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  • 101. Contreras, F.-Xabier
    et al.
    Ernst, Andreas M.
    Haberkant, Per
    Björkholm, Patrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Gönen, Basak
    Tischer, Christian
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Thiele, Christoph
    Pepperkok, Rainer
    Wieland, Felix
    Brügger, Britta
    Molecular recognition of a single sphingolipid species by a protein’s transmembrane domain2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 481, no 7382, 525-529 p.Article in journal (Refereed)
    Abstract [en]

    Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

  • 102.
    Contreras, F.-Xabier
    et al.
    Heidelberg University.
    Ernst, Andreas M
    Heidelberg University.
    Haberkant, Per
    Heidelberg University.
    Björkholm, Patrik
    Stockholm University.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Gönen, Başak
    Tischer, Christian
    Heidelberg University.
    Elofsson, Arne
    Stockholm University.
    von Heijne, Gunnar
    Stockholm University.
    Thiele, Christoph
    Heidelberg University.
    Pepperkok, Rainer
    Heidelberg University.
    Wieland, Felix
    Heidelberg University.
    Brügger, Britta
    Heidelberg University.
    Molecular recognition of a single sphingolipid species by a protein's transmembrane domain2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 481, no 7382, 525-529 p.Article in journal (Refereed)
    Abstract [en]

    Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

  • 103. Craddock, Nick
    et al.
    Hurles, Matthew E.
    Cardin, Niall
    Pearson, Richard D.
    Plagnol, Vincent
    Robson, Samuel
    Vukcevic, Damjan
    Barnes, Chris
    Conrad, Donald F.
    Giannoulatou, Eleni
    Holmes, Chris
    Marchini, Jonathan L.
    Stirrups, Kathy
    Tobin, Martin D.
    Wain, Louise V.
    Yau, Chris
    Aerts, Jan
    Ahmad, Tariq
    Andrews, T. Daniel
    Arbury, Hazel
    Attwood, Anthony
    Auton, Adam
    Ball, Stephen G.
    Balmforth, Anthony J.
    Barrett, Jeffrey C.
    Barroso, Ines
    Barton, Anne
    Bennett, Amanda J.
    Bhaskar, Sanjeev
    Blaszczyk, Katarzyna
    Bowes, John
    Brand, Oliver J.
    Braund, Peter S.
    Bredin, Francesca
    Breen, Gerome
    Brown, Morris J.
    Bruce, Ian N.
    Bull, Jaswinder
    Burren, Oliver S.
    Burton, John
    Byrnes, Jake
    Caesar, Sian
    Clee, Chris M.
    Coffey, Alison J.
    Connell, John M. C.
    Cooper, Jason D.
    Dominiczak, Anna F.
    Downes, Kate
    Drummond, Hazel E.
    Dudakia, Darshna
    Dunham, Andrew
    Ebbs, Bernadette
    Eccles, Diana
    Edkins, Sarah
    Edwards, Cathryn
    Elliot, Anna
    Emery, Paul
    Evans, David M.
    Evans, Gareth
    Eyre, Steve
    Farmer, Anne
    Ferrier, I. Nicol
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fitzgerald, Tomas
    Flynn, Edward
    Forbes, Alistair
    Forty, Liz
    Franklyn, Jayne A.
    Freathy, Rachel M.
    Gibbs, Polly
    Gilbert, Paul
    Gokumen, Omer
    Gordon-Smith, Katherine
    Gray, Emma
    Green, Elaine
    Groves, Chris J.
    Grozeva, Detelina
    Gwilliam, Rhian
    Hall, Anita
    Hammond, Naomi
    Hardy, Matt
    Harrison, Pile
    Hassanali, Neelam
    Hebaishi, Husam
    Hines, Sarah
    Hinks, Anne
    Hitman, Graham A.
    Hocking, Lynne
    Howard, Eleanor
    Howard, Philip
    Howson, Joanna M. M.
    Hughes, Debbie
    Hunt, Sarah
    Isaacs, John D.
    Jain, Mahim
    Jewell, Derek P.
    Johnson, Toby
    Jolley, Jennifer D.
    Jones, Ian R.
    Jones, Lisa A.
    Kirov, George
    Langford, Cordelia F.
    Lango-Allen, Hana
    Lathrop, G. Mark
    Lee, James
    Lee, Kate L.
    Lees, Charlie
    Lewis, Kevin
    Lindgren, Cecilia M.
    Maisuria-Armer, Meeta
    Maller, Julian
    Mansfield, John
    Martin, Paul
    Massey, Dunecan C. O.
    McArdle, Wendy L.
    McGuffin, Peter
    McLay, Kirsten E.
    Mentzer, Alex
    Mimmack, Michael L.
    Morgan, Ann E.
    Morris, Andrew P.
    Mowat, Craig
    Myers, Simon
    Newman, William
    Nimmo, Elaine R.
    O'Donovan, Michael C.
    Onipinla, Abiodun
    Onyiah, Ifejinelo
    Ovington, Nigel R.
    Owen, Michael J.
    Palin, Kimmo
    Parnell, Kirstie
    Pernet, David
    Perry, John R. B.
    Phillips, Anne
    Pinto, Dalila
    Prescott, Natalie J.
    Prokopenko, Inga
    Quail, Michael A.
    Rafelt, Suzanne
    Rayner, Nigel W.
    Redon, Richard
    Reid, David M.
    Renwick, Anthony
    Ring, Susan M.
    Robertson, Neil
    Russell, Ellie
    St Clair, David
    Sambrook, Jennifer G.
    Sanderson, Jeremy D.
    Schuilenburg, Helen
    Scott, Carol E.
    Scott, Richard
    Seal, Sheila
    Shaw-Hawkins, Sue
    Shields, Beverley M.
    Simmonds, Matthew J.
    Smyth, Debbie J.
    Somaskantharajah, Elilan
    Spanova, Katarina
    Steer, Sophia
    Stephens, Jonathan
    Stevens, Helen E.
    Stone, Millicent A.
    Su, Zhan
    Symmons, Deborah P. M.
    Thompson, John R.
    Thomson, Wendy
    Travers, Mary E.
    Turnbull, Clare
    Valsesia, Armand
    Walker, Mark
    Walker, Neil M.
    Wallace, Chris
    Warren-Perry, Margaret
    Watkins, Nicholas A.
    Webster, John
    Weedon, Michael N.
    Wilson, Anthony G.
    Woodburn, Matthew
    Wordsworth, B. Paul
    Young, Allan H.
    Zeggini, Eleftheria
    Carter, Nigel P.
    Frayling, Timothy M.
    Lee, Charles
    McVean, Gil
    Munroe, Patricia B.
    Palotie, Aarno
    Sawcer, Stephen J.
    Scherer, Stephen W.
    Strachan, David P.
    Tyler-Smith, Chris
    Brown, Matthew A.
    Burton, Paul R.
    Caulfield, Mark J.
    Compston, Alastair
    Farrall, Martin
    Gough, Stephen C. L.
    Hall, Alistair S.
    Hattersley, Andrew T.
    Hill, Adrian V. S.
    Mathew, Christopher G.
    Pembrey, Marcus
    Satsangi, Jack
    Stratton, Michael R.
    Worthington, Jane
    Deloukas, Panos
    Duncanson, Audrey
    Kwiatkowski, Dominic P.
    McCarthy, Mark I.
    Ouwehand, Willem H.
    Parkes, Miles
    Rahman, Nazneen
    Todd, John A.
    Samani, Nilesh J.
    Donnelly, Peter
    Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7289, 713-720 p.Article in journal (Refereed)
    Abstract [en]

    Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

  • 104. Craig, O. E.
    et al.
    Saul, H.
    Lucquin, A.
    Nishida, Y.
    Tache, K.
    Clarke, L.
    Thompson, A.
    Altoft, D. T.
    Uchiyama, J.
    Ajimoto, M.
    Gibbs, K.
    Isaksson, Sven
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory. Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Heron, C. P.
    Jordan, P.
    Earliest evidence for the use of pottery2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 496, no 7445, 351-354 p.Article in journal (Refereed)
    Abstract [en]

    Pottery was a hunter-gatherer innovation that first emerged in East Asia between 20,000 and 12,000 calibrated years before present(1,2) (cal BP), towards the end of the Late Pleistocene epoch, a period of time when humans were adjusting to changing climates and new environments. Ceramic container technologies were one of a range of late glacial adaptations that were pivotal to structuring subsequent cultural trajectories in different regions of the world, but the reasons for their emergence and widespread uptake are poorly understood. The first ceramic containers must have provided prehistoric hunter-gatherers with attractive new strategies for processing and consuming foodstuffs, but virtually nothing is known of how early pots were used. Here we report the chemical analysis of food residues associated with Late Pleistocene pottery, focusing on one of the best-studied prehistoric ceramic sequences in the world, the Japanese Jomon. We demonstrate that lipids can be recovered reliably from charred surface deposits adhering to pottery dating from about 15,000 to 11,800 cal BP (the Incipient Jomon period), the oldest pottery so far investigated, and that in most cases these organic compounds are unequivocally derived from processing freshwater and marine organisms. Stable isotope data support the lipid evidence and suggest that most of the 101 charred deposits analysed, from across the major islands of Japan, were derived from high-trophic-level aquatic food. Productive aquatic ecotones were heavily exploited by late glacial foragers(3), perhaps providing an initial impetus for investment in ceramic container technology, and paving the way for further intensification of pottery use by hunter-gatherers in the early Holocene epoch. Now that we have shown that it is possible to analyse organic residues from some of the world's earliest ceramic vessels, the subsequent development of this critical technology can be clarified through further widespread testing of hunter-gatherer pottery from later periods.

  • 105. Cressey, Daniel
    Geology: The next land rush2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 451, no 7174, 12-15 p.Article in journal (Refereed)
  • 106. Curtis, Bruce A.
    et al.
    Tanifuji, Goro
    Burki, Fabien
    Gruber, Ansgar
    Irimia, Manuel
    Maruyama, Shinichiro
    Arias, Maria C.
    Ball, Steven G.
    Gile, Gillian H.
    Hirakawa, Yoshihisa
    Hopkins, Julia F.
    Kuo, Alan
    Rensing, Stefan A.
    Schmutz, Jeremy
    Symeonidi, Aikaterini
    Elias, Marek
    Eveleigh, Robert J. M.
    Herman, Emily K.
    Klute, Mary J.
    Nakayama, Takuro
    Obornik, Miroslav
    Reyes-Prieto, Adrian
    Armbrust, E. Virginia
    Aves, Stephen J.
    Beiko, Robert G.
    Coutinho, Pedro
    Dacks, Joel B.
    Durnford, Dion G.
    Fast, Naomi M.
    Green, Beverley R.
    Grisdale, Cameron J.
    Hempel, Franziska
    Henrissat, Bernard
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ishida, Ken-Ichiro
    Kim, Eunsoo
    Koreny, Lude. K.
    Kroth, Peter G.
    Liu, Yuan
    Malik, Shehre-Banoo
    Maier, Uwe G.
    McRose, Darcy
    Mock, Thomas
    Neilson, Jonathan A. D.
    Onodera, Naoko T.
    Poole, Anthony M.
    Pritham, Ellen J.
    Richards, Thomas A.
    Rocap, Gabrielle
    Roy, Scott W.
    Sarai, Chihiro
    Schaack, Sarah
    Shirato, Shu
    Slamovits, Claudio H.
    Spencer, David F.
    Suzuki, Shigekatsu
    Worden, Alexandra Z.
    Zauner, Stefan
    Barry, Kerrie
    Bell, Callum
    Bharti, Arvind K.
    Crow, John A.
    Grimwood, Jane
    Kramer, Robin
    Lindquist, Erika
    Lucas, Susan
    Salamov, Asaf
    McFadden, Geoffrey I.
    Lane, Christopher E.
    Keeling, Patrick J.
    Gray, Michael W.
    Grigoriev, Igor V.
    Archibald, John M.
    Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 492, no 7427, 59-65 p.Article in journal (Refereed)
    Abstract [en]

    Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.

