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Chemical genetics of Plasmodium falciparum (2010)

W. A. Guiguemde ; A. A. Shelat ; D. Bouck ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 465(7296): 311-5. doi: 10.1038/nature09099.

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Publication Date: 2010-05-21

Description: Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874979/" 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/PMC2874979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guiguemde, W Armand -- Shelat, Anang A -- Bouck, David -- Duffy, Sandra -- Crowther, Gregory J -- Davis, Paul H -- Smithson, David C -- Connelly, Michele -- Clark, Julie -- Zhu, Fangyi -- Jimenez-Diaz, Maria B -- Martinez, Maria S -- Wilson, Emily B -- Tripathi, Abhai K -- Gut, Jiri -- Sharlow, Elizabeth R -- Bathurst, Ian -- El Mazouni, Farah -- Fowble, Joseph W -- Forquer, Isaac -- McGinley, Paula L -- Castro, Steve -- Angulo-Barturen, Inigo -- Ferrer, Santiago -- Rosenthal, Philip J -- Derisi, Joseph L -- Sullivan, David J -- Lazo, John S -- Roos, David S -- Riscoe, Michael K -- Phillips, Margaret A -- Rathod, Pradipsinh K -- Van Voorhis, Wesley C -- Avery, Vicky M -- Guy, R Kiplin -- AI045774/AI/NIAID NIH HHS/ -- AI053680/AI/NIAID NIH HHS/ -- AI067921/AI/NIAID NIH HHS/ -- AI075517/AI/NIAID NIH HHS/ -- AI075594/AI/NIAID NIH HHS/ -- AI080625/AI/NIAID NIH HHS/ -- AI082617/AI/NIAID NIH HHS/ -- AI28724/AI/NIAID NIH HHS/ -- AI35707/AI/NIAID NIH HHS/ -- AI53862/AI/NIAID NIH HHS/ -- AI772682/AI/NIAID NIH HHS/ -- CA78039/CA/NCI NIH HHS/ -- F32 AI077268/AI/NIAID NIH HHS/ -- F32 AI077268-03/AI/NIAID NIH HHS/ -- P01 AI035707/AI/NIAID NIH HHS/ -- P01 AI035707-140007/AI/NIAID NIH HHS/ -- P01 CA078039-10/CA/NCI NIH HHS/ -- P41 RR001614/RR/NCRR NIH HHS/ -- P41 RR001614-246970/RR/NCRR NIH HHS/ -- R01 AI045774/AI/NIAID NIH HHS/ -- R01 AI045774-09/AI/NIAID NIH HHS/ -- R37 AI028724/AI/NIAID NIH HHS/ -- R37 AI028724-17/AI/NIAID NIH HHS/ -- R56 AI082617/AI/NIAID NIH HHS/ -- R56 AI082617-01/AI/NIAID NIH HHS/ -- U01 AI053862/AI/NIAID NIH HHS/ -- U01 AI053862-05/AI/NIAID NIH HHS/ -- U01 AI075594-03/AI/NIAID NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 May 20;465(7296):311-5. doi: 10.1038/nature09099.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485428" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Antimalarials/*analysis/isolation & purification/*pharmacology ; Cell Line ; *Drug Discovery ; Drug Evaluation, Preclinical ; Drug Resistance/drug effects ; Drug Therapy, Combination ; Erythrocytes/drug effects/parasitology ; Humans ; Malaria, Falciparum/drug therapy/parasitology ; Mice ; Phenotype ; Phylogeny ; Plasmodium falciparum/*drug effects/*genetics/metabolism ; Reproducibility of Results ; Small Molecule Libraries/chemistry/pharmacology

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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Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding (2010)

D. Schmidt ; M. D. Wilson ; B. Ballester ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 328(5981): 1036-40. doi: 10.1126/science.1186176.

