A Systematic Review and Meta-Analysis of Pharmacogenetic Studies in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the ABCB1, IL-10, ITPA, MIF, and TNF genes that creates some genetic predisposition that reduces effectiveness or is associated with adverse events of medications used in CKD.     

Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Acquisition and Spread of Antimicrobial Resistance: A tet(X) Case Study

Understanding the mechanisms leading to the rise and dissemination of antimicrobial resistance (AMR) is crucially important for the preservation of power of antimicrobials and controlling infectious diseases. Measures to monitor and detect AMR, however, have been significantly delayed and introduced much later after the beginning of industrial production and consumption of antimicrobials. However, monitoring and detection of AMR is largely focused on bacterial pathogens, thus missing multiple key events which take place before the emergence and spread of AMR among the pathogens. In this regard, careful analysis of AMR development towards recently introduced antimicrobials may serve as a valuable example for the better understanding of mechanisms driving AMR evolution. Here, the example of evolution of tet(X), which confers resistance to the next-generation tetracyclines, is summarised and discussed. Initial mechanisms of resistance to these antimicrobials among pathogens were mostly via chromosomal mutations leading to the overexpression of efflux pumps. High-level resistance was achieved only after the acquisition of flavin-dependent monooxygenase-encoding genes from the environmental microbiota. These genes confer resistance to all tetracyclines, including the next-generation tetracyclines, and thus were termed tet(X). ISCR2 and IS26, as well as a variety of conjugative and mobilizable plasmids of different incompatibility groups, played an essential role in the acquisition of tet(X) genes from natural reservoirs and in further dissemination among bacterial commensals and pathogens. This process, which took place within the last decade, demonstrates how rapidly AMR evolution may progress, taking away some drugs of last resort from our arsenal.     

Pattern design and optimization of yarn-dyed plaid fabric using isolation niche genetic algorithm and rough set theory

Under the circumstance of perceptual consumption, it is still challenging to grasp consumer's emotions and demands due to the large search space, diversified preferences, and easy fatigue of consumers. To reduce user fatigue and enlarge search space, a novel method was presented to design and optimize the pattern of yarn-dyed plaid fabric using the isolation niche genetic algorithm and rough set theory. Each pattern was encoded as a chromosome based on the real number code. The population was initialized and evolved using INGA to maintain the diversity. The rough set theory was adopted as the fitness function of isolation niche genetic algorithm to extract the consumer's demands. After multiple evolutions, a large set of practical patterns of the yarn-dyed plaid fabric are obtained. Experiments were carried out by 24 testers of different ages and genders. The results prove that the proposed method based on the isolation niche genetic algorithm and rough set theory is feasible and effective, supplying references to the designer.     

金属增材制造技术研究热点聚类分析

为深入分析金属增材制造技术分类和发展状况,采集中国期刊全文数据库(CNKI)收录的核心期刊上的768篇科技文献,借助文献分析可视化软件CiteSpace,对关键词聚类进行了全景式描绘,构建金属增材制造技术知识图谱,揭示该技术研究分类以及演化趋势。     

改进的多层感知机在客户流失预测中的应用

针对在传统的客户流失预测数据预处理中，使用one-hot编码处理离散属性导致数据维度增加及数据过于稀疏的问题，提出了两种基于多层感知机的改进后的客户流失预测模型。其主要思想是分别使用堆叠自编码器和实体嵌入两种方法对多层感知机进行改进，通过将离散属性的高维编码数据向低维空间映射，有效地减少了one-hot编码产生的稀疏数据，增加了离散属性值之间的关联度。在对两份公开的数据集进行交叉验证后的实验结果表明，改进后的模型既有效地提高了预测的准确度，又维持了传统多层感知机模型在并行化计算方面的优势。     

低活化马氏体钢热变形行为及机理型本构建模研究

利用Gleeble-3500热模拟试验机研究了低活化马氏体钢在变形温度为850～950 ℃、应变速率为0.001～1 s^-1条件下的热变形行为。建立了流变应力本构方程，并评估了该方程的预测能力。绘制了低活化马氏体钢在不同应变下的热加工图。结果表明：在较高的应变速率条件下，该材料主要发生动态回复，在较高变形温度和较低应变速率下具有明显的动态再结晶特征；本构方程的预测结果与实验结果符合良好；变形温度870～930 ℃、应变速率0.001～0.01 s^-1和变形温度920～950 ℃、应变速率0.3～1 s^-1分别是真应变为0.4和0.6下最优的热加工区域。     

Propagation and termination of an internal crack in continuously cast austenitic stainless steel analyzed by ∑ values and the Schmid factor

The formation mechanism of an internal crack was clarified from the viewpoint of the crystallography and thermal expansion. An inverse pole figure map obtained by EBSD pattern showed that the crack propagated along the grain boundaries having high ∑ values within the columnar zone. After the crack initiation, these positions were considered to undergo cracking followed by propagation toward the equiaxed side. Near the termination position, the grains ahead of crack propagation had a Schmid factor higher than 0.45 consuming elastic strain energy. Thermal expansion measurements showed that the grain with (0 0 1) orientation had the largest expansion while that with (0 1 1) the smallest. The grain boundaries neighboring the combination of (0 0 1) and (0 1 1) grains had the largest thermal stress. Therefore, thermal stress contributed to the initiation of cracking. It was thus proposed to enlarge the equiaxed zone to prevent cracking by discontinuing the crack propagation.