Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95

Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by ¹H,¹⁵N HSQC NMR to bind in the small hydrophobic P⁰ pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.     

基于发展科学探究能力的高中化学教学实践 ——以"元素周期律"章节为例

基于学生在学习元素周期律时存在的普遍问题改进了教学实践,分析了元素周期律发展学生科学探究能力的价值,设计了四个教学环节——趣味导入,成果展示;分析规律,做出猜想;设计方案,收集证据;梳理模型,迁移应用,并提出了三点针对学生探究能力发展的教学建议.     

Chemical durability and surface alteration of lanthanide zirconates (A2Zr2O7: A = La-Yb)

Chemical durability of lanthanide zirconates (A₂Zr₂O₇) (A = La-Yb) under near-field environments is important for evaluating their application as potential nuclear waste forms. In this work, A₂Zr₂O₇ (A = La-Yb) are synthesized by spark plasma sintering with controlled microstructure and their chemical durability are evaluated in a nitric acid solution (pH = 1). Scanning transmission electron microscopy analysis reveals an amorphous passivation film either enriched with Zr or lanthanide. The complex chemistry of the passivation films can be correlated with a transition in corrosion mechanisms from a preferential release of lanthanide in La₂Zr₂O₇ to a preferential release of Zr in Er₂Zr₂O₇ and Yb₂Zr₂O₇. These results suggest a dominant mechanism of incongruent dissolution and surface reorganization for the formation of passivation films. Strong correlations are identified between the leaching rates and cation ionic size, ionic potential, electronegativity differences between A-site cation and Zr, and bonding valence sum of oxygen, suggesting important impacts of structural and bonding characteristics in controlling chemical durability of lanthanide zirconates.     

圆型限制性三体问题的动力学特征

禁行域在圆型限制性三体问题中对第三体的运动有极为重要的影响. 利用零速度曲线讨论天体禁行域与系统参数之间的关系. 禁行域与雅可比常数有关，且能影响天体的运动区域和轨道构型. 利用最大李雅普诺夫指数寻找该模型的混沌轨道，给出混沌轨道在不同系统参数下随天体初始位置的分布. 这些分布说明，当第三天体从两主天体连线的中点处释放时，容易产生混沌运动；当质量参量足够小时，体系无法产生混沌现象.     

PUL-Mediated Plant Cell Wall Polysaccharide Utilization in the Gut Bacteroidetes

Plant cell wall polysaccharides (PCWP) are abundantly present in the food of humans and feed of livestock. Mammalians by themselves cannot degrade PCWP but rather depend on microbes resident in the gut intestine for deconstruction. The dominant Bacteroidetes in the gut microbial community are such bacteria with PCWP-degrading ability. The polysaccharide utilization systems (PUL) responsible for PCWP degradation and utilization are a prominent feature of Bacteroidetes. In recent years, there have been tremendous efforts in elucidating how PULs assist Bacteroidetes to assimilate carbon and acquire energy from PCWP. Here, we will review the PUL-mediated plant cell wall polysaccharides utilization in the gut Bacteroidetes focusing on cellulose, xylan, mannan, and pectin utilization and discuss how the mechanisms can be exploited to modulate the gut microbiota.     

Phase,domain, and microstructures in Sr2+ substituted low-temperature sintering PZT-based relaxor ferroelectrics

The Ag-Pd internal electrode of multilayer piezoelectric ceramics needs to be sintered below 1000°C, and lead wires and components need to be welded with lead-free solder at 260°C. PNN–PMW–PZT–xSr piezoelectric ceramics with high Curie temperature (T_c > 260°C) were synthesized at a low sintering temperature (960°C) to meet the requirements of multilayer piezoelectric devices. The relationship between structures (phase, domain, and microstructures) and electrical properties (piezo/ferroelectric properties, and dielectric relaxation) in the Sr²⁺ substituted ceramics was investigated. Rietveld refinement and Raman spectra show that Sr²⁺ substitution can cause the phase change and increase the force constant of [BO₆] octahedron. The piezoelectric response increases with increasing the content of the tetragonal phase (CTP) in the rhombohedral-tetragonal (R-T) coexisted ceramics. The ceramics with 0.6 mol% Sr²⁺ substitution have minimum activation energy for domain wall movement (E_a) of 0.0362 eV which favors the formation of nanometer-sized domains, and possess excellent electrical properties (d₃₃ = 623 pC/N, d₃₃^* =783 pm/V, T_c =295°C). The higher the CTP, the lower the E_a. The lower E_a favors the rotation of polarization direction and extension, and is beneficial to the generation of the nanometer-size domains, resulting in high piezoelectric properties.     

基于智能建造的某大型安置房项目安全管理方法应用

某大型安置房项目施工中,应用智能建造包含的综合管理平台技术、5G传输技术、无人塔式起重机智能安装技术、智能机器人和区块链技术,降低了安全风险,提高了安全管理水平.     

一起发电机定子接地故障的分析与处理

文章介绍了海外某大型火力发电厂发生的一起发电机定子接地故障的分析和处理过程,对发电厂类似故障的处理和海外发电厂的运行和维护提供了参考。     

乘用车悬架静强度与疲劳载荷研究

为了快速获得平台悬架静强度与疲劳载荷,本文依据某A级平台5款量产车型试验场道路栽荷数据,以前麦弗逊悬架为研究对象,先对轮心载荷幅值进行统计分析,根据应力-强度干涉模型,得到该平台前悬架的强度载荷边界,及其与车辆满载轮荷的G载荷系数.再通过研究5款车型车轮轮心疲劳伪损伤与轮荷的关联关系,得到该平台悬架的疲劳栽荷.此方法可快速获得同平台悬架静强度与疲劳载荷,省去实车道路谱采集并提升了工作效率.     

Enzyme-Activated Prodrug-Based Smart Liposomes Specifically Enhance Tumor Hemoperfusion with Efficient Drug Delivery to Pancreatic Cancer Cells and Stellate Cells

Tumor-specific enhanced delivery of chemotherapeutics and modulators to tumor cells and activated pancreatic stellate cells (aPSCs), respectively, represents safer and more effective therapy for pancreatic cancer. Herein, a membrane type 1-matrix metalloproteinase (MT1-MMP)-cleavable spacer is used to assemble low-density cRGDfK onto thermosensitive liposomes loaded with phosphorylated calcipotriol (PCAL) and doxorubicin (DOX), yielding MR-T-PD. The liposome-linked cRGDfK prodrug on MR-T-PD surface is first activated by MT1-MMP, which is selectively expressed on tumor endothelial cells, to release cRGDfK. The free cRGDfK specifically promotes tumor angiogenesis, leading to 3.4-fold higher accumulation and a wider distribution of MR-T-PD in tumors. Furthermore, MR-T-PD rapidly releases PCAL and DOX into the interstitium under heat treatment. The released DOX enters tumor cells to induce apoptosis, whereas the PCAL prodrug is converted to CAL by alkaline phosphatase on the surface of aPSCs; CAL can then enter aPSCs to induce quiescence and promote the antitumor effect of DOX. Finally, by enhancing the exposure of DOX and CAL to tumor cells and aPSCs, respectively, in a tumor-specific manner, MR-T-PD exerts superior efficacy (a 5.9-fold decrease in tumor weight) without causing additional side effects. Overall, this prodrug-based smart liposome system represents a promising paradigm for pancreatic cancer therapy.