全文获取类型
收费全文 | 1778篇 |
免费 | 229篇 |
国内免费 | 6篇 |
出版年
2022年 | 16篇 |
2021年 | 26篇 |
2020年 | 8篇 |
2019年 | 13篇 |
2018年 | 22篇 |
2017年 | 13篇 |
2016年 | 37篇 |
2015年 | 78篇 |
2014年 | 71篇 |
2013年 | 81篇 |
2012年 | 114篇 |
2011年 | 106篇 |
2010年 | 66篇 |
2009年 | 63篇 |
2008年 | 87篇 |
2007年 | 92篇 |
2006年 | 92篇 |
2005年 | 78篇 |
2004年 | 78篇 |
2003年 | 59篇 |
2002年 | 55篇 |
2001年 | 64篇 |
2000年 | 54篇 |
1999年 | 76篇 |
1998年 | 28篇 |
1997年 | 27篇 |
1996年 | 20篇 |
1995年 | 20篇 |
1994年 | 14篇 |
1993年 | 18篇 |
1992年 | 50篇 |
1991年 | 37篇 |
1990年 | 39篇 |
1989年 | 28篇 |
1988年 | 36篇 |
1987年 | 28篇 |
1986年 | 26篇 |
1985年 | 19篇 |
1984年 | 16篇 |
1983年 | 12篇 |
1982年 | 11篇 |
1981年 | 10篇 |
1980年 | 11篇 |
1979年 | 12篇 |
1977年 | 12篇 |
1976年 | 9篇 |
1975年 | 10篇 |
1974年 | 10篇 |
1973年 | 11篇 |
1972年 | 10篇 |
排序方式: 共有2013条查询结果,搜索用时 31 毫秒
71.
72.
Hui-Chuan Yu Chen-Si Lin Wei-Tien Tai Chun-Yu Liu Chung-Wai Shiau Kuen-Feng Chen 《The Journal of biological chemistry》2013,288(25):18249-18259
Hepatocellular carcinoma (HCC) is the most common liver cancer and the third-leading cause of cancer death worldwide. Nilotinib is an orally available receptor tyrosine kinase inhibitor approved for chronic myelogenous leukemia. This study investigated the effect of nilotinib on HCC. Nilotinib did not induce cellular apoptosis. Instead, staining with acridine orange and microtubule-associated protein 1 light chain 3 revealed that nilotinib induced autophagy in a dose- and time-dependent manner in HCC cell lines, including PLC5, Huh-7, and Hep3B. Moreover, nilotinib up-regulated the phosphryaltion of AMP-activated kinase (AMPK) and protein phosphatase PP2A inactivation were detected after nilotinib treatment. Up-regulating PP2A activity suppressed nilotinib-induced AMPK phosphorylation and autophagy, suggesting that PP2A mediates the effect of nilotinib on AMPK phosphorylation and autophagy. Our data indicate that nilotinib-induced AMPK activation is mediated by PP2A, and AMPK activation and subsequent autophagy might be a major mechanism of action of nilotinib. Growth of PLC5 tumor xenografts in BALB/c nude mice was inhibited by daily oral treatment with nilotinib. Western blot analysis showed both increased phospho-AMPK expression and decreased PP2A activity in vivo. Together, our results reveal that nilotinib induces autophagy, but not apoptosis in HCC, and that the autophagy-inducing activity is associated with PP2A-regulated AMPK phosphorylation. 相似文献
73.
Abhay P. Sagare Robert D. Bell Alaka Srivastava Jesse D. Sengillo Itender Singh Yoichiro Nishida Nienwen Chow Berislav V. Zlokovic 《The Journal of biological chemistry》2013,288(21):15154-15166
Soluble low density lipoprotein receptor-related protein-1 (sLRP1) binds ∼70% of amyloid β-peptide (Aβ) in human plasma. In Alzheimer disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized, which results in diminished Aβ peripheral binding and higher levels of free Aβ in plasma. Experimental studies have shown that free circulating Aβ re-enters the brain and that sLRP1 and/or its recombinant wild type cluster IV (WT-LRPIV) prevent Aβ from entering the brain. Treatment of Alzheimer APPsw+/0 mice with WT-LRPIV has been shown to reduce brain Aβ pathology. In addition to Aβ, LRPIV binds multiple ligands. To enhance LRPIV binding for Aβ relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine replacing aspartic acid residues 3394, 3556, and 3674 in the calcium binding sites. Compared with WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6- and 2.7-fold higher binding affinity for Aβ40 and Aβ42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands (e.g. apolipoprotein E2, E3, and E4 (1.3–1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold), and Factor Xa (3.8-fold)). LRPIV-D3674G cleared mouse endogenous brain Aβ40 and Aβ42 25–27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw+/0 mice with LRPIV-D3674G (40 μg/kg/day) reduced Aβ40 and Αβ42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60–80% and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Aβ clearance therapy. 相似文献
74.
Elisa Tran Annabelle Chow Takeshi Goda Amy Wong Kim Blakely Michelle Rocha Samira Taeb Van C. Hoang Stanley K. Liu Urban Emmenegger 《Biochemical and biophysical research communications》2013
ATG4B belongs to the autophagin family of cysteine proteases required for autophagy, an emerging target of cancer therapy. Developing pharmacological ATG4B inhibitors is a very active area of research. However, detailed studies on the role of ATG4B during anticancer therapy are lacking. By analyzing PC-3 and C4-2 prostate cancer cells overexpressing dominant negative ATG4BC74Ain vitro and in vivo, we show that the effects of ATG4BC74A are cell type, treatment, and context-dependent. ATG4BC74A expression can either amplify the effects of cytotoxic therapies or contribute to treatment resistance. Thus, the successful clinical application of ATG4B inhibitors will depend on finding predictive markers of response. 相似文献
75.
