Roberts, Susan B -- Nower, Peter -- Johnson, Benjamin M -- Moulin, Frederic -- Nophsker, Michelle J -- Wang, Ying-Kai -- Liu, Mengping -- Rigat, Karen -- Tu, Yong -- Hewawasam, Piyasena -- Kadow, John -- Meanwell, Nicholas A -- Cockett, Mark -- Lemm, Julie A -- Kramer, Melissa -- Belema, Makonen -- Gao, Min -- England -- Nature. 2015 Nov 12;527(7577):245-8. doi: 10.1038/nature15711. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Leads Discovery and Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536115" target="_blank"〉PubMed〈/a〉

Description: Cas9 is an RNA-guided DNA endonuclease that targets foreign DNA for destruction as part of a bacterial adaptive immune system mediated by clustered regularly interspaced short palindromic repeats (CRISPR). Together with single-guide RNAs, Cas9 also functions as a powerful genome engineering tool in plants and animals, and efforts are underway to increase the efficiency and specificity of DNA targeting for potential therapeutic applications. Studies of off-target effects have shown that DNA binding is far more promiscuous than DNA cleavage, yet the molecular cues that govern strand scission have not been elucidated. Here we show that the conformational state of the HNH nuclease domain directly controls DNA cleavage activity. Using intramolecular Forster resonance energy transfer experiments to detect relative orientations of the Cas9 catalytic domains when associated with on- and off-target DNA, we find that DNA cleavage efficiencies scale with the extent to which the HNH domain samples an activated conformation. We furthermore uncover a surprising mode of allosteric communication that ensures concerted firing of both Cas9 nuclease domains. Our results highlight a proofreading mechanism beyond initial protospacer adjacent motif (PAM) recognition and RNA-DNA base-pairing that serves as a final specificity checkpoint before DNA double-strand break formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sternberg, Samuel H -- LaFrance, Benjamin -- Kaplan, Matias -- Doudna, Jennifer A -- T32GM007232/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 5;527(7576):110-3. doi: 10.1038/nature15544. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of California, Berkeley, California 94720, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA. ; Innovative Genomics Initiative, University of California, Berkeley, California 94720, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524520" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Aug 27;524(7566):387. doi: 10.1038/524387a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26310730" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Florence, T J -- Reiser, Michael B -- England -- Nature. 2015 Mar 19;519(7543):296-7. doi: 10.1038/nature14209. Epub 2015 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Research Campus, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739498" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hogan, Benjamin M -- Black, Brian L -- England -- Nature. 2015 Jun 4;522(7554):37-8.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992543" target="_blank"〉PubMed〈/a〉

Description: Activation of the mu-opioid receptor (muOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for muOR activation, here we report a 2.1 A X-ray crystal structure of the murine muOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the muOR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta2-adrenergic receptor (beta2AR) and the M2 muscarinic receptor. Comparison with active beta2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the muOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" 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/PMC4639397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Weijiao -- Manglik, Aashish -- Venkatakrishnan, A J -- Laeremans, Toon -- Feinberg, Evan N -- Sanborn, Adrian L -- Kato, Hideaki E -- Livingston, Kathryn E -- Thorsen, Thor S -- Kling, Ralf C -- Granier, Sebastien -- Gmeiner, Peter -- Husbands, Stephen M -- Traynor, John R -- Weis, William I -- Steyaert, Jan -- Dror, Ron O -- Kobilka, Brian K -- R01GM083118/GM/NIGMS NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- R37DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):315-21. doi: 10.1038/nature14886. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA. ; Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany. ; Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. ; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245379" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barratt, Alexandra -- England -- Nature. 2015 Nov 19;527(7578):S104. doi: 10.1038/527S104a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Sydney, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580156" target="_blank"〉PubMed〈/a〉

Description: Cell-cell intercalation is used in several developmental processes to shape the normal body plan. There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition. Cell competition is a conserved mechanism driving the elimination of slow-proliferating cells (so-called 'losers') by faster-proliferating neighbours (so-called 'winners') through apoptosis and is important in preventing developmental malformations and maintain tissue fitness. Here we show, using long-term live imaging of myc-driven competition in the Drosophila pupal notum and in the wing imaginal disc, that the probability of elimination of loser cells correlates with the surface of contact shared with winners. As such, modifying loser-winner interface morphology can modulate the strength of competition. We further show that elimination of loser clones requires winner-loser cell mixing through cell-cell intercalation. Cell mixing is driven by differential growth and the high tension at winner-winner interfaces relative to winner-loser and loser-loser interfaces, which leads to a preferential stabilization of winner-loser contacts and reduction of clone compactness over time. Differences in tension are generated by a relative difference in F-actin levels between loser and winner junctions, induced by differential levels of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate. Our results establish the first link between cell-cell intercalation induced by a proto-oncogene and how it promotes invasiveness and destruction of healthy tissues.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levayer, Romain -- Hauert, Barbara -- Moreno, Eduardo -- England -- Nature. 2015 Aug 27;524(7566):476-80. doi: 10.1038/nature14684. Epub 2015 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26287461" target="_blank"〉PubMed〈/a〉

