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  • 1. Baptista, Marisa A. P.
    et al.
    Keszei, Marton
    Oliveira, Mariana
    Sunahara, Karen K. S.
    Andersson, John
    Dahlberg, Carin I. M.
    Worth, Austen J.
    Lieden, Agne
    Kuo, I-Chun
    Wallin, Robert P. A.
    Snapper, Scott B.
    Eidsmo, Liv
    Scheynius, Annika
    Karlsson, Mikael C. I.
    Bouma, Gerben
    Burns, Siobhan O.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Thrasher, Adrian J.
    Nylén, Susanne
    Westerberg, Lisa S.
    Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 12175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.

  • 2. Bartelt, Alexander
    et al.
    John, Clara
    Schaltenberg, Nicola
    Berbee, Jimmy F. P.
    Worthmann, Anna
    Cherradi, M. Lisa
    Schlein, Christian
    Piepenburg, Julia
    Boon, Mariette R.
    Rinninger, Franz
    Heine, Markus
    Toedter, Klaus
    Niemeier, Andreas
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
    Fischer, Markus
    Wijers, Sander L.
    Lichtenbelt, Wouter van Marken
    Scheja, Ludger
    Rensen, Patrick C. N.
    Heeren, Joerg
    Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 15010Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE(star)3-Leiden. CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

  • 3. Bravo, Andrea G.
    et al.
    Bouchet, Sylvain
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tolu, Julie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Björn, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mateos-Rivera, Alejandro
    Bertilsson, Stefan
    Molecular composition of organic matter controls methylmercury formation in boreal lakes2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 14255Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A detailed understanding of the formation of the potent neurotoxic methylmercury is neededto explain the large observed variability in methylmercury levels in aquatic systems. While it is known that organic matter interacts strongly with mercury, the role of organic matter composition in the formation of methylmercury in aquatic systems remains poorly understood. Here we show that phytoplankton-derived organic compounds enhance mercurymethylation rates in boreal lake sediments through an overall increase of bacterial activity. Accordingly, in situ mercury methylation defines methylmercury levels in lake sediments strongly influenced by planktonic blooms. In contrast, sediments dominated by terrigenous organic matter inputs have far lower methylation rates but higher concentrations of methylmercury, suggesting that methylmercury was formed in the catchment and imported into lakes. Our findings demonstrate that the origin and molecular composition of organic matter are critical parameters to understand and predict methylmercury formation and accumulation in boreal lake sediments.

  • 4. Corbin, Laura J.
    et al.
    Tan, Vanessa Y.
    Hughes, David A.
    Wade, Kaitlin H.
    Paul, Dirk S.
    Tansey, Katherine E.
    Butcher, Frances
    Dudbridge, Frank
    Howson, Joanna M.
    Jallow, Momodou W.
    John, Catherine
    Kingston, Nathalie
    Lindgren, Cecilia M.
    O'Donavan, Michael
    O'Rahilly, Stephen
    Owen, Michael J.
    Palmer, Colin N. A.
    Pearson, Ewan R.
    Scott, Robert A.
    van Heel, David A.
    Whittaker, John
    Frayling, Tim
    Tobin, Martin D.
    Wain, Louise V.
    Smith, George Davey
    Evans, David M.
    Karpe, Fredrik
    McCarthy, Mark I.
    Danesh, John
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, SE-205 02, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
    Timpson, Nicholas J.
    Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 711Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

  • 5. Davies, Gail
    et al.
    Lam, Max
    Harris, Sarah E.
    Trampush, Joey W.
    Luciano, Michelle
    Hill, W. David
    Hagenaars, Saskia P.
    Ritchie, Stuart J.
    Marioni, Riccardo E.
    Fawns-Ritchie, Chloe
    Liewald, David C. M.
    Okely, Judith A.
    Ahola-Olli, Ari V.
    Barnes, Catriona L. K.
    Bertram, Lars
    Bis, Joshua C.
    Burdick, Katherine E.
    Christoforou, Andrea
    DeRosse, Pamela
    Djurovic, Srdjan
    Espeseth, Thomas
    Giakoumaki, Stella
    Giddaluru, Sudheer
    Gustavson, Daniel E.
    Hayward, Caroline
    Hofer, Edith
    Ikram, M. Arfan
    Karlsson, Robert
    Knowles, Emma
    Lahti, Jari
    Leber, Markus
    Li, Shuo
    Mather, Karen A.
    Melle, Ingrid
    Morris, Derek
    Oldmeadow, Christopher
    Palviainen, Teemu
    Payton, Antony
    Pazoki, Raha
    Petrovic, Katja
    Reynolds, Chandra A.
    Sargurupremraj, Muralidharan
    Scholz, Markus
    Smith, Jennifer A.
    Smith, Albert V.
    Terzikhan, Natalie
    Thalamuthu, Anbupalam
    Trompet, Stella
    van der Lee, Sven J.
    Ware, Erin B.
    Windham, B. Gwen
    Wright, Margaret J.
    Yang, Jingyun
    Yu, Jin
    Ames, David
    Amin, Najaf
    Amouyel, Philippe
    Andreassen, Ole A.
    Armstrong, Nicola J.
    Assareh, Amelia A.
    Attia, John R.
    Attix, Deborah
    Avramopoulos, Dimitrios
    Bennett, David A.
    Boehmer, Anne C.
    Boyle, Patricia A.
    Brodaty, Henry
    Campbell, Harry
    Cannon, Tyrone D.
    Cirulli, Elizabeth T.
    Congdon, Eliza
    Conley, Emily Drabant
    Corley, Janie
    Cox, Simon R.
    Dale, Anders M.
    Dehghan, Abbas
    Dick, Danielle
    Dickinson, Dwight
    Eriksson, Johan G.
    Evangelou, Evangelos
    Faul, Jessica D.
    Ford, Ian
    Freimer, Nelson A.
    Gao, He
    Giegling, Ina
    Gillespie, Nathan A.
    Gordon, Scott D.
    Gottesman, Rebecca F.
    Griswold, Michael E.
    Gudnason, Vilmundur
    Harris, Tamara B.
    Hartmann, Annette M.
    Hatzimanolis, Alex
    Heiss, Gerardo
    Holliday, Elizabeth G.
    Joshi, Peter K.
    Kahonen, Mika
    Kardia, Sharon L. R.
    Karlsson, Ida
    Kleineidam, Luca
    Knopman, David S.
    Kochan, Nicole A.
    Konte, Bettina
    Kwok, John B.
    Le Hellard, Stephanie
    Lee, Teresa
    Lehtimaki, Terho
    Li, Shu-Chen
    Liu, Tian
    Koini, Marisa
    London, Edythe
    Longstreth, Will T., Jr.
    Lopez, Oscar L.
    Loukola, Anu
    Luck, Tobias
    Lundervold, Astri J.
    Lundquist, Anders
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Lyytikainen, Leo-Pekka
    Martin, Nicholas G.
    Montgomery, Grant W.
    Murray, Alison D.
    Need, Anna C.
    Noordam, Raymond
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Ollier, William
    Papenberg, Goran
    Pattie, Alison
    Polasek, Ozren
    Poldrack, Russell A.
    Psaty, Bruce M.
    Reppermund, Simone
    Riedel-Heller, Steffi G.
    Rose, Richard J.
    Rotter, Jerome I.
    Roussos, Panos
    Rovio, Suvi P.
    Saba, Yasaman
    Sabb, Fred W.
    Sachdev, Perminder S.
    Satizabal, Claudia L.
    Schmid, Matthias
    Scott, Rodney J.
    Scult, Matthew A.
    Simino, Jeannette
    Slagboom, P. Eline
    Smyrnis, Nikolaos
    Soumare, Aicha
    Stefanis, Nikos C.
    Stott, David J.
    Straub, Richard E.
    Sundet, Kjetil
    Taylor, Adele M.
    Taylor, Kent D.
    Tzoulaki, Ioanna
    Tzourio, Christophe
    Uitterlinden, Andre
    Vitart, Veronique
    Voineskos, Aristotle N.
    Kaprio, Jaakko
    Wagner, Michael
    Wagner, Holger
    Weinhold, Leonie
    Wen, K. Hoyan
    Widen, Elisabeth
    Yang, Qiong
    Zhao, Wei
    Adams, Hieab H. H.
    Arking, Dan E.
    Bilder, Robert M.
    Bitsios, Panos
    Boerwinkle, Eric
    Chiba-Falek, Ornit
    Corvin, Aiden
    De Jager, Philip L.
    Debette, Stephanie
    Donohoe, Gary
    Elliott, Paul
    Fitzpatrick, Annette L.
    Gill, Michael
    Glahn, David C.
    Hagg, Sara
    Hansell, Narelle K.
    Hariri, Ahmad R.
    Ikram, M. Kamran
    Jukema, J. Wouter
    Vuoksimaa, Eero
    Keller, Matthew C.
    Kremen, William S.
    Launer, Lenore
    Lindenberger, Ulman
    Palotie, Aarno
    Pedersen, Nancy L.
    Pendleton, Neil
    Porteous, David J.
    Raikkonen, Katri
    Raitakari, Olli T.
    Ramirez, Alfredo
    Reinvang, Ivar
    Rudan, Igor
    Rujescu, Dan
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter W.
    Schofield, Peter R.
    Starr, John M.
    Steen, Vidar M.
    Trollor, Julian N.
    Turner, Steven T.
    Van Duijn, Cornelia M.
    Villringer, Arno
    Weinberger, Daniel R.
    Weir, David R.
    Wilson, James F.
    Malhotra, Anil
    McIntosh, Andrew M.
    Gale, Catharine R.
    Seshadri, Sudha
    Mosley, Thomas H., Jr.
    Bressler, Jan
    Lencz, Todd
    Deary, Ian J.
    Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 2098Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

  • 6. Dejonghe, Wim
    et al.
    Kuenen, Sabine
    Mylle, Evelien
    Vasileva, Mina
    Keech, Olivier
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Viotti, Corrado
    Swerts, Jef
    Fendrych, Matyas
    Ortiz-Morea, Fausto Andres
    Mishev, Kiril
    Delang, Simon
    Scholl, Stefan
    Zarza, Xavier
    Heilmann, Mareike
    Kourelis, Jiorgos
    Kasprowicz, Jaroslaw
    Nguyen, Le Son Long
    Drozdzecki, Andrzej
    Van Houtte, Isabelle
    Szatmari, Anna-Maria
    Majda, Mateusz
    Baisa, Gary
    Bednarek, Sebastian York
    Robert, Stephanie
    Audenaert, Dominique
    Testerink, Christa
    Munnik, Teun
    Van Damme, Daniel
    Heilmann, Ingo
    Schumacher, Karin
    Winne, Johan
    Friml, Jiri
    Verstreken, Patrik
    Russinova, Eugenia
    Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 11710Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ATP production requires the establishment of an electrochemical proton gradient across the inner mitochondrial membrane. Mitochondrial uncouplers dissipate this proton gradient and disrupt numerous cellular processes, including vesicular trafficking, mainly through energy depletion. Here we show that Endosidin9 (ES9), a novel mitochondrial uncoupler, is a potent inhibitor of clathrin-mediated endocytosis (CME) in different systems and that ES9 induces inhibition of CME not because of its effect on cellular ATP, but rather due to its protonophore activity that leads to cytoplasm acidification. We show that the known tyrosine kinase inhibitor tyrphostinA23, which is routinely used to block CME, displays similar properties, thus questioning its use as a specific inhibitor of cargo recognition by the AP-2 adaptor complex via tyrosine motif-based endocytosis signals. Furthermore, we show that cytoplasm acidification dramatically affects the dynamics and recruitment of clathrin and associated adaptors, and leads to reduction of phosphatidylinositol 4,5-biphosphate from the plasma membrane.

  • 7. Dudding, Tom
    et al.
    Haworth, Simon
    Lind, Penelope A.
    Sathirapongsasuti, J. Fah
    Tung, Joyce Y.
    Mitchell, Ruth
    Colodro-Conde, Lucia
    Medland, Sarah E.
    Gordon, Scott
    Elsworth, Benjamin
    Paternoster, Lavinia
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Sweden ; Department of Nutrition, Harvard. Chan School of Public Health, Harvard University, Boston USA.
    Thomas, Steven J.
    Martin, Nicholas G.
    Timpson, Nicholas J.
    Agee, Michelle
    Alipanahi, Babak
    Auton, Adam
    Bell, Robert K.
    Bryc, Katarzyna
    Elson, Sarah L.
    Fontanillas, Pierre
    Furlotte, Nicholas A.
    Hicks, Barry
    Hinds, David A.
    Huber, Karen E.
    Jewett, Ethan M.
    Jiang, Yunxuan
    Kleinman, Aaron
    Lin, Keng-Han
    Litterman, Nadia K.
    McCeight, Jennifer C.
    McIntyre, Matthew H.
    McManus, Kimberly F.
    Mountain, Joanna L.
    Noblin, Elizabeth S.
    Northover, Carrie A. M.
    Pitts, Steven J.
    Poznik, David
    Shelton, Janie F.
    Shringarpure, Suyash
    Tian, Chao
    Vacic, Vladimir
    Wang, Xin
    Wilson, Catherine H.
    Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, s. 1-12, artikel-id 1052Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

  • 8.
    Erttmann, Saskia F.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 3493Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hydrogen peroxide (H2O2) has a major function in host-microbial interactions. Although most studies have focused on the endogenous H2O2 produced by immune cells to kill microbes, bacteria can also produce H2O2. How microbial H2O2 influences the dynamics of host-microbial interactions is unclear. Here we show that H2O2 released by Streptococcus pneumoniae inhibits inflammasomes, key components of the innate immune system, contributing to the pathogen colonization of the host. We also show that the oral commensal H2O2-producing bacteria Streptococcus oralis can block inflammasome activation. This study uncovers an unexpected role of H2O2 in immune suppression and demonstrates how, through this mechanism, bacteria might restrain the immune system to co-exist with the host.

  • 9. Fang, Hanwei
    et al.
    Gomes, Ana Rita
    Klages, Natacha
    Pino, Paco
    Maco, Bohumil
    Walker, Eloise M.
    Zenonos, Zenon A.
    Angrisano, Fiona
    Baum, Jake
    Doerig, Christian
    Baker, David A.
    Billker, Oliver
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Brochet, Mathieu
    Epistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 4248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In malaria parasites, evolution of parasitism has been linked to functional optimisation. Despite this optimisation, most members of a calcium-dependent protein kinase (CDPK) family show genetic redundancy during erythrocytic proliferation. To identify relationships between phospho-signalling pathways, we here screen 294 genetic interactions among protein kinases in Plasmodium berghei. This reveals a synthetic negative interaction between a hypomorphic allele of the protein kinase G (PKG) and CDPK4 to control erythrocyte invasion which is conserved in P. falciparum. CDPK4 becomes critical when PKG-dependent calcium signals are attenuated to phosphorylate proteins important for the stability of the inner membrane complex, which serves as an anchor for the acto-myosin motor required for motility and invasion. Finally, we show that multiple kinases functionally complement CDPK4 during erythrocytic proliferation and transmission to the mosquito. This study reveals how CDPKs are wired within a stage-transcending signalling network to control motility and host cell invasion in malaria parasites.

