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  • 201.
    Hoshino, Ayuko
    et al.
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Costa-Silva, Bruno
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Shen, Tang-Long
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; National Taiwan University, Taiwan; National Taiwan University, Taiwan.
    Rodrigues, Goncalo
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; University of Porto, Portugal.
    Hashimoto, Ayako
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; University of Tokyo, Japan.
    Tesic Mark, Milica
    Rockefeller University, NY 10065 USA.
    Molina, Henrik
    Rockefeller University, NY 10065 USA.
    Kohsaka, Shinji
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Di Giannatale, Angela
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Ceder, Sophia
    Karolinska Institute, Sweden.
    Singh, Swarnima
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Williams, Caitlin
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Soplop, Nadine
    Rockefeller University, NY 10065 USA.
    Uryu, Kunihiro
    Rockefeller University, NY 10065 USA.
    Pharmer, Lindsay
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    King, Tari
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Davies, Alexander E.
    University of Calif Berkeley, CA 94720 USA.
    Ararso, Yonathan
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Zhang, Tuo
    Weill Cornell Med, NY 10021 USA.
    Zhang, Haiying
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Hernandez, Jonathan
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Weiss, Joshua M.
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Dumont-Cole, Vanessa D.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Kramer, Kimberly
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Wexler, Leonard H.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Narendran, Aru
    Alberta Childrens Prov Gen Hospital, Canada.
    Schwartz, Gary K.
    Columbia University, NY 10032 USA.
    Healey, John H.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Jorgen Labori, Knut
    Oslo University Hospital, Norway.
    Kure, Elin H.
    Oslo University Hospital, Norway.
    Grandgenett, Paul M.
    University of Nebraska Medical Centre, NE 68198 USA.
    Hollingsworth, Michael A.
    University of Nebraska Medical Centre, NE 68198 USA.
    de Sousa, Maria
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; University of Porto, Portugal.
    Kaur, Sukhwinder
    University of Nebraska Medical Centre, NE 68198 USA.
    Jain, Maneesh
    University of Nebraska Medical Centre, NE 68198 USA.
    Mallya, Kavita
    University of Nebraska Medical Centre, NE 68198 USA.
    Batra, Surinder K.
    University of Nebraska Medical Centre, NE 68198 USA.
    Jarnagin, William R.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Brady, Mary S.
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Fodstad, Oystein
    Oslo University Hospital, Norway; University of Oslo, Norway.
    Muller, Volkmar
    University of Medical Centre, Germany.
    Pantel, Klaus
    University of Medical Centre Hamburg Eppendorf, Germany.
    Minn, Andy J.
    University of Penn, PA 19104 USA.
    Bissell, Mina J.
    University of Calif Berkeley, CA 94720 USA.
    Garcia, Benjamin A.
    University of Penn, PA 19104 USA.
    Kang, Yibin
    Princeton University, NJ 08544 USA; Rutgers Cancer Institute New Jersey, NJ 08903 USA.
    Rajasekhar, Vinagolu K.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Ghajar, Cyrus M.
    Fred Hutchinson Cancer Research Centre, WA 98109 USA.
    Matei, Irina
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA.
    Peinado, Hector
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; Spanish National Cancer Research Centre CNIO, Spain.
    Bromberg, Jacqueline
    Mem Sloan Kettering Cancer Centre, NY 10065 USA; Weill Cornell Med, NY 10021 USA.
    Lyden, David
    Weill Cornell Med, NY 10021 USA; Weill Cornell Med, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Tumour exosome integrins determine organotropic metastasis2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 527, no 7578, p. 329-+Article in journal (Refereed)
    Abstract [en]

    Ever since Stephen Pagets 1889 hypothesis, metastatic organotropism has remained one of cancers greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver-and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

  • 202.
    Howes, L. M.
    et al.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Casey, A. R.
    Univ Cambridge, Inst Astron, Cambridge CB3 0HA, England..
    Asplund, M.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Keller, S. C.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Yong, D.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Nataf, D. M.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Poleski, R.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland.;Ohio State Univ, Dept Astron, Columbus, OH 43210 USA..
    Lind, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy.
    Kobayashi, C.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia.;Univ Hertfordshire, Sch Phys Astron & Math, Ctr Astrophys Res, Hatfield AL10 9AB, Herts, England..
    Owen, C. I.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Ness, M.
    Max Planck Inst Astron, D-69117 Heidelberg, Germany..
    Bessell, M. S.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Da Costa, G. S.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Schmidt, B. P.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia..
    Tisserand, P.
    Australian Natl Univ, Res Sch Astron & Astrophys, Canberra, ACT 2601, Australia.;Univ Paris 06, Univ Paris 04, F-75014 Paris, France.;CNRS, Inst Astrophys Paris, UMR 7095, F-75014 Paris, France..
    Udalski, A.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Szymanski, M. K.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Soszynski, I.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Pietrzynski, G.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland.;Univ Concepcion, Dept Astron, Concepcion, Chile..
    Ulaczyk, K.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland.;Univ Warwick, Dept Phys, Coventry CV4 7AL, W Midlands, England..
    Wyrzykowski, L.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Pietrukowicz, P.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Skowron, J.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Kozlowski, S.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Mroz, P.
    Univ Warsaw Observ, PL-00473 Warsaw, Poland..
    Extremely metal-poor stars from the cosmic dawn in the bulge of the Milky Way2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 527, no 7579, p. 484-487Article in journal (Refereed)
    Abstract [en]

    The first stars are predicted to have formed within 200 million years after the Big Bang(1), initiating the cosmic dawn. A true first star has not yet been discovered, although stars(2-4) with tiny amounts of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time(5,6). The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years(7), leading to a dearth of early, metal-poor stars(8,9). Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that most of the metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.

  • 203.
    Huang, Hailiang
    et al.
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Broad Institute of mit and Harvard, Cambridge MA, United States.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
    Fine-mapping inflammatory bowel disease loci to single-variant resolution2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 547, no 7662, p. 173-+Article in journal (Refereed)
    Abstract [en]

    Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

  • 204. Hudson, Thomas J.
    et al.
    Anderson, Warwick
    Aretz, Axel
    Barker, Anna D.
    Bell, Cindy
    Bernabe, Rosa R.
    Bhan, M. K.
    Calvo, Fabien
    Eerola, Iiro
    Gerhard, Daniela S.
    Guttmacher, Alan
    Guyer, Mark
    Hemsley, Fiona M.
    Jennings, Jennifer L.
    Kerr, David
    Klatt, Peter
    Kolar, Patrik
    Kusuda, Jun
    Lane, David P.
    Laplace, Frank
    Lu, Youyong
    Nettekoven, Gerd
    Ozenberger, Brad
    Peterson, Jane
    Rao, T. S.
    Remacle, Jacques
    Schafer, Alan J.
    Shibata, Tatsuhiro
    Stratton, Michael R.
    Vockley, Joseph G.
    Watanabe, Koichi
    Yang, Huanming
    Yuen, Matthew M. F.
    Knoppers, M.
    Bobrow, Martin
    Cambon-Thomsen, Anne
    Dressler, Lynn G.
    Dyke, Stephanie O. M.
    Joly, Yann
    Kato, Kazuto
    Kennedy, Karen L.
    Nicolas, Pilar
    Parker, Michael J.
    Rial-Sebbag, Emmanuelle
    Romeo-Casabona, Carlos M.
    Shaw, Kenna M.
    Wallace, Susan
    Wiesner, Georgia L.
    Zeps, Nikolajs
    Lichter, Peter
    Biankin, Andrew V.
    Chabannon, Christian
    Chin, Lynda
    Clement, Bruno
    de Alava, Enrique
    Degos, Francoise
    Ferguson, Martin L.
    Geary, Peter
    Hayes, D. Neil
    Johns, Amber L.
    Nakagawa, Hidewaki
    Penny, Robert
    Piris, Miguel A.
    Sarin, Rajiv
    Scarpa, Aldo
    van de Vijver, Marc
    Futreal, P. Andrew
    Aburatani, Hiroyuki
    Bayes, Monica
    Bowtell, David D. L.
    Campbell, Peter J.
    Estivill, Xavier
    Grimmond, Sean M.
    Gut, Ivo
    Hirst, Martin
    Lopez-Otin, Carlos
    Majumder, Partha
    Marra, Marco
    Ning, Zemin
    Puente, Xose S.
    Ruan, Yijun
    Stunnenberg, Hendrik G.
    Swerdlow, Harold
    Velculescu, Victor E.
    Wilson, Richard K.
    Xue, Hong H.
    Yang, Liu
    Spellman, Paul T.
    Bader, Gary D.
    Boutros, Paul C.
    Flicek, Paul
    Getz, Gad
    Guigo, Roderic
    Guo, Guangwu
    Haussler, David
    Heath, Simon
    Hubbard, Tim J.
    Jiang, Tao
    Jones, Steven M.
    Li, Qibin
    Lopez-Bigas, Nuria
    Luo, Ruibang
    Pearson, John V.
    Quesada, Victor
    Raphael, Benjamin J.
    Sander, Chris
    Speed, Terence P.
    Stuart, Joshua M.
    Teague, Jon W.
    Totoki, Yasushi
    Tsunoda, Tatsuhiko
    Valencia, Alfonso
    Wheeler, David A.
    Wu, Honglong
    Zhao, Shancen
    Zhou, Guangyu
    Stein, Lincoln D.
    Lathrop, Mark
    Ouellette, B. F. Francis
    Thomas, Gilles
    Yoshida, Teruhiko
    Axton, Myles
    Gunter, Chris
    McPherson, John D.
    Miller, Linda J.
    Kasprzyk, Arek
    Zhang, Junjun
    Haider, Syed A.
    Wang, Jianxin
    Yung, Christina K.
    Cros, Anthony
    Liang, Yong
    Gnaneshan, Saravanamuttu
    Guberman, Jonathan
    Hsu, Jack
    Chalmers, Don R. C.
    Hasel, Karl W.
    Kaan, Terry S. H.
    Knoppers, Bartha M.
    Lowrance, William W.
    Masui, Tohru
    Rodriguez, Laura Lyman
    Vergely, Catherine
    Cloonan, Nicole
    Defazio, Anna
    Eshleman, James R.
    Etemadmoghadam, Dariush
    Gardiner, Brooke B.
    Kench, James G.
    Sutherland, Robert L.
    Tempero, Margaret A.
    Waddell, Nicola J.
    Wilson, Peter J.
    Gallinger, Steve
    Tsao, Ming-Sound
    Shaw, Patricia A.
    Petersen, Gloria M.
    Mukhopadhyay, Debabrata
    DePinho, Ronald A.
    Thayer, Sarah
    Muthuswamy, Lakshmi
    Shazand, Kamran
    Beck, Timothy
    Sam, Michelle
    Timms, Lee
    Ballin, Vanessa
    Ji, Jiafu
    Zhang, Xiuqing
    Chen, Feng
    Hu, Xueda
    Yang, Qi
    Tian, Geng
    Zhang, Lianhai
    Xing, Xiaofang
    Li, Xianghong
    Zhu, Zhenggang
    Yu, Yingyan
    Yu, Jun
    Tost, Joerg
    Brennan, Paul
    Holcatova, Ivana
    Zaridze, David
    Brazma, Alvis
    Egevad, Lars
    Prokhortchouk, Egor
    Banks, Rosamonde Elizabeth
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics (closed 20130101).
    Viksna, Juris
    Pontén, Fredrik
    Skryabin, Konstantin
    Birney, Ewan
    Borg, Ake
    Borresen-Dale, Anne-Lise
    Caldas, Carlos
    Foekens, John A.
    Martin, Sancha
    Reis-Filho, Jorge S.
    Richardson, Andrea L.
    Sotiriou, Christos
    van't Veer, Laura
    Birnbaum, Daniel
    Blanche, Helene
    Boucher, Pascal
    Boyault, Sandrine
    Masson-Jacquemier, Jocelyne D.
    Pauporte, Iris
    Pivot, Xavier
    Vincent-Salomon, Anne
    Tabone, Eric
    Theillet, Charles
    Treilleux, Isabelle
    Bioulac-Sage, Paulette
    Decaens, Thomas
    Franco, Dominique
    Gut, Marta
    Samuel, Didier
    Zucman-Rossi, Jessica
    Eils, Roland
    Brors, Benedikt
    Korbel, Jan O.
    Korshunov, Andrey
    Landgraf, Pablo
    Lehrach, Hans
    Pfister, Stefan
    Radlwimmer, Bernhard
    Reifenberger, Guido
    Taylor, Michael D.
    von Kalle, Christof
    Majumder, Partha P.
    Pederzoli, Paolo
    Lawlor, Rita T.
    Delledonne, Massimo
    Bardelli, Alberto
    Gress, Thomas
    Klimstra, David
    Zamboni, Giuseppe
    Nakamura, Yusuke
    Miyano, Satoru
    Fujimoto, Akihiro
    Campo, Elias
    de Sanjose, Silvia
    Montserrat, Emili
    Gonzalez-Diaz, Marcos
    Jares, Pedro
    Himmelbauer, Heinz
    Bea, Silvia
    Aparicio, Samuel
    Easton, Douglas F.
    Collins, Francis S.
    Compton, Carolyn C.
    Lander, Eric S.
    Burke, Wylie
    Green, Anthony R.
    Hamilton, Stanley R.
    Kallioniemi, Olli P.
    Ley, Timothy J.
    Liu, Edison T.
    Wainwright, Brandon J.
    International network of cancer genome projects2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7291, p. 993-998Article in journal (Refereed)
    Abstract [en]

    The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

  • 205. Hudson, Thomas J.
    et al.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Yang, Huanming
    International Cancer Genome Consortium,
    International network of cancer genome projects2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7291, p. 993-998Article in journal (Refereed)
    Abstract [en]

    The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

  • 206. Hugot, J-P
    et al.
    Chamaillard, M
    Zouali, H
    Lesage, S
    C´zard, J-P
    Belaiche, J
    Almer, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: gastromed.
    Tysk, C
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    O'Morain, A
    Gassull, M
    Binder, V
    Finkel, Y
    Cortot, A
    Modigliani, R
    Laurent-Puig, P
    Gower-Rousseau, C
    Macry, J
    Comombel, J-F
    Sahbatou, M
    Thomas, G
    Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 411, no 6837, p. 599-603Article in journal (Refereed)
    Abstract [en]

    Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-?B, this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-?B in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

  • 207. Hung, Rayjean J
    et al.
    McKay, James D
    Gaborieau, Valerie
    Boffetta, Paolo
    Hashibe, Mia
    Zaridze, David
    Mukeria, Anush
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Mates, Dana
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Chen, Chu
    Goodman, Gary
    Field, John K
    Liloglou, Triantafillos
    Xinarianos, George
    Cassidy, Adrian
    McLaughlin, John
    Liu, Geoffrey
    Narod, Steven
    Krokan, Hans E
    Skorpen, Frank
    Elvestad, Maiken Bratt
    Hveem, Kristian
    Vatten, Lars
    Linseisen, Jakob
    Clavel-Chapelon, Françoise
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Lund, Eiliv
    Martinez, Carmen
    Bingham, Sheila
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hainaut, Pierre
    Riboli, Elio
    Ahrens, Wolfgang
    Benhamou, Simone
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Holcátová, Ivana
    Merletti, Franco
    Kjaerheim, Kristina
    Agudo, Antonio
    Macfarlane, Gary
    Talamini, Renato
    Simonato, Lorenzo
    Lowry, Ray
    Conway, David I
    Znaor, Ariana
    Healy, Claire
    Zelenika, Diana
    Boland, Anne
    Delepine, Marc
    Foglio, Mario
    Lechner, Doris
    Matsuda, Fumihiko
    Blanche, Helene
    Gut, Ivo
    Heath, Simon
    Lathrop, Mark
    Brennan, Paul
    A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q252008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 452, no 7187, p. 633-637Article in journal (Refereed)
    Abstract [en]

    Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

  • 208.
    Husu, Liisa
    et al.
    Örebro University, School of Humanities, Education and Social Sciences.
    Al-Gazali, Lihadh
    United Arab Emirates Univ, Al Ain, United Arab Emirates.
    Valian, Virginia
    CUNY Hunter Coll, New York, USA; CUNY, Graduate Center, New York NY, USA.
    Barres, Ben
    Stanford Univ, Stanford, USA.
    Wu, Ling-An
    Chinese Acad Sci, Inst Phys, Beijing, China.
    Andrei, Eva Y.
    Rutgers State Univ, Piscataway Township NJ, USA.
    Handelsman, Jo
    Yale Univ, New Haven, USA.
    Moss-Racusin, Corinne
    Yale Univ, New Haven, USA.
    Scientists of the world speak up for equality2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7439, p. 35-38Article in journal (Refereed)
    Abstract [en]

    Eight experts give their prescriptions for measures that will help to close the gender gap in national from China to Sweden

  • 209.
    Höfner, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Fresh light on stardust2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 484, no 7393, p. 172-173Article in journal (Other academic)
  • 210. Högberg, Peter
    et al.
    Nordgren, Anders
    Buchmann, Nina
    Taylor, Andrew F. S.
    Ekblad, Alf
    Örebro University, Department of Natural Sciences.
    Högberg, Mona N.
    Nyberg, Gert
    Ottosson-Löfvenius, Mikaell
    Read, David J.
    Large-scale forest girdling shows that current photosynthesis drives soil respiration2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 411, no 6839, p. 789-792Article in journal (Refereed)
    Abstract [en]

    The respiratory activities of plant roots, of their mycorrhizal fungi and of the free-living microbial heterotrophs (decomposers) in soils are significant components of the global carbon balance, but their relative contributions remain uncertain. To separate mycorrhizal root respiration from heterotrophic respiration in a boreal pine forest, we conducted a large-scale tree-girdling experiment, comprising 9 plots each containing about 120 trees. Tree-girdling involves stripping the stem bark to the depth of the current xylem at breast height terminating the supply of current photosynthates to roots and their mycorrhizal fungi without physically disturbing the delicate root-microbe-soil system. Here we report that girdling reduced soil respiration within 1-2 months by about 54% relative to respiration on ungirdled control plots, and that decreases of up to 37% were detected within 5 days. These values clearly show that the flux of current assimilates to roots is a key driver of soil respiration; they are conservative estimates of root respiration, however, because girdling increased the use of starch reserves in the roots. Our results indicate that models of soil respiration should incorporate measures of photosynthesis and of seasonal patterns of photosynthate allocation to roots.

