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.     

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.     

A Highly Sensitive,Reversible, and Bidirectional Humidity Actuator by Calcium Carbonate Ionic Oligomers Incorporated Poly(Vinylidene Fluoride)

Sensitivity and multi-directional motivation are major two factors for developing optimized humidity-response materials, which are promising for sensing, energy production, etc. Organic functional groups are commonly used as the water sensitive units through hydrogen bond interactions with water molecules in actuators. The multi-coordination ability of inorganic ions implies that the inorganic ionic compounds are potentially superior water sensitive units. However, the particle forms of inorganic ionic compounds produced by classical nucleation limit the number of exposed ions to interact with water. Recent progress on the inorganic ionic oligomers has broken through the limitation of classical nucleation, and realized the molecular-scaled incorporation of inorganic ionic compounds into an organic matrix. Here, the incorporation of hydrophilic calcium carbonate ionic oligomers into hydrophobic poly(vinylidene fluoride) (PVDF) is demonstrated. The ultra-small calcium carbonate oligomers within a PVDF film endow it with an ultra-sensitive, reversible, and bidirectional response. The motivation ability is superior to other bidirectional humidity-actuators at present, which realizes self-motivation on an ice surface, converting the chemical potential energy of the humidity gradient from ice to kinetic energy.     

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.     

Enhanced the photocatalytic activity of B–C–N–TiO2 under visible light:Synergistic effect of element doping and Z-scheme interface heterojunction constructed with Ag nanoparticles

In order to enhance the photocatalytic activity of TiO₂ under visible light, Ag nanoparticles were introduced into tridoped B–C–N–TiO₂ (TT) catalyst by photoreduction deposition. Ag/B–C–N–TiO₂ (ATT) catalysts with the functions of reducing band gap and carrier recombination were prepared. At the same time, the effect of the amount of Ag on the photocatalytic performance of ATT catalyst was investigated. Through XRD, XPS, PL and other characterization methods, the (211)/(101)/Ag interface heterojunction mechanism similar to the traditional Z-scheme heterojunction was proposed. The intervention of Ag nanoparticles changed the P–N interface heterojunction between (211)/(101) to the (211)/(101)/Ag Z-scheme interface heterojunction. The results show that ATT catalyst exhibits the highest photocatalytic activity when the molar amount of Ag is 0.005% with the MB degradation rate of the ATT catalyst (0.01707 min^?1), which is 14.59 times of TiO₂ (0.00117 min^?1) and 2.02 times of TT (0.00847 min^?1). In addition, the four cycles efficiencies of ATT for MB degradation were all above 94.00%.This study reveals the possibility of construction of Z-scheme heterojunctions between precious metal nanoparticles and different interfaces of TiO₂, and provides a reference for the construction of Z-scheme interface heterojunctions.     

CaDHN3, a Pepper (Capsicum annuum L.) Dehydrin Gene Enhances the Tolerance against Salt and Drought Stresses by Reducing ROS Accumulation

Dehydrins (DHNs) play an important role in abiotic stress tolerance in a large number of plants, but very little is known about the function of DHNs in pepper plants. Here, we isolated a Y₁SK₂-type DHN gene “CaDHN3” from pepper. To authenticate the function of CaDHN3 in salt and drought stresses, it was overexpressed in Arabidopsis and silenced in pepper through virus-induced gene silencing (VIGS). Sub-cellular localization showed that CaDHN3 was located in the nucleus and cell membrane. It was found that CaDHN3-overexpressed (OE) in Arabidopsis plants showed salt and drought tolerance phenotypic characteristics, i.e., increased the initial rooting length and germination rate, enhanced chlorophyll content, lowered the relative electrolyte leakage (REL) and malondialdehyde (MDA) content than the wild-type (WT) plants. Moreover, a substantial increase in the activities of antioxidant enzymes; including the superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX), and lower hydrogen peroxide (H₂O₂) contents and higher O₂^•− contents in the transgenic Arabidopsis plants. Silencing of CaDHN3 in pepper decreased the salt- and drought-stress tolerance, through a higher REL and MDA content, and there was more accumulation of reactive oxygen species (ROS) in the CaDHN3-silenced pepper plants than the control plants. Based on the yeast two-hybrid (Y2H) screening and Bimolecular Fluorescence Complementation (BiFC) results, we found that CaDHN3 interacts with CaHIRD11 protein in the plasma membrane. Correspondingly, the expressions of four osmotic-related genes were significantly up-regulated in the CaDHN3-overexpressed lines. In brief, our results manifested that CaDHN3 may play an important role in regulating the relative osmotic stress responses in plants through the ROS signaling pathway. The results of this study will provide a basis for further analyses of the function of DHN genes in pepper.     

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.     

Non-Platinum Group Metal Electrocatalysts toward Efficient Hydrogen Oxidation Reaction

Developing non-platinum group metal (non-PGM) electrocatalysts for the hydrogen oxidation reaction (HOR) represents the efforts towards the more economical use of hydrogen fuel cells and hydrogen energy, which has attracted tremendous attention recently. However, non-PGM electrocatalysts for the HOR are still in their early development stages as compared with the significant advances in those for the oxygen reduction reaction and hydrogen evolution reaction. Herein, this paper summarizes the recent progresses and highlights the key challenges for the rational design of non-PGM electrocatalysts, aiming to promote the development of non-PGM HOR electrocatalysts. Fundamental understandings of the HOR mechanism are firstly reviewed, where theoretical interpretations on the low HOR kinetics in alkaline media, including the hydrogen binding energy theory, the bifunctional mechanism, and the water molecule reorganization, are particularly discussed. Subsequently, progresses of typical non-PGM HOR electrocatalysts in acid and alkaline media are summarized separately. For the HOR under alkaline conditions, the superiorities and challenges of Ni-based catalysts are discussed with a particular focus as they are the most promising non-PGM electrocatalysts. Finally, this paper highlights the challenges and provide perspectives on the future development directions of non-PGM HOR electrocatalysts.