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441.
442.
Urban S Textoris-Taube K Reimann B Janek K Dannenberg T Ebstein F Seifert C Zhao F Kessler JH Halenius A Henklein P Paschke J Cadel S Bernhard H Ossendorp F Foulon T Schadendorf D Paschen A Seifert U 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(2):529-538
Control of human CMV (HCMV) infection depends on the cytotoxic activity of CD8(+) CTLs. The HCMV phosphoprotein (pp)65 is a major CTL target Ag and pp65(495-503) is an immunodominant CTL epitope in infected HLA-A*0201 individuals. As immunodominance is strongly determined by the surface abundance of the specific epitope, we asked for the components of the cellular Ag processing machinery determining the efficacy of pp65(495-503) generation, in particular, for the proteasome, cytosolic peptidases, and endoplasmic reticulum (ER)-resident peptidases. In vitro Ag processing experiments revealed that standard proteasomes and immunoproteasomes generate the minimal 9-mer peptide epitope as well as N-terminal elongated epitope precursors of different lengths. These peptides are largely degraded by the cytosolic peptidases leucine aminopeptidase and tripeptidyl peptidase II, as evidenced by increased pp65(495-503) epitope presentation after leucine aminopeptidase and tripeptidyl peptidase II knockdown. Additionally, with prolyl oligopeptidase and aminopeptidase B we identified two new Ag processing machinery components, which by destroying the pp65(495-503) epitope limit the availability of the specific peptide pool. In contrast to cytosolic peptidases, silencing of ER aminopeptidases 1 and 2 strongly impaired pp65(495-503)-specific T cell activation, indicating the importance of ER aminopeptidases in pp65(495-503) generation. Thus, cytosolic peptidases primarily interfere with the generation of the pp65(495-503) epitope, whereas ER-resident aminopeptidases enhance such generation. As a consequence, our experiments reveal that the combination of cytosolic and ER-resident peptidase activities strongly shape the pool of specific antigenic peptides and thus modulate MHC class I epitope presentation efficiency. 相似文献
443.
Rishibha Sachdev Karin Kappes-Horn Lydia Paulsen Yvonne Duernberger Catharina Pleschka Philip Denner Bishwajit Kundu Jens Reimann Ina Vorberg 《Molecular neurobiology》2018,55(11):8355-8373
Sporadic inclusion body myositis (sIBM) is the most prevalent acquired muscle disorder in the elderly with no defined etiology or effective therapy. Endoplasmic reticulum stress and deposition of myostatin, a secreted negative regulator of muscle growth, have been implicated in disease pathology. The myostatin signaling pathway has emerged as a major target for symptomatic treatment of muscle atrophy. Here, we systematically analyzed the maturation and secretion of myostatin precursor MstnPP and its metabolites in a human muscle cell line. We find that increased MsntPP protein levels induce ER stress. MstnPP metabolites were predominantly retained within the endoplasmic reticulum (ER), also evident in sIBM histology. MstnPP cleavage products formed insoluble high molecular weight aggregates, a process that was aggravated by experimental ER stress. Importantly, ER stress also impaired secretion of mature myostatin. Reduced secretion and aggregation of MstnPP metabolites were not simply caused by overexpression, as both events were also observed in wildtype cells under ER stress. It is tempting to speculate that reduced circulating myostatin growth factor could be one explanation for the poor clinical efficacy of drugs targeting the myostatin pathway in sIBM. 相似文献
444.
“山水林田湖草沙生命共同体”系统保护与修复是我国生态文明建设的重要内容。明确生命共同体的耦合机制,是科学地进行生态保护和修复工作的关键。针对当前生命共同体耦合机制不清、理论和方法不健全的问题,从耦合的视角出发,在小流域尺度上单一生态系统内部生态要素的耦合、流域尺度上不同生态系统之间的耦合、区域尺度上人与自然的耦合三个方面进行整合,在此基础上探讨了多尺度山水林田湖草沙耦合理论,提出了一般性的山水林田湖草沙耦合理论框架。梳理并比较了当前主要的生态系统模型、景观模型、统计学模型以及复合生态系统的多模型耦合方法,综合提出了一个适用于"山水林田湖草沙生命共同体"耦合研究方法。对进一步完善山水林田湖草沙一体化保护修复提出了建议,包括:一是构建多源信息数据库,推进定量化耦合机制研究;二是开展全生命周期监测与评估,探索适应性治理路径;三是强化多元主体参与,完善协同保护机制。 相似文献
445.
446.
G Grunow M Dikov H Reimann C Norden G Jermolin 《Folia haematologica (Leipzig, Germany : 1928)》1988,115(4):573-576
The serum level of myoglobin (Mb) was determined in 11 male patients with chronic ischemic heart disease (angiographically studied) by the mean of an enzyme immunoassay (EIA). By a second EIA we could detect in all our patients autoantibodies (autoAB) to Mb. While the level of Mb in all cases was normal (less than 100 ng/ml) we found differences in the level of autoAB to Mb (normal value 90-100%). 7 patients with unstable Angina pectoris exhibited decreased levels of autoAB to Mb (65%). In 4 patients with stable Angina pectoris autoAB to Mb were 93%. The physiological role of the autoAB to Mb remains still unclear. The simultaneous determination of Mb and the autoAB to Mb may be helpful in differential diagnosis of stable and unstable Angina pectoris. 相似文献
447.
448.
449.
Several fundamental questions remain enigmatic concerning human olfactory
sensitivity, including (i) whether detection threshold differences exist
between the two sides of the nose (and, if so, whether such differences are
influenced by handedness) and (ii) whether bilateral (i.e. binasal)
stimulation leads to lower thresholds than unilateral stimulation (and, if
so, whether the degree of facilitation is inversely related to general
olfactory ability). In this study, and well-validated single staircase
procedure was used to establish bilateral and unilateral detection
thresholds for the cranial nerve I stimulant phenyl ethyl alcohol in 130
right- and 33 left-handed subjects. No differences in sensitivity between
the left and right sides of the nose were observed in either group.
Bilateral thresholds were lower, on average, than unilateral thresholds
when the latter were categorized in terms of left and right nares. However,
the bilateral thresholds did not differ significantly from those of the
side of the nose with the lower threshold. Overall smell ability, as
measured by the University of Pennsylvania Smell Identification Test, did
not interact with any of the test measures. These data imply that (i) the
left and right sides of the nose do not systematically differ in detection
threshold sensitivity for either dextrals or sinistrals and (ii) if central
integration of left:right olfactory threshold sensitivity occurs, its
effects do not exceed the function of the better side of the nose.
相似文献
450.
Several cytosolic proteins have been shown to be associated with hypotonic erythrocyte ghosts via electrostatic interactions with the anion transport band 3 protein. This article considers the problems of demonstrating binding under physiological conditions and reviews the evidence for the relevance of enzyme binding to the membrane for the regulation of glycolysis. The hypotheses for the existence of topological and sequential multienzyme complexes of the glycolytic enzymes in erythrocytes are also discussed. 相似文献