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.     

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.     

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.     

高熵形状记忆合金的研究进展

高熵形状记忆合金是在等原子比NiTi合金的基础上,结合高熵合金的概念,逐渐发展起来的一种新型高温形状记忆合金。近年来,已开发出了综合性能优异的(TiZrHf)50(NiCoCu)50系和(TiZrHf)50(NiCuPd)50系高熵形状记忆合金,引起了广泛的关注和研究兴趣。本文从物相组成、微观组织、马氏体相变行为、形状记忆效应和超弹性等角度出发,综述了高熵形状记忆合金的研究进展,并对高熵形状记忆合金未来的研究重点进行了展望。     

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.     

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.     

Toward High-Performance Dihydrophenazine-Based Conjugated Microporous Polymer Cathodes for Dual-Ion Batteries through Donor–Acceptor Structural Design

Recent studies have demonstrated that dihydrophenazine (Pz) with high redox-reversibility and high theoretical capacity is an attractive building block to construct p-type polymer cathodes for dual-ion batteries. However, most reported Pz-based polymer cathodes to date still suffer from low redox activity, slow kinetics, and short cycling life. Herein, a donor–acceptor (D–A) Pz-based conjugated microporous polymer (TzPz) cathode is constructed by integrating the electron-donating Pz unit and the electron-withdrawing 2,4,6-triphenyl-1,3,5-triazine (Tz) unit into a polymer chain. The D–A type structure enhances the polymer conjugation degree and decreases the band gap of TzPz, facilitating electron transportation along the polymer skeletons. Therefore the TzPz cathode for dual-ion battery shows a high reversible capacity of 192 mAh g⁻¹ at 0.2 A g⁻¹ with excellent rate performance (108 mAh g⁻¹ at 30 A g⁻¹), which is much higher than that of its counterpart polymer BzPz produced from 1,3,5-triphenylbenzene (Bz) and Pz (148 and 44 mAh g⁻¹ at 0.2 and 10 A g⁻¹, respectively). More importantly, the TzPz cathode also shows a long and stable cyclability of more than 10 000 cycles. These results demonstrate that the D–A structural design is an efficient strategy for developing high-performance polymer cathodes for dual-ion batteries.     

Strong tribocatalytic dye degradation by tungsten bronze Ba4Nd2Fe2Nb8O30

The triboelectric effect has recently demonstrated its great potential in environmental remediation and even new energy applications for triggering a number of catalytic reactions by utilizing trivial mechanical energy. In this study, Ba₄Nd₂Fe₂Nb₈O₃₀ (BNFN) submicron powders were used to degrade organic dyes via the tribocatalytic effect. Under the frictional excitation of three PTFE stirring rods in a 5 mg/L RhB dye solution, BNFN demonstrates a high tribocatalytic degradation efficiency of 97% in 2 h. Hydroxyl radicals (?OH) and superoxide radicals (?O₂－) were also detected during the catalysis process, which proves that triboelectric energy stimulates BNFN to generate electron-hole pairs. The tribocatalysis of tungsten bronze BNFN submicron powders provides a novel and efficient method for the degradation of wastewater dye by utilizing trivial mechanical energy.     

Hydrodynamics study of a fast liquid–liquid oxidation process with in situ gas production in microreactors

Hydrodynamics characteristics of a fast and highly exothermic liquid–liquid oxidation process with in situ gas production in microreactors were studied using a newly developed experimental method. In the adipic acid synthesis through the K/A oil (the mixture of cyclohexanol and cyclohexanone) oxidation with nitric acid, bubble generation modes were divided into four categories. The gas production became more intensive, unstable, even explosive with increasing the oil phase feed rate and the temperature. A novel automatic image processing method was developed to monitor the instantaneous velocity online by tracking the gas–liquid interface. The axial velocity at the same location was unstable due to the changing gas production rate. Furthermore, the actual residence time was obtained easily with being only 36% of the space–time minimally, beneficial for establishing accurate kinetics and mass transfer models with time participation. Finally, an empirical correlation was developed to predict the actual residence time under different conditions.