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.     

Effect of phosphogypsum on saline-alkalinity and aggregate stability of bauxite residue

A column experiment was conducted to investigate the effect of phosphogypsum (PG) on the saline- alkalinity, and aggregate stability of bauxite residue. Results showed that: with increasing leaching time, the concentrations of saline-alkali ions decreased while the concentration increased in bauxite residue leachate; compared with CK (control group) treatment, pH, electric conductivity (EC), exchangeable sodium percentage (ESP), sodium absorption ratio (SAR), and exchangeable Na⁺ content of bauxite residue were reduced following PG treatment; average particle sizes in aggregates following CK and PG treatments were determined to be 155 and 193 nm, respectively. SR-μCT test results also confirmed that bauxite residue following PG treatment acquired larger aggregates and larger pore diameter. These results indicate that the PG treatment could significantly modulate the saline-alkalinity, and simultaneously enhance aggregate stability of bauxite residue, which provides a facile approach to reclaim bauxite residue disposal areas.     

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.     

功能性小麦品种的概念、类别和发展前景（网络首发、推荐阅读）

结合全球倡导的营养导向型农业和功能性食品的内容，首次提出“功能性小麦品种”的概念，将其定义为“含有对人体健康有益的活性成分，可调节人体有益代谢，能给人体健康带来某种益处或满足特定人群的特殊需求，同时可以作为日常食物的口感正常、无毒副作用的小麦品种类型”；结合疫情警示和我国进入后工业时代后，人们需求必将由“吃得饱”、“吃得好”向“吃得健康”转变，因而提出继高产品种、优质品种之后培育“功能性小麦品种”的育种目标。根据多年关于小麦淀粉、蛋白、酯类和其他成分的功能研究结果，介绍新育成的“麦黄酮”、“高色素”、“高抗性淀粉”、“富锌”、“低醇溶蛋白”和“低植酸”等功能性小麦新品种（系）的营养特性和农艺产量状况；根据“健康中国2030”规划等国家战略，进行“功能性品种培育是解决我国功能性食品‘卡脖子’的关键基础，一种功能性品种可以形成一类功能性食品，多种功能性品种可以形成我国功能性面制品产业，推动我国整个食品工业的发展”的前景展望；根据功能性品种及其食品的稳定性和可靠性是产品和市场的“生命线”，从对消费者负责的高度，提出关于“功能性农作物品种审定导向和组建功能性成分检测机构；编制有关功能性品种和食品的国家或行业标准，设立功能性食品和功能性农作物品种的商业标志，保证我国功能性农作物品种及其食品健康发展”等方面的具体建议。     

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.     

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.     

Dual-phase rare-earth-zirconate high-entropy ceramics with glass-like thermal conductivity

A series of rare earth zirconates (RE₂Zr₂O₇) high-entropy ceramics with single- and dual-phase structure were prepared. Compared with La₂Zr₂O₇ and Yb₂Zr₂O₇, the smaller “rattling” ions (Yb³⁺, Er³⁺, Y³⁺) have been incorporated into pyrochlore lattice in (La_0.2Nd_0.2Y_0.2Er_0.2Yb_0.2)₂Zr₂O₇ (LNYEY) while larger ions (La³⁺, Nd³⁺, Sm³⁺, Eu³⁺) incorporated into fluorite lattice in (La_0.2Nd_0.2Sm_0.2Gd_0.2Yb_0.2)₂Zr₂O₇ (LNSGY). Due to high-entropy lattice distortion and resonant scattering derived from smaller ions Yb³⁺, Er³⁺, and Y³⁺, LNYEY shows a lower glass-like thermal conductivity (1.62-1.59 W m^-1 K^-1, 100-600℃) than LNSGY (1.74-1.75 W m^-1 K^-1, 100-600℃). Moreover, LNYEY and LNSGY exhibit enhanced Vickers’ hardness (LNYEY, H_v = 11.47 ± 0.41 GPa; LNSGY, H_v = 10.96 ± 0.26 GPa) and thermal expansion coefficients (LNYEY, 10.45 × 10^-6 K^-1, 1000℃; LNSGY, 11.02 × 10^-6 K^-1, 1000℃). These results indicate that dual-phase rare-earth-zirconate high-entropy ceramics could be desirable for thermal barrier coatings.     

Chemical bond characteristics and infrared reflectivity spectrum of a novel microwave dielectric ceramic CaIn2O4 with near-zero τf

Orthorhombic-structured CaIn₂O₄ ceramics with a space group Pca2₁ were synthesized via a solid-state reaction method. A high relative density (95.6 %) and excellent microwave dielectric properties (ε_r ～11.28, Qf = 74,200 GHz, τ_f ～ ?4.6 ppm/°C) were obtained when the ceramics were sintered at 1375 °C for 6 h. The dielectric properties were investigated on the basis of the Phillips–Van Vechten–Levine chemical bond theory. Results indicated that the dielectric properties were mainly determined by the InO bonds in the CaIn₂O₄ ceramics. These bonds contributed more (74.65 %) to the dielectric constant than the CaO bonds (25.35 %). Furthermore, the intrinsic dielectric properties of the CaIn₂O₄ ceramics were investigated via infrared reflectivity spectroscopy. The extrapolated microwave dielectric properties were ε_r ～10.12 and Qf = 112,200 GHz. Results indicated that ion polarization is the main contributor to the dielectric constant in microwave frequency ranges.