  • 107. Dahl-Jensen, D.
    et al.
    Albert, M. R.
    Aldahan, A.
    Azuma, N.
    Balslev-Clausen, D.
    Baumgartner, M.
    Berggren, A. -M
    Bigler, M.
    Binder, T.
    Blunier, T.
    Bourgeois, J. C.
    Brook, E. J.
    Buchardt, S. L.
    Buizert, C.
    Capron, E.
    Chappellaz, J.
    Chung, J.
    Clausen, H. B.
    Cvijanovic, I.
    Davies, S. M.
    Ditlevsen, P.
    Eicher, O.
    Fischer, H.
    Fisher, D. A.
    Fleet, L. G.
    Gfeller, G.
    Gkinis, V.
    Gogineni, S.
    Goto-Azuma, K.
    Grinsted, A.
    Gudlaugsdottir, H.
    Guillevic, M.
    Hansen, S. B.
    Hansson, Margareta
    Stockholm University, Faculty of Science, Department of Physical Geography and Quaternary Geology.
    Hirabayashi, M.
    Hong, S.
    Hur, S. D.
    Huybrechts, P.
    Hvidberg, C. S.
    Iizuka, Yoshinori
    Stockholm University, Faculty of Science, Department of Physical Geography and Quaternary Geology. Hokkaido University, Japan.
    Jenk, T.
    Johnsen, S. J.
    Jones, T. R.
    Jouzel, J.
    Karlsson, N. B.
    Kawamura, K.
    Keegan, K.
    Kettner, E.
    Kipfstuhl, S.
    Kjaer, H. A.
    Koutnik, M.
    Kuramoto, T.
    Koehler, P.
    Laepple, T.
    Landais, A.
    Langen, P. L.
    Larsen, L. B.
    Leuenberger, D.
    Leuenberger, M.
    Leuschen, C.
    Li, J.
    Lipenkov, V.
    Martinerie, P.
    Maselli, O. J.
    Masson-Delmotte, V.
    McConnell, J. R.
    Miller, H.
    Mini, O.
    Miyamoto, A.
    Montagnat-Rentier, M.
    Mulvaney, R.
    Muscheler, R.
    Orsi, A. J.
    Paden, J.
    Panton, C.
    Pattyn, F.
    Petit, J. -R
    Pol, K.
    Popp, T.
    Possnert, G.
    Prie, F.
    Prokopiou, M.
    Quiquet, A.
    Rasmussen, S. O.
    Raynaud, D.
    Ren, J.
    Reutenauer, C.
    Ritz, C.
    Rockmann, T.
    Rosen, J. L.
    Rubino, M.
    Rybak, O.
    Samyn, D.
    Sapart, C. J.
    Schilt, A.
    Schmidt, A. M. Z.
    Schwander, J.
    Schuepbach, S.
    Seierstad, I.
    Severinghaus, J. P.
    Sheldon, S.
    Simonsen, S. B.
    Sjolte, J.
    Solgaard, A. M.
    Sowers, T.
    Sperlich, P.
    Steen-Larsen, H. C.
    Steffen, K.
    Steffensen, J. P.
    Steinhage, D.
    Stocker, T. F.
    Stowasser, C.
    Sturevik, A. S.
    Sturges, W. T.
    Sveinbjornsdottir, A.
    Svensson, A.
    Tison, J. -L
    Uetake, J.
    Vallelonga, P.
    van de Wal, R. S. W.
    van der Wel, G.
    Vaughn, B. H.
    Vinther, B.
    Waddington, E.
    Wegner, A.
    Weikusat, I.
    White, J. W. C.
    Wilhelms, F.
    Winstrup, M.
    Witrant, E.
    Wolff, E. W.
    Xiao, C.
    Zheng, J.
    Eemian interglacial reconstructed from a Greenland folded ice core2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 493, no 7433, 489-494 p.Article in journal (Refereed)
    Abstract [en]

    Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 +/- 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 +/- 250 metres, reaching surface elevations 122,000 years ago of 130 +/- 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future.

  • 108. Dahl-Jensen, D.
    et al.
    Albert, M. R.
    Aldahan, Ala
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Azuma, N.
    Balslev-Clausen, D.
    Baumgartner, M.
    Berggren, Ann-Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Bigler, M.
    Binder, T.
    Blunier, T.
    Bourgeois, J. C.
    Brook, E. J.
    Buchardt, S. L.
    Buizert, C.
    Capron, E.
    Chappellaz, J.
    Chung, J.
    Clausen, H. B.
    Cvijanovic, I.
    Davies, S. M.
    Ditlevsen, P.
    Eicher, O.
    Fischer, H.
    Fisher, D. A.
    Fleet, L. G.
    Gfeller, G.
    Gkinis, V.
    Gogineni, S.
    Goto-Azuma, K.
    Grinsted, A.
    Gudlaugsdottir, H.
    Guillevic, M.
    Hansen, S. B.
    Hansson, M.
    Hirabayashi, M.
    Hong, S.
    Hur, S. D.
    Huybrechts, P.
    Hvidberg, C. S.
    Iizuka, Y.
    Jenk, T.
    Johnsen, S. J.
    Jones, T. R.
    Jouzel, J.
    Karlsson, N. B.
    Kawamura, K.
    Keegan, K.
    Kettner, E.
    Kipfstuhl, S.
    Kjaer, H. A.
    Koutnik, M.
    Kuramoto, T.
    Koehler, P.
    Laepple, T.
    Landais, A.
    Langen, P. L.
    Larsen, L. B.
    Leuenberger, D.
    Leuenberger, M.
    Leuschen, C.
    Li, J.
    Lipenkov, V.
    Martinerie, P.
    Maselli, O. J.
    Masson-Delmotte, V.
    McConnell, J. R.
    Miller, H.
    Mini, O.
    Miyamoto, A.
    Montagnat-Rentier, M.
    Mulvaney, R.
    Muscheler, R.
    Orsi, A. J.
    Paden, J.
    Panton, C.
    Pattyn, F.
    Petit, J. -R
    Pol, K.
    Popp, T.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Prie, F.
    Prokopiou, M.
    Quiquet, A.
    Rasmussen, S. O.
    Raynaud, D.
    Ren, J.
    Reutenauer, C.
    Ritz, C.
    Rockmann, T.
    Rosen, J. L.
    Rubino, M.
    Rybak, O.
    Samyn, D.
    Sapart, C. J.
    Schilt, A.
    Schmidt, A. M. Z.
    Schwander, J.
    Schuepbach, S.
    Seierstad, I.
    Severinghaus, J. P.
    Sheldon, S.
    Simonsen, S. B.
    Sjolte, J.
    Solgaard, A. M.
    Sowers, T.
    Sperlich, P.
    Steen-Larsen, H. C.
    Steffen, K.
    Steffensen, J. P.
    Steinhage, D.
    Stocker, T. F.
    Stowasser, C.
    Sturevik, A. S.
    Sturges, W. T.
    Sveinbjornsdottir, A.
    Svensson, A.
    Tison, J. -L
    Uetake, J.
    Vallelonga, P.
    van de Wal, R. S. W.
    van der Wel, G.
    Vaughn, B. H.
    Vinther, B.
    Waddington, E.
    Wegner, A.
    Weikusat, I.
    White, J. W. C.
    Wilhelms, F.
    Winstrup, M.
    Witrant, E.
    Wolff, E. W.
    Xiao, C.
    Zheng, J.
    Eemian interglacial reconstructed from a Greenland folded ice core2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 493, no 7433, 489-494 p.Article in journal (Refereed)
    Abstract [en]

    Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 +/- 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 +/- 250 metres, reaching surface elevations 122,000 years ago of 130 +/- 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future.

  • 109. D'Alisa, Giacomo
    et al.
    Armiero, Marco
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, History of Science, Technology and Environment.
    De Rosa, Salvatore Paolo
    Rethink Campania's toxic-waste scandal2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 509, no 7501, 427-427 p.Article in journal (Refereed)
  • 110. Daumke, Oliver
    et al.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vallis, Yvonne
    Martens, Sascha
    Butler, P Jonathan G
    McMahon, Harvey T
    Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 449, no 7164, 923-927 p.Article in journal (Refereed)
    Abstract [en]

    The ability to actively remodel membranes in response to nucleotide hydrolysis has largely been attributed to GTPases of the dynamin superfamily, and these have been extensively studied. Eps15 homology (EH)-domain-containing proteins (EHDs/RME-1/pincher) comprise a less-well-characterized class of highly conserved eukaryotic ATPases implicated in clathrin-independent endocytosis, and recycling from endosomes. Here we show that EHDs share many common features with the dynamin superfamily, such as a low affinity for nucleotides, the ability to tubulate liposomes in vitro, oligomerization around lipid tubules in ring-like structures and stimulated nucleotide hydrolysis in response to lipid binding. We present the structure of EHD2, bound to a non-hydrolysable ATP analogue, and provide evidence consistent with a role for EHDs in nucleotide-dependent membrane remodelling in vivo. The nucleotide-binding domain is involved in dimerization, which creates a highly curved membrane-binding region in the dimer. Oligomerization of dimers occurs on another interface of the nucleotide-binding domain, and this allows us to model the EHD oligomer. We discuss the functional implications of the EHD2 structure for understanding membrane deformation.

  • 111. de lavergne, C.
    et al.
    Madec, G.
    Roquet, Fabien
    Stockholm University, Faculty of Science, Department of Meteorology .
    Holmes, R. M.
    McDougall, T. J.
    Abyssal ocean overturning shaped by seafloor distribution2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 551, no 7679, 181-186 p.Article in journal (Refereed)
    Abstract [en]

    The abyssal ocean is broadly characterized by northward flow of the densest waters and southward flow of less-dense waters above them. Understanding what controls the strength and structure of these interhemispheric flows-referred to as the abyssal overturning circulation-is key to quantifying the ocean's ability to store carbon and heat on timescales exceeding a century. Here we show that, north of 32 degrees S, the depth distribution of the seafloor compels dense southernorigin waters to flow northward below a depth of about 4 kilometres and to return southward predominantly at depths greater than 2.5 kilometres. Unless ventilated from the north, the overlying mid-depths (1 to 2.5 kilometres deep) host comparatively weak mean meridional flow. Backed by analysis of historical radiocarbon measurements, the findings imply that the geometry of the Pacific, Indian and Atlantic basins places a major external constraint on the overturning structure.

  • 112. de Vries, B. L.
    et al.
    Acke, B.
    Blommaert, J. A. D. L.
    Waelkens, C.
    Waters, L. B. F. M.
    Vandenbussche, B.
    Min, M.
    Olofsson, Göran
    Stockholm University, Faculty of Science, Department of Astronomy.
    Dominik, C.
    Decin, L.
    Barlow, M. J.
    Brandeker, Alexis
    Stockholm University, Faculty of Science, Department of Astronomy.
    Di Francesco, J.
    Glauser, A. M.
    Greaves, J.
    Harvey, P. M.
    Holland, W. S.
    Ivison, R. J.
    Liseau, R.
    Pantin, E. E.
    Pilbratt, G. L.
    Royer, P.
    Sibthorpe, B.
    Comet-like mineralogy of olivine crystals in an extrasolar proto-Kuiper belt2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 490, no 7418, 74-76 p.Article in journal (Refereed)
    Abstract [en]

    Some planetary systems harbour debris disks containing planetesimals such as asteroids and comets(1). Collisions between such bodies produce small dust particles(2), the spectral features of which reveal their composition and, hence, that of their parent bodies. A measurement of the composition of olivine crystals (Mg2-2xFe2xSiO4) has been done for the protoplanetary disk HD 100546 (refs 3, 4) and for olivine crystals in the warm inner parts of planetary systems. The latter compares well with the iron-rich olivine in asteroids(5,6) (x approximate to 0.29). In the cold outskirts of the beta Pictoris system, an analogue to the young Solar System, olivine crystals were detected(7) but their composition remained undetermined, leaving unknown how the composition of the bulk of Solar System cometary olivine grains compares with that of extrasolar comets(8,9). Here we report the detection of the 69-micrometre-wavelength band of olivine crystals in the spectrum of beta Pictoris. Because the disk is optically thin, we can associate the crystals with an extrasolar proto-Kuiper belt a distance of 15-45 astronomical units from the star (one astronomical unit is the Sun-Earth distance), determine their magnesium-rich composition (x = 0.01 +/- 0.001) and show that they make up 3.6 +/- 1.0 per cent of the total dust mass. These values are strikingly similar to those for the dust emitted by the most primitive comets in the Solar System(8-10), even though beta Pictoris is more massive and more luminous and has a different planetary system architecture.

