A hidden aggregation‐prone structure in the heart of hypoxia inducible factor prolyl hydroxylase

Prolyl hydroxylase domain‐containing protein 2 (PHD2), as one of the most important regulators of angiogenesis and metastasis of cancer cells, is a promising target for cancer therapy drug design. Progressive studies imply that abnormality in PHD2 function may be due to misfolding. Therefore, study of the PHD2 unfolding pathway paves the way for a better understanding of the influence of PHD2 mutations and cancer cell metabolites on the protein folding pathway. We study the unfolding of the PHD2 catalytic domain using differential scanning calorimetry (DSC), fluorescence spectroscopy, and discrete molecular dynamics simulations (DMD). Using computational and experimental techniques, we find that PHD2 undergoes four transitions along the thermal unfolding pathway. To illustrate PHD2 unfolding events in atomic detail, we utilize DMD simulations. Analysis of computational results indicates an intermediate species in the PHD2 unfolding pathway that may enhance aggregation propensity, explaining mutation‐independent PHD2 malfunction. Proteins 2016; 84:611–623. © 2016 Wiley Periodicals, Inc.     

Solvation structure of sodium chloride (Na+–Cl-) ion pair in acetonitrile (AN)–dimethyl formamide (DMF) mixtures

Solvation structures of Na⁺–Cl^? ion pair are investigated in acetonitrile (AN)–dimethylformamide (DMF) isodielectric mixtures. The potentials of mean force of Na⁺–Cl^? in the five compositions of mixtures show minima corresponding to a contact ion pair (CIP) and a solvent-shared ion pair (SShIP). The solvent-separated ion pair minima are present in lower mole fractions of AN (x_AN ≤ 0.50). CIPs are found to be more stable than the SShIPs. From a thermodynamic decomposition of the potentials of mean force, we find that the formation of the ion pair is entropically driven in these compositions. The most stable CIP is in pure AN. The local solvation structures around the ion pair are analysed through the running coordination numbers, excess coordination numbers, solvent orientational distributions and density profiles. We find that both Na⁺ and Cl^? are preferentially solvated by DMF.     

Molecular dynamics simulation of six β-blocker drugs passing across POPC bilayer

Six selected β-blocker drugs (alprenolol, atenolol, metoprolol, nadolol, pindolol and propranolol) passing across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer were studied using all-atom molecular dynamics simulation. The free energy profiles can be divided into two groups, according to their shapes: the free energy curve of group one (atenolol, nadolol and pindolol) has an obvious minimum while that of the other group (propranolol, metoprolol and alprenolol) is flat inside membrane. Energy analysis shows that electrostatic interaction plays an important role for the first group drugs. The hydrogen bond analysis results also certify that the first group drugs form more hydrogen bonds than the other β-blockers. The calculated permeability sequence agrees with the experimental ones. Our calculation suggests that the permeability model using potential of mean force (PMF) method can be also applied to chemically similar compounds besides chemically diverse compounds.     

抗癌药物奥沙利铂与DNA分子相互作用的研究

奥沙利铂被称为第三代铂类药物,特别对胃肠道肿瘤具有较好的疗效.目前大多数的研究表明奥沙利铂的主要作用靶点是DNA分子,但它与DNA分子形成的关键结构和作用机制仍处在探索阶段.本研究运用紫外可见吸收光谱和原子力显微镜观察探索奥沙利铂与DNA在活体外的相互作用过程,从而揭示奥沙利铂产生抗癌作用的主要分子结构基础.首先使用紫外光谱研究了较高浓度奥沙利铂与DNA的作用过程.在此基础上,进一步采用原子力显微镜在高定向热解石墨表面观察了不同浓度奥沙利铂与质粒DNA在37℃条件下作用不同时间后的结构形貌变化,分析了奥沙利铂与DNA相互作用的过程.高分辨原子力显微观察结果表明奥沙利铂与DNA作用后可导致质粒DNA的结构发生显著的变化.随着作用时间的增加,DNA分子逐渐由伸展的链状变化为相互缠绕并带有许多结点的紧密结构,最终变化为更紧密的球状结构.本研究结果表明奥沙利铂可通过化学键合作用和静电作用使质粒DNA逐渐凝集为紧密的球状结构,这种结构可能对奥沙利铂的抗癌活性和毒性产生重要影响.     

Change in knee contact force with simulated change in body weight

The relationship between obesity, weight gain and progression of knee osteoarthritis is well supported, suggesting that excessive joint loading may be a mechanism responsible for cartilage deterioration. Examining the influence of weight gain on joint compressive forces is difficult, as both muscles and ground reaction forces can have a significant impact on the forces experienced during gait. While previous studies have examined the relationship between body weight and knee forces, these studies have used models that were not validated using experimental data. Therefore, the objective of this study was to evaluate the relationship between changes in body weight and changes in knee joint contact forces for an individual's gait pattern using musculoskeletal modeling that is validated against known internal compressive forces. Optimal weighting constants were determined for three subjects to generate valid predictions of knee contact forces (KCFs) using in vivo data collection with instrumented total knee arthroplasty. A total of five simulations per walking trial were generated for each subject, from 80% to 120% body weight in 10% increments, resulting in 50 total simulations. The change in peak KCF with respect to body weight was found to be constant and subject-specific, predominantly determined by the peak force during the baseline condition at 100% body weight. This relationship may be further altered by any change in kinematics or body mass distribution that may occur as a result of a change in body weight or exercise program.     

