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Hanneke Hoelen Arnaud Zaldumbide Wouter F. van Leeuwen Ellen C. W. Torfs Marten A. Engelse Chopie Hassan Robert Jan Lebbink Eelco J. de Koning Maaike E. Resssing Arnoud H. de Ru Peter A. van Veelen Rob C. Hoeben Bart O. Roep Emmanuel J. H. J. Wiertz 《PloS one》2015,10(6)
Patients with type 1 diabetes (T1D) suffer from beta-cell destruction by CD8+ T-cells that have preproinsulin as an important target autoantigen. It is of great importance to understand the molecular mechanism underlying the processing of preproinsulin into these CD8+ T-cell epitopes. We therefore studied a pathway that may contribute to the production of these antigenic peptides: degradation of proinsulin via ER associated protein degradation (ERAD). Analysis of the MHC class I peptide ligandome confirmed the presentation of the most relevant MHC class I-restricted diabetogenic epitopes in our cells: the signal peptide-derived sequence A15-A25 and the insulin B-chain epitopes H29-A38 and H34-V42. We demonstrate that specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. This indicates that these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. These ERAD proteins therefore represent interesting targets for novel therapies aiming at the reduction and possibly also prevention of beta-cell directed auto-immune reactions in T1D. 相似文献
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Janine F. Felix Elisabeth M. de Jong Claudine P. Torfs A. de Klein Robbert J. Rottier Dick Tibboel 《Birth defects research. Part A, Clinical and molecular teratology》2009,85(9):747-754
Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) are severe congenital anomalies. Although recent years have brought significant improvement in clinical treatment, our understanding of the etiology of these defects is lagging. Many genes and genetic pathways have been implicated in the development of EA/TEF, but only a few genes have been shown to be involved in humans, in animals, or in both. Extrapolating data from animal models to humans is not always straightforward. Environmental factors may also carry a risk, but the mechanisms are yet to be elucidated. This review gives an overview of the current state of knowledge about both genetic and environmental risk factors in the etiology of EA/TEF. Birth Defects Research (Part A) 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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Torfs H Van Poyer W Poels J Swinnen E De Loof A Vanden Broeck J 《Acta biologica Hungarica》2000,51(2-4):349-354
In the locust nervous system, tyramine is the direct precursor for octopamine synthesis and, as an octopamine analogue, it can activate octopamine receptors. Furthermore, the identification of specific tyramine receptors in Locusta migratoria and Drosophila melanogaster suggests that it is an important transmitter or modulator candidate. In this paper, we report that repeated tyramine injections reduced the viability of last instar larvae of Locusta and Schistocerca. In addition, a retardation of the last ecdysis was observed as a sublethal effect of the repeated tyramine treatment. Moreover, egg deposition by adult females was also retarded and/or drastically reduced. These effects show similarity to sublethal effects described for certain "insecticidal" octopamine receptor agonists, such as formamidines and phenyliminoimidazolidines. Since certain formamidine compounds were also shown to be agonists for the cloned tyramine receptors, it cannot be excluded that some lethal or sublethal consequences of tyramine administration are the result of an interaction with specific tyramine receptors. 相似文献
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Emily Graves Allen Sallie B. Freeman Charlotte Druschel Charlotte A. Hobbs Leslie A. O’Leary Paul A. Romitti Marjorie H. Royle Claudine P. Torfs Stephanie L. Sherman 《Human genetics》2009,125(1):41-52
We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed
data from two population-based, case–control studies: Atlanta Down Syndrome Project (1989–1999) and National Down Syndrome
Project (2001–2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in
the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four
primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted
to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced
maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers
of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be ≥40 years old than
20–24 years old at the birth of the index case (95% CI = 5.6–12.9). Where nondisjunction occurred in MII, mothers were 15.1
times more likely to be ≥40 years (95% CI = 8.4–27.3). Third, the ratio of MI to MII errors differed by maternal age. The
ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group
(3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the
complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position
of the Centers for Disease Control and Prevention. 相似文献
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Genetic interrelationship between insulin-dependent diabetes mellitus, the autoimmune thyroid diseases, and rheumatoid arthritis. 总被引:5,自引:2,他引:3
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C P Torfs M C King B Huey J Malmgren F C Grumet 《American journal of human genetics》1986,38(2):170-187
To investigate the possible coinheritance of autoimmune diseases that are associated with the same HLA antigen, we studied 70 families in which at least two siblings had either type I diabetes mellitus (IDDM), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), or a combination of these diseases. HLA-A, B, and C typing was performed on all affected sibs in one generation or more. First, we estimated by sib-pair analysis the disease allele frequency (pD) and the mode of inheritance for each disease. According to the method of ascertainment entered into the analysis, the pD for ATD ranged from .120 to .180, for an additive (dominant) mode of inheritance. For RA, the pD ranged from .254 to .341, also for additive inheritance, although recessive inheritance could not be excluded. For IDDM, the pD ranged from .336 to .337 for recessive inheritance; additive inheritance was rejected. Second, we examined the distribution of shared parental haplotypes in pairs of siblings that were discordant for their autoimmune diseases. The results suggested that the same haplotype may predispose to both IDDM and ATD, or IDDM and RA, but not to both RA and ATD. Analysis of pedigrees supported this hypothesis. In 16 families typed for HLA-DR also, the haplotype predisposing to both IDDM and ATD was assigned from pedigree information to DR3 (44%), DR4 (39%), or DR5, DR6, or DR7 (5.5% each). In some families, these haplotypes segregated over several generations with ATD only (either clinical or subclinical), suggesting that in such families, ATD was a marker for a susceptibility to IDDM. In several families, an IDDM haplotype segregated with RA but not with ATD. This suggests that ATD- and RA-associated susceptibilities to IDDM may be biologically different and thus independently increase the risk of IDDM. 相似文献
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A population-based study of congenital diaphragmatic hernia. 总被引:10,自引:0,他引:10
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