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  • 401. Toledo-Arana, Alejandro
    et al.
    Dussurget, Olivier
    Nikitas, Georgios
    Sesto, Nina
    Guet-Revillet, Hélène
    Balestrino, Damien
    Loh, Edmund
    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).
    Gripenland, Jonas
    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).
    Tiensuu, Teresa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vaitkevicius, Karolis
    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).
    Barthelemy, Mathieu
    Vergassola, Massimo
    Nahori, Marie-Anne
    Soubigou, Guillaume
    Régnault, Béatrice
    Coppée, Jean-Yves
    Lecuit, Marc
    Johansson, Jörgen
    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).
    Cossart, Pascale
    The Listeria transcriptional landscape from saprophytism to virulence2009In: Nature, ISSN 0028-0836, Vol. 459, no 7249, 950-956 p.Article in journal (Refereed)
    Abstract [en]

    The bacterium Listeria monocytogenes is ubiquitous in the environment and can lead to severe food-borne infections. It has recently emerged as a multifaceted model in pathogenesis. However, how this bacterium switches from a saprophyte to a pathogen is largely unknown. Here, using tiling arrays and RNAs from wild-type and mutant bacteria grown in vitro, ex vivo and in vivo, we have analysed the transcription of its entire genome. We provide the complete Listeria operon map and have uncovered far more diverse types of RNAs than expected: in addition to 50 small RNAs (<500 nucleotides), at least two of which are involved in virulence in mice, we have identified antisense RNAs covering several open-reading frames and long overlapping 5' and 3' untranslated regions. We discovered that riboswitches can act as terminators for upstream genes. When Listeria reaches the host intestinal lumen, an extensive transcriptional reshaping occurs with a SigB-mediated activation of virulence genes. In contrast, in the blood, PrfA controls transcription of virulence genes. Remarkably, several non-coding RNAs absent in the non-pathogenic species Listeria innocua exhibit the same expression patterns as the virulence genes. Together, our data unravel successive and coordinated global transcriptional changes during infection and point to previously unknown regulatory mechanisms in bacteria.

  • 402. Tong, L. M.
    et al.
    Gattass, R. R.
    Ashcom, J. B.
    He, Sailing
    Lou, J. Y.
    Shen, M. Y.
    Maxwell, I.
    Mazur, E.
    Subwavelength-diameter silica wires for low-loss optical wave guiding2003In: Nature, ISSN 0028-0836, Vol. 426, no 6968, 816-819 p.Article in journal (Refereed)
  • 403. Traas, J.
    et al.
    Bellini, C.
    Nacry, P.
    Kronenberger, J.
    Bouchez, D.
    Caboche, M.
    Normal Differentiation Pattern in Plants Lacking Microtubular Preprophase Bands1995In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 375, no 6533, 676-677 p.Article in journal (Refereed)
    Abstract [en]

    IT is generally accepted that polarized cell expansion and the strict control of division plane alignment are prerequisites for ordered spatial development in higher plants(1). This appears to be linked to the presence of cell walls, which immobilize the cells and fix their relative positions. In this context, the cortical cytoskeleton is thought to play a central role(1-6). Interphase microtubules are often aligned perpendicular to the growth axis and it has been proposed that they control cell expansion, probably in combination with the cell wall. Another cytoskeletal array, the prephophase band, has been associated with division plane alignment. This structure, which girdles the cell at the G2 phase of the cell cycle and at prophase, precisely predicts the future division site and probably fixes it. Here we describe different mutants in Arabidopsis that are unable to form these two cortical microtubular arrays. As expected, this defect is associated with irregular cell expansion and the inability to align division planes. Surprisingly, however, the mutations do not affect differentiation patterns: all cell types and organs are in their correct relative positions.

  • 404. Tröstl, Jasmin
    et al.
    Chuang, Wayne K.
    Gordon, Hamish
    Heinritzi, Martin
    Yan, Chao
    Molteni, Ugo
    Ahlm, Lars
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Frege, Carla
    Bianchi, Federico
    Wagner, Robert
    Simon, Mario
    Lehtipalo, Katrianne
    Williamson, Christina
    Craven, Jill S.
    Duplissy, Jonathan
    Adamov, Alexey
    Almeida, Joao
    Bernhammer, Anne-Kathrin
    Breitenlechner, Martin
    Brilke, Sophia
    Dias, Antònio
    Ehrhart, Sebastian
    Flagan, Richard C.
    Franchin, Alessandro
    Fuchs, Claudia
    Guida, Roberto
    Gysel, Martin
    Hansel, Armin
    Hoyle, Christopher R.
    Jokinen, Tuija
    Junninen, Heikki
    Kangasluoma, Juha
    Keskinen, Helmi
    Kim, Jaeseok
    Krapf, Manuel
    Kürten, Andreas
    Laaksonen, Ari
    Lawler, Michael
    Leiminger, Markus
    Mathot, Serge
    Möhler, Ottmar
    Nieminen, Tuomo
    Onnela, Antti
    Petäjä, Tuukka
    Piel, Felix M.
    Miettinen, Pasi
    Rissanen, Matti P.
    Rondo, Linda
    Sarnela, Nina
    Schobesberger, Siegfried
    Sengupta, Kamalika
    Sipilä, Mikko
    Smith, James N.
    Steiner, Gerhard
    Tomè, Antònio
    Virtanen, Annele
    Wagner, Andrea C.
    Weingartner, Ernest
    Wimmer, Daniela
    Winkler, Paul M.
    Ye, Penglin
    Carslaw, Kenneth S.
    Curtius, Joachim
    Dommen, Josef
    Kirkby, Jasper
    Kulmala, Markku
    Riipinen, Ilona
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Worsnop, Douglas R.
    Donahue, Neil M.
    Baltensperger, Urs
    The role of low-volatility organic compounds in initial particle growth in the atmosphere2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 533, no 7604, 527-531 p.Article in journal (Refereed)
    Abstract [en]

    About half of present-day cloud condensation nuclei originate from atmospheric nucleation, frequently appearing as a burst of new particles near midday(1). Atmospheric observations show that the growth rate of new particles often accelerates when the diameter of the particles is between one and ten nanometres(2,3). In this critical size range, new particles are most likely to be lost by coagulation with pre-existing particles(4), thereby failing to form new cloud condensation nuclei that are typically 50 to 100 nanometres across. Sulfuric acid vapour is often involved in nucleation but is too scarce to explain most subsequent growth(5,6), leaving organic vapours as the most plausible alternative, at least in the planetary boundary layer(7-10). Although recent studies(11-13) predict that low-volatility organic vapours contribute during initial growth, direct evidence has been lacking. The accelerating growth may result from increased photolytic production of condensable organic species in the afternoon(2), and the presence of a possible Kelvin (curvature) effect, which inhibits organic vapour condensation on the smallest particles (the nano-Kohler theory)(2,14), has so far remained ambiguous. Here we present experiments performed in a large chamber under atmospheric conditions that investigate the role of organic vapours in the initial growth of nucleated organic particles in the absence of inorganic acids and bases such as sulfuric acid or ammonia and amines, respectively. Using data from the same set of experiments, it has been shown(15) that organic vapours alone can drive nucleation. We focus on the growth of nucleated particles and find that the organic vapours that drive initial growth have extremely low volatilities (saturation concentration less than 10(-4.5) micrograms per cubic metre). As the particles increase in size and the Kelvin barrier falls, subsequent growth is primarily due to more abundant organic vapours of slightly higher volatility (saturation concentrations of 10(-4.5) to 10(-0.5) micrograms per cubic metre). We present a particle growth model that quantitatively reproduces our measurements. Furthermore, we implement a parameterization of the first steps of growth in a global aerosol model and find that concentrations of atmospheric cloud concentration nuclei can change substantially in response, that is, by up to 50 per cent in comparison with previously assumed growth rate parameterizations.

  • 405.
    Turner, Anthony P. F.
    Cranfield University, UK.
    Biosensors: Switching channels makes sense1997In: Nature, ISSN 0028-0836, Vol. 387, no 6633, 555-557 p.Article in journal (Other academic)
  • 406. Uhlen, P.
    et al.
    Laestadius, A.
    Jahnukainen, T.
    Soderblom, T.
    Backhed, F.
    Celsi, G.
    Brismar, Hjalmar
    Normark, S.
    Aperia, A.
    Richter-Dahlfors, A.
    alpha-Haemolysin of uropathogenic E-coli induces Ca2+ oscillations in renal epithelial cells2000In: Nature, ISSN 0028-0836, Vol. 405, no 6787, 694-697 p.Article in journal (Refereed)
    Abstract [en]

    Pyelonephritis is one of the most common febrile diseases in children. If not treated appropriately, it causes irreversible renal damage and accounts for a large proportion of end stage renal failures(1). Renal scarring can occur in the absence of inflammatory cells, indicating that bacteria may have a direct signalling effect on renal cells(2). Intracellular calcium ([Ca2+](i)) oscillations can protect cells from the cytotoxic effects of prolonged increases in intracellular calcium(3,4). However, no pathophysiologically relevant protein that induces such oscillations has been identified. Here we show that infection by uropathogenic Escherichia coli induces a constant, low-frequency oscillatory [Ca2+](i) response in target primary rat renal epithelial cells induced by the secreted RTX (repeats-in-toxin) toxin alpha-haemolysin. The response depends on calcium influx through L-type calcium channels as well as from internal stores gated by inositol triphosphate. Internal calcium oscillations induced by alpha-haemolysin in a renal epithelial cell line stimulated production of cytokines interleukin (IL)-6 and IL-8. Our findings indicate a novel role for alpha-haemolysin in pyelonephritis: as an inducer of an oscillating second messenger response in target cells, which fine-tunes gene expression during the inflammatory response.

  • 407. Vincent, Jean-Baptiste
    et al.
    Bodewits, Dennis
    Besse, Sebastien
    Sierks, Holger
    Barbieri, Cesare
    Lamy, Philippe
    Rodrigo, Rafael
    Koschny, Detlef
    Rickman, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Keller, Horst Uwe
    Agarwal, Jessica
    A'Hearn, Michael F.
    Auger, Anne-Therese
    Barucci, M. Antonella
    Bertaux, Jean-Loup
    Bertini, Ivano
    Capanna, Claire
    Cremonese, Gabriele
    Da Deppo, Vania
    Davidsson, Bjoern
    Debei, Stefano
    De Cecco, Mariolino
    El-Maarry, Mohamed Ramy
    Ferri, Francesca
    Fornasier, Sonia
    Fulle, Marco
    Gaskell, Robert
    Giacomini, Lorenza
    Groussin, Olivier
    Guilbert-Lepoutre, Aurelie
    Gutierrez-Marques, P.
    Gutierrez, Pedro J.
    Guettler, Carsten
    Hoekzema, Nick
    Hoefner, Sebastian
    Hviid, Stubbe F.
    Ip, Wing-Huen
    Jorda, Laurent
    Knollenberg, Joerg
    Kovacs, Gabor
    Kramm, Rainer
    Kuehrt, Ekkehard
    Kueppers, Michael
    La Forgia, Fiorangela
    Lara, Luisa M.
    Lazzarin, Monica
    Lee, Vicky
    Leyrat, Cedric
    Lin, Zhong-Yi
    Lopez Moreno, Jose J.
    Lowry, Stephen
    Magrin, Sara
    Maquet, Lucie
    Marchi, Simone
    Marzari, Francesco
    Massironi, Matteo
    Michalik, Harald
    Moissl, Richard
    Mottola, Stefano
    Naletto, Giampiero
    Oklay, Nilda
    Pajola, Maurizio
    Preusker, Frank
    Scholten, Frank
    Thomas, Nicolas
    Toth, Imre
    Tubiana, Cecilia
    Large heterogeneities in comet 67P as revealed by active pits from sinkhole collapse2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 523, no 7558, 63-66 p.Article in journal (Refereed)
    Abstract [en]

    Pits have been observed on many cometary nuclei mapped by spacecraft(1-4). It has been argued that cometary pits are a signature of endogenic activity, rather than impact craters such as those on planetary and asteroid surfaces. Impact experiments(5,6) andmodels(7,8) cannot reproduce the shapes of most of the observed cometary pits, and the predicted collision rates imply that few of the pits are related to impacts(8,9). Alternative mechanisms like explosive activity(10) have been suggested, but the driving process remains unknown. Here we report that pits on comet 67P/Churyumov-Gerasimenko are active, and probably created by a sinkhole process, possibly accompanied by outbursts. We argue that after formation, pits expand slowly in diameter, owing to sublimation-driven retreat of the walls. Therefore, pits characterize how eroded the surface is: a fresh cometary surface will have a ragged structure with many pits, while an evolved surface will look smoother. The size and spatial distribution of pits imply that large heterogeneities exist in the physical, structural or compositional properties of the first few hundred metres below the current nucleus surface.

