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.     

Operating Range Scheduled Robust Dahlin Algorithm to Typical Industrial Process with Input Constraint

International Journal of Control, Automation and Systems - There is a class of typical nonlinear industrial process, which can be characterized by a first-order inertia plus pure delay model in an...     

刘家山排土场滑坡治理措施

刘家山排土场为民采排弃形成，已经出现大规模滑坡。为了保证上下游生产生活设施的安全，依据现场实际情况，结合现场调查，提出了削坡处理的方案。经过治理后，刘家山排土场平稳地渡过了雨季，目前处于稳定状态，达到了治理目的。     

Unsteady free convection of second‐grade nanofluid with a new time‐space fractional heat conduction

The Caputo and Caputo–Fabrizio derivative are applied to study a second‐grade nanofluid over a vertical plate. A comparative analysis is presented to study the unsteady free convection of a second‐grade nanofluid with a new time–space fractional heat conduction. The governing equations with mixed time–space fractional derivatives are non‐dimensionalized and solved numerically, and a comparison between the Caputo and the Caputo–Fabrizio models is made. It is found that the temperature is higher for the Caputo–Fabrizio fractional model than the Caputo model, but the higher velocity only exists near the vertical plate for the Caputo–Fabrizio model than the Caputo model. Moreover, the velocity for the Caputo model will exceed the Caputo–Fabrizio model as y evolves.     

AD HOC网络管理综述

由于AD HOC网络自身的特点，其网络管理很多方面与固定网络不同，如移动性管理和体系结构管理等。讨论了AD HOC网络管理的各个方面，并列举了各个方面的设计思路和已有的相关算法的简介。     

聚烯烃催化剂硅胶载体的制备和表征

采用并流共沉淀法制备了适用于聚烯烃催化剂的硅胶载体,为减少颗粒的聚集,在制备过程中添加一种表面活性剂。利用透射电子显微镜(TEM)、比表面积测定(BET)和X射线粉末衍射(XRD)法对制备的硅胶载体进行了表征;考察了在制备硅胶载体过程中原料硅酸钠溶液的浓度、溶液pH以及焙烧温度对产物硅胶载体的物理性能的影响。实验结果表明,硅酸钠溶液的浓度影响硅胶的初始粒子的大小,溶液pH直接影响硅酸钠的水解速率,焙烧温度影响硅胶的孔结构和比表面积。当硅酸钠溶液的浓度为0．2mol／L、溶液pH为8-9、反应温度为70℃、焙烧温度为700℃时,硅胶载体的BET比表面积为242．22m2／g、最可几孔径为16．45 nm、堆密度为0．492 1g/mL,与进口硅胶(Silica Gel 955)的物理性能相近。     

用CPLD实现SRAM工艺FPGA的安全应用

提出了一种利用CPLD产生的伪随机码来加密SRAM工艺FPGA的方法,并详细介绍了具体的电路和VHDL代码。     

3G用户细分研究

对3G用户的细分方法及3G目标市场的定位进行了初步的研究，提出了3G用户细分的体系框架和3G目标市场定位的考虑要素及初步的定位建议。     

水驱前缘测试技术在复杂砂岩油藏中的应用

对平面剩余油分布的认识，是油田开发后期的一项重要工作，水驱前缘测试是当前平面剩余油监测比较好的方法之一。水驱前缘测试技术是利用注水产生的微地震，通过检测分析微震信号来确定裂缝发育状况、水驱波及范围、优势注水方向，为评价区块水驱状况和平面剩余油分析提供直接依据。因此开展该项技术的现场试验与运用研究，对油田开发和产油增效具有重要意义。文章介绍了该技术方法的原理以及在华北复杂砂岩油藏水驱特征分析中的应用效果。     

Synthesis of amphiphilic magnetic microspheres by dispersion copolymerization of styrene and poly(ethylene oxide) macromonomer

Amphiphilic magnetic microspheres ranging in diameter from 5 to 100 µm were prepared by dispersion copolymerization of styrene and poly(ethylene oxide) vinylbenzyl (PEO‐VB) macromonomer (MPEO) in the presence of Fe₃O₄ magnetic fluid. The effects of various polymerization parameters on the average particle size were systematically investigated. The average particle size was found to increase with increasing styrene concentration and initiator concentration. It also increased with decreasing stabilizer concentration and molecular weight of MPEO. The content of the hydroxyl groups localized in the microspheres ranged from 0.01 to 0.2 mmol g^?1. © 2003 Society of Chemical Industry