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  • 1.
    Azim, Eiman
    et al.
    Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Jiang, Juan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Jessell, Thomas M
    Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Skilled reaching relies on a V2a propriospinal internal copy circuit2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7496, p. 357-363Article in journal (Refereed)
    Abstract [en]

    The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

  • 2. Bahr, Carsten
    et al.
    von Paleske, Lisa
    Uslu, Veli V
    Remeseiro, Silvia
    Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Takayama, Naoya
    Ng, Stanley W
    Murison, Alex
    Langenfeld, Katja
    Petretich, Massimo
    Scognamiglio, Roberta
    Zeisberger, Petra
    Benk, Amelie S
    Amit, Ido
    Zandstra, Peter W
    Lupien, Mathieu
    Dick, John E
    Trumpp, Andreas
    Spitz, François
    A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 553, no 7689, p. 515-520Article in journal (Refereed)
    Abstract [en]

    The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies1. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a ‘super-enhancer’2 is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells3. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a ‘blood enhancer cluster’ (BENC). We show that BENC is also essential for the maintenance of MLL–AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.

  • 3.
    Bhowmick, Asmit
    et al.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Hussein, Rana
    Department of Biology, Humboldt Universität zu Berlin, Berlin, Germany.
    Bogacz, Isabel
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Simon, Philipp S.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Ibrahim, Mohamed
    Department of Biology, Humboldt Universität zu Berlin, Berlin, Germany; Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.
    Chatterjee, Ruchira
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Doyle, Margaret D.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Cheah, Mun Hon
    Molecular Biomimetics, Department of Chemistry — Ångström, Uppsala University, Uppsala, Sweden.
    Fransson, Thomas
    Department of Theoretical Chemistry and Biology, KTH Royal Institute of Technology, Stockholm, Sweden.
    Chernev, Petko
    Molecular Biomimetics, Department of Chemistry — Ångström, Uppsala University, Uppsala, Sweden.
    Kim, In-Sik
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Makita, Hiroki
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Dasgupta, Medhanjali
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Kaminsky, Corey J.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Zhang, Miao
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Gätcke, Julia
    Department of Biology, Humboldt Universität zu Berlin, Berlin, Germany.
    Haupt, Stephanie
    Department of Biology, Humboldt Universität zu Berlin, Berlin, Germany.
    Nangca, Isabela I.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Keable, Stephen M.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Aydin, A. Orkun
    Molecular Biomimetics, Department of Chemistry — Ångström, Uppsala University, Uppsala, Sweden.
    Tono, Kensuke
    Japan Synchrotron Radiation Research Institute, Hyogo, Japan; RIKEN SPring-8 Center, Hyogo, Japan.
    Owada, Shigeki
    Japan Synchrotron Radiation Research Institute, Hyogo, Japan; RIKEN SPring-8 Center, Hyogo, Japan.
    Gee, Leland B.
    Linac Coherent Light Source, SLAC National Accelerator Laboratory, CA, Menlo Park, United States.
    Fuller, Franklin D.
    Linac Coherent Light Source, SLAC National Accelerator Laboratory, CA, Menlo Park, United States.
    Batyuk, Alexander
    Linac Coherent Light Source, SLAC National Accelerator Laboratory, CA, Menlo Park, United States.
    Alonso-Mori, Roberto
    Linac Coherent Light Source, SLAC National Accelerator Laboratory, CA, Menlo Park, United States.
    Holton, James M.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States; Department of Biochemistry and Biophysics, University of California, CA, San Francisco, United States; SSRL, SLAC National Accelerator Laboratory, CA, Menlo Park, United States.
    Paley, Daniel W.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Moriarty, Nigel W.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Mamedov, Fikret
    Molecular Biomimetics, Department of Chemistry — Ångström, Uppsala University, Uppsala, Sweden.
    Adams, Paul D.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States; Department of Bioengineering, University of California, CA, Berkeley, United States.
    Brewster, Aaron S.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Dobbek, Holger
    Department of Biology, Humboldt Universität zu Berlin, Berlin, Germany.
    Sauter, Nicholas K.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Bergmann, Uwe
    Department of Physics, University of Wisconsin–Madison, WI, Madison, United States.
    Zouni, Athina
    Department of Biology, Humboldt Universität zu Berlin, Berlin, Germany.
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Molecular Biomimetics, Department of Chemistry — Ångström, Uppsala University, Uppsala, Sweden.
    Kern, Jan
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Yano, Junko
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Yachandra, Vittal K.
    Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, CA, Berkeley, United States.
    Structural evidence for intermediates during O2 formation in photosystem II2023In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 617, no 7961, p. 629-636Article in journal (Refereed)
    Abstract [en]

    In natural photosynthesis, the light-driven splitting of water into electrons, protons and molecular oxygen forms the first step of the solar-to-chemical energy conversion process. The reaction takes place in photosystem II, where the Mn4CaO5 cluster first stores four oxidizing equivalents, the S0 to S4 intermediate states in the Kok cycle, sequentially generated by photochemical charge separations in the reaction center and then catalyzes the O–O bond formation chemistry. Here, we report room temperature snapshots by serial femtosecond X-ray crystallography to provide structural insights into the final reaction step of Kok’s photosynthetic water oxidation cycle, the S3→[S4]→S0 transition where O2 is formed and Kok’s water oxidation clock is reset. Our data reveal a complex sequence of events, which occur over micro- to milliseconds, comprising changes at the Mn4CaO5 cluster, its ligands and water pathways as well as controlled proton release through the hydrogen-bonding network of the Cl1 channel. Importantly, the extra O atom Ox, which was introduced as a bridging ligand between Ca and Mn1 during the S2→S3 transition, disappears or relocates in parallel with Yz reduction starting at approximately 700 μs after the third flash. The onset of O2 evolution, as indicated by the shortening of the Mn1–Mn4 distance, occurs at around 1,200 μs, signifying the presence of a reduced intermediate, possibly a bound peroxide.

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  • 4. Bieling, Peter
    et al.
    Laan, Liedewij
    Schek, Henry
    Munteanu, E Laura
    Sandblad, Linda
    European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany .
    Dogterom, Marileen
    Brunner, Damian
    Surrey, Thomas
    Reconstitution of a microtubule plus-end tracking system in vitro2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, no 7172, p. 1100-1105Article in journal (Refereed)
    Abstract [en]

    The microtubule cytoskeleton is essential to cell morphogenesis. Growing microtubule plus ends have emerged as dynamic regulatory sites in which specialized proteins, called plus-end-binding proteins (+TIPs), bind and regulate the proper functioning of microtubules. However, the molecular mechanism of plus-end association by +TIPs and their ability to track the growing end are not well understood. Here we report the in vitro reconstitution of a minimal plus-end tracking system consisting of the three fission yeast proteins Mal3, Tip1 and the kinesin Tea2. Using time-lapse total internal reflection fluorescence microscopy, we show that the EB1 homologue Mal3 has an enhanced affinity for growing microtubule end structures as opposed to the microtubule lattice. This allows it to track growing microtubule ends autonomously by an end recognition mechanism. In addition, Mal3 acts as a factor that mediates loading of the processive motor Tea2 and its cargo, the Clip170 homologue Tip1, onto the microtubule lattice. The interaction of all three proteins is required for the selective tracking of growing microtubule plus ends by both Tea2 and Tip1. Our results dissect the collective interactions of the constituents of this plus-end tracking system and show how these interactions lead to the emergence of its dynamic behaviour. We expect that such in vitro reconstitutions will also be essential for the mechanistic dissection of other plus-end tracking systems.

  • 5. Billker, Oliver
    et al.
    Lindo, V.
    Panico, M.
    Etienne, A. E.
    Paxton, T.
    Dell, A.
    Rogers, M.
    Sinden, R. E.
    Morris, H. R.
    Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito1998In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 392, no 6673, p. 289-292Article in journal (Refereed)
    Abstract [en]

    Malaria is transmitted from vertebrate host to mosquito vector by mature sexual blood-living stages called gametocytes. Within seconds of ingestion into the mosquito bloodmeal, gametocytes undergo gametogenesis. Induction requires the simultaneous exposure to at least two stimuli in vitro: a drop in bloodmeal temperature to 5 degrees C below that of the vertebrate host, and a rise in pH from 7.4 to 8.0-8.2. In vivo the mosquito bloodmeal has a pH of between 7.5 and 7.6. It is thought that in vivo the second inducer is an unknown mosquito-derived gametocyte-activating factor. Here we show that this factor is xanthurenic acid. We also show that low concentrations of xanthurenic acid can act together with pH to induce gametogenesis in vitro. Structurally related compounds are at least ninefold less effective at inducing gametogenesis in vitro. In Drosophila mutants with lesions in the kynurenine pathway of tryptophan metabolism (of which xanthurenic acid is a side product), no alternative active compound was detected in crude insect homogenates. These data could form the basis of the rational development of new methods of interrupting the transmission of malaria using drugs or new refractory mosquito genotypes to block parasite gametogenesis.

  • 6. Bjorkman, Anne D.
    et al.
    Myers-Smith, Isla H.
    Elmendorf, Sarah C.
    Normand, Signe
    Rueger, Nadja
    Beck, Pieter S. A.
    Blach-Overgaard, Anne
    Blok, Daan
    Cornelissen, J. Hans C.
    Forbes, Bruce C.
    Georges, Damien
    Goetz, Scott J.
    Guay, Kevin C.
    Henry, Gregory H. R.
    HilleRisLambers, Janneke
    Hollister, Robert D.
    Karger, Dirk N.
    Kattge, Jens
    Manning, Peter
    Prevey, Janet S.
    Rixen, Christian
    Schaepman-Strub, Gabriela
    Thomas, Haydn J. D.
    Vellend, Mark
    Wilmking, Martin
    Wipf, Sonja
    Carbognani, Michele
    Hermanutz, Luise
    Levesque, Esther
    Molau, Ulf
    Petraglia, Alessandro
    Soudzilovskaia, Nadejda A.
    Spasojevic, Marko J.
    Tomaselli, Marcello
    Vowles, Tage
    Alatalo, Juha M.
    Alexander, Heather D.
    Anadon-Rosell, Alba
    Angers-Blondin, Sandra
    te Beest, Mariska
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Berner, Logan
    Bjork, Robert G.
    Buchwal, Agata
    Buras, Allan
    Christie, Katherine
    Cooper, Elisabeth J.
    Dullinger, Stefan
    Elberling, Bo
    Eskelinen, Anu
    Frei, Esther R.
    Grau, Oriol
    Grogan, Paul
    Hallinger, Martin
    Harper, Karen A.
    Heijmans, Monique M. P. D.
    Hudson, James
    Huelber, Karl
    Iturrate-Garcia, Maitane
    Iversen, Colleen M.
    Jaroszynska, Francesca
    Johnstone, Jill F.
    Jorgensen, Rasmus Halfdan
    Kaarlejärvi, Elina
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Klady, Rebecca
    Kuleza, Sara
    Kulonen, Aino
    Lamarque, Laurent J.
    Lantz, Trevor
    Little, Chelsea J.
    Speed, James D. M.
    Michelsen, Anders
    Milbau, Ann
    Nabe-Nielsen, Jacob
    Nielsen, Sigrid Scholer
    Ninot, Josep M.
    Oberbauer, Steven F.
    Olofsson, Johan
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Onipchenko, Vladimir G.
    Rumpf, Sabine B.
    Semenchuk, Philipp
    Shetti, Rohan
    Collier, Laura Siegwart
    Street, Lorna E.
    Suding, Katharine N.
    Tape, Ken D.
    Trant, Andrew
    Treier, Urs A.
    Tremblay, Jean-Pierre
    Tremblay, Maxime
    Venn, Susanna
    Weijers, Stef
    Zamin, Tara
    Boulanger-Lapointe, Noemie
    Gould, William A.
    Hik, David S.
    Hofgaard, Annika
    Jonsdottir, Ingibjorg S.
    Jorgenson, Janet
    Klein, Julia
    Magnusson, Borgthor
    Tweedie, Craig
    Wookey, Philip A.
    Bahn, Michael
    Blonder, Benjamin
    van Bodegom, Peter M.
    Bond-Lamberty, Benjamin
    Campetella, Giandiego
    Cerabolini, Bruno E. L.
    Chapin, F. Stuart, III
    Cornwell, William K.
    Craine, Joseph
    Dainese, Matteo
    de Vries, Franciska T.
    Diaz, Sandra
    Enquist, Brian J.
    Green, Walton
    Milla, Ruben
    Niinemets, Ulo
    Onoda, Yusuke
    Ordonez, Jenny C.
    Ozinga, Wim A.
    Penuelas, Josep
    Poorter, Hendrik
    Poschlod, Peter
    Reich, Peter B.
    Sande, Brody
    Schamp, Brandon
    Sheremetev, Serge
    Weiher, Evan
    Plant functional trait change across a warming tundra biome2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 562, no 7725, p. 57-+Article in journal (Refereed)
    Abstract [en]

    The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature-trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.