  • 408.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Pettersson, U.
    Le Moullec, J.M.
    Tiollais, P.
    Perricaudet, M.
    Different mRNAs from the transforming region (EIB) of highly- and non-oncogenic human adenoviruses1982In: Nature, ISSN 0028-0836, Vol. 295, no 5851, 705-707 p.Article in journal (Refereed)
  • 409. Virtanen, Annele
    et al.
    Joutsensaari, Jorma
    Koop, Thomas
    Kannosto, Jonna
    Yli-Pirila, Pasi
    Leskinen, Jani
    Makela, Jyrki M.
    Holopainen, Jarmo K.
    Poeschl, Ulrich
    Kulmala, Markku
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Worsnop, Douglas R.
    Laaksonen, Ari
    An amorphous solid state of biogenic secondary organic aerosol particles2010In: Nature, ISSN 0028-0836, Vol. 467, no 7317, 824-827 p.Article in journal (Refereed)
    Abstract [en]

    Secondary organic aerosol (SOA) particles are formed in the atmosphere from condensable oxidation products of anthropogenic and biogenic volatile organic compounds (VOCs)(1-7). On a global scale, biogenic VOCs account for about 90% of VOC emissions(1,8) and of SOA formation (90 billion kilograms of carbon per year)(1-4). SOA particles can scatter radiation and act as cloud condensation or ice nuclei, and thereby influence the Earth's radiation balance and climate(1,2,5,9,10). They consist of a myriad of different compounds with varying physicochemical properties, and little information is available on the phase state of SOA particles. Gas-particle partitioning models usually assume that SOA particles are liquid(1,5,11), but here we present experimental evidence that they can be solid under ambient conditions. We investigated biogenic SOA particles formed from oxidation products of VOCs in plant chamber experiments and in boreal forests within a few hours after atmospheric nucleation events. On the basis of observed particle bouncing in an aerosol impactor and of electron microscopy we conclude that biogenic SOA particles can adopt an amorphous solid-most probably glassy-state. This amorphous solid state should provoke a rethinking of SOA processes because it may influence the partitioning of semi-volatile compounds, reduce the rate of heterogeneous chemical reactions, affect the particles' ability to accommodate water and act as cloud condensation or ice nuclei, and change the atmospheric lifetime of the particles(12-15). Thus, the results of this study challenge traditional views of the kinetics and thermodynamics of SOA formation and transformation in the atmosphere and their implications for air quality and climate.

  • 410. Vonk, J. E.
    et al.
    Sanchez-Garcia, L.
    van Dongen, B. E.
    Alling, V.
    Kosmach, D.
    Charkin, A.
    Semiletov, I. P.
    Dudarev, O. V.
    Shakhova, N.
    Roos, P.
    Eglinton, T. I.
    Andersson, A.
    Gustafsson, Ö.
    Activation of old carbon by erosion of coastal and subsea permafrost in Arctic Siberia2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 489Article in journal (Refereed)
    Abstract [en]

    The future trajectory of greenhouse gas concentrations depends on interactions between climate and the biogeosphere(1,2). Thawing of Arctic permafrost could release significant amounts of carbon into the atmosphere in this century(3). Ancient Ice Complex deposits outcropping along the similar to 7,000-kilometre-long coastline of the East Siberian Arctic Shelf (ESAS)(4,5), and associated shallow subsea permafrost(6,7), are two large pools of permafrost carbon(8), yet their vulnerabilities towards thawing and decomposition are largely unknown(9-11). Recent Arctic warming is stronger than has been predicted by several degrees, and is particularly pronounced over the coastal ESAS region(12,13). There is thus a pressing need to improve our understanding of the links between permafrost carbon and climate in this relatively inaccessible region. Here we show that extensive release of carbon from these Ice Complex deposits dominates (57 +/- 2 per cent) the sedimentary carbon budget of the ESAS, the world's largest continental shelf, overwhelming the marine and topsoil terrestrial components. Inverse modelling of the dual-carbon isotope composition of organic carbon accumulating in ESAS surface sediments, using Monte Carlo simulations to account for uncertainties, suggests that 44 +/- 10 teragrams of old carbon is activated annually from Ice Complex permafrost, an order of magnitude more than has been suggested by previous studies(14). We estimate that about two-thirds (66 +/- 16 per cent) of this old carbon escapes to the atmosphere as carbon dioxide, with the remainder being re-buried in shelf sediments. Thermal collapse and erosion of these carbon-rich Pleistocene coastline and seafloor deposits may accelerate with Arctic amplification of climate warming(2,13).

  • 411.
    Vonk, J. E.
    et al.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Sanchez-Garcia, Laura
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    van Dongen, B. E.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Alling, V.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Kosmach, D.
    Charkin, A.
    Semiletov, I. P.
    Dudarev, O. V.
    Shakhova, N.
    Roos, P.
    Eglinton, T. I.
    Andersson, A.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Gustafsson, O.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Activation of old carbon by erosion of coastal and subsea permafrost in Arctic Siberia2012In: Nature, ISSN 0028-0836, Vol. 489, no 7414, 137-140 p.Article in journal (Refereed)
    Abstract [en]

    The future trajectory of greenhouse gas concentrations depends on interactions between climate and the biogeosphere(1,2). Thawing of Arctic permafrost could release significant amounts of carbon into the atmosphere in this century(3). Ancient Ice Complex deposits outcropping along the similar to 7,000-kilometre-long coastline of the East Siberian Arctic Shelf (ESAS)(4,5), and associated shallow subsea permafrost(6,7), are two large pools of permafrost carbon(8), yet their vulnerabilities towards thawing and decomposition are largely unknown(9-11). Recent Arctic warming is stronger than has been predicted by several degrees, and is particularly pronounced over the coastal ESAS region(12,13). There is thus a pressing need to improve our understanding of the links between permafrost carbon and climate in this relatively inaccessible region. Here we show that extensive release of carbon from these Ice Complex deposits dominates (57 +/- 2 per cent) the sedimentary carbon budget of the ESAS, the world's largest continental shelf, overwhelming the marine and topsoil terrestrial components. Inverse modelling of the dual-carbon isotope composition of organic carbon accumulating in ESAS surface sediments, using Monte Carlo simulations to account for uncertainties, suggests that 44 +/- 10 teragrams of old carbon is activated annually from Ice Complex permafrost, an order of magnitude more than has been suggested by previous studies(14). We estimate that about two-thirds (66 +/- 16 per cent) of this old carbon escapes to the atmosphere as carbon dioxide, with the remainder being re-buried in shelf sediments. Thermal collapse and erosion of these carbon-rich Pleistocene coastline and seafloor deposits may accelerate with Arctic amplification of climate warming(2,13).

  • 412. Wagner, W
    et al.
    Torgerson, H
    Einsiedel, E
    Jelsoe, E
    Fredrickson, H
    Lassen, J
    Rusanen, T
    Boy, D
    de Cheveigné, S
    Hampel, J
    Stathopoulou, A
    Allansdottir, A
    Midden, C
    Nielsen, T
    Przestalski, A
    Twardowski, T
    Fjæstad, Björn
    Mid Sweden University, Faculty of Human Sciences, Department of Social Sciences.
    Olsson [Öhman], Susanna
    Mid Sweden University, Faculty of Human Sciences, Department of Social Sciences.
    Olofsson, Anna
    Mid Sweden University, Faculty of Human Sciences, Department of Social Sciences.
    Gaskell, George
    Durant, J
    Bauer, M
    Liakopoulos, M
    Europe ambivalent on biotechnology1997In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 387, 845-847 p.Article in journal (Refereed)
    Abstract [en]

    The Eurobarometer on Biotechnology (46.1) was conducted during October and November 1996. The survey conducted in each EU (European Union) country used a multi-stage random sampling procedure and provided a statistically representative sample of national residents aged 15 and over. The total sample within the EU was 16,246 respondents (about 1,000 per EU country). The survey questionnaire was designed by the authors as part of a larger study involving the comparative analysis of public perceptions, media coverage and public policy in relation to biotechnology from 1973 to the present.

  • 413.
    Wahl, Simone
    et al.
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Univ Alexandria, Med Res Inst, Clin & Expt Surg Dept, Hadara, Alexandria 21561, Egypt..
    Drong, Alexander
    Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England..
    Lehne, Benjamin
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Loh, Marie
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Inst Hlth Sci, POB 5000, FI-90014 Oulu, Finland.;Translat Lab Genet Med TLGM, Agcy Sci, Technol & Res ASTAR, 8A Biomed Grove, Singapore 138648, Singapore..
    Scott, William R.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England..
    Kunze, Sonja
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Tsai, Pei-Chien
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Zhang, Weihua
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England..
    Yang, Youwen
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Tan, Sili
    Fiorito, Giovanni
    Human Genet Fdn Torino, Turin, Italy.;Univ Torino, Dept Med Sci, Turin, Italy..
    Franke, Lude
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Guarrera, Simonetta
    Human Genet Fdn Torino, Turin, Italy.;Univ Torino, Dept Med Sci, Turin, Italy..
    Kasela, Silva
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Riia 23, EE-51010 Tartu, Estonia..
    Kriebel, Jennifer
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Richmond, Rebecca C.
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Adamo, Marco
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England..
    Afzal, Uzma
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England..
    Ala-Korpela, Mika
    Univ Oulu & Biocenter Oulu, Computat Med, Fac Med, Oulu, Finland.;Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland.;Univ Bristol & Med Res Council Integrat Epidemiol, Univ Bristol, Sch Social & Community Med, Computat Med, Bristol, Avon, England..
    Albetti, Benedetta
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Ammerpohl, Ole
    Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel Campus, Kiel, Germany..
    Apperley, Jane F.
    Imperial Coll London, Dept Med, Centre Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England..
    Beekman, Marian
    Leiden Univ Med Ctr, Mol Epidemiol, NL-2333 ZC Leiden, Netherlands..
    Bertazzi, Pier Alberto
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Black, S. Lucas
    Imperial Coll London, Dept Med, Sect Infect Dis & Immun, London W12 0NN, England..
    Blancher, Christine
    Bonder, Marc-Jan
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Brosch, Mario
    Univ Oxford, High Throughput Genom Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Tech Univ Dresden, Univ Hosp, Med Dept 1, Dresden, Germany..
    Carstensen-Kirberg, Maren
    Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany..
    de Craen, Anton J. M.
    Leiden Univ Med Ctr, Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands..
    de Lusignan, Simon
    Univ Surrey, Dept Clin & Expt Med, Guildford GU2 7PX, Surrey, England..
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Elkalaawy, Mohamed
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England.;Univ Alexandria, Med Res Inst, Clin & Expt Surg Dept, Hadara, Alexandria 21561, Egypt..
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Gaunt, Tom R.
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Hampe, Jochen
    Univ Oxford, High Throughput Genom Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Hashemi, Majid
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England..
    Isaacs, Aaron
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Jenkinson, Andrew
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England..
    Jha, Sujeet
    Dept Endocrinol, Diabet & Obes, Max Healthcare, New Delhi 110017, India..
    Kato, Norihiro
    Res Inst, Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Tokyo 1628655, Japan..
    Krogh, Vittorio
    Epidemiol & Prevent Unit, Fondazione IRCSS Ist Nazl Tumori, Milan, Italy..
    Laffan, Michael
    Imperial Coll London, Dept Med, Centre Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England..
    Meisinger, Christa
    Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Meitinger, Thomas
    German Res Ctr Environm Hlth, Int Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany.;Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Mok, Zuan Yu
    Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore..
    Motta, Valeria
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy.;Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Ng, Hong Kiat
    Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore..
    Nikolakopoulou, Zacharoula
    Natl Heart & Lung Inst, London SW3 6LY, England..
    Nteliopoulos, Georgios
    Imperial Coll London, Dept Med, Centre Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England..
    Panico, Salvatore
    Dipartmento Med Clin Chirurgia Federio II Univ, Naples, Italy..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Riia 23, EE-51010 Tartu, Estonia..
    Prokisch, Holger
    Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Rathmann, Wolfgang
    Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Biometr & Epidemiol, Dusseldorf, Germany..
    Roden, Michael
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany.;Heinrich Heine Univ Hosp Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Rota, Federica
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Rozario, Michelle Ann
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England..
    Schafmayer, Clemens
    Univ Hosp Schleswig Holstein, Dept Visceral & Thorac Surg, Kiel Campus, Kiel, Germany..
    Schramm, Katharina
    Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Siebert, Reiner
    Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel Campus, Kiel, Germany.;Univ Hosp Ulm, Inst Human Genet, Albert Einstein Allee 11, D-89081 Ulm, Germany..
    Slagboom, P. Eline
    Leiden Univ Med Ctr, Mol Epidemiol, NL-2333 ZC Leiden, Netherlands..
    Soininen, Pasi
    Univ Oulu & Biocenter Oulu, Computat Med, Fac Med, Oulu, Finland.;Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland..
    Stolk, Lisette
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat, Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany..
    Tai, E-Shyong
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119228, Singapore.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore.;Duke Natl Univ, Singapore Grad Med Sch, Singapore 169857, Singapore..
    Tarantini, Letizia
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Thorand, Barbara
    Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Tigchelaar, Ettje F.
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Tumino, Rosario
    Cancer Registry & Histopathol Unit, Civile MP Arezzo Hosp, ASP 7, Ragusa, Italy..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands..
    van Duijn, Cornelia
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    van Meurs, Joyce B. J.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Vineis, Paolo
    Imperial Coll London, Epidemiol & Publ Hlth, London, England..
    Wickremasinghe, Ananda Rajitha
    Univ Kelaniya, Dept Publ Hlth, Fac Med, Box 6,Thalagolla Rd, Ragama 11010, Sri Lanka..
    Wijmenga, Cisca
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Yang, Tsun-Po
    Yuan, Wei
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.;Inst Canc Res, Surrey SM2 5NG, England..
    Zhernakova, Alexandra
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Batterham, Rachel L.
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England.;UCL, Rayne Inst, Dept Med, Ctr Obes Res, London WC1E 6JJ, England..
    Smith, George Davey
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England.;King Abdulaziz Univ, Princess Jawhara Brahim Ctr Excellence Res Heredi, Jeddah 21589, Saudi Arabia..
    Heijmans, Bastiaan T.
    Herder, Christian
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Lindgren, Cecilia M.
    Broad Inst, Massachusetts Inst Technol & Harvard Univ, Cambridge, MA 02142 USA..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia..
    van der Harst, Pim
    Univ Med Ctr Groningen, Dept Cardiol, Univ Groningen, NL-9700 RB Groningen, Netherlands.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3511 GC Utrecht, Netherlands..
    Peters, Annette
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Illig, Thomas
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Feodor Lynen St 15, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Carl Neuberg St 1, Hannover, Germany..
    Relton, Caroline L.
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Waldenberger, Melanie
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Jaervelin, Marjo-Riitta
    Imperial Coll London, Sch Publ Hlth, MRC Hlth Protect Agcy HPE Ctr Environm & Hlth, Dept Epidemiol & Biostatist, London, England.;Univ Oulu, Bioctr Oulu, POB 5000, Oulu, Finland.;Univ Oulu, Ctr Life Course Epidemiol, Fac Med, POB 5000, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50,Box 20, Oulu, Finland..
    Bollati, Valentina
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Soong, Richie
    Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore.;Natl Univ Singapore Hosp, Dept Pathol, Singapore, Singapore..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Scott, James
    Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England..
    McCarthy, Mark I.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford NIHR Biomed Res Ctr, Churchill Hosp, Oxford OX3 7LJ, England..
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Bell, Jordana T.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Matullo, Giuseppe
    Human Genet Fdn Torino, Turin, Italy.;Univ Torino, Dept Med Sci, Turin, Italy..
    Gieger, Christian
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Kooner, Jaspal S.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England.;Imperial Coll Healthcare NHS Trust, London W12 0HS, England..
    Grallert, Harald
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England..
    Chambers, John C.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England.;Imperial Coll Healthcare NHS Trust, London W12 0HS, England.;Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore..
    Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 541, no 7635, 81-+ p.Article in journal (Refereed)
    Abstract [en]

    Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

  • 414. Wang, Jian
    et al.
    Krejci, Radovan
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Giangrandel, Scott
    Kuang, Chongai
    Barbosa, Henrique M. J.
    Brito, Joel
    Carbone, Samara
    Chi, Xuguang
    Comstock, Jennifer
    Ditas, Florian
    Lavric, Jost
    Manninen, Hanna E.
    Mei, Fan
    Moran-Zuloaga, Daniel
    Poehlker, Christopher
    Poehlker, Mira L.
    Saturno, Jorge
    Schmid, Beat
    Souza, Rodrigo A. F.
    Springston, Stephen R.
    Tomlinson, Jason M.
    Toto, Tami
    Walter, David
    Wimmer, Daniela
    Smith, James N.
    Kulmala, Markku
    Machado, Luiz A. T.
    Artaxo, Paulo
    Andreae, Meinrat O.
    Petaja, Tuukka
    Martin, Scot T.
    Amazon boundary layer aerosol concentration sustained by vertical transport during rainfall2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 539, no 7629, 416-419 p.Article in journal (Refereed)
    Abstract [en]

    The nucleation of atmospheric vapours is an important source of new aerosol particles that can subsequently grow to form cloud condensation nuclei in the atmosphere(1). Most field studies of atmospheric aerosols over continents are influenced by atmospheric vapours of anthropogenic origin (for example, ref. 2) and, in consequence, aerosol processes in pristine, terrestrial environments remain poorly understood. The Amazon rainforest is one of the few continental regions where aerosol particles and their precursors can be studied under near-natural conditions(3-5), but the origin of small aerosol particles that grow into cloud condensation nuclei in the Amazon boundary layer remains unclear(6-8). Here we present aircraft- and ground-based measurements under clean conditions during the wet season in the central Amazon basin. We find that high concentrations of small aerosol particles (with diameters of less than 50 nanometres) in the lower free troposphere are transported from the free troposphere into the boundary layer during precipitation events by strong convective downdrafts and weaker downward motions in the trailing stratiform region. This rapid vertical transport can help to maintain the population of particles in the pristine Amazon boundary layer, and may therefore influence cloud properties and climate under natural conditions.

  • 415. Wang, Kaituo
    et al.
    Sitsel, Oleg
    Meloni, Gabriele
    Autzen, Henriette Elisabeth
    Andersson, Magnus
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Klymchuk, Tetyana
    Nielsen, Anna Marie
    Rees, Douglas C.
    Nissen, Poul
    Gourdon, Pontus
    Structure and mechanism of Zn2+-transporting P-type ATPases2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 514, no 7523, 518-+ p.Article in journal (Refereed)
    Abstract [en]

    Zinc is an essential micronutrient for all living organisms. It is required for signalling and proper functioning of a range of proteins involved in, for example, DNA binding and enzymatic catalysis(1). In prokaryotes and photosynthetic eukaryotes, Zn2+-transporting P-type ATPases of class IB (ZntA) are crucial for cellular redistribution and detoxification of Zn2+ and related elements(2,3). Here we present crystal structures representing the phosphoenzyme ground state (E2P) and a dephosphorylation intermediate (E2.P-i) of ZntA from Shigella sonnei, determined at 3.2 angstrom and 2.7 angstrom resolution, respectively. The structures reveal a similar fold to Cu+-ATPases, with an amphipathic helix at the membrane interface. A conserved electronegative funnel connects this region to the intramembranous high-affinity ion-binding site and may promote specific uptake of cellular Zn2+ ions by the transporter. The E2P structure displays a wide extracellular release pathway reaching the invariant residues at the high-affinity site, including C392, C394 and D714. The pathway closes in the E2.P-i state, in which D714 interacts with the conserved residue K693, which possibly stimulates Zn2+ release as a built-in counter ion, as has been proposed for H+-ATPases. Indeed, transport studies in liposomes provide experimental support for ZntA activity without counter transport. These findings suggest a mechanistic link between P-IB-type Zn2+-ATPases and P-III-type H+-ATPases and at the same time show structural features of the extracellular release pathway that resemble P-II-type ATPases such as the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase(4,5) (SERCA) and Na+, K+-ATPase(6). These findings considerably increase our understanding of zinc transport in cells and represent new possibilities for biotechnology and biomedicine.

  • 416. Wang, Yingdi
    et al.
    Nakayama, Masanori
    Pitulescu, Mara E
    Schmidt, Tim S
    Bochenek, Magdalena L
    Sakakibara, Akira
    Adams, Susanne
    Davy, Alice
    Deutsch, Urban
    Lüthi, Urs
    Barberis, Alcide
    Benjamin, Laura E
    Mäkinen, Taija
    Nobes, Catherine D
    Adams, Ralf H
    Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 465, no 7297Article in journal (Refereed)
    Abstract [en]

    In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.

  • 417. Warren, Wesley C
    et al.
    Clayton, David F
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Arnold, Arthur P
    Hillier, Ladeana W
    Künstner, Axel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Searle, Steve
    White, Simon
    Vilella, Albert J
    Fairley, Susan
    Heger, Andreas
    Kong, Lesheng
    Ponting, Chris P
    Jarvis, Erich D
    Mello, Claudio V
    Minx, Pat
    Lovell, Peter
    Velho, Tarciso A F
    Ferris, Margaret
    Balakrishnan, Christopher N
    Sinha, Saurabh
    Blatti, Charles
    London, Sarah E
    Li, Yun
    Lin, Ya-Chi
    George, Julia
    Sweedler, Jonathan
    Southey, Bruce
    Gunaratne, Preethi
    Watson, Michael
    Nam, Kiwoong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Backström, Niclas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Smeds, Linnea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Nabholz, Benoit
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Itoh, Yuichiro
    Whitney, Osceola
    Pfenning, Andreas R
    Howard, Jason
    Völker, Martin
    Skinner, Bejamin M
    Griffin, Darren K
    Ye, Liang
    McLaren, William M
    Flicek, Paul
    Quesada, Victor
    Velasco, Gloria
    Lopez-Otin, Carlos
    Puente, Xose S
    Olender, Tsviya
    Lancet, Doron
    Smit, Arian F A
    Hubley, Robert
    Konkel, Miriam K
    Walker, Jerilyn A
    Batzer, Mark A
    Gu, Wanjun
    Pollock, David D
    Chen, Lin
    Cheng, Ze
    Eichler, Evan E
    Stapley, Jessica
    Slate, Jon
    Ekblom, Robert
    Birkhead, Tim
    Burke, Terry
    Burt, David
    Scharff, Constance
    Adam, Iris
    Richard, Hugues
    Sultan, Marc
    Soldatov, Alexey
    Lehrach, Hans
    Edwards, Scott V
    Yang, Shiaw-Pyng
    Li, Xiaoching
    Graves, Tina
    Fulton, Lucinda
    Nelson, Joanne
    Chinwalla, Asif
    Hou, Shunfeng
    Mardis, Elaine R
    Wilson, Richard K
    The genome of a songbird2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7289, 757-762 p.Article in journal (Refereed)
    Abstract [en]

    The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.

  • 418. Wedemeyer-Bohm, Sven
    et al.
    Scullion, Eamon
    Steiner, Oskar
    van der Voort, Luc Rouppe
    de la Cruz Rodriguez, Jaime
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Fedun, Viktor
    Erdelyi, Robert
    Magnetic tornadoes as energy channels into the solar corona2012In: Nature, ISSN 0028-0836, Vol. 486, no 7404, 505-508 p.Article in journal (Refereed)
    Abstract [en]

    Heating the outer layers of the magnetically quiet solar atmosphere to more than one million kelvin and accelerating the solar wind requires an energy flux of approximately 100 to 300 watts per square metre(1-6), but how this energy is transferred and dissipated there is a puzzle and several alternative solutions have been proposed. Braiding and twisting of magnetic field structures, which is caused by the convective flows at the solar surface, was suggested as an efficient mechanism for atmospheric heating(7). Convectively driven vortex flows that harbour magnetic fields are observed(8-10) to be abundant in the photosphere (the visible surface of the Sun). Recently, corresponding swirling motions have been discovered(11) in the chromosphere, the atmospheric layer sandwiched between the photosphere and the corona. Here we report the imprints of these chromospheric swirls in the transition region and low corona, and identify them as observational signatures of rapidly rotating magnetic structures. These ubiquitous structures, which resemble super-tornadoes under solar conditions, reach from the convection zone into the upper solar atmosphere and provide an alternative mechanism for channelling energy from the lower into the upper solar atmosphere.

  • 419. Wernet, Philippe
    et al.
    Kunnus, Kristjan
    Josefsson, Ida
    Stockholm University, Faculty of Science, Department of Physics.
    Rajkovic, Ivan
    Quevedo, Wilson
    Beye, Martin
    Schreck, Simon
    Grübel, Sebastian
    Scholz, Mirko
    Nordlund, Dennis
    Zhang, Wenkai
    Hartsock, Robert W.
    Schlotter, William F.
    Turner, Joshua J.
    Kennedy, Brian
    Hennies, Frank
    de Groot, Frank M. F.
    Gaffney, Kelly J.
    Techert, Simone
    Odelius, Michael
    Stockholm University, Faculty of Science, Department of Physics.
    Föhlisch, Alexander
    Orbital-specific mapping of the ligand exchange dynamics of Fe(CO)5 in solution2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 520, no 7545, 78-81 p.Article in journal (Refereed)
    Abstract [en]

    Transition-metal complexes have long attracted interest for fundamental chemical reactivity studies and possible use in solar energy conversion. Electronic excitation, ligand loss from the metal centre, or a combination of both, creates changes in charge and spin density at the metal site that need to be controlled to optimize complexes for photocatalytic hydrogen production and selective carbon-hydrogen bond activation. An understanding at the molecular level of how transition-metal complexes catalyse reactions, and in particular of the role of the short-lived and reactive intermediate states involved, will be critical for such optimization. However, suitable methods for detailed characterization of electronic excited states have been lacking. Here we show, with the use of X-ray laser-based femtosecond resolution spectroscopy and advanced quantum chemical theory to probe the reaction dynamics of the benchmark transition-metal complex Fe(CO)5 insolution, that the photoinduced removal of CO generates the 16-electron Fe(CO)4 species, a homogeneous catalyst with an electron deficiency at the Fe centre, in a hitherto unreported excited singlet state that either converts to the triplet ground state or combines with a CO or solvent molecule to regenerate a penta-coordinated Fe species on a sub-picosecond timescale. This finding, which resolves the debate about the relative importance of different spin channels in the photochemistry of Fe(CO)5 (refs 4, 16,17,18,19 and 20), was made possible by the ability of femtosecond X-ray spectroscopy to probe frontier-orbital interactions with atom specificity. We expect the method to be broadly applicable in the chemical sciences, and to complement approaches that probe structural dynamics in ultrafast processes.

