全文获取类型
收费全文 | 868篇 |
免费 | 60篇 |
国内免费 | 2篇 |
出版年
2023年 | 3篇 |
2022年 | 13篇 |
2021年 | 18篇 |
2020年 | 10篇 |
2019年 | 12篇 |
2018年 | 16篇 |
2017年 | 23篇 |
2016年 | 20篇 |
2015年 | 39篇 |
2014年 | 37篇 |
2013年 | 69篇 |
2012年 | 70篇 |
2011年 | 76篇 |
2010年 | 40篇 |
2009年 | 40篇 |
2008年 | 42篇 |
2007年 | 40篇 |
2006年 | 31篇 |
2005年 | 44篇 |
2004年 | 38篇 |
2003年 | 43篇 |
2002年 | 24篇 |
2001年 | 15篇 |
2000年 | 13篇 |
1999年 | 11篇 |
1998年 | 9篇 |
1997年 | 13篇 |
1996年 | 4篇 |
1995年 | 8篇 |
1994年 | 9篇 |
1993年 | 7篇 |
1992年 | 5篇 |
1991年 | 9篇 |
1990年 | 10篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1981年 | 4篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1978年 | 2篇 |
1976年 | 2篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1970年 | 2篇 |
1933年 | 1篇 |
排序方式: 共有930条查询结果,搜索用时 15 毫秒
41.
42.
43.
The isolation of a new type of thrombin inhibitor, called triabin, from the saliva of the hematophagous bug Triatoma pallidipennis,
has recently been described. In the in vitro platelet aggregation inhibition assay triabin has a similar potency as the thrombin
inhibitor hirudin now in phase III clinical trials. However, in another in vitro assay using a low molecular weight substrate
for thrombin, triabin does not inhibit thrombin completely even at 6 fold higher molar doses in comparison with hirudin. This
means that triabin has a novel mode of action towards thrombin making triabin into an interesting candidate as a therapeutic
agent. Recently it has been shown that a recombinant baculovirus can be efficiently used for the triabin production in insect
cells and that the yields in adherent cultures of High Five™ cells (approx. 20 mg l-1) were about 7 fold higher than in adherent
cultures of Sf9 cells (approx. 3 mg l- 1). To optimize the triabin yield from the baculovirus/insect cell expression system,
experiments were performed with suspension adapted cultures of High Five™ cells to investigate the effects of the state of
the host cell, of the multiplicity of infection, of the cell density at the time of infection and of supplementation of the
medium with nutrients and oxygen. Triabin yields of up to 200 mg l-1, as determined by an activity assay, could finally be
obtained here.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
44.
Pacheco J Shibayama M Campos R Beck DL Houpt E Petri WA Tsutsumi V 《Parasitology international》2004,53(1):35-47
The Gal/GalNAc lectin of Entamoeba histolytica trophozoites plays an important role in adhesion. The distribution and final destiny of the lectin during the interaction with host cells are poorly understood. Using monoclonal and polyclonal antibodies against the lectin we studied by immunocytochemistry the in vitro and in vivo interaction of E. histolytica trophozoites with human and hamster hepatocytes. We also analyzed the presence and distribution of the lectin in a mouse model of intestinal amoebiasis. In all cases, trophozoites were highly labeled by anti-lectin antibodies. Cultured human and hamster hepatocytes in contact with, or localized at the vicinity of parasites were also labeled by anti-lectin antibodies. Most of the labeled hepatocytes showed variable degrees of cell damage. Hepatocytes distantly localized from the parasites were also stained with the anti-lectin antibodies. Immunolabeling of tissue sections from different stages of the development of experimental amoebic liver abscess in hamsters showed inflammatory foci containing lectin-labeled trophozoites, hepatocytes, and sinusoidal and inflammatory cells. Lectin-containing hepatocytes had vacuolated cytoplasm with some nuclei with a condensed appearance. Damaged intestinal epithelium also was labeled with anti-lectin antibodies in a mouse model of intestinal amoebiasis. Electron microscopy of axenically cultured trophozoites using gold-labeled monoclonal and polyclonal anti-lectin antibody showed that plasma membrane, vacuole membranes and areas of cell cytosol were labeled. Higher deposits of gold particles in plasma membrane suggestive of cell secretion were observed. Our results demonstrated that Gal/GalNAc lectin was bound and captured by different target cells, and that host cells containing the lectin showed signs of cell damage. The contribution of lectin transfer to host cells in adherence and cell injury remains to be determined. 相似文献
45.
