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  • 1. Carreras-Puigvert, Jordi
    et al.
    Zitnik, Marinka
    Jemth, Ann-Sofie
    Carter, Megan
    Unterlass, Judith E
    Hallström, Björn
    Loseva, Olga
    Karem, Zhir
    Calderón-Montaño, José Manuel
    Lindskog, Cecilia
    Edqvist, Per-Henrik
    Matuszewski, Damian J
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion.
    Ait Blal, Hammou
    Berntsson, Ronnie P A
    Häggblad, Maria
    Martens, Ulf
    Studham, Matthew
    Lundgren, Bo
    Wählby, Carolina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Sonnhammer, Erik L L
    Lundberg, Emma
    Stenmark, Pål
    Zupan, Blaz
    Helleday, Thomas
    A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family.2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Nature communications, ISSN 2041-1723, Vol. 8, nr 1, 1541Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

  • 2.
    Beloqui, Ana
    et al.
    Catholic Univ Louvain, Louvain Drug Res Inst, Dept Adv Drug Delivery & Biomat, Brussels, Belgium..
    Brayden, David J.
    Univ Coll Dublin, Sch Vet Med, Vet Biosci Sect, Dublin, Ireland.;Univ Coll Dublin, Conway Inst, Dublin, Ireland..
    Artursson, Per
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Preat, Veronique
    Catholic Univ Louvain, Louvain Drug Res Inst, Dept Adv Drug Delivery & Biomat, Brussels, Belgium..
    des Rieux, Anne
    Catholic Univ Louvain, Louvain Drug Res Inst, Dept Adv Drug Delivery & Biomat, Brussels, Belgium.;Catholic Univ Louvain, Inst Condensed Matter & Nanosci, Louvain Le Neuve, Belgium..
    A human intestinal M-cell-like model for investigating particle, antigen and microorganism translocation2017Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 12, nr 7, 1387-1399 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The specialized microfold cells (M cells) in the follicle-associated epithelium (FAE) of intestinal Peyer's patches serve as antigen-sampling cells of the intestinal innate immune system. Unlike 'classical' enterocytes, they are able to translocate diverse particulates without digesting them. They act as pathways for microorganism invasion and mediate food tolerance by transcellular transport of intestinal microbiota and antigens. Their ability to transcytose intact particles can be used to develop oral drug delivery and oral immunization strategies. This protocol describes a reproducible and versatile human M-cell-like in vitro model. This model can be exploited to evaluate M-cell transport of microparticles and nanoparticles for protein, drug or vaccine delivery and to study bacterial adherence and translocation across M cells. The inverted in vitro M-cell model consists of three main steps. First, Caco-2 cells are seeded at the apical side of the inserts. Second, the inserts are inverted and B lymphocytes are seeded at the basolateral side of the inserts. Third, the conversion to M cells is assessed. Although various M-cell culture systems exist, this model provides several advantages over the rest: (i) it is based on coculture with well-established differentiated human cell lines; (ii) it is reproducible under the conditions described herein; (iii) it can be easily mastered; and (iv) it does not require the isolation of primary cells or the use of animals. The protocol requires skills in cell culture and microscopy analysis. The model is obtained after 3 weeks, and transport experiments across the differentiated model can be carried out over periods of up to 10 h.

