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1.
E V YoungLai M Wilkinson P Hibbert A McMahon J F Jarrell 《Canadian journal of physiology and pharmacology》1988,66(4):337-341
The binding of 125I-labelled human chorionic gonadotropin (HCG) was studied using thick slices (300 micron) of rabbit ovarian tissue. Binding was saturable, reversible, stereospecific, and of high affinity. The amount of binding was proportional to the number of slices used and could be destroyed by boiling. Ovarian slices from eight individual rabbits were found to have two binding sites for 125I-labelled HCG with KD values of 272 +/- 64 and 1263 +/- 274 pM and Bmax values of 25.7 +/- 5.3 and 94.1 +/- 18.8 fmol/mg protein, respectively. In a comparative study the KD and Bmax values were 351 +/- 151 pM and 25.3 +/- 11.1 fmol/mg protein with slices from one ovary and 134 +/- 24 pM and 109 +/- 32 fmol/mg protein with membranes from the contralateral ovary. These data suggest that the binding of HCG can be determined in live tissue. 相似文献
2.
Inagaki A Sleddens-Linkels E van Cappellen WA Hibbert RG Sixma TK Hoeijmakers JH Grootegoed JA Baarends WM 《PloS one》2011,6(8):e23155
RAD18 is an ubiquitin ligase involved in replicative damage bypass and DNA double-strand break (DSB) repair processes. We found that RPA is required for the dynamic pattern of RAD18 localization during the cell cycle, and for accumulation of RAD18 at sites of γ-irradiation-induced DNA damage. In addition, RAD18 colocalizes with chromatin-associated conjugated ubiquitin and ubiquitylated H2A throughout the cell cycle and following irradiation. This localization pattern depends on the presence of an intact, ubiquitin-binding Zinc finger domain. Using a biochemical approach, we show that RAD18 directly binds to ubiquitylated H2A and several other unknown ubiquitylated chromatin components. This interaction also depends on the RAD18 Zinc finger, and increases upon the induction of DSBs by γ-irradiation. Intriguingly, RAD18 does not always colocalize with regions that show enhanced H2A ubiquitylation. In human female primary fibroblasts, where one of the two X chromosomes is inactivated to equalize X-chromosomal gene expression between male (XY) and female (XX) cells, this inactive X is enriched for ubiquitylated H2A, but only rarely accumulates RAD18. This indicates that the binding of RAD18 to ubiquitylated H2A is context-dependent. Regarding the functional relevance of RAD18 localization at DSBs, we found that RAD18 is required for recruitment of RAD9, one of the components of the 9-1-1 checkpoint complex, to these sites. Recruitment of RAD9 requires the functions of the RING and Zinc finger domains of RAD18. Together, our data indicate that association of RAD18 with DSBs through ubiquitylated H2A and other ubiquitylated chromatin components allows recruitment of RAD9, which may function directly in DSB repair, independent of downstream activation of the checkpoint kinases CHK1 and CHK2. 相似文献
3.
Daopeng Yuan Anthony H. Keeble Richard G. Hibbert Stella Fabiane Hannah J. Gould James M. McDonnell Andrew J. Beavil Brian J. Sutton Balvinder Dhaliwal 《The Journal of biological chemistry》2013,288(30):21667-21677
Immunoglobulin E (IgE) antibodies play a fundamental role in allergic disease and are a target for therapeutic intervention. IgE functions principally through two receptors, FcϵRI and CD23 (FcϵRII). Minute amounts of allergen trigger mast cell or basophil degranulation by cross-linking IgE-bound FcϵRI, leading to an inflammatory response. The interaction between IgE and CD23 on B-cells regulates IgE synthesis. CD23 is unique among Ig receptors in that it belongs to the C-type (calcium-dependent) lectin-like superfamily. Although the interaction of CD23 with IgE is carbohydrate-independent, calcium has been reported to increase the affinity for IgE, but the structural basis for this activity has previously been unknown. We have determined the crystal structures of the human lectin-like head domain of CD23 in its Ca2+-free and Ca2+-bound forms, as well as the crystal structure of the Ca2+-bound head domain of CD23 in complex with a subfragment of IgE-Fc consisting of the dimer of Cϵ3 and Cϵ4 domains (Fcϵ3-4). Together with site-directed mutagenesis, the crystal structures of four Ca2+ ligand mutants, isothermal titration calorimetry, surface plasmon resonance, and stopped-flow analysis, we demonstrate that Ca2+ binds at the principal and evolutionarily conserved binding site in CD23. Ca2+ binding drives Pro-250, at the base of an IgE-binding loop (loop 4), from the trans to the cis configuration with a concomitant conformational change and ordering of residues in the loop. These Ca2+-induced structural changes in CD23 lead to additional interactions with IgE, a more entropically favorable interaction, and a 30-fold increase in affinity of a single head domain of CD23 for IgE. Taken together, these results suggest that binding of Ca2+ brings an extra degree of modulation to CD23 function. 相似文献
4.
