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  • American Association for the Advancement of Science (AAAS)  (7)
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  • 1
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    Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2011-11-19
    Beschreibung: Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of 〉4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration 〈 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473092/" 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/PMC3473092/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meister, Stephan -- Plouffe, David M -- Kuhen, Kelli L -- Bonamy, Ghislain M C -- Wu, Tao -- Barnes, S Whitney -- Bopp, Selina E -- Borboa, Rachel -- Bright, A Taylor -- Che, Jianwei -- Cohen, Steve -- Dharia, Neekesh V -- Gagaring, Kerstin -- Gettayacamin, Montip -- Gordon, Perry -- Groessl, Todd -- Kato, Nobutaka -- Lee, Marcus C S -- McNamara, Case W -- Fidock, David A -- Nagle, Advait -- Nam, Tae-gyu -- Richmond, Wendy -- Roland, Jason -- Rottmann, Matthias -- Zhou, Bin -- Froissard, Patrick -- Glynne, Richard J -- Mazier, Dominique -- Sattabongkot, Jetsumon -- Schultz, Peter G -- Tuntland, Tove -- Walker, John R -- Zhou, Yingyao -- Chatterjee, Arnab -- Diagana, Thierry T -- Winzeler, Elizabeth A -- R01 AI079709/AI/NIAID NIH HHS/ -- R01 AI079709-04/AI/NIAID NIH HHS/ -- R01 AI090141/AI/NIAID NIH HHS/ -- R01 AI090141-02/AI/NIAID NIH HHS/ -- R01AI090141/AI/NIAID NIH HHS/ -- WT078285/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2011 Dec 9;334(6061):1372-7. doi: 10.1126/science.1211936. Epub 2011 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22096101" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antimalarials/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Cell Line, Tumor ; *Drug Discovery ; Drug Evaluation, Preclinical ; Drug Resistance ; Erythrocytes/parasitology ; Humans ; Imidazoles/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Liver/*parasitology ; Malaria/*drug therapy/parasitology/prevention & control ; Mice ; Mice, Inbred BALB C ; Molecular Structure ; Piperazines/chemistry/pharmacokinetics/*pharmacology/therapeutic use ; Plasmodium/cytology/*drug effects/growth & development/physiology ; Plasmodium berghei/cytology/drug effects/growth & development/physiology ; Plasmodium falciparum/cytology/drug effects/growth & development/physiology ; Plasmodium yoelii/cytology/drug effects/growth & development/physiology ; Polymorphism, Single Nucleotide ; Protozoan Proteins/chemistry/genetics/metabolism ; Random Allocation ; Small Molecule Libraries ; Sporozoites/drug effects/growth & development
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
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    Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12 (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2003-12-04
    Beschreibung: During apoptosis, phosphatidylserine, which is normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and has been suggested to act as an "eat-me" signal to trigger phagocytosis. It is unclear how phagocytes recognize phosphatidylserine. Recently, a putative phosphatidylserine receptor (PSR) was identified and proposed to mediate recognition of phosphatidylserine and phagocytosis. We report that psr-1, the Caenorhabditis elegans homolog of PSR, is important for cell corpse engulfment. In vitro PSR-1 binds preferentially phosphatidylserine or cells with exposed phosphatidylserine. In C. elegans, PSR-1 acts in the same cell corpse engulfment pathway mediated by intracellular signaling molecules CED-2 (homologous to the human CrkII protein), CED-5 (DOCK180), CED-10 (Rac GTPase), and CED-12 (ELMO), possibly through direct interaction with CED-5 and CED-12. Our findings suggest that PSR-1 is likely an upstream receptor for the signaling pathway containing CED-2, CED-5, CED-10, and CED-12 proteins and plays an important role in recognizing phosphatidylserine during phagocytosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaochen -- Wu, Yi-Chun -- Fadok, Valerie A -- Lee, Ming-Chia -- Gengyo-Ando, Keiko -- Cheng, Li-Chun -- Ledwich, Duncan -- Hsu, Pei-Ken -- Chen, Jia-Yun -- Chou, Bin-Kuan -- Henson, Peter -- Mitani, Shohei -- Xue, Ding -- New York, N.Y. -- Science. 2003 Nov 28;302(5650):1563-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14645848" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): *Adaptor Proteins, Signal Transducing ; Amino Acid Sequence ; Animals ; *Apoptosis ; Caenorhabditis elegans/cytology/embryology/metabolism/*physiology ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Carrier Proteins/genetics/*metabolism ; *Cytoskeletal Proteins ; Embryo, Nonmammalian/cytology/metabolism ; Embryonic Development ; Humans ; Jumonji Domain-Containing Histone Demethylases ; Membrane Proteins/genetics/*metabolism ; Molecular Sequence Data ; Mutation ; *Phagocytosis ; Phosphatidylserines/metabolism ; Protein Binding ; Receptors, Cell Surface/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism ; Recombinant Proteins/metabolism ; Signal Transduction ; rac GTP-Binding Proteins/genetics/metabolism
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
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    Cell biology. BAR domains go on a bender (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2004-01-24
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Marcus C S -- Schekman, Randy -- New York, N.Y. -- Science. 2004 Jan 23;303(5657):479-80.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14739445" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): ADP-Ribosylation Factors/chemistry/metabolism ; Adaptor Proteins, Vesicular Transport ; Animals ; COP-Coated Vesicles/metabolism ; Carrier Proteins/chemistry/metabolism ; Cell Membrane/chemistry/*metabolism/ultrastructure ; Clathrin/metabolism ; Coated Vesicles/chemistry/metabolism/ultrastructure ; Cytoplasmic Vesicles/chemistry/*metabolism/ultrastructure ; Dimerization ; Drosophila/chemistry ; Drosophila Proteins/*chemistry/metabolism/physiology ; Dynamins/metabolism ; Endocytosis ; Exocytosis ; GTPase-Activating Proteins/chemistry/metabolism ; Nerve Tissue Proteins/*chemistry/*metabolism/physiology ; Neuropeptides/chemistry/metabolism ; Protein Binding ; Protein Structure, Secondary ; *Protein Structure, Tertiary ; *Vesicular Transport Proteins