  • 113. Decin, L.
    et al.
    Agundez, M.
    Barlow, M. J.
    Daniel, F.
    Cernicharo, J.
    Lombaert, R.
    De Beck, E.
    Royer, P.
    Vandenbussche, B.
    Wesson, R.
    Polehampton, E. T.
    Blommaert, J. A. D. L.
    De Meester, W.
    Exter, K.
    Feuchtgruber, H.
    Gear, W. K.
    Gomez, H. L.
    Groenewegen, M. A. T.
    Guelin, M.
    Hargrave, P. C.
    Huygen, R.
    Imhof, P.
    Ivison, R. J.
    Jean, C.
    Kahane, C.
    Kerschbaum, F.
    Leeks, S. J.
    Lim, T.
    Matsuura, M.
    Olofsson, Göran
    Stockholm University, Faculty of Science, Department of Astronomy.
    Posch, T.
    Regibo, S.
    Savini, G.
    Sibthorpe, B.
    Swinyard, B. M.
    Yates, J. A.
    Waelkens, C.
    Warm water vapour in the sooty outflow from a luminous carbon star2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 467, no 7311, 64-67 p.Article in journal (Refereed)
    Abstract [en]

    The detection(1) of circumstellar water vapour around the ageing carbon star IRC + 10216 challenged the current understanding of chemistry in old stars, because water was predicted(2) to be almost absent in carbon-rich stars. Several explanations for the water were postulated, including the vaporization of icy bodies (comets or dwarf planets) in orbit around the star(1), grain surface reactions(3), and photochemistry in the outer circumstellar envelope(4). With a single water line detected so far from this one carbon-rich evolved star, it is difficult to discriminate between the different mechanisms proposed. Here we report the detection of dozens of water vapour lines in the far-infrared and sub-millimetre spectrum of IRC + 10216 using the Herschel satellite(5). This includes some high-excitation lines with energies corresponding to similar to 1,000 K, which can be explained only if water is present in the warm inner sooty region of the envelope. A plausible explanation for the warm water appears to be the penetration of ultraviolet photons deep into a clumpy circumstellar envelope. This mechanism also triggers the formation of other molecules, such as ammonia, whose observed abundances(6) are much higher than hitherto predicted(7).

  • 114. DeLuca, T H
    et al.
    Zackrisson, O
    Nilsson, M C
    Sellstedt, Anita
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Quantifying nitrogen-fixation in feather moss carpets of boreal forests2002In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 419, no 6910, 917-920 p.Article in journal (Refereed)
    Abstract [en]

    Biological nitrogen (N) fixation is the primary source of N within natural ecosystems(1), yet the origin of boreal forest N has remained elusive. The boreal forests of Eurasia and North America lack any significant, widespread symbiotic N-fixing plants(1-6). With the exception of scattered stands of alder in early primary successional forests(7), N-fixation in boreal forests is considered to be extremely limited. Nitrogen-fixation in northern European boreal forests has been estimated(2) at only 0.5 kg Nha(-1) yr(-1); however, organic N is accumulated in these ecosystems at a rate of 3 kg N ha(-1) yr(-1) (ref. 8). Our limited understanding of the origin of boreal N is unacceptable given the extent of the boreal forest region, but predictable given our imperfect knowledge of N-fixation(1,9). Herein we report on a N-fixing symbiosis between a cyanobacterium (Nostoc sp.) and the ubiquitous feather moss, Pleurozium schreberi (Bird) Mitt. that alone fixes between 1.5 and 2.0 kg N ha(-1) yr(-1) in mid- to late-successional forests of northern Scandinavia and Finland. Previous efforts have probably underestimated N-fixation potential in boreal forests.

  • 115.
    Deodhar, Ganesh Bhaskar
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Philosophy, Mathematics and Science Section.
    Fine structure of K-absorption limit of silicon oxide1930In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 125, 777-778 p.Article in journal (Refereed)
    Abstract [en]

    THAT the X-ray absorption limits are not simple but show a rather complicated structure has been known now for some time. The main difficulties in their experimental investigation are in respect of (1) amount of the absorbing substance, and (2) dispersion of the spectrograph. The amount of the absorber must not be either too great or too small, otherwise the details are lost. Secondly, the dispersion must be made as large as possible to bring out all the details and measure them with the usual accuracy.

  • 116. Dethoff, Elizabeth A
    et al.
    Petzold, Katja
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chugh, Jeetender
    Casiano-Negroni, Anette
    Al-Hashimi, Hashim M
    Visualizing transient low-populated structures of RNA2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, 724-728 p.Article in journal (Refereed)
    Abstract [en]

    The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 μs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.

  • 117. Ding, Li
    et al.
    Getz, Gad
    Wheeler, David A
    Mardis, Elaine R
    McLellan, Michael D
    Cibulskis, Kristian
    Sougnez, Carrie
    Greulich, Heidi
    Muzny, Donna M
    Morgan, Margaret B
    Fulton, Lucinda
    Fulton, Robert S
    Zhang, Qunyuan
    Wendl, Michael C
    Lawrence, Michael S
    Larson, David E
    Chen, Ken
    Dooling, David J
    Sabo, Aniko
    Hawes, Alicia C
    Shen, Hua
    Jhangiani, Shalini N
    Lewis, Lora R
    Hall, Otis
    Zhu, Yiming
    Mathew, Tittu
    Ren, Yanru
    Yao, Jiqiang
    Scherer, Steven E
    Clerc, Kerstin
    Metcalf, Ginger A
    Ng, Brian
    Milosavljevic, Aleksandar
    Gonzalez-Garay, Manuel L
    Osborne, John R
    Meyer, Rick
    Shi, Xiaoqi
    Tang, Yuzhu
    Koboldt, Daniel C
    Lin, Ling
    Abbott, Rachel
    Miner, Tracie L
    Pohl, Craig
    Fewell, Ginger
    Haipek, Carrie
    Schmidt, Heather
    Dunford-Shore, Brian H
    Kraja, Aldi
    Crosby, Seth D
    Sawyer, Christopher S
    Vickery, Tammi
    Sander, Sacha
    Robinson, Jody
    Winckler, Wendy
    Baldwin, Jennifer
    Chirieac, Lucian R
    Dutt, Amit
    Fennell, Tim
    Hanna, Megan
    Johnson, Bruce E
    Onofrio, Robert C
    Thomas, Roman K
    Tonon, Giovanni
    Weir, Barbara A
    Zhao, Xiaojun
    Ziaugra, Liuda
    Zody, Michael C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Giordano, Thomas
    Orringer, Mark B
    Roth, Jack A
    Spitz, Margaret R
    Wistuba, Ignacio I
    Ozenberger, Bradley
    Good, Peter J
    Chang, Andrew C
    Beer, David G
    Watson, Mark A
    Ladanyi, Marc
    Broderick, Stephen
    Yoshizawa, Akihiko
    Travis, William D
    Pao, William
    Province, Michael A
    Weinstock, George M
    Varmus, Harold E
    Gabriel, Stacey B
    Lander, Eric S
    Gibbs, Richard A
    Meyerson, Matthew
    Wilson, Richard K
    Somatic mutations affect key pathways in lung adenocarcinoma2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 455, no 7216, 1069-1075 p.Article in journal (Refereed)
    Abstract [en]

    Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

  • 118.
    Dong, X.-P.
    et al.
    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109, United States.
    Cheng, X.
    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109, United States.
    Mills, E.
    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109, United States.
    Delling, M.
    Department of Cardiology, Children's Hospital Boston, Enders 1350, 320 Longwood Avenue, Boston, MA 02115, United States.
    Wang, F.
    Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
    Kurz, Tino
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Xu, H.
    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109, United States.
    The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 455, no 7215, 992-996 p.Article in journal (Refereed)
    Abstract [en]

    TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4). ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe3+-bound transferrin receptors, or after lysosomal degradation of ferritin-iron complexes and autophagic ingestion of iron-containing macromolecules, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe2+ transporter known at present and it is highly expressed in erythroid precursors. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe2+ transport protein. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe2+ permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe2+ at varying degrees, which correlate well with the disease severity. A comparison of TRPML1-/-ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe2+ levels, an increase in intralysosomal Fe 2+ levels and an accumulation of lipofuscin-like molecules in TRPML1-/- cells. We propose that TRPML1 mediates a mechanism by which Fe2+ is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients. ©2008 Macmillan Publishers Limited. All rights reserved.

  • 119.
    Dubrovinsky, L.
    et al.
    University of Bayreuth, Germany.
    Dubrovinskaia, N.
    University of Bayreuth, Germany.
    Bykova, E.
    University of Bayreuth, Germany; University of Bayreuth, Germany.
    Bykov, M.
    University of Bayreuth, Germany.
    Prakapenka, V.
    University of Chicago, IL 60437 USA.
    Prescher, C.
    University of Chicago, IL 60437 USA.
    Glazyrin, K.
    Deutsch Elektronen Synchrotron DESY, Germany.
    Liermann, H. -P.
    Deutsch Elektronen Synchrotron DESY, Germany.
    Hanfland, M.
    European Synchrotron Radiat Facil, France.
    Ekholm, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering.
    Feng, Qingguo
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, The Institute of Technology.
    Pourovskii, L. V.
    Linköping University, Faculty of Science & Engineering. Ecole Polytech, France.
    Katsnelson, M. I.
    Radboud University of Nijmegen, Netherlands; Ural Federal University, Russia.
    Wills, J. M.
    Los Alamos National Lab, NM 87545 USA.
    Abrikosov, Igor
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering. National University of Science and Technology MISIS, Russia.
    The most incompressible metal osmium at static pressures above 750 gigapascals2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 525, no 7568, 226-+ p.Article in journal (Refereed)
    Abstract [en]

    Metallic osmium (Os) is one of the most exceptional elemental materials, having, at ambient pressure, the highest known density and one of the highest cohesive energies and melting temperatures(1). It is also very incompressible(2-4), but its high-pressure behaviour is not well understood because it has been studied(2-6) so far only at pressures below 75 gigapascals. Here we report powder X-ray diffraction measurements on Os at multi-megabar pressures using both conventional and double-stage diamond anvil cells(7), with accurate pressure determination ensured by first obtaining self-consistent equations of state of gold, platinum, and tungsten in static experiments up to 500 gigapascals. These measurements allow us to show that Os retains its hexagonal close-packed structure upon compression to over 770 gigapascals. But although its molar volume monotonically decreases with pressure, the unit cell parameter ratio of Os exhibits anomalies at approximately 150 gigapascals and 440 gigapascals. Dynamical mean-field theory calculations suggest that the former anomaly is a signature of the topological change of the Fermi surface for valence electrons. However, the anomaly at 440 gigapascals might be related to an electronic transition associated with pressure-induced interactions between core electrons. The ability to affect the core electrons under static high-pressure experimental conditions, even for incompressible metals such as Os, opens up opportunities to search for new states of matter under extreme compression.

  • 120.
    Dubrovinsky, L.
    et al.
    Bayerisches Geoinstitut, Universität Bayreuth.
    Dubrovinskaia, N.
    Bayerisches Geoinstitut, Universität Bayreuth.
    Langenhorst, F.
    Bayerisches Geoinstitut, Universität Bayreuth.
    Dobson, D.
    Bayerisches Geoinstitut, Universität Bayreuth.
    Rubie, D.
    Bayerisches Geoinstitut, Universität Bayreuth.
    Gessgmann, C.
    Max-Planck-Institut für Chemie, Mainz.
    Abrikosov, I. A.
    Condensed Matter Theory Group, Department of Physics, Uppsala University.
    Johansson, Börje
    KTH, Superseded Departments, Materials Science and Engineering.
    Baykov, Vitaly
    KTH, Superseded Departments, Materials Science and Engineering.
    Vitos, Levente
    KTH, Superseded Departments, Materials Science and Engineering.
    Le Bihan, T.
    European Synchrotron Radiation Facility, Grenoble.
    Crichton, W. A.
    European Synchrotron Radiation Facility, Grenoble.
    Dmitriev, V.
    Swiss-Norwegian Beam Lines at ESRF, Grenoble.
    Weber, H. P.
    Swiss-Norwegian Beam Lines at ESRF, Grenoble.
    Iron-silica interaction at extreme conditions and the electrically conducting layer at the base of Earth's mantle2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 422, no 6927, 58-61 p.Article in journal (Refereed)
    Abstract [en]

    The boundary between the Earth's metallic core and its silicate mantle is characterized by strong lateral heterogeneity and sharp changes in density, seismic wave velocities, electrical conductivity and chemical composition(1-7). To investigate the composition and properties of the lowermost mantle, an understanding of the chemical reactions that take place between liquid iron and the complex Mg-Fe-Si-Al-oxides of the Earth's lower mantle is first required(8-15). Here we present a study of the interaction between iron and silica (SiO2) in electrically and laser-heated diamond anvil cells. In a multianvil apparatus at pressures up to 140 GPa and temperatures over 3,800 K we simulate conditions down to the core-mantle boundary. At high temperature and pressures below 40 GPa, iron and silica react to form iron oxide and an iron-silicon alloy, with up to 5 wt% silicon. At pressures of 85-140 GPa, however, iron and SiO2 do not react and iron-silicon alloys dissociate into almost pure iron and a CsCl-structured (B2) FeSi compound. Our experiments suggest that a metallic silicon-rich B2 phase, produced at the core-mantle boundary (owing to reactions between iron and silicate(2,9,10,13)), could accumulate at the boundary between the mantle and core and explain the anomalously high electrical conductivity of this region(6).

