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.     

Effects of Different Short-Term UV-B Radiation Intensities on Metabolic Characteristics of Porphyra haitanensis

The effects of ultraviolet (UV) radiation, particularly UV-B on algae, have become an important issue as human-caused depletion of the protecting ozone layer has been reported. In this study, the effects of different short-term UV-B radiation on the growth, physiology, and metabolism of Porphyra haitanensis were examined. The growth of P. haitanensis decreased, and the bleaching phenomenon occurred in the thalli. The contents of total amino acids, soluble sugar, total protein, and mycosporine-like amino acids (MAAs) increased under different UV-B radiation intensities. The metabolic profiles of P. haitanensis differed between the control and UV-B radiation-treated groups. Most of the differential metabolites in P. haitanensis were significantly upregulated under UV-B exposure. Short-term enhanced UV-B irradiation significantly affected amino acid metabolism, carbohydrate metabolism, glutathione metabolism, and phenylpropane biosynthesis. The contents of phenylalanine, tyrosine, threonine, and serine were increased, suggesting that amino acid metabolism can promote the synthesis of UV-absorbing substances (such as phenols and MAAs) by providing precursor substances. The contents of sucrose, D-glucose-6-phosphate, and beta-D-fructose-6-phosphate were increased, suggesting that carbohydrate metabolism contributes to maintain energy supply for metabolic activity in response to UV-B exposure. Meanwhile, dehydroascorbic acid (DHA) was also significantly upregulated, denoting effective activation of the antioxidant system. To some extent, these results provide metabolic insights into the adaptive response mechanism of P. haitanensis to short-term enhanced UV-B radiation.     

An approach to measure infill matric suction of irregular infilled rock joints under constant normal stiffness shearing

Rock joints infilled with sediments can strongly influence the strength of rock mass. As infilled joints often exist under unsaturated condition, this study investigated the influence of matric suction of infill on the overall joint shear strength. A novel technique that allows direct measurement of matric suction of infill using high capacity tensiometers (HCTs) during direct shear of infilled joints under constant normal stiffness (CNS) is described. The CNS apparatus was modified to accommodate the HCT and the procedure is explained in detail. Joint specimens were simulated by gypsum plaster using three-dimensional (3D) printed surface moulds, and filled with kaolin and sand mixture prepared at different water contents. Shear behaviours of both planar infilled joints and rough joints having joint roughness coefficients (JRCs) of 8–10 and 18–20 with the ratios of infill thickness to asperity height (t/a) equal to 0.5 were investigated. Matric suction shows predominantly unimodal behaviour during shearing of both planar and rough joints, which is closely associated with the variation of unloading rate and volumetric changes of the infill material. As expected, two-peak behaviour was observed for the rough joints and both peaks increased with the increase of infill matric suction. The results suggest that the contribution of matric suction of infill on the joint peak normalised shear stress is relatively independent of the joint roughness.     

Bearing Failure Optimization of Composite Double-Lap Bolted Joints Based on a Three-Step Strategy Marked By Feasible Region Reduction and Model Decoupling

To minimize the mass and increase the bearing failure load of composite doublelap bolted joints, a three-step optimization strategy including feasible region reduction, optimization model decoupling and optimization was presented. In feasible region reduction, the dimensions of the feasible design region were reduced by selecting dominant design variables from numerous multilevel parameters by sensitivity analyses, and the feasible regions of variables were reduced by influence mechanism analyses. In model decoupling, the optimization model with a large number of variables was divided into various sub-models with fewer variables by variance analysis. In the third step, the optimization sub-models were solved one by one using a genetic algorithm, and the modified characteristic curve method was adopted as the failure prediction method. Based on the proposed optimization method, optimization of a double-lap single-bolt joint was performed using the ANSYS^® code. The results show that the bearing failure load increased by 13.5% and that the mass decreased by 8.7% compared with those of the initial design of the joint, which validated the effectiveness of the three-step optimization strategy.     

Preparation and the effects of ion irradiation on bulk SiOC ceramics

Bulk SiOC ceramics were prepared by spark plasma sintering of polymer-derived SiOC powders, and the effects of ion irradiation on their microstructures and properties were investigated in detail. High sintering temperature was conducive to low open porosity, high bulk density, nucleation and growth of β-SiC nanodomains, and graphitization of free carbon clusters in the SiOC ceramics. Ordering of the nanodomanins is beneficial for improving hardness and modulus of the ceramics. After 70 keV He ion irradiations, the β-SiC nanocrystals and graphitic clusters were partially amorphized, and their average grain size decreased by 13.6% and 50.9%, respectively. But no bubbling or peeling occurred on the irradiated sample surface, the hardness and modulus barely changed, indicating the SiOC ceramics are promising as radiation-tolerant materials.     

Regulating the Interfacial Electronic Coupling of Fe2N via Orbital Steering for Hydrogen Evolution Catalysis

The capability of manipulating the interfacial electronic coupling is the key to achieving on-demand functionalities of catalysts. Herein, it is demonstrated that the electronic coupling of Fe₂N can be effectively regulated for hydrogen evolution reaction (HER) catalysis by vacancy-mediated orbital steering. Ex situ refined structural analysis reveals that the electronic and coordination states of Fe₂N can be well manipulated by nitrogen vacancies, which impressively exhibit strong correlation with the catalytic activities. Theoretical studies further indicate that the nitrogen vacancy can uniquely steer the orbital orientation of the active sites to tailor the electronic coupling and thus benefit the surface adsorption capability. This work sheds light on the understanding of the catalytic mechanism in real systems and could contribute to revolutionizing the current catalyst design for HER and beyond.     

从“流动的现代性”到“液态时尚”

本文主要通过齐格蒙·鲍曼的社会学著作《流动的现代性》(Liquid Modernity),讨论当代社会生活特性,并援引了原著中“Liquid”,即“液态、流动的”这一形容词,提出“液态时尚”这一与“流动的现代性”相适应的时尚概念。通过对“液态时尚”设计案例的分类分析,思考“液态时尚”在当代的社会意义和价值。