  • 7. Boussemart, Lise
    et al.
    Malka-Mahieu, Hélène
    Girault, Isabelle
    Allard, Delphine
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Inserm UMR981, F-94805 Villejuif, France.
    Tomasic, Gorana
    Thomas, Marina
    Basmadjian, Christine
    Ribeiro, Nigel
    Thuaud, Frédéric
    Mateus, Christina
    Routier, Emilie
    Kamsu-Kom, Nyam
    Agoussi, Sandrine
    Eggermont, Alexander M
    Désaubry, Laurent
    Robert, Caroline
    Vagner, Stéphan
    eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7516, p. 105-109Article in journal (Refereed)
    Abstract [en]

    In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

  • 8.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Global health estimated over two decades2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 545, no 7655, p. 421-422Article in journal (Refereed)
  • 9.
    Charpentier, Emmanuelle
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Doudna, Jennifer A.
    Biotechnology: rewriting a genome2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7439, p. 50-51Article in journal (Other academic)
  • 10.
    Chen, Changchun
    et al.
    MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
    Itakura, Eisuke
    Nelson, Geoffrey M.
    Sheng, Ming
    Laurent, Patrick
    Fenk, Lorenz A.
    Butcher, Rebecca A.
    Hegde, Ramanujan S.
    de Bono, Mario
    IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7639, p. 43-48Article in journal (Refereed)
    Abstract [en]

    Interleukin-17 (IL-17) is a major pro-inflammatory cytokine: it mediates responses to pathogens or tissue damage, and drives autoimmune diseases. Little is known about its role in the nervous system. Here we show that IL-17 has neuromodulator-like properties in Caenorhabditis elegans. IL-17 can act directly on neurons to alter their response properties and contribution to behaviour. Using unbiased genetic screens, we delineate an IL-17 signalling pathway and show that it acts in the RMG hub interneurons. Disrupting IL-17 signalling reduces RMG responsiveness to input from oxygen sensors, and renders sustained escape from 21% oxygen transient and contingent on additional stimuli. Over-activating IL-17 receptors abnormally heightens responses to 21% oxygen in RMG neurons and whole animals. IL-17 deficiency can be bypassed by optogenetic stimulation of RMG. Inducing IL-17 expression in adults can rescue mutant defects within 6 h. These findings reveal a non-immunological role of IL-17 modulating circuit function and behaviour.

  • 11. Coquel, Flavie
    et al.
    Silva, Maria-Joao
    Técher, Hervé
    Zadorozhny, Karina
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nieminuszczy, Jadwiga
    Mettling, Clément
    Dardillac, Elodie
    Barthe, Antoine
    Schmitz, Anne-Lyne
    Promonet, Alexy
    Cribier, Alexandra
    Sarrazin, Amélie
    Niedzwiedz, Wojciech
    Lopez, Bernard
    Costanzo, Vincenzo
    Krejci, Lumir
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Benkirane, Monsef
    Lin, Yea-Lih
    Pasero, Philippe
    SAMHD1 acts at stalled replication forks to prevent interferon induction2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 557, no 7703, p. 57-61Article in journal (Refereed)
    Abstract [en]

    SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS-STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

  • 12. Daumke, Oliver
    et al.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vallis, Yvonne
    Martens, Sascha
    Butler, P Jonathan G
    McMahon, Harvey T
    Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 449, no 7164, p. 923-927Article in journal (Refereed)
    Abstract [en]

    The ability to actively remodel membranes in response to nucleotide hydrolysis has largely been attributed to GTPases of the dynamin superfamily, and these have been extensively studied. Eps15 homology (EH)-domain-containing proteins (EHDs/RME-1/pincher) comprise a less-well-characterized class of highly conserved eukaryotic ATPases implicated in clathrin-independent endocytosis, and recycling from endosomes. Here we show that EHDs share many common features with the dynamin superfamily, such as a low affinity for nucleotides, the ability to tubulate liposomes in vitro, oligomerization around lipid tubules in ring-like structures and stimulated nucleotide hydrolysis in response to lipid binding. We present the structure of EHD2, bound to a non-hydrolysable ATP analogue, and provide evidence consistent with a role for EHDs in nucleotide-dependent membrane remodelling in vivo. The nucleotide-binding domain is involved in dimerization, which creates a highly curved membrane-binding region in the dimer. Oligomerization of dimers occurs on another interface of the nucleotide-binding domain, and this allows us to model the EHD oligomer. We discuss the functional implications of the EHD2 structure for understanding membrane deformation.

  • 13. DeLuca, T H
    et al.
    Zackrisson, O
    Nilsson, M C
    Sellstedt, Anita
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Quantifying nitrogen-fixation in feather moss carpets of boreal forests2002In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 419, no 6910, p. 917-920Article in journal (Refereed)
    Abstract [en]

    Biological nitrogen (N) fixation is the primary source of N within natural ecosystems(1), yet the origin of boreal forest N has remained elusive. The boreal forests of Eurasia and North America lack any significant, widespread symbiotic N-fixing plants(1-6). With the exception of scattered stands of alder in early primary successional forests(7), N-fixation in boreal forests is considered to be extremely limited. Nitrogen-fixation in northern European boreal forests has been estimated(2) at only 0.5 kg Nha(-1) yr(-1); however, organic N is accumulated in these ecosystems at a rate of 3 kg N ha(-1) yr(-1) (ref. 8). Our limited understanding of the origin of boreal N is unacceptable given the extent of the boreal forest region, but predictable given our imperfect knowledge of N-fixation(1,9). Herein we report on a N-fixing symbiosis between a cyanobacterium (Nostoc sp.) and the ubiquitous feather moss, Pleurozium schreberi (Bird) Mitt. that alone fixes between 1.5 and 2.0 kg N ha(-1) yr(-1) in mid- to late-successional forests of northern Scandinavia and Finland. Previous efforts have probably underestimated N-fixation potential in boreal forests.

  • 14. Dethoff, Elizabeth A
    et al.
    Petzold, Katja
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chugh, Jeetender
    Casiano-Negroni, Anette
    Al-Hashimi, Hashim M
    Visualizing transient low-populated structures of RNA2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, p. 724-728Article in journal (Refereed)
    Abstract [en]

    The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 μs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.

  • 15. Englund, Camilla
    et al.
    Loren, Christina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Varshney, Gaurav
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Deleuil, Fabiene
    Hallberg, Bengt
    Palmer, Ruth
    Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 425, no 6957, p. 512-516Article in journal (Refereed)
  • 16.
    Flanagan, J Randall
    et al.
    Queen's University, Kingston, Ontario K7L 3N6.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Action plans used in action observation2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, ISSN 1476-4687, Vol. 424, no 6950, p. 769-771Article in journal (Refereed)
    Abstract [en]

    How do we understand the actions of others? According to the direct matching hypothesis, action understanding results from a mechanism that maps an observed action onto motor representations of that action. Although supported by neurophysiological and brain-imaging studies, direct evidence for this hypothesis is sparse. In visually guided actions, task-specific proactive eye movements are crucial for planning and control. Because the eyes are free to move when observing such actions, the direct matching hypothesis predicts that subjects should produce eye movements similar to those produced when they perform the tasks. If an observer analyses action through purely visual means, however, eye movements will be linked reactively to the observed action. Here we show that when subjects observe a block stacking task, the coordination between their gaze and the actor's hand is predictive, rather than reactive, and is highly similar to the gaze-hand coordination when they perform the task themselves. These results indicate that during action observation subjects implement eye motor programs directed by motor representations of manual actions and thus provide strong evidence for the direct matching hypothesis.

  • 17.
    Fonfara, Ines
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    Richter, Hagen
    Bratovic, Majda
    Le Rhun, Anaïs
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    The CRISPR-associated DNA-cleaving enzyme Cpf1 also processes precursor CRISPR RNA2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, no 7600, p. 517-520Article in journal (Refereed)
    Abstract [en]

    CRISPR-Cas systems that provide defence against mobile genetic elements in bacteria and archaea have evolved a variety of mechanisms to target and cleave RNA or DNA(1). The well-studied types I, II and III utilize a set of distinct CRISPR-associated ( Cas) proteins for production of mature CRISPR RNAs (crRNAs) and interference with invading nucleic acids. In types I and III, Cas6 or Cas5d cleaves precursor crRNA (pre-crRNA)(2-5) and the mature crRNAs then guide a complex of Cas proteins ( Cascade-Cas3, type I; Csm or Cmr, type III) to target and cleave invading DNA or RNA(6-12). In type II systems, RNase III cleaves pre-crRNA base-paired with trans-activating crRNA (tracrRNA) in the presence of Cas9 (refs 13, 14). The mature tracrRNA-crRNA duplex then guides Cas9 to cleave target DNA15. Here, we demonstrate a novel mechanism in CRISPR-Cas immunity. We show that type V-A Cpf1 from Francisella novicida is a dual-nuclease that is specific to crRNA biogenesis and target DNA interference. Cpf1 cleaves pre-crRNA upstream of a hairpin structure formed within the CRISPR repeats and thereby generates intermediate crRNAs that are processed further, leading to mature crRNAs. After recognition of a 5'-YTN- 3' protospacer adjacent motif on the non-target DNA strand and subsequent probing for an eight-nucleotide seed sequence, Cpf1, guided by the single mature repeat-spacer crRNA, introduces double-stranded breaks in the target DNA to generate a 5' overhang(16). The RNase and DNase activities of Cpf1 require sequence- and structure-specific binding to the hairpin of crRNA repeats. Cpf1 uses distinct active domains for both nuclease reactions and cleaves nucleic acids in the presence of magnesium or calcium. This study uncovers a new family of enzymes with specific dual endoribonuclease and endonuclease activities, and demonstrates that type V- A constitutes the most minimalistic of the CRISPR- Cas systems so far described.

  • 18.
    Frank, Franziska
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Real-world results2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 557, no 7703, p. 130-130Article in journal (Other academic)
  • 19. Fuchsberger, Christian
    et al.
    Flannick, Jason
    Teslovich, Tanya M.
    Mahajan, Anubha
    Agarwala, Vineeta
    Gaulton, Kyle J.
    Ma, Clement
    Fontanillas, Pierre
    Moutsianas, Loukas
    McCarthy, Davis J.
    Rivas, Manuel A.
    Perry, John R. B.
    Sim, Xueling
    Blackwell, Thomas W.
    Robertson, Neil R.
    Rayner, N. William
    Cingolani, Pablo
    Locke, Adam E.
    Tajes, Juan Fernandez
    Highland, Heather M.
    Dupuis, Josee
    Chines, Peter S.
    Lindgren, Cecilia M.
    Hartl, Christopher
    Jackson, Anne U.
    Chen, Han
    Huyghe, Jeroen R.
    van de Bunt, Martijn
    Pearson, Richard D.
    Kumar, Ashish
    Mueller-Nurasyid, Martina
    Grarup, Niels
    Stringham, Heather M.
    Gamazon, Eric R.
    Lee, Jaehoon
    Chen, Yuhui
    Scott, Robert A.
    Below, Jennifer E.
    Chen, Peng
    Huang, Jinyan
    Go, Min Jin
    Stitzel, Michael L.
    Pasko, Dorota
    Parker, Stephen C. J.
    Varga, Tibor V.
    Green, Todd
    Beer, Nicola L.
    Day-Williams, Aaron G.
    Ferreira, Teresa
    Fingerlin, Tasha
    Horikoshi, Momoko
    Hu, Cheng
    Huh, Iksoo
    Ikram, Mohammad Kamran
    Kim, Bong-Jo
    Kim, Yongkang
    Kim, Young Jin
    Kwon, Min-Seok
    Lee, Juyoung
    Lee, Selyeong
    Lin, Keng-Han
    Maxwell, Taylor J.
    Nagai, Yoshihiko
    Wang, Xu
    Welch, Ryan P.
    Yoon, Joon
    Zhang, Weihua
    Barzilai, Nir
    Voight, Benjamin F.
    Han, Bok-Ghee
    Jenkinson, Christopher P.
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Manning, Alisa
    Ng, Maggie C. Y.
    Palmer, Nicholette D.
    Balkau, Beverley
    Stancakova, Alena
    Abboud, Hanna E.
    Boeing, Heiner
    Giedraitis, Vilmantas
    Prabhakaran, Dorairaj
    Gottesman, Omri
    Scott, James
    Carey, Jason
    Kwan, Phoenix
    Grant, George
    Smith, Joshua D.
    Neale, Benjamin M.
    Purcell, Shaun
    Butterworth, Adam S.
    Howson, Joanna M. M.
    Lee, Heung Man
    Lu, Yingchang
    Kwak, Soo-Heon
    Zhao, Wei
    Danesh, John
    Lam, Vincent K. L.
    Park, Kyong Soo
    Saleheen, Danish
    So, Wing Yee
    Tam, Claudia H. T.
    Afzal, Uzma
    Aguilar, David
    Arya, Rector
    Aung, Tin
    Chan, Edmund
    Navarro, Carmen
    Cheng, Ching-Yu
    Palli, Domenico
    Correa, Adolfo
    Curran, Joanne E.
    Rybin, Denis
    Farook, Vidya S.
    Fowler, Sharon P.
    Freedman, Barry I.
    Griswold, Michael
    Hale, Daniel Esten
    Hicks, Pamela J.
    Khor, Chiea-Chuen
    Kumar, Satish
    Lehne, Benjamin
    Thuillier, Dorothee
    Lim, Wei Yen
    Liu, Jianjun
    van der Schouw, Yvonne T.
    Loh, Marie
    Musani, Solomon K.
    Puppala, Sobha
    Scott, William R.
    Yengo, Loic
    Tan, Sian-Tsung
    Taylor, Herman A., Jr.
    Thameem, Farook
    Wilson, Gregory, Sr.
    Wong, Tien Yin
    Njolstad, Pal Rasmus
    Levy, Jonathan C.
    Mangino, Massimo
    Bonnycastle, Lori L.
    Schwarzmayr, Thomas
    Fadista, Joao
    Surdulescu, Gabriela L.
    Herder, Christian
    Groves, Christopher J.
    Wieland, Thomas
    Bork-Jensen, Jette
    Brandslund, Ivan
    Christensen, Cramer
    Koistinen, Heikki A.
    Doney, Alex S. F.
    Kinnunen, Leena
    Esko, Tonu
    Farmer, Andrew J.
    Hakaste, Liisa
    Hodgkiss, Dylan
    Kravic, Jasmina
    Lyssenko, Valeriya
    Hollensted, Mette
    Jorgensen, Marit E.
    Jorgensen, Torben
    Ladenvall, Claes
    Justesen, Johanne Marie
    Karajamaki, Annemari
    Kriebel, Jennifer
    Rathmann, Wolfgang
    Lannfelt, Lars
    Lauritzen, Torsten
    Narisu, Narisu
    Linneberg, Allan
    Melander, Olle
    Milani, Lili
    Neville, Matt
    Orho-Melander, Marju
    Qi, Lu
    Qi, Qibin
    Roden, Michael
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Swift, Amy
    Rosengren, Anders H.
    Stirrups, Kathleen
    Wood, Andrew R.
    Mihailov, Evelin
    Blancher, Christine
    Carneiro, Mauricio O.
    Maguire, Jared
    Poplin, Ryan
    Shakir, Khalid
    Fennell, Timothy
    DePristo, Mark
    de Angelis, Martin Hrabe
    Deloukas, Panos
    Gjesing, Anette P.
    Jun, Goo
    Nilsson, Peter
    Murphy, Jacquelyn
    Onofrio, Robert
    Thorand, Barbara
    Hansen, Torben
    Meisinger, Christa
    Hu, Frank B.
    Isomaa, Bo
    Karpe, Fredrik
    Liang, Liming
    Peters, Annette
    Huth, Cornelia
    O'Rahilly, Stephen P.
    Palmer, Colin N. A.
    Pedersen, Oluf
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Watanabe, Richard M.
    Syvanen, Ann-Christine
    Bergman, Richard N.
    Bharadwaj, Dwaipayan
    Bottinger, Erwin P.
    Cho, Yoon Shin
    Chandak, Giriraj R.
    Chan, Juliana C. N.
    Chia, Kee Seng
    Daly, Mark J.
    Ebrahim, Shah B.
    Langenberg, Claudia
    Elliott, Paul
    Jablonski, Kathleen A.
    Lehman, Donna M.
    Jia, Weiping
    Ma, Ronald C. W.
    Pollin, Toni I.
    Sandhu, Manjinder
    Tandon, Nikhil
    Froguel, Philippe
    Barroso, Ines
    Teo, Yik Ying
    Zeggini, Eleftheria
    Loos, Ruth J. F.
    Small, Kerrin S.
    Ried, Janina S.
    DeFronzo, Ralph A.
    Grallert, Harald
    Glaser, Benjamin
    Metspalu, Andres
    Wareham, Nicholas J.
    Walker, Mark
    Banks, Eric
    Gieger, Christian
    Ingelsson, Erik
    Im, Hae Kyung
    Illig, Thomas
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Buck, Gemma
    Trakalo, Joseph
    Buck, David
    Prokopenko, Inga
    Magi, Reedik
    Lind, Lars
    Farjoun, Yossi
    Owen, Katharine R.
    Gloyn, Anna L.
    Strauch, Konstantin
    Tuomi, Tiinamaija
    Kooner, Jaspal Singh
    Lee, Jong-Young
    Park, Taesung
    Donnelly, Peter
    Morris, Andrew D.
    Hattersley, Andrew T.
    Bowden, Donald W.
    Collins, Francis S.
    Atzmon, Gil
    Chambers, John C.
    Spector, Timothy D.
    Laakso, Markku
    Strom, Tim M.
    Bell, Graeme I.
    Blangero, John
    Duggirala, Ravindranath
    Tai, E. Shyong
    McVean, Gilean
    Hanis, Craig L.
    Wilson, James G.
    Seielstad, Mark
    Frayling, Timothy M.
    Meigs, James B.
    Cox, Nancy J.
    Sladek, Rob
    Lander, Eric S.
    Gabriel, Stacey
    Burtt, Noel P.
    Mohlke, Karen L.
    Meitinger, Thomas
    Groop, Leif
    Abecasis, Goncalo
    Florez, Jose C.
    Scott, Laura J.
    Morris, Andrew P.
    Kang, Hyun Min
    Boehnke, Michael
    Altshuler, David
    McCarthy, Mark I.
    The genetic architecture of type 2 diabetes2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, no 7614, p. 41-47Article in journal (Refereed)
    Abstract [en]

