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  • 1
    Publication Date: 2014-03-29
    Description: Human alterations to nutrient cycles and herbivore communities are affecting global biodiversity dramatically. Ecological theory predicts these changes should be strongly counteractive: nutrient addition drives plant species loss through intensified competition for light, whereas herbivores prevent competitive exclusion by increasing ground-level light, particularly in productive systems. Here we use experimental data spanning a globally relevant range of conditions to test the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory. This experiment, replicated in 40 grasslands on 6 continents, demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate. Nutrient addition consistently reduced local diversity through light limitation, and herbivory rescued diversity at sites where it alleviated light limitation. Thus, species loss from anthropogenic eutrophication can be ameliorated in grasslands where herbivory increases ground-level light.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Borer, Elizabeth T -- Seabloom, Eric W -- Gruner, Daniel S -- Harpole, W Stanley -- Hillebrand, Helmut -- Lind, Eric M -- Adler, Peter B -- Alberti, Juan -- Anderson, T Michael -- Bakker, Jonathan D -- Biederman, Lori -- Blumenthal, Dana -- Brown, Cynthia S -- Brudvig, Lars A -- Buckley, Yvonne M -- Cadotte, Marc -- Chu, Chengjin -- Cleland, Elsa E -- Crawley, Michael J -- Daleo, Pedro -- Damschen, Ellen I -- Davies, Kendi F -- DeCrappeo, Nicole M -- Du, Guozhen -- Firn, Jennifer -- Hautier, Yann -- Heckman, Robert W -- Hector, Andy -- HilleRisLambers, Janneke -- Iribarne, Oscar -- Klein, Julia A -- Knops, Johannes M H -- La Pierre, Kimberly J -- Leakey, Andrew D B -- Li, Wei -- MacDougall, Andrew S -- McCulley, Rebecca L -- Melbourne, Brett A -- Mitchell, Charles E -- Moore, Joslin L -- Mortensen, Brent -- O'Halloran, Lydia R -- Orrock, John L -- Pascual, Jesus -- Prober, Suzanne M -- Pyke, David A -- Risch, Anita C -- Schuetz, Martin -- Smith, Melinda D -- Stevens, Carly J -- Sullivan, Lauren L -- Williams, Ryan J -- Wragg, Peter D -- Wright, Justin P -- Yang, Louie H -- England -- Nature. 2014 Apr 24;508(7497):517-20. doi: 10.1038/nature13144. Epub 2014 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology, Evolution, and Behavior, University of Minnesota, St Paul, Minnesota 55108, USA. ; Department of Entomology, University of Maryland, College Park, Maryland 20742, USA. ; Department of Ecology, Evolution, and Organismal Biology, Iowa State University, Ames, Iowa 50011, USA. ; Institute for Chemistry and Biology of the Marine Environment, Carl-von- Ossietzky University, 26382 Wilhelmshaven, Oldenburg, Germany. ; Department of Wildland Resources and the Ecology Center, Utah State University, Logan, Utah 84322, USA. ; Instituto de Investigaciones Marinas y Costeras (IIMyC), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Mar del Plata 7600 , Argentina. ; Department of Biology, Wake Forest University, Winston-Salem, North Carolina 27109, USA. ; School of Environmental and Forest Sciences, University of Washington, Seattle, Washington 98195, USA. ; Agricultural Research Service (ARS), United States Department of Agriculture, Fort Collins, Colorado 80526, USA. ; Deptartment of Forest, Rangeland and Watershed Stewardship, Colorado State University, Fort Collins, Colorado 80523, USA. ; Department of Plant Biology, Michigan State University, East Lansing, Michigan 48824, USA. ; 1] ARC Centre of Excellence for Environmental Decisions, School of Biological Sciences, The University of Queensland, Queensland 4072, Australia [2] School of Natural Sciences, Trinity College Dublin, Dublin 2, Ireland. ; Department of Ecology and Evolutionary Biology, University of Toronto Scarborough, Ontario M1C 1A4, Canada. ; State Key Laboratory of Grassland and Agro-Ecosystems, Research Station of Alpine Meadow and