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131.
KM Smith M Guerau-de-Arellano S Costinean JL Williams A Bottoni G Mavrikis Cox AR Satoskar CM Croce MK Racke AE Lovett-Racke CC Whitacre 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(4):1567-1576
Th cell programming and function is tightly regulated by complex biological networks to prevent excessive inflammatory responses and autoimmune disease. The importance of microRNAs (miRNAs) in this process is highlighted by the preferential Th1 polarization of Dicer-deficient T cells that lack miRNAs. Using genetic knockouts, we demonstrate that loss of endogenous miR-29, derived from the miR-29ab1 genomic cluster, results in unrestrained T-bet expression and IFN-γ production. miR-29b regulates T-bet and IFN-γ via a direct interaction with the 3' untranslated regions, and IFN-γ itself enhances miR-29b expression, establishing a novel regulatory feedback loop. miR-29b is increased in memory CD4(+) T cells from multiple sclerosis (MS) patients, which may reflect chronic Th1 inflammation. However, miR-29b levels decrease significantly upon T cell activation in MS patients, suggesting that this feedback loop is dysregulated in MS patients and may contribute to chronic inflammation. miR-29 thus serves as a novel regulator of Th1 differentiation, adding to the understanding of T cell-intrinsic regulatory mechanisms that maintain a balance between protective immunity and autoimmunity. 相似文献
132.
Röring M Herr R Fiala GJ Heilmann K Braun S Eisenhardt AE Halbach S Capper D von Deimling A Schamel WW Saunders DN Brummer T 《The EMBO journal》2012,31(11):2629-2647
The dimerisation of Raf kinases involves a central cluster within the kinase domain, the dimer interface (DIF). Yet, the importance of the DIF for the signalling potential of wild-type B-Raf (B-Raf(wt)) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf(wt) and several of its gain-of-function (g-o-f) mutants. In contrast, the B-Raf(V600E), B-Raf(insT) and B-Raf(G469A) oncoproteins are remarkably resistant to mutations in the DIF. However, compared with B-Raf(wt), B-Raf(V600E) displays extended protomer contacts, increased homodimerisation and incorporation into larger protein complexes. In contrast, B-Raf(wt) and Raf-1(wt) mediated signalling triggered by oncogenic Ras as well as the paradoxical activation of Raf-1 by kinase-inactivated B-Raf require an intact DIF. Surprisingly, the B-Raf DIF is not required for dimerisation between Raf-1 and B-Raf, which was inactivated by the D594A mutation, sorafenib or PLX4720. This suggests that paradoxical MEK/ERK activation represents a two-step mechanism consisting of dimerisation and DIF-dependent transactivation. Our data further implicate the Raf DIF as a potential target against Ras-driven Raf-mediated (paradoxical) ERK activation. 相似文献
133.
Schnute ME McReynolds MD Kasten T Yates M Jerome G Rains JW Hall T Chrencik J Kraus M Cronin CN Saabye M Highkin MK Broadus R Ogawa S Cukyne K Zawadzke LE Peterkin V Iyanar K Scholten JA Wendling J Fujiwara H Nemirovskiy O Wittwer AJ Nagiec MM 《The Biochemical journal》2012,444(1):79-88
SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a K(i) of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling. 相似文献
134.
Margina D Ilie M Manda G Neagoe I Mocanu M Ionescu D Gradinaru D Ganea C 《General physiology and biophysics》2012,31(1):47-55
Quercetin and epigallocatechin gallate are two of the most abundant polyphenols in dietary plants, including apples, onions, red wine and green tea. The bioactivity of polyphenols is linked to their ability to interact with cell membranes without being internalized. The aim of the present study was to assess the short-time effect of these polyphenols on membrane anisotropy and transmembrane potential of U937 monocytes and Jurkat T lymphoblasts. Results showed that quercetin and epigallocatechin gallate induced, after 20 minutes cell exposure, a dose-dependent increase of membrane anisotropy and polarization. Anisotropy increase was correlated with the reduction of lipid peroxidation. Our results could indicate that the antioxidant capacity of the tested polyphenols is due to their stabilizing effect on the cell membranes, thus contributing to cell protection in various pathologies and as adjuvant therapy in highly toxic treatment regimens. 相似文献
135.
