全文获取类型
收费全文 | 1435篇 |
免费 | 43篇 |
国内免费 | 92篇 |
出版年
2023年 | 26篇 |
2022年 | 18篇 |
2021年 | 32篇 |
2020年 | 38篇 |
2019年 | 31篇 |
2018年 | 50篇 |
2017年 | 25篇 |
2016年 | 32篇 |
2015年 | 39篇 |
2014年 | 81篇 |
2013年 | 165篇 |
2012年 | 50篇 |
2011年 | 79篇 |
2010年 | 56篇 |
2009年 | 73篇 |
2008年 | 110篇 |
2007年 | 81篇 |
2006年 | 84篇 |
2005年 | 80篇 |
2004年 | 72篇 |
2003年 | 46篇 |
2002年 | 40篇 |
2001年 | 26篇 |
2000年 | 16篇 |
1999年 | 21篇 |
1998年 | 7篇 |
1997年 | 17篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 21篇 |
1993年 | 15篇 |
1992年 | 15篇 |
1991年 | 6篇 |
1990年 | 8篇 |
1989年 | 4篇 |
1988年 | 11篇 |
1987年 | 5篇 |
1986年 | 5篇 |
1985年 | 11篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1974年 | 4篇 |
1973年 | 2篇 |
排序方式: 共有1570条查询结果,搜索用时 203 毫秒
991.
de Medina P Paillasse MR Ségala G Khallouki F Brillouet S Dalenc F Courbon F Record M Poirot M Silvente-Poirot S 《Chemistry and physics of lipids》2011,(6):432-437
Tamoxifen is one of the major drugs used for the hormonotherapy of estrogen receptor positive breast cancers. However, its therapeutic efficacy can be limited by acquired resistance and tumor recurrence can occur after several years of treatment. Tamoxifen is known as the prototypical modulator of estrogen receptors, but other targets have been identified that could account for its pharmacology. In particular, tamoxifen binds with high affinity to the microsomal antiestrogen binding site (AEBS) and inhibits cholesterol esterification at therapeutic doses. We have recently shown that the AEBS was a hetero-oligomeric complex composed of 3β-hydroxysterol-Δ(8)-Δ(7)-isomerase and 3β-hydroxysterol-Δ(7)-reductase, that binds different structural classes of ligands, including selective estrogen receptor modulators, several sigma receptor ligands, poly-unsaturated fatty acids and ring B oxysterols. We established a link between the modulation of cholesterol metabolism by tamoxifen and other AEBS ligands and their capacity to induce breast cancer cell differentiation, apoptosis and autophagy. Moreover, we showed that the AEBS carries out cholesterol-5,6-epoxide hydrolase activity and established that cholesterol-5,6-epoxide hydrolase is a new target for tamoxifen and other AEBS ligands. Finally in this review, we report on recent data from the literature showing how the modulation of cholesterol and oxysterol metabolism can be linked to the antitumor and chemopreventive properties of tamoxifen, and give new perspectives to improve the clinical outcome of the hormonotherapy of breast cancers. 相似文献
992.
St John FJ Hurlbert JC Rice JD Preston JF Pozharski E 《Journal of molecular biology》2011,407(1):92-109
Xylanases of glycosyl hydrolase family 30 (GH30) have been shown to cleave β-1,4 linkages of 4-O-methylglucuronoxylan (MeGXn) as directed by the position along the xylan chain of an α-1,2-linked 4-O-methylglucuronate (MeGA) moiety. Complete hydrolysis of MeGXn by these enzymes results in singly substituted aldouronates having a 4-O-methylglucuronate moiety linked to a xylose penultimate from the reducing terminal xylose and some number of xylose residues toward the nonreducing terminus. This novel mode of action distinguishes GH30 xylanases from the more common xylanase families that cleave MeGXn in accessible regions. To help understand this unique biochemical function, we have determined the structure of XynC in its native and ligand-bound forms. XynC structure models derived from diffraction data of XynC crystal soaks with the simple sugar glucuronate (GA) and the tetrameric sugar 4-O-methyl-aldotetrauronate resulted in models containing GA and 4-O-methyl-aldotriuronate, respectively. Each is observed in two locations within XynC surface openings. Ligand coordination occurs within the XynC catalytic substrate binding cleft and on the structurally fused side β-domain, demonstrating a substrate targeting role for this putative carbohydrate binding module. Structural data reveal that GA acts as a primary functional appendage for recognition and hydrolysis of the MeGXn polymer by the protein. This work compares the structure of XynC with a previously reported homologous enzyme, XynA, from Erwinia chrysanthemi and analyzes the ligand binding sites. Our results identify the molecular interactions that define the unique function of XynC and homologous GH30 enzymes. 相似文献
993.