Wetland Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou, 730000 Gansu, China. ; Division of Biological Sciences, University of California, San Diego, California 92093, USA. ; Department of Biology, Imperial College at Silwood Park, Ascot, Berkshire SL5 7PY, UK. ; Department of Zoology, University of Wisconsin, Madison, Wisconsin 53706, USA. ; Department of Ecology and Evolutionary Biology, University of Colorado, Boulder Colorado 80309, USA. ; US Geological Survey, Forest and Rangeland Ecosystem Science Center, Corvallis, Oregon 97331, USA. ; Queensland University of Technology, Biogeosciences, Brisbane, Queensland 4001, Australia. ; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, UK. ; School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68588, USA. ; Berkeley Initiative for Global Change Biology, University of California, Berkeley 94704, USA. ; Department of Plant Biology, University of Illinois at Urbana-Champaign, llinois 61820, USA. ; Department of Integrative Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada. ; Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky 40546, USA. ; Australian Research Center for Urban Ecology, c/o School of Botany, University of Melbourne, Victoria 3010, Australia, and School of Biological Sciences, Monash University, Victoria 3800, Australia. ; Department of Zoology, Oregon State University, Corvallis, Oregon 97331, USA. ; CSIRO Ecosystem Sciences, Wembley, West Australia 6913, Australia. ; Swiss Federal Institute for Forest, Snow and Landscape Research, Birmensdorf 8903, Switzerland. ; Lancaster Environment Center, Lancaster University, Lancaster LA1 4YQ, UK. ; Department of Biology, Duke University, Durham, North Carolina 27708, USA. ; Department of Entomology, University of California, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670649" target="_blank"〉PubMed〈/a〉
    Keywords: *Biodiversity ; Climate ; Eutrophication/drug effects/*radiation effects ; Geography ; Herbivory/*physiology ; Human Activities ; Internationality ; *Light ; Nitrogen/metabolism/pharmacology ; Plants/drug effects/*metabolism/*radiation effects ; *Poaceae/drug effects/physiology/radiation effects ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-07-22
    Description: The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126858/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whitney, James B -- Hill, Alison L -- Sanisetty, Srisowmya -- Penaloza-MacMaster, Pablo -- Liu, Jinyan -- Shetty, Mayuri -- Parenteau, Lily -- Cabral, Crystal -- Shields, Jennifer -- Blackmore, Stephen -- Smith, Jeffrey Y -- Brinkman, Amanda L -- Peter, Lauren E -- Mathew, Sheeba I -- Smith, Kaitlin M -- Borducchi, Erica N -- Rosenbloom, Daniel I S -- Lewis, Mark G -- Hattersley, Jillian -- Li, Bei -- Hesselgesser, Joseph -- Geleziunas, Romas -- Robb, Merlin L -- Kim, Jerome H -- Michael, Nelson L -- Barouch, Dan H -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R56 AI091514/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):74-7. doi: 10.1038/nature13594. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA. ; Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Bioqual, Rockville, Maryland 20852, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25042999" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Retroviral Agents/administration & dosage/pharmacology/therapeutic use ; Carrier State/drug therapy/virology ; DNA, Viral/analysis/biosynthesis/blood ; Disease Models, Animal ; Female ; Kinetics ; Macaca mulatta/immunology/*virology ; Male ; Proviruses/genetics ; RNA, Viral/blood ; Rectum/virology ; Simian Acquired Immunodeficiency Syndrome/drug therapy/immunology/*virology ; Simian Immunodeficiency Virus/drug effects/*growth & ; development/immunology/physiology ; Time Factors ; Treatment Failure ; *Viral Load/drug effects ; Viremia/drug therapy/*virology ; Virus Replication/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-02-05
