全文获取类型
收费全文 | 1451篇 |
免费 | 103篇 |
国内免费 | 1篇 |
出版年
2023年 | 21篇 |
2022年 | 28篇 |
2021年 | 55篇 |
2020年 | 32篇 |
2019年 | 26篇 |
2018年 | 41篇 |
2017年 | 42篇 |
2016年 | 64篇 |
2015年 | 71篇 |
2014年 | 70篇 |
2013年 | 108篇 |
2012年 | 140篇 |
2011年 | 126篇 |
2010年 | 84篇 |
2009年 | 54篇 |
2008年 | 74篇 |
2007年 | 51篇 |
2006年 | 56篇 |
2005年 | 47篇 |
2004年 | 65篇 |
2003年 | 38篇 |
2002年 | 36篇 |
2001年 | 35篇 |
2000年 | 27篇 |
1999年 | 23篇 |
1998年 | 11篇 |
1997年 | 10篇 |
1996年 | 6篇 |
1995年 | 6篇 |
1994年 | 6篇 |
1993年 | 8篇 |
1992年 | 5篇 |
1991年 | 12篇 |
1990年 | 7篇 |
1989年 | 9篇 |
1988年 | 5篇 |
1987年 | 9篇 |
1986年 | 3篇 |
1985年 | 8篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1975年 | 1篇 |
1972年 | 2篇 |
1970年 | 1篇 |
排序方式: 共有1555条查询结果,搜索用时 31 毫秒
101.
Gupte R Siddam A Lu Y Li W Fujiwara Y Panupinthu N Pham TC Baker DL Parrill AL Gotoh M Murakami-Murofushi K Kobayashi S Mills GB Tigyi G Miller DD 《Bioorganic & medicinal chemistry letters》2010,20(24):7525-7528
Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA(5) GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA(5) compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics. 相似文献
102.
Greg Clark Michael Wu Noel Wat James Onyirimba Trieu Pham Niculin Herz Justin Ogoti Delmy Gomez Arinda A. Canales Gabriela Aranda Misha Blizard Taylor Nyberg Anne Terry Jonathan Torres Jian Wu Stanley J. Roux 《Plant molecular biology》2010,74(4-5):423-435
Root hairs secrete ATP as they grow, and extracellular ATP and ADP can trigger signaling pathways that regulate plant cell growth. In several plant tissues the level of extracellular nucleotides is limited in part by ectoapyrases (ecto-NTPDases), and the growth of these tissues is strongly influenced by their level of ectoapyrase expression. Both chemical inhibition of ectoapyrase activity and suppression of the expression of two ectoapyrase enzymes by RNAi in Arabidopsis resulted in inhibition of root hair growth. As assayed by a dose-response curve, different concentrations of the poorly hydrolysable nucleotides, ATPγS and ADPβS, could either stimulate (at 7.5–25 μM) or inhibit (at ≥ 150 μM) the growth rate of root hairs in less than an hour. Equal amounts of AMPS, used as a control, had no effect on root hair growth. Root hairs of nia1nia2 mutants, which are suppressed in nitric oxide (NO) production, and of atrbohD/F mutants, which are suppressed in the production of H2O2, did not show growth responses to applied nucleotides, indicating that the growth changes induced by these nucleotides in wild-type plants were likely transduced via NO and H2O2 signals. Consistent with this interpretation, treatment of root hairs with different concentrations of ATPγS induced different accumulations of NO and H2O2 in root hair tips. Two mammalian purinoceptor antagonists also blocked the growth responses induced by extracellular nucleotides, suggesting that they were initiated by a receptor-based mechanism. 相似文献
103.
Monique Deu F. Sagnard J. Chantereau C. Calatayud Y. Vigouroux J. L. Pham C. Mariac I. Kapran A. Mamadou B. Gérard J. Ndjeunga G. Bezançon 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,120(7):1301-1313
The dynamics of crop genetic diversity need to be assessed to draw up monitoring and conservation priorities. However, few surveys have been conducted in centres of diversity. Sub-Saharan Africa is the centre of origin of sorghum. Most Sahel countries have been faced with major human, environmental and social changes in recent decades, which are suspected to cause genetic erosion. Sorghum is the second staple cereal in Niger, a centre of diversity for this crop. Niger was submitted to recurrent drought period and to major social changes during these last decades. We report here on a spatio-temporal analysis of sorghum genetic diversity, conducted in 71 villages covering the rainfall gradient and range of agro-ecological conditions in Niger’s agricultural areas. We used 28 microsatellite markers and applied spatial and genetic clustering methods to investigate change in genetic diversity over a 26-year period (1976–2003). Global genetic differentiation between the two collections was very low (F st = 0.0025). Most of the spatial clusters presented no major differentiation, as measured by F st, and showed stability or an increase in allelic richness, except for two of them located in eastern Niger. The genetic clusters identified by Bayesian analysis did not show a major change between the two collections in the distribution of accessions between them or in their spatial location. These results suggest that farmers’ management has globally preserved sorghum genetic diversity in Niger. 相似文献
104.