  • 10. Fang, Jun
    et al.
    Jia, Jinping
    Makowski, Matthew
    Xu, Mai
    Wang, Zhaoming
    Zhang, Tongwu
    Hoskins, Jason W
    Choi, Jiyeon
    Han, Younghun
    Zhang, Mingfeng
    Thomas, Janelle
    Kovacs, Michael
    Collins, Irene
    Dzyadyk, Marta
    Thompson, Abbey
    O'Neill, Maura
    Das, Sudipto
    Lan, Qi
    Koster, Roelof
    Stolzenberg-Solomon, Rachael S
    Kraft, Peter
    Wolpin, Brian M
    Jansen, Pascal W T C
    Olson, Sara
    McGlynn, Katherine A
    Kanetsky, Peter A
    Chatterjee, Nilanjan
    Barrett, Jennifer H
    Dunning, Alison M
    Taylor, John C
    Newton-Bishop, Julia A
    Bishop, D Timothy
    Andresson, Thorkell
    Petersen, Gloria M
    Amos, Christopher I
    Iles, Mark M
    Nathanson, Katherine L
    Landi, Maria Teresa
    Vermeulen, Michiel
    Brown, Kevin M
    Amundadottir, Laufey T
    Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 15034Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

  • 11. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 10192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

  • 12. Ferreiro-Iglesias, Aida
    et al.
    Lesseur, Corina
    McKay, James
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Christiani, David
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Caporaso, Neil
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Kontic, Milica
    Ognjanovic, Simona
    Lissowska, Jolanta
    Szolkowska, Malgorzata
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Bolca, Ciprian
    Savic, Milan
    Ognjanovic, Miodrag
    Bojesen, Stig Egil
    Wu, Xifeng
    Albanes, Demetrios
    Aldrich, Melinda C.
    Tardon, Adonina
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    Le Marchand, Loic
    Rennert, Gadi
    Chen, Chu
    Doherty, Jennifer
    Goodman, Gary
    Bickeboeller, Heike
    Wichmann, H-Erich
    Risch, Angela
    Rosenberger, Albert
    Shen, Hongbing
    Dai, Juncheng
    Field, John K.
    Davies, Michael
    Woll, Penella
    Teare, M. Dawn
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Yuan, Jian-Min
    Hong, Yun-Chul
    Haugen, Aage
    Zienolddiny, Shanbeh
    Lam, Stephen
    Tsao, Ming-Sound
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Schabath, Matthew B.
    Andrew, Angeline
    Duell, Eric
    Melander, Olle
    Brunnstrom, Hans
    Lazarus, Philip
    Arnold, Susanne
    Slone, Stacey
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Landi, Maria Teresa
    Amos, Christopher, I
    Brennan, Paul
    Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 3927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

  • 13.
    Gamfeldt, Lars
    et al.
    SLU; Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden.
    Snäll, Tord
    SLU.
    Bagchi, Robert
    Department of Biological and Biomedical Sciences, Durham University, Durham UK.
    Jonsson, Micael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Gustafsson, Lena
    SLU.
    Kjellander, Petter
    Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences, Riddarhyttan, Sweden.
    Ruiz-Jaen, María C
    Environmental Change Institute, Oxford, UK.
    Fröberg, Mats
    SLU.
    Stendahl, Johan
    SLU.
    Philipson, Christopher D
    Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.
    Mikusiński, Grzegorz
    Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences, Riddarhyttan, Sweden.
    Andersson, Erik
    SLU; Stockholm Resilience Centre, Stockholm University, Stockholm, Sweden.
    Westerlund, Bertil
    SLU.
    Andrén, Henrik
    Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences, Riddarhyttan, Sweden.
    Moberg, Fredrik
    Stockholm Resilience Centre, Stockholm University, Stockholm, Sweden.
    Moen, Jon
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Bengtsson, Jan
    SLU.
    Higher levels of multiple ecosystem services are found in forests with more tree species2013Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, artikel-id 1340Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Forests are of major importance to human society, contributing several crucial ecosystem services. Biodiversity is suggested to positively influence multiple services but evidence from natural systems at scales relevant to management is scarce. Here, across a scale of 400,000 km(2), we report that tree species richness in production forests shows positive to positively hump-shaped relationships with multiple ecosystem services. These include production of tree biomass, soil carbon storage, berry production and game production potential. For example, biomass production was approximately 50% greater with five than with one tree species. In addition, we show positive relationships between tree species richness and proxies for other biodiversity components. Importantly, no single tree species was able to promote all services, and some services were negatively correlated to each other. Management of production forests will therefore benefit from considering multiple tree species to sustain the full range of benefits that the society obtains from forests.

  • 14. Gnanasundram, Sivakumar Vadivel
    et al.
    Pyndiah, Slovenie
    Daskalogianni, Chrysoula
    Armfield, Kate
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Wilson, Joanna B.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Inserm UMRS1162, Equipe Labellisée la Ligue Contre le Cancer, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
    PI3Kδ delta activates E2F1 synthesis in response to mRNA translation stress2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 2103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein–Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress–response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

  • 15.
    Grönlund, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Lötstedt, Per
    Elf, Johan
    Transcription factor binding kinetics constrain noise suppression via negative feedback2013Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, s. 1864-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Negative autoregulation, where a transcription factor regulates its own expression by preventing transcription, is commonly used to suppress fluctuations in gene expression. Recent single molecule in vivo imaging has shown that it takes significant time for a transcription factor molecule to bind its chromosomal binding site. Given the slow association kinetics, transcription factor mediated feedback cannot at the same time be fast and strong. Here we show that with a limited association rate follows an optimal transcription factor binding strength where noise is maximally suppressed. At the optimal binding strength the binding site is free a fixed fraction of the time independent of the transcription factor concentration. One consequence is that high-copy number transcription factors should bind weakly to their operators, which is observed for transcription factors in Escherichia coli. The results demonstrate that a binding site's strength may be uncorrelated to its functional importance.

  • 16.
    Guinea Diaz, Manuel
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Hernandez-Verdeja, Tamara
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Kremnev, Dmitry
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Crawford, Tim
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Dubreuil, Carole
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Strand, Åsa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Redox regulation of PEP activity during seedling establishment in Arabidopsis thaliana2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Activation of the plastid-encoded RNA polymerase is tightly controlled and involves a network of phosphorylation and, as yet unidentified, thiol-mediated events. Here, we characterize PLASTID REDOX INSENSITIVE2, a redox-regulated protein required for full PEP-driven transcription. PRIN2 dimers can be reduced into the active monomeric form by thioredoxins through reduction of a disulfide bond. Exposure to light increases the ratio between the monomeric and dimeric forms of PRIN2. Complementation of prin2-2 with different PRIN2 protein variants demonstrates that the monomer is required for light-activated PEP-dependent transcription and that expression of the nuclear-encoded photosynthesis genes is linked to the activity of PEP. Activation of PEP during chloroplast development likely is the source of a retrograde signal that promotes nuclear LHCB expression. Thus, regulation of PRIN2 is the thiol-mediated mechanism required for full PEP activity, with PRIN2 monomerization via reduction by TRXs providing a mechanistic link between photosynthetic electron transport and activation of photosynthetic gene expression.

  • 17. Gusev, Alexander
    et al.
    Shi, Huwenbo
    Kichaev, Gleb
    Pomerantz, Mark
    Li, Fugen
    Long, Henry W
    Ingles, Sue A
    Kittles, Rick A
    Strom, Sara S
    Rybicki, Benjamin A
    Nemesure, Barbara
    Isaacs, William B
    Zheng, Wei
    Pettaway, Curtis A
    Yeboah, Edward D
    Tettey, Yao
    Biritwum, Richard B
    Adjei, Andrew A
    Tay, Evelyn
    Truelove, Ann
    Niwa, Shelley
    Chokkalingam, Anand P
    John, Esther M
    Murphy, Adam B
    Signorello, Lisa B
    Carpten, John
    Leske, M Cristina
    Wu, Suh-Yuh
    Hennis, Anslem J M
    Neslund-Dudas, Christine
    Hsing, Ann W
    Chu, Lisa
    Goodman, Phyllis J
    Klein, Eric A
    Witte, John S
    Casey, Graham
    Kaggwa, Sam
    Cook, Michael B
    Stram, Daniel O
    Blot, William J
    Eeles, Rosalind A
    Easton, Douglas
    Kote-Jarai, ZSofia
    Al Olama, Ali Amin
    Benlloch, Sara
    Muir, Kenneth
    Giles, Graham G
    Southey, Melissa C
    Fitzgerald, Liesel M
    Gronberg, Henrik
    Wiklund, Fredrik
    Aly, Markus
    Henderson, Brian E
    Schleutker, Johanna
    Wahlfors, Tiina
    Tammela, Teuvo L J
    Nordestgaard, Børge G
    Key, Tim J
    Travis, Ruth C
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Pharoah, Paul
    Pashayan, Nora
    Khaw, Kay-Tee
    Stanford, Janet L
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Maier, Christiane
    Vogel, Walther
    Luedeke, Manuel
    Herkommer, Kathleen
    Kibel, Adam S
    Cybulski, Cezary
    Wokolorczyk, Dominika
    Kluzniak, Wojciech
    Cannon-Albright, Lisa
    Teerlink, Craig
    Brenner, Hermann
    Dieffenbach, Aida K
    Arndt, Volker
    Park, Jong Y
    Sellers, Thomas A
    Lin, Hui-Yi
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Spurdle, Amanda
    Clements, Judith A
    Teixeira, Manuel R
    Pandha, Hardev
    Michael, Agnieszka
    Paulo, Paula
    Maia, Sofia
    Kierzek, Andrzej
    Conti, David V
    Albanes, Demetrius
    Berg, Christine
    Berndt, Sonja I
    Campa, Daniele
    Crawford, E David
    Diver, W Ryan
    Gapstur, Susan M
    Gaziano, J Michael
    Giovannucci, Edward
    Hoover, Robert
    Hunter, David J
    Johansson, Mattias
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Kraft, Peter
    Le Marchand, Loic
    Lindström, Sara
    Navarro, Carmen
    Overvad, Kim
    Riboli, Elio
    Siddiq, Afshan
    Stevens, Victoria L
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Yeager, Meredith
    Trynka, Gosia
    Raychaudhuri, Soumya
    Schumacher, Frederick R
    Price, Alkes L
    Freedman, Matthew L
    Haiman, Christopher A
    Pasaniuc, Bogdan
    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 10979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  • 18.
    Hainzl, Tobias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauer-Eriksson, A. Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Signal-sequence induced conformational changes in the signal recognition particle2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 7163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane. In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. For this, signal sequence binding in the SRP54 M domain must be effectively communicated to the SRP54 NG domain that interacts with the receptor. Here we present the 2.9 angstrom crystal structure of unbound- and signal sequence bound SRP forms, both present in the asymmetric unit. The structures provide evidence for a coupled binding and folding mechanism in which signal sequence binding induces the concerted folding of the GM linker helix, the finger loop, and the C-terminal alpha helix alpha M6. This mechanism allows for a high degree of structural adaptability of the binding site and suggests how signal sequence binding in the M domain is coupled to repositioning of the NG domain.

  • 19.
    Hellström, Gustav
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Klaminder, Jonatan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Finn, Fia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Persson, Lo
    Alanärä, Anders
    Jonsson, Micael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brodin, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    GABAergic anxiolytic drug in water increases migration behaviour in salmon2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 13460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Migration is an important life-history event in a wide range of taxa, yet many migrations are influenced by anthropogenic change. Although migration dynamics are extensively studied, the potential effects of environmental contaminants on migratory physiology are poorly understood. In this study we show that an anxiolytic drug in water can promote downward migratory behaviour of Atlantic salmon (Salmo salar) in both laboratory setting and in a natural river tributary. Exposing salmon smolt to a dilute concentration of a GABAA receptor agonist (oxazepam) increased migration intensity compared with untreated smolt. These results implicate that salmon migration may be affected by human-induced changes in water chemical properties, such as acidification and pharmaceutical residues in wastewater effluent, via alterations in the GABAA receptor function.

