机械可靠性理论在铁路牵引动力管理中的应用

简要介绍了机械可靠性理论对应于铁路牵引动力的修制、修程、可靠性指标;采用可靠性理论分析了机车的检修周期、检修范围;提出了机械可靠性理论在机务牵引动力管理中的应用思路.     

Progress in Anticancer Drug Development Targeting Ubiquitination-Related Factors

Ubiquitination is extensively involved in critical signaling pathways through monitoring protein stability, subcellular localization, and activity. Dysregulation of this process results in severe diseases including malignant cancers. To develop drugs targeting ubiquitination-related factors is a hotspot in research to realize better therapy of human diseases. Ubiquitination comprises three successive reactions mediated by Ub-activating enzyme E1, Ub-conjugating enzyme E2, and Ub ligase E3. As expected, multiple ubiquitination enzymes have been highlighted as targets for anticancer drug development due to their dominant effect on tumorigenesis and cancer progression. In this review, we discuss recent progresses in anticancer drug development targeting enzymatic machinery components.     

De Novo Prediction of Drug Targets and Candidates by Chemical Similarity-Guided Network-Based Inference

Identifying drug–target interactions is a crucial step in discovering novel drugs and for drug repositioning. Network-based methods have shown great potential thanks to the straightforward integration of information from different sources and the possibility of extracting novel information from the graph topology. However, despite recent advances, there is still an urgent need for efficient and robust prediction methods. Here, we present SimSpread, a novel method that combines network-based inference with chemical similarity. This method employs a tripartite drug–drug–target network constructed from protein–ligand interaction annotations and drug–drug chemical similarity on which a resource-spreading algorithm predicts potential biological targets for both known or failed drugs and novel compounds. We describe small molecules as vectors of similarity indices to other compounds, thereby providing a flexible means to explore diverse molecular representations. We show that our proposed method achieves high prediction performance through multiple cross-validation and time-split validation procedures over a series of datasets. In addition, we demonstrate that our method performed a balanced exploration of both chemical ligand space (scaffold hopping) and biological target space (target hopping). Our results suggest robust and balanced performance, and our method may be useful for predicting drug targets, virtual screening, and drug repositioning.     

KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR

Cystic fibrosis (CF) is caused by mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), an anion-selective plasma membrane channel that mainly regulates chloride transport in a variety of epithelia. More than 2000 mutations, most of which presumed to be disease-relevant, have been identified in the CFTR gene. The single CFTR mutation F508del (deletion of phenylalanine in position 508) is present in about 90% of global CF patients in at least one allele. F508del is responsible for the defective folding and processing of CFTR, failing to traffic to the plasma membrane and undergoing premature degradation via the ubiquitin–proteasome system. CFTR is subjected to different post-translational modifications (PTMs), and the possibility to modulate these PTMs has been suggested as a potential therapeutic strategy for the functional recovery of the disease-associated mutants. Recently, the PTM mapping of CFTR has identified some lysine residues that may undergo methylation or ubiquitination, suggesting a competition between these two PTMs. Our work hypothesis moves from the idea that favors methylation over ubiquitination, e.g., inhibiting demethylation could be a successful strategy for preventing the premature degradation of unstable CFTR mutants. Here, by using a siRNA library against all the human demethylases, we identified the enzymes whose downregulation increases F508del-CFTR stability and channel function. Our results show that KDM2A and KDM3B downregulation increases the stability of F508del-CFTR and boosts the functional rescue of the channel induced by CFTR correctors.     

Factors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging

Aging causes a progressive decline in the structure and function of organs. With advancing age, an accumulation of senescent endothelial cells (ECs) contributes to the risk of developing vascular dysfunction and cardiovascular diseases, including hypertension, diabetes, atherosclerosis, and neurodegeneration. Senescent ECs undergo phenotypic changes that alter the pattern of expressed proteins, as well as their morphologies and functions, and have been linked to vascular impairments, such as aortic stiffness, enhanced inflammation, and dysregulated vascular tone. Numerous molecules and pathways, including sirtuins, Klotho, RAAS, IGFBP, NRF2, and mTOR, have been implicated in promoting EC senescence. This review summarizes the molecular players and signaling pathways driving EC senescence and identifies targets with possible therapeutic value in age-related vascular diseases.     