Charlotte E. Allen Chiau L. Chow John J. Caldwell Isaac M. Westwood Rob L. M. van Montfort Ian Collins 《Bioorganic & medicinal chemistry》2013,21(18):5707-5724
With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery. 相似文献
76.
Fungyi Chow Marianne Pedersén Mariana C. Oliveira 《Journal of applied phycology》2013,25(6):1847-1853
Nitrate reductase (NR), a key enzyme in nitrogen metabolism, has been implicated in the production of nitric oxide (NO) in plants. The effect of photosynthetic electron transport chain inhibitors and NO scavengers or donors on NR activity of Gracilaria chilensis was studied under experimental laboratory conditions. Effective quantum yield (Φ PSII) and NR activity were significantly diminished by 3-(3,4-dichlorophenyl)-1,1-dimethylurea and 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone, two photosynthetic electron flux inhibitors of photosystem (PS) II and PSI, respectively, but not by diphenyleneiodonium, a NADPH oxidase inhibitor, indicating a direct dependence of NR activity on the PSII and PSI electron flux. Nitrate reductase activity was sensitive to a decrease or increase of NO levels when NO scavenger (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) and NO donor (sodium nitroprusside) were added. Moreover, the addition of 8Br-cGMP, a secondary signal molecule, stimulated NR activity. These results evidence a modulation of the photosynthetic electron transport chain and NO balance on G. chilensis NR activity. This association could be linked to the crucial tight modulation of nitrogen assimilation and carbon metabolism to guarantee nitrite incorporation into organic compounds and to avoid toxicity by nitrite, reactive oxygen species, or nitric oxide in the cells. Nitric oxide showed to be an important signaling molecule regulating NR activity and cGMP could participate as secondary messenger on this regulation by phosphorylation and desphosphorylation processes. 相似文献
77.
David M Needham Cheryl-Emiliane T Chow Jacob A Cram Rohan Sachdeva Alma Parada Jed A Fuhrman 《The ISME journal》2013,7(7):1274-1285
Observation of short-term temporal variation in bacterial and viral communities is important for understanding patterns of aquatic microbial diversity. We collected surface seawater once daily for 38 consecutive days with seven more samples interspersed over 40 more days at one location ∼2 km from Santa Catalina Island, California. Bacterial communities were analyzed by automated ribosomal intergenic spacer analysis (ARISA) and viral communities were analyzed by terminal restriction fragment length polymorphism (TRFLP) of the conserved T4-like myoviral gene encoding the major capsid protein (g23). Common bacterial and viral taxa were consistently dominant, and relatively few displayed dramatic increases/decreases or ‘boom/bust'' patterns that might be expected from dynamic predator-prey interactions. Association network analysis showed most significant covariations (associations) occurred among bacterial taxa or among viral taxa and there were several modular (highly-interconnected) associations (P⩽0.005). Associations observed between bacteria and viruses (P⩽0.005) occurred with a median time lag of 2 days. Regression of all pairwise Bray-Curtis similarities between samples indicated a rate of bacterial community change that slows from 2.1%–0.18% per day over a week to 2 months; the rate stays around 0.4% per day for viruses. Our interpretation is that, over the scale of days, individual bacterial and viral OTUs can be dynamic and patterned; resulting in statistical associations regarded as potential ecological interactions. However, over the scale of weeks, average bacterial community variation is slower, suggesting that there is strong community-level ecological resilience, that is, a tendency to converge towards a ‘mean'' microbial community set by longer-term controlling factors. 相似文献
78.
Cheng-Chou Yu Jyh-Chin Yang Yen-Ching Chang Jiing-Guang Chuang Chung-Wu Lin Ming-Shiang Wu Lu-Ping Chow 《PloS one》2013,8(1)
Previous studies have demonstrated that valosin-containing protein (VCP) is associated with H. pylori-induced gastric carcinogenesis. By identifying the interactome of VCP overexpressed in AGS cells using a subtractive proteomics approach, we aimed to characterize the cellular responses mediated by VCP and its functional roles in H. pylori-associated gastric cancer. VCP immunoprecipitations followed by proteomic analysis identified 288 putative interacting proteins, 18 VCP-binding proteins belonged to the PI3K/Akt signaling pathway. H. pylori infection increased the interaction between Akt and VCP, Akt-dependent phosphorylation of VCP, levels of ubiquitinated proteins, and aggresome formation in AGS cells. Furthermore, phosphorylated VCP co-localized with the aggresome, bound ubiquitinated proteins, and increased the degradation of cellular regulators to protect H. pylori-infected AGS cells from apoptosis. Our study demonstrates that VCP phosphorylation following H. pylori infection promotes both gastric epithelial cell survival, mediated by the PI3K/Akt pathway, and the degradation of cellular regulators. These findings provide novel insights into the mechanisms of H. pylori infection induced gastric carcinogenesis. 相似文献
79.
80.
Yong-Ping?ZhengEmail author Timothy?Tin-Yan?Lee Kelly?Ka-Lee?Lai Benjamin?Hon-Kei?Yip Guang-Quan?Zhou Wei-Wei?Jiang James?Chung-Wai?Cheung Man-Sang?Wong Bobby?King-Wah?Ng Jack?Chun-Yiu?Cheng Tsz-Ping?Lam 《Scoliosis》2016,11(1):13