  • 121. Dubrovinsky, L. S.
    et al.
    Dubrovinskaia, N. A.
    Swamy, V.
    Muscat, J.
    Harrison, N. M.
    Ahuja, Rajeev
    Holm, B.
    Johansson, Börje
    KTH, Superseded Departments, Materials Science and Engineering.
    Materials science - The hardest known oxide2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 410, no 6829, 653-654 p.Article in journal (Refereed)
  • 122. Dujon, B
    et al.
    Albermann, K
    Aldea, M
    Alexandraki, D
    Ansorge, W
    Arino, J
    Benes, V
    Bohn, C
    BolotinFukuhara, M
    Bordonne, R
    Boyer, J
    Camasses, A
    Casamayor, A
    Casas, C
    Cheret, G
    Cziepluch, C
    DaignanFornier, B
    Dang, V
    deHaan, M
    Delius, H
    Durand, P
    Fairhead, C
    Feldmann, H
    Gaillon, L
    Galisson, F
    Gamo, J
    Gancedo, C
    Goffeau, A
    Goulding, E
    Grivell, A
    Habbig, B
    Hand, J
    Hani, J
    Hattenhorst, U
    Hebling, U
    Hernando, Y
    Herrero, E
    Heumann, K
    Hiesel, R
    Hilger, F
    Hofmann, B
    Hollenberg, P
    Hughes, B
    Jauniaux, C
    Kalogeropoulos, A
    Katsoulou, C
    Kordes, E
    Lafuente, J
    Landt, O
    Louis, J
    Maarse, C
    Madania, A
    Mannhaupt, G
    Marck, C
    Martin, P
    Mewes, W
    Michaux, G
    Paces, V
    ParleMcDermott, G
    Pearson, M
    Perrin, A
    Pettersson, B
    Poch, O
    Pohl, M
    Poirey, R
    Portetelle, D
    Pujol, A
    Purnelle, B
    Rad, R
    Rechmann, S
    Schwager, C
    Schweizer, M
    Sor, F
    Sterky, Fredrik
    KTH, Superseded Departments, Biotechnology.
    Tarassov, A
    Teodoru, C
    Tettelin, H
    Thierry, A
    Tobiasch, E
    Tzermia, M
    Uhlen, Mathias
    KTH, Superseded Departments, Biotechnology.
    Unseld, M
    Valens, M
    Vandenbol, M
    Vetter, I
    Vicek, C
    Voet, M
    Volckaert, G
    Voss, H
    Wambutt, R
    Wedler, H
    Wiemann, S
    Winsor, B
    Wolfe, H
    Zollner, A
    Zumstein, E
    Kleine, K
    The nucleotide sequence of Saccharomyces cerevisiae chromosome XV1997In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 387, no 6632, 98-102 p.Article in journal (Refereed)
    Abstract [en]

    Chromosome XV was one of the last two chromosomes of Saccharomyces cerevisiae to be discovered(1). It is the third-largest yeast chromosome after chromosomes XII and IV, and is very similar in size to chromosome VII. It alone represents 9% of the yeast genome (8% if ribosomal DNA is included). When systematic sequencing of chromosome XV was started, 93 genes or markers were identified, and most of them were mapped(2). However, very little else was known about chromosome XV which, in contrast to shorter chromosomes, had not been the object of comprehensive genetic or molecular analysis. It was therefore decided to start sequencing chromosome XV only in the third phase of the European Yeast Genome Sequencing Programme, after experience was gained on chromosomes III, XI and II (refs 3-5). The sequence of chromosome XV has been determined from a set of partly overlapping cosmid clones derived from a unique yeast strain, and physically mapped at 3.3-kilobase resolution before sequencing. As well as numerous new open reading frames (ORFs) and genes encoding tRNA or small RNA molecules, the sequence of 1,091,283 base pairs confirms the high proportion of orphan genes and reveals a number of ancestral and successive duplications with other yeast chromosomes.

  • 123.
    Dupret, Vincent
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Sanchez, Sophie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Goujet, Daniel
    Tafforeau, Paul
    Ahlberg, Per Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    A primitive placoderm sheds light on the origin of the jawed vertebrate face2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 507, no 7493, 500-503 p.Article in journal (Refereed)
    Abstract [en]

    Extant vertebrates form two clades, the jawless Cyclostomata (lampreys and hagfishes) and the jawed Gnathostomata (all other vertebrates), with contrasting facial architectures(1,2). These arise during development from just a few key differences in the growth patterns of the cranial primordia: notably, the nasal sacs and hypophysis originate from a single placode in cyclostomes but from separate placodes in gnathostomes, and infraoptic ectomesenchyme migrates forward either side of the single placode in cyclostomes but between the placodes in gnathostomes(3-8). Fossil stem gnathostomes preserve cranial anatomies rich in landmarks that provide proxies for developmental processes and allow the transition from jawless to jawed vertebrates to be broken down into evolutionary steps(7,9-12). Here we use propagation phase contrast synchrotron microtomography to image the cranial anatomy of the primitive placoderm (jawed stem gnathostome) Romundina(13), and show that itcombines jawed vertebrate architecture with cranial and cerebral proportions resembling those of cyclostomes and the galeaspid (jawless stem gnathostome) Shuyu(11). This combination seems to be primitive for jawed vertebrates, and suggests a decoupling between ectomesenchymal growth trajectory, ectomesenchymal proliferation, and cerebral shape change during the origin of gnathostomes.

  • 124. Edgar, Graham J.
    et al.
    Stuart-Smith, Rick D.
    Willis, Trevor J.
    Kininmonth, Stuart
    Stockholm University, Faculty of Science, Stockholm Resilience Centre. University of Tasmania, Australia.
    Baker, Susan C.
    Banks, Stuart
    Barrett, Neville S.
    Becerro, Mikel A.
    Bernard, Anthony T. F.
    Berkhout, Just
    Buxton, Colin D.
    Campbell, Stuart J.
    Cooper, Antonia T.
    Davey, Marlene
    Edgar, Sophie C.
    Foersterra, Guenter
    Galvan, David E.
    Irigoyen, Alejo J.
    Kushner, David J.
    Moura, Rodrigo
    Parnell, P. Ed
    Shears, Nick T.
    Soler, German
    Strain, Elisabeth M. A.
    Thomson, Russell J.
    Global conservation outcomes depend on marine protected areas with five key features2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 506, no 7487, 216-+ p.Article in journal (Refereed)
    Abstract [en]

    In line with global targets agreed under the Convention on Biological Diversity, the number of marine protected areas (MPAs) is increasing rapidly, yet socio-economic benefits generated by MPAs remain difficult to predict and under debate(1,2). MPAs often fail to reach their full potential as a consequence of factors such as illegal harvesting, regulations that legally allow detrimental harvesting, or emigration of animals outside boundaries because of continuous habitat or inadequate size of reserve(3-5). Here we show that the conservation benefits of 87 MPAs investigated worldwide increase exponentially with the accumulation of five key features: no take, well enforced, old (>10 years), large (>100 km(2)), and isolated by deep water or sand. Using effective MPAs with four or five key features as an unfished standard, comparisons of underwater survey data from effective MPAs with predictions based on survey data from fished coasts indicate that total fish biomass has declined about two-thirds from historical baselines as a result of fishing. Effective MPAs also had twice as many large (>250 mm total length) fish species per transect, five times more large fish biomass, and fourteen times more shark biomass than fished areas. Most (59%) of the MPAs studied had only one or two key features and were not ecologically distinguishable from fished sites. Our results show that global conservation targets based on area alone will not optimize protection of marine biodiversity. More emphasis is needed on better MPA design, durable management and compliance to ensure that MPAs achieve their desired conservation value.

  • 125. Eghbali, M
    et al.
    Curmi, J P
    Birnir, Bryndis
    John Curtin School of Medical Research, Australian National University.
    Gage, P W
    Hippocampal GABA(A) channel conductance increased by diazepam.1997In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 388, no 6637, 71-5 p.Article in journal (Refereed)
    Abstract [en]

    Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Here we show that the benzodiazepine diazepam can also increase the conductance of GABAA channels activated by low concentrations of GABA (0.5 or 5 microM) in rat cultured hippocampal neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAA channels tonically activated by low ambient concentrations of GABA in the extracellular environment may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.

  • 126. Egorov, A. V.
    et al.
    Hamam, B. N.
    Fransén, Erik
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Hasselmo, M. E.
    Alonso, A. A.
    Graded persistent activity in entorhinal cortex neurons2002In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 420, no 6912, 173-178 p.Article in journal (Refereed)
    Abstract [en]

    Working memory represents the ability of the brain to hold externally or internally driven information for relatively short periods of time(1,2). Persistent neuronal activity is the elementary process underlying working memory but its cellular basis remains unknown. The most widely accepted hypothesis is that persistent activity is based on synaptic reverberations in recurrent circuits. The entorhinal cortex in the parahippocampal region is crucially involved in the acquisition, consolidation and retrieval of long-term memory traces for which working memory operations are essential(2). Here we show that individual neurons from layer V of the entorhinal cortex-which link the hippocampus to extensive cortical regions(3)-respond to consecutive stimuli with graded changes in firing frequency that remain stable after each stimulus presentation. In addition, the sustained levels of firing frequency can be either increased or decreased in an input-specific manner. This firing behaviour displays robustness to distractors; it is linked to cholinergic muscarinic receptor activation, and relies on activity-dependent changes of a Ca2+-sensitive cationic current. Such an intrinsic neuronal ability to generate graded persistent activity constitutes an elementary mechanism for working memory.