  • 3. Antolín, Roberto
    et al.
    Nettelblad, Carl
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för beräkningsvetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Tillämpad beräkningsvetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gorjanc, Gregor
    Money, Daniel
    Hickey, John M.
    A hybrid method for the imputation of genomic data in livestock populations2017Ingår i: Genetics Selection Evolution, ISSN 0999-193X, E-ISSN 1297-9686, Vol. 49, 30Artikel i tidskrift (Refereegranskat)
  • 4.
    Manning, Alisa
    et al.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Highland, Heather M.
    Univ Texas MD Anderson Canc Ctr, Human Genet Ctr, Houston, TX 77030 USA.;Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA.;Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Gasser, Jessica
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Sim, Xueling
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Tukiainen, Taru
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Fontanillas, Pierre
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;23andMe, Mountain View, CA USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Rivas, Manuel A.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Locke, Adam E.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Cingolani, Pablo
    McGill Univ, Sch Comp Sci, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Pers, Tune H.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Boston Childrens Hosp, Div Endocrinol & Genet, Boston, MA USA.;Boston Childrens Hosp, Div Genom, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes, Boston, MA USA.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Vinuela, Ana
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland.;Univ Geneva, Inst Genet & Genom Geneva, Geneva, Switzerland..
    Brown, Andrew A.
    Wellcome Trust Sanger Inst, Hinxton, England.;Oslo Univ Hosp, Norwegian Ctr Mental Disorders Res, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Div Mental Hlth & Addict, Oslo, Norway..
    Wu, Ying
    Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA..
    Flannick, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA..
    Fuchsberger, Christian
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Gamazon, Eric R.
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA.;Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands..
    Gaulton, Kyle J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA..
    Im, Hae Kyung
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Teslovich, Tanya M.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Blackwell, Thomas W.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Burtt, Noel P.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Chen, Yuhui
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Green, Todd
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Hartl, Christopher
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Kang, Hyun Min
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Kumar, Ashish
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Basel, Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol Unit, Basel, Switzerland..
    Ladenvall, Claes
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Ma, Clement
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Moutsianas, Loukas
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Pearson, Richard D.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Perry, John R. B.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England.;Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Rayner, N. William
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Robertson, Neil R.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Scott, Laura J.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    van de Bunt, Martijn
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Univ Helsinki, Unit Gen Practice, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Vaasa Cent Hosp, Vaasa, Finland.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Tampere, Dept Clin Chem, Fimlab Labs, Sch Med, Tampere, Finland..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Koskinen, Seppo
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Lehtimaki, Terho
    Palotie, Aarno
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Jacobs, Suzanne B. R.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Wessel, Jennifer
    Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN USA.;Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA..
    Chu, Audrey Y.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA.;Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA..
    Blancher, Christine
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Buck, Gemma
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Buck, David
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Chines, Peter S.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Gabriel, Stacey
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Gjesing, Anette P.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Groves, Christopher J.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Huyghe, Jeroen R.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jackson, Anne U.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jun, Goo
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Murphy, Jacquelyn
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Neville, Matt
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Onofrio, Robert
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Small, Kerrin S.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Stringham, Heather M.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Trakalo, Joseph
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Banks, Eric
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Carey, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Carneiro, Mauricio O.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    DePristo, Mark
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Farjoun, Yossi
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Fennell, Timothy
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Goldstein, Jacqueline I.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Grant, George
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    de Angelis, Martin Hrabe
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Tech Univ Munich, Sch Life Sci Weihenstephan, Inst Expt Genet, Freising Weihenstephan, Germany..
    Maguire, Jared
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Neale, Benjamin M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Poplin, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Purcell, Shaun
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Psychiat, New York, NY 10029 USA..
    Schwarzmayr, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Shakir, Khalid
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Smith, Joshua D.
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA..
    Strom, Tim M.
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Neuherberg, Germany..
    Wieland, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Lindstrom, Jaana
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland..
    Brandslund, Ivan
    Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark.;Vejle Hosp, Dept Clin Biochem, Vejle, Denmark..
    Christensen, Cramer
    Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark..
    Surdulescu, Gabriela L.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Lakka, Timo A.
    Univ Eastern FinIand, Inst Biomed, Dept Physiol, Kuopio, Finland.;Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Doney, Alex S. F.
    Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee, Scotland..
    Nilsson, Peter
    Lund Univ, Fac Med, Dept Clin Sci, Malmo, Sweden..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Varga, Tibor V.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Franks, Paul W.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Rolandsson, Olov
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Rosengren, Anders H.
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Farook, Vidya S.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Thameem, Farook
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Puppala, Sobha
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Kumar, Satish
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Lehman, Donna M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Jenkinson, Christopher P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.;South Texas Vet Hlth Care Syst, Res & Dev Serv, San Antonio, TX USA..
    Curran, Joanne E.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Hale, Daniel Esten
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Fowler, Sharon P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Arya, Rector
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    DeFronzo, Ralph A.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Abboud, Hanna E.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hicks, Pamela J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Palmer, Nicholette D.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Ng, Maggie C. Y.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Freedman, Barry I.
    Wake Forest Sch Med, Dept Internal Med, Sect Nephrol, Winston Salem, NC USA..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Narisu, Narisu
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Bonnycastle, Lori L.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Swift, Amy
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Pasko, Dorota
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Wood, Andrew R.
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Pollin, Toni I.
    Univ Maryland, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Barzilai, Nir
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA..
