全文获取类型
收费全文 | 838篇 |
免费 | 66篇 |
出版年
2022年 | 9篇 |
2021年 | 14篇 |
2020年 | 10篇 |
2019年 | 15篇 |
2018年 | 17篇 |
2017年 | 7篇 |
2016年 | 17篇 |
2015年 | 29篇 |
2014年 | 28篇 |
2013年 | 53篇 |
2012年 | 66篇 |
2011年 | 46篇 |
2010年 | 28篇 |
2009年 | 30篇 |
2008年 | 45篇 |
2007年 | 49篇 |
2006年 | 29篇 |
2005年 | 28篇 |
2004年 | 34篇 |
2003年 | 30篇 |
2002年 | 33篇 |
2001年 | 16篇 |
2000年 | 16篇 |
1999年 | 19篇 |
1998年 | 10篇 |
1997年 | 8篇 |
1996年 | 8篇 |
1992年 | 8篇 |
1991年 | 10篇 |
1990年 | 8篇 |
1989年 | 16篇 |
1988年 | 8篇 |
1987年 | 6篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 12篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1980年 | 7篇 |
1979年 | 17篇 |
1978年 | 6篇 |
1977年 | 5篇 |
1976年 | 8篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1973年 | 12篇 |
1972年 | 5篇 |
1971年 | 6篇 |
1970年 | 5篇 |
排序方式: 共有904条查询结果,搜索用时 663 毫秒
101.
Manchukonda NK Sridhar B Naik PK Joshi HC Kantevari S 《Bioorganic & medicinal chemistry letters》2012,22(8):2983-2987
Facile synthesis of natural α-noscapine analogue, 9-amino-α-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-noscapine (obtained by bromination of natural α-noscapine) with NaN(3) in DMSO at 130°C in the presence of L-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-α-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units. 相似文献
102.
Dinesh Addla Balasubramanian Sridhar Anjana Devi Srinivas Kantevari 《Bioorganic & medicinal chemistry letters》2012,22(24):7475-7480
A series of novel 1-benzyl-2-butyl-4-chloroimidazole embodied 4-azafluorenone hybrids, designed via molecular hybridization approach, were synthesized in very good yields using one pot condensation of 1-benzyl-2-butyl-4-chloroimidazole-5-carboxaldehyde, 1,3-indanedione, aryl/heteroaryl methyl ketones and ammonium acetate. All the synthetic derivatives were fully characterized by spectral data and evaluated for antimicrobial activity by disc diffusion method against selected bacteria and fungal strains. Among the 15 new compounds screened, 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(furan-2-yl)-5H-indeno[1,2-b]pyridin-5-one(10k) has pronounced activity with higher zone of inhibition (ZoI) against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Aspergillus flavus and Candida albicans. Also 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(dibenzo[b,d]thiophen-2-yl)-5H-indeno [1,2-b]pyridin-5-one (10n) and 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(3-tosyl-3H-inden-1-yl)-5H-indeno[1,2-b]pyridin-5-one (10o) showed selective higher inhibitory activity against Aspergillus flavus and Candida albicans. The results demonstrated potential importance of molecular hybridization in the development of 10k as potential antimicrobial agent. 相似文献
103.
Carey J Benoff B Harish B Yuan L Lawson CL 《Protein science : a publication of the Protein Society》2012,21(1):63-74
Extensive environment-dependent rearrangement of the helix-turn-helix DNA recognition region and adjacent L-tryptophan binding pocket is reported in the crystal structure of dimeric E. coli trp aporepressor with point mutation Leu75Phe. In one of two subunits, the eight residues immediately C-terminal to the mutation are shifted forward in helical register by three positions, and the five following residues form an extrahelical loop accommodating the register shift. In contrast, the second subunit has wildtype-like conformation, as do both subunits in an isomorphous wildtype control structure. Treated together as an ensemble pair, the distorted and wildtype-like conformations of the mutant apoprotein agree more fully than either conformation alone with previously reported NOE measurements, and account more completely for its diverse biochemical and biophysical properties. The register-shifted segment Ile79-Ala80-Thr81-Ile82-Thr83 is helical in both conformations despite low helical propensity, suggesting an important structural role for the steric constraints imposed by β-branched residues in helical conformation. 相似文献
104.
105.
106.
