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  • 1.
    Abadpour, Shadab
    et al.
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Göpel, Sven O.
    AstraZeneca R&D Gothenburg, Dept CVMD Biosci, Gothenburg, Sweden..
    Schive, Simen W.
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Foss, Aksel
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Scholz, Hanne
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 1575Article in journal (Refereed)
    Abstract [en]

    One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.

  • 2.
    Adams, Hieab H. H.
    et al.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Hibar, Derrek P.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA..
    Chouraki, Vincent
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Stein, Jason L.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ N Carolina, Dept Genet, Chapel Hill, NC USA.;Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC USA..
    Nyquist, Paul A.
    Johns Hopkins Univ, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, Baltimore, MD 21218 USA..
    Renteria, Miguel E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Arias-Vasquez, Alejandro
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Desrivieres, Sylvane
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Beecham, Ashley H.
    Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Jahanshad, Neda
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA..
    Wittfeld, Katharine
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany.;Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Van der Lee, Sven J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Abramovic, Lucija
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Alhusaini, Saud
    McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada.;Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Andersson, Micael
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Arfanakis, Konstantinos
    IIT, Dept Biomed Engn, Chicago, IL 60616 USA.;Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA..
    Aribisala, Benjamin S.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Lagos State Univ, Dept Comp Sci, Lagos, Nigeria.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland..
    Armstrong, Nicola J.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;Murdoch Univ, Math & Stat, Perth, WA, Australia..
    Athanasiu, Lavinia
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Beiser, Alexa
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Bernard, Manon
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA..
    Blanken, Laura M. E.
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Blanton, Susan H.
    Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Bohlken, Marc M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Boks, Marco P.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Bralten, Janita
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Brickman, Adam M.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA.;Columbia Univ, GH Sergievsky Ctr, Med Ctr, New York, NY USA.;Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA..
    Carmichael, Owen
    Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Chakravarty, M. Mallar
    Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ, Canada..
    Chauhan, Ganesh
    Univ Bordeaux, INSERM Unit U1219, Bordeaux, France..
    Chen, Qiang
    Lieber Inst Brain Dev, Baltimore, MD USA..
    Ching, Christopher R. K.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA USA..
    Cuellar-Partida, Gabriel
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Den Braber, Anouk
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Doan, Nhat Trung
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Ehrlich, Stefan
    Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany.;Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA..
    Filippi, Irina
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Ge, Tian
    Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA..
    Giddaluru, Sudheer
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Goldman, Aaron L.
    Lieber Inst Brain Dev, Baltimore, MD USA..
    Gottesman, Rebecca F.
    Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA..
    Greven, Corina U.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands.;Kings Coll London, Med Res Council Social, Genet & Dev Psychiat Ctr, Inst Psychol Psychiat & Neurosci, London, England..
    Grimm, Oliver
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Griswold, Michael E.
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Guadalupe, Tulio
    Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands.;Int Max Planck Res Sch Language Sci, Nijmegen, Netherlands..
    Hass, Johanna
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany..
    Haukvik, Unn K.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway..
    Hilal, Saima
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore..
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria.;Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria..
    Hoehn, David
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Holmes, Avram J.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Yale Univ, Dept Psychol, New Haven, CT USA..
    Hoogman, Martine
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Janowitz, Deborah
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Jia, Tianye
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Kasperaviciute, Dalia
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England.;Imperial Coll London, Dept Med, London, England..
    Kim, Sungeun
    Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Klein, Marieke
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Kraemer, Bernd
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany..
    Lee, Phil H.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA.;Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA USA..
    Liao, Jiemin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Lopez, Lorna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Luciano, Michelle
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Macare, Christine
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Marquand, Andre
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Matarin, Mar
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England.;UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Mather, Karen A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Mattheisen, Manuel
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Copenhagen, Denmark.;Aarhus Univ, iSEQ, Ctr Integrated Sequencing, Aarhus, Denmark..
    Mazoyer, Bernard
    UMR5296 Univ Bordeaux, CNRS, CEA, Bordeaux, France..
    Mckay, David R.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    McWhirter, Rebekah
    Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia..
    Milaneschi, Yuri
    VU Univ Med Ctr GGZ Geest, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands.;VU Univ Med Ctr GGZ Geest, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Mirza-Schreiber, Nazanin
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Muetzel, Ryan L.
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Maniega, Susana Munoz
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Nho, Kwangsik
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Nugent, Allison C.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Loohuis, Loes M. Olde
    Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA..
    Oosterlaan, Jaap
    Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands..
    Papmeyer, Martina
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.;Univ Bern, Univ Hosp Psychiat, Translat Res Ctr, Div Syst Neurosci Psychopathol, CH-3012 Bern, Switzerland..
    Pappa, Irene
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands..
    Pirpamer, Lukas
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Pudas, Sara
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Puetz, Benno
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Rajan, Kumar B.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA..
    Ramasamy, Adaikalavan
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;Kings Coll London, Dept Med & Mol Genet, London, England.;Univ Oxford, Jenner Inst Labs, Oxford, England..
    Richards, Jennifer S.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Risacher, Shannon L.
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Roiz-Santianez, Roberto
    Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain..
    Rommelse, Nanda
    Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Rose, Emma J.
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland..
    Royle, Natalie A.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Rundek, Tatjana
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA..
    Saemann, Philipp G.
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Satizabal, Claudia L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Schmaal, Lianne
    Orygen, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic, Australia.;Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Schork, Andrew J.
    Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA..
    Shen, Li
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Shin, Jean
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Shumskaya, Elena
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Sprooten, Emma
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA..
    Strike, Lachlan T.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Thomson, Russell
    Tordesillas-Gutierrez, Diana
    CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain.;Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Cantabria, Spain..
    Toro, Roberto
    Inst Pasteur, Paris, France..
    Trabzuni, Daniah
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia..
    Vaidya, Dhananjay
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Van der Grond, Jeroen
    Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands..
    Van der Meer, Dennis
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Van Donkelaar, Marjolein M. J.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Van Eijk, Kristel R.
    UMC Utrecht, Human Neurogenet Unit, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Van Erp, Theo G. M.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA..
    Van Rooij, Daan
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Walton, Esther
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany..
    Westlye, Lars T.
    Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Whelan, Christopher D.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Windham, Beverly G.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Winkler, Anderson M.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Univ Oxford, FMRIB Ctr, Oxford, England..
    Woldehawariat, Girma
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Wolf, Christiane
    Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany..
    Wolfers, Thomas
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Xu, Bing
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Yang, Jingyun
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Zijdenbos, Alex
    Biospect Inc, Montreal, PQ, Canada..
    Zwiers, Marcel P.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Agartz, Ingrid
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway.;Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Aggarwal, Neelum T.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Almasy, Laura
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA.;Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA..
    Ames, David
    Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia.;Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia..
    Amouyel, Philippe
    Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France..
    Andreassen, Ole A.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Arepalli, Sampath
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Assareh, Amelia A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Barral, Sandra
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA..
    Bastin, Mark E.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Becker, James T.
    Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA.;Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Blangero, John
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    van Bokhoven, Hans
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Brodaty, Henry
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;UNSW, Dementia Collaborat Res Ctr Assessment & Better, Sydney, NSW, Australia..
    Brouwer, Rachel M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Brunner, Han G.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands..
    Buckner, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA..
    Buitelaar, Jan K.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Bulayeva, Kazima B.
    Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia..
    Cahn, Wiepke
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Calhoun, Vince D.
    Mind Res Network, Albuquerque, NM USA.;LBERI, Albuquerque, NM USA.;Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA..
    Cannon, Dara M.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland..
    Cavalleri, Gianpiero L.
    Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Chen, Christopher
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore..
    Cheng, Ching -Yu
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Cichon, Sven
    Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland.;Univ Bonn, Inst Human Genet, Bonn, Germany.;Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany..
    Cookson, Mark R.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Corvin, Aiden
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland..
    Crespo-Facorro, Benedicto
    Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Czisch, Michael
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Dale, Anders M.
    Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA..
    Davies, Gareth E.
    Avera Inst Human Genet, Sioux Falls, SD USA.;Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Gen, 75 Francis St, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    De Geus, Eco J. C.
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    De Jager, Philip L.
    Harvard Med Sch, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst, Cambridge, MA USA..
