首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   209篇
  免费   24篇
  2023年   2篇
  2021年   6篇
  2019年   8篇
  2018年   2篇
  2017年   7篇
  2016年   2篇
  2015年   5篇
  2014年   6篇
  2013年   10篇
  2012年   12篇
  2011年   8篇
  2010年   7篇
  2009年   4篇
  2008年   8篇
  2007年   8篇
  2006年   6篇
  2005年   4篇
  2004年   5篇
  2001年   4篇
  2000年   6篇
  1999年   6篇
  1998年   4篇
  1997年   5篇
  1995年   6篇
  1994年   4篇
  1993年   4篇
  1992年   5篇
  1991年   8篇
  1990年   8篇
  1989年   4篇
  1988年   4篇
  1987年   3篇
  1985年   5篇
  1983年   3篇
  1982年   2篇
  1980年   2篇
  1978年   3篇
  1977年   2篇
  1975年   2篇
  1974年   3篇
  1973年   2篇
  1969年   2篇
  1968年   5篇
  1957年   1篇
  1951年   1篇
  1948年   1篇
  1946年   1篇
  1942年   1篇
  1938年   1篇
  1936年   1篇
排序方式: 共有233条查询结果,搜索用时 15 毫秒
111.
Glycogenin initiates glycogen synthesis in an autocatalytic reaction in which individual glucose residues are covalently linked to Tyrosine 194 in order to form a short priming chain of glucose residues that is a substrate for glycogen synthase which, combined with the branching enzyme, catalyzes the bulk synthesis of glycogen. We sought to develop a new enzymatic assay to better characterize both the chemical and enzymatic characteristics of this unusual reaction. By directly detecting the reaction products using electrospray mass spectrometry this procedure permits both the visualization of the intact individual reaction species produced as a function of time and quantitation of the levels of each of species. The quantitation of the reaction agrees well with previous measurements of both catalytic rate and the change in rate as a function of average glucosylation. The results from this assay provide new insight into the mechanism by which glycogenin catalyzes the initiation reaction.  相似文献   
112.
Abe K  Aslam A  Walls AF  Sato T  Inoue H 《Life sciences》2006,79(9):898-904
Protease-activated receptors (PARs) have been implicated in the development of acute and chronic inflammatory responses. We have examined the expression of mRNA for PARs and their regulation by growth factors and cytokines in synovial fibroblasts derived from patients with rheumatoid arthritis (RA). Messenger RNA for PAR-1, -2 and -3 was detected in these cells, but not that for PAR-4. Expression of mRNA for PAR-2 was up-regulated by bFGF in a concentration-dependent manner, whereas expression of mRNA for PAR-1 and PAR-3 was not affected. Levels of mRNA encoding PAR-1, PAR-2 and PAR-3 did not increase in response to IL-1beta and TNF-alpha. Expression of mRNA for PAR-2 was maximal 12 h after addition of bFGF, and maximal levels of immunoreactive PAR-2 were reached after 24 h. Furthermore, PAR-2 agonist peptide (SLIGKV-NH(2)), but not the inactive reverse peptide (VKGILS-NH(2)), induced transitory cytosolic Ca(2+) mobilization in cells, and its response was increased by pretreatment with bFGF. An important role could be played by bFGF in the regulation of functional PAR-2 expression in cultured RA synovial fibroblasts.  相似文献   
113.
114.
Schistosomes are intravascular helminths that infect over 200 million people worldwide. Deposition of eggs by adult schistosomes stimulates Th2 responses to egg antigens and induces granulomatous pathology that is a hallmark of schistosome infection. Paradoxically, schistosomes require host immune function for their development and reproduction and for egress of parasite eggs from the host. To identify potential mechanisms by which immune cells might influence parasite development prior to the onset of egg production, we assessed immune function in mice infected with developing schistosomes. We found that pre-patent schistosome infection is associated with a loss of T cell responsiveness to other antigens and is due to a diminution in the ability of innate antigen-presenting cells to stimulate T cells. Diminution of stimulatory capacity by schistosome worms specifically affected CD11b+ cells and did not require concomitant adaptive responses. We could not find evidence for production of a diffusible inhibitor of T cells by innate cells from infected mice. Rather, inhibition of T cell responsiveness by accessory cells required cell contact and only occurred when cells from infected mice outnumbered competent APCs by more than 3∶1. Finally, we show that loss of T cell stimulatory capacity may in part be due to suppression of IL-12 expression during pre-patent schistosome infection. Modulation of CD4+ T cell and APC function may be an aspect of host immune exploitation by schistosomes, as both cell types influence parasite development during pre-patent schistosome infection.  相似文献   
115.
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.  相似文献   
116.