  • 20. Hibar, Derrek P.
    et al.
    Adams, Hieab H. H.
    Jahanshad, Neda
    Chauhan, Ganesh
    Stein, Jason L.
    Hofer, Edith
    Renteria, Miguel E.
    Bis, Joshua C.
    Arias-Vasquez, Alejandro
    Ikram, M. Kamran
    Desrivieres, Sylvane
    Vernooij, Meike W.
    Abramovic, Lucija
    Alhusaini, Saud
    Amin, Najaf
    Andersson, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Arfanakis, Konstantinos
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Athanasiu, Lavinia
    Axelsson, Tomas
    Beecham, Ashley H.
    Beiser, Alexa
    Bernard, Manon
    Blanton, Susan H.
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brickman, Adam M.
    Carmichael, Owen
    Chakravarty, M. Mallar
    Chen, Qiang
    Ching, Christopher R. K.
    Chouraki, Vincent
    Cuellar-Partida, Gabriel
    Crivello, Fabrice
    Den Braber, Anouk
    Doan, Nhat Trung
    Ehrlich, Stefan
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Gottesman, Rebecca F.
    Grimm, Oliver
    Griswold, Michael E.
    Guadalupe, Tulio
    Gutman, Boris A.
    Hass, Johanna
    Haukvik, Unn K.
    Hoehn, David
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Jorgensen, Kjetil N.
    Karbalai, Nazanin
    Kasperaviciute, Dalia
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Liewald, David C. M.
    Lopez, Lorna M.
    Luciano, Michelle
    Macare, Christine
    Marquand, Andre F.
    Matarin, Mar
    Mather, Karen A.
    Mattheisen, Manuel
    McKay, David R.
    Milaneschi, Yuri
    Maniega, Susana Munoz
    Nho, Kwangsik
    Nugent, Allison C.
    Nyquist, Paul
    Loohuis, Loes M. Olde
    Oosterlaan, Jaap
    Papmeyer, Martina
    Pirpamer, Lukas
    Puetz, Benno
    Ramasamy, Adaikalavan
    Richards, Jennifer S.
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rommelse, Nanda
    Ropele, Stefan
    Rose, Emma J.
    Royle, Natalie A.
    Rundek, Tatjana
    Saemann, Philipp G.
    Saremi, Arvin
    Satizabal, Claudia L.
    Schmaal, Lianne
    Schork, Andrew J.
    Shen, Li
    Shin, Jean
    Shumskaya, Elena
    Smith, Albert V.
    Sprooten, Emma
    Strike, Lachlan T.
    Teumer, Alexander
    Tordesillas-Gutierrez, Diana
    Toro, Roberto
    Trabzuni, Daniah
    Trompet, Stella
    Vaidya, Dhananjay
    Van der Grond, Jeroen
    Van der Lee, Sven J.
    Van der Meer, Dennis
    Van Donkelaar, Marjolein M. J.
    Van Eijk, Kristel R.
    Van Erp, Theo G. M.
    Van Rooij, Daan
    Walton, Esther
    Westlye, Lars T.
    Whelan, Christopher D.
    Windham, Beverly G.
    Winkler, Anderson M.
    Wittfeld, Katharina
    Woldehawariat, Girma
    Wolf, Christiane
    Wolfers, Thomas
    Yanek, Lisa R.
    Yang, Jingyun
    Zijdenbos, Alex
    Zwiers, Marcel P.
    Agartz, Ingrid
    Almasy, Laura
    Ames, David
    Amouyel, Philippe
    Andreassen, Ole A.
    Arepalli, Sampath
    Assareh, Amelia A.
    Barral, Sandra
    Bastin, Mark E.
    Becker, Diane M.
    Becker, James T.
    Bennett, David A.
    Blangero, John
    van Bokhoven, Hans
    Boomsma, Dorret I.
    Brodaty, Henry
    Brouwer, Rachel M.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Bulayeva, Kazima B.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cannon, Dara M.
    Cavalleri, Gianpiero L.
    Cheng, Ching-Yu
    Cichon, Sven
    Cookson, Mark R.
    Corvin, Aiden
    Crespo-Facorro, Benedicto
    Curran, Joanne E.
    Czisch, Michael
    Dale, Anders M.
    Davies, Gareth E.
    De Craen, Anton J. M.
    De Geus, Eco J. C.
    De Jager, Philip L.
    De Zubicaray, Greig I.
    Deary, Ian J.
    Debette, Stephanie
    DeCarli, Charles
    Delanty, Norman
    Depondt, Chantal
    DeStefano, Anita
    Dillman, Allissa
    Djurovic, Srdjan
    Donohoe, Gary
    Drevets, Wayne C.
    Duggirala, Ravi
    Dyer, Thomas D.
    Enzinger, Christian
    Erk, Susanne
    Espeseth, Thomas
    Fedko, Iryna O.
    Fernandez, Guillen
    Ferrucci, Luigi
    Fisher, Simon E.
    Fleischman, Debra A.
    Ford, Ian
    Fornage, Myriam
    Foroud, Tatiana M.
    Fox, Peter T.
    Francks, Clyde
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Glahn, David C.
    Gollub, Randy L.
    Goring, Harald H. H.
    Green, Robert C.
    Gruber, Oliver
    Gudnason, Vilmundur
    Guelfi, Sebastian
    Haberg, Asta K.
    Hansell, Narelle K.
    Hardy, John
    Hartman, Catharina A.
    Hashimoto, Ryota
    Hegenscheid, Katrin
    Heinz, Andreas
    Le Hellard, Stephanie
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Ho, Beng-Choon
    Hoekstra, Pieter J.
    Hoffmann, Wolfgang
    Hofman, Albert
    Holsboer, Florian
    Homuth, Georg
    Hosten, Norbert
    Hottenga, Jouke-Jan
    Huentelman, Matthew
    Pol, Hilleke E. Hulshoff
    Ikeda, Masashi
    Jack, Clifford R., Jr.
    Jenkinson, Mark
    Johnson, Robert
    Joensson, Erik G.
    Jukema, J. Wouter
    Kahn, Rene S.
    Kanai, Ryota
    Kloszewska, Iwona
    Knopman, David S.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Lemaitre, Herve
    Liu, Xinmin
    Longo, Dan L.
    Lopez, Oscar L.
    Lovestone, Simon
    Martinez, Oliver
    Martinot, Jean-Luc
    Mattay, Venkata S.
    McDonald, Colm
    McIntosh, Andrew M.
    McMahon, Francis J.
    McMahon, Katie L.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Mohnke, Sebastian
    Montgomery, Grant W.
    Morris, Derek W.
    Mosley, Thomas H.
    Muhleisen, Thomas W.
    Mueller-Myhsok, Bertram
    Nalls, Michael A.
    Nauck, Matthias
    Nichols, Thomas E.
    Niessen, Wiro J.
    Nothen, Markus M.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Ohi, Kazutaka
    Olvera, Rene L.
    Ophoff, Roel A.
    Pandolfo, Massimo
    Paus, Tomas
    Pausova, Zdenka
    Penninx, Brenda W. J. H.
    Pike, G. Bruce
    Potkin, Steven G.
    Psaty, Bruce M.
    Reppermund, Simone
    Rietschel, Marcella
    Roffman, Joshua L.
    Romanczuk-Seiferth, Nina
    Rotter, Jerome I.
    Ryten, Mina
    Sacco, Ralph L.
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter R.
    Sigursson, Sigurdur
    Simmons, Andrew
    Singleton, Andrew
    Sisodiya, Sanjay M.
    Smith, Colin
    Smoller, Jordan W.
    Soininen, Hilkka
    Steen, Vidar M.
    Stott, David J.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Tsolaki, Magda
    Tzourio, Christophe
    Uitterlinden, Andre G.
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    van der Lugt, Aad
    van der Wee, Nic J. A.
    Van Haren, Neeltje E. M.
    van't Ent, Dennis
    Van Tol, Marie-Jose
    Vardarajan, Badri N.
    Vellas, Bruno
    Veltman, Dick J.
    Voelzke, Henry
    Walter, Henrik
    Wardlaw, Joanna M.
    Wassink, Thomas H.
    Weale, Michael E.
    Weinberger, Daniel R.
    Weiner, Michael W.
    Wen, Wei
    Westman, Eric
    White, Tonya
    Wong, Tien Y.
    Wright, Clinton B.
    Zielke, Ronald H.
    Zonderman, Alan B.
    Martin, Nicholas G.
    Van Duijn, Cornelia M.
    Wright, Margaret J.
    Longstreth, W. T.
    Schumann, Gunter
    Grabe, Hans J.
    Franke, Barbara
    Launer, Lenore J.
    Medland, Sarah E.
    Seshadri, Sudha
    Thompson, Paul M.
    Ikram, M. Arfan
    Novel genetic loci associated with hippocampal volume2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 13624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  • 21. Holland, Petter
    et al.
    Knaevelsrud, Helene
    Soreng, Kristiane
    Mathai, Benan J.
    Lystad, Alf Hakon
    Pankiv, Serhiy
    Bjorndal, Gunnveig T.
    Schultz, Sebastian W.
    Lobert, Viola H.
    Chan, Robin B.
    Zhou, Bowen
    Liestol, Knut
    Carlsson, Sven R.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Melia, Thomas J.
    Di Paolo, Gilbert
    Simonsen, Anne
    HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 13889Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1-and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids.

  • 22.
    Hu, Guangzhi
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Nitze, Florian
    Gracia-Espino, Eduardo
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ma, Jingyuan
    Barzegar, Hamid Reza
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Sharifi, Tiva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Jia, Xueen
    Shchukarev, Andrey
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lu, Lu
    Ma, Chuansheng
    Yang, Guang
    Wågberg, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Small palladium islands embedded in palladium-tungsten bimetallic nanoparticles form catalytic hotspots for oxygen reduction2014Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, s. Article number: 5253-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The sluggish kinetics of the oxygen reduction reaction at the cathode side of proton exchange membrane fuel cells is one major technical challenge for realizing sustainable solutions for the transportation sector. Finding efficient yet cheap electrocatalysts to speed up this reaction therefore motivates researchers all over the world. Here we demonstrate an efficient synthesis of palladium-tungsten bimetallic nanoparticles supported on ordered mesoporous carbon. Despite a very low percentage of noble metal (palladium: tungsten = 1:8), the hybrid catalyst material exhibits a performance equal to commercial 60% platinum/Vulcan for the oxygen reduction process. The high catalytic efficiency is explained by the formation of small palladium islands embedded at the surface of the palladium-tungsten bimetallic nanoparticles, generating catalytic hotspots. The palladium islands are similar to 1 nm in diameter, and contain 10-20 palladium atoms that are segregated at the surface. Our results may provide insight into the formation, stabilization and performance of bimetallic nanoparticles for catalytic reactions.

  • 23. Ji, Xuemei
    et al.
    Bosse, Yohan
    Landi, Maria Teresa
    Gui, Jiang
    Xiao, Xiangjun
    Qian, David
    Joubert, Philippe
    Lamontagne, Maxime
    Li, Yafang
    Gorlov, Ivan
    de Biasi, Mariella
    Han, Younghun
    Gorlova, Olga
    Hung, Rayjean J.
    Wu, Xifeng
    Mckay, James
    Zong, Xuchen
    Carreras-Torres, Robert
    Christiani, David C.
    Caporaso, Neil
    Johansson, Mattias
    Liu, Geoffrey
    Bojesen, Stig E.
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeboeller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    Chen, Chu
    Teare, M. Dawn
    Field, John K.
    Kiemeney, Lambertus A.
    Lazarus, Philip
    Haugen, Aage
    Lam, Stephen
    Schabath, Matthew B.
    Andrew, Angeline S.
    Shen, Hongbing
    Hong, Yun-Chul
    Yuan, Jian-Min
    Bertazzi, Pier A.
    Pesatori, Angela C.
    Ye, Yuanqing
    Diao, Nancy
    Su, Li
    Zhang, Ruyang
    Brhane, Yonathan
    Leighl, Natasha
    Johansen, Jakob S.
    Mellemgaard, Anders
    Saliba, Walid
    Haiman, Christopher
    Wilkens, Lynne
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    van der Heijden, Erik H. F. M.
    Kim, Jin Hee
    Dai, Juncheng
    Hu, Zhibin
    Davies, Michael P. A.
    Marcus, Michael W.
    Brunnstrom, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Doherty, Jennifer
    Goodman, Gary E.
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Brueske, Irene
    Manz, Judith
    Muley, Thomas
    Risch, Angela
    Rosenberger, Albert
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Shepherd, Frances
    Tsao, Ming-Sound
    Arnold, Susanne M.
    Haura, Eric B.
    Bolca, Ciprian
    Holcatova, Ivana
    Janout, Vladimir
    Kontic, Milica
    Lissowska, Jolanta
    Mukeria, Anush
    Ognjanovic, Simona
    Orlowski, Tadeusz M.
    Scelo, Ghislaine
    Swiatkowska, Beata
    Zaridze, David
    Bakke, Per
    Skaug, Vidar
    Zienolddiny, Shanbeh
    Duell, Eric J.
    Butler, Lesley M.
    Koh, Woon-Puay
    Gao, Yu-Tang
    Houlston, Richard
    McLaughlin, John
    Stevens, Victoria
    Nickle, David C.
    Obeidat, Ma'en
    Timens, Wim
    Zhu, Bin
    Song, Lei
    Artigas, Maria Soler
    Tobin, Martin D.
    Wain, Louise V.
    Gu, Fangyi
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Tyndale, Rachel F.
    Wei, Wei-Qi
    Chanock, Stephen
    Brennan, Paul
    Amos, Christopher I.
    Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, s. 1-15, artikel-id 3221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