  • 127.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Protein synthesis: Translocation in slow motion2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 466, no 7304, 325-326 p.Article in journal (Refereed)
  • 128. Ehret, Georg B.
    et al.
    Munroe, Patricia B.
    Rice, Kenneth M.
    Bochud, Murielle
    Johnson, Andrew D.
    Chasman, Daniel I.
    Smith, Albert V.
    Tobin, Martin D.
    Verwoert, Germaine C.
    Hwang, Shih-Jen
    Pihur, Vasyl
    Vollenweider, Peter
    O'Reilly, Paul F.
    Amin, Najaf
    Bragg-Gresham, Jennifer L.
    Teumer, Alexander
    Glazer, Nicole L.
    Launer, Lenore
    Zhao, Jing Hua
    Aulchenko, Yurii
    Heath, Simon
    Sober, Siim
    Parsa, Afshin
    Luan, Jian'an
    Arora, Pankaj
    Dehghan, Abbas
    Zhang, Feng
    Lucas, Gavin
    Hicks, Andrew A.
    Jackson, Anne U.
    Peden, John F.
    Tanaka, Toshiko
    Wild, Sarah H.
    Rudan, Igor
    Igl, Wilmar
    Milaneschi, Yuri
    Parker, Alex N.
    Fava, Cristiano
    Chambers, John C.
    Fox, Ervin R.
    Kumari, Meena
    Go, Min Jin
    van der Harst, Pim
    Kao, Wen Hong Linda
    Sjogren, Marketa
    Vinay, D. G.
    Alexander, Myriam
    Tabara, Yasuharu
    Shaw-Hawkins, Sue
    Whincup, Peter H.
    Liu, Yongmei
    Shi, Gang
    Kuusisto, Johanna
    Tayo, Bamidele
    Seielstad, Mark
    Sim, Xueling
    Nguyen, Khanh-Dung Hoang
    Lehtimaki, Terho
    Matullo, Giuseppe
    Wu, Ying
    Gaunt, Tom R.
    Onland-Moret, N. Charlotte
    Cooper, Matthew N.
    Platou, Carl G. P.
    Org, Elin
    Hardy, Rebecca
    Dahgam, Santosh
    Palmen, Jutta
    Vitart, Veronique
    Braund, Peter S.
    Kuznetsova, Tatiana
    Uiterwaal, Cuno S. P. M.
    Adeyemo, Adebowale
    Palmas, Walter
    Campbell, Harry
    Ludwig, Barbara
    Tomaszewski, Maciej
    Tzoulaki, Ioanna
    Palmer, Nicholette D.
    Aspelund, Thor
    Garcia, Melissa
    Chang, Yen-Pei C.
    O'Connell, Jeffrey R.
    Steinle, Nanette I.
    Grobbee, Diederick E.
    Arking, Dan E.
    Kardia, Sharon L.
    Morrison, Alanna C.
    Hernandez, Dena
    Najjar, Samer
    McArdle, Wendy L.
    Hadley, David
    Brown, Morris J.
    Connell, John M.
    Hingorani, Aroon D.
    Day, Ian N. M.
    Lawlor, Debbie A.
    Beilby, John P.
    Lawrence, Robert W.
    Clarke, Robert
    Hopewell, Jemma C.
    Ongen, Halit
    Dreisbach, Albert W.
    Li, Yali
    Young, J. Hunter
    Bis, Joshua C.
    Kahonen, Mika
    Viikari, Jorma
    Adair, Linda S.
    Lee, Nanette R.
    Chen, Ming-Huei
    Olden, Matthias
    Pattaro, Cristian
    Bolton, Judith A. Hoffman
    Koettgen, Anna
    Bergmann, Sven
    Mooser, Vincent
    Chaturvedi, Nish
    Frayling, Timothy M.
    Islam, Muhammad
    Jafar, Tazeen H.
    Erdmann, Jeanette
    Kulkarni, Smita R.
    Bornstein, Stefan R.
    Graessler, Juergen
    Groop, Leif
    Voight, Benjamin F.
    Kettunen, Johannes
    Howard, Philip
    Taylor, Andrew
    Guarrera, Simonetta
    Ricceri, Fulvio
    Emilsson, Valur
    Plump, Andrew
    Barroso, Ine S.
    Khaw, Kay-Tee
    Weder, Alan B.
    Hunt, Steven C.
    Sun, Yan V.
    Bergman, Richard N.
    Collins, Francis S.
    Bonnycastle, Lori L.
    Scott, Laura J.
    Stringham, Heather M.
    Peltonen, Leena
    Perola, Markus
    Vartiainen, Erkki
    Brand, Stefan-Martin
    Staessen, Jan A.
    Wang, Thomas J.
    Burton, Paul R.
    Artigas, Maria Soler
    Dong, Yanbin
    Snieder, Harold
    Wang, Xiaoling
    Zhu, Haidong
    Lohman, Kurt K.
    Rudock, Megan E.
    Heckbert, Susan R.
    Smith, Nicholas L.
    Wiggins, Kerri L.
    Doumatey, Ayo
    Shriner, Daniel
    Veldre, Gudrun
    Viigimaa, Margus
    Kinra, Sanjay
    Prabhakaran, Dorairaj
    Tripathy, Vikal
    Langefeld, Carl D.
    Rosengren, Annika
    Thelle, Dag S.
    Corsi, Anna Maria
    Singleton, Andrew
    Forrester, Terrence
    Hilton, Gina
    McKenzie, Colin A.
    Salako, Tunde
    Iwai, Naoharu
    Kita, Yoshikuni
    Ogihara, Toshio
    Ohkubo, Takayoshi
    Okamura, Tomonori
    Ueshima, Hirotsugu
    Umemura, Satoshi
    Eyheramendy, Susana
    Meitinger, Thomas
    Wichmann, H. -Erich
    Cho, Yoon Shin
    Kim, Hyung-Lae
    Lee, Jong-Young
    Scott, James
    Sehmi, Joban S.
    Zhang, Weihua
    Hedblad, Bo
    Nilsson, Peter
    Smith, George Davey
    Wong, Andrew
    Narisu, Narisu
    Stancakova, Alena
    Raffel, Leslie J.
    Yao, Jie
    Kathiresan, Sekar
    O'Donnell, Christopher J.
    Schwartz, Stephen M.
    Ikram, M. Arfan
    Longstreth, W. T., Jr.
    Mosley, Thomas H.
    Seshadri, Sudha
    Shrine, Nick R. G.
    Wain, Louise V.
    Morken, Mario A.
    Swift, Amy J.
    Laitinen, Jaana
    Prokopenko, Inga
    Zitting, Paavo
    Cooper, Jackie A.
    Humphries, Steve E.
    Danesh, John
    Rasheed, Asif
    Goel, Anuj
    Hamsten, Anders
    Watkins, Hugh
    Bakker, Stephan J. L.
    van Gilst, Wiek H.
    Janipalli, Charles S.
    Mani, K. Radha
    Yajnik, Chittaranjan S.
    Hofman, Albert
    Mattace-Raso, Francesco U. S.
    Oostra, Ben A.
    Demirkan, Ayse
    Isaacs, Aaron
    Rivadeneira, Fernando
    Lakatta, Edward G.
    Orru, Marco
    Scuteri, Angelo
    Ala-Korpela, Mika
    Kangas, Antti J.
    Lyytikainen, Leo-Pekka
    Soininen, Pasi
    Tukiainen, Taru
    Wurtz, Peter
    Ong, Rick Twee-Hee
    Doerr, Marcus
    Kroemer, Heyo K.
    Voelker, Uwe
    Voelzke, Henry
    Galan, Pilar
    Hercberg, Serge
    Lathrop, Mark
    Zelenika, Diana
    Deloukas, Panos
    Mangino, Massimo
    Spector, Tim D.
    Zhai, Guangju
    Meschia, James F.
    Nalls, Michael A.
    Sharma, Pankaj
    Terzic, Janos
    Kumar, M. V. Kranthi
    Denniff, Matthew
    Zukowska-Szczechowska, Ewa
    Wagenknecht, Lynne E.
    Fowkes, F. Gerald R.
    Charchar, Fadi J.
    Schwarz, Peter E. H.
    Hayward, Caroline
    Guo, Xiuqing
    Rotimi, Charles
    Bots, Michiel L.
    Brand, Eva
    Samani, Nilesh J.
    Polasek, Ozren
    Talmud, Philippa J.
    Nyberg, Fredrik
    Kuh, Diana
    Laan, Maris
    Hveem, Kristian
    Palmer, Lyle J.
    van der Schouw, Yvonne T.
    Casas, Juan P.
    Mohlke, Karen L.
    Vineis, Paolo
    Raitakari, Olli
    Ganesh, Santhi K.
    Wong, Tien Y.
    Tai, E. Shyong
    Cooper, Richard S.
    Laakso, Markku
    Rao, Dabeeru C.
    Harris, Tamara B.
    Morris, Richard W.
    Dominiczak, Anna F.
    Kivimaki, Mika
    Marmot, Michael G.
    Miki, Tetsuro
    Saleheen, Danish
    Chandak, Giriraj R.
    Coresh, Josef
    Navis, Gerjan
    Salomaa, Veikko
    Han, Bok-Ghee
    Zhu, Xiaofeng
    Kooner, Jaspal S.
    Melander, Olle
    Ridker, Paul M.
    Bandinelli, Stefania
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wright, Alan F.
    Wilson, James F.
    Ferrucci, Luigi
    Farrall, Martin
    Tuomilehto, Jaakko
    Pramstaller, Peter P.
    Elosua, Roberto
    Soranzo, Nicole
    Sijbrands, Eric J. G.
    Altshuler, David
    Loos, Ruth J. F.
    Shuldiner, Alan R.
    Gieger, Christian
    Meneton, Pierre
    Uitterlinden, Andre G.
    Wareham, Nicholas J.
    Gudnason, Vilmundur
    Rotter, Jerome I.
    Rettig, Rainer
    Uda, Manuela
    Strachan, David P.
    Witteman, Jacqueline C. M.
    Hartikainen, Anna-Liisa
    Beckmann, Jacques S.
    Boerwinkle, Eric
    Vasan, Ramachandran S.
    Boehnke, Michael
    Larson, Martin G.
    Jarvelin, Marjo-Riitta
    Psaty, Bruce M.
    Abecasis, Goncalo R.
    Chakravarti, Aravinda
    Elliott, Paul
    van Duijn, Cornelia M.
    Newton-Cheh, Christopher
    Levy, Daniel
    Caulfield, Mark J.
    Johnson, Toby
    Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 478, no 7367, 103-109 p.Article in journal (Refereed)
    Abstract [en]

    Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

  • 129.
    Ek, Monica
    et al.
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Engblom, David
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Saha, Sipra
    Department of Medical Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Per-Johan
    Department of Medical Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Inflammatory response: pathway across the blood–brain barrier2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 410, 430-431 p.Article in journal (Refereed)
    Abstract [en]

    No abstract available.

  • 130. El Albani, Abderrazak
    et al.
    Bengtson, Stefan
    Canfield, Donald E.
    Bekker, Andrey
    Macchiarelli, Roberto
    Mazurier, Arnaud
    Hammarlund, Emma U.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Boulvais, Philippe
    Dupuy, Jean-Jacques
    Fontaine, Claude
    Fuersich, Franz T.
    Gauthier-Lafaye, Francois
    Janvier, Philippe
    Javaux, Emmanuelle
    Ossa, Frantz Ossa
    Pierson-Wickmann, Anne-Catherine
    Riboulleau, Armelle
    Sardini, Paul
    Vachard, Daniel
    Whitehouse, Martin
    Meunier, Alain
    Large colonial organisms with coordinated growth in oxygenated environments 2.1 Gyr ago2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 466, no 7302, 100-104 p.Article in journal (Refereed)
    Abstract [en]

    The evidence for macroscopic life during the Palaeoproterozoic era (2.5-1.6 Gyr ago) is controversial(1-5). Except for the nearly 2-Gyr-old coil-shaped fossil Grypania spiralis(6,7), which may have been eukaryotic, evidence for morphological and taxonomic bio-diversification of macroorganisms only occurs towards the beginning of the Mesoproterozoic era (1.6-1.0 Gyr)(8). Here we report the discovery of centimetre-sized structures from the 2.1-Gyr-old black shales of the Palaeoproterozoic Francevillian B Formation in Gabon, which we interpret as highly organized and spatially discrete populations of colonial organisms. The structures are up to 12 cm in size and have characteristic shapes, with a simple but distinct ground pattern of flexible sheets and, usually, a permeating radial fabric. Geochemical analyses suggest that the sediments were deposited under an oxygenated water column. Carbon and sulphur isotopic data indicate that the structures were distinct biogenic objects, fossilized by pyritization early in the formation of the rock. The growth patterns deduced from the fossil morphologies suggest that the organisms showed cell-to-cell signalling and coordinated responses, as is commonly associated with multicellular organization(9). The Gabon fossils, occurring after the 2.45-2.32-Gyr increase in atmospheric oxygen concentration(10), may be seen as ancient representatives of multicellular life, which expanded so rapidly 1.5 Gyr later, in the Cambrian explosion.

  • 131.
    Ellegren, Hans
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Sheldon, Ben C.
    Genetic basis of fitness differences in natural populations2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 452, no 7184, 169-175 p.Article, review/survey (Refereed)
    Abstract [en]

    Genomics profoundly influences current biology. One of many exciting consequences of this revolution is the potential for identifying and studying the genetic basis of those traits affecting fitness that are key to natural selection. Recent studies using a multitude of genomic approaches have established such genotype - phenotype relationships in natural populations, giving new insight into the genetic architecture of quantitative variation. In parallel, an emerging understanding of the quantitative genetics of fitness variation in the wild means that we are poised to see a synthesis of ecological and molecular approaches in evolutionary biology.