    Atzmon, Gil
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA.;Univ Haifa, Fac Nat Sci, Haifa, Israel..
    Glaser, Benjamin
    Hadassah Hebrew Univ, Endocrinol & Metab Serv, Med Ctr, Jerusalem, Israel..
    Thorand, Barbara
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Dept Genet Epidemiol, Munich, Germany..
    Peters, Annette
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany..
    Roden, Michael
    Heinrich Heine Univ, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;Partner Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Dept Genet Epidemiol, Munich, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany.;Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Kriebel, Jennifer
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Illig, Thomas
    German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, Germany..
    Grallert, Harald
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Gieger, Christian
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Meisinger, Christa
    German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Lannfelt, L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Griswold, Michael
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Taylor, Herman A., Jr.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Wilson, Gregory, Sr.
    Jackson State Univ, Coll Publ Serv, Jackson, MS USA..
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Oksa, Heikki
    Pirkanmaa Hosp Dist, Tampere, Finland..
    Scott, William R.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Afzal, Uzma
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Tan, Sian-Tsung
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Loh, Marie
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland.;ASTAR, Translat Lab Genet Med, Singapore, Singapore..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Sehmi, Jobanpreet
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Kooner, Jaspal Singh
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Lehne, Benjamin
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Cho, Yoon Shin
    Hallym Univ, Dept Biomed Sci, Chunchon, South Korea..
    Lee, Jong-Young
    Minist Hlth & Welf, Seoul, South Korea..
    Han, Bok-Ghee
    Korea Natl Res Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Karajamaki, Annemari
    Vaasa Hlth Care Ctr, Vaasa, Finland.;Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland..
    Qi, Qibin
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA..
    Qi, Lu
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Huang, Jinyan
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Hu, Frank B.
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Hypertens & Cardiovasc Dis, Malmo, Sweden..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Diabet & Cardiovasc Dis Genet Epidemiol, Malmo, Sweden..
    Below, Jennifer E.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Aguilar, David
    Baylor Coll Med, Cardiovasc Div, Houston, TX 77030 USA..
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Liu, Jianjun
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    Khor, Chiea-Chuen
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore..
    Chia, Kee Seng
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Lim, Wei Yen
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Cheng, Ching-Yu
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Ctr Quantitat Med, Off Clin Sci, Singapore, Singapore..
    Chan, Edmund
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
    Tai, E. Shyong
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Cardiovasc Metab Disorders Program, Singapore, Singapore..
    Aung, Tin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Linneberg, Allan
    Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Meitinger, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Neuherberg, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany..
    Tuomi, Tiinamaija
    Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Endocrinol, Helsinki, Finland..
    Hakaste, Liisa
    Folkhalsan Res Ctr, Helsinki, Finland..
    Kravic, Jasmina
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Lauritzen, Torsten
    Aarhus Univ, Dept Publ Hlth, Sect Gen Practice, Aarhus, Denmark..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Stirrups, Kathleen E.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Owen, Katharine R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Farmer, Andrew J.
    Univ Oxford, Dept Primary Care Hlth Sci, Oxford, England..
    Frayling, Timothy M.
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    O'Rahilly, Stephen P.
    Univ Cambridge, Inst Metab Sci, Med Res Labs, Cambridge, England..
    Walker, Mark
    Univ Newcastle, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Levy, Jonathan C.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hodgkiss, Dylan
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Hattersley, Andrew T.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland..
    Stancakova, Alena
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Inst Metab Sci, Med Res Labs, Cambridge, England..
    Bharadwaj, Dwaipayan
    CSIR Inst Genom & Integrat Biol, Funct Genom Unit, New Delhi, India..
    Chan, Juliana
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Chandak, Giriraj R.
    CSIR Ctr Cellular Mol Biol, Hyderabad, Andhra Pradesh, India..
    Daly, Mark J.
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Donnelly, Peter J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Ebrahim, Shah B.
    Ctr Chron Dis Control, New Delhi, India. Imperial Coll London, MRC, PHE Ctr Environm & Hlth, London, England..
    Elliott, Paul
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Fingerlin, Tasha
    Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA..
    Froguel, Philippe
    CNRS, Inst Biol Lille, Genom & Mol Physiol, Lille, France..
    Hu, Cheng
    Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Jia, Weiping
    Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Ma, Ronald C. W.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    McVean, Gilean
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Park, Taesung
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea.;Seoul Natl Univ, Dept Stat, Seoul, South Korea.;Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Prabhakaran, Dorairaj
    Ctr Chron Dis Control, New Delhi, India. Imperial Coll London, MRC, PHE Ctr Environm & Hlth, London, England..
    Sandhu, Manjinder
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Scott, James
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Sladek, Rob
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Med, Div Endocrinol & Metab, Montreal, PQ, Canada..
    Tandon, Nikhil
    All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India..
    Teo, Yik Ying
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Inst Life Sci, Singapore, Singapore.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Watanabe, Richard M.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Diabet & Obes Res Inst, Los Angeles, CA USA..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr, Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Minerva Fdn, Inst Med Res, Helsinki, Finland..
    Kesaniemi, Y. Antero
    Univ Oulu, Inst Clin Med, Fac Med, Oulu, Finland..
    Uusitupa, Matti
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Rauramaa, Rainer
    Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Palmer, Colin N. A.
    Ninewells Hosp & Med Sch, Med Res Inst, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee, Scotland..
    Prokopenko, Inga
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Morris, Andrew D.
    Ninewells Hosp & Med Sch, Clin Res Ctr, Div Mol Med, Dundee, Scotland..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Collins, Francis S.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden.;Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Dasman Diabet Inst, Dasman, Kuwait..
    Karpe, Fredrik
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Groop, Leif
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Jorgensen, Torben
    Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Kuusisto, Johanna
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Abecasis, GonOalo
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bell, Graeme I.
    Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA.;Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA..
    Blangero, John
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Cox, Nancy J.
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Duggirala, Ravindranath
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Seielstad, Mark
    Univ Calif San Francisco, Dept Lab Med, Inst Human Genet, San Francisco, CA 94143 USA.;Blood Syst Res Inst, San Francisco, CA USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Ripatti, Samuli
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Helsinki, Finland..
    Hanis, Craig L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Florez, Jose C.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA..
    Mohlke, Karen L.
    Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA..
    Meigs, James B.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA..
    Laakso, Markku
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Morris, Andrew P.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Boehnke, Michael
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Altshuler, David
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA.;MIT, Dept Biol, Cambridge, MA USA..
    McCarthy, Mark I.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Lindgren, Cecilia M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Big Data Inst, Oxford, England..
    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 7, 2019-2032 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