Experimental conditions or the presence of interacting components can lead to variations in the structural models of macromolecules. However, the role of these factors in conformational selection is often omitted by in silico methods to extract dynamic information from protein structural models. Structures of small peptides, considered building blocks for larger macromolecular structural models, can substantially differ in the context of a larger protein. This limitation is more evident in the case of modeling large multi-subunit macromolecular complexes using structures of the individual protein components. Here we report an analysis of variations in structural models of proteins with high sequence similarity. These models were analyzed for sequence features of the protein, the role of scaffolding segments including interacting proteins or affinity tags and the chemical components in the experimental conditions. Conformational features in these structural models could be rationalized by conformational selection events, perhaps induced by experimental conditions. This analysis was performed on a non-redundant dataset of protein structures from different SCOP classes. The sequence-conformation correlations that we note here suggest additional features that could be incorporated by in silico methods to extract dynamic information from protein structural models. 相似文献
107.
108.
Krishnamurthy B Mariana L Gellert SA Colman PG Harrison LC Lew AM Santamaria P Thomas HE Kay TW 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(7):4458-4464
T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) induce diabetes in nonobese diabetic (NOD) mice. TCR transgenic mice with CD8(+) T cells specific for IGRP(206-214) (NOD8.3 mice) develop accelerated diabetes that requires CD4(+) T cell help. We previously showed that immune responses against proinsulin are necessary for IGRP(206-214)-specific CD8(+) T cells to expand. In this study, we show that diabetes development is dramatically reduced in NOD8.3 mice crossed to NOD mice tolerant to proinsulin (NOD-PI mice). This indicates that immunity to proinsulin is even required in the great majority of NOD8.3 mice that have a pre-existing repertoire of IGRP(206-214)-specific cells. However, protection from diabetes could be overcome by inducing islet inflammation either by a single dose of streptozotocin or anti-CD40 agonist Ab treatment. This suggests that islet inflammation can substitute for proinsulin-specific CD4(+) T cell help to activate IGRP(206-214)-specific T cells. 相似文献
109.
The use of ordered, high-aspect ratio nanopillar arrays on the surface of silicon-based chips to enhance signal intensity in DNA microarrays is reported. These nanopillars consisting either of a single silicon dioxide substrate or a dual silicon/silicon dioxide substrate are fabricated using deep-UV lithography followed by reactive ion etching. These pillar type arrays provide a three-dimensional high surface-density platform that increases the immobilization capacity of captured probes, enhances target accessibility and reduces background noise interference in DNA microarrays, leading to improved signal-to-noise ratios, sensitivity and specificity. Consequently, it was found that the use of such nanopillars enhanced the hybridization signals by up to seven times as compared to silicon dioxide thin film substrates. In addition, hybridization of synthetic targets to capture probes that contained a single-base variation showed that the perfect matched duplex signals on dual-substrate nanopillars can be up to 23 times higher than the mismatched duplex signals, allowing the targets to be unambiguously identified. These results suggest that the nanopillars, particularly the dual-substrate pillars, are able to enhance the hybridization signals and discrimination power in nucleic acids-based detection, providing an alternative platform for improving the performance of DNA microarrays. 相似文献
110.
Bi X Wong WL Ji W Agarwal A Balasubramanian N Yang KL 《Biosensors & bioelectronics》2008,23(10):1442-1448
This paper reports the electrical detection of calcium ions by using silicon nanowires (SiNWs) as channels in a chemically gated field-effect-transistor (FET) configuration. To obtain a selective and sensitive layer for calcium sensing, the SiNWs are modified with a biologically relevant amino acid phosphotyrosine (p-Tyr), which is able to complex calcium ions with high affinity. It is found that when the p-Tyr modified SiNWs are exposed to aqueous solutions containing calcium ions, their conductances increase with the increasing of calcium concentration up to 10microM. In contrast, when the SiNWs are exposed to sodium or potassium, or when they are modified with tyrosine (Tyr), no significant increase in the conductance is observed. This finding suggests that the calcium ions complexed with the phosphate group of p-Tyr can act as a positive gate voltage on the FET device comprising of n-type SiNWs, and leads to an increase in their conductances. The FET device is also sensitive to magnesium ions. However, the response is 10 times lower than that of calcium at the same concentration. The study reported here may pave the way for designing an intracellular calcium sensor which permits the monitoring of calcium concentration in real time. 相似文献