  • 132.
    Ellegren, Hans
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Smeds, Linnea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Burri, Reto
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Ólason, Páll I.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Backström, Niclas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Kawakami, Takeshi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Künstner, Axel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Mäkinen, Hannu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nadachowska-Brzyska, Krystyna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Qvarnström, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Uebbing, Severin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Wolf, Jochen B. W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    The genomic landscape of species divergence in Ficedula flycatchers2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, 756-760 p.Article in journal (Refereed)
    Abstract [en]

    Unravelling the genomic landscape of divergence between lineages is key to understanding speciation. The naturally hybridizing collared flycatcher and pied flycatcher are important avian speciation models that show pre-as well as postzygotic isolation. We sequenced and assembled the 1.1-Gb flycatcher genome, physically mapped the assembly to chromosomes using a low-density linkage map and re-sequenced population samples of each species. Here we show that the genomic landscape of species differentiation is highly heterogeneous with approximately 50 'divergence islands' showing up to 50-fold higher sequence divergence than the genomic background. These non-randomly distributed islands, with between one and three regions of elevated divergence per chromosome irrespective of chromosome size, are characterized by reduced levels of nucleotide diversity, skewed allele-frequency spectra, elevated levels of linkage disequilibrium and reduced proportions of shared polymorphisms in both species, indicative of parallel episodes of selection. Proximity of divergence peaks to genomic regions resistant to sequence assembly, potentially including centromeres and telomeres, indicate that complex repeat structures may drive species divergence. A much higher background level of species divergence of the Z chromosome, and a lower proportion of shared polymorphisms, indicate that sex chromosomes and autosomes are at different stages of speciation. This study provides a roadmap to the emerging field of speciation genomics.

  • 133.
    Elmgren, Ragnar
    et al.
    Stockholm University, Faculty of Science, Department of Systems Ecology.
    Kumblad, Linda
    Stockholm University, Faculty of Science, Department of Systems Ecology.
    Emil, Rydin
    Baltic2020 Foundation.
    Wulff, Fredrik V.
    Stockholm University, Faculty of Science, Department of Systems Ecology.
    Political backing to save the Baltic sea2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 487, 432-432 p.Article in journal (Other (popular science, discussion, etc.))
  • 134.
    Elming, Sten-åke
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Geosciences and Environmental Engineering.
    Evidence for early Proterozoic plate tectonics from seismic reflection profiles in the Baltic Shield1990In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 348, 34-38 p.Article in journal (Refereed)
    Abstract [en]

    Plate tectonics provides the linking framework for all tectonic and magmatic activity seen today, but it is not known when plate tectonics first developed on Earth. New deep seismic reflection and coincident refraction profiles across an exposed, 1.89-Gyr-old volcanic arc complex show a 10-km-thick offset in the Moho and bivergent reflectors in the crust, which were most probably created by plate convergence, subduction and accretion during the Early Proterozoic. Hence, plate tectonic models seem to be applicable for at least the second half of Earth's history.

  • 135.
    Elmqvist, Thomas
    Stockholm University, Faculty of Science, Stockholm Resilience Centre.
    Sustainability and resilience differ2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 546, no 7658, 352-352 p.Article in journal (Other academic)
  • 136.
    Emerson, B. C.
    et al.
    University of East Anglia, UK.
    Kolm, Niclas
    University of East Anglia, UK; University of Edinburgh, UK.
    Ecology: Is speciation driven by species diversity? Reply.2005In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 438, no 7064, E2- p.Article in journal (Refereed)
  • 137.
    Emerson, B. C.
    et al.
    University of East Anglia, UK.
    Kolm, Niclas
    University of East Anglia, UK; University of Edinburgh, UK.
    Species diversity can drive speciation2005In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 434, no 7036, 1015-1017 p.Article in journal (Refereed)
    Abstract [en]

    A fundamental question in evolutionary ecology and conservation biology is: why do some areas contain greater species diversity than others? Island biogeographic theory has identified the roles of immigration and extinction in relation to area size and proximity to source areas(1,2), and the role of speciation is also recognized as an important factor(3-6). However, one as yet unexplored possibility is that species diversity itself might help to promote speciation, and indeed the central tenets of island biogeographic theory support such a prediction. Here we use data for plants and arthropods of the volcanic archipelagos of the Canary and Hawaiian Islands to address whether there is a positive relationship between species diversity and rate of diversification. Our index of diversification for each island is the proportion of species that are endemic, and we test our prediction that this increases with increasing species number. We show that even after controlling for several important physical features of islands, diversification is strongly related to species number.

  • 138. Englund, Camilla
    et al.
    Loren, Christina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Varshney, Gaurav
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Deleuil, Fabiene
    Hallberg, Bengt
    Palmer, Ruth
    Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 425, no 6957, 512-516 p.Article in journal (Refereed)
  • 139.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mitochondria in the second act2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 531, no 7592, 39-40 p.Article in journal (Other academic)
    Abstract [en]

    A large phylogenomics study reveals that the symbiotic event that led to the emergence of organelles known as mitochondria may have occurred later in the evolution of complex cells than was thought.

  • 140.
    Evans, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Sports doping vastly underestimated2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 519, no 7541, 33-33 p.Article in journal (Refereed)
  • 141.
    Flanagan, J Randall
    et al.
    Queen's University, Kingston, Ontario K7L 3N6.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Action plans used in action observation2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, ISSN 1476-4687, Vol. 424, no 6950, 769-771 p.Article in journal (Refereed)
    Abstract [en]

    How do we understand the actions of others? According to the direct matching hypothesis, action understanding results from a mechanism that maps an observed action onto motor representations of that action. Although supported by neurophysiological and brain-imaging studies, direct evidence for this hypothesis is sparse. In visually guided actions, task-specific proactive eye movements are crucial for planning and control. Because the eyes are free to move when observing such actions, the direct matching hypothesis predicts that subjects should produce eye movements similar to those produced when they perform the tasks. If an observer analyses action through purely visual means, however, eye movements will be linked reactively to the observed action. Here we show that when subjects observe a block stacking task, the coordination between their gaze and the actor's hand is predictive, rather than reactive, and is highly similar to the gaze-hand coordination when they perform the task themselves. These results indicate that during action observation subjects implement eye motor programs directed by motor representations of manual actions and thus provide strong evidence for the direct matching hypothesis.

  • 142. Foley, Jonathan A.
    et al.
    Ramankutty, Navin
    Brauman, Kate A.
    Cassidy, Emily S.
    Gerber, James S.
    Johnston, Matt
    Mueller, Nathaniel D.
    O'Connell, Christine
    Ray, Deepak K.
    West, Paul C.
    Balzer, Christian
    Bennett, Elena M.
    Carpenter, Stephen R.
    Hill, Jason
    Monfreda, Chad
    Polasky, Stephen
    Rockström, Johan
    Stockholm University, Stockholm Resilience Centre, Stockholm Environment Institute.
    Sheehan, John
    Siebert, Stefan
    Tilman, David
    Zaks, David P. M.
    Solutions for a cultivated planet2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 478, no 7369, 337-342 p.Article in journal (Refereed)
    Abstract [en]

    Increasing population and consumption are placing unprecedented demands on agriculture and natural resources. Today, approximately a billion people are chronically malnourished while our agricultural systems are concurrently degrading land, water, biodiversity and climate on a global scale. To meet the world's future food security and sustainability needs, food production must grow substantially while, at the same time, agriculture's environmental footprint must shrink dramatically. Here we analyse solutions to this dilemma, showing that tremendous progress could be made by halting agricultural expansion, closing 'yield gaps' on underperforming lands, increasing cropping efficiency, shifting diets and reducing waste. Together, these strategies could double food production while greatly reducing the environmental impacts of agriculture.

  • 143.
    Fonfara, Ines
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    Richter, Hagen
    Bratovic, Majda
    Le Rhun, Anaïs
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    The CRISPR-associated DNA-cleaving enzyme Cpf1 also processes precursor CRISPR RNA2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, no 7600, 517-520 p.Article in journal (Refereed)
    Abstract [en]

    CRISPR-Cas systems that provide defence against mobile genetic elements in bacteria and archaea have evolved a variety of mechanisms to target and cleave RNA or DNA(1). The well-studied types I, II and III utilize a set of distinct CRISPR-associated ( Cas) proteins for production of mature CRISPR RNAs (crRNAs) and interference with invading nucleic acids. In types I and III, Cas6 or Cas5d cleaves precursor crRNA (pre-crRNA)(2-5) and the mature crRNAs then guide a complex of Cas proteins ( Cascade-Cas3, type I; Csm or Cmr, type III) to target and cleave invading DNA or RNA(6-12). In type II systems, RNase III cleaves pre-crRNA base-paired with trans-activating crRNA (tracrRNA) in the presence of Cas9 (refs 13, 14). The mature tracrRNA-crRNA duplex then guides Cas9 to cleave target DNA15. Here, we demonstrate a novel mechanism in CRISPR-Cas immunity. We show that type V-A Cpf1 from Francisella novicida is a dual-nuclease that is specific to crRNA biogenesis and target DNA interference. Cpf1 cleaves pre-crRNA upstream of a hairpin structure formed within the CRISPR repeats and thereby generates intermediate crRNAs that are processed further, leading to mature crRNAs. After recognition of a 5'-YTN- 3' protospacer adjacent motif on the non-target DNA strand and subsequent probing for an eight-nucleotide seed sequence, Cpf1, guided by the single mature repeat-spacer crRNA, introduces double-stranded breaks in the target DNA to generate a 5' overhang(16). The RNase and DNase activities of Cpf1 require sequence- and structure-specific binding to the hairpin of crRNA repeats. Cpf1 uses distinct active domains for both nuclease reactions and cleaves nucleic acids in the presence of magnesium or calcium. This study uncovers a new family of enzymes with specific dual endoribonuclease and endonuclease activities, and demonstrates that type V- A constitutes the most minimalistic of the CRISPR- Cas systems so far described.

  • 144.
    Fransson, Thord
    et al.
    Naturhistoriska Riksmuseet.
    Jakobsson, Sven
    Stockholm University, Faculty of Science, Department of Zoology.
    Johansson, Patrik
    Sveriges geologiska undersökningar.
    Kullberg, Cecilia
    Stockholm University, Faculty of Science, Department of Zoology.
    Lind, Johan
    Stockholm University, Faculty of Science, Department of Zoology.
    Valllin, Adrian
    Stockholm University, Faculty of Science, Department of Zoology.
    Magnetic cues trigger extensive refuelling2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 414, 35-36 p.Article in journal (Refereed)
  • 145. Fray, Nicolas
    et al.
    Bardyn, Anaïs
    Cottin, Hervé
    Altwegg, Kathrin
    Baklouti, Donia
    Briois, Christelle
    Colangeli, Luigi
    Engrand, Cécile
    Fischer, Henning
    Glasmachers, Albrecht
    Grün, Eberhard
    Haerendel, Gerhard
    Henkel, Hartmut
    Höfner, Herwig
    Hornung, Klaus
    Jessberger, Elmar K.
    Koch, Andreas
    Krüger, Harald
    Langevin, Yves
    Lehto, Harry
    Lehto, Kirsi
    Le Roy, Léna
    Merouane, Sihane
    Modica, Paola
    Orthous-Daunay, François-Régis
    Paquette, John
    Raulin, François
    Rynö, Jouni
    Schulz, Rita
    Silén, Johan
    Siljeström, Sandra
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Steiger, Wolfgang
    Stenzel, Oliver
    Stephan, Thomas
    Thirkell, Laurent
    Thomas, Roger
    Torkar, Klaus
    Varmuza, Kurt
    Wanczek, Karl-Peter
    Zaprudin, Boris
    Kissel, Jochen
    Hilchenbach, Martin
    High-molecular-weight organic matter in the particles of comet 67P/Churyumov–Gerasimenko2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 538, no 7623, 72-74 p.Article in journal (Refereed)
    Abstract [en]

    The presence of solid carbonaceous matter in cometary dust was established by the detection of elements such as carbon, hydrogen, oxygen and nitrogen in particles from comet 1P/Halley1, 2. Such matter is generally thought to have originated in the interstellar medium3, but it might have formed in the solar nebula—the cloud of gas and dust that was left over after the Sun formed4. This solid carbonaceous material cannot be observed from Earth, so it has eluded unambiguous characterization5. Many gaseous organic molecules, however, have been observed6, 7, 8, 9; they come mostly from the sublimation of ices at the surface or in the subsurface of cometary nuclei8. These ices could have been formed from material inherited from the interstellar medium that suffered little processing in the solar nebula10. Here we report the in situ detection of solid organic matter in the dust particles emitted by comet 67P/Churyumov–Gerasimenko; the carbon in this organic material is bound in very large macromolecular compounds, analogous to the insoluble organic matter found in the carbonaceous chondrite meteorites11, 12. The organic matter in meteorites might have formed in the interstellar medium and/or the solar nebula, but was almost certainly modified in the meteorites’ parent bodies11. We conclude that the observed cometary carbonaceous solid matter could have the same origin as the meteoritic insoluble organic matter, but suffered less modification before and/or after being incorporated into the comet.