  • 420.
    Wildermuth, Stephan
    et al.
    Physikalisches Institut, Universität Heidelberg.
    Hofferberth, Sebastian
    Physikalisches Institut, Universität Heidelberg.
    Lesanovsky, Igor
    Physikalisches Institut, Universität Heidelberg.
    Haller, Elmar
    Physikalisches Institut, Universität Heidelberg.
    Andersson, L. Mauritz
    Physikalisches Institut, Universität Heidelberg.
    Groth, Sönke
    Physikalisches Institut, Universität Heidelberg.
    Bar-Joseph, Israel
    Department of Condensed Matter Physics, The Weizmann Institute of Science.
    Krüger, Peter
    Physikalisches Institut, Universität Heidelberg.
    Schmiedmayer, Jörg
    Physikalisches Institut, Universität Heidelberg.
    Bose-Einstein condensates: Microscopic magnetic-field imaging2005In: Nature, ISSN 0028-0836, Vol. 435, no 7041, 440- p.Article in journal (Other academic)
  • 421.
    Willem, Michael
    et al.
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
    Tahirovic, Sabina
    German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany..
    Busche, Marc Aurel
    Tech Univ Munich, Dept Psychiat & Psychotherapy, D-81675 Munich, Germany.;Tech Univ Munich, Inst Neurosci, D-80802 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany..
    Ovsepian, Saak V.
    German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany..
    Chafai, Magda
    Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France..
    Kootar, Scherazad
    Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France..
    Hornburg, Daniel
    Max Planck Inst Biochem, D-82152 Martinsried, Germany..
    Evans, Lewis D. B.
    Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England..
    Moore, Steven
    Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England..
    Daria, Anna
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
    Hampel, Heike
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
    Mueller, Veronika
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
    Giudici, Camilla
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
    Nuscher, Brigitte
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany..
    Wenninger-Weinzierl, Andrea
    German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany..
    Kremmer, Elisabeth
    German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.;German Res Ctr Environm Hlth, Inst Mol Immunol, D-81377 Munich, Germany..
    Heneka, Michael T.
    Univ Bonn, Clin Neurosci Unit, Dept Neurol, D-53127 Bonn, Germany.;German Ctr Neurodegenerat Dis DZNE Bonn, D-53175 Bonn, Germany..
    Thal, Dietmar R.
    Univ Ulm, Inst Pathol, Neuropathol Lab, D-89081 Ulm, Germany..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Mueller, Ulrike
    Heidelberg Univ, Funct Genom, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany..
    Livesey, Frederick J.
    Univ Cambridge, Gurdon Inst, Cambridge Stem Cell Inst, Cambridge CB2 1QN, England.;Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England..
    Meissner, Felix
    Max Planck Inst Biochem, D-82152 Martinsried, Germany..
    Herms, Jochen
    German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany..
    Konnerth, Arthur
    Tech Univ Munich, Inst Neurosci, D-80802 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany..
    Marie, Helene
    Univ Nice Sophia Antipolis, UMR 7275, CNRS, IPMC, F-06560 Valbonne, France..
    Haass, Christian
    Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany.;German Ctr Neurodegenerat Dis DZNE Munich, D-81377 Munich, Germany.;Univ Munich, Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany..
    eta-Secretase processing of APP inhibits neuronal activity in the hippocampus2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7573, 443-447 p.Article in journal (Refereed)
    Abstract [en]

    Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide(1). Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manne(r)1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo(2). Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as g-secretase activity. g-Secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A eta peptides (termed A eta-alpha and A eta-beta). CTFs produced by g-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-eta and A eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A eta-alpha. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

  • 422. Willerslev, E
    et al.
    Davison, J
    Moora, M
    Zobel, E
    Coissac, E
    Edwards, M E
    Lorenzen, E D
    Vestergård, M
    Gussarova, G
    Haile, J
    Craine, J
    Gielly, L
    Boessenkool, S
    Epp, L S
    Pearman, P B
    Cheddadi, R
    Murray, D
    Bråthen, K A
    Yoccoz, N
    Binney, H
    Crauaud, C
    Wincker, P
    Goslar, T
    Alsos, I G
    Bellemain, E
    Brysting, A K
    Elven, R
    Sønstebø, J H
    Murton, J
    Sher, A
    Rasmussen, M
    Rasmussen, R
    Mourier, T
    Cooper, A
    Austin, J
    Möller, Per
    Froese, D
    Zazula, G
    Pompanon, F
    Rioux, D
    Niderkorn, V
    Tikhonov, A
    Savvinov, G
    Roberts, R G
    MacPhee, R D E
    Gilbert, M T G
    Kjær, K H
    Orlando, L
    Brochmann, C
    Taberlet, P
    Fifty thousand years of arctic vegetation change and megafauna diet2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 506, no 7486, 47-+ p.Article in journal (Refereed)
    Abstract [en]

    Although it is generally agreed that the Arctic flora is among the youngest and least diverse on Earth, the processes that shaped it are poorly understood. Here we present 50 thousand years (kyr) of Arctic vegetation history, derived from the first large-scale ancient DNA metabarcoding study of circumpolar plant diversity. For this interval we also explore nematode diversity as a proxy for modelling vegetation cover and soil quality, and diets of herbivorous megafaunal mammals, many of which became extinct around 10 kyr bp (before present). For much of the period investigated, Arctic vegetation consisted of dry steppe-tundra dominated by forbs (non-graminoid herbaceous vascular plants). During the Last Glacial Maximum (25–15 kyr bp), diversity declined markedly, although forbs remained dominant. Much changed after 10 kyr bp, with the appearance of moist tundra dominated by woody plants and graminoids. Our analyses indicate that both graminoids and forbs would have featured in megafaunal diets. As such, our findings question the predominance of a Late Quaternary graminoid-dominated Arctic mammoth steppe.

  • 423. Wilson, Sara I
    et al.
    Rydström, A
    Trimborn, T
    Willert, K
    Nusse, R
    Jessell, T M
    Edlund, T
    The status of Wnt signalling regulates neural and epidermal fates in the chick embryo.2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 411, no 6835, 325-30 p.Article in journal (Refereed)
    Abstract [en]

    The acquisition of neural fate by embryonic ectodermal cells is a fundamental step in the formation of the vertebrate nervous system. Neural induction seems to involve signalling by fibroblast growth factors (FGFs) and attenuation of the activity of bone morphogenetic protein (BMP). But FGFs, either alone or in combination with BMP antagonists, are not sufficient to induce neural fate in prospective epidermal ectoderm of amniote embryos. These findings suggest that additional signals are involved in the specification of neural fate. Here we show that the state of Wnt signalling is a critical determinant of neural and epidermal fates in the chick embryo. Continual Wnt signalling blocks the response of epiblast cells to FGF signals, permitting the expression and signalling of BMP to direct an epidermal fate. Conversely, a lack of exposure of epiblast cells to Wnt signals permits FGFs to induce a neural fate.

  • 424.
    Wiltgren, Filip
    Linköping University, Faculty of Science & Engineering.
    SELF-LIMITED2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 535, no 7613, 586-586 p.Article in journal (Other academic)
    Abstract [en]

    n/a

  • 425. Wolff, E W
    et al.
    Fischer, H
    Fundel, F
    Ruth, U
    Twarloh, B
    Littot, G C
    Mulvaney, R
    Rothlisberger, R
    de Angelis, M
    Boutron, C F
    Hansson, M
    Jonsell, U
    Hutterli, M A
    Lambert, F
    Kaufmann, P
    Stauffer, B
    Stocker, T F
    Steffensen, J P
    Bigler, M
    Siggaard-Andersen, M L
    Udisti, R
    Becagli, S
    Castellano, E
    Severi, M
    Wagenbach, D
    Barbante, C
    Gabrielli, P
    Gaspari, V
    Southern Ocean sea-ice extent, productivity and iron flux over the past eight glacial cycles2006In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 440, no 7083, 491-496 p.Article in journal (Refereed)
    Abstract [en]

    Sea ice and dust flux increased greatly in the Southern Ocean during the last glacial period. Palaeorecords provide contradictory evidence about marine productivity in this region, but beyond one glacial cycle, data were sparse. Here we present continuous chemical proxy data spanning the last eight glacial cycles (740,000 years) from the Dome C Antarctic ice core. These data constrain winter sea-ice extent in the Indian Ocean, Southern Ocean biogenic productivity and Patagonian climatic conditions. We found that maximum sea-ice extent is closely tied to Antarctic temperature on multi-millennial timescales, but less so on shorter timescales. Biological dimethylsulphide emissions south of the polar front seem to have changed little with climate, suggesting that sulphur compounds were not active in climate regulation. We observe large glacial-interglacial contrasts in iron deposition, which we infer reflects strongly changing Patagonian conditions. During glacial terminations, changes in Patagonia apparently preceded sea-ice reduction, indicating that multiple mechanisms may be responsible for different phases of CO2 increase during glacial terminations. We observe no changes in internal climatic feedbacks that could have caused the change in amplitude of Antarctic temperature variations observed 440,000 years ago.

  • 426.
    Xiao, Changhong
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Fujita, Nobuhisa
    Miyasaka, Keiichi
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Sakamoto, Yasuhiro
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Terasaki, Osamu
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Dodecagonal tiling in mesoporous silica2012In: Nature, ISSN 0028-0836, Vol. 487, no 7407, 349-353 p.Article in journal (Refereed)
    Abstract [en]

    Recent advances in the fabrication of quasicrystals in soft matter systems have increased the length scales for quasicrystals(1) into the mesoscale range (20 to 500 angstroms). Thus far, dendritic liquid crystals(2), ABC-star polymers(3), colloids(4) and inorganic nanoparticles(5) have been reported to yield quasicrystals. These quasicrystals offer larger length scales than intermetallic quasicrystals (a few angstroms)(1,6), thus potentially leading to optical applications through the realization of a complete photonic bandgap induced via multiple scattering of light waves in virtually all directions(7-9). However, the materials remain far from structurally ideal, in contrast to their intermetallic counterparts, and fine control over the structure through a self-organization process has yet to be attained. Here we use the well-established self-assembly of surfactant micelles to produce a new class of mesoporous silicas, which exhibit 12-fold (dodecagonal) symmetry in both electron diffraction and morphology. Each particle reveals, in the 12-fold cross-section, an analogue of dodecagonal quasicrystals in the centre surrounded by 12 fans of crystalline domains in the peripheral part. The quasicrystallinity has been verified by selected-area electron diffraction and quantitative phason strain analyses on transmission electron microscope images obtained from the central region. We argue that the structure forms through a non-equilibrium growth process, wherein the competition between different micellar configurations has a central role in tuning the structure. A simple theoretical model successfully reproduces the observed features and thus establishes a link between the formation process and the resulting structure.

  • 427. Yang, Jian
    et al.
    Loos, Ruth J F
    Powell, Joseph E
    Medland, Sarah E
    Speliotes, Elizabeth K
    Chasman, Daniel I
    Rose, Lynda M
    Thorleifsson, Gudmar
    Steinthorsdottir, Valgerdur
    Mägi, Reedik
    Waite, Lindsay
    Smith, Albert Vernon
    Yerges-Armstrong, Laura M
    Monda, Keri L
    Hadley, David
    Mahajan, Anubha
    Li, Guo
    Kapur, Karen
    Vitart, Veronique
    Huffman, Jennifer E
    Wang, Sophie R
    Palmer, Cameron
    Esko, Tõnu
    Fischer, Krista
    Zhao, Jing Hua
    Demirkan, Ayşe
    Isaacs, Aaron
    Feitosa, Mary F
    Luan, Jian'an
    Heard-Costa, Nancy L
    White, Charles
    Jackson, Anne U
    Preuss, Michael
    Ziegler, Andreas
    Eriksson, Joel
    Kutalik, Zoltán
    Frau, Francesca
    Nolte, Ilja M
    Van Vliet-Ostaptchouk, Jana V
    Hottenga, Jouke-Jan
    Jacobs, Kevin B
    Verweij, Niek
    Goel, Anuj
    Medina-Gomez, Carolina
    Estrada, Karol
    Bragg-Gresham, Jennifer Lynn
    Sanna, Serena
    Sidore, Carlo
    Tyrer, Jonathan
    Teumer, Alexander
    Prokopenko, Inga
    Mangino, Massimo
    Lindgren, Cecilia M
    Assimes, Themistocles L
    Shuldiner, Alan R
    Hui, Jennie
    Beilby, John P
    McArdle, Wendy L
    Hall, Per
    Haritunians, Talin
    Zgaga, Lina
    Kolcic, Ivana
    Polasek, Ozren
    Zemunik, Tatijana
    Oostra, Ben A
    Junttila, M Juhani
    Grönberg, Henrik
    Schreiber, Stefan
    Peters, Annette
    Hicks, Andrew A
    Stephens, Jonathan
    Foad, Nicola S
    Laitinen, Jaana
    Pouta, Anneli
    Kaakinen, Marika
    Willemsen, Gonneke
    Vink, Jacqueline M
    Wild, Sarah H
    Navis, Gerjan
    Asselbergs, Folkert W
    Homuth, Georg
    John, Ulrich
    Iribarren, Carlos
    Harris, Tamara
    Launer, Lenore
    Gudnason, Vilmundur
    O'Connell, Jeffrey R
    Boerwinkle, Eric
    Cadby, Gemma
    Palmer, Lyle J
    James, Alan L
    Musk, Arthur W
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Psaty, Bruce M
    Beckmann, Jacques S
    Waeber, Gerard
    Vollenweider, Peter
    Hayward, Caroline
    Wright, Alan F
    Rudan, Igor
    Groop, Leif C
    Metspalu, Andres
    Khaw, Kay Tee
    van Duijn, Cornelia M
    Borecki, Ingrid B
    Province, Michael A
    Wareham, Nicholas J
    Tardif, Jean-Claude
    Huikuri, Heikki V
    Cupples, L Adrienne
    Atwood, Larry D
    Fox, Caroline S
    Boehnke, Michael
    Collins, Francis S
    Mohlke, Karen L
    Erdmann, Jeanette
    Schunkert, Heribert
    Hengstenberg, Christian
    Stark, Klaus
    Lorentzon, Mattias
    Ohlsson, Claes
    Cusi, Daniele
    Staessen, Jan A
    Van der Klauw, Melanie M
    Pramstaller, Peter P
    Kathiresan, Sekar
    Jolley, Jennifer D
    Ripatti, Samuli
    Jarvelin, Marjo-Riitta
    de Geus, Eco J C
    Boomsma, Dorret I
    Penninx, Brenda
    Wilson, James F
    Campbell, Harry
    Chanock, Stephen J
    van der Harst, Pim
    Hamsten, Anders
    Watkins, Hugh
    Hofman, Albert
    Witteman, Jacqueline C
    Zillikens, M Carola
    Uitterlinden, André G
    Rivadeneira, Fernando
    Zillikens, M Carola
    Kiemeney, Lambertus A
    Vermeulen, Sita H
    Abecasis, Goncalo R
    Schlessinger, David
    Schipf, Sabine
    Stumvoll, Michael
    Tönjes, Anke
    Spector, Tim D
    North, Kari E
    Lettre, Guillaume
    McCarthy, Mark I
    Berndt, Sonja I
    Heath, Andrew C
    Madden, Pamela A F
    Nyholt, Dale R
    Montgomery, Grant W
    Martin, Nicholas G
    McKnight, Barbara
    Strachan, David P
    Hill, William G
    Snieder, Harold
    Ridker, Paul M
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Frayling, Timothy M
    Hirschhorn, Joel N
    Goddard, Michael E
    Visscher, Peter M
    FTO genotype is associated with phenotypic variability of body mass index2012In: Nature, ISSN 0028-0836, Vol. 490, no 7419, 267-272 p.Article in journal (Refereed)
    Abstract [en]