It is generally accepted that esophageal adenocarcinoma arises from a Barrett's metaplastic lesion. Altered glycoprotein expression has been demonstrated in tissue from patients with Barrett's esophagus and esophageal cancer but the mechanisms regarding such changes are unknown. The bile acid deoxycholic acid (DCA) alters many cell signaling pathways and is implicated in esophageal cancer progression. We have demonstrated that DCA disrupts Golgi structure and affects protein secretion and glycosylation processes in cell lines derived from normal squamous epithelium (HET-1A) and Barrett's metaplastic epithelium (QH). Cell surface expression of glycans was identified using carbohydrate-specific probes (wheat germ agglutinate, conconavalin A, peanut agglutinin, lithocholic acid and Ulex europaeus agglutinin) that monitored N-glycosylation, O-glycosylation and core fucosylation in resting and DCA-treated cells. DCA altered intracellular localization and reduced cell surface expression of N-acetyl-D-glucosamine, α-methyl-mannopyranoside (Man/Glc) and fucose in both cell lines. Furthermore, DCA reduced the expression of epithelial growth factor receptor and E-cadherin in a manner analogous to treatment of cells with the N-glycan biosynthesis inhibitor tunicamycin. This is the first study to identify an altered Golgi structure and glycomic profile in response to DCA in esophageal epithelial cells, a process which could potentially contribute to metaplasia, dysplasia and cancer of the esophagus. 相似文献
136.
Jérémie Fournier-Dit-Chabert Victoria Vinader Ana Rita Santos Mariano Redondo-Horcajo Aurore Dreneau Ramkrishna Basak Laura Cosentino Gemma Marston Hamdy Abdel-Rahman Paul M. Loadman Steven D. Shnyder José Fernando Díaz Isabel Barasoain Robert A. Falconer Klaus Pors 《Bioorganic & medicinal chemistry letters》2012,22(24):7693-7696
Colchicine was modified at the 10-OCH3 position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62–99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery. 相似文献
137.
Gina L. Conte Matthew E. Arnegard Catherine L. Peichel Dolph Schluter 《Proceedings. Biological sciences / The Royal Society》2012,279(1749):5039-5047
Genomic and genetic methods allow investigation of how frequently the same genes are used by different populations during adaptive evolution, yielding insights into the predictability of evolution at the genetic level. We estimated the probability of gene reuse in parallel and convergent phenotypic evolution in nature using data from published studies. The estimates are surprisingly high, with mean probabilities of 0.32 for genetic mapping studies and 0.55 for candidate gene studies. The probability declines with increasing age of the common ancestor of compared taxa, from about 0.8 for young nodes to 0.1–0.4 for the oldest nodes in our study. Probability of gene reuse is higher when populations begin from the same ancestor (genetic parallelism) than when they begin from divergent ancestors (genetic convergence). Our estimates are broadly consistent with genomic estimates of gene reuse during repeated adaptation to similar environments, but most genomic studies lack data on phenotypic traits affected. Frequent reuse of the same genes during repeated phenotypic evolution suggests that strong biases and constraints affect adaptive evolution, resulting in changes at a relatively small subset of available genes. Declines in the probability of gene reuse with increasing age suggest that these biases diverge with time. 相似文献
138.
Fermentable carbohydrate alters hypothalamic neuronal activity and protects against the obesogenic environment 总被引:1,自引:0,他引:1
Anastasovska J Arora T Sanchez Canon GJ Parkinson JR Touhy K Gibson GR Nadkarni NA So PW Goldstone AP Thomas EL Hankir MK Van Loo J Modi N Bell JD Frost G 《Obesity (Silver Spring, Md.)》2012,20(5):1016-1023
Obesity has become a major global health problem. Recently, attention has focused on the benefits of fermentable carbohydrates on modulating metabolism. Here, we take a system approach to investigate the physiological effects of supplementation with oligofructose-enriched inulin (In). We hypothesize that supplementation with this fermentable carbohydrate will not only lead to changes in body weight and composition, but also to modulation in neuronal activation in the hypothalamus. Male C57BL/6 mice were maintained on a normal chow diet (control) or a high fat (HF) diet supplemented with either oligofructose-enriched In or corn starch (Cs) for 9 weeks. Compared to HF+Cs diet, In supplementation led to significant reduction in average daily weight gain (mean ± s.e.m.: 0.19 ± 0.01 g vs. 0.26 ± 0.02 g, P < 0.01), total body adiposity (24.9 ± 1.2% vs. 30.7 ± 1.4%, P < 0.01), and lowered liver fat content (11.7 ± 1.7% vs. 23.8 ± 3.4%, P < 0.01). Significant changes were also observed in fecal bacterial distribution, with increases in both Bifidobacteria and Lactobacillius and a significant increase in short chain fatty acids (SCFA). Using manganese-enhanced MRI (MEMRI), we observed a significant increase in neuronal activation within the arcuate nucleus (ARC) of animals that received In supplementation compared to those fed HF+Cs diet. In conclusion, we have demonstrated for the first time, in the same animal, a wide range of beneficial metabolic effects following supplementation of a HF diet with oligofructose-enriched In, as well as significant changes in hypothalamic neuronal activity. 相似文献
139.
