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161.
Siegel RM Muppidi JR Sarker M Lobito A Jen M Martin D Straus SE Lenardo MJ 《The Journal of cell biology》2004,167(4):735-744
Fas (CD95, APO-1, TNFRSF6) is a TNF receptor superfamily member that directly triggers apoptosis and contributes to the maintenance of lymphocyte homeostasis and prevention of autoimmunity. Although FADD and caspase-8 have been identified as key intracellular mediators of Fas signaling, it is not clear how recruitment of these proteins to the Fas death domain leads to activation of caspase-8 in the receptor signaling complex. We have used high-resolution confocal microscopy and live cell imaging to study the sequelae of early events in Fas signaling. These studies have revealed a new stage of Fas signaling in which receptor ligation leads to the formation of surface receptor oligomers that we term signaling protein oligomerization transduction structures (SPOTS). Formation of SPOTS depends on the presence of an intact Fas death domain and FADD but is independent of caspase activity. Analysis of cells expressing Fas mutations from patients with the autoimmune lymphoproliferative syndrome (ALPS) reveals that formation of SPOTS can be disrupted by distinct mechanisms in ALPS. 相似文献
162.
Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden
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Roach JC Deutsch K Li S Siegel AF Bekris LM Einhaus DC Sheridan CM Glusman G Hood L Lernmark A Janer M;Swedish Childhood Diabetes Study Group;Diabetes Incidence in Sweden Study Group 《American journal of human genetics》2006,79(4):614-627
We mapped the genetic influences for type 1 diabetes (T1D), using 2,360 single-nucleotide polymorphism (SNP) markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, initially in a survey of 363 Swedish T1D cases and controls. We confirmed prior studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, we identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; formerly IP3R3). The most significant single SNP in this region was at the center of the ITPR3 peak of association (P=1.7 x 10(-4) for the survey study). For validation, we typed an additional 761 Swedish individuals. The P value for association computed from all 1,124 individuals was 1.30 x 10(-6) (recessive odds ratio 2.5; 95% confidence interval [CI] 1.7-3.9). The estimated population-attributable risk of 21.6% (95% CI 10.0%-31.0%) suggests that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supports an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene. 相似文献
163.
Luo J Lang M Salzburger W Siegel N Stölting KN Meyer A 《Journal of experimental zoology. Part B. Molecular and developmental evolution》2006,306(6):567-574
A goldfish (Carassius auratus auratus) bacterial artificial chromosome genomic library (BAC library) was constructed from one aquarium-bred male specimen (tetraploid, 4n=100, genome size=3.52 pg/cell). The library consists of 128,352 positive clones with an average insert size of 150.4 kb, covering the genome 11-fold. All clones were spotted onto nylon filters and thus are available for screening of genomic regions of interest, such as candidate genes, gene families, or large-sized syntenic DNA regions of cyprinid species. Preliminary screens with two genes were conducted with hybridizing probes to the genes RAG1 and lgi1. RAG1 is a single-copy gene in zebrafish and is duplicated in C. a. auratus. We found a very close correlation between the number of positive BAC clones and the expected library coverage. Two copies of lgi1 were found in zebrafish. We have detected four different copies in C. a. auratus, not in the expected abundance, which indicates some variation in the coverage of the BAC library. The preliminary screens indicate that many duplicated genes that resulted from the ancient fish-specific genome duplication persist in the tetraploid goldfish genome. Hence, the BAC library will provide a useful resource for the future work on comparative genomics, polyploidy, diploidization, and evolutionary genomics in fishes. 相似文献
164.
Hettick JM Kashon ML Slaven JE Ma Y Simpson JP Siegel PD Mazurek GN Weissman DN 《Proteomics》2006,6(24):6416-6425
New methodologies for surveillance and identification of Mycobacterium tuberculosis are required to stem the spread of disease worldwide. In addition, the ability to discriminate mycobacteria at the strain level may be important to contact or source case investigations. To this end, we are developing MALDI-TOF MS methods for the identification of M. tuberculosis in culture. In this report, we describe the application of MALDI-TOF MS, as well as statistical analysis including linear discriminant and random forest analysis, to 16 medically relevant strains from four species of mycobacteria, M. tuberculosis, M. avium, M. intracellulare, and M. kansasii. Although species discrimination can be accomplished on the basis of unique m/z values observed in the MS fingerprint spectrum, discrimination at the strain level is predicted on the relative abundance of shared m/z values among strains within a species. For the 16 mycobacterial strains investigated in the present study, it is possible to unambiguously identify strains within a species on the basis of MALDI-TOF MS data. The error rate for classification of individual strains using linear discriminant analysis was 0.053 using 37 m/z variables, whereas the error rate for classification of individual strains using random forest analysis was 0.023 using only 18 m/z variables. In addition, using random forest analysis of MALDI-TOF MS data, it was possible to correctly classify bacterial strains as either M. tuberculosis or non-tuberculous with 100% accuracy. 相似文献
165.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) functions as an adaptor, positively regulating the NF-kappaB pathway. Here we report a new function of human TRAF6, the direct stimulation of apoptosis. The mechanism of apoptosis induction results from the capacity of human TRAF6 to interact and activate caspase 8. Both the C-terminal TRAF domain of human TRAF6, which directly interacts with the death effector domain of pro-caspase 8, and the N-terminal RING domain, which is required for activation of caspase 8, are necessary for the induction of apoptosis. The role of endogenous TRAF6 in regulating apoptosis was confirmed by extinguishing TRAF6 expression with specific small-hairpin RNA that resulted in diminished spontaneous apoptosis and resistance to induced apoptosis. In contrast to the human molecule, murine TRAF6 displayed less ability to induce apoptosis and a greater capacity to stimulate NF-kappaB activity. Human and murine TRAF6 are similar except in the region between zinc finger 5 and the TRAF domains. Reciprocal transfer of this connecting region completely exchanged the ability of human and murine TRAF6 to induce apoptosis and activate NF-kappaB. Unique regions of TRAF6 therefore play an important role in determining cell fate. 相似文献
166.