    There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

  • 428.
    Young, Iris D.
    et al.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Ibrahim, Mohamed
    Humboldt Univ, Inst Biol, D-10099 Berlin, Germany..
    Chatterjee, Ruchira
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Gul, Sheraz
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Fuller, Franklin D.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Koroidov, Sergey
    Umea Univ, Inst Kemi, Kemiskt Biol Ctr, S-90187 Umea, Sweden..
    Brewster, Aaron S.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Tran, Rosalie
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Alonso-Mori, Roberto
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Kroll, Thomas
    SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA.;SLAC Natl Accelerator Lab, SSRL, Menlo Pk, CA 94025 USA..
    Michels-Clark, Tara
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Laksmono, Hartawan
    SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA..
    Sierra, Raymond G.
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA.;SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA..
    Stan, Claudiu A.
    SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA..
    Hussein, Rana
    Humboldt Univ, Inst Biol, D-10099 Berlin, Germany..
    Zhang, Miao
    Humboldt Univ, Inst Biol, D-10099 Berlin, Germany..
    Douthit, Lacey
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Kubin, Markus
    Helmholtz Zentrum, Inst Methods & Instrumentat Synchrotron Radiat Re, D-14109 Berlin, Germany..
    de Lichtenberg, Casper
    Umea Univ, Inst Kemi, Kemiskt Biol Ctr, S-90187 Umea, Sweden..
    Pham, Long Vo
    Nilsson, Hakan
    Umea Univ, Inst Kemi, Kemiskt Biol Ctr, S-90187 Umea, Sweden..
    Cheah, Mun Hon
    Umea Univ, Inst Kemi, Kemiskt Biol Ctr, S-90187 Umea, Sweden..
    Shevela, Dmitriy
    Umea Univ, Inst Kemi, Kemiskt Biol Ctr, S-90187 Umea, Sweden..
    Saracini, Claudio
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Bean, Mackenzie A.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Seuffert, Ina
    Humboldt Univ, Inst Biol, D-10099 Berlin, Germany..
    Sokaras, Dimosthenis
    SLAC Natl Accelerator Lab, SSRL, Menlo Pk, CA 94025 USA..
    Weng, Tsu-Chien
    SLAC Natl Accelerator Lab, SSRL, Menlo Pk, CA 94025 USA.;Ctr High Pressure Sci & Technol Adv Res, Shanghai 201203, Peoples R China..
    Pastor, Ernest
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Weninger, Clemens
    SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA..
    Fransson, Thomas
    SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA..
    Lassalle, Louise
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Braeuer, Philipp
    Univ Oxford, Dept Biochem, S Parks Rd, Oxford OX1 3QU, England.;Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England..
    Aller, Pierre
    Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England..
    Docker, Peter T.
    Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England..
    Andi, Babak
    Brookhaven Natl Lab, Natl Synchrotron Light Source 2, Upton, NY 11973 USA..
    Orville, Allen M.
    Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England..
    Glownia, James M.
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Nelson, Silke
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Sikorski, Marcin
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Zhu, Diling
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Hunter, Mark S.
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Lane, Thomas J.
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Aquila, Andy
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Koglin, Jason E.
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Robinson, Joseph
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Liang, Mengning
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Boutet, Sebastien
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Lyubimov, Artem Y.
    Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.;Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA..
    Uervirojnangkoorn, Monarin
    Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.;Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA..
    Moriarty, Nigel W.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Liebschner, Dorothee
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Afonine, Pavel V.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Waterman, David G.
    STFC Rutherford Appleton Lab, Didcot OX11 0QX, Oxon, England.;Rutherford Appleton Lab, CCP4,Res Complex Harwell, Didcot OX11 0FA, Oxon, England..
    Evans, Gwyndaf
    Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England..
    Wernet, Philippe
    Helmholtz Zentrum, Inst Methods & Instrumentat Synchrotron Radiat Re, D-14109 Berlin, Germany..
    Dobbek, Holger
    Humboldt Univ, Inst Biol, D-10099 Berlin, Germany..
    Weis, William I.
    Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.;Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA.;Stanford Univ, Dept Struct Biol, Stanford, CA 94305 USA..
    Brunger, Axel T.
    Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.;Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.;Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA.;Stanford Univ, Dept Struct Biol, Stanford, CA 94305 USA..
    Zwart, Petrus H.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Adams, Paul D.
    Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA..
    Zouni, Athina
    Humboldt Univ, Inst Biol, D-10099 Berlin, Germany..
    Messinger, Johannes
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics. Umea Univ, Inst Kemi, Kemiskt Biol Ctr, S-90187 Umea, Sweden..
    Bergmann, Uwe
    SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA 94025 USA..
    Sauter, Nicholas K.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Kern, Jan
    SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA..
    Yachandra, Vittal K.
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Yano, Junko
    Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA..
    Structure of photosystem II and substrate binding at room temperature2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 540, no 7633, 453-457 p.Article in journal (Refereed)
    Abstract [en]

    Light-induced oxidation of water by photosystem II (PS II) in plants, algae and cyanobacteria has generated most of the dioxygen in the atmosphere. PS II, a membrane-bound multi-subunit pigment protein complex, couples the one-electron photochemistry at the reaction centre with the four-electron redox chemistry of water oxidation at the Mn4CaO5 cluster in the oxygen-evolving complex (OEC). Under illumination, the OEC cycles through five intermediate S-states (S-0 to S-4)(1), in which S-1 is the dark-stable state and S-3 is the last semi-stable state before O-O bond formation and O-2 evolution(2,3). A detailed understanding of the O-O bond formation mechanism remains a challenge, and will require elucidation of both the structures of the OEC in the different S-states and the binding of the two substrate waters to the catalytic site(4-6). Here we report the use of femtosecond pulses from an X-ray free electron laser (XFEL) to obtain damage-free, room temperature structures of dark-adapted (S-1), two-flash illuminated (2F; S-3-enriched), and ammonia-bound two-flash illuminated (2F-NH3; S-3-enriched) PS II. Although the recent 1.95 angstrom resolution structure of PS II at cryogenic temperature using an XFEL7 provided a damage-free view of the S-1 state, measurements at room temperature are required to study the structural landscape of proteins under functional conditions(8,9), and also for in situ advancement of the S-states. To investigate the water-binding site(s), ammonia, a water analogue, has been used as a marker, as it binds to the Mn4CaO5 cluster in the S-2 and S-3 states(10). Since the ammonia-bound OEC is active, the ammonia-binding Mn site is not a substrate water site(10-13). This approach, together with a comparison of the native dark and 2F states, is used to discriminate between proposed O-O bond formation mechanisms.

  • 429. Young, Iris D.
    et al.
    Ibrahim, Mohamed
    Chatterjee, Ruchira
    Gul, Sheraz
    Fuller, Franklin D.
    Koroidov, Sergey
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brewster, Aaron S.
    Tran, Rosalie
    Alonso-Mori, Roberto
    Kroll, Thomas
    Michels-Clark, Tara
    Laksmono, Hartawan
    Sierra, Raymond G.
    Stan, Claudiu A.
    Hussein, Rana
    Zhang, Miao
    Douthit, Lacey
    Kubin, Markus
    de Lichtenberg, Casper
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vo Pham, Long
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nilsson, Håkan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cheah, Mun Hon
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Shevela, Dmitriy
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Saracini, Claudio
    Bean, Mackenzie A.
    Seuffert, Ina
    Sokaras, Dimosthenis
    Weng, Tsu-Chien
    Pastor, Ernest
    Weninger, Clemens
    Fransson, Thomas
    Lassalle, Louise
    Bräuer, Philipp
    Aller, Pierre
    Docker, Peter T.
    Andi, Babak
    Orville, Allen M.
    Glownia, James M.
    Nelson, Silke
    Sikorski, Marcin
    Zhu, Diling
    Hunter, Mark S.
    Lane, Thomas J.
    Aquila, Andy
    Koglin, Jason E.
    Robinson, Joseph
    Liang, Mengning
    Boutet, Sébastien
    Lyubimov, Artem Y.
    Uervirojnangkoorn, Monarin
    Moriarty, Nigel W.
    Liebschner, Dorothee
    Afonine, Pavel V.
    Waterman, David G.
    Evans, Gwyndaf
    Wernet, Philippe
    Dobbek, Holger
    Weis, William I.
    Brunger, Axel T.
    Zwart, Petrus H.
    Adams, Paul D.
    Zouni, Athina
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry, Molecular Biomimetics, Ångström Laboratory, Uppsala University.
    Bergmann, Uwe
    Sauter, Nicholas K.
    Kern, Jan
    Yachandra, Vittal K.
    Yano, Junko
    Structure of photosystem II and substrate binding at room temperature2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 540, no 7633, 453-457 p.Article in journal (Refereed)
    Abstract [en]

    Light-induced oxidation of water by photosystem II (PS II) in plants, algae and cyanobacteria has generated most of the dioxygen in the atmosphere. PS II, a membrane-bound multi-subunit pigment protein complex, couples the one-electron photochemistry at the reaction centre with the four-electron redox chemistry of water oxidation at the Mn4CaO5 cluster in the oxygen-evolving complex (OEC). Under illumination, the OEC cycles through five intermediate S-states (S0 to S4)1, in which S1 is the dark-stable state and S3 is the last semi-stable state before O–O bond formation and O2 evolution2,3. A detailed understanding of the O–O bond formation mechanism remains a challenge, and will require elucidation of both the structures of the OEC in the different S-states and the binding of the two substrate waters to the catalytic site4–6. Here we report the use of femtosecond pulses from an X-ray free electron laser (XFEL) to obtain damage-free, room temperature structures of dark-adapted (S1), two-flash illuminated (2F; S3-enriched), and ammonia-bound two-flash illuminated (2F-NH3; S3-enriched) PS II. Although the recent 1.95 Å resolution structure of PS II at cryogenic temperature using an XFEL7 provided a damage-free view of the S1 state, measurements at room temperature are required to study the structural landscape of proteins under functional conditions8,9, and also for in situ advancement of the S-states. To investigate the water-binding site(s), ammonia, a water analogue, has been used as a marker, as it binds to the Mn4CaO5 cluster in the S2 and S3 states10. Since the ammonia-bound OEC is active, the ammonia-binding Mn site is not a substrate water site10–13. This approach, together with a comparison of the native dark and 2F states, is used to discriminate between proposed O–O bond formation mechanisms.

  • 430. Yvon-Durocher, Gabriel
    et al.
    Allen, Andrew P.
    Bastviken, David
    Conrad, Ralf
    Gudasz, Cristian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    St-Pierre, Annick
    Thanh-Duc, Nguyen
    del Giorgio, Paul A.
    Methane fluxes show consistent temperature dependence across microbial to ecosystem scales2014In: Nature, ISSN 0028-0836, Vol. 507, no 7493, 488-491 p.Article in journal (Refereed)
    Abstract [en]

    Methane (CH4) is an important greenhouse gas because it has 25 times the global warming potential of carbon dioxide (CO2) by mass over a century(1). Recent calculations suggest that atmospheric CH4 emissions have been responsible for approximately 20% of Earth's warming since pre-industrial times(2). Understanding how CH4 emissions from ecosystems will respond to expected increases in global temperature is therefore fundamental to predicting whether the carbon cycle will mitigate or accelerate climate change. Methanogenesis is the terminal step in the remineralization of organic matter and is carried out by strictly anaerobic Archaea(3). Like most other forms of metabolism, methanogenesis is temperature-dependent(4,5). However, it is not yet known how this physiological response combines with other biotic processes (for example, methanotrophy(6), substrate supply(3,7), microbial community composition(8)) and abiotic processes (for example, water-table depth(9,10)) to determine the temperature dependence of ecosystem-level CH4 emissions. It is also not known whether CH4 emissions at the ecosystem level have a fundamentally different temperature dependence than other key fluxes in the carbon cycle, such as photosynthesis and respiration. Here we use meta-analyses to show that seasonal variations in CH4 emissions from a wide range of ecosystems exhibit an average temperature dependence similar to that of CH4 production derived from pure cultures of methanogens and anaerobic microbial communities. This average temperature dependence (0.96 electron volts (eV)), which corresponds to a 57-fold increase between 0 and 30 degrees C, is considerably higher than previously observed for respiration (approximately 0.65 eV)(11) and photosynthesis (approximately 0.3 eV)(12). As a result, we show that both the emission of CH4 and the ratio of CH4 to CO2 emissions increase markedly with seasonal increases in temperature. Our findings suggest that global warming may have a large impact on the relative contributions of CO2 and CH4 to total greenhouse gas emissions from aquatic ecosystems, terrestrial wetlands and rice paddies.