GH57家族高温淀粉普鲁兰酶的结构与功能分析 总被引:1,自引:0,他引:1
摘要:淀粉普鲁兰酶(E.C. 3.2.1.1/41)同时具有淀粉酶(E.C. 3.2.1.1)和普鲁兰酶(E.C. 3.2.1.41)的功能,属于糖苷水解酶GH13和GH57家族。由于淀粉普鲁兰酶可以同时水解α-1,4和α-1,6糖苷键,在淀粉糖化工业中具有降低生产成本、提高生产效率和提高糖化率的作用。其中高温淀粉普鲁兰酶由于能够在淀粉工业液化条件下同时催化淀粉的液化和糖化反应,因此在淀粉糖化工业中更具有应用价值。另外,淀粉普鲁兰酶的双功能催化机制对酶学研究中也具有重要价值。该文就近年高温淀粉普鲁兰酶的结 相似文献
994.
Senoura T Ito S Taguchi H Higa M Hamada S Matsui H Ozawa T Jin S Watanabe J Wasaki J Ito S 《Biochemical and biophysical research communications》2011,(4):11-706
The consecutive genes BF0771–BF0774 in the genome of Bacteroidesfragilis NCTC 9343 were found to constitute an operon. The functional analysis of BF0772 showed that the gene encoded a novel enzyme, mannosylglucose phosphorylase that catalyzes the reaction, 4-O-β-d-mannopyranosyl-d-glucose + Pi → mannose-1-phosphate + glucose. Here we propose a new mannan catabolic pathway in the anaerobe, which involves 1,4-β-mannanase (BF0771), a mannobiose and/or sugar transporter (BF0773), mannobiose 2-epimerase (BF0774), and mannosylglucose phosphorylase (BF0772), finally progressing to glycolysis. This pathway is distributed in microbes such as Bacteroides, Parabacteroides, Flavobacterium, and Cellvibrio. 相似文献
995.
Glycoside phosphorylases are a special group of carbohydrate-active enzymes, with characteristics in between those of glycoside hydrolases and glycosyl transferases. The phosphorylases from family GH-112 are exceptional because they employ galactose-1-phosphate instead of glucose-1-phosphate as glycosyl donor. Different acceptor specificities have been observed in this family, ranging from l-rhamnose to GlcNAc, GalNAc and a combination of the latter. Three new phosphorylases from previously unexplored branches of the phylogenetic tree of family GH-112 have now been characterized to shed more light on this divergence in acceptor specificity. The enzymes from Erysipelothrix rhusiopathiae and Streptobacillus moniliformis were found to prefer GalNAc as acceptor, while that from Anaerococcus prevotii displays similar activities on GalNAc and GlcNAc. These results confirm the correlation between the amino acid residue at position 162 and the enzyme's specificity, i.e. a threonine in the former group and a valine in the latter. However, mutagenesis of residue 162 did not allow the rational transformation of the substrate preference, as the substitution of valine by threonine in the enzyme from Bifidobacterium longum did not tighten its specificity towards GalNAc. Unexpectedly, introducing an isoleucine at position 162 increased the preference for GlcNAc as acceptor, which illustrates that the structure-function relationships in β-galactoside phosphorylases are not yet completely understood. Several other positions have also been examined by mutational analysis but true determinants of the acceptor specificity in family GH-112 could not be identified. 相似文献
996.