Background
We have previously reported that free Heme generated during experimental cerebral malaria (ECM) in mice, is central to the pathogenesis of fatal ECM. Heme-induced up-regulation of STAT3 and CXCL10 promotes whereas up-regulation of HO-1 prevents brain tissue damage in ECM. We have previously demonstrated that Heme is involved in the induction of apoptosis in vascular endothelial cells. In the present study, we further tested the hypothesis that Heme reduces blood-brain barrier integrity during ECM by induction of apoptosis of brain vascular endothelial cells through STAT3 and its target gene matrix metalloproteinase three (MMP3) signaling.Methods
Genes associated with the JAK/STAT3 signaling pathway induced upon stimulation by Heme treatment, were assessed using real time RT2 Profile PCR arrays. A human MMP3 promoter was cloned into a luciferase reporter plasmid, pMMP3, and its activity was examined following exposure to Heme treatment by a luciferase reporter gene assay. In order to determine whether activated nuclear protein STAT3 binds to the MMP3 promoter and regulates MMP3 gene, we conducted a ChIP analysis using Heme-treated and untreated human brain microvascular endothelial cells (HBVEC), and determined mRNA and protein expression levels of MMP3 using qRT-PCR and Western blot. Apoptosis in HBVEC treated with Heme was evaluated by MTT and TUNEL assay.Results
The results show that (1) Heme activates a variety of JAK/STAT3 downstream pathways in HBVEC. STAT3 targeted genes such as MMP3 and C/EBPb (Apoptosis-related genes), are up regulated in HBVEC treated with Heme. (2) Heme-induced HBVEC apoptosis via activation of STAT3 as well as its downstream signaling molecule MMP3 and upregulation of CXCL10 and HO-1 expressions. (3) Phosphorylated STAT3 binds to the MMP3 promoter in HBVEC cells, STAT3 transcribed MMP3 and induced MMP3 protein expression in HBVEC cells.Conclusions
Activated STAT3 binds to the MMP3 promoter region and regulates MMP3 in Heme-induced endothelial cell apoptosis. 相似文献5.
Directed evolution strategies for improved enzymatic performance 总被引:1,自引:0,他引:1
The engineering of enzymes with altered activity, specificity and stability, using directed evolution techniques that mimic
evolution on a laboratory timescale, is now well established. However, the general acceptance of these methods as a route
to new biocatalysts for organic synthesis requires further improvement of the methods for both ease-of-use and also for obtaining
more significant changes in enzyme properties than is currently possible. Recent advances in library design, and methods of
random mutagenesis, combined with new screening and selection tools, continue to push forward the potential of directed evolution.
For example, protein engineers are now beginning to apply the vast body of knowledge and understanding of protein structure
and function, to the design of focussed directed evolution libraries, with striking results compared to the previously favoured
random mutagenesis and recombination of entire genes. Significant progress in computational design techniques which mimic
the experimental process of library screening is also now enabling searches of much greater regions of sequence-space for
those catalytic reactions that are broadly understood and, therefore, possible to model. 相似文献
6.