Background
The alteration of fatty acid profiles in soybean [Glycine max (L.) Merr.] to improve soybean oil quality is an important and evolving theme in soybean research to meet nutritional needs and industrial criteria in the modern market. Soybean oil with elevated oleic acid is desirable because this monounsaturated fatty acid improves the nutrition and oxidative stability of the oil. Commodity soybean oil typically contains 20% oleic acid and the target for high oleic acid soybean oil is approximately 80% of the oil; previous conventional plant breeding research to raise the oleic acid level to just 50-60% of the oil was hindered by the genetic complexity and environmental instability of the trait. The objective of this work was to create the high oleic acid trait in soybeans by identifying and combining mutations in two delta-twelve fatty acid desaturase genes, FAD2-1A and FAD2-1B. 相似文献105.
106.
107.
A covalent inhibitor targeting an intermediate conformation of the fusogenic subunit of the HIV-1 envelope complex 总被引:1,自引:0,他引:1
Jacobs A Quraishi O Huang X Bousquet-Gagnon N Nault G Francella N Alvord WG Pham N Soucy C Robitaille M Bridon D Blumenthal R 《The Journal of biological chemistry》2007,282(44):32406-32413
Peptide inhibitors corresponding to sequences in the six helix bundle structure of the fusogenic portion (gp41) of the HIV envelope glycoprotein have been successfully implemented in preventing HIV entry. These peptides bind to regions in HIV gp41 transiently exposed during the fusion reaction. In an effort to improve upon these entry inhibitors, we have successfully designed and tested peptide analogs composed of chemical spacers and reactive moieties positioned strategically to facilitate covalent attachment. Using a temperature-arrested state prime wash in vitro assay we show evidence for the trapping of a pre-six helix bundle fusion intermediate by a covalent reaction with the specific anti-HIV-1 peptide. This is the first demonstration of the trapping of an intermediate conformation of a viral envelope glycoprotein during the fusion process that occurs in live cells. The permanent specific attachment of the covalent inhibitor is projected to improve the pharmacokinetics of administration in vivo and thereby improve the long-term sustainability of peptide entry inhibitor therapy and help to expand its applicability beyond salvage therapy. 相似文献
108.
109.
Stewart CR Wilson LM Zhang Q Pham CL Waddington LJ Staples MK Stapleton D Kelly JW Howlett GJ 《Biochemistry》2007,46(18):5552-5561
Apolipoprotein amyloid deposits and lipid oxidation products are colocalized in human atherosclerotic tissue. In this study we show that the primary ozonolysis product of cholesterol, 3beta-hydroxy-5-oxo-5,6-secocholestan-6-al (KA), rapidly promotes human apolipoprotein (apo) C-II amyloid fibril formation in vitro. Previous studies show that hydrophobic aldehydes, including KA, modify proteins by the formation of a Schiff base with the lysine epsilon-amino group or N-terminal amino group. High-performance liquid chromatography, mass spectrometry, and proteolysis of KA-modified apoC-II revealed that KA randomly modified six different lysine residues, with primarily one KA attached per apoC-II molecule. Competition experiments showed that an aldehyde scavenging compound partially inhibited the ability of KA to hasten apoC-II fibril formation. Conversely, the acid derivative of KA, lacking the ability to form a Schiff base, accelerated apoC-II fibril formation, albeit to a lesser extent, suggesting that amyloidogenesis triggered by KA involves both covalent and noncovalent mechanisms. The viability of a noncovalent mechanism mediated by KA has been observed previously with alpha-synuclein aggregation, implicated in Parkinson's disease. Electron microscopy demonstrated that fibrils formed in the presence of KA had a similar morphology to native fibrils; however, the isolated KA-apoC-II covalent adducts in the absence of unmodified apoC-II formed fibrillar structures with altered ropelike morphologies. KA-mediated fibril formation by apoC-II was inhibited by the addition of the amine-containing compound hydralazine and the lipid-binding protein apoA-I. These in vitro studies suggest that the oxidized small molecule pool could trigger or hasten the aggregation of apoC-II to form amyloid deposits. 相似文献
110.