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1.
目的 探讨影响原发免疫性血小板减少症(ITP)患者树突状细胞功能异常的基因,为ITP治疗寻求新方法。 方法 随机选取ITP患者(ITP组)8例和同期入院体检健康者8例正常对照组为研究对象,分离外周单个核细胞并在体外诱导分化为单核细胞源性树突状细胞(moDCs),选取ITP组和正常对照组moDCs样本各3例,使用Illumina Hiseq平台进行转录组测序,并完成生物信息学分析。其他moDCs样本分为对照组、ITP组和ITP+雷帕霉素处理组,采用Western blotting法检测哺乳动物雷帕霉素靶蛋白复合体1(mTORC1)信号通路激活情况,采用流式细胞术检测moDCs表面分子表达,采用酶联免疫吸附(ELISA)法检测moDCs细胞因子分泌能力。 结果 差异性表达分析显示,与正常对照组相比,ITP组患者moDCs中有161个基因表达上调,320个基因表达下调,差异有统计学意义(P<0.05)。利用基因本体论(GO)和京都基因与基因组百科全书(KEGG)数据库对差异基因进行功能和分子通路注释,结果表明差异基因主要集中在T细胞分化、T细胞共刺激、T细胞活化等生物学过程和T细胞受体信号通路等信号途径。基因集富集分析(GSEA)显示,ITP组患者树突状细胞中mTORC1信号通路基因表达上调。进一步验证发现,ITP组患者moDCs中磷酸化哺乳动物雷帕霉素靶蛋白(mTOR)和mTORC1活化标志物磷酸化核糖体蛋白S6激酶(S6K)相对含量升高,同时ITP组患者moDCs共刺激分子CD80、CD86和促炎因子白介素6(IL-6)、白介素12(IL-12)的表达增加,而白介素10(IL-10)、转化生长因子-β(TGF-β)表达降低。使用mTORC1抑制剂雷帕霉素可以抑制moDCs共刺激分子CD80、CD86的表达和促炎因子IL-6、IL-12的分泌,并上调IL-10的表达,而对TGF-β的分泌无明显影响。 结论 ITP患者moDCs中mTORC1信号通路高度激活,使用mTORC1抑制剂雷帕霉素可以改善moDCs的免疫调节能力。因此,mTORC1信号通路可能是调节ITP患者moDCs功能异常的新靶点。  相似文献   
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 目的 探讨分析鹦鹉热衣原体肺炎患者的临床表现及辅助检查结果特征,以提高对该病的认识。方法 回顾性分析某医院2019年6月- 2021年8月经宏基因组二代测序(mNGS)诊断鹦鹉热衣原体肺炎的9例患者临床资料。结果 9例患者中男性7例,女性2 例,包含1例妊娠36+2周孕妇;年龄25~70岁,中位年龄63岁;临床主要表现为高热(9例)、咳嗽(9例)、咳痰(7例)。白细胞计数正常8例,淋巴细胞计数降低9例,CRP升高9例,ESR升高9例,PCT正常4例,门冬氨酸氨基转移酶和丙氨酸氨基转移酶升高6例。9例患者胸部 CT均表现为斑片或斑片实变影。经血及肺泡灌洗液mNGS确诊后使用多西环素、莫西沙星、左氧氟沙星、阿奇霉素单药治疗方案,疗程14~21 d,均好转出院。结论 鹦鹉热衣原体肺炎临床表现多样、诊断困难,mNGS检测可以快速明确病原学诊断,有助于及时启动特异性抗感染治疗,可减少抗菌药物的使用,改善预后。  相似文献   
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Oral squamous cell carcinomas (OSCCs) develop in genetically altered epithelium in the mucosal lining, also coined as fields, which are mostly not visible but occasionally present as white oral leukoplakia (OL) lesions. We developed a noninvasive genetic assay using next-generation sequencing (NGS) on brushed cells to detect the presence of genetically altered fields, including those that are not macroscopically visible. The assay demonstrated high accuracy in OL patients when brush samples were compared with biopsies as gold standard. In a cohort of Fanconi anemia patients, detection of mutations in prospectively collected oral brushes predicted oral cancer also when visible abnormalities were absent. We further provide insight in the molecular landscape of OL with frequent changes of TP53, FAT1 and NOTCH1. NGS analysis of noninvasively collected samples offers a highly accurate method to detect genetically altered fields in the oral cavity, and predicts development of OSCC in high-risk individuals. Noninvasive genetic screening can be employed to screen high-risk populations for cancer and precancer, map the extension of OL lesions beyond what is visible, map the oral cavity for precancerous changes even when visible abnormalities are absent, test accuracy of promising imaging modalities, monitor interventions and determine genetic progression as well as the natural history of the disease in the human patient.  相似文献   
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《Molecular therapy》2022,30(1):209-222
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ObjectiveTo observe the relationship between the different stages of type 2 diabetes mellitus (T2DM) and the intestinal flora and verify its underlying mechanism.MethodsT2DM rats were generated by high-fat diet (HFD) combined with intraperitoneal streptozotocin (STZ) injection. The rats were divided into four groups: the control group (fed with normal feed for 1 month), the HFD group (fed with HFD for 1 month), the T2DM group (HFD combined with STZ and blood glucose ≥11.1 mM), and the unformed T2DM model (Un-mod) group (HFD combined with STZ and blood glucose <11.1 mM). Feces were collected, and bacterial communities in the fecal samples were analyzed by 16S rRNA gene sequencing. The content of short-chain fatty acids (SCFAs) in feces was measured by gas chromatography. Western blot and quantitative real-time polymerase chain reaction were used to detect the expression of G protein-coupled receptor 41 (GPR41) and GPR43.ResultsAt different stages of T2DM, the intestinal flora and SCFAs content of rats were significantly decreased (all P < .05). Our results indicated that g__Prevotella had a significant negative correlation, and g__Ruminococcus_torques_group and g__lachnoclastic had a significant positive correlation with blood glucose. The content of SCFAs, in particular acetate and butyrate, in rat feces of different stages of T2DM were significantly reduced, as well as GPR41 and GPR43 expression. The results in the Un-mod group were similar to the T2DM group, and the expression of GPR41 and GPR43 proteins were significantly higher than those in the T2DM group (both P < .001).ConclusionThe intestinal flora–SCFAs–GPR41/GPR43 network may be important in the development of T2DM. Decreasing blood glucose levels by regulating the intestinal flora may become a new therapeutic strategy for T2DM, which has very important clinical and social values.  相似文献   
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《Genetics in medicine》2022,24(9):1814-1820
Although still in the early stages of development, the advent of fast, high-output, and cost-effective next-generation DNA sequencing technology is moving precision medicine into public health. Before this shift toward next-generation sequencing in public health settings, individual patients met geneticists after showing symptoms and through limited family screening. In the new era of precision public health, everyone is a possible participant in genetic sequencing, simply by being born (newborn screening), by donating blood (biobanking), or through population screening. These initiatives are increasingly offered to individuals throughout their life and more individuals are encountering opportunities to use DNA sequencing. This article raises awareness of these growing areas and calls for different models of public engagement and communication about genomics, including screening asymptomatic populations, obtaining consent for unspecified and unforeseen future uses of genomic data, and managing variants of uncertain significance. Given that such communication challenges loom large, established norms of practice in genomic medicine and research should be reconsidered.  相似文献   
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Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016–2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.  相似文献   
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