A penalized structural equation modeling method accounting for secondary phenotypes for variable selection on genetically regulated expression from PrediXcan for Alzheimer's disease

As the global burden of mental illness is estimated to become a severe issue in the near future, it demands the development of more effective treatments. Most psychiatric diseases are moderately to highly heritable and believed to involve many genes. Development of new treatment options demands more knowledge on the molecular basis of psychiatric diseases. Toward this end, we propose to develop new statistical methods with improved sensitivity and accuracy to identify disease‐related genes specialized for psychiatric diseases. The qualitative psychiatric diagnoses such as case control often suffer from high rates of misdiagnosis and oversimplify the disease phenotypes. Our proposed method utilizes endophenotypes, the quantitative traits hypothesized to underlie disease syndromes, to better characterize the heterogeneous phenotypes of psychiatric diseases. We employ the structural equation modeling using the liability‐index model to link multiple genetically regulated expressions from PrediXcan and the manifest variables including endophenotypes and case‐control status. The proposed method can be considered as a general method for multivariate regression, which is particularly helpful for psychiatric diseases. We derive penalized retrospective likelihood estimators to deal with the typical small sample size issue. Simulation results demonstrate the advantages of the proposed method and the real data analysis of Alzheimer's disease illustrates the practical utility of the techniques. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative database.     

Mechanism of mutant calreticulin-mediated activation of the thrombopoietin receptor in cancers

Myeloproliferative neoplasms (MPNs) are frequently driven by mutations within the C-terminal domain (C-domain) of calreticulin (CRT). CRT_Del52 and CRT_Ins5 are recurrent mutations. Oncogenic transformation requires both mutated CRT and the thrombopoietin receptor (Mpl), but the molecular mechanism of CRT-mediated constitutive activation of Mpl is unknown. We show that the acquired C-domain of CRT_Del52 mediates both Mpl binding and disulfide-linked CRT_Del52 dimerization. Cysteine mutations within the novel C-domain (C400A and C404A) and the conserved N-terminal domain (N-domain; C163A) of CRT_Del52 are required to reduce disulfide-mediated dimers and multimers of CRT_Del52. Based on these data and published structures of CRT oligomers, we identify an N-domain dimerization interface relevant to both WT CRT and CRT_Del52. Elimination of disulfide bonds and ionic interactions at both N-domain and C-domain dimerization interfaces is required to abrogate the ability of CRT_Del52 to mediate cell proliferation via Mpl. Thus, MPNs exploit a natural dimerization interface of CRT combined with C-domain gain of function to achieve cell transformation.     

IL-21单克隆抗体对MRL/lpr狼疮小鼠的治疗作用*

目的: 探讨IL-21单克隆抗体对MRL/lpr狼疮小鼠的免疫治疗作用。方法: 将20只MRL/lpr狼疮小鼠随机分为模型组和治疗组,每组10只;同年龄同性别C57BL/6小鼠10只作为正常组。治疗组小鼠每周腹腔注射IL-21单克隆抗体(100 μg),正常组及模型组小鼠每周腹腔注射等量生理盐水(100 μg),连续干预8周。干预结束后观察小鼠皮毛、活动等一般性状及浅表淋巴结大小,并采集小鼠血液、尿液及肾脏标本。采用Western blot法检测三组小鼠肾组织中IL-21蛋白表达情况;采用ELISA法比较三组小鼠血清抗ds-DNA抗体、ANA抗体、血尿素氮、肌酐和炎症因子IL-17A、TGF-β1水平;采用生物化学法比较三组小鼠24 h尿蛋白水平。结果: 与正常组比较,模型组小鼠肾组织IL-21、血清抗ds-DNA、ANA抗体水平、尿素氮、肌酐、IL-17A浓度及24 h尿蛋白水平均升高(P＜0.05),TGF-β1浓度降低(P＜0.01);与模型组比较,治疗组小鼠肾组织IL-21、血清抗ds-DNA、ANA抗体水平、尿素氮、肌酐、IL-17A浓度、24 h尿蛋白水平均降低(P＜0.05),TGF-β1浓度升高(P＜0.01)。结论: 腹腔注射IL-21单克隆抗体可改善MRL/lpr狼疮小鼠免疫功能与肾损害,提示治疗机制可能与重塑Th17/Treg相关细胞因子平衡有关。     

