全文获取类型
收费全文 | 11840篇 |
免费 | 964篇 |
国内免费 | 11篇 |
出版年
2023年 | 56篇 |
2022年 | 97篇 |
2021年 | 238篇 |
2020年 | 106篇 |
2019年 | 153篇 |
2018年 | 215篇 |
2017年 | 164篇 |
2016年 | 289篇 |
2015年 | 508篇 |
2014年 | 594篇 |
2013年 | 796篇 |
2012年 | 892篇 |
2011年 | 923篇 |
2010年 | 578篇 |
2009年 | 505篇 |
2008年 | 774篇 |
2007年 | 784篇 |
2006年 | 710篇 |
2005年 | 684篇 |
2004年 | 678篇 |
2003年 | 638篇 |
2002年 | 568篇 |
2001年 | 120篇 |
2000年 | 86篇 |
1999年 | 131篇 |
1998年 | 173篇 |
1997年 | 109篇 |
1996年 | 89篇 |
1995年 | 96篇 |
1994年 | 104篇 |
1993年 | 94篇 |
1992年 | 79篇 |
1991年 | 55篇 |
1990年 | 59篇 |
1989年 | 55篇 |
1988年 | 56篇 |
1987年 | 38篇 |
1986年 | 34篇 |
1985年 | 37篇 |
1984年 | 45篇 |
1983年 | 35篇 |
1982年 | 35篇 |
1981年 | 40篇 |
1980年 | 45篇 |
1979年 | 37篇 |
1978年 | 23篇 |
1977年 | 25篇 |
1976年 | 21篇 |
1974年 | 20篇 |
1973年 | 22篇 |
排序方式: 共有10000条查询结果,搜索用时 125 毫秒
871.
872.
Molle V Gulten G Vilchèze C Veyron-Churlet R Zanella-Cléon I Sacchettini JC Jacobs WR Kremer L 《Molecular microbiology》2010,78(6):1591-1605
The remarkable survival ability of Mycobacterium tuberculosis in infected hosts is related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate expression of these lipids in response to environmental changes are unknown. Here we demonstrate that the enoyl-ACP reductase activity of InhA, an essential enzyme of the mycolic acid biosynthetic pathway and the primary target of the anti-tubercular drug isoniazid, is controlled via phosphorylation. Thr-266 is the unique kinase phosphoacceptor, both in vitro and in vivo. The physiological relevance of Thr-266 phosphorylation was demonstrated using inhA phosphoablative (T266A) or phosphomimetic (T266D/E) mutants. Enoyl reductase activity was severely impaired in the mimetic mutants in vitro, as a consequence of a reduced binding affinity to NADH. Importantly, introduction of inhA_T266D/E failed to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment. This study suggests that phosphorylation of InhA may represent an unusual mechanism that allows M. tuberculosis to regulate its mycolic acid content, thus offering a new approach to future anti-tuberculosis drug development. 相似文献
873.
Tyagarajan S Chakravarty PK Zhou B Taylor B Eid R Fisher MH Parsons WH Wyvratt MJ Lyons KA Klatt T Li X Kumar S Williams B Felix J Priest BT Brochu RM Warren V Smith M Garcia M Kaczorowski GJ Martin WJ Abbadie C McGowan E Jochnowitz N Weber A Duffy JL 《Bioorganic & medicinal chemistry letters》2010,20(24):7479-7482
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain. 相似文献
874.
Robert M. Tynebor Meng-Hsin Chen Swaminathan R. Natarajan Edward A. O’Neill James E. Thompson Catherine E. Fitzgerald Stephen J. O’Keefe James B. Doherty 《Bioorganic & medicinal chemistry letters》2010,20(9):2765-2769
The development and synthesis of potent p38α MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed. 相似文献
875.
Liming Dong Joseph Marakovits Xinjun Hou Chuangxing Guo Samantha Greasley Eleanor Dagostino RoseAnn Ferre M. Catherine Johnson Eugenia Kraynov James Thomson Ved Pathak Brion W. Murray 《Bioorganic & medicinal chemistry letters》2010,20(7):2210-2214
Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. 相似文献
876.
Catherine S. Reed Robert W. Huigens Steven A. Rogers Christian Melander 《Bioorganic & medicinal chemistry letters》2010,20(21):6310-6312
The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC50 of 13 μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400 μM. 相似文献
877.
Romy F.J. Janser Ranjith K. Meka Zack E. Bryant Enoch A. Adogla Elizabeth K. Vogel Jaimie L. Wharton Cynthia M. Tilley Catherine N. Kaminski Seth L. Ferrey Severine Van slambrouck Wim F.A. Steelant Ingo Janser 《Bioorganic & medicinal chemistry letters》2010,20(6):1848-1850
A series of ethacrynic acid analogues, lacking the α,β-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, MCF-7/AZ. Several of the analogues were already active in the low micromolar range, whereas ethacrynic acid itself shows no potential to inhibit the migration of these cancer cells. Preliminary studies show that the presence of one or more methoxy groups at the phenyl ring of ethacrynic acid is important in order for the ethacrynic acid analogues to demonstrate an inhibitory effect on the migration. 相似文献
878.
879.
Jinxi Li Kevin Shefcheck John Callahan Catherine Fenselau 《Protein science : a publication of the Protein Society》2010,19(1):174-182
The Ara h 2 proteins are major determinants of peanut allergens. These proteins have not been fully studied at the molecular level. It has been previously proposed that there are two isoforms of Ara h 2, based on primary structures that were deduced from two reported cDNA sequences. In this report, four isoforms have been purified and characterized individually. Mass spectrometric methods have been used to determine the protein sequences and to define post‐translational modifications for all four isoforms. Two pairs of isoforms have been identified, corresponding to a long‐chain form and a form that is shorter by 12 amino acids. Each pair is further differentiated by the presence or absence of a two amino acid sequence at the carboxyl terminus of the protein. Modifications that were characterized include site‐specific hydroxylation of proline residues, but no glycosylation was found, in contrast to previous reports. 相似文献
880.
Bethany L. Wienholz Michael S. Kareta Amir H. Moarefi Catherine A. Gordon Paul A. Ginno Frédéric Chédin 《PLoS genetics》2010,6(9)
The DNTM3A and DNMT3B de novo DNA methyltransferases (DNMTs) are responsible for setting genomic DNA methylation patterns, a key layer of epigenetic information. Here, using an in vivo episomal methylation assay and extensive bisulfite methylation sequencing, we show that human DNMT3A and DNMT3B possess significant and distinct flanking sequence preferences for target CpG sites. Selection for high or low efficiency sites is mediated by the base composition at the −2 and +2 positions flanking the CpG site for DNMT3A, and at the −1 and +1 positions for DNMT3B. This intrinsic preference reproducibly leads to the formation of specific de novo methylation patterns characterized by up to 34-fold variations in the efficiency of DNA methylation at individual sites. Furthermore, analysis of the distribution of signature methylation hotspot and coldspot motifs suggests that DNMT flanking sequence preference has contributed to shaping the composition of CpG islands in the human genome. Our results also show that the DNMT3L stimulatory factor modulates the formation of de novo methylation patterns in two ways. First, DNMT3L selectively focuses the DNA methylation machinery on properly chromatinized DNA templates. Second, DNMT3L attenuates the impact of the intrinsic DNMT flanking sequence preference by providing a much greater boost to the methylation of poorly methylated sites, thus promoting the formation of broader and more uniform methylation patterns. This study offers insights into the manner by which DNA methylation patterns are deposited and reveals a new level of interplay between members of the de novo DNMT family. 相似文献