  • 211.
    Hörlein, A. J.
    et al.
    University of California, San Diego, USA.
    Näär, A. M.
    University of California, San Diego, USA.
    Heinzel, T.
    University of California, San Diego, USA.
    Torchia, J.
    University of California, San Diego, USA.
    Gloss, B.
    University of California, San Diego, USA.
    Kurokawa, R.
    University of California, San Diego, USA.
    Ryan, A.
    University of California, San Diego, USA.
    Kamei, Y.
    University of California, San Diego, USA.
    Söderström, Mats
    University of California, San Diego, USA.
    Glass, C. K.
    University of California, San Diego, USA.
    Rosenfeld, M. G.
    University of California, San Diego, USA.
    Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor1995In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 377, no 6548, p. 397-404Article in journal (Refereed)
    Abstract [en]

    Thyroid-hormone and retinoic-acid receptors exert their regulatory functions by acting as both activators and repressors of gene expression. A nuclear receptor co-repressor (N-CoR) of relative molecular mass 270K has been identified which mediates ligand-independent inhibition of gene transcription by these receptors, suggesting that the molecular mechanisms of repression by thyroid-hormone and retinoic-acid receptors are analogous to the co-repressor-dependent transcriptional inhibitory mechanisms of yeast and Drosophila.

  • 212.
    Immonen, Elina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Husby, Arild
    Univ Helsinki, FIN-00014 Helsinki, Finland..
    Norway wolf cull will hit genetic diversity2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 539, no 7627, p. 31-31Article in journal (Refereed)
  • 213. Ingall, Ellery D.
    et al.
    Diaz, Julia M.
    Longo, Amelia F.
    Oakes, Michelle
    Finney, Lydia
    Vogt, Stefan
    Lai, Barry
    Yager, Patricia L.
    Twining, Benjamin
    Brandes, Jay A.
    Role of biogenic silica in the removal of iron from the Antarctic seas2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 4, no 1981, p. 1-6Article in journal (Refereed)
  • 214. Jakobsson, Martin
    et al.
    Backman, Jan
    Rudels, Bert
    Nycander, Jonas
    Frank, Martin
    Mayer, Larry
    Jokat, Wilfried
    Sangiorgi, Francesca
    O’Regan, Matthew
    Brinkhuis, Henk
    King, John
    Moran, Kathryn
    The early Miocene onset of a ventilated circulation regime in the Arctic Ocean2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 447, no 7147, p. 986-990Article in journal (Refereed)
    Abstract [en]

    Deep-water formation in the northern North Atlantic Ocean and the Arctic Ocean is a key driver of the global thermohaline circulation and hence also of global climate(1). Deciphering the history of the circulation regime in the Arctic Ocean has long been prevented by the lack of data from cores of Cenozoic sediments from the Arctic’s deep-sea floor. Similarly, the timing of the opening of a connection between the northern North Atlantic and the Arctic Ocean, permitting deep-water exchange, has been poorly constrained. This situation changed when the first drill cores were recovered from the central Arctic Ocean(2). Here we use these cores to show that the transition from poorly oxygenated to fully oxygenated (’ventilated’) conditions in the Arctic Ocean occurred during the later part of early Miocene times. We attribute this pronounced change in ventilation regime to the opening of the Fram Strait. A palaeo-geographic and palaeo-bathymetric reconstruction of the Arctic Ocean, together with a physical oceanographic analysis of the evolving strait and sill conditions in the Fram Strait, suggests that the Arctic Ocean went from an oxygen-poor ‘lake stage’, to a transitional ‘estuarine sea’ phase with variable ventilation, and finally to the fully ventilated ‘ocean’ phase 17.5 Myr ago. The timing of this palaeo-oceanographic change coincides with the onset of the middle Miocene climatic optimum(3), although it remains unclear if there is a causal relationship between these two events.

  • 215. Jones, Felicity C.
    et al.
    Grabherr, Manfred G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chan, Yingguang Frank
    Russell, Pamela
    Mauceli, Evan
    Johnson, Jeremy
    Swofford, Ross
    Pirun, Mono
    Zody, Michael C.
    White, Simon
    Birney, Ewan
    Searle, Stephen
    Schmutz, Jeremy
    Grimwood, Jane
    Dickson, Mark C.
    Myers, Richard M.
    Miller, Craig T.
    Summers, Brian R.
    Knecht, Anne K.
    Brady, Shannon D.
    Zhang, Haili
    Pollen, Alex A.
    Howes, Timothy
    Amemiya, Chris
    Lander, Eric S.
    Di Palma, Federica
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kingsley, David M.
    The genomic basis of adaptive evolution in threespine sticklebacks2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 484, no 7392, p. 55-61Article in journal (Refereed)
    Abstract [en]

    Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature.

  • 216. Jones, Owen R.
    et al.
    Scheuerlein, Alexander
    Salguero-Gomez, Roberto
    Camarda, Carlo Giovanni
    Schaible, Ralf
    Casper, Brenda B.
    Dahlgren, Johan P.
    Ehrlén, Johan
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Garcia, Maria B.
    Menges, Eric S.
    Quintana-Ascencio, Pedro F.
    Caswell, Hal
    Baudisch, Annette
    Vaupel, James W.
    Diversity of ageing across the tree of life2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 505, no 7482, p. 169-+Article in journal (Refereed)
    Abstract [en]

    Evolution drives, and is driven by, demography. A genotype moulds its phenotype's age patterns of mortality and fertility in an environment; these two patterns in turn determine the genotype's fitness in that environment. Hence, to understand the evolution of ageing, age patterns of mortality and reproduction need to be compared for species across the tree of life. However, few studies have done so and only for a limited range of taxa. Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga. Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species, including increasing, constant, decreasing, humped and bowed trajectories for both long-and short-lived species. This diversity challenges theoreticians to develop broader perspectives on the evolution of ageing and empiricists to study the demography of more species.