Description: Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1beta elicits IL-17 expression from gamma delta (gammadelta) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of gammadelta T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of gammadelta T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system--the gammadelta T cell/IL-17/neutrophil axis--represents a new strategy to inhibit metastatic disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475637/" 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/PMC4475637/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Coffelt, Seth B -- Kersten, Kelly -- Doornebal, Chris W -- Weiden, Jorieke -- Vrijland, Kim -- Hau, Cheei-Sing -- Verstegen, Niels J M -- Ciampricotti, Metamia -- Hawinkels, Lukas J A C -- Jonkers, Jos -- de Visser, Karin E -- 11-0677/Worldwide Cancer Research/United Kingdom -- 615300/European Research Council/International -- England -- Nature. 2015 Jun 18;522(7556):345-8. doi: 10.1038/nature14282. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands. ; 1] Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands [2] Centre for Biomedical Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands. ; Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822788" target="_blank"〉PubMed〈/a〉

Description: With efficiencies derived from evolution, growth and learning, humans are very well-tuned for locomotion. Metabolic energy used during walking can be partly replaced by power input from an exoskeleton, but is it possible to reduce metabolic rate without providing an additional energy source? This would require an improvement in the efficiency of the human-machine system as a whole, and would be remarkable given the apparent optimality of human gait. Here we show that the metabolic rate of human walking can be reduced by an unpowered ankle exoskeleton. We built a lightweight elastic device that acts in parallel with the user's calf muscles, off-loading muscle force and thereby reducing the metabolic energy consumed in contractions. The device uses a mechanical clutch to hold a spring as it is stretched and relaxed by ankle movements when the foot is on the ground, helping to fulfil one function of the calf muscles and Achilles tendon. Unlike muscles, however, the clutch sustains force passively. The exoskeleton consumes no chemical or electrical energy and delivers no net positive mechanical work, yet reduces the metabolic cost of walking by 7.2 +/- 2.6% for healthy human users under natural conditions, comparable to savings with powered devices. Improving upon walking economy in this way is analogous to altering the structure of the body such that it is more energy-effective at walking. While strong natural pressures have already shaped human locomotion, improvements in efficiency are still possible. Much remains to be learned about this seemingly simple behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481882/" 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/PMC4481882/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collins, Steven H -- Wiggin, M Bruce -- Sawicki, Gregory S -- R01 NR014756/NR/NINR NIH HHS/ -- R01NR014756/NR/NINR NIH HHS/ -- England -- Nature. 2015 Jun 11;522(7555):212-5. doi: 10.1038/nature14288. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Mechanical Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, Pennsylvania 15213, USA. ; Joint Department of Biomedical Engineering, North Carolina State University and the University of North Carolina at Chapel Hill, 911 Oval Drive, Raleigh, North Carolina 27695, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830889" target="_blank"〉PubMed〈/a〉

