全文获取类型
收费全文 | 2004篇 |
免费 | 168篇 |
国内免费 | 28篇 |
出版年
2023年 | 25篇 |
2022年 | 23篇 |
2021年 | 76篇 |
2020年 | 42篇 |
2019年 | 55篇 |
2018年 | 69篇 |
2017年 | 56篇 |
2016年 | 76篇 |
2015年 | 102篇 |
2014年 | 112篇 |
2013年 | 145篇 |
2012年 | 176篇 |
2011年 | 169篇 |
2010年 | 96篇 |
2009年 | 79篇 |
2008年 | 121篇 |
2007年 | 101篇 |
2006年 | 79篇 |
2005年 | 82篇 |
2004年 | 70篇 |
2003年 | 58篇 |
2002年 | 50篇 |
2001年 | 23篇 |
2000年 | 25篇 |
1999年 | 23篇 |
1998年 | 28篇 |
1997年 | 12篇 |
1996年 | 14篇 |
1995年 | 9篇 |
1994年 | 16篇 |
1993年 | 16篇 |
1992年 | 24篇 |
1991年 | 10篇 |
1990年 | 21篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 5篇 |
1982年 | 8篇 |
1981年 | 11篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1978年 | 5篇 |
1977年 | 4篇 |
1976年 | 6篇 |
1973年 | 6篇 |
1971年 | 3篇 |
1938年 | 3篇 |
排序方式: 共有2200条查询结果,搜索用时 250 毫秒
991.
992.
Saito S Lasky JA Guo W Nguyen H Mai A Danchuk S Sullivan DE Shan B 《Biochemical and biophysical research communications》2011,408(4):630-634
Background
Endothelial barrier dysfunction (EBD) involves microtubule disassembly and enhanced cell contractility. Histone deacetylase 6 (HDAC6) deacetylates α-tubulin, and thereby destabilizes microtubules. This study investigates a role for HDAC6 in EBD.Methods
EBD was induced with thrombin ± HDAC6 inhibitors (tubacin and MC1575), and assessed by transendothelial electrical resistance (TEER). Markers for microtubule disassembly (α-tubulin and acetylated α-tubulin) and contraction (phosphorylated myosin light chain 2, P-MLC2) were measured using immunoblots and immunofluorescence.Results and conclusion
Thrombin induced a ∼50% decrease in TEER that was abrogated by the HDAC6 inhibitors. Moreover, inhibition of HDAC6 diminished edema in the lung injured by lipopolysaccharide. Lastly, inhibition of HDAC6 attenuated thrombin-induced microtubule disassembly and P-MLC2. Our results suggest that HDAC6 can be targeted to limit EBD. 相似文献993.
Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson–Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design. 相似文献
994.
995.
996.
The restriction endonuclease EcoRV binds two magnesium ions. One of these ions, Mg(A)(2+), binds to the phosphate group where the cleavage occurs and is required for catalysis, but the role of the other ion, Mg(B)(2+) is debated. Here, multiple independent molecular dynamics simulations suggest that Mg(B)(2+) is crucial for achieving a tightly bound protein-DNA complex and stabilizing a conformation that allows cleavage. In the absence of Mg(B)(2+) in all simulations the protein-DNA hydrogen bond network is significantly disrupted and the sharp kink at the central base pair step of the DNA, which is observed in the two-metal complex, is not present. Also, the active site residues rearrange in such a way that the formation of a nucleophile, required for DNA hydrolysis, is unlikely. 相似文献
997.
