全文获取类型
收费全文 | 91篇 |
免费 | 9篇 |
出版年
2023年 | 1篇 |
2019年 | 1篇 |
2017年 | 3篇 |
2016年 | 1篇 |
2015年 | 1篇 |
2014年 | 3篇 |
2013年 | 1篇 |
2012年 | 3篇 |
2011年 | 2篇 |
2009年 | 5篇 |
2008年 | 12篇 |
2007年 | 1篇 |
2006年 | 4篇 |
2005年 | 2篇 |
2004年 | 7篇 |
2003年 | 2篇 |
2002年 | 6篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 3篇 |
1974年 | 1篇 |
排序方式: 共有100条查询结果,搜索用时 15 毫秒
11.
Dragovich PS Blazel JK Ellis DA Han Q Kamran R Kissinger CR LeBrun LA Li LS Murphy DE Noble M Patel RA Ruebsam F Sergeeva MV Shah AM Showalter RE Tran CV Tsan M Webber SE Kirkovsky L Zhou Y 《Bioorganic & medicinal chemistry letters》2008,18(20):5635-5639
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed. 相似文献
12.
Hong Long Yongxin Zhu Meloney Cregor Feifei Tian Lou Coury Candice B. Kissinger Peter T. Kissinger 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2001,763(1-2)
A liquid chromatography method with multi-channel electrochemical detection was developed for the determination of epigallocatechin gallate (EGCG) in rat plasma. After administration of EGCG, blood samples were periodically collected by Culex (an automated blood sampling robot). EGCG was extracted from 50 μl of diluted blood (blood and saline at a ratio of 1:1) with ethyl acetate. Chromatographic separation was achieved within 10 min using a C8 (150×4.6 mm) 5 μm column with a mobile phase containing 20 mM sodium monochloroacetate, pH 2.8 and 12% acetonitrile at a flow-rate of 1.2 ml/min. A four-channel detector with glassy carbon electrodes was used with applied potentials of +700, 600, 500, 400 mV vs. Ag/AgCl. The limit of detection was 2 ng/ml at a signal-to-noise ratio of 3:1 and the limit of quantitation was 5 ng/ml. The calibration curve was linear over the range of 5–800 ng/ml. The intra- and inter-assay precisions were in the range of 1.3–4.5% and 2.2–4.4%, respectively. Using this method it was possible to determine plasma concentration following a single dose of EGCG to rats with good accuracy and precision. Thus the pharmacokinetic properties of EGCG in rats can be examined for intravenous, intraperitoneal and oral dosing. 相似文献
13.
14.
Ruebsam F Webber SE Tran MT Tran CV Murphy DE Zhao J Dragovich PS Kim SH Li LS Zhou Y Han Q Kissinger CR Showalter RE Lardy M Shah AM Tsan M Patel R Lebrun LA Kamran R Sergeeva MV Bartkowski DM Nolan TG Norris DA Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(12):3616-3621
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min). 相似文献
15.
Ellis DA Blazel JK Webber SE Tran CV Dragovich PS Sun Z Ruebsam F McGuire HM Xiang AX Zhao J Li LS Zhou Y Han Q Kissinger CR Showalter RE Lardy M Shah AM Tsan M Patel R LeBrun LA Kamran R Bartkowski DM Nolan TG Norris DA Sergeeva MV Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(16):4628-4632
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min). 相似文献
16.
Antonysamy SS Aubol B Blaney J Browner MF Giannetti AM Harris SF Hébert N Hendle J Hopkins S Jefferson E Kissinger C Leveque V Marciano D McGee E Nájera I Nolan B Tomimoto M Torres E Wright T 《Bioorganic & medicinal chemistry letters》2008,18(9):2990-2995
Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with 1–10 mM binding affinity (KD) were iteratively optimized to give leads with 200 nM biochemical activity and low μM cellular activity in a Replicon assay. 相似文献
17.