内质网应激在乙型脑炎病毒诱导神经元细胞凋亡中的作用及机制研究

内质网应激(Endoplasmic reticulum stress,ERS)的激活与创伤、缺血再灌注等病理刺激引起的神经元凋亡有关,流行性乙型脑炎病毒(JEV)感染能够促进神经元凋亡、激活ERS,但ERS在JEV诱导神经元细胞凋亡中的作用尚不清楚.为了研究ERS在JEV诱导神经元细胞凋亡中的作用及机制,本研究以神经细胞株SH-SY5Y为对象,感染JEV并加用ERS激动剂、ERS抑制剂或转染阴性对照(NC) siRNA、蛋白激酶R样内质网激酶(PERK)siRNA,检测细胞存活率、凋亡率、ERS蛋白PERK、肌醇必需酶-1α(IRE1α)、活化转录因子6(ATF6)及凋亡蛋白C/EBP同源蛋白(CHOP)、含半胱氨酸的天冬氨酸蛋白水解酶12(Caspase-12)、Bcl-2相关X蛋白(Bax)的表达.结果 显示:JEV组SH-SY5Y细胞的凋亡率及PERK、CHOP、Caspase-12、Bax的表达水平高于对照组,存活率低于对照组(P＜0.05),IRE1α、ATF6的表达水平与对照组比较无显著差异(P＞0.05).与JEV组比较,激动剂组SH-SY5Y细胞的凋亡率及PERK、CHOP、Caspase-12、Bax的表达水平显著增加,存活率显著降低(P＜0.05);抑制剂组SH-SY5Y细胞的凋亡率及PERK、CHOP、Caspase-12、Bax的表达水平显著降低,存活率显著增加(P＜0.05);与si-NC+JEV组比较,si-PERK+JEV组SH-SY5Y细胞的凋亡率及PERK、CHOP、Caspase-12、Bax的表达水平P显著降低,存活率显著增加(P＜0.05).以上结果表明ERS的PERK通路激活与JEV诱导神经元凋亡有关.     

2018-2019年中国流行性腮腺炎流行特征和病毒基因特征分析

阐明中国(未包括香港、澳门特别行政区和台湾地区,下同)2018-2019年流行性腮腺炎(流腮)流行特征和病毒基因特征。对2018-2019年中国流腮流行病学和病毒学监测数据进行描述流行病学和分子流行病学分析。2018-2019年中国流腮年报告发病率分别为18.65/10万和21.48/10万,15岁以下儿童和青少年是我国流腮的高发人群,分别占总病例数的85.30%和82.56%。流腮的流行具有明显的季节性特征。全国各省、自治区、直辖市份均有流腮病例报告,西部和中部地区发病率高于东部地区。2018-2019年共获得160条腮腺炎病毒(Mumps virus,MuV)SH基因序列,其中150条(93.75%)序列鉴定为F基因型MuV,在我国11个省份检测到;10条(6.25%)序列为G基因型MuV,2019年在广东、湖北和新疆3个省份检测到。和我国既往流行MuV代表株相比,2018-2019年流行的F基因型MuV代表株序列在基因亲缘性关系树上相对集中。现阶段我国流腮的流行病学特征未发生明显改变,仍呈现病毒自然流行模式;F基因型作为优势流行基因型,在我国大部分地区持续流行,但毒株的遗传多态性有所降低,这可能和我国实施1剂次腮腺炎疫苗常规免疫策略有关。G基因型MuV主要在我国局部地区流行,但流行范围在逐渐扩大。建议进一步加强两剂次腮腺炎疫苗接种工作,降低我国腮腺炎易感人群。同时持续性开展MuV流行学和病毒学监测工作,为鉴别病毒的来源,确定病毒传播途径和评估腮腺炎疫苗免疫策略奠定重要的基础。     

沙生植物沙鞭不同居群形态变异研究

以沙鞭(Psammochloa villosa Bor.)20个自然居群为研究对象,对其株高、花序长度、旗叶长度、旗叶宽度和小穗长度等12个表型性状进行形态变异研究。结果显示,12个性状群体间F值为1.832~8.958,达到显著或极显著水平,表明沙鞭不同居群表型性状存在广泛变异,且变异程度各不相同;主成分分析结果显示,前4个主成分代表了沙鞭形态多样性的82.277%,其中旗叶长度、旗叶宽度、颖片长度、小穗长度等是造成不同居群表型性状差异的主要因素;依据欧式距离对参试居群进行的UPGMA聚类分析结果表明,当遗传距离为20.5时,可以将20个沙鞭野生居群划分为两类,且各表型性状并没有依居群地理分布而聚类。