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本文报道了1例KLHL40基因复合杂合突变导致线状体肌病的病例。患儿女,生后即起病,以"气促、肌力、肌张力低"为主要表现,常规治疗后症状加重,体格检查示四肢肌力低、肌张力低,原始反射均未引出;血清肌酸激酶升高。患儿未行肌肉活检。采用全外显子组二代测序证实患儿存在KLHL40基因复合杂合突变,包括c.932G>T(p.R311L)和c.1487T>A(p.M496K),并且分别来源于父母,其中c.932G>T(p.R311L)为已发现的突变位点,c.1487T>A(p.M496K)为新发现的突变位点。线状体肌病是一种罕见的先天性肌肉疾病,肌纤维中发现线状体是特征性肌肉病理改变。病理及基因诊断是诊断线状体肌病的金标准。 相似文献
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《Biochemical pharmacology》2015,95(4):257-269
The present study sought to determine the correlation between 2-methoxyestradiol (2-MeO-E2)-induced cell cycle arrest and 2-MeO-E2-induced apoptosis. Exposure of Jurkat T cell clone (JT/Neo) to 2-MeO-E2 (0.5–1.0 μM) caused G2/M arrest, Bak activation, Δψm loss, caspase-9 and -3 activation, PARP cleavage, intracellular ROS accumulation, and apoptotic DNA fragmentation, whereas none of these events except for G2/M arrest were induced in Jurkat T cells overexpressing Bcl-2 (JT/Bcl-2). Under these conditions, Cdk1 phosphorylation at Thr-161 and dephosphorylation at Tyr-15, up-regulation of cyclin B1 expression, histone H1 phosphorylation, Cdc25C phosphorylation at Thr-48, Bcl-2 phosphorylation at Thr-56 and Ser-70, Mcl-1 phosphorylation at Ser-159/Thr-163, and Bim phosphorylation were detected irrespective of Bcl-2 overexpression. Concomitant treatment of JT/Neo cells with 2-MeO-E2 and the G1/S blocking agent aphidicolin resulted in G1/S arrest and abrogation of all apoptotic events, including Cdk1 activation, phosphorylation of Bcl-2, Mcl-1 and Bim, and ROS accumulation. The 2-MeO-E2-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by a Cdk1 inhibitor, but not by an Aurora A kinase (AURKA), Aurora B kinase (AURKB), JNK, or p38 MAPK inhibitor. Immunofluorescence microscopic analysis revealed that 2-MeO-E2-induced mitotic arrest was caused by mitotic spindle network impairment and prometaphase arrest. Whereas 10–20 μM 2-MeO-E2 reduced the proportion of intracellular polymeric tubulin to monomeric tubulin, 0.5–5.0 μM 2-MeO-E2 increased it. These results demonstrate that the apoptogenic effect of 2-MeO-E2 (0.5–1.0 μM) was attributable to mitotic spindle defect-mediated prometaphase arrest, Cdk1 activation, phosphorylation of Bcl-2, Mcl-1, and Bim, and activation of Bak and mitochondria-dependent caspase cascade. 相似文献
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Maciej Kliszczak Hana Sedlackova Ganesha P. Pitchai Werner W. Streicher Lumir Krejci Ian D. Hickson 《Oncotarget》2015,6(38):40464-40479
DNA replication is a highly coordinated process that is initiated at multiple replication origins in eukaryotes. These origins are bound by the origin recognition complex (ORC), which subsequently recruits the Mcm2-7 replicative helicase in a Cdt1/Cdc6-dependent manner. In budding yeast, two essential replication factors, Sld2 and Mcm10, are then important for the activation of replication origins. In humans, the putative Sld2 homolog, RECQ4, interacts with MCM10. Here, we have identified two mutants of human RECQ4 that are deficient in binding to MCM10. We show that these RECQ4 variants are able to complement the lethality of an avian cell RECQ4 deletion mutant, indicating that the essential function of RECQ4 in vertebrates is unlikely to require binding to MCM10. Nevertheless, we show that the RECQ4-MCM10 interaction is important for efficient replication origin firing. 相似文献
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《Vaccine》2020,38(8):2005-2015
Dengue virus (DENV) is a Flavivirus estimated to cause 390 million infections/year. Currently, there is no anti-viral specific treatment for dengue, and efficient DENV vector control is still unfeasible. Here, we designed and produced chimeric proteins containing potential immunogenic epitopes from the four DENV serotypes in an attempt to further compose safer, balanced tetravalent dengue vaccines.For this, South American DENV isolate sequences were downloaded from the NCBI/Virus Variation/Dengue virus databases and intraserotype-aligned to generate four consensuses. Four homologous DENV sequences were retrieved using BLAST and then interserotype-aligned. In parallel, sequences were subjected to linear B epitope prediction analysis. Regions of the envelope and NS1 proteins that are highly homologous among the four DENV serotypes, non-conserved antigenic regions and the most antigenic epitopes found in the C, prM, E and NS1 DENV proteins were used to construct 11 chimeric peptides. Genes encoding the chimeric proteins were commercially synthesized, and proteins were expressed, purified by affinity chromatography and further subjected to ELISA assays using sera from individuals infected with DENVs 1, 2, 3 or 4. As a proof-of-concept, the chimeric EnvEpII protein was selected to immunize BALB/c and C57BL/6 mice strains. The immunization with EnvEpII protein associated with aluminum induced an increased number of T CD4+ and CD8+ cells, high production of IgG1 and IgG2 antibodies, and increased levels of IL-2 and IL-17 cytokines, in both mouse strains. Because the EnvEpII protein associated with aluminum induced an efficient cellular response by stimulating the production of IL-2, IL-4, IL-17 and induced a robust humoral response in mice, we conclude that it resembles an efficient specific response against DENV infection. Although further experiments are required, our results indicate that epitope selection by bioinformatic tools is efficient to create recombinant proteins that can be used as candidates for the development of vaccines against infectious diseases. 相似文献