    Description: X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000 K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038304/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038304/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seibert, M Marvin -- Ekeberg, Tomas -- Maia, Filipe R N C -- Svenda, Martin -- Andreasson, Jakob -- Jonsson, Olof -- Odic, Dusko -- Iwan, Bianca -- Rocker, Andrea -- Westphal, Daniel -- Hantke, Max -- DePonte, Daniel P -- Barty, Anton -- Schulz, Joachim -- Gumprecht, Lars -- Coppola, Nicola -- Aquila, Andrew -- Liang, Mengning -- White, Thomas A -- Martin, Andrew -- Caleman, Carl -- Stern, Stephan -- Abergel, Chantal -- Seltzer, Virginie -- Claverie, Jean-Michel -- Bostedt, Christoph -- Bozek, John D -- Boutet, Sebastien -- Miahnahri, A Alan -- Messerschmidt, Marc -- Krzywinski, Jacek -- Williams, Garth -- Hodgson, Keith O -- Bogan, Michael J -- Hampton, Christina Y -- Sierra, Raymond G -- Starodub, Dmitri -- Andersson, Inger -- Bajt, Sasa -- Barthelmess, Miriam -- Spence, John C H -- Fromme, Petra -- Weierstall, Uwe -- Kirian, Richard -- Hunter, Mark -- Doak, R Bruce -- Marchesini, Stefano -- Hau-Riege, Stefan P -- Frank, Matthias -- Shoeman, Robert L -- Lomb, Lukas -- Epp, Sascha W -- Hartmann, Robert -- Rolles, Daniel -- Rudenko, Artem -- Schmidt, Carlo -- Foucar, Lutz -- Kimmel, Nils -- Holl, Peter -- Rudek, Benedikt -- Erk, Benjamin -- Homke, Andre -- Reich, Christian -- Pietschner, Daniel -- Weidenspointner, Georg -- Struder, Lothar -- Hauser, Gunter -- Gorke, Hubert -- Ullrich, Joachim -- Schlichting, Ilme -- Herrmann, Sven -- Schaller, Gerhard -- Schopper, Florian -- Soltau, Heike -- Kuhnel, Kai-Uwe -- Andritschke, Robert -- Schroter, Claus-Dieter -- Krasniqi, Faton -- Bott, Mario -- Schorb, Sebastian -- Rupp, Daniela -- Adolph, Marcus -- Gorkhover, Tais -- Hirsemann, Helmut -- Potdevin, Guillaume -- Graafsma, Heinz -- Nilsson, Bjorn -- Chapman, Henry N -- Hajdu, Janos -- R01 GM095583/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Feb 3;470(7332):78-81. doi: 10.1038/nature09748.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biophysics, Department of Cell and Molecular Biology, Uppsala University, Husargatan 3, SE-751 24 Uppsala, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293374" target="_blank"〉PubMed〈/a〉
    Keywords: Electrons ; Hot Temperature ; Lasers ; Mimiviridae/*chemistry ; Photons ; Time Factors ; X-Ray Diffraction/*instrumentation/*methods ; X-Rays
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  • 4
    Publication Date: 2011-02-05
    Description: X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals ( approximately 200 nm to 2 mum in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429598/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429598/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chapman, Henry N -- Fromme, Petra -- Barty, Anton -- White, Thomas A -- Kirian, Richard A -- Aquila, Andrew -- Hunter, Mark S -- Schulz, Joachim -- DePonte, Daniel P -- Weierstall, Uwe -- Doak, R Bruce -- Maia, Filipe R N C -- Martin, Andrew V -- Schlichting, Ilme -- Lomb, Lukas -- Coppola, Nicola -- Shoeman, Robert L -- Epp, Sascha W -- Hartmann, Robert -- Rolles, Daniel -- Rudenko, Artem -- Foucar, Lutz -- Kimmel, Nils -- Weidenspointner, Georg -- Holl, Peter -- Liang, Mengning -- Barthelmess, Miriam -- Caleman, Carl -- Boutet, Sebastien -- Bogan, Michael J -- Krzywinski, Jacek -- Bostedt, Christoph -- Bajt, Sasa -- Gumprecht, Lars -- Rudek, Benedikt -- Erk, Benjamin -- Schmidt, Carlo -- Homke, Andre -- Reich, Christian -- Pietschner, Daniel -- Struder, Lothar -- Hauser, Gunter -- Gorke, Hubert -- Ullrich, Joachim -- Herrmann, Sven -- Schaller, Gerhard -- Schopper, Florian -- Soltau, Heike -- Kuhnel, Kai-Uwe -- Messerschmidt, Marc -- Bozek, John D -- Hau-Riege, Stefan P -- Frank, Matthias -- Hampton, Christina Y -- Sierra, Raymond G -- Starodub, Dmitri -- Williams, Garth J -- Hajdu, Janos -- Timneanu, Nicusor -- Seibert, M Marvin -- Andreasson, Jakob -- Rocker, Andrea -- Jonsson, Olof -- Svenda, Martin -- Stern, Stephan -- Nass, Karol -- Andritschke, Robert -- Schroter, Claus-Dieter -- Krasniqi, Faton -- Bott, Mario -- Schmidt, Kevin E -- Wang, Xiaoyu -- Grotjohann, Ingo -- Holton, James M -- Barends, Thomas R M -- Neutze, Richard -- Marchesini, Stefano -- Fromme, Raimund -- Schorb, Sebastian -- Rupp, Daniela -- Adolph, Marcus -- Gorkhover, Tais -- Andersson, Inger -- Hirsemann, Helmut -- Potdevin, Guillaume -- Graafsma, Heinz -- Nilsson, Bjorn -- Spence, John C H -- 1R01GM095583-01/GM/NIGMS NIH HHS/ -- 1U54GM094625-01/GM/NIGMS NIH HHS/ -- R01 GM095583/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Feb 3;470(7332):73-7. doi: 10.1038/nature09750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany. henry.chapman@desy.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293373" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray/instrumentation/*methods ; Lasers ; Models, Molecular ; Nanoparticles/*chemistry ; Nanotechnology/instrumentation/*methods ; Photosystem I Protein Complex/*chemistry ; Protein Conformation ; Time Factors ; X-Rays
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  • 5
    Publication Date: 2012-09-21
    Description: The AP1 transcription factor Batf3 is required for homeostatic development of CD8alpha(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8alpha(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-gamma. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tussiwand, Roxane -- Lee, Wan-Ling -- Murphy, Theresa L -- Mashayekhi, Mona -- KC, Wumesh -- Albring, Jorn C -- Satpathy, Ansuman T -- Rotondo, Jeffrey A -- Edelson, Brian T -- Kretzer, Nicole M -- Wu, Xiaodi -- Weiss, Leslie A -- Glasmacher, Elke -- Li, Peng -- Liao, Wei -- Behnke, Michael -- Lam, Samuel S K -- Aurthur, Cora T -- Leonard, Warren J -- Singh, Harinder -- Stallings, Christina L -- Sibley, L David -- Schreiber, Robert D -- Murphy, Kenneth M -- AI076427-02/AI/NIAID NIH HHS/ -- P30 CA91842/CA/NCI NIH HHS/ -- R01 AI036629/AI/NIAID NIH HHS/ -- R01 AI076427/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):502-7. doi: 10.1038/nature11531. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigen Presentation ; Antigens, CD/metabolism ; Antigens, CD8/immunology/metabolism ; Basic-Leucine Zipper Transcription ; Factors/chemistry/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology ; CTLA-4 Antigen/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Dendritic Cells/*cytology/immunology/*metabolism ; Female ; Fibrosarcoma/immunology/metabolism/pathology ; Gene Expression Regulation ; Integrin alpha Chains/metabolism ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/metabolism ; Interleukin-12/immunology/metabolism ; Leucine Zippers ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Oncogene Protein p65(gag-jun)/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/deficiency/genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology/metabolism ; Toxoplasma/immunology
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  • 6
    Publication Date: 2012-06-16
    Description: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376394/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez-Mancera, Pedro A -- Rust, Alistair G -- van der Weyden, Louise -- Kristiansen, Glen -- Li, Allen -- Sarver, Aaron L -- Silverstein, Kevin A T -- Grutzmann, Robert -- Aust, Daniela -- Rummele, Petra -- Knosel, Thomas -- Herd, Colin -- Stemple, Derek L -- Kettleborough, Ross -- Brosnan, Jacqueline A -- Li, Ang -- Morgan, Richard -- Knight, Spencer -- Yu, Jun -- Stegeman, Shane -- Collier, Lara S -- ten Hoeve, Jelle J -- de Ridder, Jeroen -- Klein, Alison P -- Goggins, Michael -- Hruban, Ralph H -- Chang, David K -- Biankin, Andrew V -- Grimmond, Sean M -- Australian Pancreatic Cancer Genome Initiative -- Wessels, Lodewyk F A -- Wood, Stephen A -- Iacobuzio-Donahue, Christine A -- Pilarsky, Christian -- Largaespada, David A -- Adams, David J -- Tuveson, David A -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA122183/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- K01 CA122183/CA/NCI NIH HHS/ -- K01 CA122183-05/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50CA62924/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Apr 29;486(7402):266-70. doi: 10.1038/nature11114.