全文获取类型
收费全文 | 1946篇 |
免费 | 150篇 |
出版年
2023年 | 7篇 |
2021年 | 34篇 |
2020年 | 17篇 |
2019年 | 23篇 |
2018年 | 40篇 |
2017年 | 27篇 |
2016年 | 63篇 |
2015年 | 82篇 |
2014年 | 99篇 |
2013年 | 114篇 |
2012年 | 154篇 |
2011年 | 128篇 |
2010年 | 85篇 |
2009年 | 81篇 |
2008年 | 119篇 |
2007年 | 118篇 |
2006年 | 126篇 |
2005年 | 98篇 |
2004年 | 98篇 |
2003年 | 109篇 |
2002年 | 88篇 |
2001年 | 10篇 |
2000年 | 16篇 |
1999年 | 28篇 |
1998年 | 25篇 |
1997年 | 25篇 |
1996年 | 20篇 |
1995年 | 13篇 |
1994年 | 17篇 |
1993年 | 10篇 |
1992年 | 9篇 |
1991年 | 10篇 |
1990年 | 11篇 |
1989年 | 5篇 |
1988年 | 12篇 |
1987年 | 9篇 |
1986年 | 9篇 |
1985年 | 11篇 |
1984年 | 12篇 |
1983年 | 12篇 |
1982年 | 14篇 |
1981年 | 14篇 |
1980年 | 15篇 |
1979年 | 5篇 |
1978年 | 6篇 |
1977年 | 6篇 |
1976年 | 8篇 |
1975年 | 10篇 |
1974年 | 6篇 |
1973年 | 6篇 |
排序方式: 共有2096条查询结果,搜索用时 31 毫秒
101.
102.
Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity 总被引:6,自引:0,他引:6
Yu J Lo JL Huang L Zhao A Metzger E Adams A Meinke PT Wright SD Cui J 《The Journal of biological chemistry》2002,277(35):31441-31447
Bile salt export pump (BSEP) is a major bile acid transporter in the liver. Mutations in BSEP result in progressive intrahepatic cholestasis, a severe liver disease that impairs bile flow and causes irreversible liver damage. BSEP is a target for inhibition and down-regulation by drugs and abnormal bile salt metabolites, and such inhibition and down-regulation may result in bile acid retention and intrahepatic cholestasis. In this study, we quantitatively analyzed the regulation of BSEP expression by FXR ligands in primary human hepatocytes and HepG2 cells. We demonstrate that BSEP expression is dramatically regulated by ligands of the nuclear receptor farnesoid X receptor (FXR). Both the endogenous FXR agonist chenodeoxycholate (CDCA) and synthetic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types. This up-regulation was readily detectable at as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity on FXR. These results suggest BSEP as a direct target of FXR and support the recent report that the BSEP promoter is transactivated by FXR. In contrast to CDCA and GW4064, lithocholate (LCA), a hydrophobic bile acid and a potent inducer of cholestasis, strongly decreased BSEP expression. Previous studies did not identify LCA as an FXR antagonist ligand in cells, but we show here that LCA is an FXR antagonist with partial agonist activity in cells. In an in vitro co-activator association assay, LCA decreased CDCA- and GW4064-induced FXR activation with an IC(50) of 1 microm. In HepG2 cells, LCA also effectively antagonized GW4064-enhanced FXR transactivation. These data suggest that the toxic and cholestatic effect of LCA in animals may result from its down-regulation of BSEP through FXR. Taken together, these observations indicate that FXR plays an important role in BSEP gene expression and that FXR ligands may be potential therapeutic drugs for intrahepatic cholestasis. 相似文献
103.
104.
105.
Perron-Sierra F Saint Dizier D Bertrand M Genton A Tucker GC Casara P 《Bioorganic & medicinal chemistry letters》2002,12(22):3291-3296
A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics. 相似文献
106.
107.
108.
109.
Fourier transform infrared (FT-IR) spectroscopy was used to investigate the radiation-induced effects on Kocuria rosea. Bacterial suspensions at the stationary phase were exposed to increasing doses of gamma radiation. In the region 1350-840cm(-1), assigned to phosphodiester backbone, nucleic acids, and sugar rings, the radical damaging effects were dose-dependent, with the first threshold at 2.75kGy and the second at 13.75kGy inducing more striking spectral variations. Postirradiation reincubation did not significantly affect the biomolecular response, except in the spectral range 1100-1000cm(-1). These observations suggest the occurrence of new phylogenetic characteristics for K. rosea following irradiation. Moreover, two-dimensional analysis was used to highlight correlated evolutions of molecular species as radical aggression increased. The results point to an evolutionary scheme during the time course of irradiation. Thus, one- and two-dimensional IR analyses are convenient means of investigating the metabolic events following oxidative stress generated by either chemical or physical agents. 相似文献
110.