Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain

Mutations in leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent cause of Parkinson’s disease (PD). As a multidomain ROCO protein, LRRK2 is characterized by the presence of both a Ras-of-complex (ROC) GTPase domain and a kinase domain connected through the C-terminal of an ROC domain (COR). The bienzymatic ROC–COR–kinase catalytic triad indicated the potential role of GTPase domain in regulating kinase activity. However, as a functional GTPase, the detailed intrinsic regulation of the ROC activation cycle remains poorly understood. Here, combining extensive molecular dynamics simulations and Markov state models, we disclosed the dynamic structural rearrangement of ROC’s homodimer during nucleotide turnover. Our study revealed the coupling between dimerization extent and nucleotide-binding state, indicating a nucleotide-dependent dimerization-based activation scheme adopted by ROC GTPase. Furthermore, inspired by the well-known R1441C/G/H PD-relevant mutations within the ROC domain, we illuminated the potential allosteric molecular mechanism for its pathogenetic effects through enabling faster interconversion between inactive and active states, thus trapping ROC in a prolonged activated state, while the implicated allostery could provide further guidance for identification of regulatory allosteric pockets on the ROC complex. Our investigations illuminated the thermodynamics and kinetics of ROC homodimer during nucleotide-dependent activation for the first time and provided guidance for further exploiting ROC as therapeutic targets for controlling LRRK2 functionality in PD treatment.     

Density and impurity profile behaviours in HL-2A tokamak with different gas fuelling methods

The electron density profile peaking and the impurity accumulation in the HL-2A tokamak plasma are observed when three kinds of fuelling methods are separately used at different fuelling particle locations. The density profile becomes more peaked when the line-averaged electron density approaches the Greenwald density limit n_G and, consequently, impurity accumulation is often observed. A linear increase regime in the density range n_e< 0.6n_G and a saturation regime in n_e > 0.6n_G are obtained. There is no significant difference in achieved density peaking factor f_ne between the supersonic molecular beam injection (SMBI) and gas puffing into the plasma main chamber. However, the achieved f_ne is relatively low, in particular, in the case of density below 0.7n_G, when the working gas is puffed into the divertor chamber. A discharge with a density as high as 1.2n_G, i.e. n_e = 1.2n_G, can be achieved by SMBI just after siliconization as a wall conditioning. The metallic impurities, such as iron and chromium, also increase remarkably when the impurity accumulation happens. The mechanism behind the density peaking and impurity accumulation is studied by investigating both the density peaking factor versus the effective collisionality and the radiation peaking versus density peaking.     

A Fast Approach to Removing Muscle Artifacts for EEG with Signal Serialization Based Ensemble Empirical Mode Decomposition

An electroencephalogram (EEG) is an electrophysiological signal reflecting the functional state of the brain. As the control signal of the brain–computer interface (BCI), EEG may build a bridge between humans and computers to improve the life quality for patients with movement disorders. The collected EEG signals are extremely susceptible to the contamination of electromyography (EMG) artifacts, affecting their original characteristics. Therefore, EEG denoising is an essential preprocessing step in any BCI system. Previous studies have confirmed that the combination of ensemble empirical mode decomposition (EEMD) and canonical correlation analysis (CCA) can effectively suppress EMG artifacts. However, the time-consuming iterative process of EEMD may limit the application of the EEMD-CCA method in real-time monitoring of BCI. Compared with the existing EEMD, the recently proposed signal serialization based EEMD (sEEMD) is a good choice to provide effective signal analysis and fast mode decomposition. In this study, an EMG denoising method based on sEEMD and CCA is discussed. All of the analyses are carried out on semi-simulated data. The results show that, in terms of frequency and amplitude, the intrinsic mode functions (IMFs) decomposed by sEEMD are consistent with the IMFs obtained by EEMD. There is no significant difference in the ability to separate EMG artifacts from EEG signals between the sEEMD-CCA method and the EEMD-CCA method (p > 0.05). Even in the case of heavy contamination (signal-to-noise ratio is less than 2 dB), the relative root mean squared error is about 0.3, and the average correlation coefficient remains above 0.9. The running speed of the sEEMD-CCA method to remove EMG artifacts is significantly improved in comparison with that of EEMD-CCA method (p < 0.05). The running time of the sEEMD-CCA method for three lengths of semi-simulated data is shortened by more than 50%. This indicates that sEEMD-CCA is a promising tool for EMG artifact removal in real-time BCI systems.     

Ni nanoparticles encapsulated within H-type ZSM-5 crystals for upgrading palmitic acid to diesel-like fuels

Meso-Ni@HZSM-5 bi-functional catalysts were successfully post-encapsulated with about 3–7 nm Ni nanoparticles within HZSM-5 crystals,which exhibited significantly efficient conversion activity (67.4g[palmitic acid]g[Ni]^-1h^-1) of palmitic acid and 100%selectivity of hydrocarbons with the outstanding stability during recycling application,compared to the impregnated Ni/HZSM-5 catalyst (14.0 g[palmitic acid]g[Ni]^-1h^-1).     