  • 217.
    Jonsson, Bengt Gunnar
    et al.
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences.
    Pe'er, Guy
    Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
    Svoboda, Miroslav
    Czech University of Life Sciences, Prague, Czech Republic .
    Forests: not just timber plantations2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 521, no 7550, p. 32-32Article in journal (Refereed)
  • 218.
    Josefsson, Agnetha M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Magnusson, Partik K. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ylitalo, Nathalie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Quarforth-Tubbin, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pontén, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Adami, Hans-Olov
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    p53 polymorphism and risk of cervical cancer1998In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 396, no 6711, p. 531-Article in journal (Refereed)
  • 219. Joshi, Peter K
    et al.
    Esko, Tonu
    Mattsson, Hannele
    Eklund, Niina
    Gandin, Ilaria
    Nutile, Teresa
    Jackson, Anne U
    Schurmann, Claudia
    Smith, Albert V
    Zhang, Weihua
    Okada, Yukinori
    Stančáková, Alena
    Faul, Jessica D
    Zhao, Wei
    Bartz, Traci M
    Concas, Maria Pina
    Franceschini, Nora
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Vitart, Veronique
    Trompet, Stella
    Guo, Xiuqing
    Chasman, Daniel I
    O'Connel, Jeffrey R
    Corre, Tanguy
    Nongmaithem, Suraj S
    Chen, Yuning
    Mangino, Massimo
    Ruggiero, Daniela
    Traglia, Michela
    Farmaki, Aliki-Eleni
    Kacprowski, Tim
    Bjonnes, Andrew
    van der Spek, Ashley
    Wu, Ying
    Giri, Anil K
    Yanek, Lisa R
    Wang, Lihua
    Hofer, Edith
    Rietveld, Cornelius A
    McLeod, Olga
    Cornelis, Marilyn C
    Pattaro, Cristian
    Verweij, Niek
    Baumbach, Clemens
    Abdellaoui, Abdel
    Warren, Helen R
    Vuckovic, Dragana
    Mei, Hao
    Bouchard, Claude
    Perry, John R B
    Cappellani, Stefania
    Mirza, Saira S
    Benton, Miles C
    Broeckel, Ulrich
    Medland, Sarah E
    Lind, Penelope A
    Malerba, Giovanni
    Drong, Alexander
    Yengo, Loic
    Bielak, Lawrence F
    Zhi, Degui
    van der Most, Peter J
    Shriner, Daniel
    Mägi, Reedik
    Hemani, Gibran
    Karaderi, Tugce
    Wang, Zhaoming
    Liu, Tian
    Demuth, Ilja
    Zhao, Jing Hua
    Meng, Weihua
    Lataniotis, Lazaros
    van der Laan, Sander W
    Bradfield, Jonathan P
    Wood, Andrew R
    Bonnefond, Amelie
    Ahluwalia, Tarunveer S
    Hall, Leanne M
    Salvi, Erika
    Yazar, Seyhan
    Carstensen, Lisbeth
    de Haan, Hugoline G
    Abney, Mark
    Afzal, Uzma
    Allison, Matthew A
    Amin, Najaf
    Asselbergs, Folkert W
    Bakker, Stephan J L
    Barr, R Graham
    Baumeister, Sebastian E
    Benjamin, Daniel J
    Bergmann, Sven
    Boerwinkle, Eric
    Bottinger, Erwin P
    Campbell, Archie
    Chakravarti, Aravinda
    Chan, Yingleong
    Chanock, Stephen J
    Chen, Constance
    Chen, Y-D Ida
    Collins, Francis S
    Connell, John
    Correa, Adolfo
    Cupples, L Adrienne
    Smith, George Davey
    Davies, Gail
    Dörr, Marcus
    Ehret, Georg
    Ellis, Stephen B
    Feenstra, Bjarke
    Feitosa, Mary F
    Ford, Ian
    Fox, Caroline S
    Frayling, Timothy M
    Friedrich, Nele
    Geller, Frank
    Scotland, Generation
    Gillham-Nasenya, Irina
    Gottesman, Omri
    Graff, Misa
    Grodstein, Francine
    Gu, Charles
    Haley, Chris
    Hammond, Christopher J
    Harris, Sarah E
    Harris, Tamara B
    Hastie, Nicholas D
    Heard-Costa, Nancy L
    Heikkilä, Kauko
    Hocking, Lynne J
    Homuth, Georg
    Hottenga, Jouke-Jan
    Huang, Jinyan
    Huffman, Jennifer E
    Hysi, Pirro G
    Ikram, M Arfan
    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.
    Joensuu, Anni
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jousilahti, Pekka
    Jukema, J Wouter
    Kähönen, Mika
    Kamatani, Yoichiro
    Kanoni, Stavroula
    Kerr, Shona M
    Khan, Nazir M
    Koellinger, Philipp
    Koistinen, Heikki A
    Kooner, Manraj K
    Kubo, Michiaki
    Kuusisto, Johanna
    Lahti, Jari
    Launer, Lenore J
    Lea, Rodney A
    Lehne, Benjamin
    Lehtimäki, Terho
    Liewald, David C M
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Loh, Marie
    Lokki, Marja-Liisa
    London, Stephanie J
    Loomis, Stephanie J
    Loukola, Anu
    Lu, Yingchang
    Lumley, Thomas
    Lundqvist, Annamari
    Männistö, Satu
    Marques-Vidal, Pedro
    Masciullo, Corrado
    Matchan, Angela
    Mathias, Rasika A
    Matsuda, Koichi
    Meigs, James B
    Meisinger, Christa
    Meitinger, Thomas
    Menni, Cristina
    Mentch, Frank D
    Mihailov, Evelin
    Milani, Lili
    Montasser, May E
    Montgomery, Grant W
    Morrison, Alanna
    Myers, Richard H
    Nadukuru, Rajiv
    Navarro, Pau
    Nelis, Mari
    Nieminen, Markku S
    Nolte, Ilja M
    O'Connor, George T
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R
    Pankow, James S
    Patarcic, Inga
    Pavani, Francesca
    Peyser, Patricia A
    Pietilainen, Kirsi
    Poulter, Neil
    Prokopenko, Inga
    Ralhan, Sarju
    Redmond, Paul
    Rich, Stephen S
    Rissanen, Harri
    Robino, Antonietta
    Rose, Lynda M
    Rose, Richard
    Sala, Cinzia
    Salako, Babatunde
    Salomaa, Veikko
    Sarin, Antti-Pekka
    Saxena, Richa
    Schmidt, Helena
    Scott, Laura J
    Scott, William R
    Sennblad, Bengt
    Seshadri, Sudha
    Sever, Peter
    Shrestha, Smeeta
    Smith, Blair H
    Smith, Jennifer A
    Soranzo, Nicole
    Sotoodehnia, Nona
    Southam, Lorraine
    Stanton, Alice V
    Stathopoulou, Maria G
    Strauch, Konstantin
    Strawbridge, Rona J
    Suderman, Matthew J
    Tandon, Nikhil
    Tang, Sian-Tsun
    Taylor, Kent D
    Tayo, Bamidele O
    Töglhofer, Anna Maria
    Tomaszewski, Maciej
    Tšernikova, Natalia
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Vaidya, Dhananjay
    van Hylckama Vlieg, Astrid
    van Setten, Jessica
    Vasankari, Tuula
    Vedantam, Sailaja
    Vlachopoulou, Efthymia
    Vozzi, Diego
    Vuoksimaa, Eero
    Waldenberger, Melanie
    Ware, Erin B
    Wentworth-Shields, William
    Whitfield, John B
    Wild, Sarah
    Willemsen, Gonneke
    Yajnik, Chittaranjan S
    Yao, Jie
    Zaza, Gianluigi
    Zhu, Xiaofeng
    Salem, Rany M
    Melbye, Mads
    Bisgaard, Hans
    Samani, Nilesh J
    Cusi, Daniele
    Mackey, David A
    Cooper, Richard S
    Froguel, Philippe
    Pasterkamp, Gerard
    Grant, Struan F A
    Hakonarson, Hakon
    Ferrucci, Luigi
    Scott, Robert A
    Morris, Andrew D
    Palmer, Colin N A
    Dedoussis, George
    Deloukas, Panos
    Bertram, Lars
    Lindenberger, Ulman
    Berndt, Sonja I
    Lindgren, Cecilia M
    Timpson, Nicholas J
    Tönjes, Anke
    Munroe, Patricia B
    Sørensen, Thorkild I A
    Rotimi, Charles N
    Arnett, Donna K
    Oldehinkel, Albertine J
    Kardia, Sharon L R
    Balkau, Beverley
    Gambaro, Giovanni
    Morris, Andrew P
    Eriksson, Johan G
    Wright, Margie J
    Martin, Nicholas G
    Hunt, Steven C
    Starr, John M
    Deary, Ian J
    Griffiths, Lyn R
    Tiemeier, Henning
    Pirastu, Nicola
    Kaprio, Jaakko
    Wareham, Nicholas J
    Pérusse, Louis
    Wilson, James G
    Girotto, Giorgia
    Caulfield, Mark J
    Raitakari, Olli
    Boomsma, Dorret I
    Gieger, Christian
    van der Harst, Pim
    Hicks, Andrew A
    Kraft, Peter
    Sinisalo, Juha
    Knekt, Paul
    Johannesson, Magnus
    Magnusson, Patrik K E
    Hamsten, Anders
    Schmidt, Reinhold
    Borecki, Ingrid B
    Vartiainen, Erkki
    Becker, Diane M
    Bharadwaj, Dwaipayan
    Mohlke, Karen L
    Boehnke, Michael
    van Duijn, Cornelia M
    Sanghera, Dharambir K
    Teumer, Alexander
    Zeggini, Eleftheria
    Metspalu, Andres
    Gasparini, Paolo
    Ulivi, Sheila
    Ober, Carole
    Toniolo, Daniela
    Rudan, Igor
    Porteous, David J
    Ciullo, Marina
    Spector, Tim D
    Hayward, Caroline
    Dupuis, Josée
    Loos, Ruth J F
    Wright, Alan F
    Chandak, Giriraj R
    Vollenweider, Peter
    Shuldiner, Alan R
    Ridker, Paul M
    Rotter, Jerome I
    Sattar, Naveed
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    North, Kari E
    Pirastu, Mario
    Psaty, Bruce M
    Weir, David R
    Laakso, Markku
    Gudnason, Vilmundur
    Takahashi, Atsushi
    Chambers, John C
    Kooner, Jaspal S
    Strachan, David P
    Campbell, Harry
    Hirschhorn, Joel N
    Perola, Markus
    Polašek, Ozren
    Wilson, James F
    Directional dominance on stature and cognition in diverse human populations2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 523, no 7561, p. 459-462Article in journal (Refereed)
    Abstract [en]

    Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

  • 220.
    Jostins, Luke
    et al.
    Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Halfvarson, Jonas
    Örebro University Hospital. Örebro University, School of Medical Sciences.
    Cho, Judy H.
    Department of Genetics, Yale School of Medicine, New Haven CT, United States; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven CT, United States.
    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7422, p. 119-124Article in journal (Refereed)
    Abstract [en]

    Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

  • 221. Jun, C.
    et al.
    Ban, Yifang
    KTH, School of Architecture and the Built Environment (ABE), Urban Planning and Environment, Geoinformatics.
    Li, S.
    Open access to Earth land-cover map2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 514, no 7253Article in journal (Refereed)
  • 222. Jun, Chen
    et al.
    Ban, Yifang
    KTH, School of Architecture and the Built Environment (ABE), Urban Planning and Environment, Geodesy and Geoinformatics.
    Li, Songnian
    China: Open access to Earth land-cover map2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 514, no 7523, p. 434-434Article in journal (Refereed)
  • 223.
    Kanopka, Arvydas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mühleman, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inhibition by SRproteins of splicing of a regulated adenovirus pre-mRNA1996In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 381, p. 535-538Article in journal (Refereed)
    Abstract [en]

    The adenovirus L1 unit represents an example of an alternatively spliced precursor messenger (pre-mRNA) where on 5' splice can be jointed to one of two alternative 3' splice sites, producing the 52,55K or the IIIa mRNAs (Fig. 1a). Efficient usage of the distal IIIa 3' splice site requires late viral protein synthesis and is therefore confined to the late phase of virus infection. Here we show that, in extracts from uninfected cells, the classical SR proteins, which are essential splicing factors, inhibit IIIa pre-mRNA splicing by binding to an intronic repressor element and preventing recruitment of the U2 small nuclear ribonucleoprotein particle to the spliceosome. We further show that the viral repressor element has splicing-enhancer activity when appropriately placed in the pre-mRNA. Together, our results demonstrate that SR proteins function as activators or repressors of splicing depending on where on the pre-mRNA they bind.

  • 224.
    Kanopka, Arvydas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mühleman, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Petersen-Mahrt, Svend
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Estmer, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öhrmalm, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Regulation of adenovirus alternative RNAsplicing by dephosphorylation of SR proteins1998In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 393, no 6681, p. 185-187Article in journal (Refereed)
    Abstract [en]

    SR proteins are a family of essential splicing factors required for early recognition of splice sites during spliceosome assembly. They also function as alternative RNA splicing factors when overexpressed in vivo or added in excess to extracts in vitro. SR proteins are highly phosphorylated in vivo, a modification that is required for their function in spliceosome assembly and splicing catalysis. Here we show that SR proteins purified from late adenovirus-infected cells are inactivated as splicing enhancer or splicing repressor proteins by virus-induced dephosphorylation. We further show that the virus-encoded protein E4-ORF4 activates dephosphorylation by protein phosphatase 2A of HeLa SR proteins and converts their splicing properties into that of SR proteins purified from late adenovirus-infected cells. Taken together, our results suggest that E4-ORF4 is an important factor controlling the temporal shift in adenovirus alternative RNA splicing. We conclude that alternative pre-mRNA splicing, like many other biological processes, is regulated by reversible protein phosphorylation.

