Multi-site clustering and nested feature extraction for identifying autism spectrum disorder with resting-state fMRI

Brain functional connectivity (FC) derived from resting-state functional magnetic resonance imaging (rs-fMRI) has been widely employed to study neuropsychiatric disorders such as autism spectrum disorder (ASD). Existing studies usually suffer from (1) significant data heterogeneity caused by different scanners or studied populations in multiple sites, (2) curse of dimensionality caused by millions of voxels in each fMRI scan and a very limited number (tens or hundreds) of training samples, and (3) poor interpretability, which hinders the identification of reproducible disease biomarkers. To this end, we propose a Multi-site Clustering and Nested Feature Extraction (MC-NFE) method for fMRI-based ASD detection. Specifically, we first divide multi-site training data into ASD and healthy control (HC) groups. To model inter-site heterogeneity within each category, we use a similarity-driven multiview linear reconstruction model to learn latent representations and perform subject clustering within each group. We then design a nested singular value decomposition (SVD) method to mitigate inter-site heterogeneity and extract FC features by learning both local cluster-shared features across sites within each category and global category-shared features across ASD and HC groups, followed by a linear support vector machine (SVM) for ASD detection. Experimental results on 609 subjects with rs-fMRI from the ABIDE database with 21 imaging sites suggest that the proposed MC-NFE outperforms several state-of-the-art methods in ASD detection. The most discriminative FCs identified by the MC-NFE are mainly located in default mode network, salience network, and cerebellum region, which could be used as potential biomarkers for fMRI-based ASD analysis.     

核糖体生物合成与肿瘤的研究进展

核糖体生物合成是细胞内重要的生物学过程，决定了细胞内蛋白质合成的速率。在肿瘤细胞旺盛的生长压力下，肿瘤中核糖体生物合成发生异常调控。有越来越多的研究表明核糖体生物合成的异常可能会促进肿瘤的发生发展，并且它也逐渐被认为是多种肿瘤的一个可行的治疗靶点。本文简要综述了核糖体生物合成过程及其在肿瘤中的异常和调控，以及药物靶向核糖体生物合成治疗肿瘤的研究进展。     

Plasma trimethylamine N-oxide,a gut microbe–generated phosphatidylcholine metabolite,is associated with autism spectrum disorders

ObjectiveThe compositions of the gut microbiota and its metabolites were altered in individuals with Autism Spectrum Disorder (ASD). The aim of this study was to assess whether plasma levels of gut-derived metabolite trimethylamine N-oxide (TMAO) were associated with ASD and the degree of symptom severity.MethodsFrom September 2017 to January 2019, a total of three hundred and twenty-eight Chinese children (164 with ASD and 164 their age-sex matched control subjects) aged 3–8 years were included. TMAO levels in plasma were determined using high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS). Logistic regression analysis was used to examine the TMAO-ASD association.ResultsIn the study, the median age of the ASD group was 5 years (interquartile range [IQR], 4–6 years) and 129 (78.7%) were boys. The median plasma levels of TMAO in children with ASD and typically-developing (TD) children at admission were 4.2 (IQR, 3.0–5.6) μmol/l and 3.0 (2.0–4.4) μmol/l, respectively (P < 0.001). For each 1 μmol/l increase of plasma TMAO, the unadjusted and adjusted risk of ASD would be increased by 54% (with the odds ratios [OR] of 1.54; 95% confidence intervals [CI]: 1.32–1.78; P < 0.001) and 27% (1.27 [1.10–1.45], P < 0.001), respectively. Symptom severity was classified as mild-to-moderate (CARS < 37) for 66 children with ASD (40.2%). In these children, the plasma levels of TMAO were lower than in the 98 children with ASD (59.8%) whose symptoms were classified as severe (CARS > 36) (3.5[2.5–4.9] μmol/l vs. 4.5(3.7–6.0) μmol/l; P < 0.001). For each 1 μmol/l increase of plasma TMAO, the unadjusted and adjusted risk of severe autism would be increased by 61% (with the OR of 1.61 [95% CI 1.28–2.01], P < 0.001) and 31% (1.31 [1.08–1.49], P < 0.001), respectively.ConclusionsElevated plasma levels of TMAO were associated with ASD and symptom severity.     