    de Zubicaray, Greig I.
    Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia.;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia..
    Delanty, Norman
    Royal Coll Surgeons Ireland, Dublin 2, Ireland.;Beaumont Hosp, Div Neurol, Dublin 9, Ireland..
    Depondt, Chantal
    Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium..
    DeStefano, Anita L.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Dillman, Allissa
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Djurovic, Srdjan
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Oslo Univ Hosp, Dept Med Genet, Oslo, Norway..
    Donohoe, Gary
    Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland.;Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland.;Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.;Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland.;Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland..
    Drevets, Wayne C.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Janssen Res & Dev LLC, Titusville, NJ USA..
    Duggirala, Ravi
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Dyer, Thomas D.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Erk, Susanne
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Espeseth, Thomas
    Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Evans, Denis A.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA..
    Fedko, Iryna
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Fernandez, Guillen
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Ferrucci, Luigi
    NIA, Intramural Res Program, Baltimore, MD 21224 USA..
    Fisher, Simon E.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands..
    Fleischman, Debra A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Foroud, Tatiana M.
    Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA..
    Fox, Peter T.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Francks, Clyde
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands..
    Fukunaga, Masaki
    Natl Inst Physiol Sci, Div Cerebral Integrat, Aichi, Japan..
    Gibbs, J. Raphael
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Glahn, David C.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    Gollub, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Harvard Med Sch, Boston, MA USA..
    Goring, Harald H. H.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Green, Robert C.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA..
    Gruber, Oliver
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Guelfi, Sebastian
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Hansell, Narelle K.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Hardy, John
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hashimoto, Ryota
    Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan.;Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka, Japan..
    Hegenscheid, Katrin
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany..
    Heinz, Andreas
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Le Hellard, Stephanie
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Hernandez, Dena G.
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.;German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany..
    Heslenfeld, Dirk J.
    Vrije Univ Amsterdam, Dept Psychol, Amsterdam, Netherlands..
    Ho, Beng-Choon
    Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA..
    Hoekstra, Pieter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hoffmann, Wolfgang
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Holsboer, Florian
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.;HMNC Brain Hlth, Munich, Germany..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany..
    Hosten, Norbert
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Pol, Hilleke E. Hulshoff
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Ikeda, Masashi
    Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi, Japan..
    Ikram, M. Kamran
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore..
    Jack, Clifford R., Jr.
    Mayo Clin, Dept Radiol, Rochester, MN USA..
    Jenldnson, Mark
    Univ Oxford, FMRIB Ctr, Oxford, England..
    Johnson, Robert
    Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA..
    Jonsson, Erik G.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oxford, FMRIB Ctr, Oxford, England..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Kahn, Rene S.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Kanai, Ryota
    Univ Sussex, Sch Psychol, Brighton, E Sussex, England.;UCL, Inst Cognit Neurosci, London, England.;Araya Brain Imaging, Dept Neuroinformat, Tokyo, Japan..
    Kloszewska, Iwona
    Med Univ Lodz, Lodz, Poland..
    Knopman, David S.
    Mayo Clin, Dept Neurol, Rochester, MN USA..
    Kochunov, Peter
    Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA..
    Kwok, John B.
    Neurosci Res Australia, Sydney, NSW, Australia.;UNSW, Sch Med Sci, Sydney, NSW, Australia..
    Lawrie, Stephen M.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    Lemaitre, Herve
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Liu, Xinmin
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Columbia Univ, Med Ctr, New York, NY USA..
    Longo, Dan L.
    NIA, Genet Lab, NIH, Baltimore, MD 21224 USA..
    Longstreth, W. T., Jr.
    Univ Washington, Dept Neurol, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA..
    Lopez, Oscar L.
    Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA..
    Lovestone, Simon
    Univ Oxford, Dept Psychiat, Oxford, England.;Kings Coll London, NIHR Dementia Biomed Res Unit, London, England..
    Martinez, Oliver
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA..
    Martinot, Jean-Luc
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Mattay, Venkata S.
    Lieber Inst Brain Dev, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA..
    McDonald, Colm
    Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland..
    McIntosh, Andrew M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    McMahon, Katie L.
    Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia..
    McMahon, Francis J.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Mecocci, Patrizia
    Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy..
    Melle, Ingrid
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Meyer-Lindenberg, Andreas
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Mohnke, Sebastian
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Morris, Derek W.
    Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland.;Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland.;Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.;Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland.;Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland..
    Mosley, Thomas H.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Muhleisen, Thomas W.
    Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland.;Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany..
    Mueller-Myhsok, Bertram
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.;Munich Cluster Syst Neurol SyNergy, Munich, Germany.;Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England..
    Nalls, Michael A.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK eV, Partner Site Greifswald, Berlin, Germany..
    Nichols, Thomas E.
    Univ Oxford, FMRIB Ctr, Oxford, England.;Univ Warwick, Dept Stat, Coventry, W Midlands, England.;Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England..
    Niessen, Wiro J.
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC, Dept Med Informat, Rotterdam, Netherlands.;Delft Univ Technol, Fac Sci Appl, Delft, Netherlands..
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany..
    Nyberg, Lars
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Ohi, Kazutaka
    Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan..
    Olvera, Rene L.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Ophoff, Roel A.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands.;Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA..
    Pandolfo, Massimo
    Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium..
    Paus, Tomas
    Univ Toronto, Rotman Res Inst, Toronto, ON, Canada.;Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada.;Child Mind Inst, New York, NY USA..
    Pausova, Zdenka
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada.;Univ Toronto, Dept Phys, Toronto, ON, Canada.;Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Pike, G. Bruce
    Univ Calgary, Dept Radiol, Calgary, AB, Canada.;Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada..
    Potkin, Steven G.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA..
    Reppermund, Simone
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;UNSW Med, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Kensington, NSW, Australia..
    Rietschel, Marcella
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Roffman, Joshua L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA..
    Romanczuk-Seiferth, Nina
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Rotter, Jerome I.
    Univ Calif Los Angeles, Med Ctr, Ilnst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat Harbor, Torrance, CA 90509 USA..
    Ryten, Mina
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;Kings Coll London, Dept Med & Mol Genet, London, England..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Sachdev, Perminder S.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia..
    Saykin, Andrew J.
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA.;Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA..
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Schofield, Peter R.
    Neurosci Res Australia, Sydney, NSW, Australia.;UNSW, Sch Med Sci, Sydney, NSW, Australia..
    Sigurdsson, Sigurdur
    Iceland Heart Assoc, Kopavogur, Iceland..
    Simmons, Andy
    Kings Coll London, Inst Psychiat, Dept Neuroimaging, London, England.;Kings Coll London, Biomed Res Ctr Mental Hlth, London, England.;Kings Coll London, Biomed Res Unit Dementia, London, England..
    Singleton, Andrew
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Sisodiya, Sanjay M.
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England..
    Smith, Colin
    Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh, Midlothian, Scotland..
    Smoller, Jordan W.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA..
    Soininen, Hindu.
    Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland.;Kuopio Univ Hosp, Neuroctr Neurol, Kuopio, Finland..
    Srikanth, Velandai
    Peninsula Hlth & Monash Univ, Dept Med, Melbourne, Vic, Australia..
    Steen, Vidar M.
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Stott, David J.
    Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Sussmann, Jessika E.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    Thalamuthu, Anbupalam
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Tiemeier, Henning
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Toga, Arthur W.
    Univ Southern Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA USA..
    Traynor, Bryan J.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Troncoso, Juan
    Johns Hopkins Univ, Brain Resource Ctr, Baltimore, MD USA..
    Turner, Jessica A.
    Georgia State Univ, Atlanta, GA 30303 USA..
    Tzourio, Christophe
    Univ Bordeaux, Institute Neurodegenerat Disorders, CEA, CNRS,UMR 5293, Bordeaux, France..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Hernandez, Maria C. Valdes
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Van der Brug, Marcel
    Genentech Inc, San Francisco, CA 94080 USA..
    Van der Lugt, Aad
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Van der Wee, Nic J. A.
    Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands.;Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, Leiden, Netherlands..
    Van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Van Haren, Neeltje E. M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Van't Ent, Dennis
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Van Tol, Marie Jose
    Univ Groningen, Univ Med Ctr Groningen, Neuroimaging Ctr, Groningen, Netherlands..
    Vardarajan, Badri N.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA..
    Veltman, Dick J.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Vernooij, Meike W.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Walter, Henrik
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Wardlaw, Joanna M.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Wassink, Thomas H.
    Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA..
    Weale, Michael E.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Weinberger, Daniel R.
    Lieber Inst Brain Dev, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA..
    Weiner, Michael W.
    Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94143 USA..
    Wen, Wei
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    White, Tonya
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Wong, Tien Y.
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Wright, Clinton B.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Zielke, H. Ronald
    Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    DeCarli, Charles
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA..
    Schmidt, Helena
    Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    De Craen, Anton J. M.
    Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Wright, Margaret J.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia..
    Launer, Lenore J.
    NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Schumann, Gunter
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA..
    Franke, Barbara
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Debette, Stephanie
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Lieber Inst Brain Dev, Baltimore, MD USA.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France..
    Medland, Sarah E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC, Dept Neurol, Rotterdam, Netherlands..
    Thompson, Paul M.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ Western Sydney, Sch Comp Engn & Math, Parramatta, NSW, Australia..
    Novel genetic loci underlying human intracranial volume identified through genome-wide association2016In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 19, no 12, 1569-1582 p.Article in journal (Refereed)
    Abstract [en]

