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991.
992.
We report the effect of the natural polyphenolic compounds from green tea on the catalytic activity of Ribonuclease A (RNase A). The compounds behave as noncompetitive inhibitors of the protein with inhibition constants ranging from 80-1300 microM. The dissociation constants range from 50-150 microM for the RNase A-polyphenol complexes as determined by ultraviolet (UV) and circular dichroism (CD) studies. We have also investigated the changes in the secondary structure of RNase A on complex formation by CD and Fourier transformed infrared (FTIR) spectroscopy. The presence of the gallate moiety has been shown to be important for the inhibition of enzymatic activity. Docking studies for these compounds indicate that the preferred site of binding is the region encompassing residues 34-39 with possible hydrogen bonding with Lys 7 and Arg 10. Finally we have also looked at changes in the accessible surface area of the interacting residues on complex formation for an insight into the residues involved in the interaction. 相似文献
993.
Genetic deletion in mice of pregnancy-associated plasma protein A (PAPP-A), a recently identified metalloproteinase in the insulin-like growth factor system, extends by 30-40% both mean and maximum lifespan with no reduction in food intake or secondary endocrine abnormalities. Furthermore, these mice have markedly reduced incidence of spontaneous tumors. The findings implicate PAPP-A as a critical regulator of lifespan and age-related diseases, and suggest PAPP-A as a possible target to promote longevity. 相似文献
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997.
Eosinophil derived neurotoxin (EDN) is an eosinophil secretion protein and a member of the Ribonuclease A (RNase A) superfamily involved in the immune response system and inflammatory disorders. The pathological actions of EDN are strongly dependent on the enzymatic activity and therefore, it is of significant interest to discover potent and specific inhibitors of EDN. In this framework we have assessed the inhibitory potency of triazole double-headed ribonucleosides. We present here an efficient method for the heterologous production and purification of EDN together with the synthesis of nucleosides and their biochemical evaluation in RNase A and EDN. Two groups of double-headed nucleosides were synthesized by the attachment of a purine or a pyrimidine base, through a triazole group at the 3′-C position of a pyrimidine or a purine ribonucleoside, respectively. Based on previous data with mononucleosides these compounds were expected to improve the inhibitory potency for RNase A and specificity for EDN. Kinetics data revealed that despite the rational, all but one, double-headed ribonucleosides were less potent than the respective mononucleosides while they were also more specific for ribonuclease A than for EDN. Compound 11c (9-[3′-[4-[(cytosine-1-yl)methyl]-1,2,3-triazol-1-yl]-β-d-ribofuranosyl]adenine) displayed a stronger preference for EDN than for ribonuclease A and a Ki value of 58 μM. This is the first time that an inhibitor is reported to have a better potency for EDN than for RNase A. The crystal structure of EDN–11c complex reveals the structural basis of its potency and selectivity providing important guidelines for future structure-based inhibitor design efforts. 相似文献
998.
Deregulation of Wnt/β-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), and glycogen synthase kinase 3β (GSK-3β), the central negative regulator of Wnt pathway, is regarded as an important target for these diseases. Here, we report a series of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors by rational-design and synthesis, which show high selectivity against GSK-3β over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/β-catenin pathway. The structure–activity relationship of these GSK-3β inhibitors was also explored by in silico molecular docking. 相似文献
999.
为探讨妊娠及哺乳期小鼠(Mus musculus)注射麻黄素后对仔鼠肝组织TGF-β1及c-Fos表达的影响,将30例受孕小鼠随机分为对照组和麻黄素组。麻黄素组小鼠从受孕第3天开始连续腹腔注射6.0 g/L麻黄素溶液直到分娩后15天,每天注射2次,每次0.2 ml;对照组每天2次注射等量的生理盐水。称量检测仔鼠体重和肝重的变化,同时用免疫组织化学方法检测仔鼠肝组织中细胞生长因子TGF-β1和原癌基因c-Fos蛋白表达的变化。麻黄素组仔鼠体重与对照组相比显著降低(P0.05或P0.01),肝体比与对照组相比明显升高(P0.05或P0.01),仔鼠肝组织中TGF-β1和c-Fos蛋白阳性表达强度与对照组相比有不同程度的增强(P0.05或P0.01),表明妊娠及哺乳期小鼠注射麻黄素影响仔鼠肝的发育。 相似文献
1000.
Chun C. Mak 《Molecular simulation》2015,41(1-3):156-167
Charge-transfer-to-solvent excited iodide–polar solvent molecule clusters, [I? (Solv)n]*, have attracted substantial interest over the past 20 years as they can undergo intriguing relaxation processes leading ultimately to the formation of gas-phase molecular analogues of the solvated electron. In this review article, we present a comprehensive overview of the development and application of state-of-the-art first-principles molecular dynamics simulation approaches to understand and interpret the results of femtosecond photoelectron spectroscopy experiments on [I? (Solv)n]* relaxation, which point to a high degree of solvent specificity in the electron solvation dynamics. The intricate molecular details of the [I? (Solv)n]* relaxation process are presented, and by contrasting the relaxation mechanisms of clusters with several different solvents (water, methanol and acetonitrile), the molecular basis of the solvent specificity of electron solvation in [I? (Solv)n]* is uncovered, leading to a more refined view of the manifestation of electron solvation in small gas-phase clusters. 相似文献