全文获取类型
收费全文 | 527篇 |
免费 | 75篇 |
专业分类
602篇 |
出版年
2022年 | 5篇 |
2021年 | 10篇 |
2020年 | 4篇 |
2019年 | 4篇 |
2018年 | 7篇 |
2017年 | 8篇 |
2016年 | 8篇 |
2015年 | 15篇 |
2014年 | 20篇 |
2013年 | 17篇 |
2012年 | 28篇 |
2011年 | 22篇 |
2010年 | 24篇 |
2009年 | 17篇 |
2008年 | 24篇 |
2007年 | 27篇 |
2006年 | 28篇 |
2005年 | 18篇 |
2004年 | 17篇 |
2003年 | 24篇 |
2002年 | 17篇 |
2001年 | 21篇 |
2000年 | 16篇 |
1999年 | 15篇 |
1998年 | 4篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 12篇 |
1991年 | 11篇 |
1990年 | 13篇 |
1989年 | 9篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1986年 | 7篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 9篇 |
1979年 | 21篇 |
1978年 | 16篇 |
1977年 | 12篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1970年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有602条查询结果,搜索用时 15 毫秒
81.
Larsen NA de Prada P Deng SX Mittal A Braskett M Zhu X Wilson IA Landry DW 《Biochemistry》2004,43(25):8067-8076
Catalytic antibody 15A10 hydrolyzes the benzoyl ester of cocaine to form the nonpsychoactive metabolites benzoic acid and ecgonine methylester. Here, we report biochemical and structural studies that characterize the catalytic mechanism. The crystal structure of the cocaine-hydrolyzing monoclonal antibody (mAb) 15A10 has been determined at 2.35 A resolution. The binding pocket is fairly shallow and mainly hydrophobic but with a cluster of three hydrogen-bond donating residues (TrpL96, AsnH33, and TyrH35). Computational docking of the transition state analogue (TSA) indicates that these residues are appropriately positioned to coordinate the phosphonate moiety of the TSA and, hence, form an oxyanion hole. Tyrosine modification of the antibody with tetranitromethane reduced hydrolytic activity to background level. The contribution from these and other residues to catalysis and TSA binding was explored by site-directed mutagenesis of 15A10 expressed in a single chain fragment variable (scFv) format. The TyrH35Phe mutant had 4-fold reduced activity, and TrpL96Ala, TrpL96His, and AsnH33Ala mutants were all inactive. Comparison with an esterolytic antibody D2.3 revealed a similar arrangement of tryptophan, asparagine, and tyrosine residues in the oxyanion hole that stabilizes the transition state for ester hydrolysis. Furthermore, the crystal structure of the bacterial cocaine esterase (cocE) also showed that the cocE employs a tyrosine hydroxyl in the oxyanion hole. Thus, the biochemical and structural data are consistent with the catalytic antibody providing oxyanion stabilization as its major contribution to catalysis. 相似文献
82.
Neu4, a novel human lysosomal lumen sialidase, confers normal phenotype to sialidosis and galactosialidosis cells 总被引:1,自引:0,他引:1
Seyrantepe V Landry K Trudel S Hassan JA Morales CR Pshezhetsky AV 《The Journal of biological chemistry》2004,279(35):37021-37029
Three different mammalian sialidases have been described as follows: lysosomal (Neu1, gene NEU1), cytoplasmic (Neu2, gene NEU2), and plasma membrane (Neu3, gene NEU3). Because of mutations in the NEU1 gene, the inherited deficiency of Neu1 in humans causes the severe multisystemic neurodegenerative disorder sialidosis. Galactosialidosis, a clinically similar disorder, is caused by the secondary Neu1 deficiency because of genetic defects in cathepsin A that form a complex with Neu1 and activate it. In this study we describe a novel lysosomal lumen sialidase encoded by the NEU4 gene on human chromosome 2. We demonstrate that Neu4 is ubiquitously expressed in human tissues and has broad substrate specificity by being active against sialylated oligosaccharides, glycoproteins, and gangliosides. In contrast to Neu1, Neu4 is targeted to lysosomes by the mannose 6-phosphate receptor and does not require association with other proteins for enzymatic activity. Expression of Neu4 in the cells of sialidosis and galactosialidosis patients results in clearance of storage materials from lysosomes suggesting that Neu4 may be useful for developing new therapies for these conditions. 相似文献
83.
84.