  • 24. Jiang, Xia
    et al.
    Finucane, Hilary K.
    Schumacher, Fredrick R.
    Schmit, Stephanie L.
    Tyrer, Jonathan P.
    Han, Younghun
    Michailidou, Kyriaki
    Lesseur, Corina
    Kuchenbaecker, Karoline B.
    Dennis, Joe
    Conti, David V.
    Casey, Graham
    Gaudet, Mia M.
    Huyghe, Jeroen R.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline S.
    Andrulis, Irene L.
    Anton-Culver, Hoda
    Antoniou, Antonis C.
    Antonenkova, Natalia N.
    Arnold, Susanne M.
    Aronson, Kristan J.
    Arun, Banu K.
    Bandera, Elisa V.
    Barkardottir, Rosa B.
    Barnes, Daniel R.
    Batra, Jyotsna
    Beckmann, Matthias W.
    Benitez, Javier
    Benlloch, Sara
    Berchuck, Andrew
    Berndt, Sonja I.
    Bickeboeller, Heike
    Bien, Stephanie A.
    Blomqvist, Carl
    Boccia, Stefania
    Bogdanova, Natalia V.
    Bojesen, Stig E.
    Bolla, Manjeet K.
    Brauch, Hiltrud
    Brenner, Hermann
    Brenton, James D.
    Brook, Mark N.
    Brunet, Joan
    Brunnstrom, Hans
    Buchanan, Daniel D.
    Burwinkel, Barbara
    Butzow, Ralf
    Cadoni, Gabriella
    Caldes, Trinidad
    Caligo, Maria A.
    Campbell, Ian
    Campbell, Peter T.
    Cancel-Tassin, Geraldine
    Cannon-Albright, Lisa
    Campa, Daniele
    Caporaso, Neil
    Carvalho, Andre L.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Chen, Chu
    Christiani, David C.
    Claes, Kathleen B. M.
    Claessens, Frank
    Clements, Judith
    Collee, J. Margriet
    Correa, Marcia Cruz
    Couch, Fergus J.
    Cox, Angela
    Cunningham, Julie M.
    Cybulski, Cezary
    Czene, Kamila
    Daly, Mary B.
    defazio, Anna
    Devilee, Peter
    Diez, Orland
    Gago-Dominguez, Manuela
    Donovan, Jenny L.
    Doerk, Thilo
    Duell, Eric J.
    Dunning, Alison M.
    Dwek, Miriam
    Eccles, Diana M.
    Edlund, Christopher K.
    Edwards, Digna R. Velez
    Ellberg, Carolina
    Evans, D. Gareth
    Fasching, Peter A.
    Ferris, Robert L.
    Liloglou, Triantafillos
    Figueiredo, Jane C.
    Fletcher, Olivia
    Fortner, Renee T.
    Fostira, Florentia
    Franceschi, Silvia
    Friedman, Eitan
    Gallinger, Steven J.
    Ganz, Patricia A.
    Garber, Judy
    Garcia-Saenz, Jose A.
    Gayther, Simon A.
    Giles, Graham G.
    Godwin, Andrew K.
    Goldberg, Mark S.
    Goldgar, David E.
    Goode, Ellen L.
    Goodman, Marc T.
    Goodman, Gary
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Greene, Mark H.
    Gronberg, Henrik
    Gronwald, Jacek
    Guenel, Pascal
    Hakansson, Niclas
    Hall, Per
    Hamann, Ute
    Hamdy, Freddie C.
    Hamilton, Robert J.
    Hampe, Jochen
    Haugen, Aage
    Heitz, Florian
    Herrero, Rolando
    Hillemanns, Peter
    Hoffmeister, Michael
    Hogdall, Estrid
    Hong, Yun-Chul
    Hopper, John L.
    Houlston, Richard
    Hulick, Peter J.
    Hunter, David J.
    Huntsman, David G.
    Idos, Gregory
    Imyanitov, Evgeny N.
    Ingles, Sue Ann
    Isaacs, Claudine
    Jakubowska, Anna
    James, Paul
    Jenkins, Mark A.
    Johansson, Mattias
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    John, Esther M.
    Joshi, Amit D.
    Kaneva, Radka
    Karlan, Beth Y.
    Kelemen, Linda E.
    Kuhl, Tabea
    Khaw, Kay-Tee
    Khusnutdinova, Elza
    Kibel, Adam S.
    Kiemeney, Lambertus A.
    Kim, Jeri
    Kjaer, Susanne K.
    Knight, Julia A.
    Kogevinas, Manolis
    Kote-Jarai, Zsofia
    Koutros, Stella
    Kristensen, Vessela N.
    Kupryjanczyk, Jolanta
    Lacko, Martin
    Lam, Stephan
    Lambrechts, Diether
    Landi, Maria Teresa
    Lazarus, Philip
    Le, Nhu D.
    Lee, Eunjung
    Lejbkowicz, Flavio
    Lenz, Heinz-Josef
    Leslie, Goska
    Lessel, Davor
    Lester, Jenny
    Levine, Douglas A.
    Li, Li
    Li, Christopher I.
    Lindblom, Annika
    Lindor, Noralane M.
    Liu, Geoffrey
    Loupakis, Fotios
    Lubinski, Jan
    Maehle, Lovise
    Maier, Christiane
    Mannermaa, Arto
    Le Marchand, Loic
    Margolin, Sara
    May, Taymaa
    McGuffog, Lesley
    Meindl, Alfons
    Middha, Pooja
    Miller, Austin
    Milne, Roger L.
    MacInnis, Robert J.
    Modugno, Francesmary
    Montagna, Marco
    Moreno, Victor
    Moysich, Kirsten B.
    Mucci, Lorelei
    Muir, Kenneth
    Mulligan, Anna Marie
    Nathanson, Katherine L.
    Neal, David E.
    Ness, Andrew R.
    Neuhausen, Susan L.
    Nevanlinna, Heli
    Newcomb, Polly A.
    Newcomb, Lisa F.
    Nielsen, Finn Cilius
    Nikitina-Zake, Liene
    Nordestgaard, Borge G.
    Nussbaum, Robert L.
    Offit, Kenneth
    Olah, Edith
    Al Olama, Ali Amin
    Olopade, Olufunmilayo I.
    Olshan, Andrew F.
    Olsson, Hakan
    Osorio, Ana
    Pandha, Hardev
    Park, Jong Y.
    Pashayan, Nora
    Parsons, Michael T.
    Pejovic, Tanja
    Penney, Kathryn L.
    Peters, Wilbert H. M.
    Phelan, Catherine M.
    Phipps, Amanda I.
    Plaseska-Karanfilska, Dijana
    Pring, Miranda
    Prokofyeva, Darya
    Radice, Paolo
    Stefansson, Kari
    Ramus, Susan J.
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    van Rensburg, Elizabeth J.
    Riggan, Marjorie J.
    Risch, Harvey A.
    Risch, Angela
    Roobol, Monique J.
    Rosenstein, Barry S.
    Rossing, Mary Anne
    De Ruyck, Kim
    Saloustros, Emmanouil
    Sandler, Dale P.
    Sawyer, Elinor J.
    Schabath, Matthew B.
    Schleutker, Johanna
    Schmidt, Marjanka K.
    Setiawan, V. Wendy
    Shen, Hongbing
    Siegel, Erin M.
    Sieh, Weiva
    Singer, Christian F.
    Slattery, Martha L.
    Sorensen, Karina Dalsgaard
    Southey, Melissa C.
    Spurdle, Amanda B.
    Stanford, Janet L.
    Stevens, Victoria L.
    Stintzing, Sebastian
    Stone, Jennifer
    Sundfeldt, Karin
    Sutphen, Rebecca
    Swerdlow, Anthony J.
    Tajara, Eloiza H.
    Tangen, Catherine M.
    Tardon, Adonina
    Taylor, Jack A.
    Teare, M. Dawn
    Teixeira, Manuel R.
    Terry, Mary Beth
    Terry, Kathryn L.
    Thibodeau, Stephen N.
    Thomassen, Mads
    Bjorge, Line
    Tischkowitz, Marc
    Toland, Amanda E.
    Torres, Diana
    Townsend, Paul A.
    Travis, Ruth C.
    Tung, Nadine
    Tworoger, Shelley S.
    Ulrich, Cornelia M.
    Usmani, Nawaid
    Vachon, Celine M.
    Van Nieuwenhuysen, Els
    Vega, Ana
    Aguado-Barrera, Miguel Elias
    Wang, Qin
    Webb, Penelope M.
    Weinberg, Clarice R.
    Weinstein, Stephanie
    Weissler, Mark C.
    Weitzel, Jeffrey N.
    West, Catharine M. L.
    White, Emily
    Whittemore, Alice S.
    Wichmann, H-Erich
    Wiklund, Fredrik
    Winqvist, Robert
    Wolk, Alicja
    Woll, Penella
    Woods, Michael
    Wu, Anna H.
    Wu, Xifeng
    Yannoukakos, Drakoulis
    Zheng, Wei
    Zienolddiny, Shanbeh
    Ziogas, Argyrios
    Zorn, Kristin K.
    Lane, Jacqueline M.
    Saxena, Richa
    Thomas, Duncan
    Hung, Rayjean J.
    Diergaarde, Brenda
    Mckay, James
    Peters, Ulrike
    Hsu, Li
    Garcia-Closas, Montserrat
    Eeles, Rosalind A.
    Chenevix-Trench, Georgia
    Brennan, Paul J.
    Haiman, Christopher A.
    Simard, Jacques
    Easton, Douglas F.
    Gruber, Stephen B.
    Pharoah, Paul D. P.
    Price, Alkes L.
    Pasaniuc, Bogdan
    Amos, Christopher I.
    Kraft, Peter
    Lindstrom, Sara
    Shared heritability and functional enrichment across six solid cancers2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

  • 25.
    Jonsson, Sofi
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Skyllberg, Ulf
    Nilsson, Mats B.
    Lundberg, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå marina forskningscentrum (UMF).
    Andersson, Agneta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå marina forskningscentrum (UMF).
    Björn, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Differentiated availability of geochemical mercury pools controls methylmercury levels in estuarine sediment and biota2014Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, s. 4624-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neurotoxic methylmercury (MeHg) formed from inorganic divalent mercury (HgII) accumulates in aquatic biota and remains at high levels worldwide. It is poorly understood to what extent different geochemical Hg pools contribute to these levels. Here we report quantitative data on MeHg formation and bioaccumulation, in mesocosm water-sediment model ecosystems, using five HgII and MeHg isotope tracers simulating recent Hg inputs to the water phase and Hg stored in sediment as bound to natural organic matter or as metacinnabar. Calculations for an estuarine ecosystem suggest that the chemical speciation of HgII solid/adsorbed phases control the sediment Hg pool's contribution to MeHg, but that input of MeHg from terrestrial and atmospheric sources bioaccumulates to a substantially greater extent than MeHg formed in situ in sediment. Our findings emphasize the importance of MeHg loadings from catchment runoff to MeHg content in estuarine biota and we suggest that this contribution has been underestimated.

  • 26. Justice, Anne E
    et al.
    Winkler, Thomas W
    Feitosa, Mary F
    Graff, Misa
    Fisher, Virginia A
    Young, Kristin
    Barata, Llilda
    Deng, Xuan
    Czajkowski, Jacek
    Hadley, David
    Ngwa, Julius S
    Ahluwalia, Tarunveer S
    Chu, Audrey Y
    Heard-Costa, Nancy L
    Lim, Elise
    Perez, Jeremiah
    Eicher, John D
    Kutalik, Zoltan
    Xue, Luting
    Mahajan, Anubha
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 02 Malmö, Sweden.
    Wu, Joseph
    Qi, Qibin
    Ahmad, Shafqat
    Alfred, Tamuno
    Amin, Najaf
    Bielak, Lawrence F
    Bonnefond, Amelie
    Bragg, Jennifer
    Cadby, Gemma
    Chittani, Martina
    Coggeshall, Scott
    Corre, Tanguy
    Direk, Nese
    Eriksson, Joel
    Fischer, Krista
    Gorski, Mathias
    Neergaard Harder, Marie
    Horikoshi, Momoko
    Huang, Tao
    Huffman, Jennifer E
    Jackson, Anne U
    Justesen, Johanne Marie
    Kanoni, Stavroula
    Kinnunen, Leena
    Kleber, Marcus E
    Komulainen, Pirjo
    Kumari, Meena
    Lim, Unhee
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Mangino, Massimo
    Manichaikul, Ani
    Marten, Jonathan
    Middelberg, Rita P S
    Muller-Nurasyid, Martina
    Navarro, Pau
    Perusse, Louis
    Pervjakova, Natalia
    Sarti, Cinzia
    Smith, Albert Vernon
    Smith, Jennifer A
    Stancakova, Alena
    Strawbridge, Rona J
    Stringham, Heather M
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van der Most, Peter J
    Van Vliet-Ostaptchouk, Jana V
    Vedantam, Sailaja L
    Verweij, Niek
    Vink, Jacqueline M
    Vitart, Veronique
    Wu, Ying
    Yengo, Loic
    Zhang, Weihua
    Hua Zhao, Jing
    Zimmermann, Martina E
    Zubair, Niha
    Abecasis, Goncalo R
    Adair, Linda S
    Afaq, Saima
    Afzal, Uzma
    Bakker, Stephan J L
    Bartz, Traci M
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Biffar, Reiner
    Blangero, John
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Bottinger, Erwin
    Braga, Daniele
    Buckley, Brendan M
    Buyske, Steve
    Campbell, Harry
    Chambers, John C
    Collins, Francis S
    Curran, Joanne E
    de Borst, Gert J
    de Craen, Anton J M
    de Geus, Eco J C
    Dedoussis, George
    Delgado, Graciela E
    den Ruijter, Hester M
    Eiriksdottir, Gudny
    Eriksson, Anna L
    Esko, Tonu
    Faul, Jessica D
    Ford, Ian
    Forrester, Terrence
    Gertow, Karl
    Gigante, Bruna
    Glorioso, Nicola
    Gong, Jian
    Grallert, Harald
    Grammer, Tanja B
    Grarup, Niels
    Haitjema, Saskia
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hamsten, Anders
    Hansen, Torben
    Harris, Tamara B
    Hartman, Catharina A
    Hassinen, Maija
    Hastie, Nicholas D
    Heath, Andrew C
    Hernandez, Dena
    Hindorff, Lucia
    Hocking, Lynne J
    Hollensted, Mette
    Holmen, Oddgeir L
    Homuth, Georg
    Jan Hottenga, Jouke
    Huang, Jie
    Hung, Joseph
    Hutri-Kahonen, Nina
    Ingelsson, Erik
    James, Alan L
    Jansson, John-Olov
    Jarvelin, Marjo-Riitta
    Jhun, Min A
    Jorgensen, Marit E
    Juonala, Markus
    Kahonen, Mika
    Karlsson, Magnus
    Koistinen, Heikki A
    Kolcic, Ivana
    Kolovou, Genovefa
    Kooperberg, Charles
    Kramer, Bernhard K
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Lakka, Timo A
    Langenberg, Claudia
    Launer, Lenore J
    Leander, Karin
    Lee, Nanette R
    Lind, Lars
    Lindgren, Cecilia M
    Linneberg, Allan
    Lobbens, Stephane
    Loh, Marie
    Lorentzon, Mattias
    Luben, Robert
    Lubke, Gitta
    Ludolph-Donislawski, Anja
    Lupoli, Sara
    Madden, Pamela A F
    Mannikko, Reija
    Marques-Vidal, Pedro
    Martin, Nicholas G
    McKenzie, Colin A
    McKnight, Barbara
    Mellstrom, Dan
    Menni, Cristina
    Montgomery, Grant W
    Musk, Aw Bill
    Narisu, Narisu
    Nauck, Matthias
    Nolte, Ilja M
    Oldehinkel, Albertine J
    Olden, Matthias
    Ong, Ken K
    Padmanabhan, Sandosh
    Peyser, Patricia A
    Pisinger, Charlotta
    Porteous, David J
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rasmussen-Torvik, Laura J
    Rawal, Rajesh
    Rice, Treva
    Ridker, Paul M
    Rose, Lynda M
    Bien, Stephanie A
    Rudan, Igor
    Sanna, Serena
    Sarzynski, Mark A
    Sattar, Naveed
    Savonen, Kai
    Schlessinger, David
    Scholtens, Salome
    Schurmann, Claudia
    Scott, Robert A
    Sennblad, Bengt
    Siemelink, Marten A
    Silbernagel, Gunther
    Slagboom, P Eline
    Snieder, Harold
    Staessen, Jan A
    Stott, David J
    Swertz, Morris A
    Swift, Amy J
    Taylor, Kent D
    Tayo, Bamidele O
    Thorand, Barbara
    Thuillier, Dorothee
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Vandenput, Liesbeth
    Vohl, Marie-Claude
    Volzke, Henry
    Vonk, Judith M
    Waeber, Gerard
    Waldenberger, Melanie
    Westendorp, R G J
    Wild, Sarah
    Willemsen, Gonneke
    Wolffenbuttel, Bruce H R
    Wong, Andrew
    Wright, Alan F
    Zhao, Wei
    Zillikens, M Carola
    Baldassarre, Damiano
    Balkau, Beverley
    Bandinelli, Stefania
    Boger, Carsten A
    Boomsma, Dorret I
    Bouchard, Claude
    Bruinenberg, Marcel
    Chasman, Daniel I
    Chen, Yii-DerIda
    Chines, Peter S
    Cooper, Richard S
    Cucca, Francesco
    Cusi, Daniele
    Faire, Ulf de
    Ferrucci, Luigi
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 02 Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
    Froguel, Philippe
    Gordon-Larsen, Penny
    Grabe, Hans-Jorgen
    Gudnason, Vilmundur
    Haiman, Christopher A
    Hayward, Caroline
    Hveem, Kristian
    Johnson, Andrew D
    Wouter Jukema, J
    Kardia, Sharon L R
    Kivimaki, Mika
    Kooner, Jaspal S
    Kuh, Diana
    Laakso, Markku
    Lehtimaki, Terho
    Marchand, Loic Le
    Marz, Winfried
    McCarthy, Mark I
    Metspalu, Andres
    Morris, Andrew P
    Ohlsson, Claes
    Palmer, Lyle J
    Pasterkamp, Gerard
    Pedersen, Oluf
    Peters, Annette
    Peters, Ulrike
    Polasek, Ozren
    Psaty, Bruce M
    Qi, Lu
    Rauramaa, Rainer
    Smith, Blair H
    Sorensen, Thorkild I A
    Strauch, Konstantin
    Tiemeier, Henning
    Tremoli, Elena
    van der Harst, Pim
    Vestergaard, Henrik
    Vollenweider, Peter
    Wareham, Nicholas J
    Weir, David R
    Whitfield, John B
    Wilson, James F
    Tyrrell, Jessica
    Frayling, Timothy M
    Barroso, Ines
    Boehnke, Michael
    Deloukas, Panagiotis
    Fox, Caroline S
    Hirschhorn, Joel N
    Hunter, David J
    Spector, Tim D
    Strachan, David P
    van Duijn, Cornelia M
    Heid, Iris M
    Mohlke, Karen L
    Marchini, Jonathan
    Loos, Ruth J F
    Kilpelainen, Tuomas O
    Liu, Ching-Ti
    Borecki, Ingrid B
    North, Kari E
    Cupples, L Adrienne
    Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, s. 14977-14977Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

  • 27.
    Kaarlejärvi, Elina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Department of Biology, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium.
    Eskelinen, Anu
    Olofsson, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Herbivores rescue diversity in warming tundra by modulating trait-dependent species losses and gains2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Climate warming is altering the diversity of plant communities but it remains unknown which species will be lost or gained under warming, especially considering interactions with other factors such as herbivory and nutrient availability. Here, we experimentally test effects of warming, mammalian herbivory and fertilization on tundra species richness and investigate how plant functional traits affect losses and gains. We show that herbivory reverses the impact of warming on diversity: in the presence of herbivores warming increases species richness through higher species gains and lower losses, while in the absence of herbivores warming causes higher species losses and thus decreases species richness. Herbivores promote gains of short-statured species under warming, while herbivore removal and fertilization increase losses of short-statured and resource-conservative species through light limitation. Our results demonstrate that both rarity and traits forecast species losses and gains, and mammalian herbivores are essential for preventing trait-dependent extinctions and mitigate diversity loss under warming and eutrophication.

