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.     

Synthesis of nanopowders with low agglomeration by elaborating Φ values for producing Gd2O3-MgO nanocomposites with extremely fine grain sizes and high mid-infrared transparency

Refining ceramic microstructures to the nanometric range to minimize light scattering provides an interesting methodology for developing novel optical ceramic materials. In this work, we reported the fabrication and properties of a new nanocomposite optical ceramic of Gd₂O₃-MgO. The citric acid sol-gel combustion method was adopted to fabricate Gd₂O₃-MgO nanocomposites with fine-grain sizes, dense microstructures and homogeneous phase domains. Nanopowders with low agglomeration and improved sinterability can be obtained by elaborating Φ values. Further refining of the microstructure of the nanocomposites was achieved by elaborating the hot-pressing conditions. The sample sintered at 65 MPa and 1300 °C showed a quite high hardness value of 14.3 ± 0.2 GPa, a high transmittance of 80.3 %–84.7 % over the 3?6 μm wavelength range, due mainly to its extremely fine-grain size of Gd₂O₃ and MgO (93 and 78 nm, respectively) and high density.     

基于卓越工程师教育的频率特性分析课堂教学研究

频率特性分析在工程应用中具有重要的作用,在电路分析、模拟电子技术、信号与系统、自动控制理论等相关课程中都涉及到相关章节内容,在不同课程中如何根据工程应用和学生学习阶段把握具体的讲解内容和讲解方式非常重要。本文从频率特性的求解方法和具体物理意义角度开展在不同课程中讲解的方法,从时域和频域角度分别讨论其物理意义和具体的分析方法。通过渐进深化的教学过程和教学方法不断提高学生的知识掌握和应用技能,提高学生的工程意识、工程素质和工程创新能力,强化学生对于频率特性课程知识的综合应用能力。     

小型核桃脱壳分选一体机的设计

核桃不仅营养价值极高,而且核桃壳的药用价值也非常高,国内小企业和家庭在核桃硬壳脱壳加工环节,一般采用人工破壳取仁的方式,这种方式劳动强度大,人工成本高且不卫生;针对这个问题设计了一款小型的硬壳脱壳,壳仁分离分选的机器来提高生产效率,减少成本,提高收入。     

In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2^Mal, has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue GluCAB-1^Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) effect with a supportive role played by glucose metabolism. [⁶⁴Cu]Cu-GluCAB-2^Mal (99 % RCP) exhibited high serum stability with immediate binding to serum proteins. In vivo experiments for comparison between tumor targeting of [⁶⁴Cu]Cu-GluCAB-2^Mal and previous-generation [⁶⁴Cu]Cu-GluCAB-1^Mal encompassed microPET/CT imaging and biodistribution analysis in an allograft E0771 breast cancer mouse model. Tumor uptake of [⁶⁴Cu]Cu-GluCAB-2^Mal was clearly evident with twice as much accumulation as compared to its predecessor and a tumor/muscle ratio of up to 5 after 24 h. Further comparison indicated a decrease in liver accumulation for [⁶⁴Cu]Cu-Glu-CAB-2^Mal.     

Achieving fabrication of highly transparent Y2O3 ceramics via air pre-sintering by deionization treatment of suspension

An easy albeit quite effective deionization suspension treatment was adopted to alleviate the detrimental effects related to the hydrolysis of Y₂O₃ in an aqueous medium. Fabrication of highly transparent Y₂O₃ ceramics with a fine grain size via air pre-sintering and post–hot isostatic pressing (HIP) treatment without using any sintering additive was achieved using the treated suspensions. The hydrolysis issue of Y₂O₃ powder in an aqueous medium was effectively alleviated by using deionization treatment, and a well-dispersed suspension with a low concentration of dissolved Y³⁺ species was obtained. The dispersed suspensions were consolidated by the centrifugal casting method, and the green bodies derived from the suspension of 35.0 vol% solid loading showed an improved homogeneity with a relative density of 52.1%. Fully dense Y₂O₃ transparent ceramic with high transparency was obtained by pre-sintering consolidated green compacts at a low temperature of 1400°C for 16 h in air followed by a post-HIP treatment at 1550°C for 2 h under 200 MPa pressure. The sample had a fine average grain size of 690 nm. The in-line transmittance of the sample reached 83.3% and 81.8% at 1100 nm and 800 nm, respectively, very close to the theoretical values of Y₂O₃.     

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。     

Microstructure induced ultra-high energy storage density coupled with rapid discharge properties in lead-free Ba0.9Ca0.1Ti0.9Zr0.1O3–SrNb2O6 ceramics

Novel lead-free (1-x)Ba_0·9Ca_0·1Ti_0·9Zr_0·1O₃-xSrNb₂O₆ ceramics were synthesized via a two-step high energy ball milling process. The evolution of microstructural properties, phase transformation, and energy storage characteristics was comprehensively investigated to assess the applicability of material in multi-layered ceramic capacitors. The substitution of SrNb₂O₆ (SNO) in Ba_0·9Ca_0·1Ti_0·9Zr_0·1O₃ (BTCZ) has resulted in substantial improvement in materials density along with a small increase in the grain size of the synthesized ceramic. A thorough microstructural investigation indicates an excellent dispersibility and compatibility between BTCZ and SNO phases. With an increase in SNO substitution, a transition from typical ferroelectric to relaxor ferroelectric has been observed, which has led to a significantly slimmer ferroelectric loop along with frequency dispersive dielectric properties. The optimized composition (i.e., x = 0.10) exhibits an ultra-high recoverable energy density of 2.68 J/cm³ along with a moderately high energy efficiency of 83.4%. Further, SNO substituted samples have also shown an enhancement in breakdown strength. The improvement in energy storage performance and breakdown strength of SNO substituted BTCZ composites are mainly attributed to relatively homogeneous grain morphology, optimum grain size, microstructural density, and improved grain boundary interface.     

Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB ( 1 ). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.