Description: The central dogma of gene expression (DNA to RNA to protein) is universal, but in different domains of life there are fundamental mechanistic differences within this pathway. For example, the canonical molecular signals used to initiate protein synthesis in bacteria and eukaryotes are mutually exclusive. However, the core structures and conformational dynamics of ribosomes that are responsible for the translation steps that take place after initiation are ancient and conserved across the domains of life. We wanted to explore whether an undiscovered RNA-based signal might be able to use these conserved features, bypassing mechanisms specific to each domain of life, and initiate protein synthesis in both bacteria and eukaryotes. Although structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, an analogous RNA structure-based mechanism has not been observed in bacteria. Here we report our discovery that a eukaryotic viral IRES can initiate translation in live bacteria. We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 A resolution, revealing that despite differences between bacterial and eukaryotic ribosomes this IRES binds directly to both and occupies the space normally used by transfer RNAs. Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment. This IRES RNA bridges billions of years of evolutionary divergence and provides an example of an RNA structure-based translation initiation signal capable of operating in two domains of life.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352134/" 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/PMC4352134/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colussi, Timothy M -- Costantino, David A -- Zhu, Jianyu -- Donohue, John Paul -- Korostelev, Andrei A -- Jaafar, Zane A -- Plank, Terra-Dawn M -- Noller, Harry F -- Kieft, Jeffrey S -- GM-103105/GM/NIGMS NIH HHS/ -- GM-17129/GM/NIGMS NIH HHS/ -- GM-59140/GM/NIGMS NIH HHS/ -- GM-81346/GM/NIGMS NIH HHS/ -- GM-97333/GM/NIGMS NIH HHS/ -- R01 GM097333/GM/NIGMS NIH HHS/ -- R01 GM106105/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 5;519(7541):110-3. doi: 10.1038/nature14219. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. ; Center for Molecular Biology of RNA and Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California at Santa Cruz, Santa Cruz, California 95064, USA. ; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652826" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Nam Woo -- Greenberg, Roger A -- R01 CA174904/CA/NCI NIH HHS/ -- R01 GM101149/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Feb 12;518(7538):174-6. doi: 10.1038/nature14200. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25642961" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hooli, Basavaraj V -- Lill, Christina M -- Mullin, Kristina -- Qiao, Dandi -- Lange, Christoph -- Bertram, Lars -- Tanzi, Rudolph E -- England -- Nature. 2015 Apr 2;520(7545):E7-8. doi: 10.1038/nature14040.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; 1] Platform for Genome Analytics, Institutes of Neurogenetics &Integrative and Experimental Genomics, University of Lubeck, 23552 Lubeck, Germany [2] Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany [3] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; 1] Platform for Genome Analytics, Institutes of Neurogenetics &Integrative and Experimental Genomics, University of Lubeck, 23552 Lubeck, Germany [2] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany [3] School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London W6 8RP, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25832413" target="_blank"〉PubMed〈/a〉

Description: Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-pi interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullins, Elwood A -- Shi, Rongxin -- Parsons, Zachary D -- Yuen, Philip K -- David, Sheila S -- Igarashi, Yasuhiro -- Eichman, Brandt F -- R01 ES019625/ES/NIEHS NIH HHS/ -- R01CA067985/CA/NCI NIH HHS/ -- R01ES019625/ES/NIEHS NIH HHS/ -- S10RR026915/RR/NCRR NIH HHS/ -- T32 ES007028/ES/NIEHS NIH HHS/ -- T32ES07028/ES/NIEHS NIH HHS/ -- England -- Nature. 2015 Nov 12;527(7577):254-8. doi: 10.1038/nature15728. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Department of Chemistry, University of California, Davis, California 95616, USA. ; Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524531" target="_blank"〉PubMed〈/a〉

Description: Adiponectin stimulation of its receptors, AdipoR1 and AdipoR2, increases the activities of 5' AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR), respectively, thereby contributing to healthy longevity as key anti-diabetic molecules. AdipoR1 and AdipoR2 were predicted to contain seven transmembrane helices with the opposite topology to G-protein-coupled receptors. Here we report the crystal structures of human AdipoR1 and AdipoR2 at 2.9 and 2.4 A resolution, respectively, which represent a novel class of receptor structure. The seven-transmembrane helices, conformationally distinct from those of G-protein-coupled receptors, enclose a large cavity where three conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in the adiponectin-stimulated AMPK phosphorylation and UCP2 upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors. The present information will facilitate the understanding of novel structure-function relationships and the development and optimization of AdipoR agonists for the treatment of obesity-related diseases, such as type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477036/" 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/PMC4477036/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanabe, Hiroaki -- Fujii, Yoshifumi -- Okada-Iwabu, Miki -- Iwabu, Masato -- Nakamura, Yoshihiro -- Hosaka, Toshiaki -- Motoyama, Kanna -- Ikeda, Mariko -- Wakiyama, Motoaki -- Terada, Takaho -- Ohsawa, Noboru -- Hato, Masakatsu -- Ogasawara, Satoshi -- Hino, Tomoya -- Murata, Takeshi -- Iwata, So -- Hirata, Kunio -- Kawano, Yoshiaki -- Yamamoto, Masaki -- Kimura-Someya, Tomomi -- Shirouzu, Mikako -- Yamauchi, Toshimasa -- Kadowaki, Takashi -- Yokoyama, Shigeyuki -- 062164/Z/00/Z/Wellcome Trust/United Kingdom -- 089809/Wellcome Trust/United Kingdom -- BB/G02325/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Apr 16;520(7547):312-6. doi: 10.1038/nature14301. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [4] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan [4] Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage, Chiba 263-8522, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan [4] Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College, London SW7 2AZ, UK [5] Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE, UK [6] RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan. ; RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855295" target="_blank"〉PubMed〈/a〉