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699621" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoikis/genetics ; Carcinoma, Pancreatic Ductal/*enzymology/genetics/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Endopeptidases ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Mice ; Mice, Inbred C57BL ; Pancreatic Neoplasms/*enzymology/genetics/pathology ; U937 Cells ; Ubiquitin Thiolesterase/*genetics/*metabolism
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-02-18
    Description: Studies of experimental grassland communities have demonstrated that plant diversity can stabilize productivity through species asynchrony, in which decreases in the biomass of some species are compensated for by increases in others. However, it remains unknown whether these findings are relevant to natural ecosystems, especially those for which species diversity is threatened by anthropogenic global change. Here we analyse diversity-stability relationships from 41 grasslands on five continents and examine how these relationships are affected by chronic fertilization, one of the strongest drivers of species loss globally. Unmanipulated communities with more species had greater species asynchrony, resulting in more stable biomass production, generalizing a result from biodiversity experiments to real-world grasslands. However, fertilization weakened the positive effect of diversity on stability. Contrary to expectations, this was not due to species loss after eutrophication but rather to an increase in the temporal variation of productivity in combination with a decrease in species asynchrony in diverse communities. Our results demonstrate separate and synergistic effects of diversity and eutrophication on stability, emphasizing the need to understand how drivers of global change interactively affect the reliable provisioning of ecosystem services in real-world systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hautier, Yann -- Seabloom, Eric W -- Borer, Elizabeth T -- Adler, Peter B -- Harpole, W Stanley -- Hillebrand, Helmut -- Lind, Eric M -- MacDougall, Andrew S -- Stevens, Carly J -- Bakker, Jonathan D -- Buckley, Yvonne M -- Chu, Chengjin -- Collins, Scott L -- Daleo, Pedro -- Damschen, Ellen I -- Davies, Kendi F -- Fay, Philip A -- Firn, Jennifer -- Gruner, Daniel S -- Jin, Virginia L -- Klein, Julia A -- Knops, Johannes M H -- La Pierre, Kimberly J -- Li, Wei -- McCulley, Rebecca L -- Melbourne, Brett A -- Moore, Joslin L -- O'Halloran, Lydia R -- Prober, Suzanne M -- Risch, Anita C -- Sankaran, Mahesh -- Schuetz, Martin -- Hector, Andy -- England -- Nature. 2014 Apr 24;508(7497):521-5. doi: 10.1038/nature13014. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Ecology, Evolution, and Behavior, University of Minnesota, St Paul, Minnesota 55108, USA [2] Institute of Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland. ; Department of Ecology, Evolution, and Behavior, University of Minnesota, St Paul, Minnesota 55108, USA. ; Department of Wildland Resources and the Ecology Center, Utah State University, Logan, Utah 84322, USA. ; Department of Ecology, Evolution, and Organismal Biology, Iowa State University, Ames, Iowa 50011, USA. ; Institute for Chemistry and Biology of the Marine Environment, Carl-von-Ossietzky University Oldenburg, D-26111 Oldenburg, Germany. ; Department of Integrative Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada. ; Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, UK. ; School of Environmental and Forest Sciences, University of Washington, Seattle, Washington 98195, USA. ; 1] Australian Research Council Centre of Excellence for Environmental Decisions, School