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  • 1. Alex, Amal
    et al.
    Piano, Valentina
    Polley, Soumitra
    Stuiver, Marchel
    Voss, Stephanie
    Ciossani, Giuseppe
    Overlack, Katharina
    Voss, Beate
    Wohlgemuth, Sabine
    Petrovic, Arsen
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Selenko, Philipp
    Musacchio, Andrea
    Maffini, Stefano
    Electroporated recombinant proteins as tools for in vivo functional complementation, imaging and chemical biology2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e48287Article in journal (Refereed)
    Abstract [en]

    Delivery of native or chemically modified recombinant proteins into mammalian cells shows promise for functional investigations and various technological applications, but concerns that sub-cellular localization and functional integrity of delivered proteins may be affected remain high. Here, we surveyed batch electroporation as a delivery tool for single polypeptides and multi-subunit protein assemblies of the kinetochore, a spatially confined and well-studied subcellular structure. After electroporation into human cells, recombinant fluorescent Ndc80 and Mis12 multi-subunit complexes exhibited native localization, physically interacted with endogenous binding partners, and functionally complemented depleted endogenous counterparts to promote mitotic checkpoint signaling and chromosome segregation. Farnesylation is required for kinetochore localization of the Dynein adaptor Spindly. In cells with chronically inhibited farnesyl transferase activity, in vitro farnesylation and electroporation of recombinant Spindly faithfully resulted in robust kinetochore localization. Our data show that electroporation is well-suited to deliver synthetic and chemically modified versions of functional proteins, and, therefore, constitutes a promising tool for applications in chemical and synthetic biology.

  • 2.
    Allalou, Amin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Wu, Yuelong
    Ghannad-Rezaie, Mostafa
    Eimon, Peter M.
    Yanik, Mehmet Fatih
    Automated deep-phenotyping of the vertebrate brain2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23379Article in journal (Refereed)
  • 3.
    Anderl, Ines
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    New ways to make a blood cell2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e06877Article in journal (Other academic)
  • 4.
    Angiolini, Francesca
    et al.
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy;GSK Vaccines Srl, Siena, Italy.
    Belloni, Elisa
    CNR, Ist Genet Mol, Pavia, Italy.
    Giordano, Marco
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Campioni, Matteo
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Forneris, Federico
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Paola, Paronetto Maria
    Univ Roma Foro Italico, Dept Movement Human & Hlth Sci, Rome, Italy.
    Lupia, Michela
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Brandas, Chiara
    CNR, Ist Genet Mol, Pavia, Italy.
    Pradella, Davide
    CNR, Ist Genet Mol, Pavia, Italy;Univ Pavia, Pavia, Italy.
    Di Matteo, Anna
    CNR, Ist Genet Mol, Pavia, Italy.
    Giampietro, Costanza
    FIRC Inst Mol Oncol, Milan, Italy;Swiss Fed Inst Technol, Dept Mech & Proc Engn, Lab Thermodynam Emerging Technol, Zurich, Switzerland.
    Jodice, Giovanna
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Luise, Chiara
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Bertalot, Giovanni
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Freddi, Stefano
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Malinverno, Matteo
    FIRC Inst Mol Oncol, Milan, Italy.
    Irimia, Manuel
    Barcelona Inst Sci & Technol, Ctr Genom Regulat, Barcelona, Spain;Univ Pompeu Fabra, Barcelona, Spain;Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain.
    Moulton, Jon D.
    Gene Tools LLC, Philomath, OR USA.
    Summerton, James
    Gene Tools LLC, Philomath, OR USA.
    Chiapparino, Antonella
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Ghilardi, Carmen
    IRCCS, Ist Ric Farmacol Mario Negri, Lab Biol & Treatment Metastasis, Milan, Italy.
    Giavazzi, Raffaella
    IRCCS, Ist Ric Farmacol Mario Negri, Lab Biol & Treatment Metastasis, Milan, Italy.
    Nyqvist, Daniel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.
    Gabellini, Davide
    IRCCS, San Raffaele Sci Inst, Div Genet & Cell Biol, Milan, Italy.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. FIRC Inst Mol Oncol, Milan, Italy.
    Cavallaro, Ugo
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Ghigna, Claudia
    CNR, Ist Genet Mol, Pavia, Italy.
    A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e44305Article in journal (Refereed)
    Abstract [en]

    The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

  • 5.
    Baier, Florian
    et al.
    Univ British Columbia, Michael Smith Lab, Vancouver, BC, Canada.
    Hong, Nansook
    Australian Natl Univ, Res Sch Chem, Canberra, ACT, Australia.
    Yang, Gloria
    Univ British Columbia, Michael Smith Lab, Vancouver, BC, Canada.
    Pabis, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Miton, Charlotte M.
    Univ British Columbia, Michael Smith Lab, Vancouver, BC, Canada.
    Barrozo, Alexandre
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Carr, Paul D.
    Australian Natl Univ, Res Sch Chem, Canberra, ACT, Australia.
    Kamerlin, Shina C. Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Jackson, Colin J.
    Australian Natl Univ, Res Sch Chem, Canberra, ACT, Australia.
    Tokuriki, Nobuhiko
    Univ British Columbia, Michael Smith Lab, Vancouver, BC, Canada.
    Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e40789Article in journal (Refereed)
    Abstract [en]

    Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-beta-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.