    The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

  • 20.
    Fölling, Simon
    et al.
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Trotzky, Stefan
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Cheinet, Patrick
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Feld, Michael
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Saers, Robert
    Umeå University, Faculty of Science and Technology, Physics.
    Widera, Artur
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany, Institut für Angewandte Physik, Universität Bonn, 53115 Bonn, Germany.
    Müller, Torben
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany, Institute of Quantum Electronics, ETH Zürich, 8093 Zürich, Switzerland.
    Bloch, Immanuel
    Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
    Direct observation of second-order atom tunnelling2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 448, no 7157, p. 1029-1032Article in journal (Refereed)
  • 21. Grill, G.
    et al.
    Lehner, B.
    Thieme, M.
    Geenen, B.
    Tickner, D.
    Antonelli, F.
    Babu, S.
    Borrelli, P.
    Cheng, L.
    Crochetiere, H.
    Macedo, H. Ehalt
    Filgueiras, R.
    Goichot, M.
    Higgins, J.
    Hogan, Z.
    Lip, B.
    McClain, M. E.
    Meng, J.
    Mulligan, M.
    Nilsson, Christer
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Olden, J. D.
    Opperman, J. J.
    Petry, P.
    Liermann, C. Reidy
    Saenz, L.
    Salinas-Rodriguez, S.
    Schelle, P.
    Schmitt, R. J. P.
    Snider, J.
    Tan, F.
    Tockner, K.
    Valdujo, P. H.
    van Soesbergen, A.
    Zarfl, C.
    Mapping the world's free-flowing rivers2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 569, no 7755, p. 215-221Article in journal (Refereed)
    Abstract [en]

    Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them.

  • 22.
    Gudasz, Cristian
    et al.
    Limnology, Department of Ecology and Evolution, Uppsala University, Norbyvägen 18D, SE-752 36 Uppsala, Sweden.
    Bastviken, David
    Steger, Kristin
    Premke, Katrin
    Sobek, Sebastian
    Tranvik, Lars J
    Temperature-controlled organic carbon mineralization in lake sediments2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 466, no 7305, p. 478-481Article in journal (Refereed)
    Abstract [en]

    Peatlands, soils and the ocean floor are well-recognized as sites of organic carbon accumulation and represent important global carbon sinks. Although the annual burial of organic carbon in lakes and reservoirs exceeds that of ocean sediments, these inland waters are components of the global carbon cycle that receive only limited attention. Of the organic carbon that is being deposited onto the sediments, a certain proportion will be mineralized and the remainder will be buried over geological timescales. Here we assess the relationship between sediment organic carbon mineralization and temperature in a cross-system survey of boreal lakes in Sweden, and with input from a compilation of published data from a wide range of lakes that differ with respect to climate, productivity and organic carbon source. We find that the mineralization of organic carbon in lake sediments exhibits a strongly positive relationship with temperature, which suggests that warmer water temperatures lead to more mineralization and less organic carbon burial. Assuming that future organic carbon delivery to the lake sediments will be similar to that under present-day conditions, we estimate that temperature increases following the latest scenarios presented by the Intergovernmental Panel on Climate Change could result in a 4-27 per cent (0.9-6.4 Tg C yr(-1)) decrease in annual organic carbon burial in boreal lakes.

  • 23. Handa, I. Tanya
    et al.
    Aerts, Rien
    Berendse, Frank
    Berg, Matty P.
    Bruder, Andreas
    Butenschoen, Olaf
    Chauvet, Eric
    Gessner, Mark O.
    Jabiol, Jeremy
    Makkonen, Marika
    McKie, Brendan G.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Malmqvist, Bjoern
    Peeters, Edwin T. H. M.
    Scheu, Stefan
    Schmid, Bernhard
    van Ruijven, Jasper
    Vos, Veronique C. A.
    Haettenschwiler, Stephan
    Consequences of biodiversity loss for litter decomposition across biomes2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 509, no 7499, p. 218-221Article in journal (Refereed)
    Abstract [en]

    The decomposition of dead organic matter is a major determinant of carbon and nutrient cycling in ecosystems, and of carbon fluxes between the biosphere and the atmosphere(1-3). Decomposition is driven by a vast diversity of organisms that are structured in complex food webs(2,4). Identifying the mechanisms underlying the effects of biodiversity on decomposition is critical(4-6) given the rapid loss of species worldwide and the effects of this loss on human well-being(7-9). Yet despite comprehensive syntheses of studies on how biodiversity affects litter decomposition(4-6,10), key questions remain, including when, where and how biodiversity has a role and whether general patterns and mechanisms occur across ecosystems and different functional types of organism(4,9-12). Here, in field experiments across five terrestrial and aquatic locations, ranging from the subarctic to the tropics, we show that reducing the functional diversity of decomposer organisms and plant litter types slowed the cycling of litter carbon and nitrogen. Moreover, we found evidence of nitrogen transfer from the litter of nitrogen-fixing plants to that of rapidly decomposing plants, but not between other plant functional types, highlighting that specific interactions in litter mixtures control carbon and nitrogen cycling during decomposition. The emergence of this general mechanism and the coherence of patterns across contrasting terrestrial and aquatic ecosystems suggest that biodiversity loss has consistent consequences for litter decomposition and the cycling of major elements on broad spatial scales.

  • 24. Hibar, Derrek P.
    et al.
    Stein, Jason L.
    Renteria, Miguel E.
    Arias-Vasquez, Alejandro
    Desrivieres, Sylvane
    Jahanshad, Neda
    Toro, Roberto
    Wittfeld, Katharina
    Abramovic, Lucija
    Andersson, Micael
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Bernard, Manon
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brown, Andrew A.
    Chakravarty, M. Mallar
    Chen, Qiang
    Ching, Christopher R. K.
    Cuellar-Partida, Gabriel
    den Braber, Anouk
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Grimm, Oliver
    Guadalupe, Tulio
    Hass, Johanna
    Woldehawariat, Girma
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Loohuis, Loes M. Olde
    Luciano, Michelle
    Macare, Christine
    Mather, Karen A.
    Mattheisen, Manuel
    Milaneschi, Yuri
    Nho, Kwangsik
    Papmeyer, Martina
    Ramasamy, Adaikalavan
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rose, Emma J.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Saemann, Philipp G.
    Schmaal, Lianne
    Schork, Andrew J.
    Shin, Jean
    Strike, Lachlan T.
    Teumer, Alexander
    van Donkelaar, Marjolein M. J.
    van Eijk, Kristel R.
    Walters, Raymond K.
    Westlye, Lars T.
    Whelan, Christopher D.
    Winkler, Anderson M.
    Zwiers, Marcel P.
    Alhusaini, Saud
    Athanasiu, Lavinia
    Ehrlich, Stefan
    Hakobjan, Marina M. H.
    Hartberg, Cecilie B.
    Haukvik, Unn K.
    Heister, Angelien J. G. A. M.
    Hoehn, David
    Kasperaviciute, Dalia
    Liewald, David C. M.
    Lopez, Lorna M.
    Makkinje, Remco R. R.
    Matarin, Mar
    Naber, Marlies A. M.
    McKay, D. Reese
    Needham, Margaret
    Nugent, Allison C.
    Puetz, Benno
    Royle, Natalie A.
    Shen, Li
    Sprooten, Emma
    Trabzuni, Daniah
    van der Marel, Saskia S. L.
    van Hulzen, Kimm J. E.
    Walton, Esther
    Wolf, Christiane
    Almasy, Laura
    Ames, David
    Arepalli, Sampath
    Assareh, Amelia A.
    Bastin, Mark E.
    Brodaty, Henry
    Bulayeva, Kazima B.
    Carless, Melanie A.
    Cichon, Sven
    Corvin, Aiden
    Curran, Joanne E.
    Czisch, Michael
    de Zubicaray, Greig I.
    Dillman, Allissa
    Duggirala, Ravi
    Dyer, Thomas D.
    Erk, Susanne
    Fedko, Iryna O.
    Ferrucci, Luigi
    Foroud, Tatiana M.
    Fox, Peter T.
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Goering, Harald H. H.
    Green, Robert C.
    Guelfi, Sebastian
    Hansell, Narelle K.
    Hartman, Catharina A.
    Hegenscheid, Katrin
    Heinz, Andreas
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Hoekstra, Pieter J.
    Holsboer, Florian
    Homuth, Georg
    Hottenga, Jouke-Jan
    Ikeda, Masashi
    Jack, Clifford R., Jr.
    Jenkinson, Mark
    Johnson, Robert
    Kanai, Ryota
    Keil, Maria
    Kent, Jack W., Jr.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Liu, Xinmin
    Longo, Dan L.
    McMahon, Katie L.
    Meisenzah, Eva
    Melle, Ingrid
    Mahnke, Sebastian
    Montgomery, Grant W.
    Mostert, Jeanette C.
    Muehleisen, Thomas W.
    Nalls, Michael A.
    Nichols, Thomas E.
    Nilsson, Lars G.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Noethen, Markus M.
    Ohi, Kazutaka
    Olvera, Rene L.
    Perez-Iglesias, Rocio
    Pike, G. Bruce
    Potkin, Steven G.
    Reinvang, Ivar
    Reppermund, Simone
    Rietschel, Marcella
    Romanczuk-Seiferth, Nina
    Rosen, Glenn D.
    Rujescu, Dan
    Schnell, Knut
    Schofield, Peter R.
    Smith, Colin
    Steen, Vidar M.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Turner, Jessica A.
    Valdes Hernandez, Maria C.
    van't Ent, Dennis
    van der Brug, Marcel
    van der Wee, Nic J. A.
    van Tol, Marie-Jose
    Veltman, Dick J.
    Wassink, Thomas H.
    Westman, Eric
    Zielke, Ronald H.
    Zonderman, Alan B.
    Ashbrook, David G.
    Hager, Reinmar
    Lu, Lu
    McMahon, Francis J.
    Morris, Derek W.
    Williams, Robert W.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cavalleri, Gianpiero L.
    Crespo-Facorro, Benedicto
    Dale, Anders M.
    Davies, Gareth E.
    Delanty, Norman
    Depondt, Chantal
    Djurovic, Srdjan
    Drevets, Wayne C.
    Espeseth, Thomas
    Gollub, Randy L.
    Ho, Beng-Choon
    Hoffman, Wolfgang
    Hosten, Norbert
    Kahn, Rene S.
    Le Hellard, Stephanie
    Meyer-Lindenberg, Andreas
    Mueller-Myhsok, Bertram
    Nauck, Matthias
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Pandolfo, Massimo
    Penninx, Brenda W. J. H.
    Roffman, Joshua L.
    Sisodiya, Sanjay M.
    Smoller, Jordan W.
    van Bokhoven, Hans
    van Haren, Neeltje E. M.
    Voelzke, Henry
    Walter, Henrik
    Weiner, Michael W.
    Wen, Wei
    White, Tonya
    Agartz, Ingrid
    Andreassen, Ole A.
    Blangero, John
    Boomsma, Dorret I.
    Brouwer, Rachel M.
    Cannon, Dara M.
    Cookson, Mark R.
    de Geus, Eco J. C.
    Deary, Ian J.
    Donohoe, Gary
    Fernandez, Guillen
    Fisher, Simon E.
    Francks, Clyde
    Glahn, David C.
    Grabe, Hans J.
    Gruber, Oliver
    Hardy, John
    Hashimoto, Ryota
    Pol, Hilleke E. Hulshoff
    Joensson, Erik G.
    Kloszewska, Iwona
    Lovestone, Simon
    Mattay, Venkata S.
    Mecocci, Patrizia
    McDonald, Colm
    McIntosh, Andrew M.
    Ophoff, Roel A.
    Paus, Tomas
    Pausova, Zdenka
    Ryten, Mina
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Simmons, Andy
    Singleton, Andrew
    Soininen, Hilkka
    Wardlaw, Joanna M.
    Weale, Michael E.
    Weinberger, Daniel R.
    Adams, Hieab H. H.
    Launer, Lenore J.
    Seiler, Stephan
    Schmidt, Reinhold
    Chauhan, Ganesh
    Satizabal, Claudia L.
    Becker, James T.
    Yanek, Lisa
    van der Lee, Sven J.
    Ebling, Maritza
    Fischl, Bruce
    Longstreth, W. T., Jr.
    Greve, Douglas
    Schmidt, Helena
    Nyquist, Paul
    Vinke, Louis N.
    van Duijn, Cornelia M.
    Xue, Luting
    Mazoyer, Bernard
    Bis, Joshua C.
    Gudnason, Vilmundur
    Seshadri, Sudha
    Ikram, M. Arfan
    Martin, Nicholas G.
    Wright, Margaret J.
    Schumann, Gunter
    Franke, Barbara
    Thompson, Paul M., Jr.
    Medland, Sarah E.
    Common genetic variants influence human subcortical brain structures2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 520, no 7546, p. 224-U216Article in journal (Refereed)
    Abstract [en]