Diederich S Quinkler M Mai K Schöneshöfer M Baehr V Pfeiffer A Oelkers W Eigendorff E 《Hormones et métabolisme》2011,43(1):66-71
The 11β-hydroxysteroid dehydrogenases (11β-HSDs) play a pivotal role in glucocorticoid (GC) action. 11β-HSD1 is a predominant reductase, activating GCs from inert metabolites, whereas 11β-HSD2 is a potent dehydrogenase inactivating GCs. Knowing the metabolic effects of GCs, a selective inhibition of 11β-HSD1 represents a potential target for therapy of impaired glucose tolerance, insulin insensitivity and central obesity. In vitro, 11β-HSD1 is selectively inhibited by chenodesoxycholic acid (CDCA) and upregulated under GC exposure. Therefore, we aimed to investigate the effects of CDCA and prednisolone on hepatic 11β-HSD1 activity in vivo by measuring 11-reduction of orally given cortisone (E) acetate to cortisol (F). CDCA or placebo was given to 5 male healthy volunteers within a randomised cross-over trial before and after oral administration of 12.5 mg E acetate at 8:00 h. For measurement of in vivo effects of GCs on 11β-HSD1 activity, hepatic reduction of 25 mg E acetate before and after treatment with prednisolone (30 mg for 6 days) was determined in 7 healthy males. Serum GC levels were determined using a fully automated liquid chromatographic system. CDCA had no effect on the activity of 11β-HSD1 in vivo. Prednisolone therapy leads to a marked rise in serum F concentrations and an elevated F/E serum ratio. This proves GC-induced activation of hepatic 11β-HSD1, which could not be extinguished by a parallel increase of IGF-1 under prednisolone. CDCA does not affect in vivo activity of 11β-HSD1 when given in therapeutic dosages. During GC treatment, increased hepatic activation of E to F may aggravate metabolic side effects of GCs such as seen in the metabolic syndrome. 相似文献
998.
999.
Fritz C Pancotto VA Elzenga JT Visser EJ Grootjans AP Pol A Iturraspe R Roelofs JG Smolders AJ 《The New phytologist》2011,190(2):398-408
? Vascular wetland plants may substantially increase methane emissions by producing root exudates and easily degradable litter, and by providing a low-resistance diffusion pathway via their aerenchyma. However, model studies have indicated that vascular plants can reduce methane emission when soil oxygen demand is exceeded by oxygen released from roots. Here, we tested whether these conditions occur in bogs dominated by cushion plants. ? Root-methane interactions were studied by comparing methane emissions, stock and oxygen availability in depth profiles below lawns of either cushion plants or Sphagnum mosses in Patagonia. ? Cushion plants, Astelia pumila and Donatia fascicularis, formed extensive root systems up to 120 cm in depth. The cold soil (< 10°C) and highly decomposed peat resulted in low microbial activity and oxygen consumption. In cushion plant lawns, high soil oxygen coincided with high root densities, but methane emissions were absent. In Sphagnum lawns, methane emissions were substantial. High methane concentrations were only found in soils without cushion plant roots. ? This first methane study in Patagonian bog vegetation reveals lower emissions than expected. We conclude that cushion plants are capable of reducing methane emission on an ecosystem scale by thorough soil and methane oxidation. 相似文献
1000.
Kiso M Ozawa M Le MT Imai H Takahashi K Kakugawa S Noda T Horimoto T Kawaoka Y 《Journal of virology》2011,85(10):4667-4672
Like the histidine-to-tyrosine substitution at position 274 in neuraminidase (NA H274Y), an asparagine-to-serine mutation at position 294 in this protein (NA N294S) confers oseltamivir resistance to highly pathogenic H5N1 influenza A viruses. However, unlike viruses with the NA H274Y mutation, the properties of viruses possessing NA N294S are not well understood. Here, we assessed the effect of the NA N294S substitution on the replication and pathogenicity of human H5N1 viruses and on the efficacy of the NA inhibitors oseltamivir and zanamivir in mouse and ferret models. Although NA N294S-possessing H5N1 viruses were attenuated in mice and ferrets compared to their oseltamivir-sensitive counterparts, one of the infected ferrets died from systemic infection, demonstrating the potential lethality in ferrets of oseltamivir-resistant H5N1 viruses with the NA N294S substitution. The efficacy of oseltamivir, but not that of zanamivir, against an NA N294S-possessing virus was substantially impaired both in ferrets and in vitro. These results demonstrate the considerable pathogenicity of NA N294S substitution-possessing H5N1 viruses and underscore the importance of monitoring the emergence of the NA N294S mutation in circulating H5N1 viruses. 相似文献