  • 225.
    Karlsson, Anders
    et al.
    Gothenburg University, Sweden.
    Karlsson, Roger
    Gothenburg University, Sweden.
    Karlsson, Mattias
    Gothenburg University, Sweden.
    Cans, Annsofie
    Gothenburg University, Sweden.
    Strömberg, Anette
    Gothenburg University, Sweden.
    Ryttsén, Frida
    Gothenburg University, Sweden.
    Orwar, Owe
    Chalmers University of Technology, Sweden.
    Molecular engineering: Networks of nanotubes and containers2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 409, no 6817, p. 150-152Article in journal (Refereed)
  • 226.
    Karlsson, Jan
    et al.
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Byström, Pär
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Ask, Jenny
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Ask, Per
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Persson, Lennart
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Jansson, Mats
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Light limitation of nutrient-poor lake ecosystems2009In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 460, p. 506-509Article in journal (Refereed)
    Abstract [en]

    Productivity denotes the rate of biomass synthesis in ecosystems and is a fundamental characteristic that frames ecosystem function and management. Limitation of productivity by nutrient availability is an established paradigm for lake ecosystems1, 2, 3. Here, we assess the relevance of this paradigm for a majority of the world's small, nutrient-poor lakes, with different concentrations of coloured organic matter4, 5. By comparing small unproductive lakes along a water colour gradient, we show that coloured terrestrial organic matter controls the key process for new biomass synthesis (the benthic primary production) through its effects on light attenuation. We also show that this translates into effects on production and biomass of higher trophic levels (benthic invertebrates and fish). These results are inconsistent with the idea that nutrient supply primarily controls lake productivity, and we propose that a large share of the world's unproductive lakes, within natural variations of organic carbon and nutrient input, are limited by light and not by nutrients. We anticipate that our result will have implications for understanding lake ecosystem function and responses to environmental change. Catchment export of coloured organic matter is sensitive to short-term natural variability and long-term, large-scale changes, driven by climate and different anthropogenic influences6, 7. Consequently, changes in terrestrial carbon cycling will have pronounced effects on most lake ecosystems by mediating changes in light climate and productivity of lakes.

  • 227. Kaukua, Nina
    et al.
    Shahidi, Maryam Khatibi
    Konstantinidou, Chrysoula
    Dyachuk, Vyacheslav
    Kaucka, Marketa
    Furlan, Alessandro
    An, Zhengwen
    Wang, Longlong
    Hultman, Isabell
    Ahrlund-Richter, Larsa
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lopes, Natalia Assaife
    Pachnis, Vassilis
    Suter, Ueli
    Clevers, Hans
    Thesleff, Irma
    Sharpe, Paul
    Ernfors, Patrik
    Fried, Kaj
    Adameyko, Igor
    Glial origin of mesenchymal stem cells in a tooth model system2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7519, p. 551-554Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair(1). The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium(2). It has been thought for decades that the dental mesenchymal stem cells(3) giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue(4,5). Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique(6) with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.

  • 228.
    Keeling, L.
    et al.
    Dept. of Anim. Environ. and Health, Swed. Univ. of Agricultural Sciences, PO Box 234, 53223 Skara, Sweden.
    Andersson, L.
    Dept. Med. Biochem. and Microbiol., Uppsala University, Box 597, 75124 Uppsala, Sweden, Dept. of Anim. Breeding and Genetics, Swed. Univ. of Agricultural Sciences, 75124 Uppsala, Sweden.
    Schutz, K.E.
    Schütz, K.E., Dept. of Anim. Environ. and Health, Swed. Univ. of Agricultural Sciences, PO Box 234, 53223 Skara, Sweden, AgResearch, Animal Behaviour and Welfare, Private Bag 3123, Hamilton, New Zealand.
    Kerje, Susanne
    Linköping University, Department of Physics, Chemistry and Biology, Zoology .
    Fredriksson, R.
    Dept. of Anim. Breeding and Genetics, Swed. Univ. of Agricultural Sciences, 75124 Uppsala, Sweden.
    Carlborg, O.
    Carlborg, Ö., Dept. of Anim. Breeding and Genetics, Swed. Univ. of Agricultural Sciences, 75124 Uppsala, Sweden, Roslin Institute, Roslin, Midlothian EH25 9PS, United Kingdom.
    Cornwallis, C.K.
    Dept. of Animal and Plant Sciences, University of Sheffield, Sheffield S10 2TN, United Kingdom.
    Pizzari, Tom
    Linköping University, Department of Physics, Chemistry and Biology, Zoology .
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology .
    Feather pecking and victim pigmentation2004In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 431, no 7009, p. 645-646Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 229. Keeling, Linda
    et al.
    Andersson, Leif
    Schütz, Karin E
    Kerje, Susanne
    Fredriksson, Robert
    Carlborg, Örjan
    SLU.
    Cornwallis, Charles K
    Pizzari, Tommaso
    Jensen, Per
    Chicken genomics: feather-pecking and victim pigmentation.2004In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 431, no 7009Article in journal (Refereed)
    Abstract [en]

    Feather-pecking in domestic birds is associated with cannibalism and severe welfare problems. It is a dramatic example of a spiteful behaviour in which the victim's fitness is reduced for no immediate direct benefit to the perpetrator and its evolution is unexplained. Here we show that the plumage pigmentation of a chicken may predispose it to become a victim: birds suffer more drastic feather-pecking when the colour of their plumage is due to the expression of a wild recessive allele at PMEL17, a gene that controls plumage melanization, and when these birds are relatively common in a flock. These findings, obtained using an intercross between a domestic fowl and its wild ancestor, have implications for the welfare of domestic species and offer insight into the genetic changes associated with the evolution of feather-pecking during the early stages of domestication.

  • 230.
    Kharchenko, Peter V
    et al.
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Alekseyenko, Artyom A
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Schwartz, Yuri B
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Minoda, Aki
    Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA.
    Riddle, Nicole C
    Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA.
    Ernst, Jason
    MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA.
    Sabo, Peter J
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Larschan, Erica
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Gorchakov, Andrey A
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Gu, Tingting
    Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA.
    Linder-Basso, Daniela
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
    Plachetka, Annette
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Shanower, Gregory
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
    Tolstorukov, Michael Y
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Luquette, Lovelace J
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Xi, Ruibin
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Jung, Youngsook L
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Park, Richard W
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Bishop, Eric P
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Canfield, Theresa K
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Sandstrom, Richard
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Thurman, Robert E
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    MacAlpine, David M
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
    Stamatoyannopoulos, John A
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Kellis, Manolis
    MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA.
    Elgin, Sarah C R
    Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA.
    Kuroda, Mitzi I
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Pirrotta, Vincenzo
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
    Karpen, Gary H
    Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA.
    Park, Peter J
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Comprehensive analysis of the chromatin landscape in Drosophila melanogaster2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Nature, ISSN 1476-4687 EISSN, Vol. 471, no 7339, p. 480-485Article in journal (Refereed)
    Abstract [en]

    Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.

  • 231. Khmelinskii, Anton
    et al.
    Blaszczak, Ewa
    Pantazopoulou, Marina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Bernd
    Omnus, Deike J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Le Dez, Gaelle
    Brossard, Audrey
    Gunnarsson, Alexander
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Barry, Joseph D.
    Meurer, Matthias
    Kirrmaier, Daniel
    Boone, Charles
    Huber, Wolfgang
    Rabut, Gwenael
    Ljungdahl, Per O.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Knop, Michael
    Protein quality control at the inner nuclear membrane2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 516, no 7531, p. 410-+Article in journal (Refereed)
    Abstract [en]

    The nuclear envelope is a double membrane that separates the nucleus from the cytoplasm. The inner nuclear membrane (INM) functions in essential nuclear processes including chromatin organization and regulation of gene expression(1). The outer nuclear membrane is continuous with the endoplasmic reticulum and is the site of membrane protein synthesis. Protein homeostasis in this compartment is ensured by endoplasmic-reticulum-associated protein degradation (ERAD) pathways that in yeast involve the integral membrane E3 ubiquitin ligases Hrd1 and Doa10 operating with the E2 ubiquitin-conjugating enzymes Ubc6 and Ubc7 (refs 2, 3). However, little is known about protein quality control at the INM. Here we describe a protein degradation pathway at the INM in yeast (Saccharomyces cerevisiae) mediated by the Asicomplex consisting of the RING domain proteins Asi1 and Asi3 (ref. 4). We report that the Asi complex functions together with the ubiquitin-conjugating enzymes Ubc6 and Ubc7 to degrade soluble and integral membrane proteins. Genetic evidence suggests that the Asi ubiquitin ligase defines a pathway distinct from, but complementary to, ERAD. Using unbiased screening with a novel genome-wide yeast library based on a tandem fluorescent protein timer(5), we identify more than 50 substrates of the Asi, Hrd1 and Doa10 E3 ubiquitin ligases. We show that the Asi ubiquitin ligase is involved in degradation of mislocalized integral membrane proteins, thus acting to maintain and safeguard the identity of the INM.

