全文获取类型
收费全文 | 876篇 |
免费 | 82篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 21篇 |
2020年 | 7篇 |
2019年 | 9篇 |
2018年 | 20篇 |
2017年 | 7篇 |
2016年 | 20篇 |
2015年 | 31篇 |
2014年 | 37篇 |
2013年 | 57篇 |
2012年 | 90篇 |
2011年 | 61篇 |
2010年 | 49篇 |
2009年 | 45篇 |
2008年 | 57篇 |
2007年 | 50篇 |
2006年 | 37篇 |
2005年 | 52篇 |
2004年 | 49篇 |
2003年 | 67篇 |
2002年 | 61篇 |
2001年 | 8篇 |
2000年 | 8篇 |
1999年 | 16篇 |
1998年 | 12篇 |
1997年 | 9篇 |
1996年 | 6篇 |
1995年 | 1篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 8篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 5篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1978年 | 1篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有958条查询结果,搜索用时 250 毫秒
11.
M Dubois G Némoz M Lagarde A F Prigent 《Biochemical and biophysical research communications》1990,170(2):800-809
Cyclic nucleotide phosphodiesterase activity in rat heart microsomes is attributable to several isoenzymatic forms: a cyclic AMP-specific, a cyclic GMP-specific, and a cyclic GMP-stimulated enzyme. Incubation of microsomes with an exogenous phospholipase C (C. welchii) induced a marked stimulation (+126%) of cyclic AMP phosphodiesterase and a moderate stimulation (+49%) of cyclic GMP-phosphodiesterase in the membrane-bound fraction. Besides, a notable fraction of activity was solubilized by the treatment. A parallel decrease in the activating effect of cyclic GMP on the hydrolysis of cyclic AMP was observed in the membranes (down to 18% of the control effect). It resulted from a marked stimulation of the basal activity, while the activated level was unaffected. The treatment by an exogenous phospholipase D induced more moderate modifications. The addition to microsomes of oleyl,acetyl-glycerol, but not of long chain-diacylglycerols, partly reproduced the phospholipase C effect. Phosphatidate also induced variations in phosphodiesterase activity, and could thus participate in the phospholipase effects. These results suggest that endogenous phospholipases, the activity of which is modulated by hormonal stimuli, might influence phosphodiesterase activity in cardiac membranes by producing phospholipid metabolites, with potential consequences on heart contractility. 相似文献
12.
13.
Interaction of steptolysin O with sterols. 总被引:2,自引:0,他引:2
A quantitative study of the specific inhibitory power of cholesterol and other sterols on the hemolytic properties of streptolysin O is reported. This streptococcal exocellular protein is a cytolytic toxin which disrupts cytoplasmic membranes of eukaryote cells. The structural characteristics, particularly the stereochemical ones required for a steroid molecule to inhibit the cytolytic activity of streptolysin O, have been investigated in detail. By immunodiffusion techniques, in agar gel plates or tubes containing sterols, the formation of hydrophobic complexes between streptolysin O and inhibitory steroids, but not non-inhibitory steroids except lanosterol, is shown. Upon interaction with inhibitory steroids streptolysin O loses its immunoreactive properties towards neutralizing and precipitating homologous antibodies. An interpretation of the mechanism of biomembrane disorganization by streptolysin O is discussed in the light of its steroid binding properties. 相似文献
14.
Hadjila Chabane Christelle Lamazzi Valerie Thiery Alain Pierre Stephane Leonce Bruno Pfeiffer 《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):167-174
Novel thiazolocarbazole derivatives have been synthesized via the corresponding imino-1,2,3-dithiazoles. In vitro antitumor activity of these polyheterocyclic compounds was studied. 相似文献
15.
Jean Guillon Maria Mamani-Matsuda Stephane Massip Jean-Michel Leger Denis Thiolat Djavad Mossalayi 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):391-396
The synthesis of new 7-hydroxy-2-substituted-methyl-5 H -oxazolo[3,2- a] pyrimidin-5-ones derivatives, designed as structural bicyclic analogues of the iron chelator deferiprone, is described. They were tested for their ability to inhibit proliferation in human Bcr-Abl + leukemia cells. 相似文献
16.