  • 5.
    Gómez de La Torre, Teresa Zardán
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Herthnek, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    A Magnetic Nanobead-Based Read-Out Procedure for Rapid Detection of DNA Molecules2017Ingår i: Journal of Nanoscience and Nanotechnology, ISSN 1533-4880, E-ISSN 1533-4899, Vol. 17, nr 4, 2861-2864 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The presented measurement and data analysis procedure reduces the read-out time for the volume-amplified magnetic nanobead detection assay from ~30 min to only 2 min, providing fast, sensitive detection of DNA molecules. The molecular detection and amplification protocol was verified using samples containing rolling circle-amplified DNA products formed from synthetic Vibrio cholerae target DNA, with a limit of detection of 5 pM. The developed read-out method could be used to rapidly identify pathogens in a variety of applications including target screening in hospitals with limited resources, in out-patient settings and in the field.

  • 6. Bonfiglio, F
    et al.
    Hysi, P G
    Ek, Weronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karhunen, V
    Rivera, N V
    Männikkö, M
    Nordenstedt, H
    Zucchelli, M
    Bresso, F
    Williams, F
    Tornblom, H
    Magnusson, P K
    Pedersen, N L
    Ronkainen, J
    Schmidt, P T
    D'Amato, M
    A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population2017Ingår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, nr 2, e12923Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes.

    METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap).

    KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10(-5) ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds.

    CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

  • 7.
    Klar, Joakim
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ali, Zafar
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Farooq, Muhammad
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Khan, Kamal
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Iqbal, Maria
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Faryal, Sanam
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Baig, Shahid Mahmood
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers.2017Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, nr 7, 848-853 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinocerebellar ataxias (SCA) comprise a heterogeneous group of inherited neurological disorders characterized by a range of symptoms from both cerebellar and extra cerebellar structures. We investigated the cause of autosomal recessive, congenital SCA in six affected family members from a large consanguineous family. Using whole-exome sequencing, we identified a homozygous ITPR1 missense variant [c.5360T>C; p.(L1787P)] segregating in all affected individuals. Heterozygous carriers were asymptomatic despite cerebellar hypoplasia. Variants in the ITPTR1 gene have previously been associated exclusively with autosomal dominant SCA15 and SCA29 with slow or no progression. The L1787 residue is highly conserved and the leucine to proline substitution has a predicted destabilizing effect on the protein structure. Additionally, the L1787P variant is located in a domain separated from previously described and dominant-acting missense variants consistent with a distinct effect on IP3R1 tetramer structure and function. Taken together, we show for the first time that a biallelic ITPR1 missense variant may cause an autosomal recessive and infantile onset SCA29, albeit with subclinical cerebellar hypoplasia in carriers. Our findings add to the genetic complexity of SCA29 and broaden the correlations between ITPR1 variants and their clinical expression.