Identifying Drug Targets of Oral Squamous Cell Carcinoma through a Systems Biology Method and Genome-Wide Microarray Data for Drug Discovery by Deep Learning and Drug Design Specifications

In this study, we provide a systems biology method to investigate the carcinogenic mechanism of oral squamous cell carcinoma (OSCC) in order to identify some important biomarkers as drug targets. Further, a systematic drug discovery method with a deep neural network (DNN)-based drug–target interaction (DTI) model and drug design specifications is proposed to design a potential multiple-molecule drug for the medical treatment of OSCC before clinical trials. First, we use big database mining to construct the candidate genome-wide genetic and epigenetic network (GWGEN) including a protein–protein interaction network (PPIN) and a gene regulatory network (GRN) for OSCC and non-OSCC. In the next step, real GWGENs are identified for OSCC and non-OSCC by system identification and system order detection methods based on the OSCC and non-OSCC microarray data, respectively. Then, the principal network projection (PNP) method was used to extract core GWGENs of OSCC and non-OSCC from real GWGENs of OSCC and non-OSCC, respectively. Afterward, core signaling pathways were constructed through the annotation of KEGG pathways, and then the carcinogenic mechanism of OSCC was investigated by comparing the core signal pathways and their downstream abnormal cellular functions of OSCC and non-OSCC. Consequently, HES1, TCF, NF-κB and SP1 are identified as significant biomarkers of OSCC. In order to discover multiple molecular drugs for these significant biomarkers (drug targets) of the carcinogenic mechanism of OSCC, we trained a DNN-based drug–target interaction (DTI) model by DTI databases to predict candidate drugs for these significant biomarkers. Finally, drug design specifications such as adequate drug regulation ability, low toxicity and high sensitivity are employed to filter out the appropriate molecular drugs metformin, gefitinib and gallic-acid to combine as a potential multiple-molecule drug for the therapeutic treatment of OSCC.     

桥梁结构时变可靠度计算的新方法

为提高桥梁结构时变可靠度的计算效率,该文提出了新的计算方法。该方法基于结构时变可靠度分析的基本理论,利用Taylor级数展开,将可靠度计算从传统的积分运算形式转换为代数运算的形式,从而简化计算过程,提高计算效率。为了考虑桥梁初始承载力和衰减过程的不确定性,该文基于全概率方法,给出了计算劣化结构时变可靠度的显式公式。通过将该文方法应用于某钢筋混凝土桥梁进行时变可靠度分析,并与Monte Carlo模拟方法进行对比,表明了该文方法的准确性和高效性。     

光纤激光相干合成研究进展

近年来,以激光大气传输为应用背景的光束相干合成技术被广泛研究,而关于该项技术在空间光通信中的应用研究却不多。事实上,基于光束相干合成的多孔径接收天线结构可有效缓解大气湍流影响,提高空间激光通信系统的性能。本论文简要介绍了中国科学院自适应光学重点实验室面向激光大气传输应用的激光组束传输与湍流校正技术研究近况;重点介绍关于多孔径接收空间光通信系统中的光纤相干合成研究进展,主要包括基于3 dB光纤耦合器的相干合成和基于光纤偏振合束器的相干偏振合成两种方法,在空间光通信系统中具有极大的潜在应用。

     

亚帆赛间便携式高频地波雷达的海态观测

为了研究采用紧凑型接收天线的便携式高频地波雷达的目标检测性能并检验组网的可行性, 于2013年底在渤海海域进行了雷达组网试验, 并将获取的数据与船舶自动识别系统的数据进行了对比.对比结果表明:单站条件下目标漏检的情况经常发生, 导致检测概率很低.而通过双站数据融合, 可以将检测概率提高10~20个百分点, 多数情况下, 联合检测概率都超过了50%, 最高时更是达到了80%, 初步验证了便携式高频地波雷达组网探测目标的可行性.