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

  • 3.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor2017In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, 947-955 p.Article in journal (Refereed)
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

  • 4.
    Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quantifying colocalization: thresholding, void voxels and the H-coef2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, e111983- p.Article in journal (Refereed)
    Abstract [en]

    A critical step in the analysis of images is identifying the area of interest e.g. nuclei. When the nuclei are brighter than the remainder of the image an intensity can be chosen to identify the nuclei. Intensity thresholding is complicated by variations in the intensity of individual nuclei and their intensity relative to their surroundings. To compensate thresholds can be based on local rather than global intensities. By testing local thresholding methods we found that the local mean performed poorly while the Phansalkar method and a new method based on identifying the local background were superior. A new colocalization coefficient, the Hcoef, highlights a number of controversial issues. (i) Are molecular interactions measurable (ii) whether to include voxels without fluorophores in calculations, and (iii) the meaning of negative correlations. Negative correlations can arise biologically (a) because the two fluorophores are in different places or (b) when high intensities of one fluorophore coincide with low intensities of a second. The cases are distinct and we argue that it is only relevant to measure correlation using pixels that contain both fluorophores and, when the fluorophores are in different places, to just report the lack of co-occurrence and omit these uninformative negative correlation. The Hcoef could report molecular interactions in a homogenous medium. But biology is not homogenous and distributions also reflect physico-chemical properties, targeted delivery and retention. The Hcoef actually measures a mix of correlation and co-occurrence, which makes its interpretation problematic and in the absence of a convincing demonstration we advise caution, favouring separate measurements of correlation and of co-occurrence.

  • 5. Adoue, Veronique
    et al.
    Schiavi, Alicia
    Light, Nicholas
    Carlsson 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.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Kwan, Tony
    Caron, Maxime
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wang, Chuan
    Chen, Shu-Huang
    Goodall, Alison H
    Cambien, Francois
    Deloukas, Panos
    Ouwehand, Willem H
    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.
    Pastinen, Tomi
    Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs2014In: Molecular Systems Biology, ISSN 1744-4292, Vol. 10, no 10, 754- p.Article in journal (Refereed)
    Abstract [en]

    Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

  • 6.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015In: BMC Genomics, ISSN 1471-2164, Vol. 16, 390Article in journal (Refereed)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

  • 7.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, e105473- p.Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

  • 8. Ahmad, Shafqat
    et al.
    Rukh, Gull
    Varga, Tibor V.
    Ali, Ashfaq
    Kurbasic, Azra
    Shungin, Dmitry
    Ericson, Ulrika
    Koivula, Robert W.
    Chu, Audrey Y.
    Rose, Lynda M.
    Ganna, Andrea
    Qi, Qibin
    Stancakova, Alena
    Sandholt, Camilla H.
    Elks, Cathy E.
    Curhan, Gary
    Jensen, Majken K.
    Tamimi, Rulla M.
    Allin, Kristine H.
    Jorgensen, Torben
    Brage, Soren
    Langenberg, Claudia
    Aadahl, Mette
    Grarup, Niels
    Linneberg, Allan
    Pare, Guillaume
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Boehnke, Michael
    Hamsten, Anders
    Mohlke, Karen L.
    Pasquale, Louis T.
    Pedersen, Oluf
    Scott, Robert A.
    Ridker, Paul M.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Laakso, Markku
    Hansen, Torben
    Qi, Lu
    Wareham, Nicholas J.
    Chasman, Daniel I.
    Hallmans, Goran
    Hu, Frank B.
    Renstrom, Frida
    Orho-Melander, Marju
    Franks, Paul W.
    Gene x Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry2013In: PLOS Genetics, ISSN 1553-7404, Vol. 9, no 7, e1003607- p.Article in journal (Refereed)
    Abstract [en]

    Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS x physical activity interaction effect estimate (P-interaction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, P-interaction = 0.014 vs. n = 71,611, P-interaction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (P-interaction = 0.003) and the SEC16B rs10913469 (P-interaction = 0.025) variants showed evidence of SNP x physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

  • 9.
    Ahmed Osman, Omneya
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Beier, Sara
    Leibniz Inst Balt Sea Res, Warnemunde, Germany..
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Interactions of Freshwater Cyanobacteria with Bacterial Antagonists2017In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 83, no 7, UNSP e02634Article in journal (Refereed)
    Abstract [en]

    Cyanobacterial and algal mass development, or blooms, have severe effects on freshwater and marine systems around the world. Many of these phototrophs produce a variety of potent toxins, contribute to oxygen depletion, and affect water quality in several ways. Coexisting antagonists, such as cyanolytic bacteria, hold the potential to suppress, or even terminate, such blooms, yet the nature of this interaction is not well studied. We isolated 31 cyanolytic bacteria affiliated with the genera Pseudomonas, Stenotrophomonas, Acinetobacter, and Delftia from three eutrophic freshwater lakes in Sweden and selected four phylogenetically diverse bacterial strains with strong-to-moderate lytic activity. To characterize their functional responses to the presence of cyanobacteria, we performed RNA sequencing (RNA-Seq) experiments on coculture incubations, with an initial predator-prey ratio of 1: 1. Genes involved in central cellular pathways, stress-related heat or cold shock proteins, and antitoxin genes were highly expressed in both heterotrophs and cyanobacteria. Heterotrophs in coculture expressed genes involved in cell motility, signal transduction, and putative lytic activity. L, D-Transpeptidase was the only significantly upregulated lytic gene in Stenotrophomonas rhizophila EK20. Heterotrophs also shifted their central metabolism from the tricarboxylic acid cycle to the glyoxylate shunt. Concurrently, cyanobacteria clearly show contrasting antagonistic interactions with the four tested heterotrophic strains, which is also reflected in the physical attachment to their cells. In conclusion, antagonistic interactions with cyanobacteria were initiated within 24 h, and expression profiles suggest varied responses for the different cyanobacteria and studied cyanolytes. IMPORTANCE Here, we present how gene expression profiles can be used to reveal interactions between bloom-forming freshwater cyanobacteria and antagonistic heterotrophic bacteria. Species-specific responses in both heterotrophs and cyanobacteria were identified. The study contributes to a better understanding of the interspecies cellular interactions underpinning the persistence and collapse of cyanobacterial blooms.