  • 8.
    Dumanski, Jan P.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Rasi, Chiara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Davies, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ali, Abir S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Sorbye, Halfdan
    Grønbæk, Henning
    Cunningham, Janet L
    Forsberg, Lars A.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors2017Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, nr 8, 427-443 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

  • 9.
    Namuduri, Arvind Venkat
    et al.
    Karolinska Inst.
    Heras, Gabriel
    Karolinska Inst.
    Mi, Jia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Binzhou Med Univ, Peoples R China..
    Cacciani, Nicola
    Karolinska Inst.
    Hörnaeus, Katarina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Konzer, Anne
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergström Lind, Sara
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Larsson, Lars
    Karolinska Inst.
    Gastaldello, Stefano
    Karolinska Inst.
    A Proteomic Approach to Identify Alterations in the Small Ubiquitin-like Modifier (SUMO) Network during Controlled Mechanical Ventilation in Rat Diaphragm Muscle2017Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, nr 6, 1081-1097 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The small ubiquitin-like modifier (SUMO) is as a regulator of many cellular functions by reversible conjugation to a broad number of substrates. Under endogenous or exogenous perturbations, the SUMO network becomes a fine sensor of stress conditions by alterations in the expression level of SUMO enzymes and consequently changing the status of SUMOylated proteins. The diaphragm is the major inspiratory muscle, which is continuously active under physiological conditions, but its structure and function is severely affected when passively displaced for long extents during mechanical ventilation (MV). An iatrogenic condition called Ventilator-Induced Diaphragm Dysfunction (VIDD) is a major cause of failure to wean patients from ventilator support but the molecular mechanisms underlying this dysfunction are not fully understood. Using a unique experimental Intensive Care Unit (ICU) rat model allowing long-term MV, diaphragm muscles were collected in rats control and exposed to controlled MV (CMV) for durations varying between 1 and 10 days. Endogenous SUMOylated diaphragm proteins were identified by mass spectrometry and validated with in vitro SUMOylation systems. Contractile, calcium regulator and mitochondrial proteins were of specific interest due to their putative involvement in VIDD. Differences were observed in the abundance of SUMOylated proteins between glycolytic and oxidative muscle fibers in control animals and high levels of SUMOylated proteins were present in all fibers during CMV. Finally, previously reported VIDD biomarkers and therapeutic targets were also identified in our datasets which may play an important role in response to muscle weakness seen in ICU patients. Data are available via ProteomeXchange with identifier PXD006085.

  • 10.
    Thul, Peter J.
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    åkesson, Lovisa
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Wiking, Mikaela
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Mahdessian, Diana
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Geladaki, Aikaterini
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England.;Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England..
    Blal, Hammou Ait
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Alm, Tove
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bjork, Lars
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Breckels, Lisa M.
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England.;Univ Cambridge, Dept Biochem, Computat Prote Unit, Tennis Court Rd, Cambridge CB2 1QR, England..
    Backstrom, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Danielsson, Frida
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Fall, Jenny
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Gatto, Laurent
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England.;Univ Cambridge, Dept Biochem, Computat Prote Unit, Tennis Court Rd, Cambridge CB2 1QR, England..
    Gnann, Christian
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Hober, Sophia
    KTH Royal Inst Technol, Sch Biotechnol, Dept Prote, SE-10691 Stockholm, Sweden..
    Hjelmare, Martin
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Johansson, Fredric
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lee, Sunjae
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, SE-17177 Stockholm, Sweden..
    Mulvey, Claire M.
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England..
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Oksvold, Per
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Rockberg, Johan
    KTH Royal Inst Technol, Sch Biotechnol, Dept Prote, SE-10691 Stockholm, Sweden..
    Schutten, Rutger
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Sivertsson, Asa
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Stadler, Charlotte
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Sullivan, Devin P.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Tegel, Hanna
    KTH Royal Inst Technol, Sch Biotechnol, Dept Prote, SE-10691 Stockholm, Sweden..
    Winsnes, Casper
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Zhang, Cheng
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Zwahlen, Martin
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Mardinoglu, Adil
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lilley, Kathryn S.
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lundberg, Emma
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    A subcellular map of the human proteome2017Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 356, nr 6340, eaal332Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map of subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry. Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of the proteomes of 13 major organelles. Exploration of the proteomes revealed single-cell variations in abundance or spatial distribution and localization of about half of the proteins to multiple compartments. This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.

