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  • 1
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    Targeting Plasmodium PI(4)K to eliminate malaria (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-11-29
    Description: Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940870/" 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/PMC3940870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNamara, Case W -- Lee, Marcus C S -- Lim, Chek Shik -- Lim, Siau Hoi -- Roland, Jason -- Nagle, Advait -- Simon, Oliver -- Yeung, Bryan K S -- Chatterjee, Arnab K -- McCormack, Susan L -- Manary, Micah J -- Zeeman, Anne-Marie -- Dechering, Koen J -- Kumar, T R Santha -- Henrich, Philipp P -- Gagaring, Kerstin -- Ibanez, Maureen -- Kato, Nobutaka -- Kuhen, Kelli L -- Fischli, Christoph -- Rottmann, Matthias -- Plouffe, David M -- Bursulaya, Badry -- Meister, Stephan -- Rameh, Lucia -- Trappe, Joerg -- Haasen, Dorothea -- Timmerman, Martijn -- Sauerwein, Robert W -- Suwanarusk, Rossarin -- Russell, Bruce -- Renia, Laurent -- Nosten, Francois -- Tully, David C -- Kocken, Clemens H M -- Glynne, Richard J -- Bodenreider, Christophe -- Fidock, David A -- Diagana, Thierry T -- Winzeler, Elizabeth A -- 078285/Wellcome Trust/United Kingdom -- 089275/Wellcome Trust/United Kingdom -- 090534/Wellcome Trust/United Kingdom -- 096157/Wellcome Trust/United Kingdom -- R01 AI079709/AI/NIAID NIH HHS/ -- R01 AI085584/AI/NIAID NIH HHS/ -- R01 AI090141/AI/NIAID NIH HHS/ -- R01 AI103058/AI/NIAID NIH HHS/ -- R01079709/PHS HHS/ -- R01085584/PHS HHS/ -- R01AI090141/AI/NIAID NIH HHS/ -- WT078285/Wellcome Trust/United Kingdom -- WT096157/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):248-53. doi: 10.1038/nature12782. Epub 2013 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA [2]. ; 1] Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA [2]. ; Novartis Institutes for Tropical Disease, 138670 Singapore. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; Department of Parasitology, Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands. ; TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands. ; Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA. ; Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland. ; 1] Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland [2] University of Basel, CH-4003 Basel, Switzerland. ; Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts 02118, USA. ; Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. ; 1] TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands [2] Department of Medical Microbiology, Radboud University, Nijmegen Medical CentrePO Box 9101, 6500 HB Nijmegen, The Netherlands. ; Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore. ; 1] Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore [2] Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 117545 Singapore. ; 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK [2] Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot 63110, Thailand. ; 1] Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA [2] Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24284631" target="_blank"〉PubMed〈/a〉
    Keywords: 1-Phosphatidylinositol 4-Kinase/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Cytokinesis/drug effects ; Drug Resistance/drug effects/genetics ; Fatty Acids/metabolism ; Female ; Hepatocytes/parasitology ; Humans ; Imidazoles/metabolism/pharmacology ; Life Cycle Stages/drug effects ; Macaca mulatta ; Malaria/*drug therapy/*parasitology ; Male ; Models, Biological ; Models, Molecular ; Phosphatidylinositol Phosphates/metabolism ; Plasmodium/classification/*drug effects/*enzymology/growth & development ; Pyrazoles/metabolism/pharmacology ; Quinoxalines/metabolism/pharmacology ; Reproducibility of Results ; Schizonts/cytology/drug effects ; rab GTP-Binding Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Greenhouse gas fluxes over managed grasslands in Central Europe (2018)
    Wiley
    Details
    Publication Date: 2018-02-06
