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71.
Jonathan W. Yewdell 《Molecular & cellular proteomics : MCP》2022,21(7):100230
In the 35 years since the revelation that short peptides bound to major histocompatibility complex class I and II molecules are the secret of the major histocompatibility complex–restricted nature of T-cell recognition, there has been enormous progress in characterizing the immunopeptidome, the repertoire of peptide presented for immunosurveillance. Here, the major milestones in the journey are marked, the contribution of proteasome-mediated splicing to the immunopeptidome is discussed, and exciting recent findings relating the immunopeptidome to the translatome revealed by ribosome profiling (RiboSeq) is detailed. Finally, what is needed for continued progress is opined about, which includes the infusion of talented young scientists into the antigen-processing field, currently undergoing a renaissance; thanks in part to the astounding success of T-cell–based cancer immunotherapy. 相似文献
72.
目的:通过检测子痫前期(PE)患者外周血Toll样受体4(TLR4)表达及其分泌促炎细胞因子的功能,探讨单核细胞TLR4 在
PE 发病过程中的作用。方法:选取22 例子痫前期患者(PE 组)和23 例正常孕妇(HP 组)作为研究对象。经知情同意后抽取4 mL
静脉血,肝素钠抗凝。流式细胞术(FCM)检测单核细胞TLR4表达;脂多糖(LPS)刺激单核细胞18 小时,Luminex 液相芯片检测培
养上清液中肿瘤坏死因子(TNF)-alpha、白细胞介素(IL)-6、IL-12P70 和IL-10 浓度;并分析PE 患者单核细胞TLR4 阳性频率与外周
血清细胞因子浓度的相关性。结果:与HP 组相比,PE 组单核细胞TLR4 阳性细胞频率(TLR4+:23.2 (18.4-44.3) % vs59.7
(19.8-79.7) %)和平均荧光强度(MFI:32.3(27.6-49.2)vs48.6 (32.4- 93.2)明显升高,差异均有统计学意义(P<0.05);单核细胞经50
ng/mL LPS 刺激培养18 小时,PE 组上清液TNF-alpha(243.5± 15.2 pg/mLvs123± 81.3 pg/mL)、IL-6(3122.7 ± 534.2 pg/mLvs1380.4±
332 pg/mL)浓度明显高于HP 组,IL-10(84.2 ± 24.9 pg/mL vs164.5 ± 47.1 pg/mL)低于HP 组,差异均有统计学意义(P<0.05);PE 患
者单核细胞阳性频率与外周血清中细胞因子TNF-alpha、IL-6 具有相关性(r=0.634、r=0.528,P<0.05)。结论:PE 患者外周血单核细胞
TLR4表达明显增加,并处于活化状态,分泌较多的促炎细胞因子IL-6 和TNF-alpha,参与子痫前期的疾病过程。因此,抑制单核细胞
TLR4表达可能是治疗子痫前期的新途经。 相似文献
73.
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75.
The idea of a receptor reserve in mediating cellular function is well known but direct biochemical evidence has not been easy to obtain. This study stems from our results showing that L15 of epidermal growth factor (EGF) is important in both EGF receptor (EGFR) binding and activation, and the L15A analog of human EGF (hEGF) partially uncouples EGFR binding from EGFR activation (Nandagopal et al., [1996] Protein Engng 9:781-788). We address the cellular mechanism of mitogenic signal amplification by EGFR tyrosine kinase in response to L15A hEGF. L15A is partially impaired in receptor dimerization, shown by chemical cross-linking and allosteric activation of EGFR in a substrate phosphorylation assay. Immunoprecipitation experiments reveal, however, that L15A can induce EGFR autophosphorylation in intact murine keratinocytes by utilizing spare receptors, the ratio of total phosphotyrosine content per receptor being significantly lower than that elicited by wild-type. This direct biochemical evidence, based on function, of utilization of a receptor reserve for kinase stimulation suggests that an EGF variant can activate varying receptor numbers to generate the same effective response. L15A-activated receptors can stimulate mitogen-activated protein kinase (MAPK) that is important for mitogenesis. The lack of linear correlation between levels of receptor dimerization, autophosphorylation, and MAPK activation suggests that signal amplification is mediated by cooperative effects. Flow cytometric analyses show that the percentages of cells which proliferate in response to 1 nM L15A and their rate of entry into S-phase are both decreased relative to 1 nM wild-type, indicating that MAPK activation alone is insufficient for maximal stimulation of mitogenesis. Higher concentrations of L15A reverse this effect, indicating that L15A and wild-type differ in the number of receptors each activates to induce the threshold response, which may be attained by cooperative activation of receptor dimers/oligomers by van der Waal's weak forces of attraction. The maintenance of a receptor reserve underscores an effective strategy in cell survival. 相似文献
76.