of Biological Sciences, The University of Queensland, Queensland 4072, Australia [2] School of Natural Sciences, Department of Zoology, Trinity College Dublin, Dublin 2, Ireland. ; State Key Laboratory of Grassland and Agro-Ecosystems, Research Station of Alpine Meadow and Wetland Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou 730000, China. ; Department of Biology, MSC03-2020, University of New Mexico, Albuquerque, New Mexico 87131, USA. ; Instituto de Investigaciones Marinas y Costeras (IIMyC) (CONICET-UNMdP), Mar del Plata 7600, Argentina. ; Department of Zoology, University of Wisconsin, Madison, Wisconsin 53706, USA. ; Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, Colorado 80309, USA. ; United States Department of Agriculture Agricultural Research Service, Grassland Soil and Water Research Lab, Temple, Texas 76502, USA. ; Queensland University of Technology, School of Biological Sciences, Brisbane 4000, Australia. ; Department of Entomology, University of Maryland, College Park, Maryland 20742, USA. ; United States Department of Agriculture Agricultural Research Service, Agroecosystem Management Research Unit, Lincoln, Nebraska 68583, USA. ; Department of Forest, Rangeland and Watershed Stewardship, Colorado State University, Fort Collins, Colorado 80523, USA. ; School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68588, USA. ; Berkeley Initiative for Global Change Biology, University of California, Berkeley, California 94720, USA. ; Yunnan Academy of Biodiversity, Southwest Forestry University, Kunming 650224, China. ; Department of Plant and Soil Sciences, University of Kentucky, Lexington, Kentucky 40546, USA. ; 1] Australian Research Centre for Urban Ecology, Melbourne, c/o School of Botany, University of Melbourne, Victoria 3010, Australia [2] School of Biological Sciences, Monash University, Victoria 3800, Australia. ; Department of Zoology, Oregon State University, Corvallis, Oregon 97331, USA. ; CSIRO Ecosystem Sciences, Wembley, WA 6913, Australia. ; Swiss Federal Institute for Forest, Snow and Landscape Research, 8903 Birmensdorf, Switzerland. ; 1] School of Biology, University of Leeds, Leeds LS2 9JT, UK [2] National Centre for Biological Sciences, GKVK Campus, Bangalore 560065, India. ; Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531763" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biodiversity ; Biomass ; Climate ; *Eutrophication/drug effects ; Fertilizers/*adverse effects ; Geography ; International Cooperation ; *Poaceae/drug effects/physiology ; Time Factors
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  • 8
    Publication Date: 2010-04-03
    Description: African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917743/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917743/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frearson, Julie A -- Brand, Stephen -- McElroy, Stuart P -- Cleghorn, Laura A T -- Smid, Ondrej -- Stojanovski, Laste -- Price, Helen P -- Guther, M Lucia S -- Torrie, Leah S -- Robinson, David A -- Hallyburton, Irene -- Mpamhanga, Chidochangu P -- Brannigan, James A -- Wilkinson, Anthony J -- Hodgkinson, Michael -- Hui, Raymond -- Qiu, Wei -- Raimi, Olawale G -- van Aalten, Daan M F -- Brenk, Ruth -- Gilbert, Ian H -- Read, Kevin D -- Fairlamb, Alan H -- Ferguson, Michael A J -- Smith, Deborah F -- Wyatt, Paul G -- 077503/Wellcome Trust/United Kingdom -- 077705/Wellcome Trust/United Kingdom -- 085622/Wellcome Trust/United Kingdom -- 087590/Wellcome Trust/United Kingdom -- 1097737/Canadian Institutes of Health Research/Canada -- G0900138/Medical Research Council/United Kingdom -- G0900138(90614)/Medical Research Council/United Kingdom -- WT077503/Wellcome Trust/United Kingdom -- WT077705/Wellcome Trust/United Kingdom -- WT083481,/Wellcome Trust/United Kingdom -- WT085622/Wellcome Trust/United Kingdom -- England -- Nature. 2010 Apr 1;464(7289):728-32. doi: 10.1038/nature08893.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360736" target="_blank"〉PubMed〈/a〉
