Genetic and Epigenomic Modifiers of Diabetic Neuropathy

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.     

In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.     

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.     

梯度铝蜂窝夹芯板的力学行为

梯度分层铝合金蜂窝板是一种有效的吸能结构,本工作在梯度铝蜂窝结构的基础上根据梯度率的概念,通过改变蜂窝芯层的胞壁长度,设计了4种质量相同、梯度率不同的铝蜂窝夹芯结构。通过准静态压缩实验,并结合非线性有限元模拟准静态及冲击态下梯度铝蜂窝夹芯结构的变形情况及其力学性能,分析对比了相同质量下梯度铝蜂窝夹芯结构在准静态下的变形模式以及冲击载荷下分层均质蜂窝结构和不同梯度率的分层梯度蜂窝结构的动态响应和能量吸收特性。结果表明:在准静态压缩过程中,铝蜂窝梯度夹芯板的变形具有明显的局部化特征,蜂窝芯的变形为低密度优先变形直至密实,层级之间的密实化应变差随芯层密度的增大而逐渐减小;在高速冲击下,梯度蜂窝板并非严格按照准静态过程中逐级变形直至密实,而是在锤头冲击惯性及芯层密度的相互作用下整体发生的线弹性变形、弹性屈曲、塑性坍塌及密实化;另外,在本工作所设计的梯度率中,当梯度率为γ₁=0.0276时,梯度蜂窝夹芯板的吸能性达到最好,相较于同等质量下的均质蜂窝夹芯板,能量吸收提高了10.63%。     

基于GA-BP的汽车风振噪声声品质预测模型

目前对于汽车风振噪声的优化研究主要以声压级（Sound pressure level，SPL）作为单一评价指标，既不能全面反映噪声的物理属性，也无法考虑人耳对噪声的主观认知过程。为准确评价风振噪声，引入声品质，运用大涡模拟（Large eddy simulation，LES）对风振噪声进行数值仿真，根据实车道路试验判断仿真的准确性；对仿真结果进行声品质客观评价与主观评价，综合声品质客观评价参数与声品质主观评价试验结果建立BP神经网络预测模型；利用遗传算法（Genetic algorithm，GA），进一步对BP神经网络的结构参数进行优化，建立GA-BP声品质预测模型。研究结果表明，GA-BP声品质预测模型在训练速度和预测精度上都优于BP神经网络预测模型。预测模型基于声品质主客观评价结果，其预测值可以代替传统的声压级评价指标，为风振噪声提供更为准确合理的评价。     

基于PBFT区块链技术的电网企业仓储系统

提出了一种基于实用拜占庭容错(PBFT)算法的区块链技术,首先对传统的实用拜占庭容错算法原理进行了阐述,该传统算法包含前期、需求、预准备、准备、确认、答复6个阶段,但传统算法具有实时性差、缺乏惩罚机制、带宽高的缺点。针对出现的这些问题,又对传统算法进行了改进,具体涉及记账节点、共识过程以及视图切换过程。通过测试进一步证明了该改进算法的实用性,并将该算法应用于电网企业中,构建的虚拟仓库实现了联储联备,降低了库存资金的耗费,并且提高了电网企业库存管理的效率。