  • 11.
    Gremel, Gabriela
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Dijana
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Niinivirta, Marjut
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Laird, Alexander
    Univ Edinburgh, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Edinburgh Urol Canc Grp, Edinburgh, Midlothian, Scotland..
    Ljungqvist, Oscar
    Atlas Antibodies AB, Stockholm, Sweden..
    Johannesson, Henrik
    Atlas Antibodies AB, Stockholm, Sweden..
    Bergman, Julia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Navani, Sanjay
    Lab Surgpath, Bombay, Maharashtra, India..
    Khan, Naila
    Lab Surgpath, Bombay, Maharashtra, India..
    Patil, Tushar
    Lab Surgpath, Bombay, Maharashtra, India..
    Sivertsson, Asa
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Uhlen, Mathias
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Harrison, David J.
    Univ St Andrews, Sch Med, St Andrews, Fife, Scotland..
    Ullenhag, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Stewart, Grant D.
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh Urol Canc Grp, Edinburgh, Midlothian, Scotland.;Univ Cambridge, Addenbrookes Hosp, Acad Urol Grp, Box 43,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England..
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma2017Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, 9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC). Methods: Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray (n = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts (n = 181; n = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival. Results: CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203-0.719, P = 0.003). Conclusions: CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.

  • 12.
    Eriksson, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moreno, R
    Milenova, I. Yoanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Liljenfeldt, L
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Dieterich, L C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Christiansson, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karlsson, H
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ullenhag, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Alemany, R
    Loskog, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment2017Ingår i: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 24, nr 2, 92-103 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

  • 13.
    Blaha-Nelson, David
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Krüger, Dennis M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Szeler, Klaudia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ben-David, Moshe
    Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel.;Univ Toronto, Banting & Best Dept Med Res, Donnelly Ctr Cellular & Biomol Res, 160 Coll St, Toronto, ON M5S 3E1, Canada..
    Kamerlin, Shina Caroline Lynn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Active Site Hydrophobicity and the Convergent Evolution of Paraoxonase Activity in Structurally Divergent Enzymes: The Case of Serum Paraoxonase 12017Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, nr 3, 1155-1167 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Serum paraoxonase 1 (PON1) is a native lactonase capable of promiscuously hydrolyzing a broad range of substrates, including organophosphates, esters, and carbonates. Structurally, PON1 is a six-bladed beta-propeller with a flexible loop (residues 70-81) covering the active site. This loop contains a functionally critical Tyr at position 71. We have performed detailed experimental and computational analyses of the role of selected Y71 variants in the active site stability and catalytic activity in order to probe the role of Y71 in PON1's lactonase and organophosphatase activities. We demonstrate that the impact of Y71 substitutions on PON1's lactonase activity is minimal, whereas the k(cat) for the paraoxonase activity is negatively perturbed by up to 100-fold, suggesting greater mutational robustness of the native activity. Additionally, while these substitutions modulate PON1's active site shape, volume, and loop flexibility, their largest effect is in altering the solvent accessibility of the active site by expanding the active site volume, allowing additional water molecules to enter. This effect is markedly more pronounced in the organophosphatase activity than the lactonase activity. Finally, a detailed comparison of PON1 to other organophosphatases demonstrates that either a similar "gating loop" or a highly buried solvent excluding active site is a common feature of these enzymes. We therefore posit that modulating the active site hydrophobicity is a key element in facilitating the evolution of organophosphatase activity. This provides a concrete feature that can be utilized in the rational design of next-generation organophosphate hydrolases that are capable of selecting a specific reaction from a pool of viable substrates.