  • 10.
    Ajalloueian, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tavanai, Hossein
    Massuni, Mohammad
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    LeBlanc, Katarina
    Arpanaei, Ayyoob
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Investigation of Human Mesenchymal Stromal Cells Cultured on PLGA orPLGA/Chitosan Electrospun Nanofibers2015In: Journal of Bioprocessing & Biotechniques, ISSN 2155-9821, Vol. 5, no 6, 230Article in journal (Refereed)
    Abstract [en]

    We compared the viability, proliferation, and differentiation of human Mesenchymal Stromal Cells (MSC)after culture on poly(lactic-co-glycolic acid) (PLGA) and PLGA/chitosan (PLGA/CH) hybrid scaffolds. We appliedconventional and emulsion electrospinning techniques, respectively, for the fabrication of the PLGA and PLGA/CH scaffolds. Electrospinning under optimum conditions resulted in an average fiber diameter of 166 ± 33 nmfor the PLGA/CH and 680 ± 175 nm for the PLGA scaffold. The difference between the tensile strength of thePLGA and PLGA/CH nanofibers was not significant, but PLGA/CH showed a significantly lower tensile modulusand elongation at break. However, it should be noted that the extensibility of the PLGA/CH was higher than thatof the nanofibrous scaffolds of pure chitosan. As expected, a higher degree of hydrophilicity was seen with PLGA/CH, as compared to PLGA alone. The biocompatibility of the PLGA and PLGA/CH scaffolds was compared usingMTS assay as well as analysis by scanning electron microscopy and confocal microscopy. The results showed thatboth scaffold types supported the viability and proliferation of human MSC, with significantly higher rates on PLGA/CH nanofibers. Nonetheless, an analysis of gene expression of MSC grown on either PLGA or PLGA/CH showed asimilar differentiation pattern towards bone, nerve and adipose tissues.

  • 11.
    Ajalloueian, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zeiai, Said
    Fossum, Magdalena
    Hilborn, Jöns G.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Constructs of electrospun PLGA, compressed collagen and minced urothelium for minimally manipulated autologous bladder tissue expansion2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 22, 5741-5748 p.Article in journal (Refereed)
    Abstract [en]

    Bladder regeneration based on minced bladder mucosa in vivo expansion is an alternative to in vitro culturing of urothelial cells. Here, we present the design of a hybrid, electrospun poly(lactic-co-glycolide) (PLGA) - plastically compressed (PC) collagen scaffold that could allow in vivo bladder mucosa expansion. Optimisation of electrospinning was performed in order to obtain increased pore sizes and porosity to consolidate the construct and to support neovascularisation and tissue ingrowth. Tensile tests showed an increase in average tensile strength from 0.6 MPa for PC collagen to 3.57 MPa for the hybrid construct. The optimised PLGA support scaffold was placed between two collagen gels, and the minced tissue was distributed either on top or both on top and inside the construct prior to PC; this was then cultured for up to four weeks. Morphology, histology and SEM demonstrated that the construct maintained its integrity throughout cell culture. Cells from minced tissue migrated, expanded and re-organised to a confluent cell layer on the top of the construct after two weeks and formed a multilayered urothelium after four weeks. Cell morphology and phenotype was typical for urothelial mucosa during tissue culture. (C) 2014 Elsevier Ltd. All rights reserved.

  • 12. Albrecht, Eva
    et al.
    Sillanpaa, Elina
    Karrasch, Stefan
    Alves, Alexessander Couto
    Codd, Veryan
    Hovatta, Iiris
    Buxton, Jessica L.
    Nelson, Christopher P.
    Broer, Linda
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangino, Massimo
    Willemsen, Gonneke
    Surakka, Ida
    Ferreira, Manuel A. R.
    Amin, Najaf
    Oostra, Ben A.
    Backmand, Hell M.
    Peltonen, Markku
    Sarna, Seppo
    Rantanen, Taina
    Sipila, Sarianna
    Korhonen, Tellervo
    Madden, Pamela A. F.
    Gieger, Christian
    Jorres, Rudolf A.
    Heinrich, Joachim
    Behr, Juergen
    Huber, Rudolf M.
    Peters, Annette
    Strauch, Konstantin
    Wichmann, H. Erich
    Waldenberger, Melanie
    Blakemore, Alexandra I. F.
    de Geus, Eco J. C.
    Nyholt, Dale R.
    Henders, Anjali K.
    Piirila, Paeivi L.
    Rissanen, Aila
    Magnusson, Patrik K. E.
    Vinuela, Ana
    Pietilainen, Kirsi H.
    Martin, Nicholas G.
    Pedersen, Nancy L.
    Boomsma, Dorret I.
    Spector, Tim D.
    van Duijn, Cornelia M.
    Kaprio, Jaakko
    Samani, Nilesh J.
    Jarvelin, Marjo-Riitta
    Schulz, Holger
    Telomere length in circulating leukocytes is associated with lung function and disease2014In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 43, no 4, 983-992 p.Article in journal (Refereed)
    Abstract [en]

    Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

  • 13. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6519, Vol. 96, no 4, 470-476 p.Article, review/survey (Refereed)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

  • 14. Alfoeldi, Jessica
    et al.
    Di Palma, Federica
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Williams, Christina
    Kong, Lesheng
    Mauceli, Evan
    Russell, Pamela
    Lowe, Craig B.
    Glor, Richard E.
    Jaffe, Jacob D.
    Ray, David A.
    Boissinot, Stephane
    Shedlock, Andrew M.
    Botka, Christopher
    Castoe, Todd A.
    Colbourne, John K.
    Fujita, Matthew K.
    Moreno, Ricardo Godinez
    ten Hallers, Boudewijn F.
    Haussler, David
    Heger, Andreas
    Heiman, David
    Janes, Daniel E.
    Johnson, Jeremy
    de Jong, Pieter J.
    Koriabine, Maxim Y.
    Lara, Marcia
    Novick, Peter A.
    Organ, Chris L.
    Peach, Sally E.
    Poe, Steven
    Pollock, David D.
    de Queiroz, Kevin
    Sanger, Thomas
    Searle, Steve
    Smith, Jeremy D.
    Smith, Zachary
    Swofford, Ross
    Turner-Maier, Jason
    Wade, Juli
    Young, Sarah
    Zadissa, Amonida
    Edwards, Scott V.
    Glenn, Travis C.
    Schneider, Christopher J.
    Losos, Jonathan B.
    Lander, Eric S.
    Breen, Matthew
    Ponting, Chris P.
    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.
    The genome of the green anole lizard and a comparative analysis with birds and mammals2011In: Nature, ISSN 0028-0836, Vol. 477, no 7366, 587-591 p.Article in journal (Refereed)
    Abstract [en]

    The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments(1). Among amniotes, genome sequences are available for mammals and birds(2-4), but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes(2). Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds(5). We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.

  • 15.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, 7743-7748 p.Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 16.
    Ali, Zafar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Klar, Joakim
    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.
    Jameel, Mohammad
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Khan, Kamal
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Fatima, Ambrin
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Dahl, Niklas
    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.
    Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities2016In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 371, 105-111 p.Article in journal (Refereed)
    Abstract [en]

    We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance.

  • 17.
    Allen, Marie
    et al.
    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.
    Bjerke, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Origin of the U87MG glioma cell line: Good news and bad news2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 354, 354re3Article in journal (Refereed)
    Abstract [en]

    Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.

