全文获取类型
收费全文 | 2593篇 |
免费 | 172篇 |
出版年
2022年 | 16篇 |
2021年 | 19篇 |
2020年 | 25篇 |
2019年 | 24篇 |
2018年 | 37篇 |
2017年 | 23篇 |
2016年 | 48篇 |
2015年 | 73篇 |
2014年 | 75篇 |
2013年 | 146篇 |
2012年 | 133篇 |
2011年 | 128篇 |
2010年 | 81篇 |
2009年 | 81篇 |
2008年 | 117篇 |
2007年 | 137篇 |
2006年 | 154篇 |
2005年 | 123篇 |
2004年 | 132篇 |
2003年 | 140篇 |
2002年 | 131篇 |
2001年 | 80篇 |
2000年 | 76篇 |
1999年 | 75篇 |
1998年 | 24篇 |
1997年 | 26篇 |
1996年 | 19篇 |
1995年 | 15篇 |
1994年 | 17篇 |
1993年 | 21篇 |
1992年 | 46篇 |
1991年 | 37篇 |
1990年 | 34篇 |
1989年 | 36篇 |
1988年 | 25篇 |
1987年 | 25篇 |
1986年 | 21篇 |
1985年 | 25篇 |
1984年 | 25篇 |
1983年 | 27篇 |
1981年 | 20篇 |
1979年 | 19篇 |
1978年 | 18篇 |
1977年 | 18篇 |
1975年 | 16篇 |
1974年 | 21篇 |
1973年 | 17篇 |
1972年 | 23篇 |
1970年 | 16篇 |
1966年 | 15篇 |
排序方式: 共有2765条查询结果,搜索用时 46 毫秒
991.
992.
Kojima K Motoshima H Tsutsumi A Igata M Matsumura T Kondo T Kawashima J Ichinose K Furukawa N Inukai K Katayama S Goldstein BJ Nishikawa T Tsuruzoe K Araki E 《Biochemical and biophysical research communications》2008,376(2):434-438
AMP-activated protein kinase (AMPK) is a cellular energy sensor involved in multiple cell signaling pathways that has become an attractive therapeutic target for vascular diseases. It is not clear whether rottlerin, an inhibitor of protein kinase Cδ, activates AMPK in vascular cells and tissues. In the present study, we have examined the effect of rottlerin on AMPK in vascular smooth muscle cells (VSMCs) and isolated rabbit aorta. Rottlerin reduced cellular ATP and activated AMPK in VSMCs and rabbit aorta; however, inhibition of PKCδ by three different methods did not activate AMPK. Both VSMCs and rabbit aorta expressed the upstream AMPK kinase LKB1 protein, and rottlerin-induced AMPK activation was decreased in VSMCs by overexpression of dominant-negative LKB1, suggesting that LKB1 is involved in the upstream regulation of AMPK stimulated by rottlerin. These data suggest for the first time that LKB1 mediates rottlerin-induced activation of AMPK in vascular cells and tissues. 相似文献
993.
Naoi M Maruyama W Yi H Yamaoka Y Shamoto-Nagai M Akao Y Gerlach M Tanaka M Riederer P 《Journal of neurochemistry》2008,105(6):2489-2500
Parkinson's disease (PD) is characterized by selective depletion of nigral dopamine (DA) neurons containing neuromelanin (NM), suggesting the involvement of NM in the pathogenesis. This study reports induction of apoptosis by NM in SH-SY5Y cells, whereas protease-K-treated NM, synthesized DA- and cysteinyl dopamine melanin showed much less cytotoxicity. Cell death was mediated by mitochondria-mediated apoptotic pathway, namely collapse of mitochondrial membrane potential, release of cytochrome c , and activation of caspase 3, but Bcl-2 over-expression did not suppress apoptosis. NM increased sulfhydryl content in mitochondria, and a major part of it was identified as GSH, whereas dopamine melanin significantly reduced sulfhydryl levels. Western blot analysis for protein-bound GSH demonstrated that only NM reduced S -glutathionylated proteins in mitochondria and dissociated macromolecular structure of complex I. Reactive oxygen and nitrogen species were required for the deglutathionylation by NM, which antioxidants reduced significantly with prevention of apoptosis. These results suggest that NM may be related to cell death of DA neurons in PD and aging through regulation of mitochondrial redox state and S -glutathionylation, for which NM-associated protein is absolutely required. The novel function of NM is discussed in relation to the pathogenesis of PD. 相似文献
994.