  • 232.
    Kinoshita, Masaharu
    et al.
    National Institute for Physiological Sciences, Myodaiji, Okazaki .
    Matsui, Ryosuke
    Kyoto University.
    Kato, Shigeki
    Fukushima Medical University School of Medicine, Fukushima.
    Hasegawa, Taku
    Kyoto University.
    Kasahara, Hironori
    Kyoto University.
    Isa, Kaoru
    National Institute for Physiological Sciences, Myodaiji, Okazaki .
    Watakabe, Akiya
    National Institute for Basic Biology, Okazaki, he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
    Yamamori, Tetsuo
    National Institute for Basic Biology, Okazaki, he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
    Nishimura, Yukio
    National Institute for Physiological Sciences, Myodaiji, Okazaki .
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Watanabe, Dai
    Kyoto University.
    Kobayashi, Kazuto
    Fukushima Medical University School of Medicine, Fukushima.
    Isa, Tadashi
    National Institute for Physiological Sciences, Myodaiji, Okazaki , he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
    Genetic dissection of the circuit for hand dexterity in primates2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 487, no 7406, p. 235-U1510Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates(1-3). However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs)(4-6), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex-PN-motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.

  • 233. Kirkby, Jasper
    et al.
    Duplissy, Jonathan
    Sengupta, Kamalika
    Frege, Carla
    Gordon, Hamish
    Williamson, Christina
    Heinritzi, Martin
    Simon, Mario
    Yan, Chao
    Almeida, João
    Tröstl, Jasmin
    Nieminen, Tuomo
    Ortega, Ismael K.
    Wagner, Robert
    Adamov, Alexey
    Amorim, Antonio
    Bernhammer, Anne-Kathrin
    Bianchi, Federico
    Breitenlechner, Martin
    Brilke, Sophia
    Chen, Xuemeng
    Craven, Jill
    Dias, Antonio
    Ehrhart, Sebastian
    Flagan, Richard C.
    Franchin, Alessandro
    Fuchs, Claudia
    Guida, Roberto
    Hakala, Jani
    Hoyle, Christopher R.
    Jokinen, Tuija
    Junninen, Heikki
    Kangasluoma, Juha
    Kim, Jaeseok
    Krapf, Manuel
    Kürten, Andreas
    Laaksonen, Ari
    Lehtipalo, Katrianne
    Makhmutov, Vladimir
    Mathot, Serge
    Molteni, Ugo
    Onnela, Antti
    Peräkylä, Otso
    Piel, Felix
    Petäjä, Tuukka
    Praplan, Arnaud P.
    Pringle, Kirsty
    Rap, Alexandru
    Richards, Nigel A. D.
    Riipinen, Ilona
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Rissanen, Matti P.
    Rondo, Linda
    Sarnela, Nina
    Schobesberger, Siegfried
    Scott, Catherine E.
    Seinfeld, John H.
    Sipilä, Mikko
    Steiner, Gerhard
    Stozhkov, Yuri
    Stratmann, Frank
    Tomé, Antonio
    Virtanen, Annele
    Vogel, Alexander L.
    Wagner, Andrea C.
    Wagner, Paul E.
    Weingartner, Ernest
    Wimmer, Daniela
    Winkler, Paul M.
    Ye, Penglin
    Zhang, Xuan
    Hansel, Armin
    Dommen, Josef
    Donahue, Neil M.
    Worsnop, Douglas R.
    Baltensperger, Urs
    Kulmala, Markku
    Carslaw, Kenneth S.
    Curtius, Joachim
    Ion-induced nucleation of pure biogenic particles2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 533, no 7604, p. 521-526Article in journal (Refereed)
    Abstract [en]

    Atmospheric aerosols and their effect on clouds are thought to be important for anthropogenic radiative forcing of the climate, yet remain poorly understood(1). Globally, around half of cloud condensation nuclei originate from nucleation of atmospheric vapours(2). It is thought that sulfuric acid is essential to initiate most particle formation in the atmosphere(3,4), and that ions have a relatively minor role(5). Some laboratory studies, however, have reported organic particle formation without the intentional addition of sulfuric acid, although contamination could not be excluded(6,7). Here we present evidence for the formation of aerosol particles from highly oxidized biogenic vapours in the absence of sulfuric acid in a large chamber under atmospheric conditions. The highly oxygenated molecules (HOMs) are produced by ozonolysis of a-pinene. We find that ions from Galactic cosmic rays increase the nucleation rate by one to two orders of magnitude compared with neutral nucleation. Our experimental findings are supported by quantum chemical calculations of the cluster binding energies of representative HOMs. Ion-induced nucleation of pure organic particles constitutes a potentially widespread source of aerosol particles in terrestrial environments with low sulfuric acid pollution.

  • 234.
    Korn, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics.
    Grundahl, Frank
    Richard, O.
    Barklem, Paul
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics.
    Mashonkina, Ludmila
    Collet, Remo
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics.
    Piskunov, Nikolai
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics.
    Gustafsson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics.
    A probable stellar solution to the cosmological lithium discrepancy2006In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 442, no 7103, p. 657-659Article in journal (Refereed)
    Abstract [en]

    The measurement of the cosmic microwave background has strongly constrained the cosmological parameters of the Universe. When the measured density of baryons (ordinary matter) is combined with standard Big Bang nucleosynthesis calculations, the amounts of hydrogen, helium and lithium produced shortly after the Big Bang can be predicted with unprecedented precision. The predicted primordial lithium abundance is a factor of two to three higher than the value measured in the atmospheres of old stars. With estimated errors of 10 to 25%, this cosmological lithium discrepancy seriously challenges our understanding of stellar physics, Big Bang nucleosynthesis or both. Certain modifications to nucleosynthesis have been proposed, but found experimentally not to be viable. Diffusion theory, however, predicts atmospheric abundances of stars to vary with time, which offers a possible explanation of the discrepancy. Here we report spectroscopic observations of stars in the metal-poor globular cluster NGC6397 that reveal trends of atmospheric abundance with evolutionary stage for various elements. These element-specific trends are reproduced by stellar-evolution models with diffusion and turbulent mixing. We thus conclude that diffusion is predominantly responsible for the low apparent stellar lithium abundance in the atmospheres of old stars by transporting the lithium deep into the star.

  • 235. Kupitz, Christopher
    et al.
    Basu, Shibom
    Grotjohann, Ingo
    Fromme, Raimund
    Zatsepin, Nadia A
    Rendek, Kimberly N
    Hunter, Mark S
    Shoeman, Robert L
    White, Thomas A
    Wang, Dingjie
    James, Daniel
    Yang, Jay-How
    Cobb, Danielle E
    Reeder, Brenda
    Sierra, Raymond G
    Liu, Haiguang
    Barty, Anton
    Aquila, Andrew L
    Deponte, Daniel
    Kirian, Richard A
    Bari, Sadia
    Bergkamp, Jesse J
    Beyerlein, Kenneth R
    Bogan, Michael J
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Chao, Tzu-Chiao
    Conrad, Chelsie E
    Davis, Katherine M
    Fleckenstein, Holger
    Galli, Lorenzo
    Hau-Riege, Stefan P
    Kassemeyer, Stephan
    Laksmono, Hartawan
    Liang, Mengning
    Lomb, Lukas
    Marchesini, Stefano
    Martin, Andrew V
    Messerschmidt, Marc
    Milathianaki, Despina
    Nass, Karol
    Ros, Alexandra
    Roy-Chowdhury, Shatabdi
    Schmidt, Kevin
    Seibert, Marvin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Steinbrener, Jan
    Stellato, Francesco
    Yan, Lifen
    Yoon, Chunhong
    Moore, Thomas A
    Moore, Ana L
    Pushkar, Yulia
    Williams, Garth J
    Boutet, Sébastien
    Doak, R Bruce
    Weierstall, Uwe
    Frank, Matthias
    Chapman, Henry N
    Spence, John C H
    Fromme, Petra
    Serial time-resolved crystallography of photosystem II using a femtosecond X-ray laser2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7517, p. 261-265Article in journal (Refereed)
    Abstract [en]

    Photosynthesis, a process catalysed by plants, algae and cyanobacteria converts sunlight to energy thus sustaining all higher life on Earth. Two large membrane protein complexes, photosystem I and II (PSI and PSII), act in series to catalyse the light-driven reactions in photosynthesis. PSII catalyses the light-driven water splitting process, which maintains the Earth's oxygenic atmosphere. In this process, the oxygen-evolving complex (OEC) of PSII cycles through five states, S0 to S4, in which four electrons are sequentially extracted from the OEC in four light-driven charge-separation events. Here we describe time resolved experiments on PSII nano/microcrystals from Thermosynechococcus elongatus performed with the recently developed technique of serial femtosecond crystallography. Structures have been determined from PSII in the dark S1 state and after double laser excitation (putative S3 state) at 5 and 5.5 Å resolution, respectively. The results provide evidence that PSII undergoes significant conformational changes at the electron acceptor side and at the Mn4CaO5 core of the OEC. These include an elongation of the metal cluster, accompanied by changes in the protein environment, which could allow for binding of the second substrate water molecule between the more distant protruding Mn (referred to as the 'dangler' Mn) and the Mn3CaOx cubane in the S2 to S3 transition, as predicted by spectroscopic and computational studies. This work shows the great potential for time-resolved serial femtosecond crystallography for investigation of catalytic processes in biomolecules.