  • 18. Allum, Fiona
    et al.
    Shao, Xiaojian
    Guénard, Frédéric
    Simon, Marie-Michelle
    Busche, Stephan
    Caron, Maxime
    Lambourne, John
    Lessard, Julie
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kwan, Tony
    Ge, Bing
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    McCarthy, Mark I
    Deloukas, Panos
    Richmond, Todd
    Burgess, Daniel
    Spector, Timothy D
    Tchernof, André
    Marceau, Simon
    Lathrop, Mark
    Vohl, Marie-Claude
    Pastinen, Tomi
    Grundberg, Elin
    Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants2015In: Nature Communications, ISSN 2041-1723, Vol. 6, 7211Article in journal (Refereed)
    Abstract [en]

    Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

  • 19.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Welander, Hedvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lendel, Christofer
    KTH, Royal Institute of Technology, Sweden.
    Sigvardson, Jessica
    BioArctic AB, Sweden.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, 421-431 p.Article in journal (Refereed)
  • 20.
    Almlöf, Jonas Carlsson
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, B.
    Maouche, S.
    Göring, H. H. H.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enström, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brocheton, J.
    Proust, C.
    Godefroy, T.
    Sambrook, J. G.
    Jolley, J.
    Crisp-Hihn, A.
    Foad, N.
    Lloyd-Jones, H.
    Stephens, J.
    Gwilliam, R.
    Rice, C. M.
    Hengstenberg, C.
    Samani, N. J.
    Erdmann, J.
    Schunkert, H.
    Pastinen, T.
    Deloukas, P.
    Goodall, A. H.
    Ouwehand, W. H.
    Cambien, F.
    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.
    Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression2012In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 12, e52260- p.Article in journal (Refereed)
    Abstract [en]

    A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

  • 21.
    Almlöf, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Pastinen, Tomi
    Goodall, Alison H
    Cambien, François
    Deloukas, Panos
    Ouwehand, Willem H
    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.
    Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes2014In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 7, e102612- p.Article in journal (Refereed)
    Abstract [en]

    We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10-7 to 9.5×10-89. The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

  • 22.
    Almqvist, Catarina
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Karolinska Univ Hosp, Lung & Allergy Unit, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Olsson, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundholm, Cecilia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sibship and risk of asthma in a total population: A disease comparative approach2016In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, no 4, 1219-1222 p.Article in journal (Refereed)
  • 23.
    Almqvist, Helena
    et al.
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Axelsson, Hanna
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Jafari, Rozbeh
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Dan, Chen
    School of Biological Sciences, Nanyang Technological University.
    Mateus, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haraldsson, Martin
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Larsson, Andreas
    School of Biological Sciences, Nanyang Technological University.
    Martinez-Molina, Daniel
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Nordlund, Pär
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 11040Article in journal (Refereed)
    Abstract [en]

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

  • 24.
    Alonso-Saez, Laura
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zeder, Michael
    Harding, Tommy
    Pernthaler, Jakob
    Lovejoy, Connie
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pedros-Alio, Carlos
    Winter bloom of a rare betaproteobacteriurn in the Arctic Ocean2014In: Frontiers in Microbiology, ISSN 1664-302X, Vol. 5, 425- p.Article in journal (Refereed)
    Abstract [en]

    Extremely low abundance microorganisms (members of the "rare biosphere") are believed to include dormant taxa, which can sporadically become abundant following environmental triggers. Yet, microbial transitions from rare to abundant have seldom been captured in situ, and it is uncertain how widespread these transitions are. A bloom of a single ribotype (>= 99% similarity in the 16S ribosomal RNA gene) of a widespread betaproteobacterium (Janthinobacterium sp.) occurred over 2 weeks in Arctic marine waters. The Janthinobactenum population was not detected microscopically in situ in January and early February, but suddenly appeared in the water column thereafter, eventually accounting for up to 20% of bacterial cells in mid February. During the bloom, this bacterium was detected at open water sites up to 50 km apart, being abundant down to more than 300 m. This event is one of the largest monospecific bacterial blooms reported in polar oceans. It is also remarkable because Betaproteobacteria are typically found only in low abundance in marine environments. In particular, Janthinobacterium were known from non-marine habitats and had previously been detected only in the rare biosphere of seawater samples, including the polar oceans. The Arctic Janthinobacterium formed mucilagenous monolayer aggregates after short (ca. 8 h) incubations, suggesting that biofilm formation may play a role in maintaining rare bacteria in pelagic marine environments. The spontaneous mass occurrence of this opportunistic rare taxon in polar waters during the energy-limited season extends current knowledge of how and when microbial transitions between rare and abundant occur in the ocean.

  • 25.
    Alvarsson, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eklund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Carlsson, Lars
    AstraZeneca R&D.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines2014In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, no 11, 3211-3217 p.Article in journal (Refereed)
    Abstract [en]

    QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.

  • 26.
    Alvarsson, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eklund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Engkvist, Ola
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson, Lars
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Noeske, Tobias
    Ligand-Based Target Prediction with Signature Fingerprints2014In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, no 10, 2647-2653 p.Article in journal (Refereed)
    Abstract [en]

    When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology. This can be done by looking at known target binding profiles of similar compounds using chemical similarity searching. The purpose of this study was to construct and evaluate the performance of chemical fingerprints based on the molecular signature descriptor for performing target binding predictions. For the comparison we used the area under the receiver operating characteristics curve (AUC) complemented with net reclassification improvement (NRI). We created two open source signature fingerprints, a bit and a count version, and evaluated their performance compared to a set of established fingerprints with regards to predictions of binding targets using Tanimoto-based similarity searching on publicly available data sets extracted from ChEMBL. The results showed that the count version of the signature fingerprint performed on par with well-established fingerprints such as ECFP. The count version outperformed the bit version slightly; however, the count version is more complex and takes more computing time and memory to run so its usage should probably be evaluated on a case-by-case basis. The NRI based tests complemented the AUC based ones and showed signs of higher power.

  • 27.
    Alvarsson, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lampa, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Large-scale ligand-based predictive modelling using support vector machines2016In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 8, 39Article in journal (Refereed)
    Abstract [en]

    The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.

  • 28.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agarwal, Prasoon
    Zureigat, Hadil
    Österborg, Anders
    Nahi, Hareth
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, 10213-10224 p.Article in journal (Refereed)
    Abstract [en]

    Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

  • 29. Amemiya, Chris T.
    et al.
    Alfoeldi, Jessica
    Lee, Alison P.
    Fan, Shaohua
    Philippe, Herve
    MacCallum, Iain
    Braasch, Ingo
    Manousaki, Tereza
    Schneider, Igor
    Rohner, Nicolas
    Organ, Chris
    Chalopin, Domitille
    Smith, Jeramiah J.
    Robinson, Mark
    Dorrington, Rosemary A.
    Gerdol, Marco
    Aken, Bronwen
    Biscotti, Maria Assunta
    Barucca, Marco
    Baurain, Denis
    Berlin, Aaron M.
    Blatch, Gregory L.
    Buonocore, Francesco
    Burmester, Thorsten
    Campbell, Michael S.
    Canapa, Adriana
    Cannon, John P.
    Christoffels, Alan
    De Moro, Gianluca
    Edkins, Adrienne L.
    Fan, Lin
    Fausto, Anna Maria
    Feiner, Nathalie
    Forconi, Mariko
    Gamieldien, Junaid
    Gnerre, Sante
    Gnirke, Andreas
    Goldstone, Jared V.
    Haerty, Wilfried
    Hahn, Mark E.
    Hesse, Uljana
    Hoffmann, Steve
    Johnson, Jeremy
    Karchner, Sibel I.
    Kuraku, Shigehiro
    Lara, Marcia
    Levin, Joshua Z.
    Litman, Gary W.
    Mauceli, Evan
    Miyake, Tsutomu
    Mueller, M. Gail
    Nelson, David R.
    Nitsche, Anne
    Olmo, Ettore
    Ota, Tatsuya
    Pallavicini, Alberto
    Panji, Sumir
    Picone, Barbara
    Ponting, Chris P.
    Prohaska, Sonja J.
    Przybylski, Dariusz
    Saha, Nil Ratan
    Ravi, Vydianathan
    Ribeiro, Filipe J.
    Sauka-Spengler, Tatjana
    Scapigliati, Giuseppe
    Searle, Stephen M. J.
    Sharpe, Ted
    Simakov, Oleg
    Stadler, Peter F.
    Stegeman, John J.
    Sumiyama, Kenta
    Tabbaa, Diana
    Tafer, Hakim
    Turner-Maier, Jason
    van Heusden, Peter
    White, Simon
    Williams, Louise
    Yandell, Mark
    Brinkmann, Henner
    Volff, Jean-Nicolas
    Tabin, Clifford J.
    Shubin, Neil
    Schartl, Manfred
    Jaffe, David B.
    Postlethwait, John H.
    Venkatesh, Byrappa
    Di Palma, Federica
    Lander, Eric S.
    Meyer, Axel
    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.
    The African coelacanth genome provides insights into tetrapod evolution2013In: Nature, ISSN 0028-0836, Vol. 496, no 7445, 311-316 p.Article in journal (Refereed)
    Abstract [en]

    The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.