  • 6. Barrio, Alvaro Martinez
    et al.
    Lamichhaney, Sangeet
    Fan, Guangyi
    Rafati, Nima
    Pettersson, Mats
    Zhang, He
    Dainat, Jacques
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hoppner, Marc
    Jern, Patric
    Martin, Marcel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Liu, Xin
    Chen, Wenbin
    Liang, Xinming
    Shi, Chengcheng
    Fu, Yuanyuan
    Ma, Kailong
    Zhan, Xiao
    Feng, Chungang
    Gustafson, Ulla
    Rubin, Carl-Johan
    Almen, Markus Sallman
    Blass, Martina
    Casini, Michele
    Folkvord, Arild
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology.
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology.
    Lee, Simon Ming-Yuen
    Xu, Xun
    Andersson, Leif
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e12081Article in journal (Refereed)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 7.
    Bentham, James
    et al.
    Imperial Coll London, London, England..
    Di Cesare, Mariachiara
    Imperial Coll London, London, England.;Middlesex Univ, London N17 8HR, England..
    Stevens, Gretchen A.
    WHO, Geneva, Switzerland..
    Zhou, Bin
    Imperial Coll London, London, England..
    Bixby, Honor
    Imperial Coll London, London, England..
    Cowan, Melanie
    WHO, Geneva, Switzerland..
    Fortunato, Lea
    Imperial Coll London, London, England..
    Bennett, James E.
    Imperial Coll London, London, England.;Imperial Coll London, London, England..
    Danaei, Goodarz
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    Hajifathalian, Kaveh
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    Lu, Yuan
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    Riley, Leanne M.
    WHO, Geneva, Switzerland..
    Laxmaiah, Avula
    Indian Council Med Res, New Delhi, India..
    Kontis, Vasilis
    Imperial Coll London, London, England..
    Paciorek, Christopher J.
    Univ Calif Berkeley, Berkeley, CA 94720 USA..
    Riboli, Elio
    Imperial Coll London, London, England..
    Ezzati, Majid
    Imperial Coll London, London, England.;WHO Collaborating Ctr NCD Surveillance & Epidemio, London, England..
    Abdeen, Ziad A.
    Al Quds Univ, Jerusalem, Israel..
    Hamid, Zargar Abdul
    Ctr Diabet & Endocrine Care, Bengaluru, Karnataka, India..
    Abu-Rmeileh, Niveen M.
    Birzeit Univ, Birzeit, Israel..
    Acosta-Cazares, Benjamin
    Inst Mexicano Seguro Social, Mexico City, DF, Mexico..
    Adams, Robert
    Univ Adelaide, Adelaide, SA 5005, Australia..
    Aekplakorn, Wichai
    Mahidol Univ, Bangkok 10700, Thailand..
    Aguilar-Salinas, Carlos A.
    Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico..
    Agyemang, Charles
    Univ Amsterdam, NL-1012 WX Amsterdam, Netherlands..
    Ahmadvand, Alireza
    Noncommunicable Dis Res Ctr, Tehran, Iran..
    Ahrens, Wolfgang
    Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany..
    Al-Hazzaa, Hazzaa M.
    King Saud Univ, Riyadh 11451, Saudi Arabia..
    Al-Othman, Amani Rashed
    Kuwait Inst Sci Res, Safat, Kuwait..
    Al Raddadi, Rajaa
    Minist Hlth, Riyadh, Saudi Arabia..
    Ali, Mohamed M.
    WHO, Reg Off Eastern Mediterranean, Cairo, Egypt..
    Alkerwi, Ala'a
    Luxembourg Inst Hlth, Strassen, Luxembourg..
    Alvarez-Pedrerol, Mar
    ISGlobal Ctr Res Environm Epidemiol, Barcelona, Spain..
    Aly, Eman
    WHO, Reg Off Eastern Mediterranean, Cairo, Egypt..
    Amouyel, Philippe
    Lille Univ & Hosp, Lille, France..
    Amuzu, Antoinette
    London Sch Hyg & Trop Med, London, England..
    Andersen, Lars Bo
    Sogn & Fjordane Univ Coll, Sogndal, Norway..
    Anderssen, Sigmund A.
    Norwegian Sch Sport Sci, Oslo, Norway..
    Anjana, Ranjit Mohan
    Madras Diabet Res Fdn, Madras, Tamil Nadu, India..
    Aounallah-Skhiri, Hajer
    Natl Inst Publ Hlth, Tunis, Tunisia..
    Ariansen, Inger
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Aris, Tahir
    Minist Hlth Malaysia, Putrajaya, Malaysia..
    Arlappa, Nimmathota
    Indian Council Med Res, New Delhi, India..
    Arveiler, Dominique
    Univ Strasbourg, Strasbourg, France.;Strasbourg Univ Hosp, Strasbourg, France..
    Assah, Felix K.
    Univ Yaounde I, Yaounde, Cameroon..
    Avdicova, Maria
    Reg Author Publ Hlth, Banska Bystrica, Slovakia..
    Azizi, Fereidoun
    Shahid Beheshti Univ Med Sci, Tehran, Iran..
    Babu, Bontha V.
    Indian Council Med Res, New Delhi, India..
    Bahijri, Suhad
    King Abdulaziz Univ, Jeddah, Saudi Arabia..
    Balakrishna, Nagalla
    Indian Council Med Res, New Delhi, India..
    Bandosz, Piotr
    Med Univ Gdansk, Gdansk, Poland..
    Banegas, Jose R.
    Univ Autonoma Madrid, E-28049 Madrid, Spain..
    Barbagallo, Carlo M.
    Univ Palermo, I-90133 Palermo, Italy..
    Barcelo, Alberto
    Pan Amer Hlth Org, Washington, DC USA..
    Barkat, Amina
    Mohammed V Univ Rabat, Rabat, Morocco..
    Barros, Mauro V.
    Univ Pernambuco, Recife, PE, Brazil..
    Bata, Iqbal
    Dalhousie Univ, Halifax, NS B3H 3J5, Canada..
    Batieha, Anwar M.
    Jordan Univ Sci & Technol, Irbid, Jordan..
    Batista, Rosangela L.
    Univ Fed Maranhao, Sao Luis, MA, Brazil..
    Baur, Louise A.
    Univ Sydney, Sydney, NSW 2006, Australia..
    Beaglehole, Robert
    Univ Auckland, Auckland 1, New Zealand..
    Ben Romdhane, Habiba
    Univ Tunis El Manar, Tunis, Tunisia..
    Benet, Mikhail
    Univ Med Sci, Havana, Cuba..
    Bernabe-Ortiz, Antonio
    Univ Peruana Cayetano Heredia, Lima, Peru..
    Bernotine, Gailute
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Bettiol, Heloisa
    Univ Sao Paulo, BR-05508 Sao Paulo, Brazil..
    Bhagyalaxmi, Aroor
    BJ Med Coll, Ahmadabad, Gujarat, India..
    Bharadwaj, Sumit
    Chirayu Med Coll, Bhopal, Madhya Pradesh, India..
    Bhargava, Santosh K.
    Sunder Lal Jain Hosp, Delhi, India..
    Bhatti, Zaid
    Aga Khan Univ, Karachi, Pakistan..
    Bhutta, Zulfiqar A.
    Hosp Sick Children, Toronto, ON M5G 1X8, Canada..
    Bi, Hongsheng
    Shandong Univ Tradit Chinese Med, Jinan, Lixia, Peoples R China..
    Bi, Yufang
    Shanghai Jiao Tong Univ, Sch Med, Shanghai 200030, Peoples R China..
    Bjerregaard, Peter
    Univ Southern Denmark, Odense, Denmark.;Univ Greenland, Manutooq, Greenland..
    Bjertness, Espen
    Univ Oslo, N-0316 Oslo, Norway..
    Bjertness, Marius B.
    Univ Oslo, N-0316 Oslo, Norway..
    Bjorkelund, Cecilia
    Univ Gothenburg, Gothenburg, Sweden..
    Blokstra, Anneke
    Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands..
    Bo, Simona
    Univ Turin, I-10124 Turin, Italy..
    Bobak, Martin
    UCL, London WC1E 6BT, England..
    Boddy, Lynne M.
    Liverpool John Moores Univ, Liverpool L3 5UX, Merseyside, England..
    Boehm, Bernhard O.
    Nanyang Technol Univ, Singapore 639798, Singapore..
    Boeing, Heiner
    German Inst Human Nutr, Nuthetal, Germany..
    Boissonnet, Carlos P.
    CEMIC, Buenos Aires, DF, Argentina..
    Bongard, Vanina
    Univ Toulouse, Sch Med, Toulouse, France..
    Bovet, Pascal
    Minist Hlth, Victoria, Seychelles.;Univ Lausanne, CH-1015 Lausanne, Switzerland..
    Braeckman, Lutgart
    Univ Ghent, B-9000 Ghent, Belgium..
    Bragt, Marjolijn C. E.
    FrieslandCampina, Singapore, Singapore..
    Brajkovich, Imperia
    Cent Univ Venezuela, Caracas, Capital Distric, Venezuela..
    Branca, Francesco
    WHO, Geneva, Switzerland..
    Breckenkamp, Juergen
    Univ Bielefeld, Bielefeld, Germany..
    Brenner, Hermann
    German Canc Res Ctr, Heidelberg, Germany..
    Brewster, Lizzy M.
    Univ Amsterdam, NL-1012 WX Amsterdam, Netherlands..
    Brian, Garry R.
    Fred Hollows Fdn New Zealand, Dunedin, New Zealand..
    Bruno, Graziella
    Univ Turin, I-10124 Turin, Italy..
    Bueno-de-Mesquita, H. B(as)
    Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands..
    Bugge, Anna
    Univ Southern Denmark, Odense, Denmark..
    Burns, Con
    Cork Inst Technol, Bishopstown, Cork, Ireland..
    Cabrera de Leon, Antonio
    Univ La Laguna, E-38207 San Cristobal la Laguna, Spain..
    Cacciottolo, Joseph
    Univ Malta, Msida, Msd, Malta..
    Cama, Tilema
    Minist Hlth, Nukualofa, Tonga..
    Cameron, Christine
    Canadian Fitness & Lifestyle Res Inst, Ottawa, ON, Canada..
    Camolas, Jose
    CHLN, Hosp Santa Maria, Lisbon, Portugal..
    Can, Gunay
    Istanbul Univ, Fatih Istanbul, Turkey..
    Candido, Ana Paula C.
    Univ Fed Juiz De Fora, Juiz De Fora, MG, Brazil..
    Capuano, Vincenzo
    Cardiol Mercato S Severino, Mercato San Severino, SA, Italy..
    Cardoso, Viviane C.
    Univ Sao Paulo, BR-05508 Sao Paulo, Brazil..
    Carlsson, Axel C.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Carvalho, Maria J.
    Univ Porto, P-4100 Oporto, Portugal..
    Casanueva, Felipe F.
    Univ Santiago de Compostela, Santiago De Compostela, Spain..
    Casas, Juan-Pablo
    UCL, London WC1E 6BT, England..
    Caserta, Carmelo A.
    Assoc Calabrese Epatol, Pellaro, RC, Italy..
    Chamukuttan, Snehalatha
    India Diabet Res Fdn, Madras, Tamil Nadu, India..
    Chan, Angelique W.
    Duke NUS Grad Med Sch, Singapore, Singapore..
    Chan, Queenie
    Imperial Coll London, London, England..
    Chaturvedi, Himanshu K.
    Natl Inst Med Stat, New Delhi, India..
    Chaturvedi, Nishi
    UCL, London WC1E 6BT, England..
    Chen, Chien-Jen
    Acad Sinica, Taipei, Taiwan..
    Chen, Fangfang
    Capital Inst Pediat, Beijing, Peoples R China..
    Chen, Huashuai
    Duke Univ, Durham, NC 27706 USA..
    Chen, Shuohua
    Kailun Gen Hosp, Tangshan, Hebei, Peoples R China..
    Chen, Zhengming
    Univ Oxford, Oxford OX1 2JD, England..
    Cheng, Ching-Yu
    Duke NUS Grad Med Sch, Singapore, Singapore..
    Chetrit, Angela
    Gertner Inst Epidemiol & Hlth Policy Res, Tel Aviv, Israel..
    Chiolero, Arnaud
    Univ Lausanne Hosp, Lausanne, Switzerland..
    Chiou, Shu-Ti
    Minist Hlth & Welfare, Taipei, Taiwan..
    Chirita-Emandi, Adela
    Victor Babes Univ Med & Pharma Timisoara, Timisoara, Romania..
    Cho, Belong
    Seoul Natl Univ, Coll Med, Seoul 151, South Korea..
    Cho, Yumi
    Korea Ctr Dis Control & Prevnt, Daejeon, Chungcheongbuk, South Korea..
    Christensen, Kaare
    Univ Southern Denmark, Odense, Denmark..
    Chudek, Jerzy
    Med Univ Silesia, Katowice, Poland..
    Cifkova, Renata
    Charles Univ Prague, Prague, Czech Republic..
    Claessens, Frank
    Katholieke Univ Leuven, Leuven, Belgium..
    Clays, Els
    Univ Ghent, B-9000 Ghent, Belgium..
    Concin, Hans
    Agency Prevent & Social Med, Bregenz, Austria..
    Cooper, Cyrus
    Univ Southampton, Southampton SO9 5NH, Hants, England..
    Cooper, Rachel
    UCL, London WC1E 6BT, England..
    Coppinger, Tara C.
    Cork Inst Technol, Bishopstown, Cork, Ireland..
    Costanzo, Simona
    IRCCS, Ist Neurol Mediterraneo Neuromed, Milan, Italy..
    Cottel, Dominique
    Inst Pasteur, Lille, France..
    Cowell, Chris
    Westmead Univ Sydney, Sydney, NSW, Australia..
    Craig, Cora L.
    Canadian Fitness & Lifestyle Res Inst, Ottawa, ON, Canada..
    Crujeiras, Ana B.
    CIBEROBN, Madrid, Spain..
    D'Arrigo, Graziella
    CNR, Rome, Italy..
    d'Orsi, Eleonora
    Univ Fed Santa Catarina, BR-88040900 Florianopolis, SC, Brazil..
    Dallongeville, Jean
    Inst Pasteur, Lille, France..
    Damasceno, Albertino
    Eduardo Mondlane Univ, Maputo, Mozambique..
    Damsgaard, Camilla T.
    Univ Copenhagen, DK-1168 Copenhagen, Denmark..
    Dankner, Rachel
    Gertner Inst Epidemiol & Hlth Policy Res, Tel Aviv, Israel..
    Dauchet, Luc
    Lille Univ Hosp, Lille, France..
    De Backer, Guy
    Univ Ghent, B-9000 Ghent, Belgium..
    De Bacque, Dirk
    Univ Ghent, B-9000 Ghent, Belgium..
    de Gaetano, Giovanni
    IRCCS, Ist Neurol Mediterraneo Neuromed, Milan, Italy..
    De Hanauw, Stefaan
    Univ Ghent, B-9000 Ghent, Belgium..
    De Smedt, Delphine
    Univ Ghent, B-9000 Ghent, Belgium..
    Deepa, Mohan
    Madras Diabet Res Fdn, Madras, Tamil Nadu, India..
    Deev, Alexander D.
    Natl Res Ctr Prevent Med, Moscow, Russia..
    Dehghan, Abbas
    Erasmus MC, Rotterdam, Netherlands..
    Delisle, Helene
    Univ Montreal, Montreal, PQ H3C 3J7, Canada..
    Delpeuch, Francis
    Inst Rech Dev, Marseille, France..
    Deschamps, Valerie
    French Publ Hlth Agency, St Maurice, France..
    Dhana, Klodian
    Erasmus MC, Rotterdam, Netherlands..
    Di Castelnuovo, Augusto F.
    IRCCS, Ist Neurol Mediterraneo Neuromed, Milan, Italy..
    Dias-da-Costa, Juvenal Soares
    Univ Vale Rio dos Sinos, Sao Leopoldo, Brazil..
    Diaz, Alejandro
    Noncommunicable Dis Res Ctr, Tehran, Iran.;Natl Council Sci & Tech Res, Buenos Aires, DF, Argentina..
    Djalalinia, Shirin
    Do, Ha T. P.
    Natl Inst Nutr, Hanoi, Vietnam..
    Dobson, Annette J.
    Univ Queensland, Brisbane, Qld 4072, Australia..
    Donfrancesco, Chiara
    Ist Super Sanita, Rome, Italy..
    Donoso, Silvana P.
    Univ Cuenca, Cuenca, Ecuador..
    Doering, Angela
    Helmholtz Zentrum Munchen, Munich, Germany..
    Doua, Kouamelan
    Minist Sante & Lutte Contre Sida, Korhogo, Cote Ivoire..
    Drygas, Wojciech
    Cardinal Wyszynski Inst Cardiol, Warsaw, Poland..
    Dzerve, Vilnis
    Univ Latvia, Riga, Latvia..
    Egbagbe, Eruke E.
    Univ Benin, Benin, Nigeria..
    Eggertsen, Robert
    Univ Gothenburg, Gothenburg, Sweden..
    Ekelund, Ulf
    Norwegian Sch Sport Sci, Oslo, Norway..
    El Ati, Jalila
    Natl Inst Nutr & Food Technol, Tunis, Tunisia..
    Elliott, Paul
    Imperial Coll London, London, England..
    Engle-Stone, Reina
    Univ Calif Davis, Davis, CA 95616 USA..
    Erasmus, Rajiv T.
    Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa..
    Erem, Cihangir
    Karadeniz Tech Univ, Trabzon, Turkey..
    Eriksen, Loise
    Univ Southern Denmark, Odense, Denmark..
    Escobedo-de la Pena, Jorge
    Inst Mexicano Seguro Social, Mexico City, DF, Mexico..
    Evans, Alun
    Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland..
    Faeh, David
    Univ Zurich, CH-8006 Zurich, Switzerland..
    Fall, Caroline H.
    Univ Southampton, Southampton SO9 5NH, Hants, England..
    Farzadfar, Farshad
    Univ Tehran Med Sci, Tehran, Iran..
    Felix-Redondo, Francisco J.
    Ctr Salud Villanueva Serena Norte, Badajoz, Spain..
    Ferguson, Trevor S.
    Univ West Indies, Kingston, Jamaica..
    Fernandez-Berges, Daniel
    Hosp Don Benito Villanueva de la Serena, Badajoz, Spain..
    Ferrante, Daniel
    Minist Hlth, Buenos Aires, DF, Argentina..
    Ferrari, Marika
    Council Agr Res Econ, Rome, Italy..
    Ferreccio, Catterina
    Pontificia Univ Catolica Chile, Santiago, Chile..
    Ferrieres, Jean
    Univ Toulouse, Sch Med, Toulouse, France..
    Finn, Joseph D.
    Univ Manchester, Manchester M13 9PL, Lancs, England..
    Fischer, Krista
    Univ Tartu, Tartu, Estonia..
    Monterubio Flores, Eric
    Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico..
    Foeger, Bernhard
    Agency Prevent & Social Med, Bregenz, Austria..
    Foo, Leng Huat
    Univ Sains Malaysia, Gelugor, Penang, Malaysia..
    Forslund, Ann-Sofie
    Univ Lulea, S-97187 Lulea, Sweden..
    Forsner, Maria
    Dalarna Univ, Falun, Sweden..
    Fortmann, Stephen P.
    Stanford Univ, Stanford, CA 94305 USA..
    Francis, Heba M.
    WHO, Reg Off Eastern Mediterranean, Cairo, Egypt..
    Francis, Damian K.
    Univ West Indies, Kingston, Jamaica..
    do Carmo Franco, Maria
    Univ Fed Sao Paulo, Sao Paulo, Brazil..
    Franco, Oscar H.
    Erasmus MC, Rotterdam, Netherlands..
    Frontera, Guillermo
    Hosp Univ Son Espases, Palma De Mallorca, Illes Balears, Spain..
    Fuchs, Flavio D.
    Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil..
    Fuchs, Sandra C.
    Univ Fed Rio Grande do Sul, BR-90046900 Porto Alegre, RS, Brazil..
    Fujita, Yuki
    Kindai Univ, Fac Med, Higashiosaka, Osaka, Japan..
    Furusawa, Takuro
    Kyoto Univ, Kyoto 6068501, Japan..
    Gaciong, Zbigniew
    Med Univ Warsaw, Warsaw, Poland..
    Gafencu, Mihai
    Victor Babes Univ Med & Pharma Timisoara, Timisoara, Romania..
    Gareta, Dickman
    Univ KawaZulu Natal, Durban, South Africa..
    Garnett, Sarah P.
    Univ Sydney, Sydney, NSW 2006, Australia..
    Gaspoz, Jean-Michel
    Univ Hosp Geneva, Geneva, Switzerland..
    Gasull, Magda
    CIBER Epidemiol & Salud Publ, Madrid, Spain..
    Gates, Louise
    Australian Bureau Stat, Canberra, ACT, Australia..
    Geleijnse, Johanna M.
    Wageningen Univ, NL-6700 AP Wageningen, Netherlands..
    Ghasemian, Anoosheh
    Noncommunicable Dis Res Ctr, Tehran, Iran..
    Giampaoli, Simona
    Ist Super Sanita, Rome, Italy..
    Gianfagna, Francesco
    Univ Insubria, Varese, Italy..
    Giovannelli, Jonathan
    Lille Univ Hosp, Lille, France..
    Giwercman, Aleksander
    Lund Univ, S-22100 Lund, Sweden..
    Goldsmith, Rebecca A.
    Minist Hlth, Dept Nutr, Jerusalem, Israel..
    Goncalves, Helen
    Univ Fed Pelotas, Pelotas, Brazil..
    Gonzalez Gross, Marcela
    Univ Politecn Madrid, E-28040 Madrid, Spain..
    Gonzalez Rivas, Juan P.
    Andes Clin Cardiometabol Studies, Merida, Venezuela..
    Bonet Gorbea, Mariano
    Natl Inst Hyg Epidermiol & Microbiol, Havana, Cuba..
    Gottrand, Frederic
    Univ Lille 2, F-59800 Lille, France..
    Graff-Iversen, Sidsel
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Grafnetter, Dusan
    Inst Clin & Expt Med, Prague, Czech Republic..
    Grajda, Aneta
    Childrens Mem Hlth Inst, Warsaw, Poland..
    Grammatikopoulou, Maria G.
    Alexander Technol Educ Inst, Thessaloniki, Greece..
    Gregor, Ronald D.
    Dalhousie Univ, Halifax, NS B3H 3J5, Canada..
    Grodzicki, Tomasz
    Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland..
    Grontved, Anders
    Univ Southern Denmark, Odense, Denmark..
    Gruden, Grabriella
    Univ Turin, I-10124 Turin, Italy..
    Grujic, Vera
    Univ Novi Sad, YU-21000 Novi Sad, Serbia..
    Gu, Dongfeng
    Natl Ctr Cardiovasc Dis, Beijing, Peoples R China..
    Gualdi-Russo, Emanuela
    Univ Ferrara, I-44100 Ferrara, Italy..
    Guan, Ong Peng
    Singapore Eye Res Inst, Singapore, Singapore..
    Gudnason, Vilmundur
    Iceland Heart Associat, Kopavogur, Iceland..
    Guerrero, Ramiro
    Univ Icesi, Valle Del Cauca, Colombia..
    Guessous, Idris
    Univ Hosp Geneva, Geneva, Switzerland..
    Guimaraes, Andre L.
    Univ Estadual Montes Claros, Montes Claros, Brazil..
    Gulliford, Martin C.
    Kings Coll London, London WC2R 2LS, England..
    Gunnlaugsdottir, Johanna
    Iceland Heart Associat, Kopavogur, Iceland..
    Gunter, Marc
    Imperial Coll London, London, England..
    Guo, Xiuhua
    Capital Med Univ, Beijing, Peoples R China..
    Guo, Yin
    Capital Med Univ, Beijing, Peoples R China..
    Gupta, Prakash C.
    Healis Sekhsaria Inst Publ Hlth, Navi Mumbai, India..
    Gureje, Oye
    Univ Ibadan, Ibadan, Nigeria..
    Gurzkowska, Beata
    Childrens Mem Hlth Inst, Warsaw, Poland..
    Gutierrez, Laura
    Inst Clin Effect & Hlth Policy, Buenos Aires, DF, Argentina..
    Gutzwiller, Felix
    Univ Zurich, CH-8006 Zurich, Switzerland..
    Halkjaer, Jytte
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Hambleton, Ian R.
    Univ West Indies, Kingston, Jamaica..
    Hardy, Rebecca
    UCL, London WC1E 6BT, England..
    Kumar, Rachakulla Hari
    Indian Council Med Res, New Delhi, India..
    Hata, Jun
    Kyushu Univ, Fukuoka 812, Japan..
    Hayes, Alison J.
    Univ Sydney, Sydney, NSW 2006, Australia..
    He, Jiang
    Tulane Univ, New Orleans, LA 70118 USA..
    Hendriks, Marleen Ekisabeth
    Univ Amsterdam, Acad Med Ctr, NL-1012 WX Amsterdam, Netherlands..
    Hernandez Cadena, Leticia
    Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico..
    Herrala, Sauli
    Oulu Univ Hosp, Oulu, Finland..
    Heshmat, Ramin
