Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

Transverse magnetoresistance peculiarities of thermoelectric Lu-doped Bi2Te3 compound due to strong electrical disorder

The n-type thermoelectric Bi_1.9Lu_0.1Te₃ was prepared by microwave-solvothermal method and spark plasma sintering. The magnetic field and temperature dependences of transverse magnetoresistance measured within temperature 2–200 K interval allow finding the peculiarities characteristic for strongly disordered and inhomogeneous semiconductors. The first peculiarity is due to appearance of linear-in-magnetic field contribution to the total magnetoresistance reflected in a crossover from quadratic magnetoresistance at low magnetic fields to linear magnetoresistance at high magnetic fields. The linear magnetoresistance can result from the Hall resistance picked up from macroscopically distorted current paths due to local variations in stoichiometry of the compound studied. The second peculiarity is that both linear magnetoresistance magnitude and crossover field are functions of carrier mobility which is in agreement with the Parish and Littlewood model developed for disordered and inhomogeneous semiconductors. An increase in the mobility due to a decrease in temperature is accompanied by an increase in the magnetoresistance magnitude and a decrease in the crossover field. Finally, the third peculiarity is related to the remarkable deviation of the total magnetoresistance measured at various temperatures from the Kohler's rule. Presence of strong inhomogeneity and disorder in the Bi_1.9Lu_0.1Te₃ structure concluded from the magnetoresistance peculiarities can be responsible for the remarkable reduction in the total thermal conductivity of this compound.     

Role of Post-translational Modifications in Alzheimer's Disease

The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug-discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post-translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in-depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease-relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug-discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.     

共享交通的时空轨迹检索与群体发现

为解决共享交通下的共乘用户群体发现效率低、准确率不高问题，依据R-树原理建立GeoOD-Tree索引，并在此基础上提出以最大化共乘率为目标的群体发现策略。首先，对原始时空轨迹数据进行特征提取与标定处理，挖掘有效出行起讫点（OD）轨迹；其次，针对用户起讫点轨迹的特征，建立GeoOD-Tree索引进行有效的存储管理；最后，给出以最大化共乘行程为目标的群体发现模型，并运用K最近邻（KNN）查询对搜索空间剪枝压缩，提高群体发现效率。采用西安市近12000辆出租车营运轨迹数据，选取动态时间规整（DTW）等典型算法与所提算法在查询效率与准确率上进行性能对比分析。与DTW算法相比，所提算法的准确率提高了10.12%，查询效率提高了约15倍。实验结果表明提出的群体发现策略能有效提高共乘用户群体发现的准确率和效率，可有效提升共乘出行方式的出行率。     

基于多项式变换的参数估计方法

本文给出一种采用DPT估计SNCK信号时宽—带宽积的方法,并通过仿真该估计方法的性能与其它估计方法进行比较.首先给出SNCK信号参数估计的一般过程.为了便于计算和理论推导,根据估计出的中心频率将接收到的SNCK信号搬移到零频,从而进一步估计其它参数,如采用DPT估计SNCK信号时宽带宽积.本文将重点研究采用DPT算法估计SNCK信号值的方法.     

A novel approach to adaptive relational association rule mining

The paper focuses on the adaptive relational association rule mining problem. Relational association rules represent a particular type of association rules which describe frequent relations that occur between the features characterizing the instances within a data set. We aim at re-mining an object set, previously mined, when the feature set characterizing the objects increases. An adaptive relational association rule method, based on the discovery of interesting relational association rules, is proposed. This method, called ARARM (Adaptive Relational Association Rule Mining) adapts the set of rules that was established by mining the data before the feature set changed, preserving the completeness. We aim to reach the result more efficiently than running the mining algorithm again from scratch on the feature-extended object set. Experiments testing the method's performance on several case studies are also reported. The obtained results highlight the efficiency of the ARARM method and confirm the potential of our proposal.     

Critical state model for structured soil

Structure is an evident determinant for macroscopic behaviors of soils. However, this is not taken into account in most constitutive models, as structure is a rather complex issue in models. For this, it is important to develop and implement simple models that can reflect this important aspect of soil behavior. This paper tried to model structured soils based on well-established concepts, such as critical state and sub-loading. Critical state is the core of the classic Cam Clay model. The sub-loading concept implies adoption of an inner (sub-loading) yield surface, according to specific hardening rules for some internal strain-like state variables. Nakai and co-workers proposed such internal variables for controlling density (ρ) and structure (ω), using a modified stress space, called t_ij. Herein, similar variables are used in the context of the better-known invariants (p and q) of the Cam Clay model. This change requires explicit adoption of a non-associated flow rule for the sub-loading surface. This is accomplished by modifying the dilatancy ratio of the Cam Clay model, as a function of the new internal variables. These modifications are described and implemented under three-dimensional (3D) conditions. The model is then applied to simulating laboratory tests under different stress paths and the results are compared to experiments reported for different types of structured soils. The good agreements show the capacity and potential of the proposed model.     

人工免疫原理在网络入侵检测系统中的研究

文章分析了人工免疫系统的原理,简单建立了一种基于否定选择算法的网络入侵检测系统,引入了一种用于异常事件识别的r-字符块匹配规则,并对规则存在的漏洞进行了分析。     

Improving Short-Circuit Current Capacity, Resistance, and Breaking Load of OPGW Constructions by Modifying Aluminium Alloy With AlB2

This article presents a method that can be applied to molten AA-6101 alloy to improve electrical properties of the aluminium part of the optical ground wire (OPGW) used in overhead transmission lines to protect phase conductors from lightning strike and to transmit signals and data. AA-6101 alloy in casting of the log as 6 m length and 178 mm diameter for extrusion has been inoculated by AlB₂ to decrease detrimental effects of Cr, Ti, V, and Zr on the conductivity of the material. After inoculation, improved billets were extruded as 9.5 mm diameter feedstock. Required wires drawn from the feedstock according to the construction types of OPGW to be tested were exposed to aging at 175°C, 6 h (T-8). Upon completion of the back-twist and performing-type stranding process, resistance, and short-circuit current capacity and breaking load of the OPGW 88/44 constructions with other metal combinations have been examined and tested to show improvement. Results are summarized in tables and graphically.