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  • 25. Ho, Joshua W. K.
    et al.
    June, Youngsook L.
    Liu, Tao
    Alver, Burak H.
    Lee, Soohyun
    Ikegami, Kohta
    Sohn, Kyung-Ah
    Minoda, Aki
    Tolstorukov, Michael Y.
    Appert, Alex
    Parker, Stephen C. J.
    Gu, Tingting
    Kundaje, Anshul
    Riddle, Nicole C.
    Bishop, Eric
    Egelhofer, Thea A.
    Hu, Sheng'en Shawn
    Alekseyenko, Artyom A.
    Rechtsteiner, Andreas
    Asker, Dalal
    Belsky, Jason A.
    Bowmanm, Sarah K.
    Chens, Q. Brent
    Chen, Ron A. -J.
    Day, Daniel S.
    Dong, Yan
    Dose, Andrea C.
    Duan, Xikun
    Epstein, Charles B.
    Ercan, Sevinc
    Feingold, Elise A.
    Ferrari, Francesco
    Garrigues, Jacob M.
    Gehlenborg, Nils
    Good, Peter J.
    Haseley, Psalm
    He, Daniel
    Herrmann, Moritz
    Hoffman, Michael M.
    Jeffers, Tess E.
    Kharchenko, Peter V.
    Kolasinska-Zwierz, Paulina
    Kotwaliwale, Chitra V.
    Kumar, Nischay
    Langley, Sasha A.
    Larschan, Erica N.
    Latorre, Isabel
    Libbrecht, Maxwell W.
    Lin, Xueqiu
    Park, Richard
    Pazin, Michael J.
    Pham, Hoang N.
    Plachetka, Annette
    Qin, Bo
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Shoresh, Noam
    Stempor, Przemyslaw
    Vielle, Anne
    Wang, Chengyang
    Whittle, Christina M.
    Xue, Huiling
    Kingstonm, Robert E.
    Kim, Ju Han
    Bernstein, Bradley E.
    Dernburg, Abby F.
    Pirrotta, Vincenzo
    Kuroda, Mitzi I.
    Noble, William S.
    Tullius, Thomas D.
    Kellis, Manolis
    MacAlpine, David M.
    Strome, Susan
    Elgin, Sarah C. R.
    Liu, Xiaole Shirley
    Lieb, Jason D.
    Ahringer, Julie
    Karpen, Gary H.
    Park, Peter J.
    Comparative analysis of metazoan chromatin organization2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 512, no 7515, p. 449-U507Article in journal (Refereed)
    Abstract [en]

    Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms(1-3). Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths(4,5). To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

  • 26. Holmström, Mats
    et al.
    Ekenbäck, Andreas
    Institutet för rymdfysik (IRF).
    Selsis, Franck
    Penz, Thomas
    Lammer, Helmut
    Wurz, Peter
    Energetic neutral atoms as the explanation for the high-velocity hydrogen around HD 209458b2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 451, p. 970-972Article in journal (Refereed)
    Abstract [en]

    Absorption in the stellar Lyman- (Ly) line observed during the transit of the extrasolar planet HD 209458b in front of its host star reveals high-velocity atomic hydrogen at great distances from the planet1, 2. This has been interpreted as hydrogen atoms escaping from the planet's exosphere1, 3, possibly undergoing hydrodynamic blow-off4, and being accelerated by stellar radiation pressure. Energetic neutral atoms around Solar System planets have been observed to form from charge exchange between solar wind protons and neutral hydrogen from the planetary exospheres5, 6, 7, however, and this process also should occur around extrasolar planets. Here we show that the measured transit-associated Ly absorption can be explained by the interaction between the exosphere of HD 209458b and the stellar wind, and that radiation pressure alone cannot explain the observations. As the stellar wind protons are the source of the observed energetic neutral atoms, this provides a way of probing stellar wind conditions, and our model suggests a slow and hot stellar wind near HD 209458b at the time of the observations. line observed during the transit of the extrasolar planet HD 209458b in front of its host star reveals high-velocity atomic hydrogen at great distances from the planet1, 2. This has been interpreted as hydrogen atoms escaping from the planet's exosphere1, 3, possibly undergoing hydrodynamic blow-off4, and being accelerated by stellar radiation pressure. Energetic neutral atoms around Solar System planets have been observed to form from charge exchange between solar wind protons and neutral hydrogen from the planetary exospheres5, 6, 7, however, and this process also should occur around extrasolar planets. Here we show that the measured transit-associated Ly absorption can be explained by the interaction between the exosphere of HD 209458b and the stellar wind, and that radiation pressure alone cannot explain the observations. As the stellar wind protons are the source of the observed energetic neutral atoms, this provides a way of probing stellar wind conditions, and our model suggests a slow and hot stellar wind near HD 209458b at the time of the observations.

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

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

  • 28.
    Karlsson, Jan
    et al.
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Byström, Pär
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Ask, Jenny
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Ask, Per
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Persson, Lennart
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Jansson, Mats
    Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
    Light limitation of nutrient-poor lake ecosystems2009In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 460, p. 506-509Article in journal (Refereed)
    Abstract [en]

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

  • 29. Kern, Jan
    et al.
    Chatterjee, Ruchira
    Young, Iris D.
    Fuller, Franklin D.
    Lassalle, Louise
    Ibrahim, Mohamed
    Gul, Sheraz
    Fransson, Thomas
    Brewster, Aaron S.
    Alonso-Mori, Roberto
    Hussein, Rana
    Zhang, Miao
    Douthit, Lacey
    de Lichtenberg, Casper
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry—Ångström, Molecular Biomimetics, Uppsala University, Uppsala, Sweden.
    Cheah, Mun Hon
    Shevela, Dmitriy
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wersig, Julia
    Seuffert, Ina
    Sokaras, Dimosthenis
    Pastor, Ernest
    Weninger, Clemens
    Kroll, Thomas
    Sierra, Raymond G.
    Aller, Pierre
    Butryn, Agata
    Orville, Allen M.
    Liang, Mengning
    Batyuk, Alexander
    Koglin, Jason E.
    Carbajo, Sergio
    Boutet, Sébastien
    Moriarty, Nigel W.
    Holton, James M.
    Dobbek, Holger
    Adams, Paul D.
    Bergmann, Uwe
    Sauter, Nicholas K.
    Zouni, Athina
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Yano, Junko
    Yachandra, Vittal K.
    Structures of the intermediates of Kok’s photosynthetic water oxidation clock2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 563, p. 421-425Article in journal (Refereed)
    Abstract [en]

    Inspired by the period-four oscillation in flash-induced oxygen evolution of photosystem II discovered by Joliot in 1969, Kok performed additional experiments and proposed a five-state kinetic model for photosynthetic oxygen evolution, known as Kok’s S-state clock or cycle1,2. The model comprises four (meta)stable intermediates (S0, S1, S2 and S3) and one transient S4 state, which precedes dioxygen formation occurring in a concerted reaction from two water-derived oxygens bound at an oxo-bridged tetra manganese calcium (Mn4CaO5) cluster in the oxygen-evolving complex3–7. This reaction is coupled to the two-step reduction and protonation of the mobile plastoquinone QB at the acceptor side of PSII. Here, using serial femtosecond X-ray crystallography and simultaneous X-ray emission spectroscopy with multi-flash visible laser excitation at room temperature, we visualize all (meta)stable states of Kok’s cycle as high-resolution structures (2.04–2.08 Å). In addition, we report structures of two transient states at 150 and 400 µs, revealing notable structural changes including the binding of one additional ‘water’, Ox, during the S2→S3 state transition. Our results suggest that one water ligand to calcium (W3) is directly involved in substrate delivery. The binding of the additional oxygen Ox in the S3 state between Ca and Mn1 supports O–O bond formation mechanisms involving O5 as one substrate, where Ox is either the other substrate oxygen or is perfectly positioned to refill the O5 position during O2 release. Thus, our results exclude peroxo-bond formation in the S3 state, and the nucleophilic attack of W3 onto W2 is unlikely.

  • 30.
    Kharchenko, Peter V
    et al.
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Alekseyenko, Artyom A
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Schwartz, Yuri B
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Minoda, Aki
    Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA.
    Riddle, Nicole C
    Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA.
    Ernst, Jason
    MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA.
    Sabo, Peter J
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Larschan, Erica
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Gorchakov, Andrey A
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Gu, Tingting
    Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA.
    Linder-Basso, Daniela
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
    Plachetka, Annette
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Shanower, Gregory
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
    Tolstorukov, Michael Y
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Luquette, Lovelace J
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Xi, Ruibin
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Jung, Youngsook L
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Park, Richard W
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Bishop, Eric P
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Canfield, Theresa K
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Sandstrom, Richard
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Thurman, Robert E
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    MacAlpine, David M
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
    Stamatoyannopoulos, John A
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
    Kellis, Manolis
    MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA.
    Elgin, Sarah C R
    Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA.
    Kuroda, Mitzi I
    Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA.
    Pirrotta, Vincenzo
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
    Karpen, Gary H
    Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA.
    Park, Peter J
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    Comprehensive analysis of the chromatin landscape in Drosophila melanogaster2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Nature, ISSN 1476-4687 EISSN, Vol. 471, no 7339, p. 480-485Article in journal (Refereed)
    Abstract [en]

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

  • 31.
    Kinoshita, Masaharu
    et al.
    National Institute for Physiological Sciences, Myodaiji, Okazaki .
    Matsui, Ryosuke
    Kyoto University.
    Kato, Shigeki
    Fukushima Medical University School of Medicine, Fukushima.
    Hasegawa, Taku
    Kyoto University.
    Kasahara, Hironori
    Kyoto University.
    Isa, Kaoru
    National Institute for Physiological Sciences, Myodaiji, Okazaki .
    Watakabe, Akiya
    National Institute for Basic Biology, Okazaki, he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
    Yamamori, Tetsuo
    National Institute for Basic Biology, Okazaki, he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
    Nishimura, Yukio
    National Institute for Physiological Sciences, Myodaiji, Okazaki .
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Watanabe, Dai
    Kyoto University.
    Kobayashi, Kazuto
    Fukushima Medical University School of Medicine, Fukushima.
    Isa, Tadashi
    National Institute for Physiological Sciences, Myodaiji, Okazaki , he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
    Genetic dissection of the circuit for hand dexterity in primates2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 487, no 7406, p. 235-U1510Article in journal (Refereed)
    Abstract [en]

