全文获取类型
收费全文 | 21624篇 |
免费 | 1872篇 |
国内免费 | 1677篇 |
出版年
2024年 | 30篇 |
2023年 | 194篇 |
2022年 | 290篇 |
2021年 | 793篇 |
2020年 | 618篇 |
2019年 | 813篇 |
2018年 | 818篇 |
2017年 | 617篇 |
2016年 | 919篇 |
2015年 | 1392篇 |
2014年 | 1642篇 |
2013年 | 1629篇 |
2012年 | 2074篇 |
2011年 | 1912篇 |
2010年 | 1207篇 |
2009年 | 1067篇 |
2008年 | 1405篇 |
2007年 | 1276篇 |
2006年 | 1047篇 |
2005年 | 938篇 |
2004年 | 831篇 |
2003年 | 717篇 |
2002年 | 683篇 |
2001年 | 365篇 |
2000年 | 312篇 |
1999年 | 283篇 |
1998年 | 180篇 |
1997年 | 136篇 |
1996年 | 86篇 |
1995年 | 70篇 |
1994年 | 74篇 |
1993年 | 49篇 |
1992年 | 83篇 |
1991年 | 70篇 |
1990年 | 59篇 |
1989年 | 60篇 |
1988年 | 49篇 |
1987年 | 41篇 |
1986年 | 42篇 |
1985年 | 36篇 |
1984年 | 28篇 |
1983年 | 20篇 |
1982年 | 23篇 |
1981年 | 16篇 |
1980年 | 13篇 |
1979年 | 25篇 |
1977年 | 12篇 |
1975年 | 22篇 |
1974年 | 18篇 |
1973年 | 12篇 |
排序方式: 共有10000条查询结果,搜索用时 218 毫秒
1.
2.
Peng Wang Ronghua Luo Min Zhang Yaqing Wang Tianzhang Song Tingting Tao Zhongyu Li Lin Jin Hongyi Zheng Wenwen Chen Mengqian Zhao Yongtang Zheng Jianhua Qin 《Cell death & disease》2020,11(12)
COVID-19, caused by SARS-CoV-2, is an acute and rapidly developing pandemic, which leads to a global health crisis. SARS-CoV-2 primarily attacks human alveoli and causes severe lung infection and damage. To better understand the molecular basis of this disease, we sought to characterize the responses of alveolar epithelium and its adjacent microvascular endothelium to viral infection under a co-culture system. SARS-CoV-2 infection caused massive virus replication and dramatic organelles remodeling in alveolar epithelial cells, alone. While, viral infection affected endothelial cells in an indirect manner, which was mediated by infected alveolar epithelium. Proteomics analysis and TEM examinations showed viral infection caused global proteomic modulations and marked ultrastructural changes in both epithelial cells and endothelial cells under the co-culture system. In particular, viral infection elicited global protein changes and structural reorganizations across many sub-cellular compartments in epithelial cells. Among the affected organelles, mitochondrion seems to be a primary target organelle. Besides, according to EM and proteomic results, we identified Daurisoline, a potent autophagy inhibitor, could inhibit virus replication effectively in host cells. Collectively, our study revealed an unrecognized cross-talk between epithelium and endothelium, which contributed to alveolar–capillary injury during SARS-CoV-2 infection. These new findings will expand our understanding of COVID-19 and may also be helpful for targeted drug development.Subject terms: Mechanisms of disease, Viral infection 相似文献
3.
4.
5.
Michael H Woo John R Vance Ana R Otero Marcos Christian Bailly Mary-Ann Bjornsti 《The Journal of biological chemistry》2002,277(6):3813-3822
DNA topoisomerase I (Top1p) catalyzes topological changes in DNA and is the cellular target of the antitumor agent camptothecin (CPT). Non-CPT drugs that target Top1p, such as indolocarbazoles, are under clinical development. However, whether the cytotoxicity of indolocarbazoles derives from Top1p poisoning remains unclear. To further investigate indolocarbazole mechanism, rebeccamycin R-3 activity was examined in vitro and in yeast. Using a series of Top1p mutants, where substitution of residues around the active site tyrosine has well-defined effects on enzyme catalysis, we show that catalytically active, CPT-resistant enzymes remain sensitive to R-3. This indolocarbazole did not inhibit yeast Top1p activity, yet was effective in stabilizing Top1p-DNA complexes. Similar results were obtained with human Top1p, when Ser or His were substituted for Asn-722. The mutations altered enzyme function and sensitivity to CPT, yet R-3 poisoning of Top1p was unaffected. Moreover, top1delta, rad52delta yeast cells expressing human Top1p, but not catalytically inactive Top1Y723Fp, were sensitive to R-3. These data support hTop1p as the cellular target of R-3 and indicate that distinct drug-enzyme interactions at the active site are required for efficient poisoning by R-3 or CPT. Furthermore, resistance to one poison may potentiate cell sensitivity to structurally distinct compounds that also target Top1p. 相似文献
6.
To determine whether the bicyclic monoterpene olefins (-)-alpha-pinene and (-)-beta-pinene arise biosynthetically from the same monoterpene cyclase by alternate deprotonations of a common carbocationic intermediate, the product distributions arising from the acyclic precursor [10-2H3,1-3H]geranyl pyrophosphate were compared with those resulting from incubation of [1-3H]geranyl pyrophosphate with (-)-pinene cyclase from Salvia officinalis. Alteration in proportions of the olefinic products generated by the partially purified pinene cyclase resulted from the suppression of the formation of (-)-beta-pinene (C10 deprotonation) by a primary deuterium isotope effect with a compensating stimulation of the formation of (-)-alpha-pinene (C4 deprotonation). (-)-Pinene cyclase as well as (+)-pinene cyclase also exhibited a decrease in the proportion of the acyclic olefin myrcene generated from the deuteriated substrate, accompanied by a corresponding increase in the commitment to cyclized products. The observation of isotopically sensitive branching, in conjunction with quantitation of the magnitude of the secondary deuterium isotope effect on the overall rate of product formation by the (+)- and (-)-pinene cyclases as well as two other monoterpene cyclases from the same tissue, supports the biosynthetic origin of (-)-alpha-pinene and (-)-beta-pinene by alternative deprotonations of a common enzymatic intermediate. A biogenetic scheme consistent with these results is presented, and alternate proposals for the origin of the pinenes are addressed. 相似文献
7.
8.
9.
Yihao Yang Ziyan Shen Youguang Li Chenda Xu Han Xia Hao Zhuang Shengyuan Sun Min Guo Changjie Yan 《植物学报(英文版)》2022,64(10):1860-1865
Rice eating and cooking quality (ECQ) is a major concern of breeders and consumers, determining market competitiveness worldwide. Rice grain protein content (GPC) is negatively related to ECQ, making it possible to improve ECQ by manipulating GPC. However, GPC is genetically complex and sensitive to environmental conditions; therefore, little progress has been made in traditional breeding for ECQ. Here, we report that CRISPR/Cas9-mediated knockout of genes encoding the grain storage protein glutelin rapidly produced lines with downregulated GPC and improved ECQ. Our finding provides a new strategy for improving rice ECQ. 相似文献
10.