    Description: Central European grasslands are characterized by a wide range of different management practices in close geographical proximity. Site-specific management strategies strongly affect the biosphere-atmosphere exchange of the three greenhouse gases (GHG) carbon dioxide (CO 2 ), nitrous oxide (N 2 O) and methane (CH 4 ). The evaluation of environmental impacts at site level is challenging, because most in-situ measurements focus on the quantification of CO 2 exchange, while long-term N 2 O and CH 4 flux measurements at ecosystem scale remain scarce. Here, we synthesized ecosystem CO 2 , N 2 O and CH 4 fluxes from 14 managed grassland sites, quantified by eddy covariance or chamber techniques. We found that grasslands were on average a CO 2 sink (-1783 to -91 g CO 2 m −2 yr −1 ), but a N 2 O source (18 – 638 g CO 2 -eq. m −2 yr −1 ), and either a CH 4 sink or source (-9 to 488 g CO 2 -eq. m −2 yr −1 ). The net GHG balance (NGB) of nine sites where measurements of all three GHGs were available was found between -2761 and -58 g CO 2 -eq. m −2 yr −1 , with N 2 O and CH 4 emissions offsetting concurrent CO 2 uptake by on average 21 ± 6% across sites. The only positive NGB was found for one site during a restoration year with ploughing. The predictive power of soil parameters for N 2 O and CH 4 fluxes was generally low and varied considerably within years. However, after site-specific data normalization we identified environmental conditions that indicated enhanced GHG source/sink activity (‘sweet spots’) and gave a good prediction of normalized overall fluxes across sites. The application of animal slurry to grasslands increased N 2 O and CH 4 emissions. The N 2 O-N emission factor across sites was 1.8 ± 0.5%, but varied considerably at site level among the years (0.1 – 8.6%). Although grassland management lead to increased N 2 O and CH 4 emissions, the CO 2 sink strength was generally the most dominant component of the annual GHG budget. This article is protected by copyright. All rights reserved.
    Print ISSN: 1354-1013
    Electronic ISSN: 1365-2486
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering , Geography
    Published by Wiley
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  • 3
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    Transient phenomena in ecology (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-09-07
    Description: The importance of transient dynamics in ecological systems and in the models that describe them has become increasingly recognized. However, previous work has typically treated each instance of these dynamics separately. We review both empirical examples and model systems, and outline a classification of transient dynamics based on ideas and concepts from dynamical systems theory. This classification provides ways to understand the likelihood of transients for particular systems, and to guide investigations to determine the timing of sudden switches in dynamics and other characteristics of transients. Implications for both management and underlying ecological theories emerge.
    Keywords: Ecology, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    The SCALEX Campaign: Scale-Crossing Land Surface and Boundary Layer Processes in the TERENO-preAlpine Observatory (2017)
    American Meteorological Society
    Details
    Publication Date: 2017-06-01
    Description: ScaleX is a collaborative measurement campaign, collocated with a long-term environmental observatory of the German Terrestrial Environmental Observatories (TERENO) network in the mountainous terrain of the Bavarian Prealps, Germany. The aims of both TERENO and ScaleX include the measurement and modeling of land surface–atmosphere interactions of energy, water, and greenhouse gases. ScaleX is motivated by the recognition that long-term intensive observational research over years or decades must be based on well-proven, mostly automated measurement systems, concentrated in a small number of locations. In contrast, short-term intensive campaigns offer the opportunity to assess spatial distributions and gradients by concentrated instrument deployments, and by mobile sensors (ground and/or airborne) to obtain transects and three-dimensional patterns of atmospheric, surface, or soil variables and processes. Moreover, intensive campaigns are ideal proving grounds for innovative instruments, methods, and techniques to measure quantities that cannot (yet) be automated or deployed over long time periods. ScaleX is distinctive in its design, which combines the benefits of a long-term environmental-monitoring approach (TERENO) with the versatility and innovative power of a series of intensive campaigns, to bridge across a wide span of spatial and temporal scales. This contribution presents the concept and first data products of ScaleX-2015, which occurred in June–July 2015. The second installment of ScaleX took place in summer 2016 and periodic further ScaleX campaigns are planned throughout the lifetime of TERENO. This paper calls for collaboration in future ScaleX campaigns or to use our data in modelling studies. It is also an invitation to emulate the ScaleX concept at other long-term observatories.