  • 431.
    Yvon-Durocher, Gabriel
    et al.
    University of Exeter, Penryn, UK.
    Allen, Andrew P.
    Macquarie University, Sydney, Australia .
    Bastviken, David
    Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
    Conrad, Ralf
    Max-Planck-Institute for Terrestrial Microbiology, Marburg, Germany .
    Gudasz, Cristian
    Umeå University, Sweden; Uppsala University, Sweden .
    St-Pierre, Annick
    University of Quebec, Canada .
    Thanh-Duc, Nguyen
    University of New Hampshire, Durham, USA.
    del Giorgio, Paul A.
    Université du Québec à Montréal, Canada.
    Methane fluxes show consistent temperature dependence across microbial to ecosystem scales2014In: Nature, ISSN 0028-0836, Vol. 507, no 7493, 488-491 p.Article in journal (Refereed)
    Abstract [en]

    Methane (CH4) is an important greenhouse gas because it has 25 times the global warming potential of carbon dioxide (CO2) by mass over a century(1). Recent calculations suggest that atmospheric CH4 emissions have been responsible for approximately 20% of Earths warming since pre-industrial times(2). Understanding how CH4 emissions from ecosystems will respond to expected increases in global temperature is therefore fundamental to predicting whether the carbon cycle will mitigate or accelerate climate change. Methanogenesis is the terminal step in the remineralization of organic matter and is carried out by strictly anaerobic Archaea(3). Like most other forms of metabolism, methanogenesis is temperature-dependent(4,5). However, it is not yet known how this physiological response combines with other biotic processes (for example, methanotrophy(6), substrate supply(3,7), microbial community composition(8)) and abiotic processes (for example, water-table depth(9,10)) to determine the temperature dependence of ecosystem-level CH4 emissions. It is also not known whether CH4 emissions at the ecosystem level have a fundamentally different temperature dependence than other key fluxes in the carbon cycle, such as photosynthesis and respiration. Here we use meta-analyses to show that seasonal variations in CH4 emissions from a wide range of ecosystems exhibit an average temperature dependence similar to that of CH4 production derived from pure cultures of methanogens and anaerobic microbial communities. This average temperature dependence (0.96 electron volts (eV)), which corresponds to a 57-fold increase between 0 and 30 degrees C, is considerably higher than previously observed for respiration (approximately 0.65 eV)(11) and photosynthesis (approximately 0.3 eV)(12). As a result, we show that both the emission of CH4 and the ratio of CH4 to CO2 emissions increase markedly with seasonal increases in temperature. Our findings suggest that global warming may have a large impact on the relative contributions of CO2 and CH4 to total greenhouse gas emissions from aquatic ecosystems, terrestrial wetlands and rice paddies.

  • 432. Yvon-Durocher, Gabriel
    et al.
    Allen, Andrew P.
    Bastviken, David
    Conrad, Ralf
    Gudasz, Cristian
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. ARCUM.
    St-Pierre, Annick
    Thanh-Duc, Nguyen
    del Giorgio, Paul A.
    Methane fluxes show consistent temperature dependence across microbial to ecosystem scales2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 507, no 7493, 488- p.Article in journal (Refereed)
    Abstract [en]

    Methane (CH4) is an important greenhouse gas because it has 25 times the global warming potential of carbon dioxide (CO2) by mass over a century(1). Recent calculations suggest that atmospheric CH4 emissions have been responsible for approximately 20% of Earth's warming since pre-industrial times(2). Understanding how CH4 emissions from ecosystems will respond to expected increases in global temperature is therefore fundamental to predicting whether the carbon cycle will mitigate or accelerate climate change. Methanogenesis is the terminal step in the remineralization of organic matter and is carried out by strictly anaerobic Archaea(3). Like most other forms of metabolism, methanogenesis is temperature-dependent(4,5). However, it is not yet known how this physiological response combines with other biotic processes (for example, methanotrophy(6), substrate supply(3,7), microbial community composition(8)) and abiotic processes (for example, water-table depth(9,10)) to determine the temperature dependence of ecosystem-level CH4 emissions. It is also not known whether CH4 emissions at the ecosystem level have a fundamentally different temperature dependence than other key fluxes in the carbon cycle, such as photosynthesis and respiration. Here we use meta-analyses to show that seasonal variations in CH4 emissions from a wide range of ecosystems exhibit an average temperature dependence similar to that of CH4 production derived from pure cultures of methanogens and anaerobic microbial communities. This average temperature dependence (0.96 electron volts (eV)), which corresponds to a 57-fold increase between 0 and 30 degrees C, is considerably higher than previously observed for respiration (approximately 0.65 eV)(11) and photosynthesis (approximately 0.3 eV)(12). As a result, we show that both the emission of CH4 and the ratio of CH4 to CO2 emissions increase markedly with seasonal increases in temperature. Our findings suggest that global warming may have a large impact on the relative contributions of CO2 and CH4 to total greenhouse gas emissions from aquatic ecosystems, terrestrial wetlands and rice paddies.

  • 433.
    Zaremba-Niedzwiedzka, Katarzyna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fernández Cáceres, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Saw, Jimmy Hser Wah
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bäckström, Disa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Juzokaite, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vancaester, Emmelien
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Ghent, Dept Plant Syst Biol, VIB, Technol Pk 927, B-9052 Ghent, Belgium.;Univ Ghent, Dept Plant Biotechnol & Bioinformat, Technol Pk 927, B-9052 Ghent, Belgium..
    Seitz, Kiley W.
    Univ Texas Austin, Inst Marine Sci, Dept Marine Sci, Port Aransas, TX 78373 USA..
    Anantharaman, Karthik
    Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA..
    Starnawski, Piotr
    Aarhus Univ, Sect Microbiol, DK-8000 Aarhus, Denmark.;Aarhus Univ, Ctr Geomicrobiol, Dept Biosci, DK-8000 Aarhus, Denmark..
    Kjeldsen, Kasper U.
    Aarhus Univ, Sect Microbiol, DK-8000 Aarhus, Denmark.;Aarhus Univ, Ctr Geomicrobiol, Dept Biosci, DK-8000 Aarhus, Denmark..
    Stott, Matthew B.
    Extremophile Res Grp, GNS Sci, Private Bag 2000, Taupo 3352, New Zealand..
    Nunoura, Takuro
    Japan Agcy Marine Earth Sci & Technol, Res & Dev Ctr Marine Biosci, Yokosuka, Kanagawa 2370061, Japan..
    Banfield, Jillian F.
    Univ Calif Berkeley, Dept Earth & Planetary Sci, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA..
    Schramm, Andreas
    Aarhus Univ, Sect Microbiol, DK-8000 Aarhus, Denmark.;Aarhus Univ, Ctr Geomicrobiol, Dept Biosci, DK-8000 Aarhus, Denmark..
    Baker, Brett J.
    Univ Texas Austin, Inst Marine Sci, Dept Marine Sci, Port Aransas, TX 78373 USA..
    Spang, Anja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Asgard archaea illuminate the origin of eukaryotic cellular complexity2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 541, no 7637, 353-+ p.Article in journal (Refereed)
    Abstract [en]

    The origin and cellular complexity of eukaryotes represent a major enigma in biology. Current data support scenarios in which an archaeal host cell and an alphaproteobacterial (mitochondrial) endosymbiont merged together, resulting in the first eukaryotic cell. The host cell is related to Lokiarchaeota, an archaeal phylum with many eukaryotic features. The emergence of the structural complexity that characterizes eukaryotic cells remains unclear. Here we describe the 'Asgard' superphylum, a group of uncultivated archaea that, as well as Lokiarchaeota, includes Thor-, Odin- and Heimdallarchaeota. Asgard archaea affiliate with eukaryotes in phylogenomic analyses, and their genomes are enriched for proteins formerly considered specific to eukaryotes. Notably, thorarchaeal genomes encode several homologues of eukaryotic membrane-trafficking machinery components, including Sec23/24 and TRAPP domains. Furthermore, we identify thorarchaeal proteins with similar features to eukaryotic coat proteins involved in vesicle biogenesis. Our results expand the known repertoire of 'eukaryote-specific' proteins in Archaea, indicating that the archaeal host cell already contained many key components that govern eukaryotic cellular complexity.

  • 434.
    Zensus, J. A.
    et al.
    Owens Valley Radio Observatory, California Institute of Technology, Pasadena, California, USA.
    Bååth, L.B.
    Onsala Space Observatory, Chalmers University of Technology, Gothenburg, Sweden & Owens Valley Radio Observatory, California Institute of Technology, Pasadena, California, USA.
    Cohen, M. H.
    Owens Valley Radio Observatory, California Institute of Technology, Pasadena, California, USA.
    Nicolson, G. D.
    Hartebeesthoek Radio Observatory, Johannesburg, South Africa.
    The inner radio jet of 3C2731988In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 334, no 6181, 410-412 p.Article in journal (Refereed)
    Abstract [en]

    Radio maps of 3C273 obtained with very long baseline interferometry (VLBI) have been limited by low dynamic range and poor north-south resolution resulting from the low declination (2°) of this quasar1. Dramatic improvement can now be achieved using larger arrays and antennas in the Southern Hemisphere2,3. A new VLBI map, made at 5 GHz with angular resolution and dynamic range unsurpassed at this frequency for this source, shows a narrow jet extending to a projected distance lproj∼125 h-;1 parsecs from the core. Superluminal motion exists out to at least lproj≈46h-1 parsecs. Successive superluminal components emerge from the core and appear to move on a fixed curved path with similar speeds of about 1 milliarcseconds per year. © 1988 Nature Publishing Group.

  • 435. Zhang, R.
    et al.
    Zhang, Y.
    Dong, Z. C.
    Jiang, S.
    Zhang, C.
    Chen, L. G.
    Zhang, L.
    Liao, Y.
    Aizpurua, J.
    Luo, Yi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Yang, J. L.
    Hou, J. G.
    Chemical mapping of a single molecule by plasmon-enhanced Raman scattering2013In: Nature, ISSN 0028-0836, Vol. 498, no 7452, 82-86 p.Article in journal (Refereed)
    Abstract [en]

    Visualizing individual molecules with chemical recognition is a longstanding target in catalysis, molecular nanotechnology and biotechnology. Molecular vibrations provide a valuable 'finger-print' for such identification. Vibrational spectroscopy based on tip-enhanced Raman scattering allows us to access the spectral signals of molecular species very efficiently via the strong localized plasmonic fields produced at the tip apex(1-11). However, the best spatial resolution of the tip-enhanced Raman scattering imaging is still limited to 3-15 nanometres(5,12-16), which is not adequate for resolving a single molecule chemically. Here we demonstrate Raman spectral imaging with spatial resolution below one nanometre, resolving the inner structure and surface configuration of a single molecule. This is achieved by spectrally matching the resonance of the nanocavity plasmon to the molecular vibronic transitions, particularly the downward transition responsible for the emission of Raman photons. This matching is made possible by the extremely precise tuning capability provided by scanning tunnelling microscopy. Experimental evidence suggests that the highly confined and broadband nature of the nanocavity plasmon field in the tunnelling gap is essential for ultrahigh-resolution imaging through the generation of an efficient double-resonance enhancement for both Raman excitation and Raman emission. Our technique not only allows for chemical imaging at the single-molecule level, but also offers a new way to study the optical processes and photochemistry of a single molecule.

  • 436. Zheng, Hou-Feng
    et al.
    Forgetta, Vincenzo
    Hsu, Yi-Hsiang
    Estrada, Karol
    Rosello-Diez, Alberto
    Leo, Paul J.
    Dahia, Chitra L.
    Park-Min, Kyung Hyun
    Tobias, Jonathan H.
    Kooperberg, Charles
    Kleinman, Aaron
    Styrkarsdottir, Unnur
    Liu, Ching-Ti
    Uggla, Charlotta
    Evans, Daniel S.
    Nielson, Carrie M.
    Walter, Klaudia
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    McCarthy, Shane
    Eriksson, Joel
    Kwan, Tony
    Jhamai, Mila
    Trajanoska, Katerina
    Memari, Yasin
    Min, Josine
    Huang, Jie
    Danecek, Petr
    Wilmot, Beth
    Li, Rui
    Chou, Wen-Chi
    Mokry, Lauren E.
    Moayyeri, Alireza
    Claussnitzer, Melina
    Cheng, Chia-Ho
    Cheung, Warren
    Medina-Gomez, Carolina
    Ge, Bing
    Chen, Shu-Huang
    Choi, Kwangbom
    Oei, Ling
    Fraser, James
    Kraaij, Robert
    Hibbs, Matthew A.
    Gregson, Celia L.
    Paquette, Denis
    Hofman, Albert
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Tranah, Gregory J.
    Marshall, Mhairi
    Gardiner, Brooke B.
    Cremin, Katie
    Auer, Paul
    Hsu, Li
    Ring, Sue
    Tung, Joyce Y.
    Thorleifsson, Gudmar
    Enneman, Anke W.
    van Schoor, Natasja M.
    de Groot, Lisette C. P. G. M.
    van der Velde, Nathalie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Kemp, John P.
    Christiansen, Claus
    Sayers, Adrian
    Zhou, Yanhua
    Calderari, Sophie
    van Rooij, Jeroen
    Carlson, Chris
    Peters, Ulrike
    Berlivet, Soizik
    Dostie, Josee
    Uitterlinden, Andre G.
    Williams, Stephen R.
    Farber, Charles
    Grinberg, Daniel
    LaCroix, Andrea Z.
    Haessler, Jeff
    Chasman, Daniel I.
    Giulianini, Franco
    Rose, Lynda M.
    Ridker, Paul M.
    Eisman, John A.
    Nguyen, Tuan V.
    Center, Jacqueline R.
    Nogues, Xavier
    Garcia-Giralt, Natalia
    Launer, Lenore L.
    Gudnason, Vilmunder
    Mellstrom, Dan
    Vandenput, Liesbeth
    Amin, Najaf
    van Duijn, Cornelia M.
    Karlsson, Magnus K.
    Ljunggren, Osten
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    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.
    Rousseau, Francois
    Giroux, Sylvie
    Bussiere, Johanne
    Arp, Pascal P.
    Koromani, Fjorda
    Prince, Richard L.
    Lewis, Joshua R.
    Langdahl, Bente L.
    Hermann, A. Pernille
    Jensen, Jens-Erik B.
    Kaptoge, Stephen
    Khaw, Kay-Tee
    Reeve, Jonathan
    Formosa, Melissa M.
    Xuereb-Anastasi, Angela
    Akesson, Kristina
    McGuigan, Fiona E.
    Garg, Gaurav
    Olmos, Jose M.
    Zarrabeitia, Maria T.
    Riancho, Jose A.
    Ralston, Stuart H.
    Alonso, Nerea
    Jiang, Xi
    Goltzman, David
    Pastinen, Tomi
    Grundberg, Elin
    Gauguier, Dominique
    Orwoll, Eric S.
    Karasik, David
    Davey-Smith, George
    Smith, Albert V.
    Siggeirsdottir, Kristin
    Harris, Tamara B.
    Zillikens, M. Carola
    van Meurs, Joyce B. J.
    Thorsteinsdottir, Unnur
    Maurano, Matthew T.
    Timpson, Nicholas J.
    Soranzo, Nicole
    Durbin, Richard
    Wilson, ScottG.
    Ntzani, Evangelia E.
    Brown, Matthew A.
    Stefansson, Kari
    Hinds, David A.
    Spector, Tim
    Cupples, L. Adrienne
    Ohlsson, Claes
    Greenwood, Celia M. T.
    Jackson, Rebecca D.
    Rowe, David W.
    Loomis, Cynthia A.
    Evans, David M.
    Ackert-Bicknell, Cheryl L.
    Joyner, Alexandra L.
    Duncan, Emma L.
    Kiel, Douglas P.
    Rivadeneira, Fernando
    Richards, J. Brent
    Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7571, 112-+ p.Article in journal (Refereed)
    Abstract [en]