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Publication Date: 2010-04-10

Description: Transcription factors (TFs) direct gene expression by binding to DNA regulatory regions. To explore the evolution of gene regulation, we used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine experimentally the genome-wide occupancy of two TFs, CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha, in the livers of five vertebrates. Although each TF displays highly conserved DNA binding preferences, most binding is species-specific, and aligned binding events present in all five species are rare. Regions near genes with expression levels that are dependent on a TF are often bound by the TF in multiple species yet show no enhanced DNA sequence constraint. Binding divergence between species can be largely explained by sequence changes to the bound motifs. Among the binding events lost in one lineage, only half are recovered by another binding event within 10 kilobases. Our results reveal large interspecies differences in transcriptional regulation and provide insight into regulatory evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008766/" 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/PMC3008766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Dominic -- Wilson, Michael D -- Ballester, Benoit -- Schwalie, Petra C -- Brown, Gordon D -- Marshall, Aileen -- Kutter, Claudia -- Watt, Stephen -- Martinez-Jimenez, Celia P -- Mackay, Sarah -- Talianidis, Iannis -- Flicek, Paul -- Odom, Duncan T -- 062023/Wellcome Trust/United Kingdom -- 079643/Wellcome Trust/United Kingdom -- 15603/Cancer Research UK/United Kingdom -- 202218/European Research Council/International -- A15603/Cancer Research UK/United Kingdom -- WT062023/Wellcome Trust/United Kingdom -- WT079643/Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2010 May 21;328(5981):1036-40. doi: 10.1126/science.1186176. Epub 2010 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20378774" target="_blank"〉PubMed〈/a〉

Keywords: Algorithms ; Animals ; Base Sequence ; Binding Sites ; Biological Evolution ; CCAAT-Enhancer-Binding Protein-alpha/*metabolism ; Chickens/genetics ; Chromatin Immunoprecipitation ; DNA/genetics/metabolism ; Dogs ; *Evolution, Molecular ; *Gene Expression Regulation ; *Genome ; Genome, Human ; Hepatocyte Nuclear Factor 4/*metabolism ; Humans ; Liver/*metabolism ; Mice ; Opossums/genetics ; Protein Binding ; Regulatory Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Species Specificity ; Vertebrates/*genetics/metabolism

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Adsorption of copper on Pseudomonas aureofaciens: Protective role of surface exopolysaccharides (2010)

González, A. ; Shirokova, L. ; Pokrovsky, O. ; [et al.]

In: Journal of Colloid and Interface Science

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Publication Date: 2020-02-12

Keywords: 550 - Earth sciences

Type: info:eu-repo/semantics/article

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Application of the multispecimen palaeointensity method to Pleistocene lava flows from the Trans-Mexican Volcanic Belt (2010)

Michalk, D. ; Biggin, A. ; Knudsen, M. ; [et al.]

In: Physics of the Earth and Planetary Interiors

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Publication Date: 2020-02-12

Description: Despite the many advances recently made in palaeointensity (PI) studies, more high quality PI data are required for a better understanding of the full-vector evolution of the ancient geomagnetic field. In this study, we applied the recently-proposed multispecimen parallel differential pTRM (MS) method for absolute PI determination to rocks older than those studied hitherto with this method. Fifty-one lava flows from within the Trans-Mexican volcanic belt, which are generally younger than 1 Ma, returned 32 new PI estimates. Rock magnetic investigations revealed that in most cases, the remanence was carried by Ti-poor titanomagnetites of pseudo-single domain magnetic structure although titanomagnetites with higher Ti-contents and additional contributions of (titano-) haematite were also occasionally present. Comparisons with reconstructions of the global dipole moment reveal that the PI estimates from this study were, on average, around 30 per cent higher than expected. Other, mainly Thellier-type, PI data from Mexico were also observed to be high relative to global records, which could indicate that persistent non-dipole features might be responsible for the higher than expected results. However, the paucity of available data obscures the significance of this observation and the balance of evidence rather suggests an artificial biasing of most measurements towards high values. Our results seem to corroborate results from previous studies on historical lava flows and synthetic samples in which domain state effects were found to cause overestimates of the PI by up to 30 per cent in the MS method. We expect that the degree of the overestimate in the majority of these new MS results is no larger than what might be expected from Thellier experiments performed on samples with a similar given degree of multidomain behaviour. However, seven of the lava flows which were studied here using the MS method were subjected to a preceding demagnetisation step of 200 °C in order to erase viscous remanences and these may have produced results which were further biased towards higher intensities. This additional bias is expected from theoretical considerations and may represent a challenge to future application of the MS method to older rock units. It could, however, potentially be avoided in future studies by performing measurements of the sample moment at temperatures higher than the blocking temperature of any overprint.