  • 30.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaboli, Ghazal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Igl, Wilmar
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Anna C. V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rivas, Manuel A.
    Daly, Mark J.
    Schmitz, Gerd
    Hicks, Andrew A.
    Meitinger, Thomas
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    van Duijn, Cornelia
    Oostra, Ben
    Pramstaller, Peter P.
    Rudan, Igor
    Wright, Alan F.
    Wilson, James F.
    Campbell, Harry
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 5, 809-820 p.Article in journal (Refereed)
    Abstract [en]

    Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.

  • 31.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Meiring, Tracy L.
    Bunikis, Ignas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindau, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindberg, Julia Hedlund
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustavsson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mbulawa, Zizipho Z. A.
    Williamson, Anna-Lise
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comprehensive profiling of the vaginal microbiome in HIV positive women using massive parallel semiconductor sequencing2014In: Scientific Reports, ISSN 2045-2322, Vol. 4, 4398- p.Article in journal (Refereed)
    Abstract [en]

    Infections by HIV increase the risk of acquiring secondary viral and bacterial infections and methods are needed to determine the spectrum of co-infections for proper treatment. We used rolling circle amplification (RCA) and Ion Proton sequencing to investigate the vaginal microbiome of 20 HIV positive women from South Africa. A total of 46 different human papillomavirus (HPV) types were found, many of which are not detected by existing genotyping assays. Moreover, the complete genomes of two novel HPV types were determined. Abundance of HPV infections was highly correlated with real-time PCR estimates, indicating that the RCA-Proton method can be used for quantification of individual pathogens. We also identified a large number of other viral, bacterial and parasitic co-infections and the spectrum of these co-infections varied widely between individuals. Our method provides rapid detection of a broad range of pathogens and the ability to reconstruct complete genomes of novel infectious agents.

  • 32.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stewart, James B.
    Freyer, Christoph
    Hagström, Erik
    Ingman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Nils-Göran
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ultra-deep sequencing of mouse mitochondrial DNA: Mutational patterns and their origins2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 3, e1002028- p.Article in journal (Refereed)
    Abstract [en]

    Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mtDNA mutation load in the liver of normally- and prematurely-aging mice. Mice that are homozygous for an allele expressing a proof-reading-deficient mtDNA polymerase (mtDNA mutator mice) have 10-times-higher point mutation loads than their wildtype siblings. In addition, the mtDNA mutator mice have increased levels of a truncated linear mtDNA molecule, resulting in decreased sequence coverage in the deleted region. In contrast, circular mtDNA molecules with large deletions occur at extremely low frequencies in mtDNA mutator mice and can therefore not drive the premature aging phenotype. Sequence analysis shows that the main proportion of the mutation load in heterozygous mtDNA mutator mice and their wildtype siblings is inherited from their heterozygous mothers consistent with germline transmission. We found no increase in levels of point mutations or deletions in wildtype C57Bl/6N mice with increasing age, thus questioning the causative role of these changes in aging. In addition, there was no increased frequency of transversion mutations with time in any of the studied genotypes, arguing against oxidative damage as a major cause of mtDNA mutations. Our results from studies of mice thus indicate that most somatic mtDNA mutations occur as replication errors during development and do not result from damage accumulation in adult life.

  • 33.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaghlool, Ammar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wetterbom, Anna
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain2011In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 18, no 12, 1435-1440 p.Article in journal (Refereed)
    Abstract [en]

    Transcriptome sequencing allows for analysis of mature RNAs at base pair resolution. Here we show that RNA-seq can also be used for studying nascent RNAs undergoing transcription. We sequenced total RNA from human brain and liver and found a large fraction of reads (up to 40%) within introns. Intronic RNAs were abundant in brain tissue, particularly for genes involved in axonal growth and synaptic transmission. Moreover, we detected significant differences in intronic RNA levels between fetal and adult brains. We show that the pattern of intronic sequence read coverage is explained by nascent transcription in combination with co-transcriptional splicing. Further analysis of co-transcriptional splicing indicates a correlation between slowly removed introns and alternative splicing. Our data show that sequencing of total RNA provides unique insight into the transcriptional processes in the cell, with particular importance for normal brain development.

  • 34.
    Amrein, Beat A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bauer, Paul
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Duarte, Fernanda
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Janfalk Carlsson, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Naworyta, Agata
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mowbray, Sherry L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Kamerlin, Shina C. L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Expanding the catalytic triad in epoxide hydrolases and related enzymes2015In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 5, no 10, 5702-5713 p.Article in journal (Refereed)
    Abstract [en]

    Potato epoxide hydrolase 1 exhibits rich enantio- and regioselectivity in the hydrolysis of a broadrange of substrates. The enzyme can be engineered to increase the yield of optically pureproducts, as a result of changes in both enantio- and regioselectivity. It is thus highly attractive inbiocatalysis, particularly for the generation of enantiopure fine chemicals and pharmaceuticals.The present work aims to establish the principles underlying the activity and selectivity of theenzyme through a combined computational, structural, and kinetic study, using the substratetrans-stilbene oxide as a model system. Extensive empirical valence bond simulations have beenperformed on the wild-type enzyme together with several experimentally characterized mutants.We are able to computationally reproduce the differences in activities between differentstereoisomers of the substrate, and the effects of mutations in several active-site residues. Inaddition, our results indicate the involvement of a previously neglected residue, H104, which iselectrostatically linked to the general base, H300. We find that this residue, which is highlyconserved in epoxide hydrolases and related hydrolytic enzymes, needs to be in its protonatedform in order to provide charge balance in an otherwise negatively-charged active site. Our datashow that unless the active-site charge balance is correctly treated in simulations, it is notpossible to generate a physically meaningful model for the enzyme that can accurately reproduceactivity and selectivity trends. We also expand our understanding of other catalytic residues,demonstrating in particular the role of a non-canonical residue, E35, as a “backup-base” in theabsence of H300. Our results provide a detailed view of the main factors driving catalysis andregioselectivity in this enzyme, and identify targets for subsequent enzyme design efforts.

  • 35.
    Amrein, Beat Anton
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Steffen-Munsberg, Fabian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Szeler, Ireneusz
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Purg, Miha
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kulkarni, Yashraj
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamerlin, Shina Caroline Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CADEE: Computer-Aided Directed Evolution of Enzymes2017In: IUCrJ, ISSN 0972-6918, E-ISSN 2052-2525, Vol. 4, no 1, 50-64 p.Article in journal (Refereed)
    Abstract [en]

    The tremendous interest in enzymes as biocatalysts has led to extensive work in enzyme engineering, as well as associated methodology development. Here, a new framework for computer-aided directed evolution of enzymes (CADEE) is presented which allows a drastic reduction in the time necessary to prepare and analyze in silico semi-automated directed evolution of enzymes. A pedagogical example of the application of CADEE to a real biological system is also presented in order to illustrate the CADEE workflow.

