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排序方式: 共有91条查询结果,搜索用时 15 毫秒
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Lisa J. White Jennifer A. Flegg Aung Pyae Phyo Ja Hser Wiladpai-ngern Delia Bethell Christopher Plowe Tim Anderson Standwell Nkhoma Shalini Nair Rupam Tripura Kasia Stepniewska Wirichada Pan-Ngum Kamolrat Silamut Ben S. Cooper Yoel Lubell Elizabeth A. Ashley Chea Nguon Fran?ois Nosten Nicholas J. White Arjen M. Dondorp 《PLoS medicine》2015,12(4)
BackgroundArtemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker ‘Kelch 13’ and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment (''day-3''), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions.ConclusionsCharacterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in ''day-3'' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the ‘day 3’ threshold to account for initial parasitaemia and sample size. 相似文献
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Frédéric H. Vaillancourt Martine Brault Louise Pilote Nathalie Uyttersprot Elias T. Gaillard James H. Stoltz Brian L. Knight Lynn Pantages Mary McFarland Steffen Breitfelder Tim T. Chiu Louiza Mahrouche Anne-Marie Faucher Mireille Cartier Michael G. Cordingley Richard C. Bethell Huiping Jiang Peter W. White George Kukolj 《Journal of virology》2012,86(21):11595-11607
Phosphatidylinositol-4-kinase IIIα (PI4KIIIα) is an essential host cell factor for hepatitis C virus (HCV) replication. An N-terminally truncated 130-kDa form was used to reconstitute an in vitro biochemical lipid kinase assay that was optimized for small-molecule compound screening and identified potent and specific inhibitors. Cell culture studies with PI4KIIIα inhibitors demonstrated that the kinase activity was essential for HCV RNA replication. Two PI4KIIIα inhibitors were used to select cell lines harboring HCV replicon mutants with a 20-fold loss in sensitivity to the compounds. Reverse genetic mapping isolated an NS4B-NS5A segment that rescued HCV RNA replication in PIK4IIIα-deficient cells. HCV RNA replication occurs on specialized membranous webs, and this study with PIK4IIIα inhibitor-resistant mutants provides a genetic link between NS4B/NS5A functions and PI4-phosphate lipid metabolism. A comprehensive assessment of PI4KIIIα as a drug target included its evaluation for pharmacologic intervention in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice. Homozygotes that induce a knockout of the kinase domain or knock in a single amino acid substitution, kinase-defective PI4KIIIα, displayed a lethal phenotype with a fairly widespread mucosal epithelial degeneration of the gastrointestinal tract. This essential host physiologic role raises doubt about the pursuit of PI4KIIIα inhibitors for treatment of chronic HCV infection. 相似文献
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H. J. Bethell 《BMJ (Clinical research ed.)》1988,297(6641):120-121
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Wang M Ng KK Cherney MM Chan L Yannopoulos CG Bedard J Morin N Nguyen-Ba N Alaoui-Ismaili MH Bethell RC James MN 《The Journal of biological chemistry》2003,278(11):9489-9495
X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase. 相似文献
28.
Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics 总被引:40,自引:0,他引:40
Brindle JT Antti H Holmes E Tranter G Nicholson JK Bethell HW Clarke S Schofield PM McKilligin E Mosedale DE Grainger DJ 《Nature medicine》2002,8(12):1439-1444
Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins. 相似文献
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Yannopoulos CG Xu P Ni F Chan L Pereira OZ Reddy TJ Das SK Poisson C Nguyen-Ba N Turcotte N Proulx M Halab L Wang W Bédard J Morin N Hamel M Nicolas O Bilimoria D L'Heureux L Bethell R Dionne G 《Bioorganic & medicinal chemistry letters》2004,14(21):5333-5337
HCV NS5B RNA-dependent RNA polymerase (NS5B) is essential for viral replication and is therefore considered a target for antiviral drug development. From our ongoing screening effort in the search for new anti-HCV agents, a novel inhibitor 1 with low microM activity against the HCV NS5B polymerase was identified. SAR analysis indicated the optimal substitution pattern required for activity, for example, carboxylic acid group at 2-position of thiophene ring. We describe the steps taken to identify and solve the bioactive conformation of derivative 6 through the use of the transferred NOE method (trNOE). 相似文献
30.
Buxton RC Edwards B Juo RR Voyta JC Tisdale M Bethell RC 《Analytical biochemistry》2000,280(2):291-300
Determination of the sensitivity of influenza viruses to neuraminidase (NA) inhibitors is presently based on assays of NA function because, unlike available cell culture methods, the results of such assays are predictive of susceptibility in vivo. At present the most widely used substrate in assays of NA function is the fluorogenic reagent 2'-O-(4-methylumbelliferyl)-N-acetylneuraminic acid (MUN). A rapid assay with improved sensitivity is required because a proportion of clinical isolates has insufficient NA to be detectable in the current fluorogenic assay, and because some mutations associated with resistance to NA inhibitors reduce the activity of the enzyme. A chemiluminescence-based assay of NA activity has been developed that uses a 1,2-dioxetane derivative of sialic acid (NA-STAR) as the substrate. When compared with the fluorogenic assay, use of the NA-STAR substrate results in a 67-fold reduction in the limit of detection of the NA assay, from 200 pM (11 fmol) NA to 3 pM (0.16 fmol) NA. A panel of isolates from phase 2 clinical studies of zanamivir, which were undetectable in the fluorogenic assay, was tested for activity using the NA-STAR substrate. Of these 12 isolates with undetectable NA activity, 10 (83%) were found to have detectable NA activity using the NA-STAR substrate. A comparison of sensitivity to zanamivir of a panel of influenza A and B viruses using the two NA assay methods has been performed. IC(50) values for zanamivir using the NA-STAR were in the range 1.0-7.5 nM and those for the fluorogenic assay in the range 1. 0-5.7 nM (n = 6). The NA-STAR assay is a highly sensitive, rapid assay of influenza virus NA activity that is applicable to monitoring the susceptibility of influenza virus clinical isolates to NA inhibitors. 相似文献