Modulation of human immunodeficiency virus type 1 infectivity through incorporation of tetraspanin proteins 总被引:1,自引:0,他引:1
Sato K Aoki J Misawa N Daikoku E Sano K Tanaka Y Koyanagi Y 《Journal of virology》2008,82(2):1021-1033
Accumulating evidence indicates that human immunodeficiency virus type 1 (HIV-1) acquires various cellular membrane proteins in the lipid bilayer of the viral envelope membrane. Although some virion-incorporated cellular membrane proteins are known to potently affect HIV-1 infectivity, the virological functions of most virion-incorporated membrane proteins remain unclear. Among these host proteins, we found that CD63 was eliminated from the plasma membranes of HIV-1-producing T cells after activation, followed by a decrease in the amount of virion-incorporated CD63, and in contrast, an increase in the infectivity of the released virions. On the other hand, we found that CD63 at the cell surface was preferentially embedded on the membrane of released virions in an HIV-1 envelope protein (Env)-independent manner and that virion-incorporated CD63 had the potential to inhibit HIV-1 Env-mediated infection in a strain-specific manner at the postattachment entry step(s). In addition, these behaviors were commonly observed in other tetraspanin proteins, such as CD9, CD81, CD82, and CD231. However, L6 protein, whose topology is similar to that of tetraspanins but which does not belong to the tetraspanin superfamily, did not have the potential to prevent HIV-1 infection, despite its successful incorporation into the released particles. Taken together, these results suggest that tetraspanin proteins have the unique potential to modulate HIV-1 infectivity through incorporation into released HIV-1 particles, and our findings may provide a clue to undiscovered aspects of HIV-1 entry. 相似文献
995.
Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice 总被引:1,自引:0,他引:1
Sato Y Kajiyama S Amano A Kondo Y Sasaki T Handa S Takahashi R Fukui M Hasegawa G Nakamura N Fujinawa H Mori T Ohta M Obayashi H Maruyama N Ishigami A 《Biochemical and biophysical research communications》2008,375(3):346-350
Hydrogen is an established anti-oxidant that prevents acute oxidative stress. To clarify the mechanism of hydrogen’s effect in the brain, we administered hydrogen-rich pure water (H2) to senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize vitamin C (VC), also a well-known anti-oxidant. These KO mice were divided into three groups; recipients of H2, VC, or pure water (H2O), administered for 33 days. VC levels in H2 and H2O groups were <6% of those in the VC group. Subsequently, superoxide formation during hypoxia-reoxygenation treatment of brain slices from these groups was estimated by a real-time biography imaging system, which models living brain tissues, with Lucigenin used as chemiluminescence probe for superoxide. A significant 27.2% less superoxide formed in the H2 group subjected to ischemia-reperfusion than in the H2O group. Thus hydrogen-rich pure water acts as an anti-oxidant in the brain slices and prevents superoxide formation. 相似文献
996.
997.
Endoplasmic reticulum (ER)-derived compartments are found in many plant species. Although it has been assumed that aggregation induces formation of the ER-derived compartments in plant seed cells, the effect of aggregation on the trafficking from the ER to the Golgi has not yet been elucidated. In this study, we used an aggregated type of red fluorescent protein (DsRED) to investigate the effect of aggregation on sorting in seed cells. DsRED fused to the Golgi sorting determinant was found mainly in large globular structures derived from the ER where ER-resident proteins were excluded. These results indicate that aggregation of the Golgi protein blocks transport from the ER to the Golgi. 相似文献
998.