  • 36.
    Andersson, Jan O
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Double peaks reveal rare diplomonad sex2012In: Trends in Parasitology, ISSN 1471-4922, E-ISSN 1471-5007, Vol. 28, no 2, 46-52 p.Article in journal (Refereed)
    Abstract [en]

    Diplomonads, single-celled eukaryotes, are unusual in having two nuclei. Each nucleus contains two copies of the genome and is transcriptionally active. It has long been assumed that diplomonads in general and Giardia intestinalis in particular are asexual. Genomic and population genetic data now challenge that assumption and extensive allelic sequence heterogeneity has been reported in some but not all examined diplomonad lineages. Here it is argued, in contrast to common assumptions, that allelic differences indicate recent sexual events, and isolates that have divided asexually for many generations have lost their allelic variation owing to within-cell recombination. Consequently, directed studies of the allelic sequence heterogeneity in diverse diplomonad lineages are likely to reveal details about the enigmatic diplomonad sexual life cycle.

  • 37.
    Andersson, Jan O
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Phylogenomic approaches underestimate eukaryotic gene transfer2012In: Mobile Genetic Elements, Vol. 2, no 1, 59-62 p.Article in journal (Refereed)
    Abstract [en]

    Phylogenomic approaches have shown that eukaryotes acquire genes via gene transfer. However, there are two fundamental problems for most of these analyses; only transfers from prokaryotes are analyzed and the screening procedures applied assume that gene transfer is rare for eukaryotes. Directed studies of the impact of gene transfer on diverse eukaryotic lineages produce a much more complex picture. Many gene families are affected by multiple transfer events from prokaryotes to eukaryotes, and transfers between eukaryotic lineages are routinely detected. This suggests that the assumptions applied in traditional phylogenomic approaches are too naïve and result in many false negatives. This issue was recently addressed by identifying and analyzing the evolutionary history of 49 patchily distributed proteins shared between Dictyostelium and bacteria. The vast majority of these gene families showed strong indications of gene transfers, both between and within the three domains of life. However, only one of these was previously reported as a gene transfer candidate using a traditional phylogenomic approach. This clearly illustrates that more realistic assumptions are urgently needed in genome-wide studies of eukaryotic gene transfer.

  • 38.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    How selective sweeps in domestic animals provide new insight into biological mechanisms2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 271, no 1, 1-14 p.Article, review/survey (Refereed)
    Abstract [en]

    Genetic studies of domestic animals are of general interest because there is more phenotypic diversity to explore in these species than in any experimental organism. Some mutations with favourable phenotypic effects have been highly enriched and gone through selective sweeps during the process of domestication and selective breeding. Three such selective sweeps are described in this review. All three mutations are intronic and constitute cis-acting regulatory mutations. Two of the mutations constitute structural changes (one duplication and one copy number expansion). These examples illustrate a general trend that noncoding mutations and structural changes have both contributed significantly to the evolution of phenotypic diversity in domestic animals. How the molecular characterization of trait loci in domestic animals can provide new basic knowledge of relevance for human medicine is discussed.

  • 39.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molecular consequences of animal breeding2013In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 23, no 3, 295-301 p.Article in journal (Refereed)
    Abstract [en]

    The phenotypic diversity in domestic animals provides a unique opportunity to study genotype-phenotype relationships. The identification of causal mutations provides an insight into what types of mutations have contributed to phenotypic evolution in domestic animals. Whole genome sequencing has revealed that fixation of null alleles that inactivate genes, which are essential under natural conditions but disadvantageous on the farm, has not been a common mechanism for genetic adaptation in domestic animals. Numerous examples have been revealed where structural changes cause specific phenotypic effects by altering transcriptional regulation. An emerging feature is also the evolution of alleles by the accumulation of several consecutive mutations which affect gene function.

  • 40.
    Andersson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish University of Agricultural Sciences.
    Archibald, Alan L.
    Bottema, Cynthia D.
    Brauning, Rudiger
    Burgess, Shane C.
    Burt, Dave W.
    Casas, Eduardo
    Cheng, Hans H.
    Clarke, Laura
    Couldrey, Christine
    Dalrymple, Brian P.
    Elsik, Christine G.
    Foissac, Sylvain
    Giuffra, Elisabetta
    Groenen, Martien A.
    Hayes, Ben J.
    Huang, LuSheng S.
    Khatib, Hassan
    Kijas, James W.
    Kim, Heebal
    Lunney, Joan K.
    McCarthy, Fiona M.
    McEwan, John C.
    Moore, Stephen
    Nanduri, Bindu
    Notredame, Cedric
    Palti, Yniv
    Plastow, Graham S.
    Reecy, James M.
    Rohrer, Gary A.
    Sarropoulou, Elena
    Schmidt, Carl J.
    Silverstein, Jeffrey
    Tellam, Ross L.
    Tixier-Boichard, Michele
    Tosser-Klopp, Gwenola
    Tuggle, Christopher K.
    Vilkki, Johanna
    White, Stephen N.
    Zhao, Shuhong
    Zhou, Huaijun
    Coordinated international action to accelerate genome-to-phenome with FAANG, the Functional Annotation of Animal Genomes project2015In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16Article in journal (Refereed)
    Abstract [en]

    We describe the organization of a nascent international effort, the Functional Annotation of Animal Genomes (FAANG) project, whose aim is to produce comprehensive maps of functional elements in the genomes of domesticated animal species.

  • 41.
    Andersson, Marlene
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Jia, Qiupin
    Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, P.R. China..
    Abella, Ana
    ETSI de Caminos and Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain..
    Lee, Xiau-Yeen
    ETSI de Caminos and Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain..
    Landreh, Michael
    Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK..
    Purhonen, Pasi
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden..
    Hebert, Hans
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden..
    Tenje, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Biomedical Engineering, Lund University, Lund, Sweden..
    Robinson, Carol V.
    Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK..
    Meng, Qing
    Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, P.R. China..
    Plaza, Gustavo R.
    ETSI de Caminos and Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain..
    Johansson, Jan
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.; Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.; Karolinska Institutet.
    Rising, Anna
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.;Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.; Karolinska Institutet.
    Biomimetic spinning of artificial spider silk from a chimeric minispidroin2017In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, no 3, 262-264 p.Article in journal (Refereed)
    Abstract [en]

    Herein we present a chimeric recombinant spider silk protein (spidroin) whose aqueous solubility equals that of native spider silk dope and a spinning device that is based solely on aqueous buffers, shear forces and lowered pH. The process recapitulates the complex molecular mechanisms that dictate native spider silk spinning and is highly efficient; spidroin from one liter of bacterial shake-flask culture is enough to spin a kilometer of the hitherto toughest as-spun artificial spider silk fiber.

  • 42.
    Andersson, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Konrad, Anna
    Ashok, Nikhil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hober, Sophia
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Antibodies Biotinylated Using a Synthetic Z-domain from Protein A Provide Stringent In Situ Protein Detection2013In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 61, no 11, 773-784 p.Article in journal (Refereed)
    Abstract [en]

    Antibody-based protein profiling on a global scale using immunohistochemistry constitutes an emerging strategy for mapping of the human proteome, which is crucial for an increased understanding of biological processes in the cell. Immunohistochemistry is often performed indirectly using secondary antibodies for detection, with the benefit of signal amplification. Direct immunohistochemistry instead brings the advantage of multiplexing; however, it requires labeling of the primary antibody. Many antibody-labeling kits do not specifically target IgG and may therefore cause labeling of stabilizing proteins present in the antibody solution. A new conjugation method has been developed that utilizes a modified Z-domain of protein A (ZBPA) to specifically target the Fc part of antibodies. The aim of the present study was to compare the ZBPA conjugation method and a commercially available labeling kit, Lightning-Link, for in situ protein detection. Fourteen antibodies were biotinylated with each method and stained using immunohistochemistry. For all antibodies tested, ZBPA biotinylation resulted in distinct immunoreactivity without off-target staining, regardless of the presence of stabilizing proteins in the buffer, whereas the majority of the Lightning-Link biotinylated antibodies displayed a characteristic pattern of nonspecific staining. We conclude that biotinylated ZBPA domain provides a stringent method for antibody biotinylation, advantageous for in situ protein detection in tissues.

  • 43.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Danielsson, Angelika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlen, Mathias
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues2014In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 12, e115911- p.Article in journal (Refereed)
    Abstract [en]

    Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics. Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.

