Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

High-Tg porous polyimide films with low dielectric constant derived from spiro-(adamantane-2,9′(2′,7′-diamino)-fluorene)

Porous polyimide (PI) films with low dielectric constants and excellent thermal properties have been a pressing demand for the next generation of high-performance, miniature, and ultrathin microelectronic devices. A series of novel porous PI films containing fluorenyl-adamantane groups were prepared successfully via thermolysis of poly(ethylene glycol) (PEG) added in the PI matrix. The cross-sectional morphologies of porous PI films showed closed pores with diameters ranging from 135 to 158 nm, which were uniform and regular in shape without interconnectivity. These porous PI films exhibited excellent thermal properties with a glass-transition temperature at 376 °C whereas the 5% weight loss temperature in air excess of 405 °C due to enhanced rigidity afforded by fluorenyl-adamantane groups. Accompanied by thermolysis content of PEG increasing from 0 to 20 wt %, the density of porous PI films decreased, and the corresponding porosity grew significantly from 0 to 11.48%. Depending on porosity, the dielectric constant and dielectric loss of porous PI films significantly declined from 2.89 to 2.37 and from 0.050 to 0.021, respectively. These excellent properties benefit the as-prepared porous PI films for application as interlayer dielectrics, integrated circuit chips, or multichip modules in microelectronic fields. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47313.     

四川盆地上三叠统划分对比研究

四川盆地上三叠统对比长期存在混乱，给盆地整体评价带来困难。通过岩石地层、地震地层、事件地层及高分辨率旋回地层等多种方法讨论了须家河组与香溪群各岩性段的对比关系，得出了全盆地上三叠统的对比关系；指出须四段底可近似看成等时界面；须家河组下部地层自西向东、向南逐层超覆在雷口坡组之上，上部地层在盆地西北部自东南向西北方向剥蚀层位渐次变老。文章建议四川盆地上三叠统废除“香溪群”，统一使用“须家河组”，以利于对全盆地上三叠统进行油气资源整体评价与深化研究。     

强捻棉纱针织产品的性能研究

通过对强捻棉纱针织产品进行服用性能测试，得出强捻纱织物具有良好的服用性能。     

企业虚拟人力资源管理面临的问题及对策分析

在对企业虚拟人力资源管理内涵及特征进行阐述的基础上，分析了虚拟人力资源在信息技术、时间和空间上的柔性特征，会对员工工作模式、员工职业生涯等方面产生影响，从而产生了诸如员工利益、企业安全、多头领导、有效沟通等问题，并提出了建议和对策。     

A decision support system for interactive decision making - Part II: analysis and output interpretation

For pt.I see ibid., p.42-55 (2003). The development of a comprehensive decision support system, GMCR II, for the systematic study of real-world interactive decision problems is presented. The companion paper (Part I), discusses how GMCR II elicits, stores, and manages conflict models; here (Part II), the focus is on GMCR IIs analysis and output interpretation subsystems. Specifically, this paper describes the powerful and efficient analysis engine contained in GMCR II, its informative output presentation and interpretation facilities, and a number of follow-up analyses. Furthermore, an illustrative case study is used to demonstrate how GMCR II can be conveniently applied in practice.     

300 m级高拱坝设计与施工三维可视化仿真研究

双曲拱坝的C2连续曲面的三维模型表达困难,以双曲拱坝函数方程为基础引入CATIA三维软件,实现交互式设计和分析。同时,完成双曲拱坝细部模型的基于规则的智能化设计。基于大坝详细设计的三维成果,利用组件技术对模型数据进行提取和利用,制定施工方案并进行施工方案的动态可视化仿真。     

热声制冷机及其改进实验研究

热声制冷作为一种很有前途的制冷方法，在国内外相关领域引起了极大兴趣。热声制冷机由声发生器、共振管、板叠及高、低温换热器等部分组成。对声驱动器的振动膜及其冷却系统、气体弹簧系统、高、低温换热器进行了初步改进，使制冷机冷端温降从原来的12℃提高到27℃左右，这是目前国内报道的最大温降。     

Al、Mo含量对铸造钛合金力学性能的影响

运用正交实验 ,考察了Al、Mo含量对Ti Al Mo 1Zr系铸造钛合金力学性能的影响。试验结果表明 :随Al、Mo含量提高 ,铸造合金的强度增加 ,塑性和冲击韧性降低 ,但Al、Mo的交互作用却使合金塑性提高 ,强度和冲击韧性降低     

像增强型夜视系统的图像信息传递

在分析了像增强夜视系统信息传递的基础上，指出像增强器输出端荧光屏至人眼的图像传递过程，构成了像增强夜视系统信息传递量的限制．提出了采用系统信息传递量作为夜视系统设计与评价的方法，利用这种方法可以发现在像增强器增益足以补偿光谱选道衰减的条件下，采用彩色像增强可以大幅度增加夜视系统传输的信息量．