  • 236.
    Kurokawa, R.
    et al.
    University of California, San Diego, USA.
    Söderström, Mats
    University of California, San Diego, USA.
    Hörlein, A.
    University of California, San Diego, USA.
    Halachmi, S.
    Dana Farber Cancer Institute, Boston, Massachusetts, USA .
    Brown, M.
    Dana Farber Cancer Institute, Boston, Massachusetts, USA .
    Rosenfeld, M. G.
    University of California, San Diego, USA.
    Glass, C. K.
    University of California, San Diego, USA.
    Polarity-specific activities of retinoic acid receptors determined by a co-repressor.1995In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 377, no 6548, p. 451-454Article in journal (Refereed)
    Abstract [en]

    Retinoic acid receptors (RARs) and retinoid-X receptors (RXRs) activate or repress transcription by binding as heterodimers to DNA-response elements that generally consist of two direct repeat half-sites of consensus sequence AGGTCA. On response elements consisting of direct repeats spaced by five base pairs (DR + 5 elements), RAR/RXR heterodimers activate transcription in response to RAR-specific ligands, such as all-trans-retinoic acid (RA). In contrast, on elements consisting of direct repeats spaced by one base pair (DR + 1 elements), RAR/RXR heterodimers exhibit little or no response to activating ligands and repress RXR-dependent transcription. Here we show that ligand-dependent transactivation by RAR on DR + 5 elements requires the dissociation of a new nuclear receptor co-repressor, N-CoR, and recruitment of the putative co-activators p140 and p160. Surprisingly, on DR + 1 elements, N-CoR remains associated with RAR/RXR heterodimers even in the presence of RAR ligands, resulting in constitutive repression. These observations indicate that DNA-response elements can allosterically regulate RAR-co-repressor interactions to determine positive or negative regulation of gene expression.

  • 237.
    Kusumbe, Anjali P.
    et al.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Ramasamy, Saravana K.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Itkin, Tomer
    Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel..
    Mae, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Langen, Urs H.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lapidot, Tsvee
    Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel..
    Adams, Ralf H.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Age-dependent modulation of vascular niches for haematopoietic stem cells2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, no 7599, p. 380-+Article in journal (Refereed)
    Abstract [en]

    Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells(1-6). The properties of nicheforming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-beta (PDGFR beta)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFR beta-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.

  • 238. Lamichhaney, Sangeet
    et al.
    Berglund, Jonas
    Almen, Markus Sallman
    Maqbool, Khurram
    Grabherr, Manfred
    Martinez-Barrio, Alvaro
    Promerova, Marta
    Rubin, Carl-Johan
    Wang, Chao
    Zamani, Neda
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Grant, B. Rosemary
    Grant, Peter R.
    Webster, Matthew T.
    Andersson, Leif
    Evolution of Darwin's finches and their beaks revealed by genome sequencing2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7539Article in journal (Refereed)
    Abstract [en]

    Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives' Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial. development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis) a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and thereby, to an expanded utilization of food resources.

  • 239.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Almen, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Maqbool, Khurram
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Martinez-Barrio, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Promerova, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zamani, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grant, B. Rosemary
    Grant, Peter R.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolution of Darwin's finches and their beaks revealed by genome sequencing2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7539Article in journal (Refereed)
    Abstract [en]

    Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives' Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial. development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis) a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and thereby, to an expanded utilization of food resources.

  • 240.
    Langner, Joakim
    et al.
    SMHI, Research Department, Air quality.
    RODHE, H
    CRUTZEN, PJ
    ZIMMERMANN, P
    ANTHROPOGENIC INFLUENCE ON THE DISTRIBUTION OF TROPOSPHERIC SULFATE AEROSOL1992In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 359, no 6397, p. 712-716Article in journal (Refereed)
    Abstract [en]

    HUMAN activities have increased global emissions of sulphur gases by about a factor of three during the past century, leading to increased sulphate aerosol concentrations, mainly in the Northern Hemisphere. Sulphate aerosols can affect the climate directly, by increasing the backscattering of solar radiation in cloud-free air, and indirectly, by providing additional cloud condensation nuclei1-4. Here we use a global transport-chemistry model to estimate the changes in the distribution of tropospheric sulphate aerosol and deposition of non-seasalt sulphur that have occurred since pre-industrial times. The increase in sulphate aerosol concentration is small over the Southern Hemisphere oceans, but reaches a factor of 100 over northern Europe in winter. Our calculations indicate, however, that at most 6% of the anthropogenic sulphur emissions is available for the formation of new aerosol particles. This is because about one-half of the sulphur dioxide is deposited on the Earth's surface, and most of the remainder is oxidized in cloud droplets so that the sulphate becomes associated with pre-existing particles. Even so, the rate of formation of new sulphate particles may have doubled since pre-industrial times.

  • 241. Lappalainen, Tuuli
    et al.
    Sammeth, Michael
    Friedländer, Marc R
    't Hoen, Peter A C
    Monlong, Jean
    Rivas, Manuel A
    Gonzàlez-Porta, Mar
    Kurbatova, Natalja
    Griebel, Thasso
    Ferreira, Pedro G
    Barann, Matthias
    Wieland, Thomas
    Greger, Liliana
    van Iterson, Maarten
    Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ribeca, Paolo
    Pulyakhina, Irina
    Esser, Daniela
    Giger, Thomas
    Tikhonov, Andrew
    Sultan, Marc
    Bertier, Gabrielle
    Macarthur, Daniel G
    Lek, Monkol
    Lizano, Esther
    Buermans, Henk P J
    Padioleau, Ismael
    Schwarzmayr, Thomas
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ongen, Halit
    Kilpinen, Helena
    Beltran, Sergi
    Gut, Marta
    Kahlem, Katja
    Amstislavskiy, Vyacheslav
    Stegle, Oliver
    Pirinen, Matti
    Montgomery, Stephen B
    Donnelly, Peter
    McCarthy, Mark I
    Flicek, Paul
    Strom, Tim M
    Lehrach, Hans
    Schreiber, Stefan
    Sudbrak, Ralf
    Carracedo, Angel
    Antonarakis, Stylianos E
    Häsler, Robert
    Syvänen, 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.
    van Ommen, Gert-Jan
    Brazma, Alvis
    Meitinger, Thomas
    Rosenstiel, Philip
    Guigó, Roderic
    Gut, Ivo G
    Estivill, Xavier
    Dermitzakis, Emmanouil T
    Transcriptome and genome sequencing uncovers functional variation in humans2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 501, no 7468, p. 506-511Article in journal (Refereed)
    Abstract [en]

    Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

  • 242.
    Larsbrink, Johan
    et al.
    KTH, School of Biotechnology (BIO), Glycoscience.
    Rogers, Theresa E.
    Hemsworth, Glyn R.
    McKee, Lauren S.
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Tauzin, Alexandra S.
    Spadiut, Oliver
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Klinter, Stefan
    KTH, School of Biotechnology (BIO), Glycoscience.
    Pudlo, Nicholas A.
    Urs, Karthik
    Koropatkin, Nicole M.
    Creagh, A. Louise
    Haynes, Charles A.
    Kelly, Amelia G.
    Nilsson Cederholm, Stefan
    KTH, School of Biotechnology (BIO), Glycoscience.
    Davies, Gideon J.
    Martens, Eric C.
    Brumer, Harry
    KTH, School of Biotechnology (BIO), Glycoscience.
    A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 506, no 7489, p. 498-502Article in journal (Refereed)
    Abstract [en]

    A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables(1). Owing to the paucity of alimentary enzymes encoded by the human genome(2), our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut(3,4). The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides(5,6) whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear(1,7,8). Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health(9-12).

  • 243.
    Larsson, Josefin
    et al.
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Fransson, Claes
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Östlin, Göran
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Gröningsson, P.
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Jerkstrand, Anders
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Kozma, Cecilia
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Sollerman, Jesper
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Challis, P.
    Kirshner, R. P.
    Chevalier, R. A.
    Heng, K.
    McCray, R.
    Suntzeff, N. B.
    Bouchet, P.
    Crotts, A.
    Danziger, J.
    Dwek, E.
    France, K.
    Garnavich, P. M.
    Lawrence, S. S.
    Leibundgut, B.
    Lundqvist, Peter
    Stockholm University, Faculty of Science, Department of Astronomy. Stockholm University, Faculty of Science, The Oskar Klein Centre for Cosmo Particle Physics (OKC).
    Panagia, N.
    Pun, C. S. J.
    Smith, N.
    Sonneborn, G.
    Wang, L.
    Wheeler, J. C.
    X-ray illumination of the ejecta of supernova 1987A2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 474, no 7352, p. 484-486Article in journal (Refereed)
    Abstract [en]

    When a massive star explodes as a supernova, substantial amounts of radioactive elements-primarily (56)Ni, (57)Ni and (44)Ti-are produced(1). After the initial flash of light from shock heating, the fading light emitted by the supernova is due to the decay of these elements(2). However, after decades, the energy powering a supernova remnant comes from the shock interaction between the ejecta and the surrounding medium(3). The transition to this phase has hitherto not been observed: supernovae occur too infrequently in the Milky Way to provide a young example, and extragalactic supernovae are generally too faint and too small. Here we report observations that show this transition in the supernova SN 1987A in the Large Magellanic Cloud. From 1994 to 2001, the ejecta faded owing to radioactive decay of (44)Ti as predicted. Then the flux started to increase, more than doubling by the end of 2009. We show that this increase is the result of heat deposited by X-rays produced as the ejecta interacts with the surrounding material. In time, the X-rays will penetrate farther into the ejecta, enabling us to analyse the structure and chemistry of the vanished star.