  • 44.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundberg, Mårten
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Pristovsek, Nusa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ibrahim, Ahmed
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Natl Res Ctr, Div Pharmaceut Ind, Dokki 12622, Egypt..
    Jonsson, Philip
    Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Human Oncol & Pathogenesis Program, New York, NY 10065 USA..
    Katona, Borbala
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Clausson, Carl-Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramström, Margareta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Williams, Cecilia
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden..
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Insufficient antibody validation challenges oestrogen receptor beta research2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 15840Article in journal (Refereed)
    Abstract [en]

    The discovery of oestrogen receptor beta (ER beta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ER alpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ER beta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ER beta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ER beta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

  • 45.
    Ankarklev, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franzen, Oscar
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. KISP, Sci Life Lab, S-17165 Solna, Sweden..
    Peirasmaki, Dimitra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jerlstrom-Hultqvist, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lebbad, Marianne
    Publ Hlth Agcy Sweden, Dept Microbiol, SE-17182 Solna, Sweden..
    Andersson, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Bjorn
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden.;KISP, Sci Life Lab, S-17165 Solna, Sweden..
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comparative genomic analyses of freshly isolated Giardia intestinalis assemblage A isolates2015In: BMC Genomics, ISSN 1471-2164, Vol. 16, 697Article in journal (Refereed)
    Abstract [en]

    Background: The diarrhea-causing protozoan Giardia intestinalis makes up a species complex of eight different assemblages (A-H), where assemblage A and B infect humans. Comparative whole-genome analyses of three of these assemblages have shown that there is significant divergence at the inter-assemblage level, however little is currently known regarding variation at the intra-assemblage level. We have performed whole genome sequencing of two sub-assemblage AII isolates, recently axenized from symptomatic human patients, to study the biological and genetic diversity within assemblage A isolates. Results: Several biological differences between the new and earlier characterized assemblage A isolates were identified, including a difference in growth medium preference. The two AII isolates were of different sub-assemblage types (AII-1 [AS175] and AII-2 [AS98]) and showed size differences in the smallest chromosomes. The amount of genetic diversity was characterized in relation to the genome of the Giardia reference isolate WB, an assemblage AI isolate. Our analyses indicate that the divergence between AI and AII is approximately 1 %, represented by similar to 100,000 single nucleotide polymorphisms (SNP) distributed over the chromosomes with enrichment in variable genomic regions containing surface antigens. The level of allelic sequence heterozygosity (ASH) in the two AII isolates was found to be 0.25-0.35 %, which is 25-30 fold higher than in the WB isolate and 10 fold higher than the assemblage AII isolate DH (0.037 %). 35 protein-encoding genes, not found in the WB genome, were identified in the two AII genomes. The large gene families of variant-specific surface proteins (VSPs) and high cysteine membrane proteins (HCMPs) showed isolate-specific divergences of the gene repertoires. Certain genes, often in small gene families with 2 to 8 members, localize to the variable regions of the genomes and show high sequence diversity between the assemblage A isolates. One of the families, Bactericidal/ Permeability Increasing-like protein (BPIL), with eight members was characterized further and the proteins were shown to localize to the ER in trophozoites. Conclusions: Giardia genomes are modular with highly conserved core regions mixed up by variable regions containing high levels of ASH, SNPs and variable surface antigens. There are significant genomic variations in assemblage A isolates, in terms of chromosome size, gene content, surface protein repertoire and gene polymorphisms and these differences mainly localize to the variable regions of the genomes. The large genetic differences within one assemblage of G. intestinalis strengthen the argument that the assemblages represent different Giardia species.

  • 46. Antolín, Roberto
    et al.
    Nettelblad, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gorjanc, Gregor
    Money, Daniel
    Hickey, John M.
    A hybrid method for the imputation of genomic data in livestock populations2017In: Genetics Selection Evolution, ISSN 0999-193X, E-ISSN 1297-9686, Vol. 49, 30Article in journal (Refereed)
  • 47.
    Anvari, Ebrahim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wang, Xuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, 40-46 p.Article in journal (Refereed)
    Abstract [en]

    Background. It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1-receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance. Methods. Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high-fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests. Results. Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet-induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice. Conclusion. Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction.

  • 48.
    Anvari, Ebrahim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wikström, Per
    Walum, Erik
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice2015In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 49, no 11, 1308-1318 p.Article in journal (Refereed)
    Abstract [en]

    In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose-induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS-mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes.

  • 49. Arase, Mayu
    et al.
    Horiguchi, Kana
    Ehata, Shogo
    Morikawa, Masato
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tsutsumi, Shuichi
    Aburatani, Hiroyuki
    Miyazono, Kohei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koinuma, Daizo
    Transforming growth factor-beta-induced lncRNA-Smad7 inhibits apoptosis of mouse breast cancer JygMC(A) cells2014In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 105, no 8, 974-982 p.Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor (TGF)-beta exhibits both pro-apoptotic and anti-apoptotic effects on epithelial cells in a context-dependent manner. The anti-apoptotic function of TGF-beta is mediated by several downstream regulatory mechanisms, and has been implicated in the tumor-progressive phenotype of breast cancer cells. We conducted RNA sequencing of mouse mammary gland epithelial (NMuMG) cells and identified a long non-coding RNA, termed lncRNA-Smad7, which has anti-apoptotic functions, as a target of TGF-beta lncRNA-Smad7 was located adjacent to the mouse Smad7 gene, and its expression was induced by TGF-beta in all of the mouse mammary gland epithelial cell lines and breast cancer cell lines that we evaluated. Suppression of lncRNA-Smad7 expression cancelled the anti-apoptotic function of TGF-beta In contrast, forced expression of lncRNA-Smad7 rescued apoptosis induced by a TGF-beta type I receptor kinase inhibitor in the mouse breast cancer cell line JygMC(A). The anti-apoptotic effect of lncRNA-Smad7 appeared to occur independently of the transcriptional regulation by TGF-beta of anti-apoptotic DEC1 and pro-apoptotic Bim proteins. Small interfering RNA for lncRNA-Smad7 did not alter the process of TGF-beta-induced epithelial-mesenchymal transition, phosphorylation of Smad2 or expression of the Smad7 gene, suggesting that the contribution of this lncRNA to TGF-beta functions may be restricted to apoptosis. Our findings suggest a complex mechanism for regulating the anti-apoptotic and tumor-progressive aspects of TGF-beta signaling.

  • 50.
    Arendt, Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cairns, K. M.
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Fac Sci, Sydney, NSW, Australia..
    Ballard, J. W. O.
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Fac Sci, Sydney, NSW, Australia..
    Savolainen, P.
    Royal Inst Technol KTH, Sch Biotechnol, Sci Life Lab, Solna, Sweden..
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Diet adaptation in dog reflects spread of prehistoric agriculture2016In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 117, no 5, 301-306 p.Article in journal (Refereed)
    Abstract [en]

    Adaptations allowing dogs to thrive on a diet rich in starch, including a significant AMY2B copy number gain, constituted a crucial step in the evolution of the dog from the wolf. It is however not clear whether this change was associated with the initial domestication, or represents a secondary shift related to the subsequent development of agriculture. Previous efforts to study this process were based on geographically limited data sets and low-resolution methods, and it is therefore not known to what extent the diet adaptations are universal among dogs and whether there are regional differences associated with alternative human subsistence strategies. Here we use droplet PCR to investigate worldwide AMY2B copy number diversity among indigenous as well as breed dogs and wolves to elucidate how a change in dog diet was associated with the domestication process and subsequent shifts in human subsistence. We find that AMY2B copy numbers are bimodally distributed with high copy numbers (median 2n(AMY2B)=11) in a majority of dogs but no, or few, duplications (median 2n(AMY2B)=3) in a small group of dogs originating mostly in Australia and the Arctic. We show that this pattern correlates geographically to the spread of prehistoric agriculture and conclude that the diet change may not have been associated with initial domestication but rather the subsequent development and spread of agriculture to most, but not all regions of the globe.

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