基于网络药理学和实验验证探讨香菇多糖抑制三阴乳腺癌的作用机制

目的 基于网络药理学研究香菇多糖抑制三阴乳腺癌（TNBC）的作用机制并采用细胞和动物实验进行验证。方法 通过GeneCards数据库和DisGeNET数据库筛选与TNBC相关基因靶点，利用TCMID、PubChem、SwissTargetPrediction和GeneCards数据库查询香菇多糖相关基因靶点。使用Sangerbox软件进行基因本体论（GO）富集和京都基因与基因组百科全书（KEGG）通路富集分析。结合STRING数据库与Cytoscape 3.7.0软件将共同靶点进行可视化处理，筛选核心靶点，构建"化合物-靶点-通路"网络。利用Metascape软件进行转录因子及相关调控基因特异富集。体外培养小鼠TNBC细胞4T1和人TNBC细胞MDA-MB-231，磺酰罗丹明B染色法观察香菇多糖（31.25、62.5、125、250、500、1 000μg·mL^-1）对细胞存活率的影响；健康雌性BABLC小鼠sc接种1×10⁶个4T1-Luc细胞构建TNBC模型，通过小动物活体成像系统观察香菇多糖（100、200 mg·kg^-1）对肿瘤生长的影响，实时荧光定量PCR （qRT-PCR）技术检测肿瘤组织信号转导和转录活化因子3（STAT3）和血管内皮生长因子A （VEGFA） mRNA表达。结果 数据库及软件分析得到香菇多糖治疗TNBC关键靶点52个，靶点主要涉及PI3K-Akt、AGE-RAGE、HIF-1、MAPK信号通路和肿瘤蛋白多糖相关通路，PPI分析得到VEGFA、STAT3、MAPK1、IL2、TNF、RELA、AKT1、MAPK3、BCL2L1和HSP90AA1 10个hub基因。与对照组比较，香菇多糖对4T1和MDA-MB-231细胞存活率均有显著抑制作用（P<0.05、0.01），且作用呈浓度相关性；在给药14、21d后，与模型组比较，香菇多糖能够剂量相关性地抑制小鼠TNBC肿瘤的生长，高剂量组差异显著（P<0.05、0.01），21 d抑制率达到（91.9±4.7）%；与对照组比较，香菇多糖给药后能够剂量相关性抑制STAT3和VEGFA的mRNA表达，高剂量组差异显著（P<0.05、0.01）。结论 香菇多糖可通过多靶点、多途径协同作用抑制TNBC的生长。     

Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration

Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P?=?0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P?=?0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.

     

人源瞬时受体电位M2型通道Nudix水解酶9同源结构域的提取和纯化

摸索人源瞬时受体电位M2型通道（TRPM2）羧基端Nudix水解酶9（NUDT9）同源结构域（NUDT9-H）的蛋白提取和纯化方法。 异丙基硫代半乳糖苷诱导表达的Rosetta（DE3）大肠埃希菌菌株经超声破碎和离心后，将收集到的上清液与GST磁珠结合并用还原型谷胱甘肽洗脱以抽提GST-NUDT9-H融合蛋白，浓缩离心后再经分子排阻色谱层析纯化，最后经凝血酶酶切并与GST磁珠结合即得NUDT9-H蛋白。 含有0.5%的十二烷基-β-D-麦芽糖苷（DDM）裂解溶液体系和0.025%的DDM分子排阻层析色谱溶液体系能够提高GST-NUDT9-H融合蛋白的稳定性，再按每2 mg融合蛋白加入1 U凝血酶切割24 h，即获得高纯度NUDT9-H蛋白。 NUDT9-H蛋白稳定性较差，提取和纯化体系中需添加DDM以稳定其构象从而提高目的蛋白的产量和纯度。