全文获取类型
收费全文 | 222篇 |
免费 | 16篇 |
专业分类
238篇 |
出版年
2023年 | 1篇 |
2022年 | 3篇 |
2021年 | 5篇 |
2020年 | 3篇 |
2019年 | 5篇 |
2018年 | 3篇 |
2017年 | 1篇 |
2016年 | 3篇 |
2015年 | 7篇 |
2014年 | 12篇 |
2013年 | 18篇 |
2012年 | 8篇 |
2011年 | 17篇 |
2010年 | 17篇 |
2009年 | 12篇 |
2008年 | 13篇 |
2007年 | 9篇 |
2006年 | 12篇 |
2005年 | 13篇 |
2004年 | 20篇 |
2003年 | 13篇 |
2002年 | 8篇 |
2001年 | 7篇 |
2000年 | 3篇 |
1999年 | 3篇 |
1998年 | 4篇 |
1997年 | 1篇 |
1994年 | 1篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1979年 | 1篇 |
1977年 | 1篇 |
排序方式: 共有238条查询结果,搜索用时 15 毫秒
71.
Multicellular organization and tissue construction has evolved along essentially different lines in plants and animals. Since plants do not run away, but are anchored in the soil, their tissues are more or less firm and stiff. This strength stems 相似文献
72.
Stéphane L. Bogen Ashok Arasappan Francisco Velazquez Melissa Blackman Regina Huelgas Weidong Pan Elise Siegel Latha G. Nair Srikanth Venkatraman Zhuyan Guo Ronald Doll Neng-Yang Shih F. George Njoroge 《Bioorganic & medicinal chemistry》2010,18(5):1854-1865
Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world’s population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P4 pocket by introducing a new sulfonamide moiety and optimization of the P1/P1′ capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P1 residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey. 相似文献
73.
74.
75.
Automation of lead compound design in silico given the structure of the protein target and a definition of its active site vies for the top of the wish list in any drug discovery programme. We present here an enumeration of steps starting from chemical templates and propose a solution at the state of the art, in the form of a system independent comprehensive computational pathway. This methodology is illustrated with cyclooxygenase-2 (COX-2) as a target. We built candidate molecules including a few Non Steroidal Anti-inflammatory Drugs (NSAIDs) from chemical templates, passed them through empirical filters to assess drug-like properties, optimized their geometries, derived partial atomic charges via quantum calculations, performed Monte Carlo docking, carried out molecular mechanics and developed free energy estimates with Molecular Mechanics Generalized Born Solvent Accessibility (MMGBSA) methodology for each of the candidate molecules. For the case of aspirin, we also conducted molecular dynamics on the enzyme, the drug and the complex with explicit solvent followed by binding free energy analysis. Collectively, the results obtained from the above studies viz. sorting of drugs from non-drugs, semi-quantitative estimates of binding free energies, amply demonstrate the viability of the strategy proposed for lead selection/design for biomolecular targets. 相似文献
76.
Aging and acyl-CoA binding protein alter mitochondrial glycerol-3-phosphate acyltransferase activity
It is well known that cellular function declines with age. Since phosphatidic acid (PtdOH) biosynthesis is central to the generation of membrane phospholipids, the hypothesis that aging decreases PtdOH biosynthesis was tested. Glycerol-3-phosphate acyltransferase (GPAT) and lysophosphatidic acid acyltransferase (LAT) activities were examined in isolated mitochondria and microsomes from young and old rat liver. The results show that mitochondrial GPAT preference for palmitoyl-CoA over oleoyl-CoA was only observed if albumin or acyl-CoA binding protein (ACBP) were present in the assay in the young rats. Furthermore, mitochondrial GPAT activity was significantly reduced in the presence of albumin and ACBP in aged mitochondria using palmitoyl-CoA as the substrate. These data show, for the first time, that mitochondrial GPAT acyl-CoA preference is due to the presence of a protein that binds acyl-CoAs, not the enzyme itself, and that aging significantly reduces mitochondrial GPAT activity. 相似文献
77.
78.
79.
Shankar SL Krupski M Parashar B Okwuaka C O'Guin K Mani S Shafit-Zagardo B 《Journal of neurochemistry》2004,90(3):702-711
In this study we evaluated UCN-01, a small molecule that inhibits protein kinases by interacting with the ATP-binding site, as a potential anti-cancer agent for neuroblastoma. UCN-01 was effective at inducing apoptosis in six neuroblastoma cell lines with diverse cellular and genetic phenotypes. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assays, detection of active caspase-3 and cleaved poly ADP-ribose polymerase (PARP) confirmed that UCN-01 induced apoptosis. Cell cycle analysis determined that the UCN-01 treated cells accumulated in S phase by 16 h. Unlike vinblastine and docetaxel that increased survivin expression, UCN-01 treatment did not increase X-linked inhibitor of apoptosis protein (XIAP) and survivin levels. Analysis of specific phosphoepitopes on chk1/2, Akt, and GSK3beta following UCN-01 treatment determined that there was no significant change in phospho-chk1/2. However, there was decreased immunoreactivity at Ser473 and Thr308 of Akt and Ser9 of GSK3beta by 4 h indicating that the Akt survival pathway and downstream signalling was compromised. Thus, UCN-01 was effective at inducing apoptosis in neuroblastoma cell lines. 相似文献
80.
To establish the relevance of the cell wall in metal ion transport, cobalt uptake was examined in Neurospora crassa. Cobalt taken up was largely surface bound (>90%), resulting in a release of calcium and magnesium. Surface-bound cobalt could not enter intracellular locations upon further incubation of mycelia in a metal-free medium. Saturation of the surface with one metal augured subsequent dose-dependent entry of a different metal into intracellular locations. In comparison with the cobalt-resistant mutant, the cobalt-sensitive strain of N. crassa bound less cobalt on the surface but with significant intracellular accumulation. Our results demonstrate the importance of the cell wall in metal transport, toxicity, and resistance in fungi. 相似文献