  • 14.
    Owers, Katharine A.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi. Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA..
    Sjödin, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Schlebusch, Carina M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Skoglund, Pontus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Soodyall, Himla
    Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, Div Human Genet, Johannesburg, South Africa.;Natl Hlth Lab Serv, Johannesburg, South Africa..
    Jakobsson, Mattias
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Adaptation to infectious disease exposure in indigenous Southern African populations2017Ingår i: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 284, nr 1852, 20170226Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetic analyses can provide information about human evolutionary history that cannot always be gleaned from other sources. We evaluated evidence of selective pressure due to introduced infectious diseases in the genomes of two indigenous southern African San groups-the double dagger Khomani who had abundant contact with other people migrating into the region and the more isolated Ju vertical bar'hoansi. We used a dual approach to test for increased selection on immune genes compared with the rest of the genome in these groups. First, we calculated summary values of statistics that measure genomic signatures of adaptation to contrast selection signatures in immune genes and all genes. Second, we located regions of the genome with extreme values of three selection statistics and examined these regions for enrichment of immune genes. We found stronger and more abundant signals of selection in immune genes in the double dagger Khomani than in the Ju vertical bar'hoansi. We confirm this finding within each population to avoid effects of different demographic histories of the two populations. We identified eight immune genes that have potentially been targets of strong selection in the double dagger Khomani, whereas in the Juj'hoansi, no immune genes were found in the genomic regions with the strongest signals of selection. We suggest that the more abundant signatures of selection at immune genes in the double dagger Khomani could be explained by their more frequent contact with immigrant groups, which likely led to increased exposure and adaptation to introduced infectious diseases.

  • 15.
    Byström, Sanna
    et al.
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, S-17165 Solna, Sweden..
    Fredolini, Claudia
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, S-17165 Solna, Sweden..
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nyaiesh, Etienne-Nicholas
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, S-17165 Solna, Sweden..
    Drobin, Kimi
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, S-17165 Solna, Sweden..
    Uhlen, Mathias
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, S-17165 Solna, Sweden..
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Sjukhus, S-80188 Gavle, Sweden.;Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden..
    Ponten, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, S-17165 Solna, Sweden..
    Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence2017Ingår i: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, nr 3, 385-395 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Blood-based proteomic profiling may aid and expand our understanding of diseases and their different phenotypes. The aim of the presented study was to profile serum samples from patients with malignant melanoma using affinity proteomic assays to describe proteins in the blood stream that are associated to stage or recurrence of melanoma. MATERIAL AND METHODS: Multiplexed protein analysis was conducted using antibody suspension bead arrays. A total of 232 antibodies against 132 proteins were selected from (i) a screening with 4595 antibodies and 32 serum samples from melanoma patients and controls, (ii) antibodies used for immunohistochemistry, (iii) protein targets previously related with melanoma. The analysis was performed with 149 serum samples from patients with malignant melanoma. Antibody selectivity was then assessed by Western blot, immunocapture mass spectrometry, and epitope mapping. Lastly, indicative antibodies were applied for IHC analysis of melanoma tissues. RESULTS: Serum levels of regucalcin (RGN) and syntaxin 7 (STX7) were found to be lower in patients with both recurring tumors and a high Breslow's thickness (T-stage 3/4) compared to low thickness (T-stage 1/2) without disease recurrence. Serum levels of methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) were instead elevated in sera of T3/4 patients with recurrence. The analysis of tissue sections with S100A6 and MTHFD1L showed positive staining in a majority of patients with melanoma, and S100A6 was significantly associated to T-stage. CONCLUSIONS: Our findings provide a starting point to further study RGN, STX7, MTHFD1L and S100A6 in serum to elucidate their involvement in melanoma progression and to assess a possible contribution to support clinical indications.

  • 16.
    Roos, Vendela
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Dept Hlth Sci, Div Geriatr Med, Malmo, Sweden..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity2017Ingår i: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, nr 3, 118-123 s.Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors. Methods: BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population-based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m(2), overweight/BMI 25-30 kg/m(2), and obesity/BMI > 30 kg/m(2)) and MetS status (+/-, NCEP criteria). A wide range of lifestyle factors related to physical activity, smoking, alcohol, sleep quality, working conditions, quality of life and stress, and eating patterns were assessed using a questionnaire. Results: Prevalent MetS (23% in the sample) was associated with less physical activity (P < 0.0001), more TV watching (P < 0.0001), more years of smoking (P < 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P < 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes. Conclusions: This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development.