    Chron Dis Res Ctr, Tehran, Iran..
    Hihtaniemi, Ilpo Tapani
    Imperial Coll London, London, England..
    Ho, Sai Yin
    Univ Hong Kong, Pok Fu Lam, Peoples R China..
    Ho, Suzanne C.
    Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China..
    Hobbs, Michael
    Univ Western Australia, Nedlands, WA 6009, Australia..
    Hofman, Albert
    Erasmus MC, Rotterdam, Netherlands..
    Hormiga, Claudi M.
    Fdn Oftalmol Santander, Bucaramanga, Colombia..
    Horta, Bernardo L.
    Univ Fed Pelotas, Pelotas, Brazil.;Univ Fed Pelotas, Pelotas, RS, Brazil..
    Houti, Leila
    Univ Oran 1, Es Senia, Colombia..
    Howitt, Christina
    Univ West Indies, Kingston, Jamaica..
    Htay, Thein Thein
    Independent Publ Hlth Specialist, Yangon, Myanmar..
    Htet, Aung Soe
    Htike, Maung Maung Than
    Int Relat Div, Nay Pyi Taw, Myanmar..
    Hu, Yonghua
    Peking Univ, Hlth Sci Ctr, Beijing, Peoples R China..
    Husseini, Abdullatif
    Birzeit Univ, Birzeit, Israel..
    Huu, Chinh Nguyen
    Huybrechts, Inge
    Int Agency Res Canc, Lyon, France..
    Hwalla, Nahla
    Amer Univ Beirut, Beirut, Lebanon..
    Iacoviello, Licia
    IRCCS, Ist Neurol Mediterraneo Neuromed, Milan, Italy..
    Iannone, Anna G.
    Cardiol Mercato S Severino, Mercato San Severino, SA, Italy..
    Ibrahim, Mohsen M.
    Cairo Univ, Giza, Egypt..
    Ikeda, Nayu
    Natl Inst Hlth & Nutr, Tokyo, Japan..
    Ikram, M. Arfan
    Erasmus MC, Rotterdam, Netherlands..
    Irazola, Vilma E.
    Inst Clin Effect & Hlth Policy, Buenos Aires, DF, Argentina..
    Islam, Muhammad
    Aga Khan Univ, Karachi, Pakistan..
    Ivkovic, Vanja
    UHC Zagreb, Zagreb, Croatia..
    Iwasaki, Masanori
    Niigata Univ, Niigata 95021, Japan..
    Jackson, Rod T.
    Univ Auckland, Auckland 1, New Zealand..
    Jacobs, Jeremy M.
    Hadassah Univ, Med Ctr, Jerusalem, Israel..
    Jafar, Tazeen
    Duke NUS Grad Med Sch, Singapore, Singapore..
    Jamil, Kazi M.
    Kuwait Inst Sci Res, Safat, Kuwait..
    Jamrozik, Konrad
    Univ Adelaide, Adelaide, SA 5005, Australia..
    Janszky, Imre
    Norwegian Univ Sci & Technol, Trondheim, Norway..
    Jasienska, Grazyna
    Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland..
    Jelakovic, Bojan
    Univ Zagreb, Sch Med, Zagreb 41000, Croatia..
    Jiang, Chao Qiang
    Guangzhou 12th Hosp, Guangzhou, Guangdong, Peoples R China..
    Joffres, Michel
    Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada..
    Johansson, Mattias
    Int Agency Res Canc, Lyon, France..
    Jonas, Jost B.
    Heidelberg Univ, D-69115 Heidelberg, Germany..
    Jorgensen, Torben
    Res Ctr Prevent & Hlth, Glostrup, Denmark..
    Joshi, Pradeep
    WHO, Org Country Off, Delhi, India.;Nat Inst Epidemiol, Madras, Tamil Nadu, India..
    Juolevi, Anne
    Natl Inst Hlth & Welfare, Oulu, Finland..
    Jurak, Gregor
    Univ Ljubljana, Ljubljana 61000, Slovenia..
    Juresa, Vesno
    Univ Zagreb, Zagreb 41000, Croatia..
    Kaaks, Rudolf
    German Canc Res Ctr, Heidelberg, Germany..
    Kafatos, Anthony
    Univ Crete, Rethimnon, Greece..
    Kalter-Leibovici, Ofra
    Gertner Inst Epidemiol & Hlth Policy Res, Tel Aviv, Israel..
    Kapantais, Efthymios
    Hellenic Med Associat Obes, Athens, Greece..
    Kasaeian, Amir
    Univ Tehran Med Sci, Tehran, Iran..
    Katz, Joanne
    Johns Hopkins Bloomberg Sch Publ Hlth, Bloomberg, MD USA..
    Kaur, Prabhdeep
    Kavousi, Maryam
    Erasmus MC, Rotterdam, Netherlands..
    Keil, Ulrich
    Univ Munster, Munster, Germany..
    Boker, Lital Keinan
    Israel Ctr Dis Control, Ramat Gan, Israel..
    Keinanen-Kiukaanniemi, Sirkka
    Oulu Univ Hosp, Oulu, Finland..
    Kelishadi, Roya
    Res Inst Primordial Prevent of Noncommunicabl Dis, Esfahan, Iran..
    Kemper, Han C. G.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Kengne, Andre P.
    South African Med Res Council, Tygerberg, South Africa..
    Kersting, Mathilde
    Res Inst Child Nutr, Dortmund, Germany..
    Key, Timothy
    Univ Oxford, Oxford OX1 2JD, England..
    Khader, Yousef Saleh
    Jordan Univ Sci & Technol, Irbid, Jordan..
    Khalili, Davood
    Shahid Beheshti Univ Med Sci, Tehran, Iran..
    Khang, Young-Ho
    Seoul Natl Univ, Seoul 151, South Korea..
    Khaw, Kay-Tee H.
    Univ Cambridge, Cambridge CB2 1TN, England..
    Khouw, Ilse M. S. L.
    FrieslandCampina, Singapore, Singapore..
    Kiechl, Stefan
    Med Univ Innsbruck, A-6020 Innsbruck, Austria..
    Killewo, Japhet
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania..
    Kim, Jeongseon
    Natl Canc Ctr, Ilsandong Gu, Goyang Si, South Korea..
    Klimont, Jeannette
    Stat Austria, Vienna, Austria..
    Klumbiene, Jurate
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Koirala, Bhawesh
    BP Koirala Inst Hlth Sci, Dharan, Nepal..
    Kolle, Elin
    Norwegian Sch Sport Sci, Oslo, Norway..
    Kolsteren, Patrick
    Inst Trop Med, Antwerp, Belgium..
    Korrovits, Paul
    Tartu Univ Clin, Tartu, Estonia..
    Koskinen, Seppo
    Natl Inst Hlth & Welfare, Oulu, Finland..
    Kouda, Katsuyasu
    Kindai Univ, Fac Med, Higashiosaka, Osaka, Japan..
    Koziel, Slawomir
    Polish Acad Sci, Anthropol Unit in Wroclaw, PL-00901 Warsaw, Poland..
    Kratzer, Wolfgang
    Univ Hosp Ulm, Ulm, Germany..
    Krokstad, Steinar
    Norwegian Univ Sci & Technol, Trondheim, Norway..
    Kromhout, Daan
    Wageningen Univ, NL-6700 AP Wageningen, Netherlands..
    Kruger, Herculina S.
    North West Univ, Mmabatho, Mahikeng, South Africa..
    Kubinova, Ruzena
    Natl Inst Publ Hlth, Prague, Czech Republic..
    Kujala, Urho M.
    Univ Jyvaskyla, SF-40351 Jyvaskyla, Finland..
    Kula, Krzysztof
    Med Univ Lodz, Lodz, Poland..
    Kulaga, Zbigniew
    Childrens Mem Hlth Inst, Warsaw, Poland..
    Kumar, R. Krishna
    Amrita Inst Med Sci, Kochi, Kerala, India..
    Kurjata, Pawel
    Cardinal Wyszynski Inst Cardiol, Warsaw, Poland..
    Kusuma, Yadlapalli S.
    All India Inst Med Sci, New Delhi 110029, India..
    Kuulasmaa, Kari
    Natl Inst Hlth & Welfare, Oulu, Finland..
    Kyobutungi, Catherine
    African Populat & Hlth Res Ctr, Nairobi, Kenya..
    Laamiri, Fatima Zahra
    Higher Inst Nursing Profess & Tech, Casablanca, Morocco..
    Laatikainen, Tiina
    Natl Inst Hlth & Welfare, Oulu, Finland..
    Lachat, Carl
    Univ Ghent, B-9000 Ghent, Belgium..
    Laid, Youcef
    Natl Inst Publ Hlth Algeria, Algiers, Algeria..
    Lam, Tai Hing
    Univ Hong Kong, Pok Fu Lam, Peoples R China..
    Landrove, Orlando
    Minist Salud Publ, Havana, Cuba..
    Lanska, Vera
    Inst Clin & Expt Med, Prague, Czech Republic..
    Lappas, Georg
    Sahlgrens Acad, Gothenburg, Sweden..
    Larijani, Bagher
    Endocrinol & Metabol Res Ctr, Tehran, Iran..
    Laugsand, Lars E.
    Norwegian Univ Sci & Technol, Trondheim, Norway..
    Bao, Khanh Le Nguyen
    Le, Tuyen D
    Leclercq, Catherine
    Food & Agr Org, Rome, Italy..
    Lee, Jeannette
    Natl Univ Singapore, Singapore 117548, Singapore..
    Lee, Jeonghee
    Natl Canc Ctr, Ilsandong Gu, Goyang Si, South Korea..
    Lehtimaki, Terho
    Tampere Univ Hosp, Tampere, Finland..
    Lekhraj, Rampal
    Univ Putra Malaysia, Serdang 43400, Malaysia..
    Leon-Munoz, Luz M.
    Univ Autonoma Madrid, E-28049 Madrid, Spain..
    Li, Yanping
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.;Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    Lilly, Christa L.
    West Virginia Univ, Morgantown, WV 26506 USA..
    Lim, Wei-Yen
    Natl Univ Singapore, Singapore 117548, Singapore..
    Fernanda Lima-Costa, M.
    Fundacao Oswaldo Cruz, Rene Rachou Res Inst, Rio De Janeiro, Brazil..
    Lin, Hsien-Ho
    Natl Taiwan Univ, Taipei, Taiwan..
    Lin, Xu
    Univ Chinese Acad Sci, Beijing, Peoples R China..
    Linneberg, Allan
    Res Ctr Prevent & Hlth, Glostrup, Denmark..
    Lissner, Lauren
    Univ Gothenburg, Gothenburg, Sweden..
    Litwin, Mieczyslaw
    Childrens Mem Hlth Inst, Warsaw, Poland..
    Liu, Jing
    Capital Med Univ, Beijing Anzhen Hosp, Beijing, Peoples R China..
    Lorbeer, Roberto
    Univ Med Greifswald, Greifswald, Germany..
    Lotufo, Paulo A.
    Univ Sao Paulo, BR-05508 Sao Paulo, Brazil..
    Eugenio Lozano, Jose
    Consejeria Sanidad Junta Castilla & Leon, Madrid, Spain..
    Luksiene, Dalia
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Lundqvist, Annamari
    Lunet, Nuno
    Univ Porto, P-4100 Oporto, Portugal..
    Ma, Guansheng
    Peking Univ, Beijing, Peoples R China..
    Ma, Jun
    Peking Univ, Beijing, Peoples R China..
    Machado-Coelho, George L. L.
    Univ Fed Ouro Preto, Ouro Preto, MG, Brazil..
    Machi, Suka
    Jikei Univ, Sch Med, Tokyo, Japan..
    Maggi, Stefania
    CNR, Rome, Italy..
    Magliano, Dianna J.
    Baker IDI Heart & Diabetes Inst, Melbourne, Vic, Australia..
    Maire, Bernard
    Inst Rech Dev, Marseille, France..
    Makdisse, Marcia
    Hosp Israelita Albert Einstein, Sao Paulo, Brazil..
    Malekzadeh, Reza
    Univ Tehran Med Sci, Tehran, Iran..
    Malhotra, Rahul
    Duke NUS Grad Med Sch, Singapore, Singapore..
    Rao, Kodavanti Mallikharjuna
    Indian Council Med Res, New Delhi, India..
    Malyutina, Sofia
    Inst Internal & Prevent Med, Novosibirsk, Russia..
    Manios, Yannis
    Harokopio Univ, Kallithea, Greece..
    Mann, Jim I.
    Univ Otago, Dunedin, New Zealand..
    Manzato, Enzo
    Univ Padua, I-35100 Padua, Italy..
    Margozzini, Paula
    Pontificia Univ Catolica Chile, Santiago, Chile..
    Markey, Oonagh
    Univ Reading, Reading RG6 2AH, Berks, England..
    Marques-Vidal, Pedro
    Univ Lausanne, CH-1015 Lausanne, Switzerland..
    Marrugat, Jaume
    Inst Hosp Mar Invest Med, Barcelona, Spain..
    Martin-Prevel, Yves
    Inst Rech Dev, Marseille, France..
    Martorell, Reynaldo
    Emory Univ, Atlanta, GA 30322 USA..
    Masoodi, Shariq R.
    Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India..
    Mathiesen, Ellisiv B.
    UiT Arctic Univ Norway, Tromso, Norway..
    Matsha, Tandi E.
    Cape Peninsula Univ Technol, Cape Town, South Africa..
    Mazur, Artur
    Univ Rzeszow, Rzeszow, Poland..
    Mbanya, Jean Claude N.
    Univ Yaounde I, Yaounde, Cameroon..
    McFarlane, Shelly R.
    Univ West Indies, Kingston, Jamaica..
    McGarvey, Stephen T.
    Brown Univ, Providence, RI 02912 USA..
    McKee, Martin
    London Sch Hyg & Trop Med, London, England..
    McLachlan, Stela
    Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland..
    McLean, Rachael M.
    Univ Otago, Dunedin, New Zealand..
    McNulty, Breige A.
    Univ Coll Dublin, Dublin, Ireland..
    Yusof, Safiah Md
    Univ Teknol MARA, Shah Alam, Selangor, Malaysia..
    Mediene-Benchekor, Sounnia
    Univ Oran 1, Es Senia, Colombia..
    Meirhaeghe, Aline
    INSERM, F-75654 Paris 13, France..
    Meisinger, Christa
    Helmholtz Zentrum Munchen, Munich, Germany..
    Menezes, Ana Maria B.
    Univ Fed Pelotas, Pelotas, Brazil.;Univ Fed Pelotas, Pelotas, RS, Brazil..
    Mensink, Gert B. M.
    Robert Koch Inst, Berlin, Germany..
    Meshram, Indrapal I.
    Indian Council Med Res, New Delhi, India..
    Metspalu, Andres
    Univ Tartu, Tartu, Estonia..
    Mi, Jie
    Capital Inst Pediat, Beijing, Peoples R China..
    Michaelsen, Kim F.
    Univ Copenhagen, DK-1168 Copenhagen, Denmark..
    Mikkel, Kairit
    Univ Tartu, Tartu, Estonia..
    Miller, Jody C.
    Univ Otago, Dunedin, New Zealand..
    Francisco Miquel, Juan
    Pontificia Univ Catolica Chile, Santiago, Chile..
    Jaime Miranda, J.
    Univ Peruana Cayetano Heredia, Lima, Peru..
    Misigoj-Durakovic, Marjeta
    Univ Zagreb, Zagreb 41000, Croatia..
    Mohamed, Mostafa K.
    Ain Shams Univ, Cairo, Egypt..
    Mohammad, Kazem
    Univ Tehran Med Sci, Tehran, Iran..
    Mohammadifard, Noushin
    Isfahan Cardiovasc Res Ctr, Esfahan, Iran..
    Mohan, Viswanathan
    Madras Diabet Res Fdn, Madras, Tamil Nadu, India..
    Yusoff, Muhammad Fadhli Mohd
    Minist Hlth Malaysia, Putrajaya, Malaysia..
    Molbo, Drude
    Univ Copenhagen, DK-1168 Copenhagen, Denmark..
    Moller, Niels C.
    Univ Southern Denmark, Odense, Denmark..
    Molnar, Denes
    Univ Pecs, Pecs, Hungary..
    Mondo, Charles K.
    Mulago Hosp, Kampala, Uganda..
    Monterrubio, Eric A.
    Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico..
    Monyeki, Kotsedi Daniel K.
    Univ Med Sci, Havana, Cuba.;Univ Limpopo, Polokwane, South Africa..
    Moreira, Leila B.
    Univ Fed Rio Grande do Sul, BR-90046900 Porto Alegre, RS, Brazil..
    Morejon, Alain
    Moreno, Luis A.
    Univ Zaragoza, E-50009 Zaragoza, Spain..
    Morgan, Karen
    RCSI Dublin, Dublin, Ireland..
    Mortensen, Erik Lykke
    Univ Copenhagen, DK-1168 Copenhagen, Denmark..
    Moschonis, George
    Harokopio Univ, Kallithea, Greece..
    Mossakowska, Malgorzata
    Int Inst Mol & Cell Biol, Warsaw, Poland..
    Mostafa, Aya
    Ain Shams Univ, Cairo, Egypt..
    Mota, Jorge
    Univ Porto, P-4100 Oporto, Portugal..
    Motlagh, Mohammad Esmaeel
    Ahvaz Jundishapur Univ Med Sci, Ahwaz, Iran..
    Motta, Jorge
    Gorgas Mem Inst Publ Hlth, Panama City, Panama..
    Mu, Thet Thet
    Dept Publ Hlth, Naypyidaw, Myanmar..
    Muiesan, Maria Lorenza
    Univ Brescia, I-25121 Brescia, Italy..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, Munich, Germany..
    Murphy, Neil
    Imperial Coll London, London, England..
    Mursu, Jaakko
    Univ Eastern Finland, Joensuu, Finland..
    Murtagh, Elaine M.
    Mary Immaculate Coll, Limerick, Ireland..
    Musa, Kamarul Imran
    Univ Sains Malaysia, Kota Baharu, Malaysia..
    Musil, Vera
    Univ Zagreb, Zagreb 41000, Croatia..
    Nagel, Gabriele
    Univ Ulm, D-89069 Ulm, Germany..
    Nakamura, Harunobu
    Kobe Univ, Kobe, Hyogo, Japan..
    Namesna, Jana
    Reg Author Publ Hlth, Banska Bystrica, Slovakia..
    Nang, Ei Ei K.
    Natl Univ Singapore, Singapore 117548, Singapore..
    Nangia, Vinay B.
    Suraj Eye Inst, Nagpur, Maharashtra, India..
    Nankap, Martin
    Helen Keller Int, Yaounde, Cameroon..
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    Healis Sekhsaria Inst Publ Hlth, Navi Mumbai, India..
    Maria Navarrete-Munoz, Eva
    CIBER Epidemiol & Salud Publ, Madrid, Spain..
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    West Virginia Univ, Morgantown, WV 26506 USA..
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    Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland..
    Neovius, Martin
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Nervi, Flavio
    Pontificia Univ Catolica Chile, Santiago, Chile..
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    Robert Koch Inst, Berlin, Germany..
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    Univ Pharm & Med Ho Chi Minh City, Ho Chi Minh City, Vietnam..
    Nguyen, Quang Ngoc
    Nieto-Martinez, Ramfis E.
    Univ Ctr Occidental Lisandro Alvarado, Huetamo De Nunez, Mich, Venezuela..
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    Shanghai Jiao Tong Univ, Sch Med, Shanghai 200030, Peoples R China..
    Ninomiya, Toshiharu
    Kyushu Univ, Fukuoka 812, Japan..
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    Heartfile, Islamabad, Pakistan..
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    CNR, Rome, Italy..
    Norat, Teresa
    Imperial Coll London, London, England..
    Noto, Davide
    Univ Palermo, I-90133 Palermo, Italy..
    Al Nsour, Mohannad
    Eastern Mediterranean Publ Hlth Network, Amman, Jordan..
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    Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland..
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    Korea Ctr Dis Control & Prevnt, Daejeon, Chungcheongbuk, South Korea..
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    Kuwait Inst Sci Res, Safat, Kuwait..
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    Univ Vale Rio dos Sinos, Sao Leopoldo, RS, Brazil..
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    Natl Food Nutr Inst, Warsaw, Poland..
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    Minist Hlth Malaysia, Putrajaya, Malaysia..
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    Istanbul Univ, Fatih Istanbul, Turkey..
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    Pan Amer Hlth Org, Washington, DC USA..
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    Univ Puerto Rico, Mayaguez, PR USA..
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    Res Ctr Prevent & Hlth, Glostrup, Denmark..
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    MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
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    Univ Novi Sad, YU-21000 Novi Sad, Serbia..
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    Fdn Oftalmol Santander, Bucaramanga, Colombia..
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    Aarhus Univ, DK-8000 Aarhus C, Denmark..
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    Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana..
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    Inst Social & Prevent Med, Bern, Switzerland..
    Padez, Cristina
    Univ Coimbra, P-3000 Coimbra, Portugal..
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    Univ Latvia, Riga, Latvia..
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    Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland..
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    Canc Prevent & Res Inst, Florence, Italy..
    Palloni, Alberto
    Univ Wisconsin, Madison, WI 53706 USA..
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    Ist Super Sanita, Rome, Italy..
    Panda-Jonas, Songhomitra
    Heidelberg Univ, D-69115 Heidelberg, Germany..
    Panza, Francesco
    Univ Bari, I-70121 Bari, Italy..
    Parnell, Winsome R.
    Univ Otago, Dunedin, New Zealand..
    Parsaeian, Mahboubeh
    Univ Tehran Med Sci, Tehran, Iran..
    Pecin, Ivan
    Univ Zagreb, Zagreb 41000, Croatia..
    Pednekar, Mangesh S.
    Healis Sekhsaria Inst Publ Hlth, Navi Mumbai, India..
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    Univ Med Ctr Utrecht, Utrecht, Netherlands..
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    Fundacao Oswaldo Cruz, Rene Rachou Res Inst, Rio De Janeiro, Brazil..
    Peltonen, Markku
    Natl Inst Hlth & Welfare, Oulu, Finland..
    Pereira, Alexandre C.
    Inst Heart, Sao Paulo, Brazil..
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    Univ Puerto Rico, Mayaguez, PR USA..
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    Helmholtz Zentrum Munchen, Munich, Germany..
    Petkeviciene, Janina
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Peykari, Niloofar
    Noncommunicable Dis Res Ctr, Tehran, Iran..
    Pham, Son Thai
    Pigeot, Iris
    Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany..
    Pikhart, Hynek
    UCL, London WC1E 6BT, England..
    Pilav, Aida
    Fed Minist Hlth, Sarajevo, Bosnia & Herceg..
    Pilotto, Lorenza
    Cardiovasc Prevent Ctr, Udine, Italy..
    Pistelli, Francesco
    Univ Hosp Pisa, Pisa, Italy..
    Pitakaka, Freda
    Univ New South Wales, Sydney, NSW 2052, Australia..
    Piwonska, Aleksandra
    Cardinal Wyszynski Inst Cardiol, Warsaw, Poland..
    Plans-Rubio, Pedro
    Publ Hlth Agcy Catalonia, Barcelona, Spain..
    Poh, Bee Koon
    Univ Kebangsaan Malaysia, Bangi 43600, Malaysia..
    Porta, Miquel
    Inst Hosp Mar Invest Med, Barcelona, Spain..
    Portegies, Marileen L. P.
    Erasmus MC, Rotterdam, Netherlands..
    Poulimeneas, Dimitrios
    Alexander Technol Educ Inst, Thessaloniki, Greece..
    Pradeepa, Rajendra
    Madras Diabet Res Fdn, Madras, Tamil Nadu, India..
    Prashant, Mathur
    Indian Council Med Res, New Delhi, India..
