首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   1532956篇
  免费   134968篇
  国内免费   5737篇
  2021年   17195篇
  2020年   15981篇
  2019年   20052篇
  2018年   22144篇
  2017年   20049篇
  2016年   32243篇
  2015年   47932篇
  2014年   56988篇
  2013年   83602篇
  2012年   49283篇
  2011年   38085篇
  2010年   49531篇
  2009年   49888篇
  2008年   32946篇
  2007年   30831篇
  2006年   34271篇
  2005年   34359篇
  2004年   32987篇
  2003年   30191篇
  2002年   27730篇
  2001年   45249篇
  2000年   42358篇
  1999年   39160篇
  1998年   25776篇
  1997年   25782篇
  1996年   24818篇
  1995年   24262篇
  1994年   24001篇
  1993年   22984篇
  1992年   32692篇
  1991年   30669篇
  1990年   28973篇
  1989年   29472篇
  1988年   26876篇
  1987年   25221篇
  1986年   23900篇
  1985年   25537篇
  1984年   24583篇
  1983年   21513篇
  1982年   21300篇
  1981年   20410篇
  1980年   19035篇
  1979年   20420篇
  1978年   18845篇
  1977年   18060篇
  1976年   16922篇
  1975年   16553篇
  1974年   17132篇
  1973年   17459篇
  1972年   14911篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
Porphyromonas gingivalis is a peptide-fermenting asaccharolytic periodontal pathogen. Its genome contains several genes encoding cysteine peptidases other than gingipains. One of these genes (PG1055) encodes a protein called Tpr (thiol protease) that has sequence similarity to cysteine peptidases of the papain and calpain families. In this study we biochemically characterize Tpr. We found that the 55-kDa Tpr inactive zymogen proteolytically processes itself into active forms of 48, 37, and 33 kDa via sequential truncations at the N terminus. These processed molecular forms of Tpr are associated with the bacterial outer membrane where they are likely responsible for the generation of metabolic peptides required for survival of the pathogen. Both autoprocessing and activity were dependent on calcium concentrations >1 mm, consistent with the protein''s activity within the intestinal and inflammatory milieus. Calcium also stabilized the Tpr structure and rendered the protein fully resistant to proteolytic degradation by gingipains. Together, our findings suggest that Tpr is an example of a bacterial calpain, a calcium-responsive peptidase that may generate substrates required for the peptide-fermenting metabolism of P. gingivalis. Aside from nutrient generation, Tpr may also be involved in evasion of host immune response through degradation of the antimicrobial peptide LL-37 and complement proteins C3, C4, and C5. Taken together, these results indicate that Tpr likely represents an important pathogenesis factor for P. gingivalis.  相似文献   
2.
Connecdenn 1/2 are DENN (differentially expressed in normal and neoplastic cells) domain-bearing proteins that function as GEFs (guanine nucleotide exchange factors) for the small GTPase Rab35. Disruption of connecdenn/Rab35 function leads to defects in the recycling of multiple cargo proteins from endosomes with altered cell function, yet the regulation of connecdenn GEF activity is unexplored. We now demonstrate that connecdenn 1/2 are autoinhibited such that the purified, full-length proteins have significantly less Rab35 binding and GEF activity than the isolated DENN domain. Both proteins are phosphorylated with prominent phosphorylation sites between residues 500 and 600 of connecdenn 1. A large scale proteomics screen revealed that connecdenn 1 is phosphorylated at residues Ser-536 and Ser-538 in an Akt-dependent manner in response to insulin stimulation of adipocytes. Interestingly, we find that an Akt inhibitor reduces connecdenn 1 interaction with Rab35 after insulin treatment of adipocytes. Remarkably, a peptide flanking Ser-536/Ser-538 binds the DENN domain of connecdenn 1, whereas a phosphomimetic peptide does not. Moreover, connecdenn 1 interacts with 14-3-3 proteins, and this interaction is also disrupted by Akt inhibition and by mutation of Ser-536/Ser-538. We propose that Akt phosphorylation of connecdenn 1 downstream of insulin activation regulates connecdenn 1 function through an intramolecular interaction.  相似文献   
3.
Axonal regeneration after injury to the CNS is hampered by myelin‐derived inhibitors, such as Nogo‐A. Natural products, such as green tea, which are neuroprotective and safe for long‐term therapy, would complement ongoing various pharmacological approaches. In this study, using nerve growth factor‐differentiated neuronal‐like Neuroscreen‐1 cells, we show that extremely low concentrations of unfractionated green tea polyphenol mixture (GTPP) and its active ingredient, epigallocatechin‐3‐gallate (EGCG), prevent both the neurite outgrowth‐inhibiting activity and growth cone‐collapsing activity of Nogo‐66 (C‐terminal domain of Nogo‐A). Furthermore, a synergistic interaction was observed among GTPP constituents. This preventive effect was dependent on 67‐kDa laminin receptor (67LR) to which EGCG binds with high affinity. The antioxidants N‐acetylcysteine and cell‐permeable catalase abolished this preventive effect of GTPP and EGCG, suggesting the involvement of sublethal levels of H2O2 in this process. Accordingly, exogenous sublethal concentrations of H2O2, added as a bolus dose (5 μM) or more effectively through a steady‐state generation (1–2 μM), mimicked GTPP in counteracting the action of Nogo‐66. Exogenous H2O2 mediated this action by bypassing the requirement of 67LR. Taken together, these results show for the first time that GTPP and EGCG, acting through 67LR and elevating intracellular sublethal levels of H2O2, inhibit the antineuritogenic action of Nogo‐A.

  相似文献   

4.
Recent studies have emphasized the important role of microRNA (miRNA) clusters and common target genes in disease progression. Despite the known involvement of the miR‐192/215 family in many human diseases, its biological role in Hirschsprung disease (HSCR) remains undefined. In this study, we explored the role of the miR‐192/215 family in the pathogenesis of HSCR. Quantitative real‐time PCR and western blotting measured relative expression levels of miRNAs, mRNAs, and proteins in 80 HSCR patients and 77 normal colon tissues. Targets were evaluated by dual‐luciferase reporter assays, and the functional effects of miR‐192/215 on human 293T and SH‐SY5Y cells were detected by the Transwell assay, CCK8 assay and flow cytometry. MiR‐192/215 was significantly down‐regulated in HSCR tissue samples, and their knockdown inhibited cell migration and proliferation in the human 293T and SH‐SY5Y cell lines. Nidogen 1 (NID1) was confirmed as a common target gene of miR‐192/215 by dual‐luciferase reporter gene assay and its expression was inversely correlated with that of miR‐192/215 in tissue samples and cell lines. Silencing of NID1 could rescue the extent of the suppressing effects by miR‐192/215 inhibitor. The down‐regulation of miR‐192/215 may contribute to HSCR development by targeting NID1.

  相似文献   

5.
6.
7.
8.
9.
10.
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号