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1.
Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS.  相似文献   
2.
Eukaryotic protein kinases are typically strictly controlled by second messenger binding, protein/protein interactions, dephosphorylations or similar processes. None of these regulatory mechanisms is known to work for protein kinase CK2 (former name “casein kinase 2”), an acidophilic and constitutively active eukaryotic protein kinase. CK2 predominantly exists as a heterotetrameric holoenzyme composed of two catalytic subunits (CK2α) complexed to a dimer of non-catalytic subunits (CK2β). One model of CK2 regulation was proposed several times independently by theoretical docking of the first CK2 holoenzyme structure. According to this model, the CK2 holoenzyme forms autoinhibitory aggregates correlated with trans-autophosphorylation and driven by the down-regulatory affinity between an acidic loop of CK2β and the positively charged substrate binding region of CK2α from a neighboring CK2 heterotetramer. Circular trimeric aggregates in which one-half of the CK2α chains show the predicted inhibitory proximity between those regions were detected within the crystal packing of the human CK2 holoenzyme. Here, we present further in vitro support of the “regulation-by-aggregation” model by an alternative crystal form in which CK2 tetramers are arranged as approximately linear aggregates coinciding essentially with the early predictions. In this assembly, the substrate binding region of every CK2α chain is blocked by a CK2β acidic loop from a neighboring tetramer. We found these crystals with CK2Andante that contains a CK2β variant mutated in a CK2α-contact helix and described to be responsible for a prolonged circadian rhythm in Drosophila. The increased propensity of CK2Andante to form aggregates with completely blocked active sites may contribute to this phenotype.  相似文献   
3.
目的:探索醛脱氢酶1A1(aldehyde dehydrogenase 1A1,ALDH1A1)在肺腺癌细胞(lung adenocarcinoma cell,LAC)化疗耐药中的作用及机制,为肺癌临床治疗和新型药物的研发提供实验依据。方法:采用慢病毒载体构建ALDH1A1高表达肺腺癌细胞模型,并通过流式细胞术和western blot技术对该细胞模型进行验证。通过CCK8法检测ALDH1A1高表达肺腺癌细胞对肺癌治疗药物顺铂(cisplatin,DDP)、紫杉醇(paclitaxcel)、厄洛替尼(erlotinib)和吉非替尼(gefitinib)的耐药性。通过检测肿瘤干细胞(cancer stem cell,CSC)分子标志物、上皮-间质转化(Epithelial-Mesenchymal Transition,EMT)分子标志物及细胞迁移能力探讨ALDH1A1高表达对肺腺癌细胞的干性和EMT特征的影响。双硫仑(disulfiram,DSF)是ALDH的抑制剂,我们通过CCK8法和transwell细胞迁移实验探究DSF对肺腺癌细胞体外生长和迁移能力的影响,体内实验探究DSF和厄洛替尼联合用药对HCC827-ALDH1A1细胞皮下异种移植瘤生长的影响。结果:ALDH1A1高表达诱导肺腺癌细胞对厄洛替尼、吉非替尼、紫杉醇和顺铂产生不同程度的耐药,干细胞标志物CD44、CD133蛋白表达上调,EMT间充质标志物vimentin蛋白表达上调,transwell实验结果显示ALDH1A1高表达肺腺癌细胞的迁移能力增强,使用ALDH靶向抑制剂DSF能选择性抑制ALDH1A1高表达肺腺癌细胞所增高的迁移能力并克服HCC827-ALDH1A1细胞皮下异种移植瘤的生长,延缓体内耐药。结论:ALDH1A1能诱导肺腺癌细胞对多种抗肺癌药物产生耐药并发生干细胞样转化,靶向抑制ALDH酶活性可克服由ALDH1A1高表达所产生的耐药,为肺癌的临床治疗提供新的思路。  相似文献   
4.
目的:研究张家口市大气颗粒物对慢性阻塞性肺疾病(COPD)的影响,并分析大气颗粒物对不同特征人群的影响。方法:从张家口市医保办公室获取张家口市2013年1月1日-2015年12月31日两家三甲医院COPD患者的住院病历资料,从中国环境监测总站网站获取大气污染物的监测数据,从张家口市气象局获取气象资料。建立广义相加模型(GAM),在控制长期趋势、星期几效应和温湿度影响后,应用条件Logitic回归方法评估PM_(2.5)、PM_(10)对COPD住院人次的影响。根据患者不同特征(性别、年龄、季节)进行分层分析,评估颗粒物污染的高危人群。结果:研究纳入两家三甲医院,共1984例住院COPD患者,其中男性患者1258例(63.4%)、女性患者726例(36.6%),≥75岁患者678例(34.2%),60~75岁患者936例(47.2%)、芨60岁患者370例(18.6%)。2013-2015年PM_(2.5)、PM_(10)年均浓度分别为[(36.54±20.34)μg/m~3、(84.37±52.54)μg/m~3],[(34.50±27.08)μg/m~3、(78.43±69.78)μg/m~3],[(32.04±21.35)μg/m~3、(75.46±50.02)μg/m~3],两者在移动平均滞后3d时,对COPD的影响最大,即PM_(2.5)每增加10μg/m~3,COPD住院人次增加1.90%(95%CI:1.002-1.033,P0.05),PM_(10)每增加10μg/m~3,COPD住院人次增加2.10%(95%CI:1.005-1.045,P0.05)。分层分析结果显示:PM_(2.5)、PM_(10)每升高10μg/m~3,女性COPD患者住院人次增加1.09%、1.14%,差异具有统计学意义(P0.05);≥75岁患者,COPD住院人次增加1.03%、0.99%,差异具有统计学意义(P0.05);而年龄芨60岁、60~75岁、男性以及季节分层分析中,PM_(2.5)、PM_(10)浓度与COPD住院人次无统计学意义(P0.05)。结论:颗粒物污染会增加COPD住院率,≥75岁的老年患者及女性患者更敏感。  相似文献   
5.