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

  • 32. Kinyoki, Damaris K.
    et al.
    Osgood-Zimmerman, Aaron E.
    Pickering, Brandon V.
    Schaeffer, Lauren E.
    Marczak, Laurie B.
    Lazzar-Atwood, Alice
    Collison, Michael L.
    Henry, Nathaniel J.
    Abebe, Zegeye
    Adamu, Abdu A.
    Adekanmbi, Victor
    Ahmadi, Keivan
    Ajumobi, Olufemi
    Al-Eyadhy, Ayman
    Al-Raddadi, Rajaa M.
    Alahdab, Fares
    Alijanzadeh, Mehran
    Alipour, Vahid
    Altirkawi, Khalid
    Amini, Saeed
    Andrei, Catalina Liliana
    Antonio, Carl Abelardo T.
    Arabloo, Jalal
    Aremu, Olatunde
    Asadi-Aliabadi, Mehran
    Atique, Suleman
    Ausloos, Marcel
    Avila, Marco
    Awasthi, Ashish
    Ayala Quintanilla, Beatriz Paulina
    Azari, Samad
    Badawi, Alaa
    Baernighausen, Till Winfried
    Bassat, Quique
    Baye, Kaleab
    Bedi, Neeraj
    Bekele, Bayu Begashaw
    Bell, Michelle L.
    Bhattacharjee, Natalia V.
    Bhattacharyya, Krittika
    Bhattarai, Suraj
    Bhutta, Zulfiqar A.
    Biadgo, Belete
    Bikbov, Boris
    Briko, Andrey Nikolaevich
    Britton, Gabrielle
    Burstein, Roy
    Butt, Zahid A.
    Car, Josip
    Castaneda-Orjuela, Carlos A.
    Castro, Franz
    Cerin, Ester
    Chipeta, Michael G.
    Chu, Dinh-Toi
    Cork, Michael A.
    Cromwell, Elizabeth A.
    Cuevas-Nasu, Lucia
    Dandona, Lalit
    Dandona, Rakhi
    Daoud, Farah
    Das Gupta, Rajat
    Weaver, Nicole Davis
    De Leo, Diego
    De Neve, Jan-Walter
    Deribe, Kebede
    Desalegn, Beruk Berhanu
    Deshpande, Aniruddha
    Desta, Melaku
    Diaz, Daniel
    Tadese Dinberu, Mesfin
    Doku, David Teye
    Dubey, Manisha
    Duraes, Andre R.
    Dwyer-Lindgren, Laura
    Earl, Lucas
    Effiong, Andem
    Zaki, Maysaa El Sayed
    El Tantawi, Maha
    El-Khatib, Ziad
    Eshrati, Babak
    Fareed, Mohammad
    Faro, Andre
    Fereshtehnejad, Seyed-Mohammad
    Filip, Irina
    Fischer, Florian
    Foigt, Nataliya A.
    Folayan, Morenike Oluwatoyin
    Fukumoto, Takeshi
    Gebrehiwot, Tsegaye Tewelde
    Gezae, Kebede Embaye
    Ghajar, Alireza
    Gill, Paramjit Singh
    Gona, Philimon N.
    Gopalani, Sameer Vali
    Grada, Ayman
    Guo, Yuming
    Haj-Mirzaian, Arvin
    Haj-Mirzaian, Arya
    Hall, Jason B.
    Hamidi, Samer
    Henok, Andualem
    Prado, Bernardo Hernandez
    Herrero, Mario
    Herteliu, Claudiu
    Hoang, Chi Linh
    Hole, Michael K.
    Hossain, Naznin
    Hosseinzadeh, Mehdi
    Hu, Guoqing
    Islam, Sheikh Mohammed Shariful
    Jakovljevic, Mihajlo
    Jha, Ravi Prakash
    Jonas, Jost B.
    Jozwiak, Jacek Jerzy
    Kahsay, Amaha
    Kanchan, Tanuj
    Karami, Manoochehr
    Kasaeian, Amir
    Khader, Yousef Saleh
    Khan, Ejaz Ahmad
    Khater, Mona M.
    Kim, Yun Jin
    Kimokoti, Ruth W.
    Kisa, Adnan
    Kochhar, Sonali
    Kosen, Soewarta
    Koyanagi, Ai
    Krishan, Kewal
    Defo, Barthelemy Kuate
    Kumar, G. Anil
    Kumar, Manasi
    Lad, Sheetal D.
    Lami, Faris Hasan
    Lee, Paul H.
    Levine, Aubrey J.
    Li, Shanshan
    Linn, Shai
    Lodha, Rakesh
    Abd El Razek, Hassan Magdy
    Abd El Razek, Muhammed Magdy
    Majdan, Marek
    Majeed, Azeem
    Malekzadeh, Reza
    Malta, Deborah Carvalho
    Mamun, Abdullah A.
    Mansournia, Mohammad Ali
    Martins-Melo, Francisco Rogerlandio
    Masaka, Anthony
    Massenburg, Benjamin Ballard
    Mayala, Benjamin K.
    Mejia-Rodriguez, Fabiola
    Melku, Mulugeta
    Mendoza, Walter
    Mensah, George A.
    Miazgowski, Tomasz
    Miller, Ted R.
    Mini, G. K.
    Mirrakhimov, Erkin M.
    Moazen, Babak
    Darwesh, Aso Mohammad
    Mohammed, Shafiu
    Mohebi, Farnam
    Mokdad, Ali H.
    Moodley, Yoshan
    Moradi, Ghobad
    Moradi-Lakeh, Maziar
    Moraga, Paula
    Morrison, Shane Douglas
    Mosser, Jonathan F.
    Mousavi, Seyyed Meysam
    Mueller, Ulrich Otto
    Murray, Christopher J. L.
    Mustafa, Ghulam
    Naderi, Mehdi
    Naghavi, Mohsen
    Najafi, Farid
    Nangia, Vinay
    Ndwandwe, Duduzile Edith
    Negoi, Ionut
    Ngunjiri, Josephine W.
    Nguyen, Huong Lan Thi
    Nguyen, Long Hoang
    Nguyen, Son Hoang
    Nie, Jing
    Nnaji, Chukwudi A.
    Noubiap, Jean Jacques
    Shiadeh, Malihe Nourollahpour
    Nyasulu, Peter S.
    Ogbo, Felix Akpojene
    Olagunju, Andrew T.
    Olusanya, Bolajoko Olubukunola
    Olusanya, Jacob Olusegun
    Ortiz-Panozo, Eduardo
    Otstavnov, Stanislav S.
    Mahesh, P. A.
    Pana, Adrian
    Pandey, Anamika
    Pati, Sanghamitra
    Patil, Snehal T.
    Patton, George C.
    Perico, Norberto
    Pigott, David M.
    Pirsaheb, Meghdad
    Piwoz, Ellen G.
    Postma, Maarten J.
    Pourshams, Akram
    Prakash, Swayam
    Quintana, Hedley
    Radfar, Amir
    Rafiei, Alireza
    Rahimi-Movaghar, Vafa
    Rai, Rajesh Kumar
    Rajati, Fatemeh
    Rawaf, David Laith
    Rawaf, Salman
    Rawat, Rahul
    Remuzzi, Giuseppe
    Renzaho, Andre M. N.
    Rios-Gonzalez, Carlos
    Roever, Leonardo
    Ross, Jennifer M.
    Rostami, Ali
    Sadat, Nafis
    Safari, Yahya
    Safdarian, Mahdi
    Sahebkar, Amirhossein
    Salam, Nasir
    Salamati, Payman
    Salimi, Yahya
    Salimzadeh, Hamideh
    Samy, Abdallah M.
    Sartorius, Benn
    Sathian, Brijesh
    Schipp, Megan F.
    Schwebel, David C.
    Senbeta, Anbissa Muleta
    Sepanlou, Sadaf G.
    Shaikh, Masood Ali
    Levy, Teresa Shamah
    Shamsi, Mohammadbagher
    Sharafi, Kiomars
    Sharma, Rajesh
    Sheikh, Aziz
    Shil, Apurba
    Silva, Diego Augusto Santos
    Singh, Jasvinder A.
    Sinha, Dhirendra Narain
    Soofi, Moslem
    Sudaryanto, Agus
    Sufiyan, Mu'awiyyah Babale
    Tabares-Seisdedos, Rafael
    Tadesse, Birkneh Tilahun
    Temsah, Mohamad-Hani
    Terkawi, Abdullah Sulieman
    Tessema, Zemenu Tadesse
    Thorne-Lyman, Andrew L.
    Tovani-Palone, Marcos Roberto
    Tran, Bach Xuan
    Tran, Khanh Bao
    Ullah, Irfan
    Uthman, Olalekan A.
    Vaezghasemi, Masoud
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Vaezi, Afsane
    Valdez, Pascual R.
    Vanderheide, John
    Veisani, Yousef
    Violante, Francesco S.
    Vlassov, Vasily
    Vu, Giang Thu
    Vu, Linh Gia
    Waheed, Yasir
    Walson, Judd L.
    Wang, Yafeng
    Wang, Yuan-Pang
    Wangia, Elizabeth N.
    Werdecker, Andrea
    Xu, Gelin
    Yamada, Tomohide
    Yisma, Engida
    Yonemoto, Naohiro
    Younis, Mustafa Z.
    Yousefifard, Mahmoud
    Yu, Chuanhua
    Bin Zaman, Sojib
    Zamani, Mohammad
    Zhang, Yunquan
    Kassebaum, Nicholas J.
    Hay, Simon I.
    Mapping child growth failure across low- and middle-income countries2020In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 577, no 7789, p. 231-234Article in journal (Refereed)
    Abstract [en]

    Childhood malnutrition is associated with high morbidity and mortality globally. Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood. Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0-59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards. The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z-score, respectively, that is more than two standard deviations below the World Health Organization's median growth reference standards for a healthy population. Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for example, states or provinces); the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes. Building from our previous work mapping CGF in Africa, here we provide the first, to our knowledge, mapped highspatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99% of affected children live, aggregated to policy-relevant first and second (for example, districts or counties) administrativelevel units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and progress exist across and within countries; our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications.

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

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

  • 34. Leebens-Mack, James H.
    et al.
    Barker, Michael S.
    Carpenter, Eric J.
    Deyholos, Michael K.
    Gitzendanner, Matthew A.
    Graham, Sean W.
    Grosse, Ivo
    Li, Zheng
    Melkonian, Michael
    Mirarab, Siavash
    Porsch, Martin
    Quint, Marcel
    Rensing, Stefan A.
    Soltis, Douglas E.
    Soltis, Pamela S.
    Stevenson, Dennis W.
    Ullrich, Kristian K.
    Wickett, Norman J.
    DeGironimo, Lisa
    Edger, Patrick P.
    Jordon-Thaden, Ingrid E.
    Joya, Steve
    Liu, Tao
    Melkonian, Barbara
    Miles, Nicholas W.
    Pokorny, Lisa
    Quigley, Charlotte
    Thomas, Philip
    Villarreal, Juan Carlos
    Augustin, Megan M.
    Barrett, Matthew D.
    Baucom, Regina S.
    Beerling, David J.
    Benstein, Ruben Maximilian
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Biffin, Ed
    Brockington, Samuel F.
    Burge, Dylan O.
    Burris, Jason N.
    Burris, Kellie P.
    Burtet-Sarramegna, Valerie
    Caicedo, Ana L.
    Cannon, Steven B.
    Cebi, Zehra
    Chang, Ying
    Chater, Caspar
    Cheeseman, John M.
    Chen, Tao
    Clarke, Neil D.
    Clayton, Harmony
    Covshoff, Sarah
    Crandall-Stotler, Barbara J.
    Cross, Hugh
    dePamphilis, Claude W.
    Der, Joshua P.
    Determann, Ron
    Dickson, Rowan C.
    Di Stilio, Veronica S.
    Ellis, Shona
    Fast, Eva
    Feja, Nicole
    Field, Katie J.
    Filatov, Dmitry A.
    Finnegan, Patrick M.
    Floyd, Sandra K.
    Fogliani, Bruno
    Garcia, Nicolas
    Gateble, Gildas
    Godden, Grant T.
    Goh, Falicia (Qi Yun)
    Greiner, Stephan
    Harkess, Alex
    Heaney, James Mike
    Helliwell, Katherine E.
    Heyduk, Karolina
    Hibberd, Julian M.
    Hodel, Richard G. J.
    Hollingsworth, Peter M.
    Johnson, Marc T. J.
    Jost, Ricarda
    Joyce, Blake
    Kapralov, Maxim V.
    Kazamia, Elena
    Kellogg, Elizabeth A.
    Koch, Marcus A.
    Von Konrat, Matt
    Konyves, Kalman
    Kutchan, Toni M.
    Lam, Vivienne
    Larsson, Anders
    Leitch, Andrew R.
    Lentz, Roswitha
    Li, Fay-Wei
    Lowe, Andrew J.
    Ludwig, Martha
    Manos, Paul S.
    Mavrodiev, Evgeny
    McCormick, Melissa K.
    McKain, Michael
    McLellan, Tracy
    McNeal, Joel R.
    Miller, Richard E.
    Nelson, Matthew N.
    Peng, Yanhui
    Ralph, Paula
    Real, Daniel
    Riggins, Chance W.
    Ruhsam, Markus
    Sage, Rowan F.
    Sakai, Ann K.
    Scascitella, Moira
    Schilling, Edward E.
    Schlosser, Eva-Marie
    Sederoff, Heike
    Servick, Stein
    Sessa, Emily B.
    Shaw, A. Jonathan
    Shaw, Shane W.
    Sigel, Erin M.
    Skema, Cynthia
    Smith, Alison G.
    Smithson, Ann
    Stewart, C. Neal, Jr.
    Stinchcombe, John R.
    Szovenyi, Peter
    Tate, Jennifer A.
    Tiebel, Helga
    Trapnell, Dorset
    Villegente, Matthieu
    Wang, Chun-Neng
    Weller, Stephen G.
    Wenzel, Michael
    Weststrand, Stina
    Westwood, James H.
    Whigham, Dennis F.
    Wu, Shuangxiu
    Wulff, Adrien S.
    Yang, Yu
    Zhu, Dan
    Zhuang, Cuili
    Zuidof, Jennifer
    Chase, Mark W.
    Pires, J. Chris
    Rothfels, Carl J.
    Yu, Jun
    Chen, Cui
    Chen, Li
    Cheng, Shifeng
    Li, Juanjuan
    Li, Ran
    Li, Xia
    Lu, Haorong
    Ou, Yanxiang
    Sun, Xiao
    Tan, Xuemei
    Tang, Jingbo
    Tian, Zhijian
    Wang, Feng
    Wang, Jun
    Wei, Xiaofeng
    Xu, Xun
    Yan, Zhixiang
    Yang, Fan
    Zhong, Xiaoni
    Zhou, Feiyu
    Zhu, Ying
    Zhang, Yong
    Ayyampalayam, Saravanaraj
    Barkman, Todd J.
    Nguyen, Nam-Phuong
    Matasci, Naim
    Nelson, David R.
    Sayyari, Erfan
    Wafula, Eric K.
    Walls, Ramona L.
    Warnow, Tandy
    An, Hong
    Arrigo, Nils
    Baniaga, Anthony E.
    Galuska, Sally
    Jorgensen, Stacy A.
    Kidder, Thomas I.
    Kong, Hanghui
    Lu-Irving, Patricia
    Marx, Hannah E.
    Qi, Xinshuai
    Reardon, Chris R.
    Sutherland, Brittany L.
    Tiley, George P.
    Welles, Shana R.
    Yu, Rongpei
    Zhan, Shing
    Gramzow, Lydia
    Theissen, Gunter
    Wong, Gane Ka-Shu
    One thousand plant transcriptomes and the phylogenomics of green plants2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 574, no 7780, p. 679-+Article in journal (Refereed)
    Abstract [en]