  • 28. Karlberg, Tobias
    et al.
    Hornyak, Peter
    Pinto, Ana Filipa
    Milanova, Stefina
    Ebrahimi, Mahsa
    Lindberg, Mikael J.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Püllen, Nikolai
    Nordström, Axel
    Löverli, Elinor
    Caraballo, Remi
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wong, Emily V.
    Näreoja, Katja
    Thorsell, Ann-Gerd
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    De la Cruz, Enrique M.
    Björkegren, Camilla
    Schüler, Herwig
    14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 3785Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.

  • 29. Kern, Jan
    et al.
    Tran, Rosalie
    Alonso-Mori, Roberto
    Koroidov, Sergey
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Echols, Nathaniel
    Hattne, Johan
    Ibrahim, Mohamed
    Gul, Sheraz
    Laksmono, Hartawan
    Sierra, Raymond G.
    Gildea, Richard J.
    Han, Guangye
    Hellmich, Julia
    Lassalle-Kaiser, Benedikt
    Chatterjee, Ruchira
    Brewster, Aaron S.
    Stan, Claudiu A.
    Gloeckner, Carina
    Lampe, Alyssa
    DiFiore, Doertee
    Milathianaki, Despina
    Fry, Alan R.
    Seibert, M. Marvin
    Koglin, Jason E.
    Gallo, Erik
    Uhlig, Jens
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Zwart, Petrus H.
    Skinner, David E.
    Bogan, Michael J.
    Messerschmidt, Marc
    Glatzel, Pieter
    Williams, Garth J.
    Boutet, Sebastien
    Adams, Paul D.
    Zouni, Athina
    Messinger, Johannes
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauter, Nicholas K.
    Bergmann, Uwe
    Yano, Junko
    Yachandra, Vittal K.
    Taking snapshots of photosynthetic water oxidation using femtosecond X-ray diffraction and spectroscopy2014Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, s. 4371-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dioxygen we breathe is formed by light-induced oxidation of water in photosystem II. O-2 formation takes place at a catalytic manganese cluster within milliseconds after the photosystem II reaction centre is excited by three single-turnover flashes. Here we present combined X-ray emission spectra and diffraction data of 2-flash (2F) and 3-flash (3F) photosystem II samples, and of a transient 3F' state (250 mu s after the third flash), collected under functional conditions using an X-ray free electron laser. The spectra show that the initial O-O bond formation, coupled to Mn reduction, does not yet occur within 250 mu s after the third flash. Diffraction data of all states studied exhibit an anomalous scattering signal from Mn but show no significant structural changes at the present resolution of 4.5 angstrom. This study represents the initial frames in a molecular movie of the structural changes during the catalytic reaction in photosystem II.

  • 30. Kilpelainen, Tuomas O.
    et al.
    Bentley, Amy R.
    Noordam, Raymond
    Sung, Yun Ju
    Schwander, Karen
    Winkler, Thomas W.
    Jakupovic, Hermina
    Chasman, Daniel I.
    Manning, Alisa
    Ntalla, Ioanna
    Aschard, Hugues
    Brown, Michael R.
    de las Fuentes, Lisa
    Franceschini, Nora
    Guo, Xiuqing
    Vojinovic, Dina
    Aslibekyan, Stella
    Feitosa, Mary F.
    Kho, Minjung
    Musani, Solomon K.
    Richard, Melissa
    Wang, Heming
    Wang, Zhe
    Bartz, Traci M.
    Bielak, Lawrence F.
    Campbell, Archie
    Dorajoo, Rajkumar
    Fisher, Virginia
    Hartwig, Fernando P.
    Horimoto, Andrea R. V. R.
    Li, Changwei
    Lohman, Kurt K.
    Marten, Jonathan
    Sim, Xueling
    Smith, Albert V.
    Tajuddin, Salman M.
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Evangelou, Evangelos
    Gao, Chuan
    Graff, Mariaelisa
    Harris, Sarah E.
    He, Meian
    Hsu, Fang-Chi
    Jackson, Anne U.
    Zhao, Jing Hua
    Kraja, Aldi T.
    Kuehnel, Brigitte
    Laguzzi, Federica
    Lyytikainen, Leo-Pekka
    Nolte, Ilja M.
    Rauramaa, Rainer
    Riaz, Muhammad
    Robino, Antonietta
    Rueedi, Rico
    Stringham, Heather M.
    Takeuchi, Fumihiko
    van der Most, Peter J.
    Varga, Tibor V.
    Verweij, Niek
    Ware, Erin B.
    Wen, Wanqing
    Li, Xiaoyin
    Yanek, Lisa R.
    Amin, Najaf
    Arnett, Donna K.
    Boerwinkle, Eric
    Brumat, Marco
    Cade, Brian
    Canouil, Mickael
    Chen, Yii-Der Ida
    Concas, Maria Pina
    Connell, John
    de Mutsert, Renee
    de Silva, H. Janaka
    de Vries, Paul S.
    Demirkan, Ayse
    Ding, Jingzhong
    Eaton, Charles B.
    Faul, Jessica D.
    Friedlander, Yechiel
    Gabriel, Kelley P.
    Ghanbari, Mohsen
    Giulianini, Franco
    Gu, Chi Charles
    Gu, Dongfeng
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hunt, Steven C.
    Ikram, M. Arfan
    Jonas, Jost B.
    Koh, Woon-Puay
    Komulainen, Pirjo
    Krieger, Jose E.
    Kritchevsky, Stephen B.
    Kutalik, Zoltan
    Kuusisto, Johanna
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Leander, Karin
    Lemaitre, Rozenn N.
    Lewis, Cora E.
    Liang, Jingjing
    Alizadeh, Behrooz Z.
    Boezen, H. Marike
    Franke, Lude
    Navis, Gerjan
    Rots, Marianne
    Swertz, Morris
    Wolffenbuttel, Bruce H. R.
    Wijmenga, Cisca
    Liu, Jianjun
    Magi, Reedik
    Manichaikul, Ani
    Meitinger, Thomas
    Metspalu, Andres
    Milaneschi, Yuri
    Mohlke, Karen L.
    Mosley, Thomas H., Jr.
    Murray, Alison D.
    Nalls, Mike A.
    Nang, Ei-Ei Khaing
    Nelson, Christopher P.
    Nona, Sotoodehnia
    Norris, Jill M.
    Nwuba, Chiamaka Vivian
    O'Connell, Jeff
    Palmer, Nicholette D.
    Papanicolau, George J.
    Pazoki, Raha
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Porteous, David J.
    Poveda, Alaitz
    Raitakari, Olli T.
    Rich, Stephen S.
    Risch, Neil
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Schreiner, Pamela J.
    Scott, Robert A.
    Sidney, Stephen S.
    Sims, Mario
    Smith, Jennifer A.
    Snieder, Harold
    Sofer, Tamar
    Starr, John M.
    Sternfeld, Barbara
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Tsai, Michael Y.
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    van der Ende, M. Yldau
    van Heemst, Diana
    Voortman, Trudy
    Waldenberger, Melanie
    Wennberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Wilson, Gregory
    Xiang, Yong-Bing
    Yao, Jie
    Yu, Caizheng
    Yuan, Jian-Min
    Zhao, Wei
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    de Faire, Ulf
    Deary, Ian J.
    Elliott, Paul
    Esko, Tonu
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Kato, Norihiro
    Laakso, Markku
    Lakka, Timo A.
    Lehtimaaki, Terho
    Magnusson, Patrik K. E.
    Oldehinkel, Albertine J.
    Penninx, Brenda W. J. H.
    Samani, Nilesh J.
    Shu, Xiao-Ou
    van der Harst, Pim
    Van Vliet-Ostaptchouk, Jana V.
    Vollenweider, Peter
    Wagenknecht, Lynne E.
    Wang, Ya X.
    Wareham, Nicholas J.
    Weir, David R.
    Wu, Tangchun
    Zheng, Wei
    Zhu, Xiaofeng
    Evans, Michele K.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Harvard T. H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, USA; OCDEM, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
    Gudnason, Vilmundur
    Hayward, Caroline
    Horta, Bernardo L.
    Kelly, Tanika N.
    Liu, Yongmei
    North, Kari E.
    Pereira, Alexandre C.
    Ridker, Paul M.
    Tai, E. Shyong
    van Dam, Rob M.
    Fox, Ervin R.
    Kardia, Sharon L. R.
    Liu, Ching-Ti
    Mook-Kanamori, Dennis O.
    Province, Michael A.
    Redline, Susan
    van Duijn, Cornelia M.
    Rotter, Jerome I.
    Kooperberg, Charles B.
    Gauderman, W. James
    Psaty, Bruce M.
    Rice, Kenneth
    Munroe, Patricia B.
    Fornage, Myriam
    Cupples, L. Adrienne
    Rotimi, Charles N.
    Morrison, Alanna C.
    Rao, Dabeeru C.
    Loos, Ruth J. F.
    Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 376Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

  • 31. Kilpelainen, Tuomas O.
    et al.
    Carli, Jayne F. Martin
    Skowronski, Alicja A.
    Sun, Qi
    Kriebel, Jennifer
    Feitosa, Mary F.
    Hedman, Asa K.
    Drong, Alexander W.
    Hayes, James E.
    Zhao, Jinghua
    Pers, Tune H.
    Schick, Ursula
    Grarup, Niels
    Kutalik, Zoltan
    Trompet, Stella
    Mangino, Massimo
    Kristiansson, Kati
    Beekman, Marian
    Lyytikainen, Leo-Pekka
    Eriksson, Joel
    Henneman, Peter
    Lahti, Jari
    Tanaka, Toshiko
    Luan, Jian'an
    Del Greco M, Fabiola
    Pasko, Dorota
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö 20502, Sweden.
    Willems, Sara M.
    Mahajan, Anubha
    Rose, Lynda M.
    Guo, Xiuqing
    Liu, Yongmei
    Kleber, Marcus E.
    Perusse, Louis
    Gaunt, Tom
    Ahluwalia, Tarunveer S.
    Sung, Yun Ju
    Ramos, Yolande F.
    Amin, Najaf
    Amuzu, Antoinette
    Barroso, Ines
    Bellis, Claire
    Blangero, John
    Buckley, Brendan M.
    Boehringer, Stefan
    Chen, Yii-Der I.
    de Craen, Anton J. N.
    Crosslin, David R.
    Dale, Caroline E.
    Dastani, Zari
    Day, Felix R.
    Deelen, Joris
    Delgado, Graciela E.
    Demirkan, Ayse
    Finucane, Francis M.
    Ford, Ian
    Garcia, Melissa E.
    Gieger, Christian
    Gustafsson, Stefan
    Hallmans, Goran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Hankinson, Susan E.
    Havulinna, Aki S.
    Herder, Christian
    Hernandez, Dena
    Hicks, Andrew A.
    Hunter, David J.
    Illig, Thomas
    Ingelsson, Erik
    Ioan-Facsinay, Andreea
    Jansson, John-Olov
    Jenny, Nancy S.
    Jorgensen, Marit E.
    Jorgensen, Torben
    Karlsson, Magnus
    Koenig, Wolfgang
    Kraft, Peter
    Kwekkeboom, Joanneke
    Laatikainen, Tiina
    Ladwig, Karl-Heinz
    LeDuc, Charles A.
    Lowe, Gordon
    Lu, Yingchang
    Marques-Vidal, Pedro
    Meisinger, Christa
    Menni, Cristina
    Morris, Andrew P.
    Myers, Richard H.
    Mannisto, Satu
    Nalls, Mike A.
    Paternoster, Lavinia
    Peters, Annette
    Pradhan, Aruna D.
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J.
    Rathmann, Wolfgang
    Rice, Treva K.
    Richards, J. Brent
    Ridker, Paul M.
    Sattar, Naveed
    Savage, David B.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Timpson, Nicholas J.
    Vandenput, Liesbeth
    van Heemst, Diana
    Uh, Hae-Won
    Vohl, Marie-Claude
    Walker, Mark
    Wichmann, Heinz-Erich
    Widen, Elisabeth
    Wood, Andrew R.
    Yao, Jie
    Zeller, Tanja
    Zhang, Yiying
    Meulenbelt, Ingrid
    Kloppenburg, Margreet
    Astrup, Arne
    Sorensen, Thorkild I. A.
    Sarzynski, Mark A.
    Rao, D. C.
    Jousilahti, Pekka
    Vartiainen, Erkki
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Kajantie, Eero
    Osmond, Clive
    Palotie, Aarno
    Eriksson, Johan G.
    Heliovaara, Markku
    Knekt, Paul B.
    Koskinen, Seppo
    Jula, Antti
    Perola, Markus
    Huupponen, Risto K.
    Viikari, Jorma S.
    Kahonen, Mika
    Lehtimaki, Terho
    Raitakari, Olli T.
    Mellstrom, Dan
    Lorentzon, Mattias
    Casas, Juan P.
    Bandinelli, Stefanie
    Maerz, Winfried
    Isaacs, Aaron
    van Dijk, Ko W.
    van Duijn, Cornelia M.
    Harris, Tamara B.
    Bouchard, Claude
    Allison, Matthew A.
    Chasman, Daniel I.
    Ohlsson, Claes
    Lind, Lars
    Scott, Robert A.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Ferrucci, Luigi
    Frayling, Timothy M.
    Pramstaller, Peter P.
    Borecki, Ingrid B.
    Waterworth, Dawn M.
    Bergmann, Sven
    Waeber, Gerard
    Vollenweider, Peter
    Vestergaard, Henrik
    Hansen, Torben
    Pedersen, Oluf
    Hu, Frank B.
    Slagboom, P. Eline
    Grallert, Harald
    Spector, Tim D.
    Jukema, J. W.
    Klein, Robert J.
    Schadt, Erik E.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachussetts 02115, USA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö 20502, Sweden.
    Lindgren, Cecilia M.
    Leibel, Rudolph L.
    Loos, Ruth J. F.
    Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 10494Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P < 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P < 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  • 32. Klein, Alison P.
    et al.
    Wolpin, Brian M.
    Risch, Harvey A.
    Stolzenberg-Solomon, Rachael Z.
    Mocci, Evelina
    Zhang, Mingfeng
    Canzian, Federico
    Childs, Erica J.
    Hoskins, Jason W.
    Jermusyk, Ashley
    Zhong, Jun
    Chen, Fei
    Albanes, Demetrius
    Andreotti, Gabriella
    Arslan, Alan A.
    Babic, Ana
    Bamlet, William R.
    Beane-Freeman, Laura
    Berndt, Sonja I.
    Blackford, Amanda
    Borges, Michael
    Borgida, Ayelet
    Bracci, Paige M.
    Brais, Lauren
    Brennan, Paul
    Brenner, Hermann
    Bueno-de-Mesquita, Bas
    Buring, Julie
    Campa, Daniele
    Capurso, Gabriele
    Cavestro, Giulia Martina
    Chaffee, Kari G.
    Chung, Charles C.
    Cleary, Sean
    Cotterchio, Michelle
    Dijk, Frederike
    Duell, Eric J.
    Foretova, Lenka
    Fuchs, Charles
    Funel, Niccola
    Gallinger, Steven
    Gaziano, J. Michael M.
    Gazouli, Maria
    Giles, Graham G.
    Giovannucci, Edward
    Goggins, Michael
    Goodman, Gary E.
    Goodman, Phyllis J.
    Hackert, Thilo
    Haiman, Christopher
    Hartge, Patricia
    Hasan, Manal
    Hegyi, Peter
    Helzlsouer, Kathy J.
    Herman, Joseph
    Holcatova, Ivana
    Holly, Elizabeth A.
    Hoover, Robert
    Hung, Rayjean J.
    Jacobs, Eric J.
    Jamroziak, Krzysztof
    Janout, Vladimir
    Kaaks, Rudolf
    Khaw, Kay-Tee
    Klein, Eric A.
    Kogevinas, Manolis
    Kooperberg, Charles
    Kulke, Matthew H.
    Kupcinskas, Juozas
    Kurtz, Robert J.
    Laheru, Daniel
    Landi, Stefano
    Lawlor, Rita T.
    Lee, I. -Min
    LeMarchand, Loic
    Lu, Lingeng
    Malats, Nuria
    Mambrini, Andrea
    Mannisto, Satu
    Milne, Roger L.
    Mohelnikova-Duchonova, Beatrice
    Neale, Rachel E.
    Neoptolemos, John P.
    Oberg, Ann L.
    Olson, Sara H.
    Orlow, Irene
    Pasquali, Claudio
    Patel, Alpa V.
    Peters, Ulrike
    Pezzilli, Raffaele
    Porta, Miquel
    Real, Francisco X.
    Rothman, Nathaniel
    Scelo, Ghislaine
    Sesso, Howard D.
    Severi, Gianluca
    Shu, Xiao-Ou
    Silverman, Debra
    Smith, Jill P.
    Soucek, Pavel
    Sund, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Talar-Wojnarowska, Renata
    Tavano, Francesca
    Thornquist, Mark D.
    Tobias, Geoffrey S.
    Van Den Eeden, Stephen K.
    Vashist, Yogesh
    Visvanathan, Kala
    Vodicka, Pavel
    Wactawski-Wende, Jean
    Wang, Zhaoming
    Wentzensen, Nicolas
    White, Emily
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Kraft, Peter
    Li, Donghui
    Chanock, Stephen
    Obazee, Ofure
    Petersen, Gloria M.
    Amundadottir, Laufey T.
    Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