    Price, Jacqueline F.
    Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland..
    Puiu, Maria
    Victor Babes Univ Med & Pharma Timisoara, Timisoara, Romania..
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    Tartu Univ Clin, Tartu, Estonia..
    Qasrawi, Radwan F.
    Al Quds Univ, Jerusalem, Israel..
    Qorbani, Mostafa
    Alborz Univ Med Sci, Karaj, Iran..
    Bao, Tran Quoc
    Radic, Ivana
    Univ Novi Sad, YU-21000 Novi Sad, Serbia..
    Radisauskas, Ricardas
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Rahman, Mahmudur
    Inst Epidemiol Dis Control & Res, Dhaka, Bangladesh..
    Raitakari, Olli
    Turku Univ Hosp, Turku, Finland..
    Raj, Manu
    Amrita Inst Med Sci, Kochi, Kerala, India..
    Rao, Sudha Ramachandra
    Nat Inst Epidemiol, Madras, Tamil Nadu, India..
    Ramachandran, Ambady
    India Diabet Res Fdn, Madras, Tamil Nadu, India..
    Ramke, Jacqueline
    Univ New South Wales, Sydney, NSW 2052, Australia..
    Ramos, Rafel
    Inst Univ Invest Atencio Primaria Jordi Gol, Barcelona, Spain..
    Rampal, Sanjay
    Univ Malaya, Kuala Lumpur, Malaysia..
    Rasmussen, Finn
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Redon, Josep
    Univ Valencia, E-46003 Valencia, Spain..
    Reganit, Paul Ferdinand M.
    Univ Philippines, Quezon City 1101, Philippines..
    Ribeiro, Robespierre
    Minas Gerais State Secretariat Hlth, Belo Horizonte, MG, Brazil..
    Rigo, Fernando
    Hlth Ctr San Agustin, Palma De Mallorca, Spain..
    de Wit, Tobias F. Rinke
    PharmAccess Fdn, Amsterdam, Netherlands..
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    Hosp Israelita Albert Einstein, Sao Paulo, Brazil..
    Rivera, Juan A.
    Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico..
    Robinson, Sian M.
    Univ Southampton, Southampton SO9 5NH, Hants, England..
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    Publ Hlth Agcy Canada, Ottawa, ON, Canada..
    Rodri-guez-Artalejo, Fernando
    Univ Autonoma Madrid, E-28049 Madrid, Spain..
    del Cristo Rodriguez-Perez, Maria
    Canarian Hlth Serv, Tenerife, Canary Islands, Spain..
    Rodriguez-Villamizar, Laura A.
    Univ Ind Santander, Santander, Colombia..
    Rojas-Martinez, Rosalba
    Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico..
    Rojroongwasinkul, Nipa
    Mahidol Univ, Bangkok 10700, Thailand..
    Romaguera, Dora
    CIBEROBN, Madrid, Spain..
    Ronkainen, Kimmo
    Univ Eastern Finland, Joensuu, Finland..
    Rosengren, Annika
    Univ Gothenburg, Gothenburg, Sweden..
    Rouse, Ian
    Fiji Natl Univ, Nasinu, Fiji..
    Rubinstein, Adolfo
    Inst Clin Effect & Hlth Policy, Buenos Aires, DF, Argentina..
    Ruhli, Frank J.
    Univ Zurich, CH-8006 Zurich, Switzerland..
    Rui, Ornelas
    Univ Madeira, Funchal, Portugal..
    Sandra Ruiz-Betancourt, Blanca
    Inst Mexicano Seguro Social, Mexico City, DF, Mexico..
    Horimoto, Andrea R. V. Russo
    Inst Heart, Sao Paulo, Brazil..
    Rutkowski, Marcin
    Med Univ Gdansk, Gdansk, Poland..
    Sabanayagam, Charumathi
    Singapore Eye Res Inst, Singapore, Singapore..
    Sachdev, Harshpal S.
    Sitaram Bhartia Inst Sci & Res, Delhi, India..
    Saidi, Olfa
    Fac Med Tunis, Tunis, Tunisia..
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    French Publ Hlth Agency, St Maurice, France..
    Salazar Martinez, Eduardo
    Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico..
    Salomaa, Veikko
    Natl Inst Hlth & Welfare, Oulu, Finland..
    Salonen, Jukka T.
    Univ Helsinki, FIN-00014 Helsinki, Finland..
    Salvetti, Massimo
    Univ Brescia, I-25121 Brescia, Italy..
    Sanchez-Abanto, Jose
    Natl Inst Hlth, Lima, Peru..
    Sandjaja,
    Sans, Susana
    Catalan Dept Hlth, Barcelona, Spain..
    Santos, Diana A.
    Univ Lisbon, P-1699 Lisbon, Portugal..
    Santos, Osvaldo
    Inst Prevent Med & Publ Hlth, Lisbon, Portugal..
    dos Santos, Renata Nunes
    Univ Sao Paulo Clin Hosp, Sao Paulo, Brazil..
    Santos, Rute
    Univ Porto, P-4100 Oporto, Portugal..
    Saramies, Jouko L.
    South Karelia Social & Hlth Care Dist, Lappeenranta, Finland..
    Sardinha, Luis B.
    Univ Lisbon, P-1699 Lisbon, Portugal..
    Sarrafzadegan, Nizal
    Isfahan Cardiovasc Res Ctr, Esfahan, Iran..
    Saum, Kai-Uwe
    German Canc Res Ctr, Heidelberg, Germany..
    Savva, Savvas C.
    Res & Educ Inst Child Hlth, Strovolos, Cyprus..
    Scazufca, Marcia
    Univ Sao Paulo Clin Hosp, Sao Paulo, Brazil..
    Rosario, Angelika Schaffrath
    Robert Koch Inst, Berlin, Germany..
    Schargrodsky, Herman
    Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina..
    Schienkiewitz, Anja
    Robert Koch Inst, Berlin, Germany..
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    Rigshosp, Copenhagen, Denmark..
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    Univ Fed Santa Catarina, BR-88040900 Florianopolis, SC, Brazil..
    Schultsz, Constance
    Univ Amsterdam, Acad Med Ctr, NL-1012 WX Amsterdam, Netherlands..
    Schutte, Aletta E.
    North West Univ, MRC, Mmabatho, Mahikeng, South Africa..
    Sein, Aye Aye
    Minist Hlth, Naypyidaw, Myanmar..
    Sen, Abhijit
    Norwegian Univ Sci & Technol, Trondheim, Norway..
    Senbanjo, Idowu O.
    Lagos State Univ, Coll Med, Lagos, Nigeria..
    Sepanlou, Sadaf G.
    Digest Dis Res Ctr, Tehran, Iran..
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    Natl Res Ctr Prevent Med, Moscow, Russia..
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    BP Koirala Inst Hlth Sci, Dharan, Nepal..
    Shaw, Jonathan E.
    Baker IDI Heart & Diabetes Inst, Melbourne, Vic, Australia..
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    Univ Tokyo, Tokyo 1138654, Japan..
    Shin, Dong Wook
    Seoul Natl Univ, Coll Med, Seoul 151, South Korea..
    Shin, Youchan
    Singapore Eye Res Inst, Singapore, Singapore..
    Shiri, Rahman
    Finnish Inst Occupat Hlth, Helsinki, Finland..
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    Singapore Eye Res Inst, Singapore, Singapore..
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    Amer Univ Beirut, Beirut, Lebanon..
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    Univ Fed Maranhao, Sao Luis, MA, Brazil..
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    Univ Fed Santa Catarina, BR-88040900 Florianopolis, SC, Brazil..
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    India Diabet Res Fdn, Madras, Tamil Nadu, India..
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    St Vincents Hosp, Darlinghurst, NSW, Australia..
    Simons, Leon A.
    Univ New South Wales, Sydney, NSW 2052, Australia..
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    Karolinska Inst, S-10401 Stockholm, Sweden..
    Slowikowska-Hilczer, Jolanta
    Med Univ Lodz, Lodz, Poland..
    Slusarczyk, Przemyslaw
    Int Inst Mol & Cell Biol, Warsaw, Poland..
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    London Sch Hyg & Trop Med, London, England..
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    Univ Oxford, Oxford OX1 2JD, England..
    Snijder, Marieke B.
    Univ Amsterdam, Acad Med Ctr, NL-1012 WX Amsterdam, Netherlands..
    So, Hung-Kwan
    Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China..
    Sobngwi, Eugene
    Univ Yaounde I, Yaounde, Cameroon..
    Soderberg, Stefan
    Umea Univ, S-90187 Umea, Sweden..
    Soekatri, Moesijanti Y. E.
    Hlth Polytech Inst, Kebayoran Baru, Jakarta, Indonesia..
    Solfrizzi, Vincenzo
    Univ Bari, I-70121 Bari, Italy..
    Sonestedt, Emily
    Lund Univ, S-22100 Lund, Sweden..
    Song, Yi
    Peking Univ, Beijing, Peoples R China..
    Sorensen, Thorkild I. A.
    Univ Copenhagen, DK-1168 Copenhagen, Denmark..
    Soric, Maroje
    Univ Zagreb, Zagreb 41000, Croatia..
    Jerome, Charles Sossa
    Inst Reg Sante Publ, Cotonou, Benin..
    Soumare, Aicha
    Staessen, Jan A.
    Univ Leuven, Leuven, Belgium..
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    Univ Ljubljana, Ljubljana 61000, Slovenia..
    Stathopoulou, Maria G.
    INSERM, F-75654 Paris 13, France..
    Staub, Kaspar
    Univ Zurich, CH-8006 Zurich, Switzerland..
    Stavreski, Bill
    Heart Fdn, Canberra, ACT, Australia..
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    Norwegian Sch Sport Sci, Oslo, Norway..
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    Univ Bonn, Bonn, Germany..
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    Emory Univ, Atlanta, GA 30322 USA..
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    Sotiria Hosp, Athens, Greece..
    Stessman, Jochanan
    Hadassah Univ, Med Ctr, Jerusalem, Israel..
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    Helmholtz Zentrum Munchen, Munich, Germany..
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    Helmholtz Zentrum Munchen, Munich, Germany..
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    Lund Univ, S-22100 Lund, Sweden..
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    Natl Inst Publ Hlth, Natl Inst Hyg, Warsaw, Poland..
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    Swansea Univ, Swansea, W Glam, Wales..
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    Univ Amsterdam, NL-1012 WX Amsterdam, Netherlands..
    Strufaldi, Maria Wany
    Univ Fed Sao Paulo, Sao Paulo, Brazil..
    Sun, Chien-An
    Fu Jen Catholic Univ, New Taipei, Taiwan..
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    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Sung, Yn-Tz
    Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China..
    Sunyer, Jordi
    ISGlobal Ctr Res Environm Epidemiol, Barcelona, Spain..
    Suriyawongpaisal, Paibul
    Mahidol Univ, Bangkok 10700, Thailand..
    Swinburn, Boyd A.
    Univ Auckland, Auckland 1, New Zealand..
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    Univ Philippines, Quezon City 1101, Philippines..
    Szponar, Lucjan
    Natl Food Nutr Inst, Warsaw, Poland..
    Tai, E. Shyong
    Natl Univ Singapore, Singapore 117548, Singapore..
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    Univ Tartu, Tartu, Estonia..
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    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Tang, Line
    Res Ctr Prevent & Hlth, Glostrup, Denmark..
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    Peking Univ, Hlth Sci Ctr, Beijing, Peoples R China..
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    Univ KawaZulu Natal, Durban, South Africa..
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    Peking Univ, Beijing, Peoples R China..
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    Minist Hlth, Amman, Jordan..
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    Univ Southern Denmark, Odense, Denmark..
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    Natl Inst Hlth, Lima, Peru..
    Taylor, Anne
    Univ Adelaide, Adelaide, SA 5005, Australia..
    Tchibindat, Felicite
    UNICEF, Yaounde, Cameroon..
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    Karolinska Inst, S-10401 Stockholm, Sweden..
    Thijs, Lutgarde
    Univ Leuven, Leuven, Belgium..
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    Res Ctr Prevent & Hlth, Glostrup, Denmark..
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    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
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    Natl Inst Hlth & Welfare, Oulu, Finland..
    Tolstrup, Janne S.
    Univ Southern Denmark, Odense, Denmark..
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    Karadeniz Tech Univ, Trabzon, Turkey..
    Topor-Madry, Roman
    Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland..
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    IB SALUT Area Salut Menorca, Balearic Isl, Spain..
    Toselli, Stefania
    Univ Bologna, I-40126 Bologna, Italy..
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    Inst Rech Dev, Marseille, France..
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    Hellenic Hlth Fdn, Athens, Greece..
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    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
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    Univ Pharm & Med Ho Chi Minh City, Ho Chi Minh City, Vietnam..
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    Govt Med Coll, Bhavnagar, Gujarat, India..
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    Sefako Makgatho Hlth Sci Univ, Pretoria, South Africa..
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    Univ West Indies, Kingston, Jamaica..
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    Univ Eastern Finland, Joensuu, Finland..
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    Dasman Diabetes Inst, Kuwait, Kuwait..
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    Minist Hlth, Wellington, New Zealand..
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    Karolinska Inst, S-10401 Stockholm, Sweden..
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    Hellenic Med Associat Obes, Athens, Greece..
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    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
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    Meharry Med Coll, Nashville, TN USA..
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    Med Univ Innsbruck, A-6020 Innsbruck, Austria..
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    Dokuz Eylul Univ, TR-35210 Alsancak, Turkey..
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    Univ Tampere, Tays Eye Ctr, FIN-33101 Tampere, Finland..
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    Pontificia Univ Catolica Chile, Santiago, Chile..
    Vale, Susana
    Univ Porto, P-4100 Oporto, Portugal..
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    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
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    Univ Med Ctr Utrecht, Utrecht, Netherlands..
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    Univ Ghent, B-9000 Ghent, Belgium..
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    Univ Med Ctr Utrecht, Utrecht, Netherlands..
    van Valkengoed, Irene G. M.
    Univ Amsterdam, Acad Med Ctr, NL-1012 WX Amsterdam, Netherlands..
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    Katholieke Univ Leuven, Leuven, Belgium..
    Vanuzzo, Diego
    Ctr Prevenz Cardiovasc Udine, Udine, Italy..
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    Norwegian Univ Sci & Technol, Trondheim, Norway..
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    Consejeria Sanidad Junta Castilla & Leon, Madrid, Spain..
    Velasquez-Melendez, Gustavo
    Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil..
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    Univ Insubria, Varese, Italy..
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    Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands..
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    Inst Trop Med, Antwerp, Belgium..
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    Univ Fed Pelotas, Pelotas, RS, Brazil..
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    Italian Natl Res Council, Rome, Italy..
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    Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands..
    Viikari-Juntura, Eira
    Finnish Inst Occupat Hlth, Helsinki, Finland..
    Vineis, Paolo
    Imperial Coll London, London, England..
    Vioque, Jesus
    Univ Miguel Hernandez, Alicante, Spain..
    Virtanen, Jyrki K.
    Univ Eastern Finland, Joensuu, Finland..
    Visvikis-Siest, Sophie
    Univ Leuven, Leuven, Belgium..
    Viswanathan, Bharathi
    Minist Hlth, Victoria, Seychelles..
    Vollenweider, Peter
    Univ Lausanne Hosp, Lausanne, Switzerland..
    Voutilainen, Sari
    Univ Eastern Finland, Joensuu, Finland..
    Vrdoljak, Ana
    UHC Zagreb, Zagreb, Croatia..
    Vrijheid, Martine
    ISGlobal Ctr Res Environm Epidemiol, Barcelona, Spain..
    Wade, Alisha N.
    Univ Witwatersrand, ZA-2050 Johannesburg, South Africa..
    Wagner, Aline
    Univ Strasbourg, Strasbourg, France..
    Walton, Janette
    Univ Coll Cork, Cork, Ireland..
    Mohamud, Wan Nazaimoon Wan
    Inst Med Res, Kuala Lumpur, Malaysia..
    Wang, Ming-Dong
    Publ Hlth Agcy Canada, Ottawa, ON, Canada..
    Wang, Qian
    Xinjiang Med Univ, Urumqi, Xinjiang, Peoples R China..
    Wang, Ya Xing
    Beijing Tongren Hosp, Beijing, Fengtai, Peoples R China..
    Wannamethee, S. Goya
    UCL, London WC1E 6BT, England..
    Wareham, Nicholas
    Univ Cambridge, Cambridge CB2 1TN, England..
    Weerasekera, Deepa
    Minist Hlth, Wellington, New Zealand..
    Whincup, Peter H.
    St Georges Univ London, London, England..
    Widhalm, Kurt
    Med Univ Vienna, Vienna, Austria..
    Widyahening, Indah S.
    Univ Indonesia, Depok City, West Java, Indonesia..
    Wiecek, Andrzej
    Med Univ Silesia, Katowice, Poland..
    Wijga, Alet H.
    Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands..
    Wilks, Rainford J.
    Univ West Indies, Kingston, Jamaica..
    Willeit, Johann
    Med Univ Innsbruck, A-6020 Innsbruck, Austria..
    Wilsgaard, Tom
    UiT Arctic Univ Norway, Tromso, Norway..
    Wojtyniak, Bogdan
    Natl Inst Publ Hlth, Natl Inst Hyg, Warsaw, Poland..
    Wong, Jyh Eiin
    Univ Kebangsaan Malaysia, Bangi 43600, Malaysia..
    Wong, Tien Yin
    Duke NUS Grad Med Sch, Singapore, Singapore..
    Woo, Jean
    Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China..
    Woodward, Mark
    Univ Sydney, Sydney, NSW 2006, Australia.;Univ Oxford, Oxford OX1 2JD, England..
    Wu, Frederick C.
    Univ Manchester, Manchester M13 9PL, Lancs, England..
    Wu, Jianfeng
    Shandong Univ Tradit Chinese Med, Jinan, Lixia, Peoples R China..
    Wu, Shou Ling
    Kailun Gen Hosp, Tangshan, Hebei, Peoples R China..
    Xu, Haiquan
    Minist Agr, Inst Food & Nutr Dev, Beijing, Peoples R China..
    Xu, Liang
    Capital Med Univ, Beijing, Peoples R China..
    Yamborisut, Uruwan
    Mahidol Univ, Bangkok 10700, Thailand..
    Yan, Weili
    Fudan Univ, Childrens Hosp, Minhang, Shanghai, Peoples R China..
    Yang, Xiaoguang
    Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China..
    Yardim, Nazan
    Minist Hlth, Ankara, Turkey..
    Ye, Xingwang
    Univ Chinese Acad Sci, Beijing, Peoples R China..
    Yiallouros, Panayiotis K.
    Univ Cyprus, CY-1678 Nicosia, Cyprus..
    Yoshihara, Akihiro
    Niigata Univ, Niigata 95021, Japan..
    You, Qi Sheng
    Capital Med Univ, Beijing, Peoples R China..
    Younger-Coleman, Novie O.
    Univ West Indies, Kingston, Jamaica..
    Yusoff, Ahmad F.
    Minist Hlth Malaysia, Putrajaya, Malaysia..
    Zainuddin, Ahmad A.
    Univ Teknol MARA, Shah Alam, Selangor, Malaysia..
    Zambon, Sabina
    Univ Padua, I-35100 Padua, Italy..
    Zdrojewski, Tomasz
    Med Univ Gdansk, Gdansk, Poland..
    Zeng, Yi
    Duke Univ, Durham, NC 27706 USA..
    Zhao, Dong
    Capital Med Univ, Beijing Anzhen Hosp, Beijing, Peoples R China..
    Zhao, Wenhua
    Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China..
    Zheng, Yingfeng
    Singapore Eye Res Inst, Singapore, Singapore..
    Zhou, Maigeng
    Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China..
    Zhu, Dan
    Inner Mongolia Med Univ, Hohhot, Inner Mongolia, Peoples R China..
    Zimmermann, Esther
    Bispebjerg Hosp, Copenhagen, Denmark.;Frederiksberg Univ Hosp, Frederiksberg, Denmark..
    Cisneros, Julio Zuniga
    Gorgas Mem Inst Publ Hlth, Panama City, Panama..
    A century of trends in adult human height2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e13410Article in journal (Refereed)
    Abstract [en]

    Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.

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    Wilsgaard, Tom
    Wojtyniak, Bogdan
    Wong, Jyh Eiin
    Wong, Tien Yin
    Woo, Jean
    Woodward, Mark
    Wu, Frederick C.
    Wu, Jianfeng
    Wu, Shou Ling
    Xu, Haiquan
    Xu, Liang
    Yamborisut, Uruwan
    Yan, Weili
    Yang, Xiaoguang
    Yardim, Nazan
    Ye, Xingwang
    Yiallouros, Panayiotis K.
    Yoshihara, Akihiro
    You, Qi Sheng
    Younger-Coleman, Novie O.
    Yusoff, Ahmad F.
    Zainuddin, Ahmad A.
    Zambon, Sabina
    Zdrojewski, Tomasz
    Zeng, Yi
    Zhao, Dong
    Zhao, Wenhua
    Zheng, Yingfeng
    Zhou, Maigeng
    Zhu, Dan
    Zimmermann, Esther
    Cisneros, Julio Zuniga
    A century of trends in adult human height2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e13410Article in journal (Refereed)
    Abstract [en]

    Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.

  • 9. Bentham, James
    et al.
    Ezzati, Majid
    A century of trends in adult human height2016In: eLIFE, E-ISSN 2050-084X, ISSN 2050-084X, Vol. 5, p. 1-29, article id e13410Article in journal (Refereed)
    Abstract [en]

    Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.

  • 10.
    Birznieks, Ingvars
    et al.
    UNSW Sydney, Australia; Neurosci Res Australia, Australia; Western Sydney Univ, Australia.
    Mcintyre, Sarah
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Neurosci Res Australia, Australia; Western Sydney Univ, Australia.
    Nilsson, Hanna Maria
    Linköping University. Sweden; Neurosci Res Australia, Australia.
    Nagi, Saad
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Western Sydney Univ, Australia.
    Macefield, Vaughan G.
    Neurosci Res Australia, Australia; Western Sydney Univ, Australia; Baker Heart and Diabet Inst, Australia.
    Mahns, David A.
    Western Sydney Univ, Australia.
    Vickery, Richard M.
    UNSW Sydney, Australia; Neurosci Res Australia, Australia.
    Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46510Article in journal (Refereed)
    Abstract [en]

    The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies amp;lt; 60 Hz) and vibratory hum (frequencies amp;gt; 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.

  • 11.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bass, Joseph
    Decoding obesity in the brainstem.2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e16393Article in journal (Refereed)
    Abstract [en]

    Neurons in the brainstem are the input for a neural circuit that integrates nutrient signals to control feeding behavior.

  • 12.
    Chen, Ruoqing
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Regodón Wallin, Amanda
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Valdimarsdóttir, Unnur
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Ye, Weimin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Tiemeier, Henning
    Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Child and Adolescent Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Czene, Kamila
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Childhood injury after a parental cancer diagnosis2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e08500Article in journal (Refereed)
    Abstract [en]

    A parental cancer diagnosis is psychologically straining for the whole family. We investigated whether a parental cancer diagnosis is associated with a higher-than-expected risk of injury among children by using a Swedish nationwide register-based cohort study. Compared to children without parental cancer, children with parental cancer had a higher rate of hospital contact for injury during the first year after parental cancer diagnosis (hazard ratio [HR]=1.27, 95% confidence interval [CI]=1.22-1.33), especially when the parent had a comorbid psychiatric disorder after cancer diagnosis (HR=1.41, 95% CI=1.08-1.85). The rate increment declined during the second and third year after parental cancer diagnosis (HR=1.10, 95% CI=1.07-1.14) and became null afterwards (HR=1.01, 95% CI=0.99-1.03). Children with parental cancer also had a higher rate of repeated injuries than the other children (HR=1.13, 95% CI= 1.12-1.15). Given the high rate of injury among children in the general population, our findings may have important public health implications.