  • 146.
    Fuchsberger, Christian
    et al.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria.;Univ Lubeck, European Acad Bolzano Bozen EURAC, Ctr Biomed, Bolzano, Italy..
    Flannick, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Agarwala, Vineeta
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA..
    Gaulton, Kyle J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Ma, Clement
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Fontanillas, Pierre
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Moutsianas, Loukas
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    McCarthy, Davis J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Rivas, Manuel A.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Perry, John R. B.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England.;Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Sim, Xueling
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Blackwell, Thomas W.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Robertson, Neil R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Rayner, N. William
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Cingolani, Pablo
    McGill Univ, Sch Comp Sci, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Locke, Adam E.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Tajes, Juan Fernandez
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Highland, Heather M.
    Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Human Genet Ctr, Houston, TX 77030 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Chines, Peter S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Lindgren, Cecilia M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Hartl, Christopher
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Chen, Han
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Huyghe, Jeroen R.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    van de Bunt, Martijn
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Pearson, Richard D.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Kumar, Ashish
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Basel, Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol, Basel, Switzerland..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Gamazon, Eric R.
    Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Lee, Jaehoon
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Chen, Yuhui
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Below, Jennifer E.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Chen, Peng
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Huang, Jinyan
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Go, Min Jin
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Stitzel, Michael L.
    Jackson Lab Genom Med, Farmington, CT USA..
    Pasko, Dorota
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Parker, Stephen C. J.
    Univ Michigan, Dept Computat Med, Ann Arbor, MI USA.;Univ Michigan, Dept Bioinformat & Human Genet, Ann Arbor, MI USA..
    Varga, Tibor V.
    Lund Univ, Genet & Mol Epidemiol Unit, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden..
    Green, Todd
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Beer, Nicola L.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Day-Williams, Aaron G.
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Fingerlin, Tasha
    Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA..
    Horikoshi, Momoko
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hu, Cheng
    Shanghai Jiao Tong Univ, Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Huh, Iksoo
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Ikram, Mohammad Kamran
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Kim, Bong-Jo
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Kim, Yongkang
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Kim, Young Jin
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Kwon, Min-Seok
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Lee, Juyoung
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Lee, Selyeong
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Lin, Keng-Han
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Maxwell, Taylor J.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Nagai, Yoshihiko
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada..
    Wang, Xu
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Welch, Ryan P.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Yoon, Joon
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Zhang, Weihua
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Barzilai, Nir
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA..
    Voight, Benjamin F.
    Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA..
    Han, Bok-Ghee
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Jenkinson, Christopher P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.;South Texas Vet Hlth Care Syst, Res, San Antonio, TX USA..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Manning, Alisa
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Ng, Maggie C. Y.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA..
    Palmer, Nicholette D.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Balkau, Beverley
    INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France..
    Stancakova, Alena
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland..
    Abboud, Hanna E.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Boeing, Heiner
    German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Prabhakaran, Dorairaj
    Ctr Chron Dis Control, New Delhi, India..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Scott, James
    Univ London Imperial Coll Sci Technol & Med, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England..
    Carey, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Kwan, Phoenix
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Grant, George
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Smith, Joshua D.
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA..
    Neale, Benjamin M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA..
    Purcell, Shaun
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Psychiat, New York, NY 10029 USA..
    Butterworth, Adam S.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Howson, Joanna M. M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Lee, Heung Man
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Kwak, Soo-Heon
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul, South Korea..
    Zhao, Wei
    Univ Penn, Dept Med, Philadelphia, PA 19104 USA..
    Danesh, John
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England..
    Lam, Vincent K. L.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Park, Kyong Soo
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul, South Korea.;Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea.;Seoul Natl Univ, Coll Med, Seoul, South Korea..
    Saleheen, Danish
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    So, Wing Yee
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Tam, Claudia H. T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Afzal, Uzma
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Aguilar, David
    Baylor Coll Med, Div Cardiovasc, Houston, TX 77030 USA..
    Arya, Rector
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Aung, Tin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Chan, Edmund
    Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
    Navarro, Carmen
    IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain.;Univ Murcia, CIBERESP, Murcia, Spain.;Univ Murcia, Sch Med, Unit Prevent Med & Publ Hlth, E-30001 Murcia, Spain..
    Cheng, Ching-Yu
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Palli, Domenico
    Canc Res & Prevent Inst ISPO, Florence, Italy..
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Rybin, Denis
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Farook, Vidya S.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Fowler, Sharon P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Freedman, Barry I.
    Wake Forest Sch Med, Nephrol Sect, Dept Internal Med, Winston Salem, NC USA..
    Griswold, Michael
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Hale, Daniel Esten
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Hicks, Pamela J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Khor, Chiea-Chuen
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    Kumar, Satish
    Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Lehne, Benjamin
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Thuillier, Dorothee
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France..
    Lim, Wei Yen
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Liu, Jianjun
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Loh, Marie
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland.;ASTAR, TLGM, Singapore, Singapore..
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Puppala, Sobha
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Scott, William R.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Yengo, Loic
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France..
    Tan, Sian-Tsung
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England..
    Taylor, Herman A., Jr.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Thameem, Farook
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Wilson, Gregory, Sr.
    Jackson State Univ, Coll Publ Serv, Jackson, MS USA..
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Njolstad, Pal Rasmus
    Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway.;Haukeland Hosp, Dept Pediat, Bergen, Norway..
    Levy, Jonathan C.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Schwarzmayr, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Surdulescu, Gabriela L.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Herder, Christian
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Groves, Christopher J.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Wieland, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Brandslund, Ivan
    Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark.;Vejle Hosp, Dept Clin Biochem, Vejle, Denmark..
    Christensen, Cramer
    Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Minerva Fdn, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland..
    Doney, Alex S. F.
    Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee, Scotland..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA..
    Farmer, Andrew J.
    Univ Oxford, Nuffield Dept Primary Care Hlth Sci, Oxford, England..
    Hakaste, Liisa
    Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland..
    Hodgkiss, Dylan
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Kravic, Jasmina
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Lyssenko, Valeriya
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Jorgensen, Torben
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Inst Hlth Sci, Dept Publ Hlth, Copenhagen, Denmark.;Aalborg Univ, Med, Aalborg, Denmark..
    Ladenvall, Claes
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Karajamaki, Annemari
    Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland.;Vaasa Hlth Care Ctr, Ctr Diabet, Vaasa, Finland..
    Kriebel, Jennifer
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Rathmann, Wolfgang
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lauritzen, Torsten
    Aarhus Univ, Sect Gen Practice, Dept Publ Hlth, Aarhus, Denmark..
    Narisu, Narisu
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Linneberg, Allan
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Melander, Olle
    Lund Univ, Dept Clin Sci Hypertens & Cardiovasc, Malmo, Sweden..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Neville, Matt
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci Diabet & Cardiovasc Dis, Genet Epidemiol, Malmo, Sweden..
    Qi, Lu
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Qi, Qibin
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA..
    Roden, Michael
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Univ Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Rolandsson, Olov
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Swift, Amy
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Rosengren, Anders H.
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Stirrups, Kathleen
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Wood, Andrew R.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Blancher, Christine
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Carneiro, Mauricio O.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Maguire, Jared
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Poplin, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Shakir, Khalid
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Fennell, Timothy
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    DePristo, Mark
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    de Angelis, Martin Hrabe
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Expt Genet, Neuherberg, Germany.;Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Freising Weihenstephan, Germany..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Gjesing, Anette P.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jun, Goo
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Nilsson, Peter
    Lund Univ, Dept Clin Sci, Med, Malmo, Sweden..
    Murphy, Jacquelyn
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Onofrio, Robert
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Thorand, Barbara
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Meisinger, Christa
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Hu, Frank B.
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Karpe, Fredrik
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Huth, Cornelia
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    O'Rahilly, Stephen P.
    Univ Cambridge, Inst Metab Sci, Metab Res Labs, Cambridge, England..
    Palmer, Colin N. A.
    Univ Dundee, Ninewells Hosp & Med Sch, Pat Macpherson Ctr Pharmacogenet & Pharmacogen, Dundee, Scotland..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio, Finland..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Autonomous Univ Madrid, Univ Hosp LaPaz, Inst Invest Sanitaria Hosp Univ LaPaz IdiPAZ, Madrid, Spain.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Watanabe, Richard M.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dabet & Obes Res Inst, Los Angeles, CA USA..
    Syvanen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergman, Richard N.
    Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA USA..
    Bharadwaj, Dwaipayan
    CSIR IGIB, Funct Genom Unit, New Delhi, India..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Cho, Yoon Shin
    Hallym Univ, Dept Biomed Sci, Chunchon, South Korea..
    Chandak, Giriraj R.
    CSIR Ctr Cellular & Mol Biol, Hyderabad, Telangana, India..
    Chan, Juliana C. N.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Chia, Kee Seng
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Daly, Mark J.
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Ebrahim, Shah B.
    Ctr Chron Dis Control, New Delhi, India..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Elliott, Paul
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England..
    Jablonski, Kathleen A.
    George Washington Univ, Biostat Ctr, Rockville, MD USA..
    Lehman, Donna M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Jia, Weiping
    Shanghai Jiao Tong Univ, Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Ma, Ronald C. W.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Pollin, Toni I.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.;Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Sandhu, Manjinder
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Tandon, Nikhil
    All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India..
    Froguel, Philippe
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England.;Univ Cambridge, Inst Metab Sci, Metab Res Labs, Cambridge, England..
    Teo, Yik Ying
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Inst Life Sci, Singapore, Singapore.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Small, Kerrin S.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    DeFronzo, Ralph A.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Grallert, Harald
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Glaser, Benjamin
    Hadassah Hebrew Univ Med Ctr, Endocrinol & Metab Serv, Jerusalem, Israel..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Sch Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Banks, Eric
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Gieger, Christian
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Im, Hae Kyung
    Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Illig, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, NH, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, NH, Germany..
    Franks, Paul W.
    Lund Univ, Genet & Mol Epidemiol Unit, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Buck, Gemma
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Trakalo, Joseph
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Buck, David
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Farjoun, Yossi
    Broad Inst, Data Sci & Data Engn, Cambridge, MA USA..
    Owen, Katharine R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Tuomi, Tiinamaija
    Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland.;Univ Helsinki, FIMM, Helsinki, Finland..
    Kooner, Jaspal Singh
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Lee, Jong-Young
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Park, Taesung
    Seoul Natl Univ, Dept Stat, Seoul, South Korea.;Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Donnelly, Peter
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Morris, Andrew D.
    Ninewells Hosp & Med Sch, Ctr Mol Med, Clin Res Ctr, Dundee, Scotland.;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Hattersley, Andrew T.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Collins, Francis S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Atzmon, Gil
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA.;Univ Haifa, Dept Nat Sci, Haifa, Israel..
    Chambers, John C.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Laakso, Markku
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Strom, Tim M.
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Bell, Graeme I.
    Univ Chicago, Dept Med Genet, Chicago, IL 60637 USA.;Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA..
    Blangero, John
    Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Duggirala, Ravindranath
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Tai, E. Shyong
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Duke NUS Med Sch Singapore, Cardiovasc & Metab Disorders Program, Singapore, Singapore..
    McVean, Gilean
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England..
    Hanis, Craig L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Seielstad, Mark
    Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA.;Blood Syst Res Inst, San Francisco, CA USA..
    Frayling, Timothy M.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Meigs, James B.
    Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Cox, Nancy J.
    Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Sladek, Rob
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Med, Div Endocrinol & Metab, Montreal, PQ, Canada..
    Lander, Eric S.
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Gabriel, Stacey
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Burtt, Noel P.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Groop, Leif
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Univ Helsinki, FIMM, Helsinki, Finland..
    Abecasis, Goncalo
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Florez, Jose C.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA..
    Scott, Laura J.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Kang, Hyun Min
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Altshuler, David
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA.;MIT, Dept Biol, Cambridge, MA USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    The genetic architecture of type 2 diabetes2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, no 7614, 41-47 p.Article in journal (Refereed)
    Abstract [en]