Kuo AY Lee JC Magnin G Siegel PB Denbow DM 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2006,144(3):359-364
Effect of reserpine on body weight (BW), feed intake (FI), brain and plasma catecholamine and indoleamine concentrations in high- (HWS) and low- (LWS) weight selected lines of chickens was investigated. Chicks from each line were assigned to three treatment groups and injected intraperitoneally with 0, 1.25, or 2.50 mg/kg of reserpine at hatch, and again at 5 weeks-of-age. Chick BW and FI were determined weekly. At 7 weeks-of-age, 12 males and females from each group were sacrificed for neurotransmitter analysis. In the HWS line there was a dose-dependent decrease in BW through 7 weeks-of-age, whereas in the LWS line BW decreased only through the first 2 weeks-of-age. In the LWS line, norepinephrine (NE), epinephrine, and 3,4-dihydroxyphenylacetate concentrations decreased in the brain in a linear and quadratic manner in response to reserpine, but not in the HWS line. Both lines showed linear decreases in dopamine levels in response to reserpine; however, serotonin was not affected by reserpine. Chickens in the HWS line had greater plasma NE, and lower 5-hydroxyindoleacetic acid than those in the LWS line. In conclusion, it appears that chickens from the HWS line were more sensitive to the BW reducing effects of reserpine than those from the LWS line, with the latter appearing to have greater sympathetic nervous system activity. 相似文献
167.
Siegel RM 《Nature reviews. Immunology》2006,6(4):308-317
Caspases are responsible for crucial aspects of inflammation and immune-cell death that are disrupted in a number of genetic autoimmune and autoinflammatory diseases. The caspase family of proteases can be divided into pro-apoptotic and pro-inflammatory members based on their substrate specificity and participation in separate signalling cascades. However, as discussed here, evidence has emerged over the past few years that a number of the caspases thought to be involved solely in apoptosis also contribute to specific aspects of immune-cell development, activation and differentiation, and can even protect cells from some forms of cell death. 相似文献
168.
169.
Chêne A Vembar SS Rivière L Lopez-Rubio JJ Claes A Siegel TN Sakamoto H Scheidig-Benatar C Hernandez-Rivas R Scherf A 《Nucleic acids research》2012,40(7):3066-3077
In Plasmodium falciparum, perinuclear subtelomeric chromatin conveys monoallelic expression of virulence genes. However, proteins that directly bind to chromosome ends are poorly described. Here we identify a novel DNA/RNA-binding protein family that bears homology to the archaeal protein Alba (Acetylation lowers binding affinity). We isolated three of the four PfAlba paralogs as part of a molecular complex that is associated with the P. falciparum-specific TARE6 (Telomere-Associated Repetitive Elements 6) subtelomeric region and showed in electromobility shift assays (EMSAs) that the PfAlbas bind to TARE6 repeats. In early blood stages, the PfAlba proteins were enriched at the nuclear periphery and partially co-localized with PfSir2, a TARE6-associated histone deacetylase linked to the process of antigenic variation. The nuclear location changed at the onset of parasite proliferation (trophozoite-schizont), where the PfAlba proteins were also detectable in the cytoplasm in a punctate pattern. Using single-stranded RNA (ssRNA) probes in EMSAs, we found that PfAlbas bind to ssRNA, albeit with different binding preferences. We demonstrate for the first time in eukaryotes that Alba-like proteins bind to both DNA and RNA and that their intracellular location is developmentally regulated. Discovery of the PfAlbas may provide a link between the previously described subtelomeric non-coding RNA and the regulation of antigenic variation. 相似文献
170.