  • 13.
    Clement, Alice
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Flinders Univ S Australia, Coll Sci & Engn, Adelaide, SA, Australia;Museum Victoria, Dept Sci, Melbourne, Vic, Australia.
    King, Benedict
    Flinders Univ S Australia, Coll Sci & Engn, Adelaide, SA, Australia;Nat Biodivers Ctr, Leiden, Netherlands.
    Giles, Sam
    Univ Oxford, Dept Earth Sci, Oxford, England.
    Choo, Brian
    Flinders Univ S Australia, Coll Sci & Engn, Adelaide, SA, Australia.
    Ahlberg, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Young, Gavin C.
    Australian Natl Univ, Res Sch Phys & Engn, Dept Appl Math, Canberra, ACT, Australia;Australian Museum, Res Inst, Sydney, NSW, Australia.
    Long, John A.
    Flinders Univ S Australia, Coll Sci & Engn, Adelaide, SA, Australia;Museum Victoria, Dept Sci, Melbourne, Vic, Australia.
    Neurocranial anatomy of an enigmatic Early Devonian fish sheds light on early osteichthyan evolution2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e34349Article in journal (Refereed)
    Abstract [en]

    The skull of 'Ligulalepis' from the Early Devonian of Australia (AM-F101607) has significantly expanded our knowledge of early osteichthyan anatomy, but its phylogenetic position has remained uncertain. We herein describe a second skull of 'Ligulalepis' and present micro-CT data on both specimens to reveal novel anatomical features, including cranial endocasts. Several features previously considered to link 'Ligulalepis' with actinopterygians are now considered generalized osteichthyan characters or of uncertain polarity. The presence of a lateral cranial canal is shown to be variable in its development between specimens. Other notable new features include the presence of a pineal foramen, the some detail of skull roof sutures, the shape of the nasal capsules, a placoderm-like hypophysial vein, and a chondrichthyan-like labyrinth system. New phylogenetic analyses place 'Ligulalepis' as a stem osteichthyan, specifically as the sister taxon to 'psarolepids' plus crown osteichthyans. The precise position of 'psarolepids' differs between parsimony and Bayesian analyses.

  • 14. de Boer, Lieke
    et al.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Dayan, Peter
    Backman, Lars
    Guitart-Masip, Marc
    Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e2642Article in journal (Refereed)
    Abstract [en]

    Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.

  • 15. Dijk, Wieneke
    et al.
    Heine, Markus
    Vergnes, Laurent
    Boon, Mariëtte R.
    Schaart, Gert
    Hesselink, Matthijs K. C.
    Reue, Karen
    Lichtenbelt, Wouter D. van Marken
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Rensen, Patrick C. N.
    Heeren, Joerg
    Kersten, Sander
    ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e08428Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold.

  • 16.
    Farsi, Zohreh
    et al.
    Max Planck Inst Biophys Chem, Dept Neurobiol, Gottingen, Germany.;Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany..
    Gowrisankaran, Sindhuja
    Univ Med Ctr Gottingen, European Neurosci Inst, Synapt Vesicle Dynam Grp, Gottingen, Germany..
    Krunic, Matija
    Univ Med Ctr Gottingen, European Neurosci Inst, Synapt Vesicle Dynam Grp, Gottingen, Germany..
    Rammner, Burkhard
    Sciloop, Hamburg, Germany..
    Woehler, Andrew
    Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany..
    Lafer, Eileen M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA.;Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA..
    Mim, Carsten
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Jahn, Reinhard
    Max Planck Inst Biophys Chem, Dept Neurobiol, Gottingen, Germany..
    Milosevic, Ira
    Univ Med Ctr Gottingen, European Neurosci Inst, Synapt Vesicle Dynam Grp, Gottingen, Germany..
    Clathrin coat controls synaptic vesicle acidification by blocking vacuolar ATPase activity2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e32569Article in journal (Refereed)
    Abstract [en]

    Newly-formed synaptic vesicles (SVs) are rapidly acidified by vacuolar adenosine triphosphatases (vATPases), generating a proton electrochemical gradient that drives neurotransmitter loading. Clathrin-mediated endocytosis is needed for the formation of new SVs, yet it is unclear when endocytosed vesicles acidify and refill at the synapse. Here, we isolated clathrin-coated vesicles (CCVs) from mouse brain to measure their acidification directly at the single vesicle level. We observed that the ATP-induced acidification of CCVs was strikingly reduced in comparison to SVs. Remarkably, when the coat was removed from CCVs, uncoated vesicles regained ATP-dependent acidification, demonstrating that CCVs contain the functional vATPase, yet its function is inhibited by the clathrin coat. Considering the known structures of the vATPase and clathrin coat, we propose a model in which the formation of the coat surrounds the vATPase and blocks its activity. Such inhibition is likely fundamental for the proper timing of SV refilling.

  • 17.
    Feng, Chungang
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pettersson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rafati, Nima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Casini, Michele
    Swedish Univ Agr Sci, Dept Aquat Resources, Inst Marine Res, Lysekil, Sweden..
    Folkvord, Arild
    Univ Bergen, Dept Biol, Bergen, Norway.;Hjort Ctr Marine Ecosyst Dynam, Bergen, Norway.;Inst Marine Res, Bergen, Norway..
    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. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Moderate nucleotide diversity in the Atlantic herring is associated with a low mutation rate2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23907Article in journal (Refereed)
    Abstract [en]

    The Atlantic herring is one of the most abundant vertebrates on earth but its nucleotide diversity is moderate (pi = 0.3%), only three-fold higher than in human. Here, we present a pedigree-based estimation of the mutation rate in this species. Based on whole-genome sequencing of four parents and 12 offspring, the estimated mutation rate is 2.0 x 10(-9) per base per generation. We observed a high degree of parental mosaicism indicating that a large fraction of these de novo mutations occurred during early germ cell development. The estimated mutation rate the lowest among vertebrates analyzed to date - partially explains the discrepancy between the rather low nucleotide diversity in herring and its huge census population size. But a species like the herring will never reach its expected nucleotide diversity because of fluctuations in population size over the millions of years it takes to build up high nucleotide diversity.

  • 18.
    Forcier, Talitha L.
    et al.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA.
    Ayaz, Andalus
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA.
    Gill, Manraj S.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA;MIT, Dept Biol, Cambridge, MA 02139 USA.
    Jones, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA;CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA.
    Phillips, Rob
    CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA.
    Kinney, Justin B.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA.
    Measuring cis-regulatory energetics in living cells using allelic manifolds2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e40618Article in journal (Refereed)
    Abstract [en]

    Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of 'allelic manifolds', a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and sigma(70) RNA polymerase. Doing so, we consistently obtained energetic measurements precise to similar to 0.1 kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.

    Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).

  • 19.
    Grimm, Lin
    et al.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld, Australia.
    Nakajima, Hiroyuki
    Natl Cerebral & Cardiovasc Ctr Res Inst, Dept Cell Biol, Osaka, Japan.
    Chaudhury, Smrita
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld, Australia.
    Bower, Neil, I
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld, Australia.
    Okuda, Kazuhide S.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld, Australia.
    Cox, Andrew G.
    Peter MacCallum Canc Ctr, Organogenesis & Canc Program, Canc Metab Program, Melbourne, Vic, Australia;Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic, Australia.
    Harvey, Natasha L.
    Univ South Australia, SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld, Australia.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr Res Inst, Dept Cell Biol, Osaka, Japan.
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld, Australia.
    Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e42881Article in journal (Refereed)
    Abstract [en]

    Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. The Hippo pathway and effectors Yap and Taz control organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that YAP displays dynamic changes in lymphatic progenitors and Yap1 is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear YAP in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage.

  • 20.
    Grinberg, Inna Rozman
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lundin, Daniel
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Hasan, Mahmudul
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Lund Univ, Dept Biochem & Struct Biol, Lund, Sweden..
    Crona, Mikael
    Swedish Ophan Biovitrum AB, Stockholm, Sweden..
    Jonna, Venkateswara Rao
    Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden..
    Loderer, Chrishtoph
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Sahlin, Margareta
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Markova, Natalia
    Malvern Instruments Inc, Malvern, Sweden..
    Borovok, Ilya
    Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, Tel Aviv, Israel..
    Berggren, Gustav
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Hofer, Anders
    Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden..
    Logan, Derek T.
    Lund Univ, Dept Biochem & Struct Biol, Lund, Sweden..
    Sjöberg, Britt-Marie
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e31529Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, the ATP-cone, has been found exclusively in the catalytic subunit. In two class I RNR subclasses whose catalytic subunit lacks the ATP-cone, we discovered ATP-cones in the radical-generating subunit. The ATP-cone in the Leeuwenhoekiella blandensis radical-generating subunit regulates activity via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP induces non-productive tetramers, resulting in different holoenzymes. The tetramer forms by interactions between ATP-cones, shown by a 2.45 A crystal structure. We also present evidence for an (MnMnIV)-Mn-III metal center. In summary, lack of an ATP-cone domain in the catalytic subunit was compensated by transfer of the domain to the radical-generating subunit. To our knowledge, this represents the first observation of transfer of an allosteric domain between components of the same enzyme complex.

  • 21.
    Grinberg, Inna Rozman
    et al.
    Stockholm University.
    Lundin, Daniel
    Stockholm University.
    Hasan, Mahmudul
    Stockholm University ; Lund University.
    Crona, Mikael
    Swedish Ophan Biovitrum AB.
    Jonna, Venkateswara Rao
    Umeå University.
    Loderer, Chrishtoph
    Stockholm University.
    Sahlin, Margareta
    Stockholm University.
    Markova, Natalia
    Malvern Instruments Inc.
    Borovok, Ilya
    Tel Aviv University, Israel.
    Berggren, Gustav
    Uppsala University.
    Hofer, Anders
    Umeå University.
    Logan, Derek T.
    Lund University.
    Sjöberg, Britt-Marie
    Stockholm University.
    Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e31529Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, the ATP-cone, has been found exclusively in the catalytic subunit. In two class I RNR subclasses whose catalytic subunit lacks the ATP-cone, we discovered ATP-cones in the radical-generating subunit. The ATP-cone in the Leeuwenhoekiella blandensis radical-generating subunit regulates activity via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP induces non-productive tetramers, resulting in different holoenzymes. The tetramer forms by interactions between ATP-cones, shown by a 2.45 A crystal structure. We also present evidence for an (MnMnIV)-Mn-III metal center. In summary, lack of an ATP-cone domain in the catalytic subunit was compensated by transfer of the domain to the radical-generating subunit. To our knowledge, this represents the first observation of transfer of an allosteric domain between components of the same enzyme complex.

  • 22. Guan, Jikui
    et al.
    Umapathy, Ganesh
    Yamazaki, Yasuo
    Wolfstetter, Georg
    Mendoza-Garcia, Patricia
    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Pfeifer, Kathrin
    Mohammed, Ateequrrahman
    Hugosson, Fredrik
    Zhang, Hongbing
    Hsu, Amy W
    Halenbeck, Robert
    Hallberg, Bengt
    Palmer, Ruth H
    FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e09811Article in journal (Refereed)
    Abstract [en]

    Aberrant activation of anaplastic lymphoma kinase (ALK) has been described in a range of human cancers, including non-small cell lung cancer and neuroblastoma (Hallberg and Palmer, 2013). Vertebrate ALK has been considered to be an orphan receptor and the identity of the ALK ligand(s) is a critical issue. Here we show that FAM150A and FAM150B are potent ligands for human ALK that bind to the extracellular domain of ALK and in addition to activation of wild-type ALK are able to drive 'superactivation' of activated ALK mutants from neuroblastoma. In conclusion, our data show that ALK is robustly activated by the FAM150A/B ligands and provide an opportunity to develop ALK-targeted therapies in situations where ALK is overexpressed/activated or mutated in the context of the full length receptor.

  • 23.
    Gucek, Alenka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gandasi, Nikhil R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Omar-Hmeadi, Muhmmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bakke, Marit
    Univ Bergen, Dept Biomed, Bergen, Norway.
    Doskeland, Stein O.
    Univ Bergen, Dept Biomed, Bergen, Norway.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e41711Article in journal (Refereed)
    Abstract [en]

    Regulated exocytosis establishes a narrow fusion pore as initial aqueous connection to the extracellular space, through which small transmitter molecules such as ATP can exit. Co-release of polypeptides and hormones like insulin requires further expansion of the pore. There is evidence that pore expansion is regulated and can fail in diabetes and neurodegenerative disease. Here, we report that the cAMP-sensor Epac2 (Rap-GEF4) controls fusion pore behavior by acutely recruiting two pore-restricting proteins, amisyn and dynamin-1, to the exocytosis site in insulin-secreting beta-cells. cAMP elevation restricts and slows fusion pore expansion and peptide release, but not when Epac2 is inactivated pharmacologically or in Epac2(-/-) (Rapgef4(-/-)) mice. Consistently, overexpression of Epac2 impedes pore expansion. Widely used antidiabetic drugs (GLP-1 receptor agonists and sulfonylureas) activate this pathway and thereby paradoxically restrict hormone release. We conclude that Epac2/cAMP controls fusion pore expansion and thus the balance of hormone and transmitter release during insulin granule exocytosis.

  • 24.
    Harada, Bryan T.
    et al.
    Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA.;Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA..
    Hwang, William L.
    Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA.;Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.;Harvard Univ, Sch Med, Harvard MIT MD PhD Program, Boston, MA USA..
    Deindl, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.;Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA..
    Chatterjee, Nilanjana
    Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Smithville, TX USA.;Univ Calif San Francisco, Sch Med, San Francisco, CA USA..
    Bartholomew, Blaine
    Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Smithville, TX USA..
    Zhuang, Xiaowei
    Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA.;Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.;Harvard Univ, Dept Phys, Cambridge, MA 02138 USA..
    Stepwise nucleosome translocation by RSC remodeling complexes2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e10051Article in journal (Refereed)
    Abstract [en]

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1-2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome.

  • 25.
    Holm, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Mandava, Chandra Sekhar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    The mechanism of error induction by the antibiotic viomycin provides insight into the fidelity mechanism of translation2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46124Article in journal (Refereed)
    Abstract [en]

    Applying pre-steady state kinetics to an Escherichia-coli-based reconstituted translation system, we have studied how the antibiotic viomycin affects the accuracy of genetic code reading. We find that viomycin binds to translating ribosomes associated with a ternary complex (TC) consisting of elongation factor Tu (EF-Tu), aminoacyl tRNA and GTP, and locks the otherwise dynamically flipping monitoring bases A1492 and A1493 into their active conformation. This effectively prevents dissociation of near- and non-cognate TCs from the ribosome, thereby enhancing errors in initial selection. Moreover, viomycin shuts down proofreading-based error correction. Our results imply a mechanism in which the accuracy of initial selection is achieved by larger backward rate constants toward TC dissociation rather than by a smaller rate constant for GTP hydrolysis for near- and non-cognate TCs. Additionally, our results demonstrate that translocation inhibition, rather than error induction, is the major cause of cell growth inhibition by viomycin.