  • 33. Kormin, Dmitrii
    et al.
    Borot, Antonin
    Ma, Guangjin
    Dallari, William
    Bergues, Boris
    Aladi, Mark
    Földes, Istvan B.
    Veisz, Laszlo
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Max-Planck-Institut für Quantenoptik, D-85748 Garching, Germany.
    Spectral interferometry with waveform-dependent relativistic high-order harmonics from plasma surfaces2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 4992Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The interaction of ultra-intense laser pulses with matter opened the way to generate the shortest light pulses available nowadays in the attosecond regime. Ionized solid surfaces, also called plasma mirrors, are promising tools to enhance the potential of attosecond sources in terms of photon energy, photon number and duration especially at relativistic laser intensities. Although the production of isolated attosecond pulses and the understanding of the underlying interactions represent a fundamental step towards the realization of such sources, these are challenging and have not yet been demonstrated. Here, we present laser-waveform-dependent high-order harmonic radiation in the extreme ultraviolet spectral range supporting well-isolated attosecond pulses, and utilize spectral interferometry to understand its relativistic generation mechanism. This unique interpretation of the measured spectra provides access to unrevealed temporal and spatial properties such as spectral phase difference between attosecond pulses and field-driven plasma surface motion during the process.

  • 34.
    Kovermann, Michael
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Grundström, Christin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauer-Eriksson, A. Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauer, Uwe H
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wolf-Watz, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Structural basis for catalytically restrictive dynamics of a high-energy enzyme state2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 7644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An emerging paradigm in enzymology is that transient high-energy structural states play crucial roles in enzymatic reaction cycles. Generally, these high-energy or ‘invisible’ states cannot be studied directly at atomic resolution using existing structural and spectroscopic techniques owing to their low populations or short residence times. Here we report the direct NMR-based detection of the molecular topology and conformational dynamics of a catalytically indispensable high-energy state of an adenylate kinase variant. On the basis of matching energy barriers for conformational dynamics and catalytic turnover, it was found that the enzyme’s catalytic activity is governed by its dynamic interconversion between the high-energy state and a ground state structure that was determined by X-ray crystallography. Our results show that it is possible to rationally tune enzymes’ conformational dynamics and hence their catalytic power—a key aspect in rational design of enzymes catalysing novel reactions.

  • 35. Langefeld, Carl D.
    et al.
    Ainsworth, Hannah C.
    Graham, Deborah S. Cunninghame
    Kelly, Jennifer A.
    Comeau, Mary E.
    Marion, Miranda C.
    Howard, Timothy D.
    Ramos, Paula S.
    Croker, Jennifer A.
    Morris, David L.
    Sandling, Johanna K.
    Almlof, Jonas Carlsson
    Acevedo-Vasquez, Eduardo M.
    Alarcon, Graciela S.
    Babini, Alejandra M.
    Baca, Vicente
    Bengtsson, Anders A.
    Berbotto, Guillermo A.
    Bijl, Marc
    Brown, Elizabeth E.
    Brunner, Hermine I.
    Cardiel, Mario H.
    Catoggio, Luis
    Cervera, Ricard
    Cucho-Venegas, Jorge M.
    Rantapää Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    D'Alfonso, Sandra
    Da Silva, Berta Martins
    de la Rua Figueroa, Inigo
    Doria, Andrea
    Edberg, Jeffrey C.
    Endreffy, Emoke
    Esquivel-Valerio, Jorge A.
    Fortin, Paul R.
    Freedman, Barry I.
    Frostegard, Johan
    Garcia, Mercedes A.
    Garcia de la Torre, Ignacio
    Gilkeson, Gary S.
    Gladman, Dafna D.
    Gunnarsson, Iva
    Guthridge, Joel M.
    Huggins, Jennifer L.
    James, Judith A.
    Kallenberg, Cees G. M.
    Kamen, Diane L.
    Karp, David R.
    Kaufman, Kenneth M.
    Kottyan, Leah C.
    Kovacs, Laszlo
    Laustrup, Helle
    Lauwerys, Bernard R.
    Li, Quan-Zhen
    Maradiaga-Cecena, Marco A.
    Martin, Javier
    McCune, Joseph M.
    McWilliams, David R.
    Merrill, Joan T.
    Miranda, Pedro
    Moctezuma, Jose F.
    Nath, Swapan K.
    Niewold, Timothy B.
    Orozco, Lorena
    Ortego-Centeno, Norberto
    Petri, Michelle
    Pineau, Christian A.
    Pons-Estel, Bernardo A.
    Pope, Janet
    Raj, Prithvi
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Russell, Laurie P.
    Sabio, Jose M.
    Aguilar-Salinas, Carlos A.
    Scherbarth, Hugo R.
    Scorza, Raffaella
    Seldin, Michael F.
    Sjowall, Christopher
    Svenungsson, Elisabet
    Thompson, Susan D.
    Toloza, Sergio M. A.
    Truedsson, Lennart
    Tusie-Luna, Teresa
    Vasconcelos, Carlos
    Vila, Luis M.
    Wallace, Daniel J.
    Weisman, Michael H.
    Wither, Joan E.
    Bhangale, Tushar
    Oksenberg, Jorge R.
    Rioux, John D.
    Gregersen, Peter K.
    Syvanen, Ann-Christine
    Ronnblom, Lars
    Criswell, Lindsey A.
    Jacob, Chaim O.
    Sivils, Kathy L.
    Tsao, Betty P.
    Schanberg, Laura E.
    Behrens, Timothy W.
    Silverman, Earl D.
    Alarcon-Riquelme, Marta E.
    Kimberly, Robert P.
    Harley, John B.
    Wakeland, Edward K.
    Graham, Robert R.
    Gaffney, Patrick M.
    Vyse, Timothy J.
    Transancestral mapping and genetic load in systemic lupus erythematosus2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 16021Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

  • 36.
    Laumonnerie, Christophe
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Tong, Yong Guang
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Alstermark, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Wilson, Sara I.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Commissural axonal corridors instruct neuronal migration in the mouse spinal cord2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 7028Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Unravelling how neurons are guided during vertebrate embryonic development has wide implications for understanding the assembly of the nervous system. During embryogenesis, migration of neuronal cell bodies and axons occurs simultaneously, but to what degree they influence each other's development remains obscure. We show here that within the mouse embryonic spinal cord, commissural axons bisect, delimit or preconfigure ventral interneuron cell body position. Furthermore, genetic disruption of commissural axons results in abnormal ventral interneuron cell body positioning. These data suggest that commissural axonal fascicles instruct cell body position by acting either as border landmarks (axon-restricted migration), which to our knowledge has not been previously addressed, or acting as cellular guides. This study in the developing spinal cord highlights an important function for the interaction of cell bodies and axons, and provides a conceptual proof of principle that is likely to have overarching implications for the development of neuronal architecture.

  • 37. Lu, Yingchang
    et al.
    Day, Felix R.
    Gustafsson, Stefan
    Buchkovich, Martin L.
    Na, Jianbo
    Bataille, Veronique
    Cousminer, Diana L.
    Dastani, Zari
    Drong, Alexander W.
    Esko, Tonu
    Evans, David M.
    Falchi, Mario
    Feitosa, Mary F.
    Ferreira, Teresa
    Hedman, Asa K.
    Haring, Robin
    Hysi, Pirro G.
    Iles, Mark M.
    Justice, Anne E.
    Kanoni, Stavroula
    Lagou, Vasiliki
    Li, Rui
    Li, Xin
    Locke, Adam
    Lu, Chen
    Magi, Reedik
    Perry, John R. B.
    Pers, Tune H.
    Qi, Qibin
    Sanna, Marianna
    Schmidt, Ellen M.
    Scott, William R.
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Lund University Diabetes Centre, Department of Clinical Science, Genetic and Molecular Epidemiology Unit, Skåne University Hosptial, 205 02 Malmö, Sweden.
    Teumer, Alexander
    Vinkhuyzen, Anna A. E.
    Walker, Ryan W.
    Westra, Harm-Jan
    Zhang, Mingfeng
    Zhang, Weihua
    Zhao, Jing Hua
    Zhu, Zhihong
    Afzal, Uzma
    Ahluwalia, Tarunveer Singh
    Bakker, Stephan J. L.
    Bellis, Claire
    Bonnefond, Amelie
    Borodulin, Katja
    Buchman, Aron S.
    Cederholm, Tommy
    Choh, Audrey C.
    Choi, Hyung Jin
    Curran, Joanne E.
    de Groot, Lisette C. P. G. M.
    De Jager, Philip L.
    Dhonukshe-Rutten, Rosalie A. M.
    Enneman, Anke W.
    Eury, Elodie
    Evans, Daniel S.
    Forsen, Tom
    Friedrich, Nele
    Fumeron, Frederic
    Garcia, Melissa E.
    Gartner, Simone
    Han, Bok-Ghee
    Havulinna, Aki S.
    Hayward, Caroline
    Hernandez, Dena
    Hillege, Hans
    Ittermann, Till
    Kent, Jack W.
    Kolcic, Ivana
    Laatikainen, Tiina
    Lahti, Jari
    Leach, Irene Mateo
    Lee, Christine G.
    Lee, Jong-Young
    Liu, Tian
    Liu, Youfang
    Lobbens, Stephane
    Loh, Marie
    Lyytikainen, Leo-Pekka
    Medina-Gomez, Carolina
    Michaelsson, Karl
    Nalls, Mike A.
    Nielson, Carrie M.
    Oozageer, Laticia
    Pascoe, Laura
    Paternoster, Lavinia
    Polasek, Ozren
    Ripatti, Samuli
    Sarzynski, Mark A.
    Shin, Chan Soo
    Narancic, Nina Smolej
    Spira, Dominik
    Srikanth, Priya
    Steinhagen-Thiessen, Elisabeth
    Sung, Yun Ju
    Swart, Karin M. A.
    Taittonen, Leena
    Tanaka, Toshiko
    Tikkanen, Emmi
    van der Velde, Nathalie
    van Schoor, Natasja M.
    Verweij, Niek
    Wright, Alan F.
    Yu, Lei
    Zmuda, Joseph M.
    Eklund, Niina
    Forrester, Terrence
    Grarup, Niels
    Jackson, Anne U.
    Kristiansson, Kati
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Lichtner, Peter
    Luan, Jian'an
    Mahajan, Anubha
    Mannisto, Satu
    Palmer, Cameron D.
    Ried, Janina S.
    Scott, Robert A.
    Stancakova, Alena
    Wagner, Peter J.
    Demirkan, Ayse
    Doring, Angela
    Gudnason, Vilmundur
    Kiel, Douglas P.
    Kuhnel, Brigitte
    Mangino, Massimo
    Mcknight, Barbara
    Menni, Cristina
    O'Connell, Jeffrey R.
    Oostra, Ben A.
    Shuldiner, Alan R.
    Song, Kijoung
    Vandenput, Liesbeth
    van Duijn, Cornelia M.
    Vollenweider, Peter
    White, Charles C.
    Boehnke, Michael
    Boettcher, Yvonne
    Cooper, Richard S.
    Forouhi, Nita G.
    Gieger, Christian
    Grallert, Harald
    Hingorani, Aroon
    Jorgensen, Torben
    Jousilahti, Pekka
    Kivimaki, Mika
    Kumari, Meena
    Laakso, Markku
    Langenberg, Claudia
    Linneberg, Allan
    Luke, Amy
    Mckenzie, Colin A.
    Palotie, Aarno
    Pedersen, Oluf
    Peters, Annette
    Strauch, Konstantin
    Tayo, Bamidele O.
    Wareham, Nicholas J.
    Bennett, David A.
    Bertram, Lars
    Blangero, John
    Bluher, Matthias
    Bouchard, Claude
    Campbell, Harry
    Cho, Nam H.
    Cummings, Steven R.
    Czerwinski, Stefan A.
    Demuth, Ilja
    Eckardt, Rahel
    Eriksson, Johan G.
    Ferrucci, Luigi
    Franco, Oscar H.
    Froguel, Philippe
    Gansevoort, Ron T.
    Hansen, Torben
    Harris, Tamara B.
    Hastie, Nicholas
    Heliovaara, Markku
    Hofman, Albert
    Jordan, Joanne M.
    Jula, Antti
    Kahonen, Mika
    Kajantie, Eero
    Knekt, Paul B.
    Koskinen, Seppo
    Kovacs, Peter
    Lehtimaki, Terho
    Lind, Lars
    Liu, Yongmei
    Orwoll, Eric S.
    Osmond, Clive
    Perola, Markus
    Perusse, Louis
    Raitakari, Olli T.
    Rankinen, Tuomo
    Rao, D. C.
    Rice, Treva K.
    Rivadeneira, Fernando
    Rudan, Igor
    Salomaa, Veikko
    Sorensen, Thorkild I. A.
    Stumvoll, Michael
    Tonjes, Anke
    Towne, Bradford
    Tranah, Gregory J.
    Tremblay, Angelo
    Uitterlinden, Andre G.
    van der Harst, Pim
    Vartiainen, Erkki
    Viikari, Jorma S.
    Vitart, Veronique
    Vohl, Marie-Claude
    Volzke, Henry
    Walker, Mark
    Wallaschofski, Henri
    Wild, Sarah
    Wilson, James F.
    Yengo, Loic
    Bishop, D. Timothy
    Borecki, Ingrid B.
    Chambers, John C.
    Cupples, L. Adrienne
    Dehghan, Abbas
    Deloukas, Panos
    Fatemifar, Ghazaleh
    Fox, Caroline
    Furey, Terrence S.
    Franke, Lude
    Han, Jiali
    Hunter, David J.
    Karjalainen, Juha
    Karpe, Fredrik
    Kaplan, Robert C.
    Kooner, Jaspal S.
    McCarthy, Mark I.
    Murabito, Joanne M.
    Morris, Andrew P.
    Bishop, Julia A. N.
    North, Kari E.
    Ohlsson, Claes
    Ong, Ken K.
    Prokopenko, Inga
    Richards, J. Brent
    Schadt, Eric E.
    Spector, Tim D.
    Widen, Elisabeth
    Willer, Cristen J.
    Yang, Jian
    Ingelsson, Erik
    Mohlke, Karen L.
    Hirschhorn, Joel N.
    Pospisilik, John Andrew
    Zillikens, M. Carola
    Lindgren, Cecilia
    Kilpelainen, Tuomas Oskari
    Loos, Ruth J. F.
    New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 10495Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P < 5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