    Green plants (Viridiplantae) include around 450,000-500,000 species(1,2) of great diversity and have important roles in terrestrial and aquatic ecosystems. Here, as part of the One Thousand Plant Transcriptomes Initiative, we sequenced the vegetative transcriptomes of 1,124 species that span the diversity of plants in a broad sense (Archaeplastida), including green plants (Viridiplantae), glaucophytes (Glaucophyta) and red algae (Rhodophyta). Our analysis provides a robust phylogenomic framework for examining the evolution of green plants. Most inferred species relationships are well supported across multiple species tree and supermatrix analyses, but discordance among plastid and nuclear gene trees at a few important nodes highlights the complexity of plant genome evolution, including polyploidy, periods of rapid speciation, and extinction. Incomplete sorting of ancestral variation, polyploidization and massive expansions of gene families punctuate the evolutionary history of green plants. Notably, we find that large expansions of gene families preceded the origins of green plants, land plants and vascular plants, whereas whole-genome duplications are inferred to have occurred repeatedly throughout the evolution of flowering plants and ferns. The increasing availability of high-quality plant genome sequences and advances in functional genomics are enabling research on genome evolution across the green tree of life.

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

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

  • 36. Lien, Sigbjorn
    et al.
    Koop, Ben F.
    Sandve, Simen R.
    Miller, Jason R.
    Kent, Matthew P.
    Nome, Torfinn
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Leong, Jong S.
    Minkley, David R.
    Zimin, Aleksey
    Grammes, Fabian
    Grove, Harald
    Gjuvsland, Arne
    Walenz, Brian
    Hermansen, Russell A.
    von Schalburg, Kris
    Rondeau, Eric B.
    Di Genova, Alex
    Samy, Jeevan K. A.
    Vik, Jon Olav
    Vigeland, Magnus D.
    Caler, Lis
    Grimholt, Unni
    Jentoft, Sissel
    Vage, Dag Inge
    de Jong, Pieter
    Moen, Thomas
    Baranski, Matthew
    Palti, Yniv
    Smith, Douglas R.
    Yorke, James A.
    Nederbragt, Alexander J.
    Tooming-Klunderud, Ave
    Jakobsen, Kjetill S.
    Jiang, Xuanting
    Fan, Dingding
    Liberles, David A.
    Vidal, Rodrigo
    Iturra, Patricia
    Jones, Steven J. M.
    Jonassen, Inge
    Maass, Alejandro
    Omholt, Stig W.
    Davidson, William S.
    The Atlantic salmon genome provides insights into rediploidization2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 533, no 7602, p. 200-205Article in journal (Refereed)
    Abstract [en]

    The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.

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  • 37. Lloyd-Price, Jason
    et al.
    Arze, Cesar
    Ananthakrishnan, Ashwin N.
    Schirmer, Melanie
    Avila-Pacheco, Julian
    Poon, Tiffany W.
    Andrews, Elizabeth
    Ajami, Nadim J.
    Bonham, Kevin S.
    Brislawn, Colin J.
    Casero, David
    Courtney, Holly
    Gonzalez, Antonio
    Graeber, Thomas G.
    Hall, A. Brantley
    Lake, Kathleen
    Landers, Carol J.
    Mallick, Himel
    Plichta, Damian R.
    Prasad, Mahadev
    Rahnavard, Gholamali
    Sauk, Jenny
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
    Vazquez-Baeza, Yoshiki
    White, Richard A., III
    Braun, Jonathan
    Denson, Lee A.
    Jansson, Janet K.
    Knight, Rob
    Kugathasan, Subra
    McGovern, Dermot P. B.
    Petrosino, Joseph F.
    Stappenbeck, Thaddeus S.
    Winter, Harland S.
    Clish, Clary B.
    Franzosa, Eric A.
    Vlamakis, Hera
    Xavier, Ramnik J.
    Huttenhower, Curtis
    Bishai, Jason
    Bullock, Kevin
    Deik, Amy
    Dennis, Courtney
    Kaplan, Jess L.
    Khalili, Hamed
    McIver, Lauren J.
    Moran, Christopher J.
    Nguyen, Long
    Pierce, Kerry A.
    Schwager, Randall
    Sirota-Madi, Alexandra
    Stevens, Betsy W.
    Tan, William
    ten Hoeve, Johanna J.
    Weingart, George
    Wilson, Robin G.
    Yajnik, Vijay
    Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 569, no 7758, p. 655-661Article in journal (Refereed)
    Abstract [en]

    Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

  • 38. Locke, Adam E.
    et al.
    Kahali, Bratati
    Berndt, Sonja I.
    Justice, Anne E.
    Pers, Tune H.
    Day, Felix R.
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L.
    Yang, Jian
    Croteau-Chonka, Damien C.
    Esko, Tonu
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Kutalik, Zoltan
    Luan, Jian'an
    Maegi, Reedik
    Randall, Joshua C.
    Winkler, Thomas W.
    Wood, Andrew R.
    Workalemahu, Tsegaselassie
    Faul, Jessica D.
    Smith, Jennifer A.
    Zhao, Jing Hua
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Asa K.
    Karjalainen, Juha
    Schmidt, Ellen M.
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L.
    Bragg-Gresham, L.
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B.
    Feenstra, Bjarke
    Feitosa, Mary F.
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U.
    Kanoni, Stavroula
    Kleber, Marcus E.
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Leach, Irene Mateo
    Medina-Gomez, Carolina
    Medland, Sarah E.
    Nalls, Michael A.
    Palmer, Cameron D.
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J.
    Prokopenko, Inga
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology.
    Stancakova, Alena
    Strawbridge, Rona J.
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W.
    van Settee, Jessica
    Van Vliet-Ostaptchouk, Jana V.
    Wang, Zhaoming
    Yengo, Loic
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Arnlov, Johan
    Arscott, Gillian M.
    Attwood, Antony P.
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N.
    Bellis, Claire
    Bennett, Amanda J.
    Berne, Christian
    Blagieva, Roza
    Blueher, Matthias
    Bohringer, Stefan
    Bonnycastle, Lori L.
    Boettcher, Yvonne
    Boyd, Heather A.
    Bruinenberg, Marcel
    Caspersen, Ida H.
    Chen, Yii-Der Ida
    Clarke, Robert
    Daw, E. Warwick
    de Craen, Anton J. M.
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S. F.
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M.
    Garcia, Melissa E.
    Geller, Frank
    Giedraitis, Vilmantas
    Gigante, Bruna
    Go, Alan S.
    Golay, Alain
    Goodall, Alison H.
    Gordon, Scott D.
    Gorski, Mathias
    Grabe, Hans-Joergen
    Grallert, Harald
    Grammer, Tanja B.
    Graessler, Jurgen
    Gronberg, Henrik
    Groves, Christopher J.
    Gusto, Gaeelle
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hartman, Catharina A.
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L.
    Helmer, Qinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L.
    Jeff, Janina M.
    Johansson, Asa
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R.
    Lichtner, Peter
    Lind, Lars
    Lindstrom, Jaana
    Lo, Ken Sin
    Lobbens, Stephane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, Francois
    Magnusson, Patrik K. E.
    Mahajan, Anubha
    McArdle, Wendy L.
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L.
    Morken, Mario A.
    Mulas, Antonella
    Mueller, Gabriele
    Mueller-Nurasyid, Martina
    Musk, Arthur W.
    Nagaraja, Ramaiah
    Noethen, Markus M.
    Nolte, Ilja M.
    Pilz, Stefan
    Rayner, Nigel W.
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Rettig, Rainer
    Ried, Janina S.
    Ripke, Stephan
    Robertson, Neil R.
    Rose, Lynda M.
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R.
    Scott, William R.
    Seufferlein, Thomas
    Shi, Jianxin
    Smith, Albert Vernon
    Smolonska, Joanna
    Stanton, Alice V.
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M.
    Sundstrom, Johan
    Swertz, Morris A.
    Swift, Amy J.
    Syvanen, Ann-Christine
    Tan, Sian-Tsung
    Tayo, Bamidele O.
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P.
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C.
    Vermeulen, Sita H.
    Verweij, Niek
    Vonk, Judith M.
    Waite, Lindsay L.
    Warren, Helen R.
    Waterworth, Dawn
    Weedon, Michael N.
    Wilkens, Lynne R.
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K.
    Wong, Andrew
    Wrightl, Alan F.
    Zhang, Qunyuan
    Brennan, Eoin P.
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W.
    Eriksson, Per
    Franco-Cereceda, Anders
    Gadin, Jesper R.
    Gharavi, Ali G.
    Goddard, Michael E.
    Handsaker, Robert E.
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P.
    Ma, Baoshan
    McCarroll, Steven A.
    McKnight, Amy J.
    Min, Josine L.
    Moffatt, Miriam F.
    Montgomery, Grant W.
    Murabito, Joanne M.
    Nicholson, George
    Nyholt, Dale R.
    Okada, Yukinori
    Perry, John R. B.
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M.
    Sandholm, Niina
    Scott, Robert A.
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    van 't Hooft, Ferdinand M.
    Vinkhuyzen, Anna A. E.
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T.
    Heath, Andrew C.
    Arveiler, Dominique
    Bakker, Stephan J. L.
    Beilby, John
    Bergman, Richard N.
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J.
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I.
    Chines, Peter S.
    Collins, Francis S.
    Crawford, Dana C.
    Cupples, L. Adrienne
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M.
    Dominiczak, Anna F.
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G.
    Farrall, Martin
    Felix, Stephan B.
    Ferrannini, Ele
    Ferrieres, Jean
    Ford, Ian
    Forouhi, Nita G.
    Forrester, Terrence
    Franco, Oscar H.
    Gansevoort, Ron T.
    Gejman, Pablo V.
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hall, Alistair S.
    Harris, Tamara B.
    Hattersley, Andrew T.
    Hicks, Andrew A.
    Hindorff, Lucia A.
    Hingorani, Aroon D.
    Hofman, Albert
    Homuth, Georg
    Hovingh, G. Kees
    Humphries, Steve E.
    Hunt, Steven C.
    Hypponen, Elina
    Illig, Thomas
    Jacobs, Kevin B.
    Jarvelin, Marjo-Riitta
    Joeckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Jukema, J. Wouter
    Jula, Antti M.
    Kaprio, Jaakko
    Kastelein, John J. P.
    Keinanen-Kiukaanniemi, Sirkka M.
    Kiemeney, Lambertus A.
    Knekt, Paul
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T.
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A.
    Langenberg, Claudia
    Le Marchand, Laic
    Lehtimaki, Terho
    Lyssenko, Valeriya
    Mannisto, Satu
    Marette, Andre
    Matise, Tara C.
    McKenzie, Colin A.
    McKnight, Barbara
    Moll, Frans L.
    Morris, Andrew D.
    Morris, Andrew P.
    Murray, Jeffrey C.
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J.
    Ong, Ken K.
    Madden, Pamela A. F.
    Pasterkamp, Gerard
    Peden, John F.
    Peters, Annette
    Postma, Dirkje S.
    Pramstaller, Peter P.
    Price, Jackie F.
    Qi, Lu
    Raitakari, Olli T.
    Rankinen, Tuomo
    Rao, D. C.
    Rice, Treva K.
    Ridker, Paul M.
    Rioux, John D.
    Ritchie, Marylyn D.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Saramines, Jouko
    Sarzynski, Mark A.
    Schunkert, Heribert
    Schwarz, Peter E. H.
    Sever, Peter
    Shuldiner, Alan R.
    Sinisalo, Juha
    Stolk, Ronald P.
    Strauch, Konstantin
    Toenjes, Anke
    Tregouet, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Voelker, Uwe
    Waeber, Gerard
    Willemsen, Gonneke
    Witteman, Jacqueline C.
    Zillikens, M. Carola
    Adair, Linda S.
    Amouyel, Philippe
    Asselbergs, Folkert W.
    Assimes, Themistocles L.
    Bochud, Murielle
    Boehm, Bernhard O.
    Boerwinkle, Eric
    Bornstein, Stefan R.
    Bottinger, Erwin P.
    Bouchard, Claude
    Cauchi, Stephane
    Chambers, John C.
    Chanock, Stephen J.
    Cooper, Richard S.
    de Bakker, Paul I. W.
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Froguel, Philippe
    Groop, Leif C.
    Haiman, Christopher A.
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J.
    Hveem, Kristian
    Kaplan, Robert C.
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G.
    Maerz, Winfried
    Melbve, Mads
    Metspalu, Andres
    Moebus, Susanne
    Munroe, Patricia B.
    Njolstad, Inger
    Oostra, Ben A.
    Palmer, Colin N. A.
    Pedersen, Nancy L.
    Perola, Markus
    Perusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E.
    Saleheen, Danish
    Sattar, Naveed
    Schadt, Eric E.
    Schlessinger, David
    Slagboom, P. Eline
    Snieder, Harold
    Spector, Tim D.
    Thorsteinsdottir, Unnu R.
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J.
    Watkins, Hugh
    Weir, David R.
    Wichmann, H-Erich
    Wilson, James F.
    Zanen, Pieter
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Heid, Iris M.
    O'Connell, Jeffrey R.
    Strachan, David P.
    Stefansson, Kari
    van Duijri, Cornelia M.
    Abecasis, Goncalo R.
    Franke, Lude
    Frayling, Timothy M.
    McCarthy, Mark I.
    Visscher, Peter M.
    Scherag, Andre
    Willer, Cristen J.
    Boehnke, Michael
    Mohlke, Karen L.
    Lindgren, Cecilia M.
    Beckmann, Jacques S.
    Barroso, Ines
    North, Kari E.
    Ingelsson, Erik
    Hirschhorn, Joel N.
    Loos, Ruth J. F.
    Speliotes, Elizabeth K.
    Genetic studies of body mass index yield new insights for obesity biology2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 197-U401Article in journal (Refereed)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 39.
    Makarova, Tatiana L
    et al.
    Umeå University, Faculty of Science and Technology, Physics.
    Sundqvist, Bertil
    Umeå University, Faculty of Science and Technology, Physics.
    Höhne, Roland
    Esquinazi, Pablo
    Kopelevich, Yakov
    Scharff, Peter
    Davydov, Valerii A.
    Kashevarova, Ludmila S.
    Rakhmaninova, Aleksandra V.
    Magnetic Carbon2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 413, no 6857, p. 716-718Article in journal (Refereed)
    Abstract [en]

    Paper retracted.