    The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

  • 147. Fuchsberger, Christian
    et al.
    Flannick, Jason
    Teslovich, Tanya M.
    Mahajan, Anubha
    Agarwala, Vineeta
    Gaulton, Kyle J.
    Ma, Clement
    Fontanillas, Pierre
    Moutsianas, Loukas
    McCarthy, Davis J.
    Rivas, Manuel A.
    Perry, John R. B.
    Sim, Xueling
    Blackwell, Thomas W.
    Robertson, Neil R.
    Rayner, N. William
    Cingolani, Pablo
    Locke, Adam E.
    Tajes, Juan Fernandez
    Highland, Heather M.
    Dupuis, Josee
    Chines, Peter S.
    Lindgren, Cecilia M.
    Hartl, Christopher
    Jackson, Anne U.
    Chen, Han
    Huyghe, Jeroen R.
    van de Bunt, Martijn
    Pearson, Richard D.
    Kumar, Ashish
    Mueller-Nurasyid, Martina
    Grarup, Niels
    Stringham, Heather M.
    Gamazon, Eric R.
    Lee, Jaehoon
    Chen, Yuhui
    Scott, Robert A.
    Below, Jennifer E.
    Chen, Peng
    Huang, Jinyan
    Go, Min Jin
    Stitzel, Michael L.
    Pasko, Dorota
    Parker, Stephen C. J.
    Varga, Tibor V.
    Green, Todd
    Beer, Nicola L.
    Day-Williams, Aaron G.
    Ferreira, Teresa
    Fingerlin, Tasha
    Horikoshi, Momoko
    Hu, Cheng
    Huh, Iksoo
    Ikram, Mohammad Kamran
    Kim, Bong-Jo
    Kim, Yongkang
    Kim, Young Jin
    Kwon, Min-Seok
    Lee, Juyoung
    Lee, Selyeong
    Lin, Keng-Han
    Maxwell, Taylor J.
    Nagai, Yoshihiko
    Wang, Xu
    Welch, Ryan P.
    Yoon, Joon
    Zhang, Weihua
    Barzilai, Nir
    Voight, Benjamin F.
    Han, Bok-Ghee
    Jenkinson, Christopher P.
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Manning, Alisa
    Ng, Maggie C. Y.
    Palmer, Nicholette D.
    Balkau, Beverley
    Stancakova, Alena
    Abboud, Hanna E.
    Boeing, Heiner
    Giedraitis, Vilmantas
    Prabhakaran, Dorairaj
    Gottesman, Omri
    Scott, James
    Carey, Jason
    Kwan, Phoenix
    Grant, George
    Smith, Joshua D.
    Neale, Benjamin M.
    Purcell, Shaun
    Butterworth, Adam S.
    Howson, Joanna M. M.
    Lee, Heung Man
    Lu, Yingchang
    Kwak, Soo-Heon
    Zhao, Wei
    Danesh, John
    Lam, Vincent K. L.
    Park, Kyong Soo
    Saleheen, Danish
    So, Wing Yee
    Tam, Claudia H. T.
    Afzal, Uzma
    Aguilar, David
    Arya, Rector
    Aung, Tin
    Chan, Edmund
    Navarro, Carmen
    Cheng, Ching-Yu
    Palli, Domenico
    Correa, Adolfo
    Curran, Joanne E.
    Rybin, Denis
    Farook, Vidya S.
    Fowler, Sharon P.
    Freedman, Barry I.
    Griswold, Michael
    Hale, Daniel Esten
    Hicks, Pamela J.
    Khor, Chiea-Chuen
    Kumar, Satish
    Lehne, Benjamin
    Thuillier, Dorothee
    Lim, Wei Yen
    Liu, Jianjun
    van der Schouw, Yvonne T.
    Loh, Marie
    Musani, Solomon K.
    Puppala, Sobha
    Scott, William R.
    Yengo, Loic
    Tan, Sian-Tsung
    Taylor, Herman A., Jr.
    Thameem, Farook
    Wilson, Gregory, Sr.
    Wong, Tien Yin
    Njolstad, Pal Rasmus
    Levy, Jonathan C.
    Mangino, Massimo
    Bonnycastle, Lori L.
    Schwarzmayr, Thomas
    Fadista, Joao
    Surdulescu, Gabriela L.
    Herder, Christian
    Groves, Christopher J.
    Wieland, Thomas
    Bork-Jensen, Jette
    Brandslund, Ivan
    Christensen, Cramer
    Koistinen, Heikki A.
    Doney, Alex S. F.
    Kinnunen, Leena
    Esko, Tonu
    Farmer, Andrew J.
    Hakaste, Liisa
    Hodgkiss, Dylan
    Kravic, Jasmina
    Lyssenko, Valeriya
    Hollensted, Mette
    Jorgensen, Marit E.
    Jorgensen, Torben
    Ladenvall, Claes
    Justesen, Johanne Marie
    Karajamaki, Annemari
    Kriebel, Jennifer
    Rathmann, Wolfgang
    Lannfelt, Lars
    Lauritzen, Torsten
    Narisu, Narisu
    Linneberg, Allan
    Melander, Olle
    Milani, Lili
    Neville, Matt
    Orho-Melander, Marju
    Qi, Lu
    Qi, Qibin
    Roden, Michael
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Swift, Amy
    Rosengren, Anders H.
    Stirrups, Kathleen
    Wood, Andrew R.
    Mihailov, Evelin
    Blancher, Christine
    Carneiro, Mauricio O.
    Maguire, Jared
    Poplin, Ryan
    Shakir, Khalid
    Fennell, Timothy
    DePristo, Mark
    de Angelis, Martin Hrabe
    Deloukas, Panos
    Gjesing, Anette P.
    Jun, Goo
    Nilsson, Peter
    Murphy, Jacquelyn
    Onofrio, Robert
    Thorand, Barbara
    Hansen, Torben
    Meisinger, Christa
    Hu, Frank B.
    Isomaa, Bo
    Karpe, Fredrik
    Liang, Liming
    Peters, Annette
    Huth, Cornelia
    O'Rahilly, Stephen P.
    Palmer, Colin N. A.
    Pedersen, Oluf
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Watanabe, Richard M.
    Syvanen, Ann-Christine
    Bergman, Richard N.
    Bharadwaj, Dwaipayan
    Bottinger, Erwin P.
    Cho, Yoon Shin
    Chandak, Giriraj R.
    Chan, Juliana C. N.
    Chia, Kee Seng
    Daly, Mark J.
    Ebrahim, Shah B.
    Langenberg, Claudia
    Elliott, Paul
    Jablonski, Kathleen A.
    Lehman, Donna M.
    Jia, Weiping
    Ma, Ronald C. W.
    Pollin, Toni I.
    Sandhu, Manjinder
    Tandon, Nikhil
    Froguel, Philippe
    Barroso, Ines
    Teo, Yik Ying
    Zeggini, Eleftheria
    Loos, Ruth J. F.
    Small, Kerrin S.
    Ried, Janina S.
    DeFronzo, Ralph A.
    Grallert, Harald
    Glaser, Benjamin
    Metspalu, Andres
    Wareham, Nicholas J.
    Walker, Mark
    Banks, Eric
    Gieger, Christian
    Ingelsson, Erik
    Im, Hae Kyung
    Illig, Thomas
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Buck, Gemma
    Trakalo, Joseph
    Buck, David
    Prokopenko, Inga
    Magi, Reedik
    Lind, Lars
    Farjoun, Yossi
    Owen, Katharine R.
    Gloyn, Anna L.
    Strauch, Konstantin
    Tuomi, Tiinamaija
    Kooner, Jaspal Singh
    Lee, Jong-Young
    Park, Taesung
    Donnelly, Peter
    Morris, Andrew D.
    Hattersley, Andrew T.
    Bowden, Donald W.
    Collins, Francis S.
    Atzmon, Gil
    Chambers, John C.
    Spector, Timothy D.
    Laakso, Markku
    Strom, Tim M.
    Bell, Graeme I.
    Blangero, John
    Duggirala, Ravindranath
    Tai, E. Shyong
    McVean, Gilean
    Hanis, Craig L.
    Wilson, James G.
    Seielstad, Mark
    Frayling, Timothy M.
    Meigs, James B.
    Cox, Nancy J.
    Sladek, Rob
    Lander, Eric S.
    Gabriel, Stacey
    Burtt, Noel P.
    Mohlke, Karen L.
    Meitinger, Thomas
    Groop, Leif
    Abecasis, Goncalo
    Florez, Jose C.
    Scott, Laura J.
    Morris, Andrew P.
    Kang, Hyun Min
    Boehnke, Michael
    Altshuler, David
    McCarthy, Mark I.
    The genetic architecture of type 2 diabetes2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, no 7614, 41-47 p.Article in journal (Refereed)
    Abstract [en]

    The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

  • 148.
    Fälthammar, Carl-Gunne
    et al.
    KTH, Superseded Departments, Alfvén Laboratory. KTH, School of Electrical Engineering (EES), Space and Plasma Physics.
    Akasofu, S.I.
    Alfvén, Hannes
    KTH, Superseded Departments, Alfvén Laboratory. KTH, School of Electrical Engineering (EES), Space and Plasma Physics.
    Significance of magnetospheric research for progress in astrophysics1978In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 275, 185-188 p.Article in journal (Refereed)
  • 149.
    Fölling, Simon
    et al.
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Trotzky, Stefan
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Cheinet, Patrick
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Feld, Michael
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Saers, Robert
    Umeå University, Faculty of Science and Technology, Physics.
    Widera, Artur
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany, Institut für Angewandte Physik, Universität Bonn, 53115 Bonn, Germany.
    Müller, Torben
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany, Institute of Quantum Electronics, ETH Zürich, 8093 Zürich, Switzerland.
    Bloch, Immanuel
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Direct observation of second-order atom tunnelling2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 448, no 7157, 1029-1032 p.Article in journal (Refereed)
  • 150. Gad, Helge
    et al.
    Koolmeister, Tobias
    Jemth, Ann-Sofie
    Eshtad, Saeed
    Jacques, Sylvain A.
    Strom, Cecilia E.
    Svensson, Linda M.
    Schultz, Niklas
    Lundback, Thomas
    Einarsdottir, Berglind Osk
    Saleh, Aljona
    Gokturk, Camilla
    Baranczewski, Pawel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berntsson, Ronnie P. -A.
    Gustafsson, Robert
    Stromberg, Kia
    Sanjiv, Kumar
    Jacques-Cordonnier, Marie-Caroline
    Desroses, Matthieu
    Gustavsson, Anna-Lena
    Olofsson, Roger
    Johansson, Fredrik
    Homan, Evert J.
    Loseva, Olga
    Brautigam, Lars
    Johansson, Lars
    Hoglund, Andreas
    Hagenkort, Anna
    Pham, Therese
    Altun, Mikael
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Vikingsson, Svante
    Evers, Bastiaan
    Henriksson, Martin
    Vallin, Karl S. A.
    Wallner, Olov A.
    Hammarstrom, Lars G. J.
    Wiita, Elisee
    Almlof, Ingrid
    Kalderen, Christina
    Axelsson, Hanna
    Djureinovic, Tatjana
    Puigvert, Jordi Carreras
    Haggblad, Maria
    Jeppsson, Fredrik
    Martens, Ulf
    Lundin, Cecilia
    Lundgren, Bo
    Granelli, Ingrid
    Jensen, Annika Jenmalm
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nilsson, Jonas A.
    Stenmark, Pal
    Scobie, Martin
    Berglund, Ulrika Warpman
    Helleday, Thomas
    MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7495, 215-221 p.Article in journal (Refereed)
    Abstract [en]

    Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

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