Keywords: 550 - Earth sciences

Type: info:eu-repo/semantics/article

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Late Holocene climate variability in the southwestern Mediterranean region: an integrated marine and terrestrial geochemical approach (2010)

Martin-Puertas, C. ; Jiménez-Espejo, F. ; Martínez-Ruiz, F. ; [et al.]

In: Climate of the Past

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Publication Date: 2020-02-12

Description: A combination of marine (Alboran Sea cores, ODP 976 and TTR 300 G) and terrestrial (Zo˜nar Lake, Andalucia, Spain) geochemical proxies provides a highresolution reconstruction of climate variability and human influence in the southwestern Mediterranean region for the last 4000 years at inter-centennial resolution. Proxies respond to changes in precipitation rather than temperature alone. Our combined terrestrial and marine archive documents a succession of dry and wet periods coherent with the North Atlantic climate signal. A dry period occurred prior to 2.7 cal ka BP – synchronously to the global aridity crisis of the third-millennium BC – and during the Medieval Climate Anomaly (1.4–0.7 cal ka BP).Wetter conditions prevailed from 2.7 to 1.4 cal ka BP. Hydrological signatures during the Little Ice Age are highly variable but consistent with more humidity than the Medieval Climate Anomaly. Additionally, Pb anomalies in sediments at the end of the Bronze Age suggest anthropogenic pollution earlier than the Roman Empire development in the Iberian Peninsula. The Late Holocene climate evolution of the in the study area confirms the see-saw pattern between the eastern and western Mediterranean regions and the higher influence of the North Atlantic dynamics in the western Mediterranean.

Keywords: 550 - Earth sciences

Type: info:eu-repo/semantics/article

Format: application/pdf

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Gran Canaria temporary broadband seismic network: an study of the seismicity and Earth structure (2010)

Almendros, J. ; de Lis Mancilla, F. ; Martinez-Arevalo, C. ; [et al.]

In: Geophysical Research Abstracts Vol. 12, EGU2010-12481-2, 2010

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Publication Date: 2020-02-12

Description: The present project is a joint effort between different institutions to deploy a dense seismic network at Gran Canaria island (Canary Islands, Spain). The interstation distance is around 20 km. The broadband seismic network is composed of one permanent (Guralp CMG-3T 120 s) and five temporary stations (Guralp CMG-3ESP 60 s). The permanent station is a 120 s Guralp CMG-3T and belongs to the Canary Island Seismic Network, run by the Instituto Geográfico Nacional (IGN) of Spain. The temporary stations are 60 s Guralp CMG-3ESP, provided by the GFZ seismic pool. The deployment was carried out in December 2009. The stations will be recording during two years. The improvement of the seismic network allow us to tackle the following issues: the detection and analysis of any local seismicity of tectonic and/or volcanic origin at Gran Canaria island; to contribute to the understanding of the regional seismicity with special interest in the oceanic channel between Tenerife and Gran Canaria Island in collaboration with a project running a dense temporary seismic network in Tenerife; to study the crustal and upper mantle structure, under Gran Canaria to constrain the crustal structure, the source of the volcanism, and better sample the mantle discontinuities and anisotropy. To study the Earth structure, we use receiver function analysis, ambient seismic noise and SKS anisotropy techniques, This project is part of a long-term research of the crustal and the mantle structure of the Canary Islands, which has started with Gran Canaria and Tenerife Islands and will eventually continue with the rest of the archipelago. The origin of the Canary Islands is generally attributed to a broad mantle upwelling under a slow moving plate, resulting in spatially and temporally distributed volcanic activity and a large number of seamounts and islands. A controversial discussion has been going on about the factors that control the evolution of the volcanic edifices, the type of the melting anomaly (a single, well defined mantle plume of a larger area of diffuse mantle upwelling), and the tectonic control of this evolution. This study is foreseen to provide important clues to understand the volcanic structure and tectonic evolution of the Gran Canaria Island.

Keywords: 550 - Earth sciences

Type: info:eu-repo/semantics/conferenceObject

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