Alpha-melanocyte-stimulating hormone mediates melanin-concentrating hormone-induced anorexigenic action in goldfish 总被引:1,自引:0,他引:1
Shimakura S Miura T Maruyama K Nakamachi T Uchiyama M Kageyama H Shioda S Takahashi A Matsuda K 《Hormones and behavior》2008,53(2):323-328
In goldfish, intracerebroventricular (ICV) administration of melanin-concentrating hormone (MCH) inhibits feeding behavior, and fasting decreases hypothalamic MCH-like immunoreactivity. However, while MCH acts as an anorexigenic factor in goldfish, in rodents MCH has an orexigenic effect. Therefore, we examined the involvement of two anorexigenic neuropeptides, alpha-melanocyte-stimulating hormone (alpha-MSH) and corticotropin-releasing hormone (CRH), in the anorexigenic action of MCH in goldfish, using an alpha-MSH receptor antagonist, HS024, and a CRH receptor antagonist, alpha-helical CRH((9-41)). ICV injection of HS024, but not alpha-helical CRH((9-41)), suppressed MCH-induced anorexigenic action for a 60-min observation period. We then examined, using a real-time PCR method, whether MCH affects the levels of mRNAs encoding various orexigenic neuropeptides, including neuropeptide Y (NPY), orexin, ghrelin and Agouti-related peptide (AgRP), in the goldfish diencephalon. ICV administration of MCH at a dose sufficient to inhibit food consumption decreased the expression of mRNAs for NPY and ghrelin, but not for orexin and AgRP. These results indicate that the anorexigenic action of MCH in the goldfish brain is mediated by the alpha-MSH signaling pathway and is accompanied by inhibition of NPY and ghrelin synthesis. 相似文献
999.
1000.
Nakajima T Yukawa O Tsuji H Ohyama H Wang B Tatsumi K Hayata I Hama-Inaba H 《Mutation research》2006,595(1-2):29-36
Protein kinase Cdelta (PKCdelta) has an important role in radiation-induced apoptosis. The expression and function of PKCdelta in radiation-induced apoptosis were assessed in a radiation-sensitive mouse thymic lymphoma cell line, 3SBH5, and its radioresistant variant, XR223. Rottlerin, a PKCdelta-specific inhibitor, completely abolished radiation-induced apoptosis in 3SBH5. Radiation-induced PKCdelta activation correlated with the degradation of PKCdelta, indicating that PKCdelta activation through degradation is involved in radiation-induced apoptosis in radiosensitive 3SBH5. In radioresistant XR223, radiation-induced PKCdelta activation was lower than that in radiosensitive 3SBH5. Cytosol PKCdelta levels in 3SBH5 decreased markedly after irradiation, while those in XR223 did not. There was no apparent change after irradiation in the membrane fractions of either cell type. In addition, basal cytosol PKCdelta levels in XR223 were higher than those in 3SBH5. These results suggest that the radioresistance in XR223 to radiation-induced apoptosis is due to a difference in the regulation of radiation-induced PKCdelta activation compared to that of 3SBH5. On the other hand, Atm(-/-) mouse thymic lymphoma cells were more radioresistant to radiation-induced apoptosis than wild-type mouse thymic lymphoma cells. Irradiated wild-type cells, but not Atm(-/-) cells, had decreased PKCdelta levels, indicating that the Atm protein is involved in radiation-induced apoptosis through the induction of PKCdelta degradation. The decreased Atm protein levels induced by treatment with Atm small interfering RNA had no effect on radiation-induced apoptosis in 3SBH5 cells. These results suggest that the regulation of radiation-induced PKCdelta activation, which is distinct from the Atm-mediated cascade, determines radiation sensitivity in radiosensitive 3SBH5 cells. 相似文献