  • 38. Lund, Harald
    et al.
    Pieber, Melanie
    Parsa, Roham
    Han, Jinming
    Grommisch, David
    Ewing, Ewoud
    Kular, Lara
    Needhamsen, Maria
    Espinosa, Alexander
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Butovsky, Oleg
    Jagodic, Maja
    Zhang, Xing-Mei
    Harris, Robert A.
    Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 4845Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.

  • 39. Lunetta, Kathryn L.
    et al.
    Day, Felix R.
    Sulem, Patrick
    Ruth, Katherine S.
    Tung, Joyce Y.
    Hinds, David A.
    Esko, Tonu
    Elks, Cathy E.
    Altmaier, Elisabeth
    He, Chunyan
    Huffman, Jennifer E.
    Mihailov, Evelin
    Porcu, Eleonora
    Robino, Antonietta
    Rose, Lynda M.
    Schick, Ursula M.
    Stolk, Lisette
    Teumer, Alexander
    Thompson, Deborah J.
    Traglia, Michela
    Wang, Carol A.
    Yerges-Armstrong, Laura M.
    Antoniou, Antonis C.
    Barbieri, Caterina
    Coviello, Andrea D.
    Cucca, Francesco
    Demerath, Ellen W.
    Dunning, Alison M.
    Gandin, Ilaria
    Grove, Megan L.
    Gudbjartsson, Daniel F.
    Hocking, Lynne J.
    Hofman, Albert
    Huang, Jinyan
    Jackson, Rebecca D.
    Karasik, David
    Kriebel, Jennifer
    Lange, Ethan M.
    Lange, Leslie A.
    Langenberg, Claudia
    Li, Xin
    Luan, Jian'an
    Maegi, Reedik
    Morrison, Alanna C.
    Padmanabhan, Sandosh
    Pirie, Ailith
    Polasek, Ozren
    Porteous, David
    Reiner, Alex P.
    Rivadeneira, Fernando
    Rudan, Igor
    Sala, Cinzia F.
    Schlessinger, David
    Scott, Robert A.
    Stoeckl, Doris
    Visser, Jenny A.
    Voelker, Uwe
    Vozzi, Diego
    Wilson, James G.
    Zygmunt, Marek
    Boerwinkle, Eric
    Buring, Julie E.
    Crisponi, Laura
    Easton, Douglas F.
    Hayward, Caroline
    Hu, Frank B.
    Liu, Simin
    Metspalu, Andres
    Pennell, Craig E.
    Ridker, Paul M.
    Strauch, Konstantin
    Streeten, Elizabeth A.
    Toniolo, Daniela
    Uitterlinden, Andre G.
    Ulivi, Sheila
    Voelzke, Henry
    Wareham, Nicholas J.
    Wellons, Melissa
    Franceschini, Nora
    Chasman, Daniel I.
    Thorsteinsdottir, Unnur
    Murray, Anna
    Stefansson, Kari
    Murabito, Joanne M.
    Ong, Ken K.
    Perry, John R. B.
    Forouhi, Nita G.
    Kerrison, Nicola D.
    Sharp, Stephen J.
    Sims, Matt
    Barroso, Ines
    Deloukas, Panos
    McCarthy, Mark I.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Boeing, Heiner
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gonzalez, Carlos
    Grioni, Sara
    Kaaks, Rudolf
    Key, Timothy J.
    Navarro, Carmen
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Riboli, Elio
    Smith, Blair H.
    Campbell, Archie
    Deary, Ian J.
    McIntosh, Andrew M.
    Rare coding variants and X-linked loci associated with age at menarche2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 7756Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

  • 40. MacDougall, Andrew S.
    et al.
    Harvey, Eric
    McCune, Jenny L.
    Nilsson, Karin A.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Department of Integrative Biology, University Of Guelph, Guelph, Ontario, Canada N1G 2W1.
    Bennett, Joseph
    Firn, Jennifer
    Bartley, Timothy
    Grace, James B.
    Kelly, Jocelyn
    Tunney, Tyler D.
    McMeans, Bailey
    Matsuzaki, Shin-Ichiro S.
    Kadoya, Taku
    Esch, Ellen
    Cazelles, Kevin
    Lester, Nigel
    McCann, Kevin S.
    Context-dependent interactions and the regulation of species richness in freshwater fish2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 973Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Species richness is regulated by a complex network of scale-dependent processes. This complexity can obscure the influence of limiting species interactions, making it difficult to determine if abiotic or biotic drivers are more predominant regulators of richness. Using integrative modeling of freshwater fish richness from 721 lakes along an 11 degrees latitudinal gradient, we find negative interactions to be a relatively minor independent predictor of species richness in lakes despite the widespread presence of predators. Instead, interaction effects, when detectable among major functional groups and 231 species pairs, were strong, often positive, but contextually dependent on environment. These results are consistent with the idea that negative interactions internally structure lake communities but do not consistently 'scale-up' to regulate richness independently of the environment. The importance of environment for interaction outcomes and its role in the regulation of species richness highlights the potential sensitivity of fish communities to the environmental changes affecting lakes globally.

  • 41. Machiela, Mitchell J
    et al.
    Zhou, Weiyin
    Karlins, Eric
    Sampson, Joshua N
    Freedman, Neal D
    Yang, Qi
    Hicks, Belynda
    Dagnall, Casey
    Hautman, Christopher
    Jacobs, Kevin B
    Abnet, Christian C
    Aldrich, Melinda C
    Amos, Christopher
    Amundadottir, Laufey T
    Arslan, Alan A
    Beane-Freeman, Laura E
    Berndt, Sonja I
    Black, Amanda
    Blot, William J
    Bock, Cathryn H
    Bracci, Paige M
    Brinton, Louise A
    Bueno-de-Mesquita, H Bas
    Burdett, Laurie
    Buring, Julie E
    Butler, Mary A
    Canzian, Federico
    Carreón, Tania
    Chaffee, Kari G
    Chang, I-Shou
    Chatterjee, Nilanjan
    Chen, Chu
    Chen, Constance
    Chen, Kexin
    Chung, Charles C
    Cook, Linda S
    Crous Bou, Marta
    Cullen, Michael
    Davis, Faith G
    De Vivo, Immaculata
    Ding, Ti
    Doherty, Jennifer
    Duell, Eric J
    Epstein, Caroline G
    Fan, Jin-Hu
    Figueroa, Jonine D
    Fraumeni, Joseph F
    Friedenreich, Christine M
    Fuchs, Charles S
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Gaudet, Mia M
    Gaziano, J Michael
    Giles, Graham G
    Gillanders, Elizabeth M
    Giovannucci, Edward L
    Goldin, Lynn
    Goldstein, Alisa M
    Haiman, Christopher A
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hankinson, Susan E
    Harris, Curtis C
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holly, Elizabeth A
    Hong, Yun-Chul
    Hoover, Robert N
    Hsiung, Chao A
    Hu, Nan
    Hu, Wei
    Hunter, David J
    Hutchinson, Amy
    Jenab, Mazda
    Johansen, Christoffer
    Khaw, Kay-Tee
    Kim, Hee Nam
    Kim, Yeul Hong
    Kim, Young Tae
    Klein, Alison P
    Klein, Robert
    Koh, Woon-Puay
    Kolonel, Laurence N
    Kooperberg, Charles
    Kraft, Peter
    Krogh, Vittorio
    Kurtz, Robert C
    LaCroix, Andrea
    Lan, Qing
    Landi, Maria Teresa
    Marchand, Loic Le
    Li, Donghui
    Liang, Xiaolin
    Liao, Linda M
    Lin, Dongxin
    Liu, Jianjun
    Lissowska, Jolanta
    Lu, Lingeng
    Magliocco, Anthony M
    Malats, Nuria
    Matsuo, Keitaro
    McNeill, Lorna H
    McWilliams, Robert R
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Mirabello, Lisa
    Moore, Lee
    Olson, Sara H
    Orlow, Irene
    Park, Jae Yong
    Patiño-Garcia, Ana
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M
    Pooler, Loreall
    Prescott, Jennifer
    Prokunina-Olsson, Ludmila
    Purdue, Mark P
    Qiao, You-Lin
    Rajaraman, Preetha
    Real, Francisco X
    Riboli, Elio
    Risch, Harvey A
    Rodriguez-Santiago, Benjamin
    Ruder, Avima M
    Savage, Sharon A
    Schumacher, Fredrick
    Schwartz, Ann G
    Schwartz, Kendra L
    Seow, Adeline
    Wendy Setiawan, Veronica
    Severi, Gianluca
    Shen, Hongbing
    Sheng, Xin
    Shin, Min-Ho
    Shu, Xiao-Ou
    Silverman, Debra T
    Spitz, Margaret R
    Stevens, Victoria L
    Stolzenberg-Solomon, Rachael
    Stram, Daniel
    Tang, Ze-Zhong
    Taylor, Philip R
    Teras, Lauren R
    Tobias, Geoffrey S
    Van Den Berg, David
    Visvanathan, Kala
    Wacholder, Sholom
    Wang, Jiu-Cun
    Wang, Zhaoming
    Wentzensen, Nicolas
    Wheeler, William
    White, Emily
    Wiencke, John K
    Wolpin, Brian M
    Wong, Maria Pik
    Wu, Chen
    Wu, Tangchun
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S
    Xia, Lucy
    Yang, Hannah P
    Yang, Pan-Chyr
    Yu, Kai
    Zanetti, Krista A
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Zhou, Baosen
    Ziegler, Regina G
    Perez-Jurado, Luis A
    Caporaso, Neil E
    Rothman, Nathaniel
    Tucker, Margaret
    Dean, Michael C
    Yeager, Meredith
    Chanock, Stephen J
    Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 11843Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.