  • 26.
    Hu, Xuchen
    et al.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Matsumoto, Ken
    VIB KU Leuven Ctr Canc Biol CCB, Leuven, Belgium.
    Jung, Rachel S.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Weston, Thomas A.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Heizer, Patrick J.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    He, Cuiwen
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Sandoval, Norma P.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Allan, Christopher M.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Tu, Yiping
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Vinters, Harry V.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA.
    Liau, Linda M.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurosurg, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, David Geffen Sch Med, JCCC, Los Angeles, CA 90095 USA.
    Ellison, Rochelle M.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Morales, Jazmin E.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Baufeld, Lynn J.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, David Geffen Sch Med, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA.
    Bayley, Nicholas A.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, David Geffen Sch Med, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden.
    Beigneux, Anne P., I
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Nathanson, David A.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, David Geffen Sch Med, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA.
    Gerhardt, Holger
    VIB KU Leuven Ctr Canc Biol CCB, Leuven, Belgium;Max Delbruck Ctr Mol Med, Berlin, Germany.
    Young, Stephen G.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA.
    Fong, Loren G.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.
    Jian, Haibo
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA;Univ Western Australia, Sch Mol Sci, Perth, WA, Australia.
    GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e47178Article in journal (Refereed)
    Abstract [en]

    GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent from the capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in the capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We use NanoSIMS imaging to show that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.

  • 27.
    Hultqvist, Greta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Åberg, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Camilloni, Carlo
    Univ Cambridge, Dept Chem, Cambridge, England.;Tech Univ Munich, Dept Chem, Munich, Germany.;Tech Univ Munich, Inst Adv Study, Munich, Germany..
    Sundell, Gustav
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Andersson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dogan, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Chi, Celestine N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ETH, Lab Phys Chem, Zurich, Switzerland.
    Vendruscolo, Michele
    Univ Cambridge, Dept Chem, Cambridge, England.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden..
    Emergence and evolution of an interaction between intrinsically disordered proteins2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e16059Article in journal (Refereed)
    Abstract [en]

    Protein-protein interactions involving intrinsically disordered proteins are important for cellular function and common in all organisms. However, it is not clear how such interactions emerge and evolve on a molecular level. We performed phylogenetic reconstruction, resurrection and biophysical characterization of two interacting disordered protein domains, CID and NCBD. CID appeared after the divergence of protostomes and deuterostomes 450-600 million years ago, while NCBD was present in the protostome/deuterostome ancestor. The most ancient CID/NCBD formed a relatively weak complex (K(d similar to)5 mu M). At the time of the first vertebrate-specific whole genome duplication, the affinity had increased (K-d\similar to 200 nM) and was maintained in further speciation. Experiments together with molecular modeling using NMR chemical shifts suggest that new interactions involving intrinsically disordered proteins may evolve via a low-affinity complex which is optimized by modulating direct interactions as well as dynamics, while tolerating several potentially disruptive mutations.

  • 28. Hultqvist, Greta
    et al.
    Åberg, Emma
    Camilloni, Carlo
    Sundell, Gustav N.
    Andersson, Eva
    Dogan, Jakob
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Uppsala University, Sweden.
    Chi, Celestine N.
    Vendruscolo, Michele
    Jemth, Per
    Emergence and evolution of an interaction between intrinsically disordered proteins2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e16059Article in journal (Refereed)
    Abstract [en]

    Protein-protein interactions involving intrinsically disordered proteins are important for cellular function and common in all organisms. However, it is not clear how such interactions emerge and evolve on a molecular level. We performed phylogenetic reconstruction, resurrection and biophysical characterization of two interacting disordered protein domains, CID and NCBD. CID appeared after the divergence of protostomes and deuterostomes 450-600 million years ago, while NCBD was present in the protostome/deuterostome ancestor. The most ancient CID/NCBD formed a relatively weak complex (K(d similar to)5 mu M). At the time of the first vertebrate-specific whole genome duplication, the affinity had increased (K-d\similar to 200 nM) and was maintained in further speciation. Experiments together with molecular modeling using NMR chemical shifts suggest that new interactions involving intrinsically disordered proteins may evolve via a low-affinity complex which is optimized by modulating direct interactions as well as dynamics, while tolerating several potentially disruptive mutations.

  • 29. Jelenkovic, A.
    et al.
    Hur, Y. -M
    Sund, R.
    Yokoyama, Y.
    Siribaddana, S. H.
    Hotopf, M.
    Sumathipala, A.
    Rijsdijk, F.
    Tan, Q.
    Zhang, D.
    Pang, Z.
    Aaltonen, S.
    Heikkilä, K.
    Öncel, S.Y.
    Aliev, F.
    Rebato, E.
    Tarnoki, A. D.
    Tarnoki, D. L.
    Christensen, K.
    Skytthe, A.
    Kyvik, K. O.
    Silberg, J. L.
    Eaves, L. J.
    Maes, H. H.
    Cutler, T. L.
    Hopper, J. L.
    Ordoñana, J. R.
    Sánchez-Romera, J. F.
    Colodro-Conde, L.
    Cozen, W.
    Hwang, A. E.
    Mack, T. M.
    Sung, J.
    Song, Y. -M
    Yang, S.
    Lee, K.
    Franz, C. E.
    Kremen, W. S.
    Lyons, M. J.
    Busjahn, A.
    Nelson, T. L.
    Whitfield, K. E.
    Kandler, C.
    Jang, K. L.
    Gatz, M.
    Butler, D. A.
    Stazi, M. A.
    Fagnani, C.
    D’Ippolito, C.
    Duncan, G. E.
    Buchwald, D.
    Derom, C. A.
    Vlietinck, R. F.
    Loos, R. J.
    Martin, N. G.
    Medland, S. E.
    Montgomery, G. W.
    Jeong, H. -U
    Swan, G. E.
    Krasnow, R.
    Magnusson, P. K.
    Pedersen, N. L.
    Dahl-Aslan, Anna K.
    Jönköping University, School of Health and Welfare, HHJ, Institute of Gerontology. Jönköping University, School of Health and Welfare, HHJ. ARN-J (Aging Research Network - Jönköping).
    McAdams, T. A.
    Eley, T. C.
    Gregory, A. M.
    Tynelius, P.
    Baker, L. A.
    Tuvblad, C.
    Bayasgalan, G.
    Narandalai, D.
    Lichtenstein, P.
    Spector, T. D.
    Mangino, M.
    Lachance, G.
    Bartels, M.
    Van Beijsterveldt, T. C.
    Willemsen, G.
    Alexandra Burt, S.
    Klump, K. L.
    Harris, J. R.
    Brandt, I.
    Nilsen, T. S.
    Krueger, R. F.
    McGue, M.
    Pahlen, S.
    Corley, R. P.
    Hjelmborg, J. V. B.
    Goldberg, J. H.
    Iwatani, Y.
    Watanabe, M.
    Honda, C.
    Inui, F.
    Rasmussen, F.
    Huibregtse, B. M.
    Boomsma, D. I.
    Sørensen, T. I. A.
    Kaprio, J.
    Silventoinen, K.
    Genetic and environmental influences on adult human height across birth cohorts from 1886 to 19942016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e20320Article in journal (Refereed)
    Abstract [en]

    Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

  • 30.
    Jelenkovic, Aline
    et al.
    Department of Social Research, University of Helsinki, Helsinki, Finland; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, Los Angeles, United States.
    Silvertoinen, Karri
    Department of Social Research, University of Helsinki, Helsinki, Finland; Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan.
    Genetic and environmental influences on adult human height across birth cohorts from 1886 to 19942016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e20320Article in journal (Refereed)
    Abstract [en]

    Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

  • 31. Kaucka, Marketa
    et al.
    Zikmund, Tomas
    Tesarova, Marketa
    Gyllborg, Daniel
    Hellander, Andreas
    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.
    Jaros, Josef
    Kaiser, Jozef
    Petersen, Julian
    Szarowska, Bara
    Newton, Phillip T.
    Dyachuk, Vyacheslav
    Li, Lei
    Qian, Hong
    Johansson, Anne-Sofie
    Mishina, Yuji
    Currie, Josh
    Tanaka, Elly M.
    Erickson, Alek
    Dudley, Andrew
    Brismar, Hjalmar
    Southam, Paul
    Coen, Enrico
    Chen, Min
    Weinstein, Lee S.
    Hampl, Ales
    Arenas, Ernest
    Chagin, Andrei S.
    Fried, Kaj
    Adameyko, Igor
    Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e25902Article in journal (Refereed)
  • 32. Kaucka, Marketa
    et al.
    Zikmund, Tomas
    Tesarova, Marketa
    Gyllborg, Daniel
    Hellander, Andreas
    Jaros, Josef
    Kaiser, Jozef
    Petersen, Julian
    Szarowska, Bara
    Newton, Phillip T.
    Dyachuk, Vyacheslav
    li, Lei
    Qian, Hong
    Johansson, Anne-Sofie
    Mishina, Yuji
    Currie, Joshua D.
    Tanaka, Elly M.
    Erickson, Alek
    Dudley, Andrew
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Southam, Paul
    Coen, Enrico
    Chen, Min
    Weinstein, Lee S.
    Hampl, Ales
    Arenas, Ernest
    Chagin, Andrei S.
    Fried, Kaj
    Adameyko, Igor
    Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e25902Article in journal (Refereed)
    Abstract [en]

    Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale.

  • 33. Kimanius, Dari
    et al.
    Forsberg, Bjorn O.
    Scheres, Sjors H. W.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. Stockholm University, Sweden.
    Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-22016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e18722Article in journal (Refereed)
    Abstract [en]

    By reaching near-atomic resolution for a wide range of specimens, single-particle cryo-EM structure determination is transforming structural biology. However, the necessary calculations come at large computational costs, which has introduced a bottleneck that is currently limiting throughput and the development of new methods. Here, we present an implementation of the RELION image processing software that uses graphics processors (GPUs) to address the most computationally intensive steps of its cryo-EM structure determination workflow. Both image classification and high-resolution refinement have been accelerated more than an order-of-magnitude, and template-based particle selection has been accelerated well over two orders-of-magnitude on desktop hardware. Memory requirements on GPUs have been reduced to fit widely available hardware, and we show that the use of single precision arithmetic does not adversely affect results. This enables high-resolution cryo-EM structure determination in a matter of days on a single workstation.

  • 34.
    Kimanius, Dari
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Forsberg, Björn O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Scheres, Sjors H. W.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-22016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e18722Article in journal (Refereed)
    Abstract [en]

    By reaching near-atomic resolution for a wide range of specimens, single-particle cryo-EM structure determination is transforming structural biology. However, the necessary calculations come at large computational costs, which has introduced a bottleneck that is currently limiting throughput and the development of new methods. Here, we present an implementation of the RELION image processing software that uses graphics processors (GPUs) to address the most computationally intensive steps of its cryo-EM structure determination workflow. Both image classification and high-resolution refinement have been accelerated more than an order-of-magnitude, and template-based particle selection has been accelerated well over two orders-of-magnitude on desktop hardware. Memory requirements on GPUs have been reduced to fit widely available hardware, and we show that the use of single precision arithmetic does not adversely affect results. This enables high-resolution cryo-EM structure determination in a matter of days on a single workstation.

  • 35. Koenig, Daniel
    et al.
    Hagmann, Jörg
    Li, Rachel
    Bemm, Felix
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Nueffer, Barbara
    Wright, Stephen
    Weigel, Detlef
    Long-term balancing selection drives evolution of immunity genes in Capsella2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e43606Article in journal (Refereed)
    Abstract [en]

    Genetic drift is expected to remove polymorphism from populations over long periods of time, with the rate of polymorphism loss being accelerated when species experience strong reductions in population size. Adaptive forces that maintain genetic variation in populations, or balancing selection, might counteract this process. To understand the extent to which natural selection can drive the retention of genetic diversity, we document genomic variability after two parallel species-wide bottlenecks in the genus Capsella. We find that ancestral variation preferentially persists at immunity related loci, and that the same collection of alleles has been maintained in different lineages that have been separated for several million years. By reconstructing the evolution of the disease-related locus MLO2b, we find that divergence between ancient haplotypes can be obscured by referenced based re-sequencing methods, and that trans-specific alleles can encode substantially diverged protein sequences. Our data point to long-term balancing selection as an important factor shaping the genetics of immune systems in plants and as the predominant driver of genomic variability after a population bottleneck.

  • 36.
    Krotee, Pascal
    et al.
    Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
    Rodriguez, Jose A.
    Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
    Sawaya, Michael R.
    Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
    Cascio, Duilio
    Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
    Reyes, Francis E.
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA..
    Shi, Dan
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA..
    Hattne, Johan
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA..
    Nannenga, Brent L.
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA..
    Oskarsson, Marie E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Philipp, Stephan
    Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA..
    Griner, Sarah
    Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
    Jiang, Lin
    Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA.;Univ Calif Los Angeles, BRI, Los Angeles, CA USA..
    Glabe, Charles G.
    Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA.;King Abdulaziz Univ, Dept Biochem, Fac Sci, Jeddah, Saudi Arabia.;King Abdulaziz Univ, King Fahd Med Res Ctr, Expt Biochem Unit, Jeddah, Saudi Arabia..
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gonen, Tamir
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA..
    Eisenberg, David S.
    Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
    Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity2017In: eLIFE, E-ISSN 2050-084X, Vol. 6Article in journal (Refereed)
    Abstract [en]

    hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic beta-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of beta-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile beta-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.

  • 37.
    Kudva, Renuka
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tian, Pengfei
    Pardo-Avila, Fátima
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Best, Robert B.
    Bernstein, Harris D.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The shape of the bacterial ribosome exit tunnel affects cotranslational protein folding2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e36326Article in journal (Refereed)
    Abstract [en]

    The E. coli ribosome exit tunnel can accommodate small folded proteins, while larger ones fold outside. It remains unclear, however, to what extent the geometry of the tunnel influences protein folding. Here, using E. coli ribosomes with deletions in loops in proteins uL23 and uL24 that protrude into the tunnel, we investigate how tunnel geometry determines where proteins of different sizes fold. We find that a 29-residue zinc-finger domain normally folding close to the uL23 loop folds deeper in the tunnel in uL23 Delta loop ribosomes, while two similar to 100 residue proteins normally folding close to the uL24 loop near the tunnel exit port fold at deeper locations in uL24 Delta loop ribosomes, in good agreement with results obtained by coarse-grained molecular dynamics simulations. This supports the idea that cotranslational folding commences once a protein domain reaches a location in the exit tunnel where there is sufficient space to house the folded structure.

  • 38. Kur, Esther
    et al.
    Kim, Jiha
    Tata, Aleksandra
    Comin, Cesar H
    Harrington, Kyle I
    Costa, Luciano da F
    Bentley, Katie
    Gu, Chenghua
    Temporal modulation of collective cell behavior controls vascular network topology.2016In: eLIFE, E-ISSN 2050-084X, Vol. 5Article in journal (Refereed)
    Abstract [en]

    Vascular network density determines the amount of oxygen and nutrients delivered to host tissues, but how the vast diversity of densities is generated is unknown. Reiterations of endothelial-tip-cell selection, sprout extension and anastomosis are the basis for vascular network generation, a process governed by VEGF/Notch feedback loop. Here, we find that temporal regulation of this feedback loop, a previously unexplored dimension, is the key mechanism to determine vascular density. Iterating between computational modeling and in vivo live imaging, we demonstrate that the rate of tip-cell selection determines the length of linear sprout extension at the expense of branching, dictating network density. We provide the first example of a host tissue-derived signal (Semaphorin3E-Plexin-D1) that accelerates tip cell selection rate, yielding a dense network. We propose that temporal regulation of this critical, iterative aspect of network formation could be a general mechanism, and additional temporal regulators may exist to sculpt vascular topology.