Astrinidis A Senapedis W Coleman TR Henske EP 《The Journal of biological chemistry》2003,278(51):51372-51379
Tuberous sclerosis complex is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, and benign tumors of the brain, skin, heart, and kidneys. Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin. Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle. In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (Thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex. These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle. 相似文献
46.
Lätti S Leskinen M Shiota N Wang Y Kovanen PT Lindstedt KA 《Journal of cellular physiology》2003,195(1):130-138
Degranulated mast cells are present in the subendothelial space of eroded (de-endothelialized) coronary atheromas. Upon degranulation, mast cells secrete into the surrounding tissue an array of preformed and newly synthesized mediators, including proapoptotic molecules, such as chymase and TNF-alpha. In a co-culture system involving rat serosal mast cells and rat cardiac (microvascular) endothelial cells, we could show, by means of competitive RT-PCR, immunoblotting, immunocytochemistry, annexin staining, flow cytometry, and DNA-laddering, that stimulation of mast cells with ensuing degranulation rapidly (within 30 min) down-regulated the expression of both bcl-2 mRNA and protein, with subsequent induction of apoptosis in the endothelial cells. The major effect of bcl-2 down-regulation resided in the exocytosed granule remnants, a minor effect also being present in the granule remnant-free supernatant. No significant changes were observed in the expression levels of the pro-apoptotic protein, bax. The mast cell-mediated apoptotic effect was partially (70%) dependent on the presence of TNF-alpha and involved the translocation of cytochrome C from mitochondria into cytoplasm. These results are the first to show that one of the cell types present in the atherosclerotic plaques, namely the mast cell, by releasing both granule-remnant-bound and soluble TNF-alpha, may contribute to the erosion of atherosclerotic plaques by inducing apoptosis in adjacent endothelial cells. Published 2003 Wiley-Liss, Inc. 相似文献
47.
Lindstedt L Lee M Oörni K Brömme D Kovanen PT 《Biochemical and biophysical research communications》2003,312(4):1019-1024
In atherosclerosis, accumulation of cholesterol in macrophages may partially depend on its defective removal by high-density lipoproteins (HDL). We studied the proteolytic effect of cathepsins F, S, and K on HDL(3) and on lipid-free apoA-I, and its consequence on their function as inductors of cholesterol efflux from cholesterol-filled mouse peritoneal macrophages in vitro. Incubation of HDL(3) with cathepsin F or S, but not with cathepsin K, led to rapid loss of prebeta-HDL, and reduced cholesterol efflux by 50% in only 1min. Cathepsins F or K partially degraded lipid-free apoA-I and reduced its ability to induce cholesterol efflux, whereas cathepsin S totally degraded apoA-I, leading to complete loss of apoA-I cholesterol acceptor function. These results suggest that cathepsin-secreting cells induce rapid depletion of lipid-poor (prebeta-HDL) and lipid-free apoA-I and inhibit cellular cholesterol efflux, so tending to promote the formation and maintenance of foam cells in atherosclerotic lesions. 相似文献
48.
49.
Antipsychotic drug treatment is known to modulate gene expression in experimental animals. In this study, candidate target genes for antipsychotic drug action were searched using microarrays after acute clozapine treatment (1, 6 and 24 h) in the rat prefrontal cortex. Microarray data clustering with a self-organizing map algorithm revealed differential expression of genes involved in presynaptic function following acute clozapine treatment. The differential expression of 35 genes most profoundly regulated in expression arrays was further examined using in situ hybridization following acute clozapine, and chronic clozapine and haloperidol treatments. Acute administration of clozapine regulated the expression of chromogranin A, synaptotagmin V and calcineurin A mRNAs in the cortex. Chronic clozapine treatment induced differential cortical expression of chromogranin A, son of sevenless (SoS) and Sec-1. Chronic treatment with haloperidol regulated the mRNA expression of inhibitor of DNA-binding 2 (ID-2) and Rab-12. Furthermore, the expression of visinin-like proteins-1, -2 and -3 was regulated by chronic drug treatments in various brain regions. Our data suggest that acute and chronic treatments with haloperidol and clozapine modulate the expression of genes involved in synaptic function and in regulation of intracellular Ca2+ in cortex. 相似文献
50.
The regions of securin and cyclin B proteins recognized by the ubiquitination machinery are natively unfolded 总被引:1,自引:0,他引:1
The proteins securin and cyclin B are destroyed in mitosis by the ubiquitin/proteasome system. This destruction is important to mitotic progression. The N-terminal regions of these proteins contain the sequence features recognized by the ubiquitination system. We have demonstrated using circular dichroism and 1-D and 2-D nuclear magnetic resonance that these rather substantial regions are natively unfolded. Based on these findings, we propose a model that helps to explain previously enigmatic observations. 相似文献