  • 42. Matejcic, Marco
    et al.
    Saunders, Edward J.
    Dadaev, Tokhir
    Brook, Mark N.
    Wang, Kan
    Sheng, Xin
    Al Olama, Ali Amin
    Schumacher, Fredrick R.
    Ingles, Sue A.
    Govindasami, Koveela
    Benlloch, Sara
    Berndt, Sonja I.
    Albanes, Demetrius
    Koutros, Stella
    Muir, Kenneth
    Stevens, Victoria L.
    Gapstur, Susan M.
    Tangen, Catherine M.
    Batra, Jyotsna
    Clements, Judith
    Gronberg, Henrik
    Pashayan, Nora
    Schleutker, Johanna
    Wolk, Alicja
    West, Catharine
    Mucci, Lorelei
    Kraft, Peter
    Cancel-Tassin, Geraldine
    Sorensen, Karina D.
    Maehle, Lovise
    Grindedal, Eli M.
    Strom, Sara S.
    Neal, David E.
    Hamdy, Freddie C.
    Donovan, Jenny L.
    Travis, Ruth C.
    Hamilton, Robert J.
    Rosenstein, Barry
    Lu, Yong-Jie
    Giles, Graham G.
    Kibel, Adam S.
    Vega, Ana
    Bensen, Jeanette T.
    Kogevinas, Manolis
    Penney, Kathryn L.
    Park, Jong Y.
    Stanford, Janet L.
    Cybulski, Cezary
    Nordestgaard, Borge G.
    Brenner, Hermann
    Maier, Christiane
    Kim, Jeri
    Teixeira, Manuel R.
    Neuhausen, Susan L.
    De Ruyck, Kim
    Razack, Azad
    Newcomb, Lisa F.
    Lessel, Davor
    Kaneva, Radka
    Usmani, Nawaid
    Claessens, Frank
    Townsend, Paul A.
    Gago-Dominguez, Manuela
    Roobol, Monique J.
    Menegaux, Florence
    Khaw, Kay-Tee
    Cannon-Albright, Lisa A.
    Pandha, Hardev
    Thibodeau, Stephen N.
    Schaid, Daniel J.
    Wiklund, Fredrik
    Chanock, Stephen J.
    Easton, Douglas F.
    Eeles, Rosalind A.
    Kote-Jarai, Zsofia
    Conti, David V.
    Haiman, Christopher A.
    Henderson, Brian E.
    Stern, Mariana C.
    Thwaites, Alison
    Guy, Michelle
    Whitmore, Ian
    Morgan, Angela
    Fisher, Cyril
    Hazel, Steve
    Livni, Naomi
    Cook, Margaret
    Fachal, Laura
    Weinstein, Stephanie
    Freeman, Laura E. Beane
    Hoover, Robert N.
    Machiela, Mitchell J.
    Lophatananon, Artitaya
    Carter, Brian D.
    Goodman, Phyllis
    Moya, Leire
    Srinivasan, Srilakshmi
    Kedda, Mary-Anne
    Yeadon, Trina
    Eckert, Allison
    Eklund, Martin
    Cavalli-Bjoerkman, Carin
    Dunning, Alison M.
    Sipeky, Csilla
    Hakansson, Niclas
    Elliott, Rebecca
    Ranu, Hardeep
    Giovannucci, Edward
    Turman, Constance
    Hunter, David J.
    Cussenot, Olivier
    Orntoft, Torben Falck
    Lane, Athene
    Lewis, Sarah J.
    Davis, Michael
    Key, Tim J.
    Brown, Paul
    Kulkarni, Girish S.
    Zlotta, Alexandre R.
    Fleshner, Neil E.
    Finelli, Antonio
    Mao, Xueying
    Marzec, Jacek
    MacInnis, Robert J.
    Milne, Roger
    Hopper, John L.
    Aguado, Miguel
    Bustamante, Mariona
    Castano-Vinyals, Gemma
    Gracia-Lavedan, Esther
    Cecchini, Lluis
    Stampfer, Meir
    Ma, Jing
    Sellers, Thomas A.
    Geybels, Milan S.
    Park, Hyun
    Zachariah, Babu
    Kolb, Suzanne
    Wokolorczyk, Dominika
    Lubinski, Jan
    Kluzniak, Wojciech
    Nielsen, Sune F.
    Weisher, Maren
    Cuk, Katarina
    Vogel, Walther
    Luedeke, Manuel
    Logothetis, Christopher J.
    Paulo, Paula
    Cardoso, Marta
    Maia, Sofia
    Silva, Maria P.
    Steele, Linda
    Ding, Yuan Chun
    De Meerleer, Gert
    De Langhe, Sofie
    Thierens, Hubert
    Lim, Jasmine
    Tan, Meng H.
    Ong, Aik T.
    Lin, Daniel W.
    Kachakova, Darina
    Mitkova, Atanaska
    Mitev, Vanio
    Parliament, Matthew
    Jenster, Guido
    Bangma, Christopher
    Schroder, F. H.
    Truong, Therese
    Koudou, Yves Akoli
    Michael, Agnieszka
    Kierzek, Andrzej
    Karlsson, Ami
    Broms, Michael
    Wu, Huihai
    Aukim-Hastie, Claire
    Tillmans, Lori
    Riska, Shaun
    McDonnell, Shannon K.
    Dearnaley, David
    Spurdle, Amanda
    Gardiner, Robert
    Hayes, Vanessa
    Butler, Lisa
    Taylor, Renea
    Papargiris, Melissa
    Saunders, Pamela
    Kujala, Paula
    Talala, Kirsi
    Taari, Kimmo
    Bentzen, Soren
    Hicks, Belynda
    Vogt, Aurelie
    Hutchinson, Amy
    Cox, Angela
    George, Anne
    Toi, Ants
    Evans, Andrew
    van der Kwast, Theodorus H.
    Imai, Takashi
    Saito, Shiro
    Zhao, Shan-Chao
    Ren, Guoping
    Zhang, Yangling
    Yu, Yongwei
    Wu, Yudong
    Wu, Ji
    Zhou, Bo
    Pedersen, John
    Lobato-Busto, Ramon
    Manuel Ruiz-Dominguez, Jose
    Mengual, Lourdes
    Alcaraz, Antonio
    Pow-Sang, Julio
    Herkommer, Kathleen
    Vlahova, Aleksandrina
    Dikov, Tihomir
    Christova, Svetlana
    Carracedo, Angel
    Tretarre, Brigitte
    Rebillard, Xavier
    Mulot, Claire
    Adolfsson, Jan
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
    Johansson, Jan-Erik
    Martin, Richard M.
    Thompson, Ian M., Jr.
    Chambers, Suzanne
    Aitken, Joanne
    Horvath, Lisa
    Haynes, Anne-Maree
    Tilley, Wayne
    Risbridger, Gail
    Aly, Markus
    Nordstrom, Tobias
    Pharoah, Paul
    Tammela, Teuvo L. J.
    Murtola, Teemu
    Auvinen, Anssi
    Burnet, Neil
    Barnett, Gill
    Andriole, Gerald
    Klim, Aleksandra
    Drake, Bettina F.
    Borre, Michael
    Kerns, Sarah
    Ostrer, Harry
    Zhang, Hong-Wei
    Cao, Guangwen
    Lin, Ji
    Ling, Jin
    Li, Meiling
    Feng, Ninghan
    Li, Jie
    He, Weiyang
    Guo, Xin
    Sun, Zan
    Wang, Guomin
    Guo, Jianming
    Southey, Melissa C.
    FitzGerald, Liesel M.
    Marsden, Gemma
    Gomez-Caamano, Antonio
    Carballo, Ana
    Peleteiro, Paula
    Calvo, Patricia
    Szulkin, Robert
    Llorca, Javier
    Dierssen-Sotos, Trinidad
    Gomez-Acebo, Ines
    Lin, Hui-Yi
    Ostrander, Elaine A.
    Bisbjerg, Rasmus
    Klarskov, Peter
    Roder, Martin Andreas
    Iversen, Peter
    Holleczek, Bernd
    Stegmaier, Christa
    Schnoeller, Thomas
    Bohnert, Philipp
    John, Esther M.
    Ost, Piet
    Teo, Soo-Hwang
    Gamulin, Marija
    Kulis, Tomislav
    Kastelan, Zeljko
    Slavov, Chavdar
    Popov, Elenko
    Van den Broeck, Thomas
    Joniau, Steven
    Larkin, Samantha
    Esteban Castelao, Jose
    Martinez, Maria Elena
    van Schaik, Ron H. N.
    Xu, Jianfeng
    Lindstrom, Sara
    Riboli, Elio
    Berry, Clare
    Siddiq, Afshan
    Canzian, Federico
    Kolonel, Laurence N.
    Le Marchand, Loic
    Freedman, Matthew
    Cenee, Sylvie
    Sanchez, Marie
    Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 382Artikel i tidskrift (Refereegranskat)
  • 43.
    Mu, Yabing
    et al.
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Sundar, Reshma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Thakur, Noopur
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Ekman, Maria
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Gudey, Shyam Kumar
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Yakymovych, Mariya
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Hermansson, Annika
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Dimitriou, Helen
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Bengoechea-Alonso, Maria Teresa
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Ericsson, Johan
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Landström, Marene
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer2011Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, nr 330, s. 11-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transforming growth factor beta (TGF beta) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGF beta binding to type II and type I serine/threonine kinase receptors (T beta RII and T beta RI) causes activation of different intracellular signaling pathways. T beta RI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGF beta, via TRAF6, causes Lys63-linked polyubiquitination of T beta RI, promoting cleavage of T beta RI by TNF-alpha converting enzyme (TACE), in a PKC zeta-dependent manner. The liberated intracellular domain (ICD) of T beta RI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGF beta-induced invasion of cancer cells is TACE- and PKC zeta-dependent and the T beta RI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for T beta RI in TGF beta mediated tumour invasion.

  • 44.
    Nilsson, Håkan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Rappaport, Fabrice
    Boussac, Alain G P
    Messinger, Johannes
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Substrate-water exchange in photosystem II is arrested before dioxygen formation2014Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, s. 4305-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Light-driven oxidation of water into dioxygen, catalysed by the oxygen-evolving complex (OEC) in photosystem II, is essential for life on Earth and provides the blueprint for devices for producing fuel from sunlight. Although the structure of the OEC is known at atomic level for its dark-stable state, the mechanism by which water is oxidized remains unsettled. Important mechanistic information was gained in the past two decades by mass spectrometric studies of the H2 18O/H2 16O substrate-water exchange in the four (semi) stable redox states of the OEC. However, until now such data were not attainable in the transient states formed immediately before the O-O bond formation. Using modified photosystem II complexes displaying up to 40-fold slower O2 production rates, we show here that in the transient state the substrate-water exchange is dramatically slowed as compared with the earlier S states. This further constrains the possible sites for substrate-water binding in photosystem II.

  • 45.
    Panda, Swarupa
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    The deubiquitinase MYSM1 dampens NOD2-mediated inflammation and tissue damage by inactivating the RIP2 complex2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 4654Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    NOD2 is essential for antimicrobial innate immunity and tissue homeostasis, but require tight regulation to avert pathology. A focal point of NOD2 signaling is RIP2, which upon polyubiquitination nucleates the NOD2:RIP2 complex, enabling signaling events leading to inflammation, yet the precise nature and the regulation of the polyubiquitins coordinating this process remain unclear. Here we show that NOD2 signaling involves conjugation of RIP2 with lysine 63 (K63), K48 and M1 polyubiquitin chains, as well as with non-canonical K27 chains. In addition, we identify MYSM1 as a proximal deubiquitinase that attenuates NOD2:RIP2 complex assembly by selectively removing the K63, K27 and M1 chains, but sparing the K48 chains. Consequently, MYSM1 deficient mice have unrestrained NOD2-mediated peritonitis, systemic inflammation and liver injury. This study provides a complete overview of the polyubiquitins in NOD2:RIP2 signaling and reveal MYSM1 as a central negative regulator restricting these polyubiquitins to prevent excessive inflammation.

  • 46.
    Parkash, Vimal
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kulkarni, Yashraj
    ter Beek, Josy
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shcherbakova, Polina V.
    Kamerlin, Shina Caroline Lynn
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase epsilon2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The most frequently recurring cancer-associated DNA polymerase epsilon (Pol epsilon) mutation is a P286R substitution in the exonuclease domain. While originally proposed to increase genome instability by disrupting exonucleolytic proofreading, the P286R variant was later found to be significantly more pathogenic than Pol epsilon proofreading deficiency per se. The mechanisms underlying its stronger impact remained unclear. Here we report the crystal structure of the yeast orthologue, Pol epsilon-P301R, complexed with DNA and an incoming dNTP. Structural changes in the protein are confined to the exonuclease domain, with R301 pointing towards the exonuclease site. Molecular dynamics simulations suggest that R301 interferes with DNA binding to the exonuclease site, an outcome not observed with the exonuclease-inactive Pol epsilon-D290A, E292A variant lacking the catalytic residues. These results reveal a distinct mechanism of exonuclease inactivation by the P301R substitution and a likely basis for its dramatically higher mutagenic and tumorigenic effects.

  • 47. Peixoto, Tiago P.
    et al.
    Rosvall, Martin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Modelling sequences and temporal networks with dynamic community structures2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 582Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In evolving complex systems such as air traffic and social organisations, collective effects emerge from their many components' dynamic interactions. While the dynamic interactions can be represented by temporal networks with nodes and links that change over time, they remain highly complex. It is therefore often necessary to use methods that extract the temporal networks' large-scale dynamic community structure. However, such methods are subject to overfitting or suffer from effects of arbitrary, a priori-imposed timescales, which should instead be extracted from data. Here we simultaneously address both problems and develop a principled data-driven method that determines relevant timescales and identifies patterns of dynamics that take place on networks, as well as shape the networks themselves. We base our method on an arbitrary-order Markov chain model with community structure, and develop a nonparametric Bayesian inference framework that identifies the simplest such model that can explain temporal interaction data.

  • 48.
    Pietra, Stefano
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Gustavsson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Kiefer, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Kalmbach, Lothar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Hörstedt, Per
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå Core Facility Electron Microscopy, Umeå University.
    Ikeda, Yoshihisa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Stepanova, Anna N.
    Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695, USA.
    Alonso, Jose M.
    Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695, USA.
    Grebe, Markus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Arabidopsis SABRE and CLASP interact to stabilize cell division plane orientation and planar polarity2013Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, s. 2779-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The orientation of cell division and the coordination of cell polarity within the plane of the tissue layer (planar polarity) contribute to shape diverse multicellular organisms. The root of Arabidopsis thaliana displays regularly oriented cell divisions, cell elongation and planar polarity providing a plant model system to study these processes. Here we report that the SABRE protein, which shares similarity with proteins of unknown function throughout eukaryotes, has important roles in orienting cell division and planar polarity. SABRE localizes at the plasma membrane, endomembranes, mitotic spindle and cell plate. SABRE stabilizes the orientation of CLASP-labelled preprophase band microtubules predicting the cell division plane, and of cortical microtubules driving cell elongation. During planar polarity establishment, sabre is epistatic to clasp at directing polar membrane domains of Rho-of-plant GTPases. Our findings mechanistically link SABRE to CLASP-dependent microtubule organization, shedding new light on the function of SABRE-related proteins in eukaryotes.

  • 49.
    Reichstein, Birte
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Persson, Lennart
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    De Roos, Andre M.
    Univ Amsterdam, Inst Biodivers & Ecosyst Dynam, NL-1090 GE Amsterdam, Netherlands.
    Ontogenetic asymmetry modulates population biomass production and response to harvest2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 6441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patterns in biomass production are determined by resource input (productivity) and trophic transfer efficiency. At fixed resource input, variation in consumer biomass production has been related to food quality, metabolic type and diversity among species. In contrast, intraspecific variation in individual body size because of ontogenetic development, which characterizes the overwhelming majority of taxa, has been largely neglected. Here we show experimentally in a long-term multigenerational study that reallocating constant resource input in a two-stage consumer system from an equal resource delivery to juveniles and adults to an adult-biased resource delivery is sufficient to cause more than a doubling of total consumer biomass. We discuss how such changes in consumer stage-specific resource allocation affect the likelihood for alternative stable states in harvested populations as a consequence of stage-specific overcompensation in consumer biomass and thereby the risk of catastrophic collapses in exploited populations.

  • 50. Richmond, Erinn K.
    et al.
    Rosi, Emma J.
    Walters, David M.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hamilton, Stephen K.
    Brodin, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Department of Wildlife Fish, and Environmental Studies, SLU, Umeå 90187, Sweden.
    Sundelin, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Grace, Michael R.
    A diverse suite of pharmaceuticals contaminates stream and riparian food webs2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 4491Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A multitude of biologically active pharmaceuticals contaminate surface waters globally, yet their presence in aquatic food webs remain largely unknown. Here, we show that over 60 pharmaceutical compounds can be detected in aquatic invertebrates and riparian spiders in six streams near Melbourne, Australia. Similar concentrations in aquatic invertebrate larvae and riparian predators suggest direct trophic transfer via emerging adult insects to riparian predators that consume them. As representative vertebrate predators feeding on aquatic invertebrates, platypus and brown trout could consume some drug classes such as antidepressants at as much as one-half of a recommended therapeutic dose for humans based on their estimated prey consumption rates, yet the consequences for fish and wildlife of this chronic exposure are unknown. Overall, this work highlights the potential exposure of aquatic and riparian biota to a diverse array of pharmaceuticals, resulting in exposures to some drugs that are comparable to human dosages.

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