    Keywords: Acyltransferases/*antagonists & inhibitors/metabolism ; Aminopyridines/chemistry/metabolism/pharmacology/therapeutic use ; Animals ; Antiparasitic Agents/chemistry/metabolism/*pharmacology/*therapeutic use ; Enzyme Assays ; Enzyme Inhibitors/chemistry/metabolism/pharmacology/therapeutic use ; Female ; Humans ; Mice ; Molecular Structure ; Pyrazoles/chemistry/metabolism/pharmacology/therapeutic use ; Rats ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use ; Time Factors ; Trypanosoma brucei brucei/*drug effects/*enzymology/growth & development ; Trypanosomiasis, African/*drug therapy/*parasitology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2012-12-14
    Description: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Besnard, Jeremy -- Ruda, Gian Filippo -- Setola, Vincent -- Abecassis, Keren -- Rodriguiz, Ramona M -- Huang, Xi-Ping -- Norval, Suzanne -- Sassano, Maria F -- Shin, Antony I -- Webster, Lauren A -- Simeons, Frederick R C -- Stojanovski, Laste -- Prat, Annik -- Seidah, Nabil G -- Constam, Daniel B -- Bickerton, G Richard -- Read, Kevin D -- Wetsel, William C -- Gilbert, Ian H -- Roth, Bryan L -- Hopkins, Andrew L -- 083481/Wellcome Trust/United Kingdom -- BB/FOF/PF/15/09/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J010510/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MH082441/MH/NIMH NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Automation ; Drug Delivery Systems ; *Drug Design ; Female ; *Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Theoretical ; Pharmacological Phenomena ; Reproducibility of Results
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  • 10
    Publication Date: 2011-10-04
    Description: Chemical ozone destruction occurs over both polar regions in local winter-spring. In the Antarctic, essentially complete removal of lower-stratospheric ozone currently results in an ozone hole every year, whereas in the Arctic, ozone loss is highly variable and has until now been much more limited. Here we demonstrate that chemical ozone destruction over the Arctic in early 2011 was--for the first time in the observational record--comparable to that in the Antarctic ozone hole. Unusually long-lasting cold conditions in the Arctic lower stratosphere led to persistent enhancement in ozone-destroying forms of chlorine and to unprecedented ozone loss, which exceeded 80 per cent over 18-20 kilometres altitude. Our results show that Arctic ozone holes are possible even with temperatures much milder than those in the Antarctic. We cannot at present predict when such severe Arctic ozone depletion may be matched or exceeded.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manney, Gloria L -- Santee, Michelle L -- Rex, Markus -- Livesey, Nathaniel J -- Pitts, Michael C -- Veefkind, Pepijn -- Nash, Eric R -- Wohltmann, Ingo -- Lehmann, Ralph -- Froidevaux, Lucien -- Poole, Lamont R -- Schoeberl, Mark R -- Haffner, David P -- Davies, Jonathan -- Dorokhov, Valery -- Gernandt, Hartwig -- Johnson, Bryan -- Kivi, Rigel -- Kyro, Esko -- Larsen, Niels -- Levelt, Pieternel F -- Makshtas, Alexander -- McElroy, C Thomas -- Nakajima, Hideaki -- Parrondo, Maria Concepcion -- Tarasick, David W -- von der Gathen, Peter -- Walker, Kaley A -- Zinoviev, Nikita S -- England -- Nature. 2011 Oct 2;478(7370):469-75. doi: 10.1038/nature10556.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jet Propulsion Laboratory, California Institute of Technology, Pasadena, California 91109, USA. Gloria.L.Manney@jpl.nasa.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964337" target="_blank"〉PubMed〈/a〉
    Keywords: Antarctic Regions ; Arctic Regions ; Atmosphere/*chemistry ; Chlorine/chemistry ; *Environmental Monitoring ; History, 20th Century ; History, 21st Century ; Ozone/*analysis/chemistry/history ; Seasons ; Time Factors
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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