  • 40. Mancio-Silva, Liliana
    et al.
    Slavic, Ksenija
    Grilo Ruivo, Margarida T.
    Grosso, Ana Rita
    Modrzynska, Katarzyna K.
    Vera, Iset Medina
    Sales-Dias, Joana
    Gomes, Ana Rita
    MacPherson, Cameron Ross
    Crozet, Pierre
    Adamo, Mattia
    Baena-Gonzalez, Elena
    Tewari, Rita
    Llinás, Manuel
    Billker, Oliver
    Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    Mota, Maria M.
    Nutrient sensing modulates malaria parasite virulence2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 547, no 7662, p. 213-216Article in journal (Refereed)
    Abstract [en]

    The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host, primarily for nutrient supply. Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signalling networks that enable cells to sense and adapt to varying environmental conditions. Canonical nutrient-sensing pathways are presumed to be absent from the causative agent of malaria, Plasmodium, thus raising the question of whether these parasites can sense and cope with fluctuations in host nutrient levels. Here we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status. KIN shares homology with SNF1/AMPKα, and yeast complementation studies suggest that it is part of a functionally conserved cellular energy-sensing pathway. Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence.

  • 41. Marouli, Eirini
    et al.
    Graff, Mariaelisa
    Medina-Gomez, Carolina
    Lo, Ken Sin
    Wood, Andrew R.
    Kjaer, Troels R.
    Fine, Rebecca S.
    Lu, Yingchang
    Schurmann, Claudia
    Highland, Heather M.
    Rueger, Sina
    Thorleifsson, Gudmar
    Justice, Anne E.
    Lamparter, David
    Stirrups, Kathleen E.
    Turcot, Valerie
    Young, Kristin L.
    Winkler, Thomas W.
    Esko, Tonu
    Karaderi, Tugce
    Locke, Adam E.
    Masca, Nicholas G. D.
    Ng, Maggie C. Y.
    Mudgal, Poorva
    Rivas, Manuel A.
    Vedantam, Sailaja
    Mahajan, Anubha
    Guo, Xiuqing
    Abecasis, Goncalo
    Aben, Katja K.
    Adair, Linda S.
    Alam, Dewan S.
    Albrecht, Eva
    Allin, Kristine H.
    Allison, Matthew
    Amouyel, Philippe
    Appel, Emil V.
    Arveiler, Dominique
    Asselbergs, Folkert W.
    Auer, Paul L.
    Balkau, Beverley
    Banas, Bernhard
    Bang, Lia E.
    Benn, Marianne
    Bergmann, Sven
    Bielak, Lawrence F.
    Blueher, Matthias
    Boeing, Heiner
    Boerwinkle, Eric
    Boeger, Carsten A.
    Bonnycastle, Lori L.
    Bork-Jensen, Jette
    Bots, Michiel L.
    Bottinger, Erwin P.
    Bowden, Donald W.
    Brandslund, Ivan
    Breen, Gerome
    Brilliant, Murray H.
    Broer, Linda
    Burt, Amber A.
    Butterworth, Adam S.
    Carey, David J.
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Chen, Yii-Der Ida
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audrey Y.
    Cocca, Massimiliano
    Collins, Francis S.
    Cook, James P.
    Corley, Janie
    Galbany, Jordi Corominas
    Cox, Amanda J.
    Cuellar-Partida, Gabriel
    Danesh, John
    Davies, Gail
    de Bakker, Paul I. W.
    de Borst, Gert J.
    de Denus, Simon
    de Groot, Mark C. H.
    de Mutsert, Renee
    Deary, Ian J.
    Dedoussis, George
    Demerath, Ellen W.
    den Hollander, Anneke I.
    Dennis, Joe G.
    Di Angelantonio, Emanuele
    Drenos, Fotios
    Du, Mengmeng
    Dunning, Alison M.
    Easton, Douglas F.
    Ebeling, Tapani
    Edwards, Todd L.
    Ellinor, Patrick T.
    Elliott, Paul
    Evangelou, Evangelos
    Farmaki, Aliki-Eleni
    Faul, Jessica D.
    Feitosa, Mary F.
    Feng, Shuang
    Ferrannini, Ele
    Ferrario, Marco M.
    Ferrieres, Jean
    Florez, Jose C.
    Ford, Ian
    Fornage, Myriam
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Frikke-Schmidt, Ruth
    Galesloot, Tessel E.
    Gan, Wei
    Gandin, Ilaria
    Gasparini, Paolo
    Giedraitis, Vilmantas
    Giri, Ayush
    Girotto, Giorgia
    Gordon, Scott D.
    Gordon-Larsen, Penny
    Gorski, Mathias
    Grarup, Niels
    Grove, Megan L.
    Gudnason, Vilmundur
    Gustafsson, Stefan
    Hansen, Torben
    Harris, Kathleen Mullan
    Harris, Tamara B.
    Hattersley, Andrew T.
    Hayward, Caroline
    He, Liang
    Heid, Iris M.
    Heikkila, Kauko
    Helgeland, Oyvind
    Hernesniemi, Jussi
    Hewitt, Alex W.
    Hocking, Lynne J.
    Hollensted, Mette
    Holmen, Oddgeir L.
    Hovingh, G. Kees
    Howson, Joanna M. M.
    Hoyng, Carel B.
    Huang, Paul L.
    Hveem, Kristian
    Ikram, M. Arfan
    Ingelsson, Erik
    Jackson, Anne U.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jarvik, Gail P.
    Jensen, Gorm B.
    Jhun, Min A.
    Jia, Yucheng
    Jiang, Xuejuan
    Johansson, Stefan
    Jorgensen, Marit E.
    Jorgensen, Torben
    Jousilahti, Pekka
    Jukema, J. Wouter
    Kahali, Bratati
    Kahn, Rene S.
    Kahonen, Mika
    Kamstrup, Pia R.
    Kanoni, Stavroula
    Kaprio, Jaakko
    Karaleftheri, Maria
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kee, Frank
    Keeman, Renske
    Kiemeney, Lambertus A.
    Kitajima, Hidetoshi
    Kluivers, Kirsten B.
    Kocher, Thomas
    Komulainen, Pirjo
    Kontto, Jukka
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kovacs, Peter
    Kriebel, Jennifer
    Kuivaniemi, Helena
    Kury, Sebastien
    Kuusisto, Johanna
    La Bianca, Martina
    Laakso, Markku
    Lakka, Timo A.
    Lange, Ethan M.
    Lange, Leslie A.
    Langefeld, Carl D.
    Langenberg, Claudia
    Larson, Eric B.
    Lee, I-Te
    Lehtimaki, Terho
    Lewis, Cora E.
    Li, Huaixing
    Li, Jin
    Li-Gao, Ruifang
    Lin, Honghuang
    Lin, Li-An
    Lin, Xu
    Lind, Lars
    Lindstrom, Jaana
    Linneberg, Allan
    Liu, Yeheng
    Liu, Yongmei
    Lophatananon, Artitaya
    Luan, Jian'an
    Lubitz, Steven A.
    Lyytikainen, Leo-Pekka
    Mackey, David A.
    Madden, Pamela A. F.
    Manning, Alisa K.
    Mannisto, Satu
    Marenne, Gaelle
    Marten, Jonathan
    Martin, Nicholas G.
    Mazul, Angela L.
    Meidtner, Karina
    Metspalu, Andres
    Mitchell, Paul
    Mohlke, Karen L.
    Mook-Kanamori, Dennis O.
    Morgan, Anna
    Morris, Andrew D.
    Morris, Andrew P.
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Nalls, Mike A.
    Nauck, Matthias
    Nelson, Christopher P.
    Neville, Matt
    Nielsen, Sune F.
    Nikus, Kjell
    Njolstad, Pal R.
    Nordestgaard, Borge G.
    Ntalla, Ioanna
    O'Connel, Jeffrey R.
    Oksa, Heikki
    Loohuis, Loes M. Olde
    Ophoff, Roel A.
    Owen, Katharine R.
    Packard, Chris J.
    Padmanabhan, Sandosh
    Palmer, Colin N. A.
    Pasterkamp, Gerard
    Patel, Aniruddh P.
    Pattie, Alison
    Pedersen, Oluf
    Peissig, Peggy L.
    Peloso, Gina M.
    Pennell, Craig E.
    Perola, Markus
    Perry, James A.
    Perry, John R. B.
    Person, Thomas N.
    Pirie, Ailith
    Polasek, Ozren
    Posthuma, Danielle
    Raitakari, Olli T.
    Rasheed, Asif
    Rauramaa, Rainer
    Reilly, Dermot F.
    Reiner, Alex P.
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ridker, Paul M.
    Rioux, John D.
    Robertson, Neil
    Robino, Antonietta
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Rudan, Igor
    Ruth, Katherine S.
    Saleheen, Danish
    Salomaa, Veikko
    Samani, Nilesh J.
    Sandow, Kevin
    Sapkota, Yadav
    Sattar, Naveed
    Schmidt, Marjanka K.
    Schreiner, Pamela J.
    Schulze, Matthias B.
    Scott, Robert A.
    Segura-Lepe, Marcelo P.
    Shah, Svati
    Sim, Xueling
    Sivapalaratnam, Suthesh
    Small, Kerrin S.
    Smith, Albert Vernon
    Smith, Jennifer A.
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Starr, John M.
    Steinthorsdottir, Valgerdur
    Stringham, Heather M.
    Stumvoll, Michael
    Surendran, Praveen
    t Hart, Leen M.
    Tansey, Katherine E.
    Tardif, Jean-Claude
    Taylor, Kent D.
    Teumer, Alexander
    Thompson, Deborah J.
    Thorsteinsdottir, Unnur
    Thuesen, Betina H.
    Toenjes, Anke
    Tromp, Gerard
    Trompet, Stella
    Tsafantakis, Emmanouil
    Tuomilehto, Jaakko
    Tybjaerg-Hansen, Anne
    Tyrer, Jonathan P.
    Uher, Rudolf
    Uitterlinden, Andre G.
    Ulivi, Sheila
    van der Laan, Sander W.
    Van Der Leij, Andries R.
    van Duijn, Cornelia M.
    van Schoor, Natasja M.
    van Setten, Jessica
    Varbo, Anette
    Varga, Tibor V.
    Varma, Rohit
    Edwards, Digna R. Velez
    Vermeulen, Sita H.
    Vestergaard, Henrik
    Vitart, Veronique
    Vogt, Thomas F.
    Vozzi, Diego
    Walker, Mark
    Wang, Feijie
    Wang, Carol A.
    Wang, Shuai
    Wang, Yiqin
    Wareham, Nicholas J.
    Warren, Helen R.
    Wessel, Jennifer
    Willems, Sara M.
    Wilson, James G.
    Witte, Daniel R.
    Woods, Michael O.
    Wu, Ying
    Yaghootkar, Hanieh
    Yao, Jie
    Yao, Pang
    Yerges-Armstrong, Laura M.
    Young, Robin
    Zeggini, Eleftheria
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Jing Hua
    Zhao, Wei
    Zheng, He
    Zhou, Wei
    Rotter, Jerome I.
    Boehnke, Michael
    Kathiresan, Sekar
    McCarthy, Mark I.
    Willer, Cristen J.
    Stefansson, Kari
    Borecki, Ingrid B.
    Liu, Dajiang J.
    North, Kari E.
    Heard-Costa, Nancy L.
    Pers, Tune H.
    Lindgren, Cecilia M.
    Oxvig, Claus
    Kutalik, Zoltan
    Rivadeneira, Fernando
    Loos, Ruth J. F.
    Frayling, Timothy M.
    Hirschhorn, Joel N.
    Deloukas, Panos
    Lettre, Guillaume
    Rare and low-frequency coding variants alter human adult height2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7640, p. 186-190Article in journal (Refereed)
    Abstract [en]

    Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

  • 42. Mathieson, Iain
    et al.
    Lillie, Malcolm
    Reich, David
    The Genomic History of Southeastern Europe2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 555, no 695, p. 197-203Article in journal (Refereed)
    Abstract [en]

    Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to understand the dynamics of this process, we analysed genome-wide ancient DNA data from 225 individuals who lived in southeastern Europe and surrounding regions between 12000 and 500 bc. We document a west–east cline of ancestry in indigenous huntergatherers and, in eastern Europe, the early stages in the formation of Bronze Age steppe ancestry. We show that the first farmers of northern and western Europe dispersed through southeastern Europe with limited hunter-gatherer admixture, but that some early groups in the southeast mixed extensively with hunter-gatherers without the sex-biased admixture that prevailed later in the north and west. We also show that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe.