    Print ISSN: 0003-0007
    Electronic ISSN: 1520-0477
    Topics: Geography , Physics
    Published by American Meteorological Society
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  • 5
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    Ann-dimensional competitive Lotka Volterra system is generically determined by the edges of its carrying simplex (2002)
    Institute of Physics
    Details
    Publication Date: 2002-10-04
    Print ISSN: 0951-7715
    Electronic ISSN: 1361-6544
    Topics: Mathematics , Physics
    Published by Institute of Physics
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  • 6
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    Elemental mercury fluxes over a sub-alpine grassland determined with two micrometeorological methods (2008)
    Elsevier
    Details
    Publication Date: 2008-04-01
    Print ISSN: 1352-2310
    Electronic ISSN: 1873-2844
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Geosciences , Physics
    Published by Elsevier
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  • 7
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    Summertime elemental mercury exchange of temperate grasslands on an ecosystem-scale (2008)
    Copernicus
    Details
    Publication Date: 2008-02-04
    Description: In order to estimate the air-surface mercury exchange of grasslands in temperate climate regions, fluxes of gaseous elemental mercury (GEM) were measured at two sites in Switzerland and one in Austria during summer 2006. Two classic micrometeorological methods (aerodynamic and modified Bowen ratio) have been applied to estimate net GEM exchange rates and to determine the response of the GEM flux to changes in environmental conditions (e.g. heavy rain, summer ozone) on an ecosystem-scale. Both methods proved to be appropriate to estimate fluxes on time scales of a few hours and longer. Average dry deposition rates up to 4.3 ng m−2 h−1 and mean deposition velocities up to 0.10 cm s−1 were measured, which indicates that during the active vegetation period temperate grasslands are a small net sink for atmospheric mercury. With increasing ozone concentrations depletion of GEM was observed, but could not be quantified from the flux signal. Night-time deposition fluxes of GEM were measured and seem to be the result of mercury co-deposition with condensing water. Effects of rain and of grass cuts could also be observed, but were of minor magnitude.
    Electronic ISSN: 1680-7375
    Topics: Geosciences
    Published by Copernicus on behalf of European Geosciences Union.
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  • 8
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    Summertime elemental mercury exchange of temperate grasslands on an ecosystem-scale (2008)
    Copernicus
    Details
    Publication Date: 2008-12-22
    Description: In order to estimate the air-surface mercury exchange of grasslands in temperate climate regions, fluxes of gaseous elemental mercury (GEM) were measured at two sites in Switzerland and one in Austria during summer 2006. Two classic micrometeorological methods (aerodynamic and modified Bowen ratio) have been applied to estimate net GEM exchange rates and to determine the response of the GEM flux to changes in environmental conditions (e.g. heavy rain, summer ozone) on an ecosystem-scale. Both methods proved to be appropriate to estimate fluxes on time scales of a few hours and longer. Average dry deposition rates up to 4.3 ng m−2 h−1 and mean deposition velocities up to 0.10 cm s−1 were measured, which indicates that during the active vegetation period temperate grasslands are a small net sink for atmospheric mercury. With increasing ozone concentrations depletion of GEM was observed, but could not be quantified from the flux signal. Night-time deposition fluxes of GEM were measured and seem to be the result of mercury co-deposition with condensing water. Effects of grass cuts could also be observed, but were of minor magnitude.
    Print ISSN: 1680-7316
    Electronic ISSN: 1680-7324
    Topics: Geosciences
    Published by Copernicus on behalf of European Geosciences Union.
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  • 9
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    Linking carbon and water cycles using stable isotopes across scales: progress and challenges (2011)
    Copernicus
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    Publication Date: 2011-03-15
    Description: Stable isotope analysis is a powerful tool for tracing biogeochemical processes in the carbon and water cycles. One particularly powerful approach is to employ multiple isotopes where the simultaneous assessment of the D/H,18O/16O and/or 13C/12C in different compounds provide a unique means to investigate the coupling of water and carbon fluxes at various temporal and spatial scales. Here, we present a research update on recent advances in our process-based understanding of the utilization of carbon, oxygen and hydrogen isotopes to lend insight into carbon and water cycling. We highlight recent technological developments and approaches, their strengths and methodological precautions with examples covering scales from minutes to centuries and from the leaf to the globe.
    Print ISSN: 1810-6277
    Electronic ISSN: 1810-6285
    Topics: Biology , Geosciences
    Published by Copernicus on behalf of European Geosciences Union.
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  • 10
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    The TERENO Pre-Alpine Observatory: Integrating Meteorological, Hydrological, and Biogeochemical Measurements and Modeling (2018)
    Soil Science Society of America
    Details
    Publication Date: 2018-01-01
    Electronic ISSN: 1539-1663
    Topics: Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by Soil Science Society of America
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