Li Z  Ptak D  Zhang L  Walls EK  Zhong W  Leung YF 《PloS one》2012,7(6):e40132
Phenylthiourea (PTU) is commonly used for inhibiting melanization of zebrafish embryos. In this study, the standard treatment with 0.2 mM PTU was demonstrated to specifically reduce eye size in larval fish starting at three days post-fertilization. This effect is likely the result of a reduction in retinal and lens size of PTU-treated eyes and is not related to melanization inhibition. This is because the eye size of tyr, a genetic mutant of tyrosinase whose activity is inhibited in PTU treatment, was not reduced. As PTU contains a thiocarbamide group which is presented in many goitrogens, suppressing thyroid hormone production is a possible mechanism by which PTU treatment may reduce eye size. Despite the fact that thyroxine level was found to be reduced in PTU-treated larvae, thyroid hormone supplements did not rescue the eye size reduction. Instead, treating embryos with six goitrogens, including inhibitors of thyroid peroxidase (TPO) and sodium-iodide symporter (NIS), suggested an alternative possibility. Specifically, three TPO inhibitors, including those that do not possess thiocarbamide, specifically reduced eye size; whereas none of the NIS inhibitors could elicit this effect. These observations indicate that TPO inhibition rather than a general suppression of thyroid hormone synthesis is likely the underlying cause of PTU-induced eye size reduction. Furthermore, the tissue-specific effect of PTU treatment might be mediated by an eye-specific TPO expression. Compared with treatment with other tyrosinase inhibitors or bleaching to remove melanization, PTU treatment remains the most effective approach. Thus, one should use caution when interpreting results that are obtained from PTU-treated embryos.  相似文献   
117.
Glycogen is the main storage form of glucose in the brain. In contrast with previous beliefs, brain glycogen has recently been shown to play important roles in several brain functions. A fraction of metabolized glucose molecules are being shunted through glycogen before reentering the glycolytic pathway, a phenomenon known as the glycogen shunt. The significance of glycogen in astrocyte energetics is underlined by high activity of the glycogen shunt and the finding that inhibition of glycogen degradation, under some conditions leads to a disproportional increase in glycolytic activity, so-called glycolytic supercompensation. Glycogen phosphorylase, the key enzyme in glycogen degradation, is expressed in two different isoforms in brain, the muscle and the brain isoform. Recent studies have illustrated how these are differently regulated. In the present study, we investigate the role of the two isoforms in glycolytic supercompensation in cultured astrocytes with the expression of either one of the isoforms silenced by siRNA knockdown. When reintroducing glucose to glucose-starved astrocytes, glycolytic activity increased dramatically. Interestingly, the increase was 30% higher in astrocytes not expressing the muscle isoform of glycogen phosphorylase. Based on these results and previously published data we couple the muscle isoform of glycogen phosphorylase to glycolytic supercompensation and glycogen shunt activity, giving insights to the underlying mechanistic of these phenomena.  相似文献   
118.
A novel algorithm is presented which models protein-protein interactions using surface complementarity. The method is applied to antibody-antigen docking. A steric scoring scheme, based upon a soft potential, is used to assess complementarity, and a simple electrostatic model is then used to remove infeasible interactions. The soft potential allows for structural changes that occur during docking. Biochemical knowledge is necessary to reduce the number of docking orientations produced by the method to a manageable size. The information used includes the known epitope residues and a single loose distance constraint. The method is applied to all three crystallographically determined antibody-lysozyme complexes, HyHEL-10, D1.3 and HyHEL-5. For the first time, a predicted antibody structure (that of D1.3) is used as a docking target. In the four systems modelled, the method identifies between 15 and 40 possible docking orientations. The root-mean-square (r.m.s.) deviation between these orientations and the relevant crystallographic complex is measured in the interface region. For all four complexes an orientation is found with r.m.s. deviation in the range 1.9 A and 4.8 A. The algorithm is implemented on a single instruction/multiple datastream (SI/MD) architecture computer. The use of a parallel architecture computer ensures detailed coverage of the search space, whilst still maintaining a search time of two days.  相似文献   
119.
The effects of the mitogenic monoclonal antibody OKT3 on the metabolic changes preceding DNA synthesis during the activation of human peripheral blood mononuclear cells were compared with those induced by PHA. The aspects studied included uridine transport, the incorporation of inositol into phospholipids, Na+-dependent amino acid uptake, and protein synthesis. All four parameters were increased in response to the ligation of the T lymphocyte receptor recognized by OKT3. These changes were apparent as early as the corresponding changes induced by PHA. However, the increases in uridine uptake and inositol incorporation were disproportionately reduced when compared to those caused by PHA, and no evidence of high-dose inhibition was seen in cells activated by OKT3. This suggests that at least some lectin-induced changes in metabolism are mediated through additional mechanisms, probably involving distinct receptors.  相似文献   
120.
We report a method of inducing antigen production in dendritic cells by in vivo targeting with lentiviral vectors that specifically bind to the dendritic cell-surface protein DC-SIGN. To target dendritic cells, we enveloped the lentivector with a viral glycoprotein from Sindbis virus engineered to be DC-SIGN-specific. In vitro, this lentivector specifically transduced dendritic cells and induced dendritic cell maturation. A high frequency (up to 12%) of ovalbumin (OVA)-specific CD8(+) T cells and a significant antibody response were observed 2 weeks after injection of a targeted lentiviral vector encoding an OVA transgene into naive mice. This approach also protected against the growth of OVA-expressing E.G7 tumors and induced regression of established tumors. Thus, lentiviral vectors targeting dendritic cells provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号