The protistan phylum Apicomplexa contains many important pathogens and is the subject of intense genome sequencing efforts. Based upon the genome sequences from seven apicomplexan species and a ciliate outgroup, we identified 268 single-copy genes suitable for phylogenetic inference. Both concatenation and consensus approaches inferred the same species tree topology. This topology is consistent with most prior conceptions of apicomplexan evolution based upon ultrastructural and developmental characters, that is, the piroplasm genera Theileria and Babesia form the sister group to the Plasmodium species, the coccidian genera Eimeria and Toxoplasma are monophyletic and are the sister group to the Plasmodium species and piroplasm genera, and Cryptosporidium forms the sister group to the above mentioned with the ciliate Tetrahymena as the outgroup. The level of incongruence among gene trees appears to be high at first glance; only 19% of the genes support the species tree, and a total of 48 different gene-tree topologies are observed. Detailed investigations suggest that the low signal-to-noise ratio in many genes may be the main source of incongruence. The probability of being consistent with the species tree increases as a function of the minimum bootstrap support observed at tree nodes for a given gene tree. Moreover, gene sequences that generate high bootstrap support are robust to the changes in alignment parameters or phylogenetic method used. However, caution should be taken in that some genes can infer a "wrong" tree with strong support because of paralogy, model violations, or other causes. The importance of examining multiple, unlinked genes that possess a strong phylogenetic signal cannot be overstated. 相似文献
18.
Hyunwoo Park Steven Weier Fareha Razvi Pamela A. Peña Neil A. Sims Jennica Lowell Cory Hungate Karma Kissinger Gavin Key Paul Fraser Johnathan A. Napier Edgar B. Cahoon Tom E. Clemente 《Plant biotechnology journal》2017,15(2):227-236
Soya bean (Glycine max (L.) Merr.) is sought after for both its oil and protein components. Genetic approaches to add value to either component are ongoing efforts in soya bean breeding and molecular biology programmes. The former is the primary vegetable oil consumed in the world. Hence, its primary usage is in direct human consumption. As a means to increase its utility in feed applications, thereby expanding the market of soya bean coproducts, we investigated the simultaneous displacement of marine ingredients in aquafeeds with soya bean‐based protein and a high Omega‐3 fatty acid soya bean oil, enriched with alpha‐linolenic and stearidonic acids, in both steelhead trout (Oncorhynchus mykiss) and Kampachi (Seriola rivoliana). Communicated herein are aquafeed formulations with major reduction in marine ingredients that translates to more total Omega‐3 fatty acids in harvested flesh. Building off of these findings, subsequent efforts were directed towards a genetic strategy that would translate to a prototype design of an optimal identity‐preserved soya bean‐based feedstock for aquaculture, whereby a multigene stack approach for the targeted synthesis of two value‐added output traits, eicosapentaenoic acid and the ketocarotenoid, astaxanthin, were introduced into the crop. To this end, the systematic introduction of seven transgenic cassettes into soya bean, and the molecular and phenotypic evaluation of the derived novel events are described. 相似文献
19.
Stwora-Wojczyk MM Kissinger JC Spitalnik SL Wojczyk BS 《International journal for parasitology》2004,34(3):309-322
The initiation of mucin-type O-glycosylation is catalysed by a family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (EC 2.4.1.41). These enzymes are responsible for the transfer of N-acetylgalactosamine from the nucleotide sugar donor, UDP-GalNAc, to the hydroxyl group on specific serine or threonine residues in acceptor proteins. By screening a Toxoplasma gondii cDNA library, three distinct isoforms of the ppGalNAc-T gene family were cloned. Two additional isoforms were identified and partially cloned following analysis of the T. gondii genome sequence database. All of the cloned and identified ppGalNAc-T's are type II membrane proteins that share up to 50% amino acid sequence identity within the conserved catalytic domain. They each contain an N-terminal cytoplasmic domain, a hydrophobic transmembrane domain, and a lumenal domain; the latter consists of stem, catalytic, and lectin-like domains. Moreover, each of this ppGalNAc-T's contains important sequence motifs that are typical for this class of glycosyltransferases. These include a glycosyltransferase 1 motif containing the DXH sequence, a Gal/GalNAc-T motif, and the CLD and QXW sequence motifs located in alpha-, beta-, and gamma-repeats present within the lectin-like domain. The coding regions of T. gondii ppGalNAc-T1, -T2, and -T3 reside in multiple exons ranging in number from 6 to 10. Our results demonstrate that mucin-type O-glycosylation in T. gondii is catalysed by a multimember gene family, which is evolutionarily conserved from single-celled eukaryotes through nematodes and insects up to mammals. Taken together, this information creates the basis for future studies of the function of the ppGalNAc-T gene family in the pathobiology of this apicomplexan parasite. 相似文献
20.
Bharath Balu Chitra Chauhan Steven P Maher Douglas A Shoue Jessica C Kissinger Malcolm J Fraser John H Adams 《BMC microbiology》2009,9(1):83