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41.
Sengupta S Jayaraman P Chilton PM Casella CR Mitchell TC 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(10):6083-6091
Activated T cell death (ATCD) after peak clonal expansion is required for effective homeostasis of the immune system. Using a mouse model of T cell clonal expansion and contraction, we found that regulation of the proapoptotic kinase glycogen synthase kinase (GSK)-3beta plays a decisive role in determining the extent to which T cells are eliminated after activation. Involvement of GSK-3beta in ATCD was tested by measuring T cell survival after GSK-3beta inhibition, either ex vivo with chemical and pharmacological inhibitors or in vivo by retroviral expression of a dominant-negative form of GSK-3. We also measured amounts of inactivating phosphorylation of GSK-3beta (Ser9) in T cells primed in the presence or absence of LPS. Our results show that GSK-3beta activity is required for ATCD and that its inhibition promoted T cell survival. Adjuvant treatment in vivo maintained GSK-3beta (Ser9) phosphorylation in activated T cells, whereas with adjuvant-free stimulation it peaked and then decayed as the cells became susceptible to ATCD. We conclude that the duration of GSK-3beta inactivation determines activated T cell survival and that natural adjuvant stimulation decreases the severity of clonal contraction in part by keeping a critical proapoptotic regulatory factor, GSK-3beta, inactivated. 相似文献
42.
Kaushal R Pal P Alwell K Haverbusch M Flaherty M Moomaw C Sekar P Kissela B Kleindorfer D Chakraborty R Broderick J Deka R Woo D 《Human genetics》2007,121(5):601-607
Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However,
replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively
recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically
matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association
with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW.
Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes,
hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P = 0.019 and P < 10−4, respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association
was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association
with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes
were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we
report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks. 相似文献
43.
Biological phenomena at the cellular level can be represented by various types of mathematical formulations. Such representations
allow us to carry out numerical simulations that provide mechanistic insights into complex behaviours of biological systems
and also generate hypotheses that can be experimentally tested. Currently, we are particularly interested in spatio-temporal
representations of dynamic cellular phenomena and how such models can be used to understand biological specificity in functional
responses. This review describes the capability and limitations of the approaches used to study spatio-temporal dynamics of
cell signalling components. 相似文献
44.
Ewa Kaniewska Alicja Sielicka Padmini Sarathchandra Iwona Pelikant-Małecka Mariola Olkowicz Ewa M. Słomińska 《Nucleosides, nucleotides & nucleic acids》2014,33(4-6):305-312
Extracellular nucleotides control mechanisms such as thrombosis or inflammation that are important in several pathologies, including heart valve disease and calcification. Ectonucleoside triphosphate diphosphohydrolase 1 (eNTPD1, CD39) and ecto-5′-nucleotidase (e5NT, CD73) are ectoenzymes that convert adenosine triphosphate to adenosine diphosphate, adenosine monophosphate and finally to adenosine. Changes in activities of these enzymes influence extracellular nucleotide concentrations and therefore could be involved in valve pathology. This study aimed to analyze type of cells, specific area, level of expression and biochemical function of CD39 and CD73 in pig aortic valves. Samples were collected from aortic valves of domestic pigs. Histological sections were cut from paraffin embedded tissue blocks. Following incubation with primary antibody against CD39 or CD73, washing and secondary goat anti-rabbit secondary antibodies, slides were viewed with NanoZoomer scanner. Substantial expression CD39 and CD73 was observed in two main types of valve cells: endothelial and valve interstitial cells. Subsequently, biochemical function of CD39 and CD73 was evaluated in cells cultured from pig aortic valve. Breakdown of extracellular nucleotides added to cell medium was analyzed with high performance liquid chromatography. In the interstitial cells, the CD73 products formation was much faster than in endothelium, while for the CD39 activity this relation was opposite. Expression and high concentration of CD39 and CD73 products in endothelium are expected, but presence of CD73 in valve interstitial cells is a surprise. We conclude that CD39 and CD73 and their enzymatic activities that convert extracellular nucleotides are highly expressed and could have special function in the valve. 相似文献
45.
RP Brinãs A Sundgren P Sahoo S Morey K Rittenhouse-Olson GE Wilding W Deng JJ Barchi 《Bioconjugate chemistry》2012,23(8):1513-1523
The development of vaccines against specific types of cancers will offer new modalities for therapeutic intervention. Here, we describe the synthesis of a novel vaccine construction prepared from spherical gold nanoparticles of 3-5 nm core diameters. The particles were coated with both the tumor-associated glycopeptides antigens containing the cell-surface mucin MUC4 with Thomsen Friedenreich (TF) antigen attached at different sites and a 28-residue peptide from the complement derived protein C3d to act as a B-cell activating "molecular adjuvant". The synthesis entailed solid-phase glycopeptide synthesis, design of appropriate linkers, and attachment chemistry of the various molecules to the particles. Attachment to the gold surface was mediated by a novel thiol-containing 33 atom linker which was further modified to be included as a third "spacer" component in the synthesis of several three-component vaccine platforms. Groups of mice were vaccinated either with one of the nanoplatform constructs or with control particles without antigen coating. Evaluation of sera from the immunized animals in enzyme immunoassays (EIA) against each glycopeptide antigen showed a small but statistically significant immune response with production of both IgM and IgG isotypes. Vaccines with one carbohydrate antigen (B, C, and E) gave more robust responses than the one with two contiguous disaccharides (D), and vaccine E with a TF antigen attached to threonine at the 10th position of the peptide was selected for IgG over IgM suggesting isotype switching. The data suggested that this platform may be a viable delivery system for tumor-associated glycopeptide antigens. 相似文献
46.
