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.     

Supply chain network design under the risk of uncertain disruptions

Facility disruptions in the supply chain often lead to catastrophic consequences, although they occur rarely. The low frequency and non-repeatability of disruptive events also make it impossible to estimate the disruption probability accurately. Therefore, we construct an uncertain programming model to design the three-echelon supply chain network with the disruption risk, in which disruptions are considered as uncertain events. Under the constraint of satisfying customer demands, the model optimises the selection of retailers with uncertain disruptions and the assignment of customers and retailers, in order to minimise the expected total cost of network design. In addition, we simplify the proposed model by analysing its properties and further linearise the simplified model. A Lagrangian relaxation algorithm for the linearised model and a genetic algorithm for the simplified model are developed to solve medium-scale problems and large-scale problems, respectively. Finally, we illustrate the effectiveness of proposed models and algorithms through several numerical examples.     

Shape optimization of bi-directional flow passage components based on a genetic algorithm and computational fluid dynamics

The inlet/outlet is an important part of a water conveyance system in a pumped storage power station (PSPS). Its hydraulic characteristics are directly related to the operation and economic benefit of the PSPS. Frequent changes between inflow and outflow operations pose significant challenges in the design of the inlet/outlet diffusion segment shape. In this study, an effective optimization method, including three-dimensional parametric modelling, computational fluid dynamics and a genetic algorithm, is introduced and coupled to the design of the diffusion segment shape. The hydraulic characteristics of bi-directional flow, including the head loss, velocity uneven distribution and uneven discharge distribution, are selected as the objective function in the optimization method. Using this method, the recommended shape of the inlet/outlet is studied and its hydraulic characteristics are discussed. The results indicate that the optimized inlet/outlet has better performance.     

New empirical correlation for estimation of vaporization enthalpy of algerian saharan blend petroleum fractions

A Real-coded Genetic Algorithm has been used to develop a new correlation to estimate the enthalpy of vaporization for pure compounds and petroleum fractions as a function of the normal boiling point and specific gravity. In developing the correlation 80% of the data was used and the remaining are used for validation. The results of the proposed correlations are compared to others in literature. The comparison indicates that the proposed model is simple to use and more accurate than the most common correlations for predicting the enthalpy of vaporization of pure compounds and petroleum fractions.     

基于协同优化算法的流速仪检定系统设计

提出了一种小型轻便的流速仪检定系统的设计方案,并运用改进的多学科协同优化方法求解各学科设计变量的最优解。首先介绍了算法思想及改进措施,并根据系统设计要求建立了各学科的设计变量、目标函数和约束条件；其次,运用遗传算法求解各学科设计变量的最优解,并根据优化结果完善了系统的设计方案,同时运用计算机仿真等方法验证了优化结果的可行性。结果表明,优化后的检定系统满足流体力学效应、匀速运动时间、系统重量等设计要求,同时证明了协同优化算法解决多学科设计优化问题的有效性。     

A dimensional reduction approach to modulate the core ruminal microbiome associated with methane emissions via selective breeding

The rumen is a complex microbial system of substantial importance in terms of greenhouse gas emissions and feed efficiency. This study proposes combining metagenomic and host genomic data for selective breeding of the cow hologenome toward reduced methane emissions. We analyzed nanopore long reads from the rumen metagenome of 437 Holstein cows from 14 commercial herds in 4 northern regions in Spain. After filtering, data were treated as compositional. The large complexity of the rumen microbiota was aggregated, through principal component analysis (PCA), into few principal components (PC) that were used as proxies of the core metagenome. The PCA allowed us to condense the huge and fuzzy taxonomical and functional information from the metagenome into a few PC. Bivariate animal models were applied using these PC and methane production as phenotypes. The variability condensed in these PC is controlled by the cow genome, with heritability estimates for the first PC of ~0.30 at all taxonomic levels, with a large probability (>83%) of the posterior distribution being >0.20 and with the 95% highest posterior density interval (95%HPD) not containing zero. Most genetic correlation estimates between PC1 and methane were large (≥0.70), with most of the posterior distribution (>82%) being >0.50 and with its 95%HPD not containing zero. Enteric methane production was positively associated with relative abundance of eukaryotes (protozoa and fungi) through the first component of the PCA at phylum, class, order, family, and genus. Nanopore long reads allowed the characterization of the core rumen metagenome using whole-metagenome sequencing, and the purposed aggregated variables could be used in animal breeding programs to reduce methane emissions in future generations.