    The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

  • 437.
    Zheng, Hou-Feng
    et al.
    McGill Univ, Dept Med, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Biostat, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada..
    Forgetta, Vincenzo
    McGill Univ, Dept Med, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Biostat, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada..
    Hsu, Yi-Hsiang
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA..
    Estrada, Karol
    Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA.;Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Rosello-Diez, Alberto
    Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA..
    Leo, Paul J.
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia..
    Dahia, Chitra L.
    Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA.;Hosp Special Surg, Tissue Engn Regenerat & Repair Program, New York, NY 10021 USA..
    Park-Min, Kyung Hyun
    Hosp Special Surg, Rheumatol Div, New York, NY 10021 USA..
    Tobias, Jonathan H.
    Univ Bristol, Sch Clin Sci, Bristol BS10 5NB, Avon, England.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Kleinman, Aaron
    23andMe, Res Dept, Mountain View, CA 94041 USA..
    Styrkarsdottir, Unnur
    deCODE Genet, Dept Populat Genom, IS-101 Reykjavik, Iceland..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Uggla, Charlotta
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden..
    Evans, Daniel S.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94158 USA..
    Nielson, Carrie M.
    Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Bone Mineral Unit, Portland, OR 97239 USA..
    Walter, Klaudia
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Pettersson-Kymmer, Ulrika
    Umea Univ, Dept Pharmacol, S-90187 Umea, Sweden.;Umea Univ, Dept Clin Neurosci, S-90187 Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, SE-90187 Umea, Sweden..
    McCarthy, Shane
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Eriksson, Joel
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden..
    Kwan, Tony
    McGill Univ, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada..
    Jhamai, Mila
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Trajanoska, Katerina
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Memari, Yasin
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Min, Josine
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Huang, Jie
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Danecek, Petr
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Wilmot, Beth
    Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Dept Med & Clin Informat, Portland, OR 97239 USA..
    Li, Rui
    McGill Univ, Dept Med, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Biostat, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada..
    Chou, Wen-Chi
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA..
    Mokry, Lauren E.
    McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada..
    Moayyeri, Alireza
    UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Claussnitzer, Melina
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA..
    Cheng, Chia-Ho
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA..
    Cheung, Warren
    McGill Univ, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada..
    Medina-Gomez, Carolina
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Ge, Bing
    McGill Univ, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada..
    Chen, Shu-Huang
    McGill Univ, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada..
    Choi, Kwangbom
    Univ Rochester, Ctr Musculoskeletal Res, Rochester, NY 14642 USA..
    Oei, Ling
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Fraser, James
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada..
    Kraaij, Robert
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Hibbs, Matthew A.
    Univ Rochester, Ctr Musculoskeletal Res, Rochester, NY 14642 USA.;Trinity Univ, Dept Comp Sci, San Antonio, TX 78212 USA..
    Gregson, Celia L.
    Univ Bristol, Musculoskeletal Res Unit, Bristol BS10 5NB, Avon, England..
    Paquette, Denis
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Wibom, Carl
    Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden..
    Tranah, Gregory J.
    Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Bone Mineral Unit, Portland, OR 97239 USA..
    Marshall, Mhairi
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia..
    Gardiner, Brooke B.
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia..
    Cremin, Katie
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia..
    Auer, Paul
    Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53726 USA..
    Hsu, Li
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Ring, Sue
    Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England..
    Tung, Joyce Y.
    23andMe, Res Dept, Mountain View, CA 94041 USA..
    Thorleifsson, Gudmar
    deCODE Genet, Dept Stat, IS-101 Reykjavik, Iceland..
    Enneman, Anke W.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    van Schoor, Natasja M.
    Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, NL-1007 MB Amsterdam, Netherlands..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Dept Human Nutr, NL-6700 EV Wageningen, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Acad Med Ctr, Sect Geriatr, Dept Internal Med, NL-1105 Amsterdam, Netherlands..
    Melin, Beatrice
    Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden..
    Kemp, John P.
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Christiansen, Claus
    Nord Biosci, DK-2730 Herlev, Denmark..
    Sayers, Adrian
    Univ Bristol, Musculoskeletal Res Unit, Bristol BS10 5NB, Avon, England..
    Zhou, Yanhua
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Calderari, Sophie
    INSERM, UMRS 1138, Cordeliers Res Ctr, F-75006 Paris, France.;Univ Paris 06, Inst Cardiometab & Nutr, F-75013 Paris, France..
    van Rooij, Jeroen
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Carlson, Chris
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Berlivet, Soizik
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada..
    Dostie, Josee
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Williams, Stephen R.
    Univ Virginia, Ctr Publ Hlth Genom, Dept Med, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Dept Cardiovasc Med, Charlottesville, VA 22908 USA..
    Farber, Charles
    Univ Virginia, Ctr Publ Hlth Genom, Dept Med, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Dept Cardiovasc Med, Charlottesville, VA 22908 USA..
    Grinberg, Daniel
    Univ Barcelona, Dept Genet, E-08028 Barcelona, Spain.;Ctr Biomed Network Res Rare Dis CIBERER, U720, Barcelona 28029, Spain.;Univ Barcelona, Inst Biomed, Dept Human Mol Genet, E-08028 Barcelona, Spain..
    LaCroix, Andrea Z.
    Univ Calif San Diego, Womens Hlth Ctr Excellence Family Med & Publ Hlth, San Diego, CA 92103 USA..
    Haessler, Jeff
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Chasman, Daniel I.
    Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Giulianini, Franco
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Ridker, Paul M.
    Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Eisman, John A.
    Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW 2010, Australia.;Univ Notre Dame Australia, Sch Med Sydney, Sydney, NSW 6959, Australia.;NSW Univ, St Vincents Hosp, Sydney, NSW 2010, Australia.;NSW Univ, Sch Clin, Sydney, NSW 2010, Australia..
    Nguyen, Tuan V.
    Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW 2010, Australia.;NSW Univ, St Vincents Hosp, Sydney, NSW 2010, Australia.;NSW Univ, Sch Clin, Sydney, NSW 2010, Australia..
    Center, Jacqueline R.
    Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW 2010, Australia.;NSW Univ, St Vincents Hosp, Sydney, NSW 2010, Australia.;NSW Univ, Sch Clin, Sydney, NSW 2010, Australia..
    Nogues, Xavier
    Univ Virginia, Ctr Publ Hlth Genom, Dept Med, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Dept Cardiovasc Med, Charlottesville, VA 22908 USA.;Inst Hosp Mar Invest Med, Musculoskeletal Res Grp, Barcelona 08003, Spain.;Univ Autonoma Barcelona, Hosp Mar, Dept Internal Med, E-08193 Barcelona, Spain..
    Garcia-Giralt, Natalia
    Inst Hosp Mar Invest Med, Musculoskeletal Res Grp, Barcelona 08003, Spain.;Inst Hlth Carlos III, Cooperat Res Network Aging & Fragil RETICEF, Madrid 28029, Spain..
    Launer, Lenore L.
    NIA, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA..
    Gudnason, Vilmunder
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Mellstrom, Dan
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden..
    Vandenput, Liesbeth
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands..
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands..
    Karlsson, Magnus K.
    Skane Univ Hosp, Dept Orthopaed, S-20502 Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Svensson, Olle
    Umea Univ, Dept Surg & Perioperat Sci, S-90185 Umea, Sweden..
    Hallmans, Goran
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90187 Umea, Sweden..
    Rousseau, Francois
    Univ Laval, Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ G1V 0A6, Canada.;CHU Quebec, Ctr Rech, Axe Sante Populat & Prat Optimales Sante, Quebec City, PQ G1V 4G2, Canada..
    Giroux, Sylvie
    CHU Quebec, Ctr Rech, Axe Sante Populat & Prat Optimales Sante, Quebec City, PQ G1V 4G2, Canada..
    Bussiere, Johanne
    CHU Quebec, Ctr Rech, Axe Sante Populat & Prat Optimales Sante, Quebec City, PQ G1V 4G2, Canada..
    Arp, Pascal P.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Koromani, Fjorda
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Prince, Richard L.
    Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia.;Univ Western Australia, Dept Med, Perth, WA 6009, Australia..
    Lewis, Joshua R.
    Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia.;Univ Western Australia, Dept Med, Perth, WA 6009, Australia..
    Langdahl, Bente L.
    Aarhus Univ Hosp, Dept Endocrinol & Internal Med, DK-8000 Aarhus C, Denmark..
    Hermann, A. Pernille
    Odense Univ Hosp, Dept Endocrinol, DK-5000 Odense C, Denmark..
    Jensen, Jens-Erik B.
    Hvidovre Univ Hosp, Dept Endocrinol, DK-2650 Hvidovre, Denmark..
    Kaptoge, Stephen
    UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England..
    Khaw, Kay-Tee
    Univ Cambridge, Clin Gerontol Unit, Cambridge CB2 2QQ, England..
    Reeve, Jonathan
    Univ Cambridge, Med & Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Univ Oxford, Botnar Res Ctr, Inst Musculoskeletal Sci, Oxford OX3 7LD, England..
    Formosa, Melissa M.
    Univ Malta, Dept Appl Biomed Sci, Fac Hlth Sci, MSD-2080 Msida, Malta..
    Xuereb-Anastasi, Angela
    Univ Malta, Dept Appl Biomed Sci, Fac Hlth Sci, MSD-2080 Msida, Malta..
    Akesson, Kristina
    Skane Univ Hosp, Dept Orthopaed, S-20502 Malmo, Sweden.;Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, S-20502 Lund, Sweden..
    McGuigan, Fiona E.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, S-20502 Lund, Sweden..
    Garg, Gaurav
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, S-20502 Lund, Sweden..
    Olmos, Jose M.
    Univ Cantabria, Dept Med & Psychiat, Santander 39011, Spain.;Hosp UM Valdecilla IDIVAL, Dept Internal Med, Santander 39008, Spain..
    Zarrabeitia, Maria T.
    Univ Cantabria, Dept Legal Med, Santander 39011, Spain..
    Riancho, Jose A.
    Univ Cantabria, Dept Med & Psychiat, Santander 39011, Spain.;Hosp UM Valdecilla IDIVAL, Dept Internal Med, Santander 39008, Spain..
    Ralston, Stuart H.
    Univ Edinburgh, Inst Genet & Mol Med, Western Gen Hosp, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Alonso, Nerea
    Univ Edinburgh, Inst Genet & Mol Med, Western Gen Hosp, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Jiang, Xi
    Univ Connecticut, Ctr Hlth, Coll Dent Med, Dept Reconstruct Sci, Farmington, CT 06030 USA..
    Goltzman, David
    McGill Univ, Dept Med & Physiol, Montreal, PQ H4A 3J1, Canada..
    Pastinen, Tomi
    McGill Univ, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada..
    Grundberg, Elin
    McGill Univ, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada..
    Gauguier, Dominique
    INSERM, UMRS 1138, Cordeliers Res Ctr, F-75006 Paris, France.;Univ Paris 06, Inst Cardiometab & Nutr, F-75013 Paris, France..
    Orwoll, Eric S.
    Oregon Hlth & Sci Univ, Bone Mineral Unit, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA..
    Karasik, David
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Bar Ilan Univ, Fac Med Galilee, IL-13010 Safed, Israel..
    Davey-Smith, George
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Smith, Albert V.
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Siggeirsdottir, Kristin
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland..
    Harris, Tamara B.
    NIA, Lab Epidemiol, NIH, Bethesda, MD 20892 USA..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    van Meurs, Joyce B. J.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Thorsteinsdottir, Unnur
    deCODE Genet, Dept Populat Genom, IS-101 Reykjavik, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Maurano, Matthew T.
    Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA..
    Timpson, Nicholas J.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Soranzo, Nicole
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Durbin, Richard
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Wilson, ScottG.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.;Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Med & Pharmacol, Crawley 6009, Australia..
    Ntzani, Evangelia E.
    Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece.;Brown Univ, Sch Publ Hlth, Dept Hlth Serv Policy & Practice, Providence, RI 02903 USA..
    Brown, Matthew A.
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia..
    Stefansson, Kari
    Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.;deCODE Genet, IS-101 Reykjavik, Iceland..
    Hinds, David A.
    23andMe, Res Dept, Mountain View, CA 94041 USA..
    Spector, Tim
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA..
    Ohlsson, Claes
    Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden..
    Greenwood, Celia M. T.
    McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Gerald Bronfman Ctr, Dept Oncol, Montreal, PQ H2W 1S6, Canada..
    Jackson, Rebecca D.
    Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA..
    Rowe, David W.
    Univ Connecticut, Ctr Hlth, Coll Dent Med, Dept Reconstruct Sci, Farmington, CT 06030 USA..
    Loomis, Cynthia A.
    NYU, Sch Med, Ronald O Perelman Dept Dermatol, New York, NY 10016 USA.;NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA..
    Evans, David M.
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Ackert-Bicknell, Cheryl L.
    Univ Rochester, Ctr Musculoskeletal Res, Rochester, NY 14642 USA..
    Joyner, Alexandra L.
    Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA..
    Duncan, Emma L.
    Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.;Royal Brisbane & Womens Hosp, Dept Diabet & Endocrinol, Brisbane, Qld 4029, Australia..
    Kiel, Douglas P.
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA..
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;NCHA, NGI, NL-2300 RC Leiden, Netherlands..
    Richards, J. Brent
    McGill Univ, Dept Med, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Biostat, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7571, 112-+ p.Article in journal (Refereed)
    Abstract [en]