Plasminogen activator and collagenase production by cultured capillary endothelial cells 总被引:16,自引:17,他引:16 下载免费PDF全文
Cultured bovine capillary endothelial (BCE) cells produce low levels of collagenolytic activity and significant amounts of the serine protease plasminogen activator (PA). When grown in the presence of nanomolar quantities of the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), BCE cells produced 5-15 times more collagenolytic activity and 2-10 times more PA than untreated cells. The enhanced production of these enzymes was dependent on the dose of TPA used, with maximal response at 10(-7) to 10(-8) M. Phorbol didecanoate (PDD), an analog of TPA which is an active tumor promoter, also increased protease production. 4-O-methyl-TPA and 4α-PDD, two analogs of TPA which are inactive as tumor promoters, had no effect on protease production. Increased PA and collagenase activities were detected within 7.5 and 19 h, respectively, after the addition of TPA. The TPA-stimulated BCE cells synthesized a urokinase-type PA and a typical vertebrate collagenase. BCE cells were compared with bovine aortic endothelial (BAE) cells and bovine embryonic skin (BES) fibroblasts with respect to their production of protease in response to TPA. Under normal growth conditions, low levels of collagenolyic activity were detected in the culture fluids from BCE, BAE, and BES cells. BCE cells produced 5-13 times the basal levels of collagenolytic activity in response to TPA, whereas BAE cells and BES fibroblasts showed a minimal response to TPA. Both BCE and BAE cells exhibited relatively high basal levels of PA, the production of which was stimulated approximately threefold by the addition of TPA. The observation that BCE cells and not BAE cells produced high levels of both PA and collagenase activities in response to TPA demonstrates a significant difference between these two types of endothelial cells and suggests that the enhanced detectable activities are a property unique to bovine capillary and microvessel and endothelial cells. 相似文献
7.
Using a gentle vacuum technique essential oils were distilled from the leaves of six clones (29 different trees) of Eucalyptus camaldulensis which had previously been propagated by CSIRO, from four seed lots collected from an area of southern Australia bounded approximately by latitude 26 degrees S and longitude 142 degrees E. Inspection of the analyses of the oils together with principal components analysis (PCA) of the gas chromatograms shows that corresponding profiles (for those clones studied in groups of two, three, four and 20), as indicated by the scores of the principal components, are almost independent of environmental and seasonal conditions. 相似文献
8.
Szule JA Jarvis SE Hibbert JE Spafford JD Braun JE Zamponi GW Wessel GM Coorssen JR 《The Journal of biological chemistry》2003,278(27):24251-24254
Complexes of specific presynaptic proteins have been hypothesized to drive or catalyze the membrane fusion steps of exocytosis. Here we use a stage-specific preparation to test the roles of SNAREs, synaptotagmin, and SNARE-binding proteins in the mechanism of Ca2+-triggered membrane fusion. Excess exogenous proteins, sufficient to block SNARE interactions, did not inhibit either the Ca2+ sensitivity, extent, or kinetics of fusion. In contrast, despite a limited effect on SNARE and synaptotagmin densities, treatments with high doses of chymotrypsin markedly inhibited fusion. Conversely, low doses of chymotrypsin had no effect on the Ca2+ sensitivity or extent of fusion but did alter the kinetic profile, indicating a more direct involvement of other proteins in the triggered fusion pathway. SNAREs, synaptotagmin, and their immediate binding partners are critical to exocytosis at a stage other than membrane fusion, although they may still influence the triggered steps. 相似文献
9.
Liu M Guo S Hibbert JM Jain V Singh N Wilson NO Stiles JK 《Cytokine & growth factor reviews》2011,22(3):121-130
C–X–C motif chemokine 10 (CXCL10) also known as interferon γ-induced protein 10 kDa (IP-10) or small-inducible cytokine B10 is a cytokine belonging to the CXC chemokine family. CXCL10 binds CXCR3 receptor to induce chemotaxis, apoptosis, cell growth and angiostasis. Alterations in CXCL10 expression levels have been associated with inflammatory diseases including infectious diseases, immune dysfunction and tumor development. CXCL10 is also recognized as a biomarker that predicts severity of various diseases. A review of the emerging role of CXCL10 in pathogenesis of infectious diseases revealed diverse roles of CXCL10 in disease initiation and progression. The potential utilization of CXCL10 as a therapeutic target for infectious diseases is discussed. 相似文献
10.