  • 244.
    Lassance, J-M
    et al.
    Department of Biology, Lund University, 22362 Lund, Sweden.
    Groot, A T
    Department of Entomology, Max-Planck Institute for Chemical Ecology, 07745 Jena, Germany.
    Liénard, M A
    Department of Biology, Lund University, 22362 Lund, Sweden.
    Antony, B
    Department of Biology, Lund University, 22362 Lund, Sweden.
    Borgwardt, C
    Department of Entomology, Max-Planck Institute for Chemical Ecology, 07745 Jena, Germany.
    Andersson, Fredrik
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences, Engineering and Mathematics.
    Hedenström, Erik
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences, Engineering and Mathematics.
    Heckel, D G
    Department of Entomology, Max-Planck Institute for Chemical Ecology, 07745 Jena, Germany.
    Löfstedt, C
    Department of Biology, Lund University, 22362 Lund, Sweden.
    Allelic variation in a fatty-acyl reductase gene causes divergence in moth sex pheromones2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 466, no 7305, p. 486-489Article in journal (Refereed)
    Abstract [en]

    Pheromone-based behaviours are crucial in animals from insects to mammals, and reproductive isolation is often based on pheromone differences. However, the genetic mechanisms by which pheromone signals change during the evolution of new species are largely unknown. In the sexual communication system of moths (Insecta: Lepidoptera), females emit a species-specific pheromone blend that attracts males over long distances. The European corn borer, Ostrinia nubilalis, consists of two sex pheromone races, Z and E, that use different ratios of the cis and trans isomers of acetate pheromone components. This subtle difference leads to strong reproductive isolation in the field between the two races, which could represent a first step in speciation. Female sex pheromone production and male behavioural response are under the control of different major genes, but the identity of these genes is unknown. Here we show that allelic variation in a fatty-acyl reductase gene essential for pheromone biosynthesis accounts for the phenotypic variation in female pheromone production, leading to race-specific signals. Both the cis and trans isomers of the pheromone precursors are produced by both races, but the precursors are differentially reduced to yield opposite ratios in the final pheromone blend as a result of the substrate specificity of the enzymes encoded by the Z and E alleles. This is the first functional characterization of a gene contributing to intraspecific behavioural reproductive isolation in moths, highlighting the importance of evolutionary diversification in a lepidopteran-specific family of reductases. Accumulation of substitutions in the coding region of a single biosynthetic enzyme can produce pheromone differences resulting in reproductive isolation, with speciation as a potential end result.

     

     

  • 245.
    Laurell, Fredrik
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Laser Physics.
    Margulis, W.
    Lesche, B.
    Imagingthe χ2 grating in a frequency doubling fibre1995In: Nature, ISSN 0028-0836, E-ISSN 1476-4687Article in journal (Refereed)
  • 246. Lavik, Gaute
    et al.
    Stührmann, Torben
    Brüchert, Volker
    Stockholm University, Faculty of Science, Department of Geology and Geochemistry. Geokemi. Stockholm University.
    van der Plas, Anja
    Ministry of Fisheries and Marine Resources.
    Mohrholz, Volker
    Baltic Sea Research Institute.
    Mussmann, Marc
    Max-Planck Institute for marine Microbiology.
    Lam, Phyllis
    Max-Planck Institute for marine Microbiology.
    Fuchs, Bernhard
    Max-Planck Institute for marine Microbiology.
    Amann, Rudolf
    Max-Planck Institute for marine Microbiology.
    Lass, Uli
    Baltic Sea Research Institute.
    Kuypers, Marcel
    Max-Planck Institute for Marine Microbiology.
    Detoxification of sulphidic African shelf waters by blooming chemolithotrophs2009In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 457, no 7229, p. 581-584Article in journal (Refereed)
  • 247. Lazaridis, Iosif
    et al.
    Patterson, Nick
    Mittnik, Alissa
    Renaud, Gabriel
    Mallick, Swapan
    Kirsanow, Karola
    Sudmant, Peter H.
    Schraiber, Joshua G.
    Castellano, Sergi
    Lipson, Mark
    Berger, Bonnie
    Economou, Christos
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory.
    Bollongino, Ruth
    Fu, Qiaomei
    Bos, Kirsten I.
    Nordenfelt, Susanne
    Li, Heng
    de Filippo, Cesare
    Pruefer, Kay
    Sawyer, Susanna
    Posth, Cosimo
    Haak, Wolfgang
    Hallgren, Fredrik
    Fornander, Elin
    Rohland, Nadin
    Delsate, Dominique
    Francken, Michael
    Guinet, Jean-Michel
    Wahl, Joachim
    Ayodo, George
    Babiker, Hamza A.
    Bailliet, Graciela
    Balanovska, Elena
    Balanovsky, Oleg
    Barrantes, Ramiro
    Bedoya, Gabriel
    Ben-Ami, Haim
    Bene, Judit
    Berrada, Fouad
    Bravi, Claudio M.
    Brisighelli, Francesca
    Busby, George B. J.
    Cali, Francesco
    Churnosov, Mikhail
    Cole, David E. C.
    Corach, Daniel
    Damba, Larissa
    van Driem, George
    Dryomov, Stanislav
    Dugoujon, Jean-Michel
    Fedorova, Sardana A.
    Romero, Irene Gallego
    Gubina, Marina
    Hammer, Michael
    Henn, Brenna M.
    Hervig, Tor
    Hodoglugil, Ugur
    Jha, Aashish R.
    Karachanak-Yankova, Sena
    Khusainova, Rita
    Khusnutdinova, Elza
    Kittles, Rick
    Kivisild, Toomas
    Klitz, William
    Kucinskas, Vaidutis
    Kushniarevich, Alena
    Laredj, Leila
    Litvinov, Sergey
    Loukidis, Theologos
    Mahley, Robert W.
    Melegh, Bela
    Metspalu, Ene
    Molina, Julio
    Mountain, Joanna
    Nakkalajarvi, Klemetti
    Nesheva, Desislava
    Nyambo, Thomas
    Osipova, Ludmila
    Parik, Jueri
    Platonov, Fedor
    Posukh, Olga
    Romano, Valentino
    Rothhammer, Francisco
    Rudan, Igor
    Ruizbakiev, Ruslan
    Sahakyan, Hovhannes
    Sajantila, Antti
    Salas, Antonio
    Starikovskaya, Elena B.
    Tarekegn, Ayele
    Toncheva, Draga
    Turdikulova, Shahlo
    Uktveryte, Ingrida
    Utevska, Olga
    Vasquez, Rene
    Villena, Mercedes
    Voevoda, Mikhail
    Winkler, Cheryl A.
    Yepiskoposyan, Levon
    Zalloua, Pierre
    Zemunik, Tatijana
    Cooper, Alan
    Capelli, Cristian
    Thomas, Mark G.
    Ruiz-Linares, Andres
    Tishkoff, Sarah A.
    Singh, Lalji
    Thangaraj, Kumarasamy
    Villems, Richard
    Comas, David
    Sukernik, Rem
    Metspalu, Mait
    Meyer, Matthias
    Eichler, Evan E.
    Burger, Joachim
    Slatkin, Montgomery
    Paeaebo, Svante
    Kelso, Janet
    Reich, David
    Krause, Johannes
    Ancient human genomes suggest three ancestral populations for present-day Europeans2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7518, p. 409-+Article in journal (Refereed)
    Abstract [en]

    We sequenced the genomes of a similar to 7,000-year-old farmer from Germany and eight similar to 8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes(1-4) with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians(3), who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had similar to 44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.

  • 248.
    Lazazzera, Beth A
    et al.
    University of California Los Angeles.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genetics: Location affects sporulation2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 525, no 7567, p. 42-43Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Monitored changes in the number of copies of a gene during DNA replication control the timing of sporulation in bacteria. This discovery links replication to the concept that a gene's location on a chromosome can influence cell traits.

  • 249. Lee, Chiara
    et al.
    Kang, Hae Joo
    von Ballmoos, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Newstead, Simon
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dotson, David L.
    Iwata, So
    Beckstein, Oliver
    Cameron, Alexander D.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Imperial College London .
    A two-domain elevator mechanism for sodium/proton antiport2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 501, no 7468, p. 573-577Article in journal (Refereed)
    Abstract [en]

    Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets(2). The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli(1,3), for which both electron microscopy and crystal structures are available(4-6). NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein(1,4). Likemany Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur(7). The only reported NhaA crystal structure so far is of the low pH inactivated form(4). Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 angstrom resolution, solved from crystals grown at pH7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding(1,8,9) directly, a role supported hereby molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20 degrees against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second(3), Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.

  • 250. Li, X P
    et al.
    Bjorkman, O
    Shih, C
    Grossman, A R
    Rosenquist, M
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Niyogi, K K
    A pigment-binding protein essential for regulation of photosynthetic light harvesting2000In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 403, no 6768, p. 391-395Article in journal (Refereed)
    Abstract [en]

    Photosynthetic light harvesting in plants is regulated in response to changes in incident light intensity. Absorption of light that exceeds a plant's capacity for fixation of CO2 results in thermal dissipation of excitation energy in the pigment antenna of photosystem II by a poorly understood mechanism. This regulatory process, termed nonphotochemical quenching, maintains the balance between dissipation and utilization of light energy to minimize generation of oxidizing molecules, thereby protecting the plant against photo-oxidative damage. To identify specific proteins that are involved in nonphotochemical quenching, we have isolated mutants of Arabidopsis thaliana that cannot dissipate excess absorbed light energy. Here we show that the gene encoding PsbS, an intrinsic chlorophyll-binding protein of photosystem II, is necessary for nonphotochemical quenching but not for efficient light harvesting and photosynthesis, These results indicate that PsbS may be the site for nonphotochemical quenching, a finding that has implications for the functional evolution of pigment-binding proteins.

2345678 201 - 250 of 478
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