傅里叶变换红外光谱用于胃镜样品的检测

应用傅里叶变换红外光谱(FTIR) 法对184例不同病理状态的胃镜下活检组织样品进行检测和分析,结果表明,慢性浅表性胃炎的基本谱图特征包括：较强的酰胺Ⅱ带;1 460 cm-1处的峰强高于1 400 cm-1处的峰强。典型的胃癌组织的谱图特征包括：较低的酰胺Ⅱ带;1 460 cm-1处的峰强低于1 400 cm-1处的峰强;1 300 cm-1的峰强明显增加。慢性萎缩性胃炎呈现出部分胃癌的光谱特征。这一结果表明,应用FTIR可以对胃镜下活检的小块组织进行鉴别诊断。     

Modulational instability of ion—acoustic waves in a warm plasma

Using the standard reductive perturbation technique,a nonlinear Schroedinger equation is derived to study the modulational instability of finite-amplitude ion-acoustic waves in a non-magnetized warm plasma.It is found that the inclusion of ion temperature in the equation modifies the nature of the ion-acoustic wave stability and the soliton stuctures.The effects of ion plasma temperature on the modulational stability and ion-acoustic wave properties are inestigated in detail.     

Dichloro(2,2′‐diamino‐4,4′‐bi‐1,3‐thiazole‐N3,N3′)copper(II)

The title complex, [CuCl₂(C₆H₆N₄S₂)], has a flattened tetrahedral coordination. The Cu^II atom is located on a twofold rotation axis and is coordinated by two N atoms from a chelating 2,2′‐di­amino‐4,4′‐bi‐1,3‐thia­zole ligand and by two Cl atoms. Intramolecular hydrogen bonding exists between the amino groups of the 2,2′‐di­amino‐4,4′‐bi‐1,3‐thia­zole ligand and the Cl atoms. The intermolecular separation of 3.425 (1) Å between parallel bi­thia­zole rings suggests there is a π–π interaction between them.     

Theoretical Investigating Mechanisms of Drug-Resistance Generated by Mutation-Induced Changes in Influenza Viruses

Influenza A (A/H\begin{document}$ x $\end{document}N\begin{document}$ y $\end{document}) is a significant public health concern due to its high infectiousness and mortality. Neuraminidase, which interacts with sialic acid (SIA) in host cells, has become an essential target since its highly conserved catalytic center structure, while resistance mutations have already generated. Here, a detailed investigation of the drug resistance mechanism caused by mutations was performed for subtype N9 (A/H7N9). Molecular dynamics simulation and alanine-scanning-interaction-entropy method (ASIE) were used to explore the critical differences between N9 and Zanamivir (ZMR) before and after R294K mutation. The results showed that the mutation caused the hydrogen bond between Arg294 and ZMR to break, then the hydrogen bonding network was disrupted, leading to weakened binding ability and resistance. While in wild type (A/H7N9\begin{document}$ ^{ \rm{WT}} $\end{document}), this hydrogen bond was initially stable. Meanwhile, N9 derived from A/H11N9 was obtained as an R292K mutation. Then the relative binding free energy of N9 with five inhibitors (SIA, DAN, ZMR, G28, and G39) was predicted, basically consistent with experimental values, indicating that the calculated results were reliable by ASIE. In addition, Arg292 and Tyr406 were hot spots in the A/H11N9\begin{document}$ ^{ \rm{WT}} $\end{document}-drugs. However, Lys292 was not observed as a favorable contributing residue in A/H11N9\begin{document}$ ^{ \rm{R292K}} $\end{document}, which may promote resistance. In comparison, Tyr406 remained the hotspot feature when SIA, ZMR, and G28 binding to A/H11N9\begin{document}$ ^{ \rm{R292K}} $\end{document}. Combining the two groups, we speculate that the resistance was mainly caused by the disruption of the hydrogen bonding network and the transformation of hotspots. This study could guide novel drug delivery of drug-resistant mutations in the treatment of A/H\begin{document}$ x $\end{document}N9.     

气相色谱与串联质谱联用检测血清中脱氢表雄酮

在晚期前列腺癌雄激素全阻断治疗最终导致前列腺癌雄激素非依赖性的转变过程中,肾上腺分泌脱氢表雄酮(DHEA)被认为是重要的诱因。本研究主要利用睾丸摘除(去势)大鼠模型,对血清中DHEA浓度进行测定。采用了气相色谱与串联质谱联用(GC-MS/MS)技术,建立了高灵敏度的测定大鼠血清中脱氢表雄酮(DHEA)的方法。样品经过甲醇沉蛋白,而后固相萃取提取血清中微量的DHEA,通过七氟丁酸酐(HF-BA)衍生,采用GC-MS/MS测定。对固相萃取条件、衍生化条件以及质谱测定条件进行优化。DHEA在0.1~100μg/L范围内线性良好,相关系数r为0.9996;在2~50μg/L浓度范围内,加标回收率在99%~106%之间;相对标准偏差小于5%。本方法灵敏度高,选择性好,可满足临床对于血清样品中DHEA的测定要求。对去势大鼠血清中DHEA测定结果表明,去势后DHEA明显上升。     

金属氧化物在蛋白质组学研究中的应用

本文对近年来金属氧化物在蛋白质组学研究中发挥的作用进行了综述。重点介绍了该类化合物在蛋白质样品富集、固定化酶反应器、生物传感器和生物移植材料等方面的应用,并展望了其在蛋白质组学研究中的发展前景。