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
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    Spiroindolones, a potent compound class for the treatment of malaria (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2010-09-04
    Beschreibung: Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050001/" 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/PMC3050001/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rottmann, Matthias -- McNamara, Case -- Yeung, Bryan K S -- Lee, Marcus C S -- Zou, Bin -- Russell, Bruce -- Seitz, Patrick -- Plouffe, David M -- Dharia, Neekesh V -- Tan, Jocelyn -- Cohen, Steven B -- Spencer, Kathryn R -- Gonzalez-Paez, Gonzalo E -- Lakshminarayana, Suresh B -- Goh, Anne -- Suwanarusk, Rossarin -- Jegla, Timothy -- Schmitt, Esther K -- Beck, Hans-Peter -- Brun, Reto -- Nosten, Francois -- Renia, Laurent -- Dartois, Veronique -- Keller, Thomas H -- Fidock, David A -- Winzeler, Elizabeth A -- Diagana, Thierry T -- R01 AI059472/AI/NIAID NIH HHS/ -- R01 AI059472-04/AI/NIAID NIH HHS/ -- R01 AI059472-05/AI/NIAID NIH HHS/ -- R01AI059472/AI/NIAID NIH HHS/ -- WT078285/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2010 Sep 3;329(5996):1175-80. doi: 10.1126/science.1193225.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Swiss Tropical and Public Health Institute, Parasite Chemotherapy, CH-4002 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20813948" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adenosine Triphosphatases/antagonists & inhibitors/chemistry/genetics/metabolism ; Animals ; Antimalarials/administration & dosage/chemistry/pharmacokinetics/*pharmacology ; Cell Line ; Drug Discovery ; Drug Resistance ; Erythrocytes/parasitology ; Female ; Genes, Protozoan ; Humans ; Indoles/administration & dosage/chemistry/pharmacokinetics/*pharmacology ; Malaria/*drug therapy/parasitology ; Male ; Mice ; Models, Molecular ; Mutant Proteins/antagonists & inhibitors/chemistry/metabolism ; Mutation ; Parasitic Sensitivity Tests ; Plasmodium berghei/*drug effects ; Plasmodium falciparum/*drug effects/genetics/growth & development ; Plasmodium vivax/*drug effects/growth & development ; Protein Synthesis Inhibitors/administration & ; dosage/chemistry/pharmacokinetics/pharmacology ; Protozoan Proteins/biosynthesis/chemistry/genetics/metabolism ; Rats ; Rats, Wistar ; Spiro Compounds/administration & dosage/chemistry/pharmacokinetics/*pharmacology
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
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    Holographic deep learning for rapid optical screening of anthrax spores (2017)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2017-08-05
    Beschreibung: Establishing early warning systems for anthrax attacks is crucial in biodefense. Despite numerous studies for decades, the limited sensitivity of conventional biochemical methods essentially requires preprocessing steps and thus has limitations to be used in realistic settings of biological warfare. We present an optical method for rapid and label-free screening of Bacillus anthracis spores through the synergistic application of holographic microscopy and deep learning. A deep convolutional neural network is designed to classify holographic images of unlabeled living cells. After training, the network outperforms previous techniques in all accuracy measures, achieving single-spore sensitivity and subgenus specificity. The unique "representation learning" capability of deep learning enables direct training from raw images instead of manually extracted features. The method automatically recognizes key biological traits encoded in the images and exploits them as fingerprints. This remarkable learning ability makes the proposed method readily applicable to classifying various single cells in addition to B. anthracis , as demonstrated for the diagnosis of Listeria monocytogenes , without any modification. We believe that our strategy will make holographic microscopy more accessible to medical doctors and biomedical scientists for easy, rapid, and accurate point-of-care diagnosis of pathogens.
    Digitale ISSN: 2375-2548
    Thema: Allgemeine Naturwissenschaft
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
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    A mid-Cretaceous embryonic-to-neonate snake in amber from Myanmar (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2018-07-19
    Beschreibung: We present the first known fossilized snake embryo/neonate preserved in early Late Cretaceous (Early Cenomanian) amber from Myanmar, which at the time, was an island arc including terranes from Austral Gondwana. This unique and very tiny snake fossil is an articulated postcranial skeleton, which includes posterior precloacal, cloacal, and caudal vertebrae, and details of squamation and body shape; a second specimen preserves a fragment of shed skin interpreted as a snake. Important details of skeletal ontogeny, including the stage at which snake zygosphene-zygantral joints began to form along with the neural arch lamina, are preserved. The vertebrae show similarities to those of fossil Gondwanan snakes, suggesting a dispersal route of Gondwanan faunas to Laurasia. Finally, the new species is the first Mesozoic snake to be found in a forested environment, indicating greater ecological diversity among early snakes than previously thought.
    Digitale ISSN: 2375-2548
    Thema: Allgemeine Naturwissenschaft
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
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    Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publikationsdatum: 2018-01-12
    Beschreibung: Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.
    Schlagwort(e): Genetics, Microbiology
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Geologie und Paläontologie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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