Background
Trypanosoma cruzi is the causative agent of Chagas'' Disease. The parasite has a complex population structure, with six major evolutionary lineages, some of which have apparently resulted from ancestral hybridization events. Because there are important biological differences between these lineages, strain typing methods are essential to study the T. cruzi species. Currently, there are a number of typing methods available for T. cruzi, each with its own advantages and disadvantages. However, most of these methods are based on the amplification of a variable number of loci.Methodology/Principal Findings
We present a simple typing assay for T. cruzi, based on the amplification of a single polymorphic locus: the TcSC5D gene. When analyzing sequences from this gene (a putative lathosterol/episterol oxidase) we observed a number of interesting polymorphic sites, including 1 tetra-allelic, and a number of informative tri- and bi-allelic SNPs. Furthermore, some of these SNPs were located within the recognition sequences of two commercially available restriction enzymes. A double digestion with these enzymes generates a unique restriction pattern that allows a simple classification of strains in six major groups, corresponding to DTUs TcI–TcIV, the recently proposed Tcbat lineage, and TcV/TcVI (as a group). Direct sequencing of the amplicon allows the classification of strains into seven groups, including the six currently recognized evolutionary lineages, by analyzing only a few discriminant polymorphic sites.Conclusions/Significance
Based on these findings we propose a simple typing assay for T. cruzi that requires a single PCR amplification followed either by restriction fragment length polymorphism analysis, or direct sequencing. In the panel of strains tested, the sequencing-based method displays equivalent inter-lineage resolution to recent multi- locus sequence typing assays. Due to their simplicity and low cost, the proposed assays represent a good alternative to rapidly screen strain collections, providing the cornerstone for the development of robust typing strategies. 相似文献140.
Yuanfeng Hao Yingying Wang Zhenbang Chen Dan Bland Sishen Li Gina Brown-Guedira Jerry Johnson 《Molecular breeding : new strategies in plant improvement》2012,30(3):1453-1464
Soil-borne wheat mosaic virus (SBWMV) is considered to be one of the most important diseases in winter wheat regions of the central and southeastern United States. Utilization of resistant cultivars is the most efficient and environmentally friendly means of control. To identify potential quantitative trait loci (QTL) or effective gene(s) for SBWMV resistance, two independent recombinant inbred line populations, Pioneer 26R61/AGS 2000 (PR61/A2000, 178 lines) and AGS 2020/LA 95135 (A2020/LA, 130 lines), were developed. Pioneer 26R61 and AGS 2020 were resistant to SBWMV, and AGS 2000 and LA 95135 were susceptible. Based on the whole genome genotyping for the PR61/A2000 population and targeted mapping of chromosome 5D for the A2020/LA, the same major QTL QSbm.uga-5DL was identified in all environments with highly significant LOD values, explaining up to 62 and 65?% of the total phenotypic variation in the PR61/A2000 and A2020/LA populations, respectively. The location of the resistance QTL coincided with previously published SBCMV resistance genes Sbm1, Sbm Claire and Sbm Tremie on the long arm of chromosome 5D. A conserved locus was therefore proposed for conditioning SBWMV/SBCMV resistance in common wheat. Validation of the QTL using the flanking markers Xbarc177 and Xbarc161 in three cultivars and three elite lines with Pioneer 26R61 in their pedigrees indicated that the markers were suitable for marker-assisted selection. 相似文献