Improving anterior deltoid activity in a musculoskeletal shoulder model – an analysis of the torque-feasible space at the sternoclavicular joint

Modelling the shoulder's musculature is challenging given its mechanical and geometric complexity. The use of the ideal fibre model to represent a muscle's line of action cannot always faithfully represent the mechanical effect of each muscle, leading to considerable differences between model-estimated and in vivo measured muscle activity. While the musculo–tendon force coordination problem has been extensively analysed in terms of the cost function, only few works have investigated the existence and sensitivity of solutions to fibre topology. The goal of this paper is to present an analysis of the solution set using the concepts of torque-feasible space (TFS) and wrench-feasible space (WFS) from cable-driven robotics. A shoulder model is presented and a simple musculo–tendon force coordination problem is defined. The ideal fibre model for representing muscles is reviewed and the TFS and WFS are defined, leading to the necessary and sufficient conditions for the existence of a solution. The shoulder model's TFS is analysed to explain the lack of anterior deltoid (DLTa) activity. Based on the analysis, a modification of the model's muscle fibre geometry is proposed. The performance with and without the modification is assessed by solving the musculo–tendon force coordination problem for quasi-static abduction in the scapular plane. After the proposed modification, the DLTa reaches 20% of activation.     

Neuromuscular performance of Bandal Chagui: Comparison of subelite and elite taekwondo athletes

With the aim of comparing kinematic and neuromuscular parameters of Bandal Chagui kicks between 7 elite and 7 subelite taekwondo athletes, nine Bandal Chaguis were performed at maximal effort in a selective reaction time design, simulating the frequency of kicks observed in taekwondo competitions. Linear and angular leg velocities were recorded through 3D motion capture system. Ground reaction forces (GRF) were evaluated by a force platform, and surface electromyographic (sEMG) signals were evaluated in the vastus lateralis, biceps femoris, rectus femoris, tensor fasciae lata, adductor magnus, gluteus maximus, gluteus medius, and gastrocnemius lateralis muscles of the kicking leg. sEMG data were processed to obtain the cocontraction indices (CI) of antagonist vs. overall (agonist and antagonist) muscle activity. CI was measured for the hip and knee, in flexion and extension, and for hip abduction. Premotor, reaction (kinetic and kinematic), and kicking times were evaluated. Timing parameters, except kinetic reaction time, were faster in elite athletes. Furthermore, CI and angular velocity during knee extension, foot and knee linear velocity, and horizontal GRF were significantly higher in elite than in subelite athletes. In conclusion, selected biomechanical parameters of Bandal Chagui appear to be useful in controlling the training status of the kick and in orienting the training goal of black belt competitors.     

MVIC运动不能提高大学生篮球运动员的激活后增强效应

本研究旨在探讨激活后增强效应(post-activation potentiation, PAP)对大学生篮球运动员上肢力量表现和肌肉损伤指标的影响,以及不同最大自主等长收缩(maximal voluntary isometric contraction, MVIC)时间诱发激活后增强效应后,对卧推(bench press throw, BPT)表现的影响。本研究招募30名大学生男性篮球运动员进行重复交叉实验。所有受试者均接受3组3 s卧推MVICs (3 MVICs)、3组5 s卧推MVICs (5 MVICs)、对照控制(CON)共3次干预,记录推掷高度与杠铃腾空时间,并分析推掷高度、力量与功率的峰值。研究表明:3 MVICs、5 MVICs、CON处理后,卧推高度在后测各时间点皆显著低于前测平均值,功率峰值在第4分钟、第8分钟及后测平均值上,皆显著低于前测平均值。但是,力量峰值在后测各时间点与前测平均值均无显著性差异。本研究初步认为给予较长的组间恢复时间,3 MVICs、5 MVICs产生肌肉疲劳的程度可能高于诱发PAP的程度,进而无法提升训练良好运动员的上肢爆发力表现。     

Magnetic Field–Suppressed Lithium Dendrite Growth for Stable Lithium‐Metal Batteries

Lithium metal is the most attractive anode material due to its extremely high specific capacity, minimum potential, and low density. However, uncontrollable growth of lithium dendrite results in severe safety and cycling stability concerns, which hinders the application in next generation secondary batteries. In this paper, a new and facile method imposing a magnetic field to lithium metal anodes is proposed. That is, the lithium ions suffering Lorentz force due to the electromagnetic fields are put into spiral motion causing magnetohydrodynamics (MHD) effect. This MHD effect can effectively promote mass transfer and uniform distribution of lithium ions to suppress the dendrite growth as well as obtain uniform and compact lithium deposition. The results show that the lithium metal electrodes within the magnetic field exhibit excellent cycling and rate performance in a symmetrical battery. Additionally, full batteries using limited lithium metal as anodes and commercial LiFePO₄ as cathodes show improved performance within the magnetic field. In summary, a new and facile strategy of suppressing lithium dendrites using the MHD effect by imposing a magnetic field is proposed, which may be generalized to other advanced alkali metal batteries.     

Polarization of Myosin II Refines Tissue Material Properties to Buffer Mechanical Stress

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