The brown planthopper (BPH), Nilaparvata lugens (Stål), is one of the major pests of rice throughout Asia. Extensive use of insecticides for suppressing N. lugens has resulted in the development of insecticide resistance leading to frequent control failures in the field. The aim of the present study was to evaluate resistance in the field populations of N. lugens from major rice growing states of South India to various insecticides. We also determined the activity of detoxifying enzymes (esterases [ESTs], glutathione S‐transferases [GSTs], and mixed‐function oxidases [MFOs]). Moderate levels of resistance were detected in the field populations to acephate, thiamethoxam and buprofezin (resistance factors 1.05–20.92 fold, 4.52–14.99 fold, and 1.00–18.09 fold, respectively) as compared with susceptible strain while there were low levels of resistance to imidacloprid (resistance factor 1.23–6.70 fold) and complete sensitivity to etofenoprox (resistance factor 1.05–1.66 fold). EST activities in the field populations were 1.06 to 3.09 times higher than the susceptible strain while for GST and MFO the ratios varied from 1.29 to 3.41 and 1.03 to 1.76, respectively. The EST activity was found to be correlated to acephate resistance (r = 0.999, P ≥ 0.001). The high selection pressure of organophosphate, neonicotinoid, and insect growth regulator (IGR) in the field is likely to be contributing for resistance in BPH to multiple insecticides, leading to control failures. The results obtained will be beneficial to IPM recommendations for the use of effective insecticides against BPH.  相似文献   
6.
7.
Unique species of ceramide (Cer) with very-long-chain polyunsaturated fatty acid (VLCPUFA), mainly 28–32 carbon atoms, 4–5 double bonds, in nonhydroxy and 2-hydroxy forms (n-V Cer and h-V Cer, respectively), are generated in rat spermatozoa from the corresponding sphingomyelins during the acrosomal reaction. The aim of this study was to determine the properties of these sperm-distinctive ceramides in Langmuir monolayers. Individual Cer species were isolated by HPLC and subjected to analysis of surface pressure, surface potential, and Brewster angle microscopy (BAM) as a function of molecular packing. In comparison with known species of Cer, n-V Cer and h-V Cer species showed much larger mean molecular areas and increased molecular dipole moments in liquid expanded phases, which suggest bending and partial hydration of the double bonded portion of the VLCPUFA. The presence of the 2-hydoxyl group induced a closer molecular packing in h-V Cer than in their chain-matched n-V Cer. In addition, all these Cer species showed liquid-expanded to liquid-condensed transitions at room temperature. Existence of domain segregation was confirmed by BAM. Additionally, thermodynamic analysis suggests a phase transition close to the physiological temperature for VLCPUFA-Cers if organized as bulk dispersions.  相似文献   
8.
Novel synthetic mimics of antimicrobial peptides have been developed to exhibit structural properties and antimicrobial activity similar to those of natural antimicrobial peptides (AMPs) of the innate immune system. These molecules have a number of potential advantages over conventional antibiotics, including reduced bacterial resistance, cost-effective preparation, and customizable designs. In this study, we investigate a family of nylon-3 polymer-based antimicrobials. By combining vesicle dye leakage, bacterial permeation, and bactericidal assays with small-angle X-ray scattering (SAXS), we find that these polymers are capable of two interdependent mechanisms of action: permeation of bacterial membranes and binding to intracellular targets such as DNA, with the latter necessarily dependent on the former. We systemically examine polymer-induced membrane deformation modes across a range of lipid compositions that mimic both bacteria and mammalian cell membranes. The results show that the polymers' ability to generate negative Gaussian curvature (NGC), a topological requirement for membrane permeation and cellular entry, in model Escherichia coli membranes correlates with their ability to permeate membranes without complete membrane disruption and kill E. coli cells. Our findings suggest that these polymers operate with a concentration-dependent mechanism of action: at low concentrations permeation and DNA binding occur without membrane disruption, while at high concentrations complete disruption of the membrane occurs. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.  相似文献   
9.
10.
利用线性混合效应模型模拟杉木人工林枝条生物量   总被引:2,自引:0,他引:2  
基于福建省将乐林场45株人工杉木解析木的572组枝条生物量数据,采用线性混合效应模型方法,建立杉木人工林枝条总生物量和枝、叶生物量的预测模型,并利用独立样本数据对模型进行检验.结果表明: 线性混合效应模型比传统多元线性回归模型的拟合精度高.不同随机效应参数的组合,其混合模型的精度不同.考虑异方差结构的混合模型能够消除数据间的异方差性,其精度更高,其中,对于枝条总生物量和叶生物量模型,以指数函数作为异方差结构时的模型精度最高;对于枝生物量模型,以常数加幂函数作为异方差结构时的模型精度最高.模型检验结果表明:对于杉木人工林枝条生物量预测模型,考虑随机效应和异方差结构的线性混合模型的检验精度比传统多元线性回归模型的精度有明显提高.  相似文献   
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