Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump

The calcium pump (sarco/endoplasmic reticulum Ca²⁺-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca²⁺ during muscle relaxation. Active Ca²⁺ transport by SERCA involves the structural transition from a low-Ca²⁺ affinity E2 state toward a high-Ca²⁺ affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca²⁺ ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump.     

Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.     

橡胶轮胎和软管用高强度钢帘线盘条的研发

为了减轻汽车重量,提高燃油消耗,研制了高强度钢帘线用线材。然而,开发高强度钢帘线的难点是必须同时获得高强度和良好的塑性。为了解决这一问题,通过分析拉丝过程中钢丝组织和力学性能的变化,研究了拉丝过程中的分层机理,提高了拉丝的塑性。采用1.0%C过共析钢和优化的拉拔工艺,在实验室可获得4400 MPa级钢帘线。     

Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Microstructural and mechanical properties assessment of transient liquid phase bonding of CoCuFeMnNi high entropy alloy

The transient liquid phase (TLP) bonding of CoCuFeMnNi high entropy alloy (HEA) was studied. The TLP bonding was performed using AWS BNi-2 interlayer at 1050 °C with the TLP bonding time of 20, 60, 180 and 240 min. The effect of bonding time on the joint microstructure was characterized by SEM and EDS. Microstructural results confirmed that complete isothermal solidification occurred approximately at 240 min of bonding time. For samples bonded at 20, 60 and 180 min, athermal solidification zone was formed in the bonding area which included Cr-rich boride and Mn₃Si intermetallic compound. For all samples, the γ solid solution was formed in the isothermal solidification zone of the bonding zone. To evaluate the effect of TLP bonding time on mechanical properties of joints, the shear strength and micro-hardness of joints were measured. The results indicated a decrement of micro-hardness in the bonding zone and an increment of micro-hardness in the adjacent zone of joints. The minimum and maximum values of shear strength were 100 and 180 MPa for joints with the bonding time of 20 and 240 min, respectively.     

Tropfenbewegung und Stofftransport in technischen Flüssig/flüssig-Systemen. Teil 2: Auswirkung von Grenzflächeneffekten und Verunreinigungen

The design of a liquid/liquid contact apparatus necessitates the knowledge of fluid dynamics and mass transfer in the dispersion. Prediction of process parameters is challenging due to swarm and interfacial effects. Single drop investigations are suitable to enable a sophisticated dimensioning based on few simple experiments combined with published theories and correlations. In the first part of this article, the fundamentals of fluid dynamics and mass transfer in absence of interfacial effects were explained. Here, an overview of relevant interfacial phenomena and the influence of different substances typically occurring in technical applications as impurities or accompanying components is given.     

Computational Fluid Dynamics versus Experiment: An Investigation on Liquid Weeping of Nye Trays

The weeping phenomenon was investigated using some experimental tests and a numerical model. The tests were performed within a 1.22‐m‐diameter pilot‐scale column including two chimney trays and two Nye test trays with an air‐water system. The rates of weeping were measured in the Nye trays with two heights of the weir and a hole area of 5 %. Moreover, the weeping rates in the outlet and inlet halves of the Nye tray and the total weeping rate were calculated. In the next step, an Eulerian‐Eulerian computational fluid dynamics (CFD) technique was used. The results show good agreement between the attained CFD findings and the experimental data.     

机械设备故障规律及运行趋势预测方法综述

对于机械设备的故障运行问题,技术人员应当深入研究机械设备的故障规律,并研究出运行趋势的预测方法,从传感器的检测时间间隔与使用数量等方面加以深入的研究。本文介绍了机械设备运行状态的故障预测方法,并将机械设备运行状态的故障预测方法总结为三个步骤,分别是数据获取、处理与设备寿命预测,结合这些内容,提出了关于机械设备故障运行的一些方法,旨在为相关技术人员提供参考依据。     

Detailed analysis on thermal,microstructural, mechanical,and morphological features of side chain liquid crystalline polymer/isotactic polypropylene graft copolymers: Effect of grafted and ungrafted polymer units

The main scope of this comprehensive study is to investigate the effects of poly(p-benzophenoneoxycarbonylphenyl acrylate), poly(BPOCPA), which presenting as only graft units or both graft and ungrafted units in the matrix, on the fundamental features of isotactic polypropylene (IPP). The graft copolymerization of BPOCPA onto IPP was performed with the aid of bulk melt polymerization at varying monomer content levels ranging from 5% to 40%. The thermal behavior, crystal quality, mechanical performance, and surface morphology of the samples were investigated by means of differential scanning calorimeter, X-ray diffractometer (XRD), universal mechanical test, and scanning electron microscope (SEM) techniques. Thermal analyses depicted that there existed the noteworthy enhancements in both crystalline melting temperatures and percent crystallinities of matrix polymers. Furthermore, according to XRD results, a and b parameters increased significantly at low percentages of the graft units, while the parameter c decreased in all products in consistence with the content. As for the mechanical characterization, the grafting led to remarkable improvements in modulus, tensile and impact strength of the products. SEM micrographs indicated that the samples were completely homogeneous without any phase separation and the products exhibited brittle nature with some ductility.     

FE-SEA方法在平台支持船噪声预报中的应用

平台支持船由于作业需要通常配备有动力定位系统,其在侧推工况下舱室噪声超标较为严重。针对这个问题采用计算流体力学(CFD)方法,得到侧推螺旋桨作用在导管上的脉动压力,并将时域计算结果转换成噪声计算的激励条件。采用有限元(FE)与统计能量分析(SEA)混合方法建立船体中频段FE-SEA耦合模型并建立船体高频段SEA模型,对某65 m AHTS船侧推工况下全频段(63 Hz~8000 Hz)舱室噪声进行预报,分析该船噪声分布规律及主要影响因素。并建立起全船的SEA模型,在中频段对比SEA与FE-SEA两种方法得到的舱室声压级频谱曲线,验证了使用混合模型的必要性。