全文获取类型
收费全文 | 752篇 |
免费 | 82篇 |
专业分类
834篇 |
出版年
2019年 | 5篇 |
2018年 | 11篇 |
2017年 | 6篇 |
2016年 | 15篇 |
2015年 | 23篇 |
2014年 | 24篇 |
2013年 | 35篇 |
2012年 | 30篇 |
2011年 | 33篇 |
2010年 | 33篇 |
2009年 | 33篇 |
2008年 | 30篇 |
2007年 | 33篇 |
2006年 | 32篇 |
2005年 | 38篇 |
2004年 | 25篇 |
2003年 | 22篇 |
2002年 | 25篇 |
2001年 | 18篇 |
2000年 | 17篇 |
1999年 | 22篇 |
1998年 | 17篇 |
1997年 | 15篇 |
1996年 | 8篇 |
1995年 | 10篇 |
1994年 | 5篇 |
1993年 | 14篇 |
1992年 | 7篇 |
1991年 | 17篇 |
1990年 | 11篇 |
1989年 | 15篇 |
1988年 | 21篇 |
1987年 | 12篇 |
1986年 | 13篇 |
1985年 | 13篇 |
1984年 | 7篇 |
1983年 | 9篇 |
1982年 | 22篇 |
1981年 | 4篇 |
1979年 | 12篇 |
1978年 | 7篇 |
1977年 | 10篇 |
1975年 | 6篇 |
1974年 | 6篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1971年 | 10篇 |
1970年 | 6篇 |
1969年 | 9篇 |
1967年 | 4篇 |
排序方式: 共有834条查询结果,搜索用时 0 毫秒
91.
Henson BS Neubig RR Jang I Ogawa T Zhang Z Carey TE D'Silva NJ 《The Journal of biological chemistry》2005,280(24):22564-22571
92.
Mendoza FJ Henson ES Gibson SB 《Biochemical and biophysical research communications》2005,331(4):1089-1098
During apoptotic stimulation, the serine threonine kinase, MEKK1, is cleaved into an activated 91 kDa kinase fragment. This cleavage is mediated by caspase 3 and leads to further caspase 3 activation and apoptosis. Forced expression of the 91 kDa kinase fragment induces apoptosis through changes in membrane potential of the mitochondria mediated by permeability transition pore opening. MEKK1 activation, however, fails to release cytochrome c from the mitochondria. Herein, we determined that overexpression of MEKK1 causes mitochondrial Smac/Diablo release correlating with MEKK1-induced apoptosis. Furthermore, using siRNA that lowers Smac/Diablo expression, MEKK1-induced apoptosis was significantly reduced. Mouse embryonic fibroblast cells lacking MEKK1 expression are also resistant to etoposide-induced mitochondrial Smac/Diablo release. In contrast, etoposide-induced mitochondrial cytochrome c release was not inhibited. MEKK1 also activates the MAP kinase JNK, but MEKK1-induced mitochondrial Smac/Diablo release and apoptosis are independent of MEKK1 mediated JNK activation. Taken together, release of Smac/Diablo from the mitochondria plays a role in MEKK1-induced apoptosis. 相似文献
93.
Oxidants inhibit ERK/MAPK and prevent its ability to delay neutrophil apoptosis downstream of mitochondrial changes and at the level of XIAP 总被引:7,自引:0,他引:7
Gardai SJ Whitlock BB Xiao YQ Bratton DB Henson PM 《The Journal of biological chemistry》2004,279(43):44695-44703
Normal spontaneous apoptosis in neutrophils is enhanced by "stress" stimuli such as tumor necrosis factor-alpha, Fas ligand, and oxidants, and this effect is inhibited by anti-apoptotic stimuli including granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, and formylmethionine-leucine-phenylalanine. In this report we demonstrate that anti-apoptotic stimuli protect neutrophils from stress-induced apoptosis via activation of the ERK/MAPK pathway. The protection occurs downstream of mitochondrial alterations assessed as a decrease in membrane potential concomitant with enhanced cytochrome c release. ERK activation was shown to inhibit apoptosis by maintaining levels of XIAP, which is normally decreased in the presence of the pro-apoptotic/stress stimuli. This report also demonstrates that potent intra- and extracellular oxidants inhibit the protective effect of ERK. Oxidant-dependent inhibition of ERK was because of activation of p38 MAPK and activation of the protein phosphatases PP1 and PP2A. Our data suggest that ERK suppresses stress-induced apoptosis downstream of mitochondrial alterations by maintaining XIAP levels and that oxidants block this effect through activation of p38 and protein phosphatases. 相似文献
94.
Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils 总被引:6,自引:0,他引:6
Gardai SJ Hildeman DA Frankel SK Whitlock BB Frasch SC Borregaard N Marrack P Bratton DL Henson PM 《The Journal of biological chemistry》2004,279(20):21085-21095
Although important for apoptosis, the mechanism of Bax regulation is poorly understood. This study demonstrates that phosphorylation of Ser(184) regulates Bax activity. The phosphorylation required phosphatidylinositol 3-kinase/Akt activation and appeared to be mediated by Akt itself. In the serine-phosphorylated form, Bax was detected in the cytoplasm, could not be immunoprecipitated with the activation-specific antibody 6A7, and promoted heterodimerization with Mcl-1, Bcl-x(L), and A1. Apoptotic neutrophils possessed reduced levels of serine-phosphorylated Bax correlating with an increase in activated Bax as well as an increase in the amount of Bax found translocated to the mitochondria. We suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members. 相似文献
95.
