全文获取类型
收费全文 | 872篇 |
免费 | 63篇 |
专业分类
935篇 |
出版年
2022年 | 2篇 |
2021年 | 7篇 |
2020年 | 3篇 |
2019年 | 6篇 |
2018年 | 7篇 |
2017年 | 10篇 |
2016年 | 17篇 |
2015年 | 15篇 |
2014年 | 29篇 |
2013年 | 48篇 |
2012年 | 48篇 |
2011年 | 64篇 |
2010年 | 37篇 |
2009年 | 33篇 |
2008年 | 41篇 |
2007年 | 64篇 |
2006年 | 70篇 |
2005年 | 62篇 |
2004年 | 57篇 |
2003年 | 59篇 |
2002年 | 38篇 |
2001年 | 13篇 |
2000年 | 12篇 |
1999年 | 17篇 |
1998年 | 14篇 |
1997年 | 9篇 |
1996年 | 12篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 6篇 |
1992年 | 20篇 |
1991年 | 21篇 |
1990年 | 13篇 |
1989年 | 12篇 |
1988年 | 8篇 |
1987年 | 7篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 3篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1965年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有935条查询结果,搜索用时 0 毫秒
91.
92.
93.
Invasive tumour cells, such as gliomas, frequently express EGF (epidermal growth factor) receptor at a high level and they exhibit enhanced cell migration in response to EGF. We reported previously that tumour cell migration is associated with ectodomain cleavage of CD44, the major adhesion molecule that is implicated in tumour invasion and metastasis, and that the cleavage is enhanced by ligation of CD44. In the present study, we show that EGF promotes CD44 cleavage and CD44-dependent cell migration. Introduction of a dominant-negative mutant of the small GTPase Rac1 or depletion of Rac1 by RNAi (RNA interference) abrogated CD44 cleavage induced by EGF. Treatment with PD98059, an inhibitor for MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase), also suppressed the CD44 cleavage. Furthermore, RNAi studies showed that EGF induced ADAM10 (a disintegrin and metalloproteinase 10)-dependent CD44 cleavage and cell migration. These results indicate that EGF induces ADAM10-mediated CD44 cleavage through Rac1 and mitogen-activated protein kinase activation, and thereby promotes tumour cell migration and invasion. 相似文献
94.
EbrAB in Bacillus subtilis belongs to a novel small multidrug resistance (SMR) family of multidrug efflux pumps. EmrE in Escherichia coli, a representative of SMR, functions as a homo-oligomer in the membrane. On the other hand, EbrAB requires a hetero-oligomeric configuration consisting of two polypeptides, EbrA and EbrB. Although both polypeptides have a high sequence similarity, expression of either single polypeptide does not confer the multidrug-resistance. We performed mutation studies on EbrA and B to determine why EbrAB requires the hetero-oligomerization. Mutants of EbrA and B lacking both the hydrophilic loops and the C-terminus regions conferred the multidrug-resistance solely by each protein. This suggests that the hydrophilic loops and the C-terminus regions constrain them to their respective conformations upon the formation of the functional hetero-oligomer. 相似文献
95.