Effector proteins are virulence factors that promote pathogenesis by interfering with various cellular events and are delivered directly into host cells by the secretion systems of many Gram‐negative bacteria. Type III effector protein XOO4466 from the plant pathogen Xanthomonas oryzae pv. oryzae (XopQXoo) and XopQ homologs from other phytopathogens have been predicted to be nucleoside hydrolases based on their sequence similarities. However, despite such similarities, recent structural and functional studies have revealed that XopQXoo does not exhibit the expected activity of a nucleoside hydrolase. On the basis of the conservation of a Ca2+ coordination shell of a ribose‐binding site and the spacious active site in XopQXoo, we hypothesized that a novel compound containing a ribosyl moiety could serve as a substrate for XopQXoo. Here, we report the crystal structure of XopQXoo in complex with adenosine diphosphate ribose (ADPR), which is involved in regulating cytoplasmic Ca2+ concentrations in eukaryotic cells. ADPR is bound to the active site of XopQXoo with its ribosyl end tethered to the Ca2+ coordination shell. The binding of ADPR is further stabilized by interactions mediated by hydrophobic residues that undergo ligand‐induced conformational changes. These data showed that XopQXoo is capable of binding a novel chemical bearing a ribosyl moiety, thereby providing the first step toward understanding the functional role of XopQXoo. Proteins 2014; 82:2910–2914. © 2014 Wiley Periodicals, Inc. 相似文献
997.
The prospect for computer‐aided refinement of stereoselective enzymes is further validated by simulating the ester hydrolysis by the wild‐type and mutants of CalB, focusing on the challenge of dealing with strong steric effects and entropic contributions. This was done using the empirical valence bond (EVB) method in a quantitative screening of the enantioselectivity, considering both kcat and kcat/KM of the R and S stereoisomers. Although the simulations require very extensive sampling for convergence they give encouraging results and major validation, indicating that our approach offers a powerful tool for computer‐aided design of enantioselective enzymes. This is particularly true in cases with large changes in steric effects where alternative approaches may have difficulties in capturing the interplay between steric clashes with the reacting substrate and protein flexibility. Proteins 2014; 82:1387–1399. © 2014 Wiley Periodicals, Inc. 相似文献
998.
《Bioorganic & medicinal chemistry letters》2014,24(9):2193-2197
A series of inhibitors of the soluble epoxide hydrolase (sEH) containing two urea groups has been developed. Inhibition potency of the described compounds ranges from 2.0 μM to 0.4 nM. 1,6-(Hexamethylene)bis[(adamant-1-yl)urea] (3b) was found to be a potent slow tight binding inhibitor (IC50 = 0.5 nM) with a strong binding to sEH (Ki = 3.1 nM) and a moderately long residence time on the enzyme (koff = 1.05 × 10−3 s−1; t1/2 = 11 min). 相似文献
999.
1000.
Accumulated evidence points to a key role for endocannabinoids in cell migration, and here we sought to characterize the role of these substances in early events that modulate communication between endothelial cells and leukocytes. We found that 2-arachidonoylglycerol (2-AG) was able to initiate and complete the leukocyte adhesion cascade, by modulating the expression of selectins. A short exposure of primary human umbilical vein endothelial cells (HUVECs) to 2-AG was sufficient to prime them towards an activated state: within 1 h of treatment, endothelial cells showed time-dependent plasma membrane expression of P- and E-selectins, which both trigger the initial steps (i.e., capture and rolling) of leukocyte adhesion. The effect of 2-AG was mediated by CB1 and CB2 receptors and was long lasting, because endothelial cells incubated with 2-AG for 1 h released the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) for up to 24 h. Consistently, TNF-α-containing medium was able to promote leukocyte recruitment: human Jurkat T cells grown in conditioned medium derived from 2-AG-treated HUVECs showed enhanced L-selectin and P-selectin glycoprotein ligand-1 (PSGL1) expression, as well as increased efficiency of adhesion and trans-migration. In conclusion, our in vitro data indicate that 2-AG, by acting on endothelial cells, might indirectly promote leukocyte recruitment, thus representing a potential therapeutic target for treatment of diseases where impaired endothelium/leukocyte interactions take place. 相似文献