  • 39.
    Landegren, Nils
    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. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.
    Rosen, Lindsey B.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Bioinformat Infrastruct, Dept Med Sci, Uppsala, Sweden.
    Eriksson, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Smith, Gustav
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;MIT, Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02139 USA;Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden.
    Ferre, Elise M. N.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Brodin, Petter
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, Stockholm, Sweden;Karolinska Univ Hosp, Dept Newborn Med, Stockholm, Sweden.
    Sharon, Donald
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Snyder, Michael
    Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden;Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Lionakis, Michail
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Anderson, Mark
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Kampe, Olle
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Univ Bergen, KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e43578Article in journal (Other academic)
    Abstract [en]

    The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.

  • 40.
    Larsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Univ Miami, FL USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    KCNE1 tunes the sensitivity a: K(v)7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e37257Article in journal (Refereed)
    Abstract [en]

    The voltage-gated potassium channel K(v)7.1 and the auxiliary subunit KCNE1 together form the cardiac I-Ks channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate K(v)7.1 via an electrostatic mechanism. The activating effect was abolished when K(v)7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of K(v)7.1 restored PUFA effects on K(v)7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of K(v)7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on K(v)7.1. This mechanistic understanding of how KCNE1 alters K(v)7.1 pharmacology is essential for development of drugs targeting the I-Ks channel.

  • 41.
    Levendosky, Robert F.
    et al.
    Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD 21218 USA..
    Sabantsev, Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Deindl, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bowman, Gregory D.
    Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD 21218 USA..
    The Chd1 chromatin remodeler shifts hexasomes unidirectionally2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e21356Article in journal (Refereed)
    Abstract [en]

    Despite their canonical two-fold symmetry, nucleosomes in biological contexts are often asymmetric: functionalized with post-translational modifications (PTMs), substituted with histone variants, and even lacking H2A/H2B dimers. Here we show that the Widom 601 nucleosome positioning sequence can produce hexasomes in a specific orientation on DNA, providing a useful tool for interrogating chromatin enzymes and allowing for the generation of nucleosomes with precisely defined asymmetry. Using this methodology, we demonstrate that the Chd1 chromatin remodeler from Saccharomyces cerevisiae requires H2A/H2B on the entry side for sliding, and thus, unlike the back-and-forth sliding observed for nucleosomes, Chd1 shifts hexasomes unidirectionally. Chd1 takes part in chromatin reorganization surrounding transcribing RNA polymerase II (Pol II), and using asymmetric nucleosomes we show that ubiquitin-conjugated H2B on the entry side stimulates nucleosome sliding by Chd1. We speculate that biased nucleosome and hexasome sliding due to asymmetry contributes to the packing of arrays observed in vivo.

  • 42.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL, USA.
    Larsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Berro-Soria, Rene
    University of Miami, FL, USA.
    Hjorth Bentzen, Bo
    The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Larson, H. Peter
    University of Miami, FL, USA.
    Fatty acid analogue N-arachidonoyl taurine restores function of I-Ks channels with diverse long QT mutations2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e20272Article in journal (Refereed)
    Abstract [en]

    About 300 loss-of-function mutations in the I-Ks channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved I-Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.

  • 43.
    Lind, Peter A
    et al.
    New Zealand Institute for Advanced Study, Massey, New; Allan Wilson Centre for Molecular Ecology and Evolution, Massey University, Auckland.
    Farr, Andrew D
    Rainey, Paul B
    Experimental evolution reveals hidden diversity in evolutionary pathways2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e07074Article in journal (Refereed)
    Abstract [en]

    Replicate populations of natural and experimental organisms often show evidence of parallel genetic evolution, but the causes are unclear. The wrinkly spreader morph of Pseudomonas fluorescens arises repeatedly during experimental evolution. The mutational causes reside exclusively within three pathways. By eliminating these, 13 new mutational pathways were discovered with the newly arising WS types having fitnesses similar to those arising from the commonly passaged routes. Our findings show that parallel genetic evolution is strongly biased by constraints and we reveal the genetic bases. From such knowledge, and in instances where new phenotypes arise via gene activation, we suggest a set of principles: evolution proceeds firstly via pathways subject to negative regulation, then via promoter mutations and gene fusions, and finally via activation by intragenic gain-of-function mutations. These principles inform evolutionary forecasting and have relevance to interpreting the diverse array of mutations associated with clinically identical instances of disease in humans.

  • 44.
    Lind, Peter A
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). New Zealand Institute for Advanced Study, Massey University at Albany, Auckland, New Zealand.
    Libby, Eric
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. New Zealand Institute for Advanced Study, Massey University at Albany, Auckland, New Zealand ; 3 Santa Fe Institute, New Mexico, United States.
    Herzog, Jenny
    Rainey, Paul B
    Predicting mutational routes to new adaptive phenotypes2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, p. 1-31, article id e38822Article in journal (Refereed)
    Abstract [en]

    Predicting evolutionary change poses numerous challenges. Here we take advantage of the model bacterium Pseudomonas fluorescens in which the genotype-to-phenotype map determining evolution of the adaptive ‘wrinkly spreader’ (WS) type is known. We present mathematical descriptions of three necessary regulatory pathways and use these to predict both the rate at which each mutational route is used and the expected mutational targets. To test predictions, mutation rates and targets were determined for each pathway. Unanticipated mutational hotspots caused experimental observations to depart from predictions but additional data led to refined models. A mismatch was observed between the spectra of WS-causing mutations obtained with and without selection due to low fitness of previously undetected WS-causing mutations. Our findings contribute toward the development of mechanistic models for forecasting evolution, highlight current limitations, and draw attention to challenges in predicting locus-specific mutational biases and fitness effects.

  • 45. Lump, Edina
    et al.
    Castellano, Laura M
    Meier, Christoph
    Seeliger, Janine
    Erwin, Nelli
    Sperlich, Benjamin
    Stürzel, Christina M
    Usmani, Shariq
    Hammond, Rebecca M
    von Einem, Jens
    Gerold, Gisa
    Kreppel, Florian
    Bravo-Rodriguez, Kenny
    Pietschmann, Thomas
    Holmes, Veronica M
    Palesch, David
    Zirafi, Onofrio
    Weissman, Drew
    Sowislok, Andrea
    Wettig, Burkhard
    Heid, Christian
    Kirchhoff, Frank
    Weil, Tanja
    Klärner, Frank-Gerrit
    Schrader, Thomas
    Bitan, Gal
    Sanchez-Garcia, Elsa
    Winter, Roland
    Shorter, James
    Münch, Jan
    A molecular tweezer antagonizes seminal amyloids and HIV infection2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e05397Article in journal (Refereed)
    Abstract [en]

    Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.

  • 46. Ly, T.
    et al.
    Whigham, A.
    Clarke, R.
    Brenes-Murillo, A. J.
    Estes, B.
    Mahdessian, Diana
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wadsworth, P.
    Lamond, A. I.
    Proteomic analysis of cell cycle progression in asynchronous cultures, including mitotic subphases, using PRIMMUS2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e27574Article in journal (Refereed)
    Abstract [en]

    The temporal regulation of protein abundance and post-translational modifications is a key feature of cell division. Recently, we analysed gene expression and protein abundance changes during interphase under minimally perturbed conditions (Ly et al., 2014, 2015). Here, we show that by using specific intracellular immunolabelling protocols, FACS separation of interphase and mitotic cells, including mitotic subphases, can be combined with proteomic analysis by mass spectrometry. Using this PRIMMUS (PRoteomic analysis of Intracellular iMMUnolabelled cell Subsets) approach, we now compare protein abundance and phosphorylation changes in interphase and mitotic fractions from asynchronously growing human cells. We identify a set of 115 phosphorylation sites increased during G2, termed ‘early risers’. This set includes phosphorylation of S738 on TPX2, which we show is important for TPX2 function and mitotic progression. Further, we use PRIMMUS to provide the first a proteome-wide analysis of protein abundance remodeling between prophase, prometaphase and anaphase.

  • 47.
    Mair, Andrea
    et al.
    Vienna, Austria.
    Pedrotti, Lorenzo
    Würzburg, Germany.
    Wurzinger, Bernhard
    Vienna, Austria.
    Anrather, Dorothea
    Vienna, Austria.
    Simeunovic, Andrea
    Vienna, Austria.
    Weiste, Christoph
    Würzburg, Germany.
    Valerio, Concetta
    Oeiras, Portugal.
    Dietrich, Katrin
    Würzburg, Germany.
    Kirchler, Tobias
    Tübingen, Germany.
    Nägele, Thomas
    Vienna, Austria.
    Vicente Carbajosa, Jesús
    Madrid, Spain.
    Hanson, Johannes
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Molecular Plant Physiology, Utrecht University, Utrecht, The Netherlands.
    Baena-González, Elena
    Oeiras, Portugal.
    Chaban, Christina
    Tübingen, Germany.
    Weckwerth, Wolfram
    Vienna, Austria.
    Dröge-Laser, Wolfgang
    Würzburg, Germany.
    Teige, Markus
    Vienna, Austria.
    SnRK1-triggered switch of bZIP63 dimerization mediates the low-energy response in plants2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e05828Article in journal (Refereed)
    Abstract [en]

    Metabolic adjustment to changing environmental conditions, particularly balancing of growth and defense responses, is crucial for all organisms to survive. The evolutionary conserved AMPK/Snf1/SnRK1 kinases are well-known metabolic master regulators in the low-energy response in animals, yeast and plants. They act at two different levels: by modulating the activity of key metabolic enzymes, and by massive transcriptional reprogramming. While the first part is well established, the latter function is only partially understood in animals and not at all in plants. Here we identified the Arabidopsis transcription factor bZIP63 as key regulator of the starvation response and direct target of the SnRK1 kinase. Phosphorylation of bZIP63 by SnRK1 changed its dimerization preference, thereby affecting target gene expression and ultimately primary metabolism. A bzip63 knock-out mutant exhibited starvation-related phenotypes, which could be functionally complemented by wild type bZIP63, but not by a version harboring point mutations in the identified SnRK1 target sites.

  • 48.
    Maldanis, L.
    et al.
    University of Campinas, Brazil; Brazilian Biosciences National Laboratory, Brazil.
    Carvalho, M.
    Brazilian Biosciences National Laboratory, Brazil; University of São Paulo, Brazil.
    Ramos Almeida, M.
    University of Campinas, Brazil.
    Freitas, F. I.
    Geopark Araripe, Brazil.
    De Andrade, J. A. F. G.
    Ministry of Mines and Energy, Brazil.
    Nunes, R. S.
    Brazilian Synchrotron Light Laboratory, Brazil.
    Rochitte, C. E.
    University of São Paulo, Brazil.
    Poppi, R. J.
    University of Campinas, Brazil.
    Freitas, R. O.
    Brazilian Synchrotron Light Laboratory, Brazil.
    Rodrigues, F.
    University of São Paulo, Brazil.
    Siljeström, Sandra
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Alves Lima, F.
    Brazilian Synchrotron Light Laboratory, Brazil.
    Galante, D.
    Brazilian Synchrotron Light Laboratory, Brazil.
    Carvalho, I. S.
    Federal University of Rio de Janeiro, Brazil.
    Perez, C. A.
    Brazilian Synchrotron Light Laboratory, Brazil.
    de Carvalho, M. R.
    University of São Paulo, Brazil.
    Bettini, J.
    Brazilian Nanotechnology National Laboratory, Brazil.
    Fernandez, V.
    European Synchrotron Radiation Facility, France.
    Xavier-Neto, J.
    Brazilian Biosciences National Laboratory, Brazil.
    Heart fossilization is possible and informs the evolution of cardiac outflow tract in vertebrates2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, no APRIL2016, article id e14698Article in journal (Refereed)
    Abstract [en]

    Elucidating cardiac evolution has been frustrated by lack of fossils. One celebrated enigma in cardiac evolution involves the transition from a cardiac outflow tract dominated by a Multi-Valved conus arteriosus in basal actinopterygians, to an outflow tract commanded by the Non- Valved, elastic, bulbus arteriosus in higher actinopterygians. We demonstrate that cardiac preservation is possible in the extinct fish Rhacolepis buccalis from the Brazilian Cretaceous. Using X-Ray synchrotron microtomography, we show that Rhacolepis fossils display hearts with a conus arteriosus containing at least five valve rows. This represents a transitional morphology between the primitive, multivalvar, conal condition and the derived, monovalvar, bulbar state of the outflow tract in modern actinopterygians. Our data rescue a Long-Lost cardiac phenotype (119-113 Ma) and suggest that outflow tract simplification in actinopterygians is compatible with a gradual, rather than a drastic saltation event. Overall, our results demonstrate the feasibility of studying cardiac evolution in fossils.

  • 49.
    Martínez Barrio, Álvaro
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fan, Guangyi
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; BGI-Shenzhen, Shenzen, China; 5 College of Physics, Qingdao University, Qingdao, China .
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, He
    BGI-Shenzhen, Shenzen, China; College of Physics, Qingdao University, Qingdao, China.
    Dainat, Jacques
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Xin
    BGI-Shenzhen, Shenzen, China.
    Chen, Wenbin
    BGI-Shenzhen, Shenzhen, China.
    Liang, Xinming
    BGI-Shenzhen, Shenzhen, China.
    Shi, Chengcheng
    BGI-Shenzhen, Shenzhen, China.
    Fu, Yuanyuan
    BGI-Shenzhen, Shenzhen, China.
    Ma, Kailong
    BGI-Shenzhen, Shenzhen, China.
    Zhan, Xiao
    BGI-Shenzhen, Shenzhen, China.
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafson, Ulla
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blass, Martina
    Department of Aquatic Resources, Institute of Coastal Research, Swedish University of Agricultural Sciences, Öregrund, Sweden.
    Casini, Michele
    Swedish University of Agricultural Sciences, Department of Aquatic Resources, Institute of Marine Research.
    Folkvord, Arild
    Department of Biology, University of Bergen, Bergen, Norway; Hjort Center of Marine Ecosystem Dynamics, Bergen, Norway; Institute of Marine Research, Bergen, Norway .
    Laikre, Linda
    Department of Zoology, Stockholm University.
    Ryman, Nils
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Lee, Simon Ming-Yuen Lee
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao.
    Xu, Xun
    BGI-Shenzhen, Shenzhen, China.
    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. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Veterinary Integrative Biosciences, Texas A&M University, Texas, United States.
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e12081Article in journal (Refereed)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 50.
    Matsuda, Ryo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hosono, Chie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Samakovlis, Christos
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Justus Liebig University of Giessen, Germany.
    Saigo, Kaoru
    Multipotent versus differentiated cell fate selection in the developing Drosophila airways2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e09646Article in journal (Refereed)
    Abstract [en]

    Developmental potentials of cells are tightly controlled at multiple levels. The embryonic Drosophila airway tree is roughly subdivided into two types of cells with distinct developmental potentials: a proximally located group of multipotent adult precursor cells (P-fate) and a distally located population of more differentiated cells (D-fate). We show that the GATA-family transcription factor (TF) Grain promotes the P-fate and the POU-homeobox TF Ventral veinless (Vvl/Drifter/U-turned) stimulates the D-fate. Hedgehog and receptor tyrosine kinase (RTK) signaling cooperate with Vvl to drive the D-fate at the expense of the P-fate while negative regulators of either of these signaling pathways ensure P-fate specification. Local concentrations of Decapentaplegic/BMP, Wingless/Wnt, and Hedgehog signals differentially regulate the expression of D-factors and P-factors to transform an equipotent primordial field into a concentric pattern of radially different morphogenetic potentials, which gradually gives rise to the distal-proximal organization of distinct cell types in the mature airway.

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