Decreased serum concentrations of nitric oxide metabolites among Chinese in an endemic area of chronic arsenic poisoning in inner Mongolia 总被引:17,自引:0,他引:17
Pi J Kumagai Y Sun G Yamauchi H Yoshida T Iso H Endo A Yu L Yuki K Miyauchi T Shimojo N 《Free radical biology & medicine》2000,28(7):1137-1142
Prolonged exposure to arsenic results in peripheral and cardiovascular manifestations, as does impaired production of endothelial nitric oxide (NO). In vitro studies have indicated that endothelial cells undergo damage by arsenic. However, no information has been available on the relationship between NO synthesis and chronic arsenic poisoning in humans. The present study was designed to reveal this question. The subjects were 33 habitants who continued to drink well water containing high concentrations of inorganic arsenic (mean value = 0.41 microg/ml) for about 18 years in Inner Mongolia, China, and 10 other people who lived in this area but exposed to minimal concentrations of arsenic (mean value = 0.02 microg/ml) were employed as controls. Mean blood concentration of total arsenic was six times higher in exposed subjects than controls; 42.1 vs. 7.3 ng/ml, p <.001. Mean serum concentration of nitrite/nitrate, stable metabolites of endogenous NO, was lower in arsenic-exposed subjects than in controls: 24.7 vs. 51.6 microM, p<.001. In total samples, an inverse correlation with serum nitrite/nitrate levels was strong for blood inorganic arsenic (r = -0.52, p <.001) and less strong for its metabolites, monomethyl arsenic (r = -0.45, p<.005) and dimethyl arsenic (r = -0.37, p<.05). Furthermore, serum nitrite/nitrate concentration was significantly correlated with nonprotein sulfhydryl level in whole blood (r = 0.58, p<.001). In an in vitro study, we demonstrated that inorganic arsenite or arsenate suppresses the activity of endothelial NO synthase in human umbilical vein endothelial cells. These results suggest that long-term exposure to arsenic by drinking well water possibly reduces NO production in endothelial cells, resulting in a decrease in reduced nitrite/nitrate concentrations. Peripheral vascular disorders caused by arsenic may be attributable in part to impairment of NO production in vivo. 相似文献
96.
Niiyama K Mase T Takahashi H Naya A Katsuki K Nagase T Ito S Hayama T Hisaka A Ozaki S Ihara M Yano M Fukuroda T Noguchi K Nishikibe M Ishikawa K 《Bioorganic & medicinal chemistry》2002,10(8):2461-2470
Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model. 相似文献
97.
Boger DL Fecik RA Patterson JE Miyauchi H Patricelli MP Cravatt BF 《Bioorganic & medicinal chemistry letters》2000,10(23):2613-2616
Fatty acid amide hydrolase (FAAH), also referred to as oleamide hydrolase and anandamide amidohydrolase, is a serine hydrolase responsible for the degradation of endogenous oleamide and anandamide, fatty acid amides that function as chemical messengers. FAAH hydrolyzes a range of fatty acid amides, and the present study examines the relative rates of hydrolysis of a variety of natural and unnatural fatty acid primary amide substrates using pure recombinant rat FAAH. 相似文献
98.
Hiroya Miyamoto Eri Katsuyama Yoshiteru Miyauchi Hiroko Hoshi Kana Miyamoto Yuiko Sato Tami Kobayashi Ryotaro Iwasaki Shigeyuki Yoshida Tomoaki Mori Hiroya Kanagawa Atsuhiro Fujie Wu Hao Hideo Morioka Morio Matsumoto Yoshiaki Toyama Takeshi Miyamoto 《The Journal of biological chemistry》2012,287(39):32479-32484
99.
Tanabe K Ishizaki J Ando Y Ito T Nishimoto S 《Bioorganic & medicinal chemistry letters》2012,22(4):1682-1685
We prepared a 5-fluorodeoxyuridine (5-FdUrd) derivative possessing azide methyl group (N(3)-FdUrd) as a novel radiation-activated prodrug. The parent antitumor agent, 5-FdUrd, was released efficiently from N(3)-FdUrd by hypoxic X-irradiation. On the other hand, the activation of N(3)-FdUrd was suppressed upon X-irradiation under aerobic conditions. A biological assay using A549 cells revealed that the cytotoxicity of N(3)-FdUrd was significantly enhanced by hypoxic X-irradiation. 相似文献
100.
Nishikawa-Shimono R Sekiguchi Y Koami T Kawamura M Wakasugi D Watanabe K Wakahara S Matsumoto K Takayama T 《Bioorganic & medicinal chemistry letters》2012,22(9):3305-3310
Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 enzymes (IC(50)>10 μM). 相似文献