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11.
Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
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. 相似文献
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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. 相似文献
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四川盆地上三叠统划分对比研究 总被引:36,自引:6,他引:30
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。 相似文献
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泥化软化性F_5断层是故县大坝坝基范围内最大的一条断层,位于左岸,对左坝肩的稳定极为不利,采用水泥灌浆处理无效,故改用化学灌浆处理。选用EAA化学浆材,采用“优选组合配方综合施灌”的创新施工工艺,效果良好,为今后低渗透性复杂的泥化软化性断层的防渗加固处理,提供了新的依据和途径。 相似文献
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Wangcun JiaHuihe Qiu 《International Journal of Heat and Mass Transfer》2002,45(20):4141-4150
The phenomenon of droplets impacting and evaporating on a hot surface is of interest in many areas of engineering. Quantitative measurement of these processes provides great help to reveal the physics behind. A novel technique was developed to quantitatively measure the volume evolution and contact diameter of an evaporating microdroplet on a hot surface utilizing interference fringe scattering method. In this method, fine fringes produced by the interference of two coherent laser beams was scattered by the droplet and projected onto a screen. The profile and volume of the droplet can be derived from the spatial fringe spacing on the screen. The number of total fringes measurable on the screen was used to determine the instantaneous contact diameter of the microdroplet. Validation experiments demonstrated that the measurement errors are less than ±5% and ±1% for microdroplet volume and contact diameter, respectively. By using this method, the dynamic of droplet impingement, evaporation and boiling using ethanol, pure water and water solution of a surfactant (sodium dodecyl sulfate) with impact velocity of 7.5 m/s and diameters ranged from 0.19 to 0.46 mm were investigated. 相似文献
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中国珠宝销售的可持续发展 总被引:2,自引:1,他引:1
通过对改革开放20多年来中国珠宝业发展的回顾与分析, 认为在激烈的市场竞争中, 珠宝业要达到可持续发展必须具备6个要素: (1)敬业精神; (2)信用意识; (3)创新意识和创新能力; (4)激励机制和团队精神; (5)资本营运和资源整合能力; (6)关系营销技巧. 相似文献
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