Faustino RS Rousseau DC Landry MN Kostenuk AL Pierce GN 《Canadian journal of physiology and pharmacology》2006,84(3-4):469-475
ERK-2 MAP kinase activation induces inhibitory effects on nuclear protein import in vascular smooth muscle cells. The mechanism and characteristics of this effect of ERK-2 were investigated. An unusual dose-dependent effect of ERK-2 on nuclear protein import was identified. At higher concentrations (1 microg/mL) of ERK-2, nuclear protein import was stimulated, whereas lower concentrations (0.04 microg/mL) inhibited import. Intermediate concentrations exerted intermediate effects. The stimulatory and inhibitory effects at the 2 different ERK-2 concentrations were observed in both conventional, permeabilized cell assays of nuclear protein import and with in situ microinjection of smooth muscle cells. The biphasic effects of ERK-2 on import were also found for the other 2 members of the MAPK family, p38 and JNK. RanGAP was identified by structural analysis as a candidate target protein responsible for mediating the effects of ERK-2. After pretreatment with high concentrations of ERK-2, RanGAP activity was significantly increased by approximately 50%. In contrast, low concentrations of ERK-2 significantly attenuated RanGAP activity. These results demonstrate that all 3 members of the MAPK family can alter nuclear protein import in opposite directions depending upon the concentration of ERK-2 used. RanGAP represents the MAP kinase target whereby nuclear transport can be stimulated or inhibited. 相似文献
85.
Millet R Maes L Landry V Sergheraert C Davioud-Charvet E 《Bioorganic & medicinal chemistry letters》2002,12(24):3601-3604
A series of 5-nitro-2-furancarbohydrazides were synthesized. In vitro antitrypanosomal activities of these compounds were determined against the closely related protozoa Trypanosoma cruzi Trypanosoma brucei and discussed in relation to potential targets. 相似文献
86.
Marc Landry Evelyne Vila-Porcile André Calas 《The journal of histochemistry and cytochemistry》2004,52(5):617-627
Whatever the protocol used, electron microscopic immunogold detection still suffers from a lack of sensitivity. In rat supraoptico-posthypophyseal neurons, unlabeled secretory granules are always detectable after electron microscopic immunocytochemistry, and their real status remains questionable. To improve the sensitivity of this approach, we assessed a protocol to visualize either one or the other of co-localized neuropeptides, i.e., vasopressin or galanin, after two successive rounds of immunogold with the same primary antibody performed on both faces of the grid. The use of different-sized gold particles enabled us to visualize the respective contribution of each face of the section to the final labeling. Our results showed a moderate but significant increase in both the proportion of labeled granules and the labeling intensity. Although limited, this improvement of immunogold detection strengthens the relevance of quantitative studies at the electron microscopic level, likely to reveal fine variations of the neuron peptidergic content. However, this enhancement depended on the peptide studied. The present data confirmed a progressive decrease of vasopressin immunoreactivity, already suggested by the single-staining procedure, all along the hypothalamo-posthypophyseal tract. In contrast, labeling intensity for galanin remained steady. Finally, our double-face labeling supported a preferential routing of galanin-containing secretory granules towards dendrites. 相似文献
87.
Differential expression of fatty acid synthase genes,Acl, Fat and Kas,in Capsicum fruit 总被引:1,自引:0,他引:1
Aluru MR Mazourek M Landry LG Curry J Jahn M O'Connell MA 《Journal of experimental botany》2003,54(388):1655-1664
88.
W. Roodly Archer Benoît Lamarche Olivier Driaz Nancy Landry Louise Corneau Jean‐Pierre Desprs Jean Bergeron Patrick Couture Nathalie Bergeron 《Obesity (Silver Spring, Md.)》2003,11(8):978-986
Objective: To examine the extent to which variations in body composition modulate changes in the lipid profile in response to the ad libitum consumption of a diet rich in carbohydrates (CHOs) (high‐CHO diet: 58% of energy as CHOs) or high in fat and in monounsaturated fatty acids (MUFAs) (high‐MUFA diet: 40% of energy as fat, 23% as MUFAs). Research Methods and Procedures: Sixty‐three men were randomly assigned to one of the two diets that they consumed for 6 to 7 weeks. Body composition and fasting plasma lipid levels were measured at the beginning and the end of the dietary intervention. Results: The high‐CHO and high‐MUFA diets induced significant and comparable reductions in body weight and waist circumference. These changes were accompanied by significant and comparable (p < 0.01) reductions in total plasma cholesterol and low‐density lipoprotein cholesterol levels. However, the high‐MUFA diet had more beneficial effects on plasma triglyceride concentrations (p < 0.01) and on plasma high‐density lipoprotein cholesterol levels (p = 0.02) compared with the high‐CHO diet. Diet‐induced changes in waist circumference were significantly associated with changes in low‐density lipoprotein cholesterol levels in the high‐CHO group (r = 0.39, p = 0.03) but not in the high‐MUFA group (r = 0.16, p = 0.38). Discussion: Improvements in plasma lipids induced by the ad libitum consumption of a high‐CHO diet seem to be partly mediated by changes in body weight, whereas lipid changes induced by the high‐MUFA diet seem to be independent of changes in body weight. 相似文献
89.
90.