  • 43. Mayor, Jordan R.
    et al.
    Sanders, Nathan J.
    Classen, Aimee T.
    Bardgett, Richard D.
    Clement, Jean-Christophe
    Fajardo, Alex
    Lavorel, Sandra
    Sundqvist, Maja K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Center for Macroecology, Evolution and Climate, The Natural History Museum of Denmark, University of Copenhagen DK-2100, Copenhagen Ø, Denmark.
    Bahn, Michael
    Chisholm, Chelsea
    Cieraad, Ellen
    Gedalof, Ze'ev
    Grigulis, Karl
    Kudo, Gaku
    Oberski, Daniel L.
    Wardle, David A.
    Elevation alters ecosystem properties across temperate treelines globally2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7639, p. 91-95Article in journal (Refereed)
    Abstract [en]

    Temperature is a primary driver of the distribution of biodiversity as well as of ecosystem boundaries(1,2). Declining temperature with increasing elevation in montane systems has long been recognized as a major factor shaping plant community biodiversity, metabolic processes, and ecosystem dynamics(3,4). Elevational gradients, as thermoclines, also enable prediction of long-term ecological responses to climate warming(5-7). One of the most striking manifestations of increasing elevation is the abrupt transitions from forest to treeless alpine tundra(8). However, whether there are globally consistent above-and belowground responses to these transitions remains an open question(4). To disentangle the direct and indirect effects of temperature on ecosystem properties, here we evaluate replicate treeline ecotones in seven temperate regions of the world. We find that declining temperatures with increasing elevation did not affect tree leaf nutrient concentrations, but did reduce ground-layer community-weighted plant nitrogen, leading to the strong stoichiometric convergence of ground-layer plant community nitrogen to phosphorus ratios across all regions. Further, elevation-driven changes in plant nutrients were associated with changes in soil organic matter content and quality (carbon to nitrogen ratios) and microbial properties. Combined, our identification of direct and indirect temperature controls over plant communities and soil properties in seven contrasting regions suggests that future warming may disrupt the functional properties of montane ecosystems, particularly where plant community reorganization outpaces treeline advance.

  • 44. McElreath, Richard
    et al.
    Luttbeg, barney
    Fogarty, Sean P
    Brodin, Tomas
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Sih, Andrew
    Evolution of animal personalities2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, p. E5-Article in journal (Refereed)
  • 45. Mishra, Aniket
    et al.
    Malik, Rainer
    Hachiya, Tsuyoshi
    Jürgenson, Tuuli
    Namba, Shinichi
    Posner, Daniel C.
    Kamanu, Frederick K.
    Koido, Masaru
    Le Grand, Quentin
    Shi, Mingyang
    He, Yunye
    Georgakis, Marios K.
    Caro, Ilana
    Krebs, Kristi
    Liaw, Yi-Ching
    Vaura, Felix C.
    Lin, Kuang
    Slagsvold Winsvold, Bendik
    Srinivasasainagendra, Vinodh
    Parodi, Livia
    Bae, Hee-Joon
    Chauhan, Ganesh
    Chong, Michael R.
    Tomppo, Liisa
    Akinyemi, Rufus
    Roshchupkin, Gennady V.
    Habib, Naomi
    Jee, Yon Ho
    Thomassen, Jesper Qvist
    Abedi, Vida
    Cárcel-Márquez, Jara
    Nygaard, Marianne
    Leonard, Hampton L.
    Yang, Chaojie
    Yonova-Doing, Ekaterina
    Knol, Maria J.
    Lewis, Adam J.
    Judy, Renae L.
    Ago, Tetsuro
    Amouyel, Philippe
    Armstrong, Nicole D.
    Bakker, Mark K.
    Bartz, Traci M.
    Bennett, David A.
    Bis, Joshua C.
    Bordes, Constance
    Børte, Sigrid
    Cain, Anael
    Ridker, Paul M.
    Cho, Kelly
    Chen, Zhengming
    Cruchaga, Carlos
    Cole, John W.
    de Jager, Phil L.
    de Cid, Rafael
    Endres, Matthias
    Ferreira, Leslie E.
    Geerlings, Mirjam I.
    Gasca, Natalie C.
    Gudnason, Vilmundur
    Hata, Jun
    He, Jing
    Heath, Alicia K.
    Ho, Yuk-Lam
    Havulinna, Aki S.
    Hopewell, Jemma C.
    Hyacinth, Hyacinth I.
    Inouye, Michael
    Jacob, Mina A.
    Jeon, Christina E.
    Jern, Christina
    Kamouchi, Masahiro
    Keene, Keith L.
    Kitazono, Takanari
    Kittner, Steven J.
    Konuma, Takahiro
    Kumar, Amit
    Lacaze, Paul
    Launer, Lenore J.
    Lee, Keon-Joo
    Lepik, Kaido
    Li, Jiang
    Li, Liming
    Manichaikul, Ani
    Markus, Hugh S.
    Marston, Nicholas A.
    Meitinger, Thomas
    Mitchell, Braxton D.
    Montellano, Felipe A.
    Morisaki, Takayuki
    Mosley, Thomas H.
    Nalls, Mike A.
    Nordestgaard, Børge G.
    O'Donnell, Martin J.
    Okada, Yukinori
    Onland-Moret, N. Charlotte
    Ovbiagele, Bruce
    Peters, Annette
    Psaty, Bruce M.
    Rich, Stephen S.
    Rosand, Jonathan
    Sabatine, Marc S.
    Sacco, Ralph L.
    Saleheen, Danish
    Sandset, Else Charlotte
    Salomaa, Veikko
    Sargurupremraj, Muralidharan
    Sasaki, Makoto
    Satizabal, Claudia L.
    Schmidt, Carsten O.
    Shimizu, Atsushi
    Smith, Nicholas L.
    Sloane, Kelly L.
    Sutoh, Yoichi
    Sun, Yan V.
    Tanno, Kozo
    Tiedt, Steffen
    Tatlisumak, Turgut
    Torres-Aguila, Nuria P.
    Tiwari, Hemant K.
    Trégouët, David-Alexandre
    Trompet, Stella
    Tuladhar, Anil Man
    Tybjærg-Hansen, Anne
    van Vugt, Marion
    Vibo, Riina
    Verma, Shefali S.
    Wiggins, Kerri L.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Woo, Daniel
    Wilson, Peter W. F.
    Xu, Huichun
    Yang, Qiong
    Yoon, Kyungheon
    Millwood, Iona Y.
    Gieger, Christian
    Ninomiya, Toshiharu
    Grabe, Hans J.
    Jukema, J. Wouter
    Rissanen, Ina L.
    Strbian, Daniel
    Kim, Young Jin
    Chen, Pei-Hsin
    Mayerhofer, Ernst
    Howson, Joanna M. M.
    Irvin, Marguerite R.
    Adams, Hieab
    Wassertheil-Smoller, Sylvia
    Christensen, Kaare
    Ikram, Mohammad A.
    Rundek, Tatjana
    Worrall, Bradford B.
    Lathrop, G. Mark
    Riaz, Moeen
    Simonsick, Eleanor M.
    Kõrv, Janika
    França, Paulo H. C.
    Zand, Ramin
    Prasad, Kameshwar
    Frikke-Schmidt, Ruth
    de Leeuw, Frank-Erik
    Liman, Thomas
    Haeusler, Karl Georg
    Ruigrok, Ynte M.
    Heuschmann, Peter Ulrich
    Longstreth, W. T.
    Jung, Keum Ji
    Bastarache, Lisa
    Paré, Guillaume
    Damrauer, Scott M.
    Chasman, Daniel I.
    Rotter, Jerome I.
    Anderson, Christopher D.
    Zwart, John-Anker
    Niiranen, Teemu J.
    Fornage, Myriam
    Liaw, Yung-Po
    Seshadri, Sudha
    Fernández-Cadenas, Israel
    Walters, Robin G.
    Ruff, Christian T.
    Owolabi, Mayowa O.
    Huffman, Jennifer E.
    Milani, Lili
    Kamatani, Yoichiro
    Dichgans, Martin
    Debette, Stephanie
    Stroke genetics informs drug discovery and risk prediction across ancestries2022In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 611, no 7934, p. 115-123Article in journal (Refereed)
    Abstract [en]

    Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

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  • 46.
    Mishra, Anu
    et al.
    Imperial College London, London, UK.
    Zhou, Bin
    Imperial College London, London, UK.
    Rodriguez-Martinez, Andrea
    Imperial College London, London, UK.
    Bixby, Honor
    McGill University, Montreal, Québec, Canada.
    Diminishing benefits of urban living for children and adolescents' growth and development2023In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 615, p. 874-883Article in journal (Refereed)
    Abstract [en]

    Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1-6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5-19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m-2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.

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  • 47. NCD Risk Factor Collaboration (NCD-RisC),
    Forsner, Maria (Contributor)
    Umeå University, Faculty of Medicine, Department of Nursing.
    Söderberg, Stefan (Contributor)
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundqvist, Robert (Contributor)
    Norrbotten County Council, Luleå, Sweden.
    Rising rural body-mass index is the main driver of the global obesity epidemic in adults2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 569, no 7755, p. 260-264Article in journal (Refereed)
    Abstract [en]

    Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities1,2. This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity3,4,5,6. Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

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  • 48.
    Nilsson, Christer
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Flood warnings: [review of "The future of large dams" by T. Scudder]2005In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 435, no 7045, p. 1031-1031Article, book review (Other academic)
  • 49. Novak, R
    et al.
    Henriques, B
    Charpentier, E
    Normark, S
    Tuomanen, E
    Emergence of vancomycin tolerance in Streptococcus pneumoniae.1999In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 399, no 6736, p. 590-593Article in journal (Refereed)
    Abstract [en]

    Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis. Multiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort. Emergence of vancomycin resistance in this community-acquired bacterium would be catastrophic. Antibiotic tolerance, the ability of bacteria to survive but not grow in the presence of antibiotics, is a precursor phenotype to resistance. Here we show that loss of function of the VncS histidine kinase of a two-component sensor-regulator system in S. pneumoniae produced tolerance to vancomycin and other classes of antibiotic. Bacterial two-component systems monitor environmental parameters through a sensor histidine-kinase/phosphatase, which phosphorylates/dephosphorylates a response regulator that in turn mediates changes in gene expression. These results indicate that signal transduction is critical for the bactericidal activity of antibiotics. Experimental meningitis caused by the vncS mutant failed to respond to vancomycin. Clinical isolates tolerant to vancomycin were identified and DNA sequencing revealed nucleotide alterations in vncS. We conclude that broad antibiotic tolerance of S. pneumoniae has emerged in the community by a molecular mechanism that eliminates sensitivity to the current cornerstone of therapy, vancomycin.

  • 50. Nystedt, Björn
    et al.
    Street, Nathaniel Robert
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Wetterbom, Anna
    Zuccolo, Andrea
    Lin, Yao-Cheng
    Scofield, Douglas G.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Vezzi, Francesco
    Delhomme, Nicolas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Giacomello, Stefania
    Alexeyenko, Andrey
    Vicedomini, Riccardo
    Sahlin, Kristoffer
    Sherwood, Ellen
    Elfstrand, Malin
    Gramzow, Lydia
    Holmberg, Kristina
    Hällman, Jimmie
    Keech, Olivier
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Klasson, Lisa
    Koriabine, Maxim
    Kucukoglu, Melis
    Käller, Max
    Luthman, Johannes
    Lysholm, Fredrik
    Niittylä, Totte
    Olson, Åke
    Rilakovic, Nemanja
    Ritland, Carol
    Rosselló, Josep A.
    Sena, Juliana
    Svensson, Thomas
    Talavera-López, Carlos
    Theißen, Günter
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Vanneste, Kevin
    Wu, Zhi-Qiang
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Zhang, Bo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Zerbe, Philipp
    Arvestad, Lars
    Bhalerao, Rishikesh
    Bohlmann, Joerg
    Bousquet, Jean
    Gil, Rosario Garcia
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    de Jong, Pieter
    MacKay, John
    Morgante, Michele
    Ritland, Kermit
    Sundberg, Björn
    Thompson, Stacey Lee
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Van de Peer, Yves
    Andersson, Björn
    Nilsson, Ove
    Ingvarsson, Pär K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Lundeberg, Joakim
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    The Norway spruce genome sequence and conifer genome evolution2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 497, no 7451, p. 579-584Article in journal (Refereed)
    Abstract [en]

    Conifers have dominated forests for more than 200 million years and are of huge ecological and economic importance. Here we present the draft assembly of the 20-gigabase genome of Norway spruce (Picea abies), the first available for any gymnosperm. The number of well-supported genes (28,354) is similar to the >100 times smaller genome of Arabidopsis thaliana, and there is no evidence of a recent whole-genome duplication in the gymnosperm lineage. Instead, the large genome size seems to result from the slow and steady accumulation of a diverse set of long-terminal repeat transposable elements, possibly owing to the lack of an efficient elimination mechanism. Comparative sequencing of Pinus sylvestris, Abies sibirica, Juniperus communis, Taxus baccata and Gnetum gnemon reveals that the transposable element diversity is shared among extant conifers. Expression of 24-nucleotide small RNAs, previously implicated in transposable element silencing, is tissue-specific and much lower than in other plants. We further identify numerous long (>10,000 base pairs) introns, gene-like fragments, uncharacterized long non-coding RNAs and short RNAs. This opens up new genomic avenues for conifer forestry and breeding.

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