Christelle Lamazzi Hadjila Chabane Valerie Thiery Alain Pierre Stephane Leonce Bruno Pfeiffer 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):397-401
Novel thiazolocarbazole derivatives 4 and 5 have been synthesized via the corresponding imino-1,2,3-dithiazoles 3. In vitro antitumor activity of these polyheterocyclic compounds was studied and the results show that 2-cyano derivatives exhibit a medium in vitro antiproliferative effect. 相似文献
17.
Vanessa Desplat Ambre Geneste Marc-Antoine Begorre Solene Belisle Fabre Stephane Brajot Stephane Massip 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):648-658
Akt kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel Akt kinase inhibitors, based on a quinoxaline or pyrazinone scaffold. A series of new substituted pyrrolo[1,2-a]quinoxaline derivatives, structural analogues of these active quinoxaline or pyrazinone pharmacophores, was synthesized from various substituted 2-nitroanilines or 1,2-phenylenediamine via multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937 and HL60, and the breast cancer cell line MCF7. Three of these human cell lines (K562, U937 and MCF7) exhibited an active phosphorylated Akt form. The most promising active pyrroloquinoxalines were found to be 1a that inhibited K562 cell line proliferation with an IC50 of 4.5 μM, and 1h that inhibited U937 and MCF7 cell lines with IC50 of 5 and 8 μM, respectively. These two candidates exhibited more potent activities than the reference inhibitor A6730. 相似文献
18.
Jean-Jacques Legrand Cecile Fisch Pierre-Olivier Guillaumat Jean-Marc Pavard Mahmoud Attia Stephane De Jouffrey 《Biomarkers》2013,18(1):63-77
The ovariectomized old cynomolgus monkey is a recognized model of human osteoporosis, and the same species can be used for the assessment of the efficacy and potential toxicity of agents intended to prevent or treat osteoporosis. Several assays have been developed that can measure the same biochemical markers of bone turnover as are used in human patients for the diagnosis and treatment follow-up of bone-related diseases, including osteoporosis. The aim of the present study was to describe the results obtained with these assays in normal control monkeys, their variations with age and sex, and their sensitivity in monitoring the bone turnover induced by ovariectomy in old skeletally mature cynomolgus monkeys. Seven old cynomolgus monkeys were bilaterally ovariectomized and 13 age-matched monkeys were sham-operated. Bone mineral density and biochemical markers were measured before and at regular intervals after surgery for up to 20 months. Total alkaline phosphatase (total ALP), bone-specific alkaline phosphatase isoenzyme (bone ALP) and osteocalcin (OC) were highly correlated to the decrease in bone mineral density (BMD) induced by ovariectomy. Deoxypyridinoline (DPD) measured by enzyme-linked immunoassay was insensitive to the bone resorption induced by ovariectomy, but cross-linked N-telopeptide (NTX-I) was higher in ovariectomized monkeys than in control monkeys. These results demonstrate that reliable biochemical parameters are available to adequately monitor and provide insight into osteoclastic bone resorption and osteoblastic bone formation, the two components of bone turnover in this animal model, and can thus be used to assess the efficacy and toxicity of potential therapeutic agents. 相似文献
19.
Vincent M. Lam Pieter Beerepoot Stephane Angers Ali Salahpour 《Traffic (Copenhagen, Denmark)》2013,14(7):778-784
The trafficking of membrane proteins is dynamic and contributes to the homeostatic control of their cell surface localization and their function in signal transduction. Therefore, it is important to have sensitive techniques that allow measurement of surface expression. The current assays for such measurement are time consuming and low throughput. Here, we describe a quantitative, one‐step and potentially high‐throughput assay, using the β‐lactamase enzyme (βlac) as a reporter, for measurement of surface expression of proteins. In this assay, the βlac is fused to the extracellular portion of the plasma membrane protein of interest. To selectively measure surface expression, a cell‐impermeable substrate of βlac, nitrocefin, is used. We demonstrate the utility of the βlac assay using well‐established paradigms of internalization and molecular chaperoning, applied to two G‐protein‐coupled receptors and a monoamine transporter. Considering its simplicity and low cost, this assay could become a standard technique in the measurement of protein surface expression . 相似文献
20.