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.     

基于光谱分类模型的保险杠物证无损研究

采用中红外光谱结合化学计量学的方法对车用保险杠碎片进行鉴别，分别对52个车用保险杠碎片样本的全波段光谱数据、指纹区光谱数据和主成分分析降维后的光谱数据建立Fisher判别分析和K近邻算法2种分类模型，并对分类结果进行比较。结果表明，主成分分析提取特征变量后构建的分类模型，分类的准确率更高，对聚丙烯（PP）、PP/滑石粉、PP/滑石粉/碳酸钙（CaCO₃）3种类型的样本分类准确率达到92.3 %，对PP/滑石粉类型中的10种品牌样本分类准确率达到88.9 %，分类结果理想；在构建的2种分类模型中，Fisher判别分析模型的分类率远高于K近邻算法模型，分析认为K近邻算法模型受到样本不均衡的影响；中红外光谱结合化学计量学可以实现对车用保险杠碎片的准确区分，且满足快速、无损的检验要求。     

Monoclonal antibody‐targeted polymeric nanoparticles for cancer therapy – future prospects

Although combination therapy for cancer utilising monoclonal antibodies in conjunction with chemotherapeutic drugs has resulted in increases in 5 year survivals, there nevertheless remains significant morbidity and mortality associated with systemic delivery of cytotoxic drugs. The advent of living radical polymerisation has resulted in complex and elegant nanoparticle structures that can be engineered to passively target a drug payload for cancer treatment. This presents a therapeutic modality whereby biodistribution and consequently systemic toxicity can be reduced, while focusing drug delivery to the tumour site. Nanoparticle delivery can be enhanced by attachment of a targeting monoclonal antibody fragment to facilitate tumour cell uptake through endocytosis, and so increase therapeutic efficacy. In this way, monoclonal antibodies can be supercharged by carrying a payload consisting of a cocktail of conventional chemotherapeutic drugs and siRNA. This review will focus on antibody‐targeted polymeric nanoparticles to cancer cells, and methods and technologies for synthesising such antibody‐targeted nanoparticles. The review is confined to polymeric‐based nanoparticles as these offer some advantages over liposomal nanoparticles and may circumvent some of the pitfalls in nanomedicine. Development of these antibody based polymeric nanoparticles and future directions for therapy are highlighted in this review. © 2014 Society of Chemical Industry     

Inhibitory Monoclonal Antibodies and Their Recombinant Derivatives Targeting Surface-Exposed Carbonic Anhydrase XII on Cancer Cells

Monoclonal and recombinant antibodies are widely used for the diagnostics and therapy of cancer. They are generated to interact with cell surface proteins which are usually involved in the development and progression of cancer. Carbonic anhydrase XII (CA XII) contributes to the survival of tumors under hypoxic conditions thus is considered a candidate target for antibody-based therapy. In this study, we have generated a novel collection of monoclonal antibodies (MAbs) against the recombinant extracellular domain of CA XII produced in HEK-293 cells. Eighteen out of 24 MAbs were reactive with cellular CA XII on the surface of live kidney and lung cancer cells as determined by flow cytometry. One MAb 14D6 also inhibited the enzymatic activity of recombinant CA XII as measured by the stopped-flow assay. MAb 14D6 showed the migrastatic effect on human lung carcinoma A549 and renal carcinoma A498 cell lines in a ‘wound healing’ assay. It did not reduce the growth of multicellular lung and renal cancer spheroids but reduced the cell viability by the ATP Bioluminescence assay. Epitope mapping revealed the surface-exposed amino acid sequence (35-FGPDGENS-42) close to the catalytic center of CA XII recognized by the MAb 14D6. The variable regions of the heavy and light chains of MAb 14D6 were sequenced and their complementarity-determining regions were defined. The obtained variable sequences were used to generate recombinant antibodies in two formats: single-chain fragment variable (scFv) expressed in E. coli and scFv fused to human IgG1 Fc fragment (scFv-Fc) expressed in Chinese Hamster Ovary (CHO) cells. Both recombinant antibodies maintained the same specificity for CA XII as the parental MAb 14D6. The novel antibodies may represent promising tools for CA XII-related cancer research and immunotherapy.     

放顶煤开采顶煤裂隙分布与块度的相关研究

用实测构造裂隙分布和发育程度及其与工作面布置关系，研究其对顶煤破碎冒落块度特征和顶煤采出率的影响。根据裂隙组数、方位及发育程度，选择相适应的工作面布置，能改善顶煤冒放性，即组数多、间距小、匹配合理，则冒块越小，冒放性越好。     

Fragility analysis for ballistic design

Effective structural design to resist ballistic effects such as small arms or fragmenting weapons has been a goal since weapons were developed. Approaches currently in use for ballistic design are predominantly deterministic and allow designers to decide what wall thickness should be used to stop a prescribed projectile impacting at a predefined velocity. The research presented in this paper provides a framework for conducting reliability analysis of structures subjected to bullet and fragment demands. Thus, pseudo-fragility curves are developed for the limit states related to spall and perforation of wall panels, residual velocities of bullets and fragments, and injury to personnel. The pseudo-fragility analysis provides engineers and owners with a tool to quickly assess the reliability of a wall system subjected to high velocity, low mass projectiles. In particular, the proposed analysis method allows designers and owners to determine the probability of spall and perforation, residual velocity, and injury as a function of wall thickness or threat standoff distance.

Abbreviations: Cumulative distribution function (CDF): Gives the probability that a stochastic variable ‘X’, with a proper probability density function, is equal to or less than a value (x). Coefficient of variation (COV): The quotient of the standard deviation and the mean     

从池州孝肃街的保护更新规划探讨"历史风貌片段"

从“城市发展”与“历史碎片”的碰撞中引发出对于“历史风貌片段”的探讨。文中具体以池州市教肃街保护更新研究为例，讨论了历史风貌片段保护与发展的现状、意义、原则与方法，并初步提出了保护与改造的一些具体的方法和途径。     

油气井用隔板起爆器的起爆能力

为了提高油气井用隔板起爆器的起爆能力,在传统隔板起爆器的基础上,改变了其受主装药盲孔的几何结构和受主装药结构,设计出一种油气井用隔板起爆器,并对其进行了起爆能力的实验研究.实验结果显示,油气井用隔板起爆器起爆油气井耐温传爆管的最大空气隙距离为85 mm,而传统隔板起爆器和油气井耐温传爆管分别为20 mm和65 mm,因...     

含能破片战斗部毁伤效应研究

为提高战斗部的毁伤效能,对含能破片战斗部开展了探索研究,介绍了含能破片战斗部的概念和特点,设计制备了AI/PTFE(聚四氟乙烯)质量比为30∶70配方的含能破片战斗部,对2.5,10,20 mm钢质靶进行侵彻实验,研究了该含能破片对靶板侵彻能力及靶后毁伤效率.试验结果表明:50 mm口径含能破片战斗部穿透了20 mm厚...     

钨破片侵彻舰艇装甲薄弱部位毁伤效能评估

模拟了末端制导反舰导弹在侵彻舰艇装甲时末制导弹爆炸模型,得出破片飞行的初速度,再通过 ANSYS/LS-DYNA进行不同速度和质量及形状的钨合金破片侵彻装甲薄弱部位的数值模拟,得出高速自锻破片能够对装甲毁坏,但会使装甲出现反弹,侵彻深度不及中等速度破片;尖头破片出现较大应力集中,未到侵彻深度会使破片破坏;得到毁坏薄装甲的最小破片质量,为薄弱装甲防护提供了参考。