Manaka J Kuraishi T Shiratsuchi A Nakai Y Higashida H Henson P Nakanishi Y 《The Journal of biological chemistry》2004,279(46):48466-48476
The mechanism of phagocytic elimination of dying cells in Drosophila is poorly understood. This study was undertaken to examine the recognition and engulfment of apoptotic cells by Drosophila hemocytes/macrophages in vitro and in vivo. In the in vitro analysis, l(2)mbn cells (a cell line established from larval hemocytes of a tumorous Drosophila mutant) were used as phagocytes. When l(2)mbn cells were treated with the molting hormone 20-hydroxyecdysone, the cells acquired the ability to phagocytose apoptotic S2 cells, another Drosophila cell line. S2 cells undergoing cycloheximide-induced apoptosis exposed phosphatidylserine on their surface, but their engulfment by l(2)mbn cells did not seem to be mediated by phosphatidylserine. The level of Croquemort, a candidate phagocytosis receptor of Drosophila hemocytes/macrophages, increased in l(2)mbn cells after treatment with 20-hydroxyecdysone, whereas that of Draper, another candidate phagocytosis receptor, remained unchanged. However, apoptotic cell phagocytosis was reduced when the expression of Draper, but not of Croquemort, was inhibited by RNA interference in hormone-treated l(2)mbn cells. We next examined whether Draper is responsible for the phagocytosis of apoptotic cells in vivo using an assay for engulfment based on assessing DNA degradation of apoptotic cells in dICAD mutant embryos (which only occurred after ingestion by the phagocytes). RNA interference-mediated decrease in the level of Draper in embryos of mutant flies was accompanied by a decrease in the number of cells containing fragmented DNA. Furthermore, histochemical analyses of dispersed embryonic cells revealed that the level of phagocytosis of apoptotic cells by hemocytes/macrophages was reduced when Draper expression was inhibited. These results indicate that Drosophila hemocytes/macrophages execute Draper-mediated phagocytosis to eliminate apoptotic cells. 相似文献
96.
McAdams RM Mustafa SB Shenberger JS Dixon PS Henson BM DiGeronimo RJ 《American journal of physiology. Lung cellular and molecular physiology》2006,291(2):L166-L174
The treatment of severe lung disease often requires the use of high concentrations of oxygen coupled with the need for assisted ventilation, potentially exposing the pulmonary epithelium to both reactive oxygen species and nonphysiological cyclic stretch. Whereas prolonged hyperoxia is known to cause increased cell injury, cyclic stretch may result in either cell proliferation or injury depending on the pattern and degree of exposure to mechanical deformation. How hyperoxia and cyclic stretch interact to affect the pulmonary epithelium in vitro has not been previously investigated. This study was performed using human alveolar epithelial A549 cells to explore the combined effects of cyclic stretch and hyperoxia on cell proliferation and viability. Under room air conditions, cyclic stretch did not alter cell viability at any time point and increased cell number after 48 h compared with unstretched controls. After exposure to prolonged hyperoxia, cell number and [(3)H]thymidine incorporation markedly decreased, whereas evidence of oxidative stress and nonapoptotic cell death increased. The combination of cyclic stretch with hyperoxia significantly mitigated the negative effects of prolonged hyperoxia alone on measures of cell proliferation and viability. In addition, cyclic stretch resulted in decreased levels of oxidative stress over time in hyperoxia-exposed cells. Our results suggest that cyclic stretch, as applied in this study, can minimize the detrimental effects of hyperoxia on alveolar epithelial A549 cells. 相似文献
97.
98.
Freire-de-Lima CG Xiao YQ Gardai SJ Bratton DL Schiemann WP Henson PM 《The Journal of biological chemistry》2006,281(50):38376-38384
Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and anti-immunogenic with generation of anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-beta in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-gamma and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO). By use of a dominant negative TGFbetaII receptor, TGF-beta signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF-beta itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore appears to drive the balanced inflammatory mediator responses. Arachidonic acid release, COX-2, and prostaglandin synthase expression were shown to be significantly dependent on the TGF-beta production. On the other hand, a requirement for TGF-beta was also shown in the inhibition of thromboxane synthase and thromboxanes, of 5-lipoxygenase and sulfidopeptide leukotrienes, as well as of inducible nitric-oxide synthase and NO. TGF-beta-dependent induction of arginase was also found and would further limit the NO generation. Finally, apoptotic cells stimulated production of 15-lipoxygenase and 15-hydroxyeicosatetraenoic acid, a potentially anti-inflammatory pathway acting through peroxisome proliferator-activated receptor-gamma, and lipoxin A(4) production, which were also up-regulated by a TGF-beta-dependent pathway in this system. These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF-beta production. 相似文献
99.
Henson MS O'Brien TD 《ILAR journal / National Research Council, Institute of Laboratory Animal Resources》2006,47(3):234-242
Feline diabetes mellitus (FDM) closely resembles human type 2 diabetes mellitus (T2DM) in many respects including clinical, physiological, and pathological features of the disease. These features include age of onset of FDM in middle age, association with obesity, residual but declining insulin secretion, development of islet amyloid deposits, loss of approximately 50% of beta-cell mass, and development of complications in several organ systems including peripheral polyneuropathy and retinopathy. Many of the pathological aspects of the disease are also experimentally inducible, facilitating study of the pathogenesis of these lesions. Physiological aspects of FDM and obesity are also well studied in the cat and provide an excellent basis for comparative studies of human T2DM. The relatively short generation time of cats along with breed predispositions to development of FDM may allow for more rapid screening and identification of genetic markers for diabetes susceptibility. FDM, in both spontaneous and inducible forms, therefore provides a good animal model of human T2DM and may provide additional insights into the pathogenesis of this important condition. 相似文献
100.
MD Barense II Groen AC Lee LK Yeung SM Brady M Gregori N Kapur TJ Bussey LM Saksida RN Henson 《Neuron》2012,75(1):157-167
Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain. 相似文献