    The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

  • 438. Zhu, M.
    et al.
    Ahlberg, Per E.
    Natural History Museum of London .
    Zhao, W.
    Jia , L.
    First Devonian tetrapod from Asia2002In: Nature, ISSN 0028-0836, Vol. 420, 760-761 p.Article in journal (Refereed)
  • 439. Zhu, M.
    et al.
    Yu, X.
    Ahlberg, Per E.
    Natural History Museum of London .
    A primitive sarcopterygian fish with an eyestalk.2001In: Nature, ISSN 0028-0836, Vol. 410, 81-84 p.Article in journal (Refereed)
  • 440. Zhu, Min
    et al.
    Ahlberg, Per E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Evolutionary Organism Biology.
    The origin of the internal nostril of tetrapods2004In: Nature, ISSN 0028-0836, Vol. 432, no 7013, 94-97 p.Article in journal (Refereed)
  • 441. Zhu, Min
    et al.
    Yu, Xiaobo
    Ahlberg, Per Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Choo, Brian
    Lu, Jing
    Qiao, Tuo
    Qu, Qingming
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Zhao, Wenjin
    Jia, Liantao
    Blom, Henning
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Zhu, You'an
    A Silurian placoderm with osteichthyan-like marginal jaw bones2013In: Nature, ISSN 0028-0836, Vol. 502, no 7470, 188-+ p.Article in journal (Refereed)
    Abstract [en]

    The gnathostome (jawed vertebrate) crown group comprises two extant clades with contrasting character complements. Notably, Chondrichthyes (cartilaginous fish) lack the large dermal bones that characterize Osteichthyes (bony fish and tetrapods). The polarities of these differences, and the morphology of the last common ancestor of crown gnathostomes, are the subject of continuing debate. Here we describe a three-dimensionally preserved 419-million-year-old placoderm fish from the Silurian of China that represents the first stem gnathostome with dermal marginal jaw bones (premaxilla, maxilla and dentary), features previously restricted to Osteichthyes. A phylogenetic analysis places the new form near the top of the gnathostome stem group but does not fully resolve its relationships to other placoderms. The analysis also assigns all acanthodians to the chondrichthyan stem group. These results suggest that the last common ancestor of Chondrichthyes and Osteichthyes had a macromeric dermal skeleton, and provide a new framework for studying crown gnathostome divergence.

  • 442. Zisoulis, Dimitrios G.
    et al.
    Kai, Zoya S.
    Chang, Roger K.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Pasquinelli, Amy E.
    Autoregulation of microRNA biogenesis by let-7 and Argonaute2012In: Nature, ISSN 0028-0836, Vol. 486, no 7404, 541-U140 p.Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) comprise a large family of small RNA molecules that post-transcriptionally regulate gene expression in many biological pathways(1). Most miRNAs are derived from long primary transcripts that undergo processing by Drosha to produce similar to 65-nucleotide precursors that are then cleaved by Dicer, resulting in the mature 22-nucleotide forms(2,3). Serving as guides in Argonaute protein complexes, mature miRNAs use imperfect base pairing to recognize sequences in messenger RNA transcripts, leading to translational repression and destabilization of the target messenger RNAs4,5. Here we show that the miRNA complex also targets and regulates non-coding RNAs that serve as substrates for the miRNA-processing pathway. We found that the Argonaute protein in Caenorhabditis elegans, ALG-1, binds to a specific site at the 3' end of let-7 miRNA primary transcripts and promotes downstream processing events. This interaction is mediated by mature let-7 miRNA through a conserved complementary site in its own primary transcript, thus creating a positive-feedback loop. We further show that ALG-1 associates with let-7 primary transcripts in nuclear fractions. Argonaute also binds let-7 primary transcripts in human cells, demonstrating that the miRNA pathway targets non-coding RNAs in addition to protein-coding messenger RNAs across species. Moreover, our studies in C. elegans reveal a novel role for Argonaute in promoting biogenesis of a targeted transcript, expanding the functions of the miRNA pathway in gene regulation. This discovery of autoregulation of let-7 biogenesis establishes a new mechanism for controlling miRNA expression.

  • 443.
    Zody, Michael
    et al.
    Broad Institute.
    Garber, Manuel
    Broad Institute.
    Adams, David
    The Wellcome Trust Sanger Institute.
    Sharpe, Ted
    Broad Institute.
    Harrow, Jennifer
    The Wellcome Trust Sanger Institute.
    Lupski, James
    Baylor College of Medicine, Department of Molecular and Human Genetics.
    Nicholson, Christine
    The Wellcome Trust Sanger Institute.
    Searle, Steven
    The Wellcome Trust Sanger Institute.
    Wilming, Laurens
    The Wellcome Trust Sanger Institute.
    Young, Sarah
    Broad Institute.
    Abouelleil, Amr
    Broad Institute.
    Allen, Nicole
    Broad Institute.
    Bi, Weimin
    Baylor College of Medicine, Department of Molecular and Human Genetics.
    Bloom, Toby
    Broad Institute.
    Borowsky, Mark
    Broad Institute.
    Bugalter, Boris
    Broad Institute.
    Butler, Jonathan
    Broad Institute.
    Chang, Jean
    Broad Institute.
    Chen, Chao-Kung
    The Wellcome Trust Sanger Institute.
    Cook, April
    Broad Institute.
    Corum, Benjamin
    Broad Institute.
    Cuomo, Christina
    Broad Institute.
    de Jong, Pieter
    Children's Hospital Oakland Research Institute.
    DeCaprio, David
    Broad Institute.
    Dewar, Ken
    Broad Institute.
    FitzGerald, Michael
    Broad Institute.
    Gilbert, James
    The Wellcome Trust Sanger Institute.
    Gibson, Richard
    The Wellcome Trust Sanger Institute.
    Gnerre, Sante
    Broad Institute.
    Goldstein, Steven
    University of Wisconsin-Madison, Laboratory for Molecular and Computational Genomics.
    Grafham, Darren
    The Wellcome Trust Sanger Institute.
    Grocock, Russell
    The Wellcome Trust Sanger Institute.
    Hafez, Nabil
    Broad Institute.
    Hagopian, Daniel
    Broad Institute.
    Hart, Elizabeth
    The Wellcome Trust Sanger Institute.
    Hosage Norman, Catherine
    Broad Institute.
    Humphray, Sean
    The Wellcome Trust Sanger Institute.
    Jaffe, David
    Broad Institute.
    Jones, Matt
    The Wellcome Trust Sanger Institute.
    Kamal, Michael
    Broad Institute.
    Khodiyan, Varsha
    University College London, Department of Biology.
    LaButti, Kurt
    Broad Institute.
    Laird, Gavin
    The Wellcome Trust Sanger Institute.
    Lehoczky, Jessica
    Broad Institute.
    Liu, Xiaohong
    Broad Institute.
    Lokyitsang, Tashi
    Broad Institute.
    Loveland, Jane
    The Wellcome Trust Sanger Institute.
    Lui, Annie
    Broad Institute.
    Macdonald, Pendexter
    Broad Institute.
    Major, John
    Broad Institute.
    Matthews, Lucy
    The Wellcome Trust Sanger Institute.
    Mauceli, Evan
    Broad Institute.
    McCarroll, Steven
    Broad Institute.
    Mihalev, Atanas
    Broad Institute.
    Mudge, Jonathan
    The Wellcome Trust Sanger Institute.
    Nguyen, Cindy
    Broad Institute.
    Nicol, Robert
    Broad Institute.
    O'Leary, Sinéad
    Broad Institute.
    Osoegawa, Kazutoyo
    Children's Hospital Oakland Research Institute.
    Schwartz, David
    University of Wisconsin-Madison, Laboratory for Molecular and Computational Genomics.
    Shaw-Smith, Charles
    The Wellcome Trust Sanger Institute.
    Stankiewicz, Pawel
    Baylor College of Medicine, Department of Molecular and Human Genetics.
    Steward, Charles
    The Wellcome Trust Sanger Institute.
    Swarbreck, David
    The Wellcome Trust Sanger Institute.
    Venkataraman, Vijay
    Broad Institute.
    Whittaker, Charles
    Broad Institute.
    Yang, Xiaoping
    Broad Institute.
    Zimmer, Andrew
    Broad Institute.
    Bradley, Allan
    The Wellcome Trust Sanger Institute.
    Hubbard, Tim
    The Wellcome Trust Sanger Institute.
    Birren, Bruce
    Broad Institute.
    Rogers, Jane
    The Wellcome Trust Sanger Institute.
    Lander, Eric
    Broad Institute.
    Nusbaum, Chad
    Broad Institute.
    DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage2006In: Nature, ISSN 0028-0836, Vol. 440, no 7087, 1045-1049 p.Article in journal (Refereed)
    Abstract [en]

    Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

  • 444.
    Zody, Michael
    et al.
    Broad Institute.
    Garber, Manuel
    Broad Institute.
    Sharpe, Ted
    Broad Institute.
    Young, Sarah
    Broad Institute.
    Rowen, Lee
    Institute for Systems Biology.
    O'Neill, Keith
    Broad Institute.
    Whittaker, Charles
    Broad Institute.
    Kamal, Michael
    Broad Institute.
    Chang, Jean
    Broad Institute.
    Cuomo, Christina
    Broad Institute.
    Dewar, Ken
    Broad Institute.
    FitzGerald, Michael
    Broad Institute.
    Kodira, Chinnappa
    Broad Institute.
    Madan, Anup
    Institute for Systems Biology.
    Qin, Shizhen
    Institute for Systems Biology.
    Yang, Xiaoping
    Broad Institute.
    Abbasi, Nissa
    Institute for Systems Biology.
    Abouelleil, Amr
    Broad Institute.
    Arachchi, Harindra
    Broad Institute.
    Baradarani, Lida
    Institute for Systems Biology.
    Birditt, Brian
    Institute for Systems Biology.
    Bloom, Scott
    Institute for Systems Biology.
    Bloom, Toby
    Broad Institute.
    Borowsky, Mark
    Broad Institute.
    Burke, Jeremy
    Institute for Systems Biology.
    Butler, Jonathan
    Broad Institute.
    Cook, April
    Broad Institute.
    DeArellano, Kurt
    Broad Institute.
    DeCaprio, David
    Broad Institute.
    Dorris, Lester
    Broad Institute.
    Dors, Monica
    Institute for Systems Biology.
    Eichler, Evan
    University of Washington, Department of Genome Sciences.
    Engels, Reinhard
    Broad Institute.
    Fahey, Jessica
    Institute for Systems Biology.
    Fleetwood, Peter
    Institute for Systems Biology.
    Friedman, Cynthia
    Fred Hutchinson Cancer Research Center, Division of Human Biology.
    Gearin, Gary
    Broad Institute.
    Hall, Jennifer
    Broad Institute.
    Hensley, Grace
    Institute for Systems Biology.
    Johnson, Ericka
    Institute for Systems Biology.
    Jones, Charlien
    Broad Institute.
    Kamat, Asha
    Broad Institute.
    Kaur, Amardeep
    Institute for Systems Biology.
    Locke, Devin
    University of Washington, Department of Genome Sciences.
    Madan, Anuradha
    Institute for Systems Biology.
    Munson, Glen
    Broad Institute.
    Jaffe, David
    Broad Institute.
    Lui, Annie
    Broad Institute.
    Macdonald, Pendexter
    Broad Institute.
    Mauceli, Evan
    Broad Institute.
    Naylor, Jerome
    Broad Institute.
    Nesbitt, Ryan
    Institute for Systems Biology.
    Nicol, Robert
    Broad Institute.
    O'Leary, Sinéad
    Broad Institute.
    Ratcliffe, Amber
    Institute for Systems Biology.
    Rounsley, Steven
    Broad Institute.
    She, Xinwei
    University of Washington, Department of Genome Sciences.
    Sneddon, Katherine
    University College London, Department of Biology.
    Stewart, Sandra
    Institute for Systems Biology.
    Sougnez, Carrie
    Broad Institute.
    Stone, Sabrina
    Broad Institute.
    Topham, Kerri
    Broad Institute.
    Vincent, Dascena
    Institute for Systems Biology.
    Wang, Shunguang
    Broad Institute.
    Zimmer, Andrew
    Broad Institute.
    Birren, Bruce
    Broad Institute.
    Hood, Leroy
    Institute for Systems Biology.
    Lander, ic
    Broad Institute.
    Nusbaum, Chad
    Broad Institute.
    Analysis of the DNA sequence and duplication history of human chromosome 152006In: Nature, ISSN 0028-0836, Vol. 440, no 7084, 671-675 p.Article in journal (Refereed)
    Abstract [en]

    Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplication in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.

  • 445. Zopf, David
    et al.
    Ohlson, Sten
    HyClone Laboratories, Inc., 1725 South State Highway 89-91, Logan, Utah 84321, USA.
    Weak-affinity Chromatography1990In: Nature, ISSN 0028-0836, Vol. 346, 87-88 p.Article in journal (Refereed)
    Abstract [en]

    Weak-affinity chromatography is a new method using readily reversible biospecific recognition as the basis for chromatographic separations. 

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