Masaoka A Gassman NR Kedar PS Prasad R Hou EW Horton JK Bustin M Wilson SH 《The Journal of biological chemistry》2012,287(33):27648-27658
In mammalian cells, the nucleosome-binding protein HMGN1 (high mobility group N1) affects the structure and function of chromatin and plays a role in repair of damaged DNA. HMGN1 affects the interaction of DNA repair factors with chromatin and their access to damaged DNA; however, not all of the repair factors affected have been identified. Here, we report that HMGN1 affects the self-poly(ADP-ribosyl)ation (i.e., PARylation) of poly(ADP-ribose) polymerase-1 (PARP-1), a multifunctional and abundant nuclear enzyme known to recognize DNA lesions and promote chromatin remodeling, DNA repair, and other nucleic acid transactions. The catalytic activity of PARP-1 is activated by DNA with a strand break, and this results in self-PARylation and PARylation of other chromatin proteins. Using cells obtained from Hmgn1(-/-) and Hmgn1(+/+) littermate mice, we find that in untreated cells, loss of HMGN1 protein reduces PARP-1 self-PARylation. A similar result was obtained after MMS treatment of these cells. In imaging experiments after low energy laser-induced DNA damage, less PARylation at lesion sites was observed in Hmgn1(-/-) than in Hmgn1(+/+) cells. The HMGN1 regulation of PARP-1 activity could be mediated by direct protein-protein interaction as HMGN1 and PARP-1 were found to interact in binding assays. Purified HMGN1 was able to stimulate self-PARylation of purified PARP-1, and in experiments with cell extracts, self-PARylation was greater in Hmgn1(+/+) than in Hmgn1(-/-) extract. The results suggest a regulatory role for HMGN1 in PARP-1 activation. 相似文献
47.
Dr. P. Padmini Dr. S. K. Rakshit Dr. A. Baradarajan 《Bioprocess and biosystems engineering》1993,9(2-3):103-106
A change of the reaction rate was observed for the lipasecatalysed hydrolysis of ricebran oil in a batch stirred tank reactor using immobilized lipase enzyme as compared to free enzyme. The reactor rate was observed to be controlled mainly by factors like temperature, pH, initial enzyme concentration, initial substrate concentration and initial products concentration. 相似文献
48.
Tannic acid mordanting reveals the periplasm, the area between the outer membrane and the inner membrane of gram-negative bacteria, Rhizobium gp., Escherichia colt and Enterobacter aeregenes, as an electron-dense layer continuous with the inner leaflet of the outer membrane. The method involves 18 hr of tannic acid treatment after fixation in aldehyde prior to osmium tetroxide postfixation, followed by conventional electron microscopy. 相似文献
49.
Chemically induced carcinogenesis models in the rat are widely used for studying the biology of cancer and for developing and evaluating cancer prevention strategies. The azoxymethane(AOM)-induced rat colon tumor is a valuable tool for studying the interaction between tumor development and exogenous factors. Malignant conditions are characterized by enhanced levels of lipid peroxidative products, protein bound carbohydrates indicative of membrane damage and an ineffective antioxidant scavenging system. In the present study, AOM-induced rat showed lipid peroxidative damage, alterations in the membrane glycoprotein component and antioxidant defense system, along with ultrastructural changes like disruption in goblet cell and its membrane, swollen mitochondria with cristae dispersed, elongated endoplasmic reticulum and other features of neoplastic invasion. Berberine significantly attenuated the increases in lipid peroxidation, protein bound carbohydrates and enhanced the antioxidative status. The present study suggests that berberine prevents the appearance of malignant morphology and ultrastructural changes of AOM induced cancer by producing apoptosis like changes. Thus berberine inhibits neoplastic transformation by the induction of antioxidant defence system and ability to induce apoptotic like changes—thus elucidating its anti cancer role. 相似文献
50.
Horton JK Stefanick DF Naron JM Kedar PS Wilson SH 《The Journal of biological chemistry》2005,280(16):15773-15785
Mouse fibroblasts, deficient in DNA polymerase beta, are hypersensitive to monofunctional DNA methylating agents such as methyl methanesulfonate (MMS). Both wild-type and, in particular, repair-deficient DNA polymerase beta null cells are highly sensitized to the cytotoxic effects of MMS by 4-amino-1,8-naphthalimide (4-AN), an inhibitor of poly(ADP-ribose) polymerase (PARP) activity. Experiments with synchronized cells suggest that exposure during S-phase of the cell cycle is required for the 4-AN effect. 4-AN elicits a similar extreme sensitization to the thymidine analog, 5-hydroxymethyl-2'-deoxyuridine, implicating the requirement for an intermediate of DNA repair. In PARP-1-expressing fibroblasts treated with a combination of MMS and 4-AN, a complete inhibition of DNA synthesis is apparent after 4 h, and by 24 h, all cells are arrested in S-phase of the cell cycle. Continuous incubation with 4-AN is required to maintain the cell cycle arrest. Caffeine, an inhibitor of the upstream checkpoint kinases ATM (ataxia telangiectasia-mutated) and ATR (ATM and Rad3-related), has no effect on the early inhibition of DNA synthesis, but cells are no longer able to maintain the block after 8 h. Instead, the addition of caffeine leads to arrest of cells in G(2)/M rather than S-phase after 24 h. Analysis of signaling pathways in cell extracts reveals an activation of Chk1 after treatment with MMS and 4-AN, which can be suppressed by caffeine. Our results suggest that inhibition of PARP activity results in sensitization to MMS through maintenance of an ATR and Chk1-dependent S-phase checkpoint. 相似文献