Sébastien Lavoué Kouji Nakayama Dean R. Jerry Yusuke Yamanoue Naoki Yagishita Nobuaki Suzuki Mutsumi Nishida Masaki Miya 《Gene》2014
Delineation of the fish family Percichthyidae (Percomorphaceae) has a long and convoluted history, with recent morphological-based studies restricting species members to South American and Australian freshwater and catadromous temperate perches. Four recent nuclear gene-based phylogenetic studies, however, found that the Percichthyidae was not monophyletic and was nested within a newly discovered inter-familial clade of Percomorphaceae, the Centrarchiformes, which comprises the Centrarchidae and 12 other families. Here, we reexamined the systematics of the Percichthyidae and Centrarchiformes based on new mitogenomic information. Our mitogenomic results are globally congruent with the recent nuclear gene-based studies although the overall amount of phylogenetic signal of the mitogenome is lower. They do not support the monophyly of the Percichthyidae, because the catadromous genus Percalates is not exclusively related to the freshwater percichthyids. The Percichthyidae (minus Percalates) and Percalates belong to a larger clade, equivalent to the Centrarchiformes, but their respective sister groups are unresolved. Because all recent analyses recover a monophyletic Centrarchiformes but with substantially different intra-relationships, we performed a simultaneous analysis for a character set combining the mitogenome and 19 nuclear genes previously published, for 22 centrarchiform taxa. This analysis furthermore indicates that the Centrarchiformes are divided into three lineages and the superfamily Cirrhitoidea is monophyletic as well as the temperate and freshwater centrarchiform perch-like fishes. It also clarifies some of the relationships within the freshwater Percichthyidae. 相似文献
77.
78.
Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression 总被引:5,自引:0,他引:5
Co-localization of activated microglia and damaged neurones seen in brain injury suggests microglia-induced neurodegeneration. Activated microglia release two potential neurotoxins, excitatory amino acids and nitric oxide (NO), but their contribution to mechanisms of injury is poorly understood. Using co-cultures of rat microglia and embryonic cortical neurones, we show that inducible NO synthase (iNOS)-derived NO aloneis responsible for neuronal death from interferon gamma (IFNgamma) +lipopolysaccharide (LPS)-activated microglia. Neurones remain sensitive to NO irrespective of maturation state but, whereas blocking NMDA receptor activation with MK801 has no effect on NO-mediated toxicity to immature neurones, MK801 rescues 60-70% of neurones matured in culture for 12 days. Neuronal expression of NMDA receptors increases with maturation in culture, accounting for increased susceptibility to excitotoxins seen in more mature cultures. We show that MK801 delays the death of more mature neurones caused by the NO-donor DETA/NO indicating that NO elicits an excitotoxic mechanism, most likely through neuronal glutamate release. Thus, similar concentrations of nitric oxide cause neuronal death by two distinct mechanisms: NO acts directly upon immature neurones but indirectly, via NMDA receptors, on more mature neurones. Our results therefore extend existing evidence for NO-mediated toxicity and show a complex interaction between inflammatory and excitotoxic mechanisms of injury in mature neurones. 相似文献
79.
Michal Grzmil Brian A. Hemmings 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(7):1371-1380
Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). 相似文献
80.
The relative ability of ovine follicle stimulating hormone and itsβ-subunit, two potential candidates for male contraceptive vaccine, to generate antibodies in monkeys capable of bioneutralizing
follicle stimulating hormone was assessed usingin vitro model systems. Antiserum against native ovine follicle stimulating hormone was found to be highly specific to the intact
form with no cross-reactivity with either of the two subunits while the antiserum againstβ-subunit of follicle stimulating hormone could bind to theβ-subunit in its free form as well as when it is combined withα-subunit to form the intact hormone. Both antisera could block the binding of the hormone to the receptor if the hormone was
preincubated with the antibody. However, the follicle stimulating hormoneβ-antisera could only inhibit the binding of the hormone partially (33% inhibition) if the antibody and receptor were mixed
prior to the addition of the hormone, while antisera to the native follicle stimulating hormone could block the binding completely
(100% inhibition) in the same experiment. Similarly antisera to the native follicle stimulating hormone was significantly
effective in blocking (100%) response to follicle stimulating hormone but not theβ-subunit antisera (0%) as checked using anin vitro granulosa cell system. Thus the probability of obtaining antibodies of greater bioneutralization potential is much higher
if intact hormone is used as an antigen rather than itsβ-subunit as a vaccine.
Majority of the work reported here was carried out during the tenure of Visiting Scientist fellowship awarded by the MRC Canada
to the first author. 相似文献