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.     

Multi-objective layout optimization for an orbital propellant depot

Structural and Multidisciplinary Optimization - The overall layout optimization design of an orbital propellant depot involves the optimization of shape, size, and positions of propellant tanks in...     

Mechanism of smoke suppression by melamine in rigid polyurethane foam

The smoke suppression of rigid polyurethane foam (RPUF) modified by melamine was investigated based on three sections: the condensed phase, the carbon layer, and the gas phase. In the condensed phase, the results of thermogravimetry, X‐ray photoelectron spectroscopy (XPS) N1S spectrum, and Fourier transform infrared spectroscopy indicated that melamine could suppress the degradation of RPUF by reacting with the aromatic hydrocarbons. It also reduced the smoke generation because the volatilizable aromatic hydrocarbons were the principal smoke precursors in a fire. In the carbon layer, the decrease from 38.50% to 24.76% of the inner layer oxygen content identified by XPS full‐spectrum and C1S spectrum indicated that melamine could prevent oxygen from transferring into the inner foam by the formation of an enhanced surface carbon layer, and the enhanced carbon layer could also block the release of smoke precursors. In the gas phase, the content of total aromatic hydrocarbons declined to 59.12% according to pyrolysis gaseous chromatography mass spectroscopy and indicated that melamine could reduce the smoke precursors. The results of smoke density chamber and cone calorimeter tests revealed that the addition of the melamine could decrease the smoke density of burning RPUF. Copyright © 2014 John Wiley & Sons, Ltd.     

Owner’s Risk Allocation and Contractor’s Role Behavior in a Project: A Parallel-mediation Model

Risk allocation decisions are of critical importance in project management. The present study proposes an explanation for how risk allocation in a contract motivates a contractor to cooperate with a project owner. Theories of risk allocation and trust were used to motivate the research. Using a survey methodology, we collected data concerning 124 construction projects in China. We found that risk allocation influenced the contractor’s role behavior through the contractor’s feeling of being trusted but not the contractor’s trust in the owner. Feeling of being trusted partially mediated the effect of risk allocation on the contractor’s in-role (i.e., contractual) behavior and fully mediated the effect on extra-role behavior. The study introduces a social and psychological view of the impacts of risk allocation to the project and engineering management literature. We contribute to theory by arguing and demonstrating the mediating effect of trust on the relationship between risk allocation and contractor behavior. From a practical standpoint, we conclude that contractual risk allocation has a significant impact on building a trusting relationship between owners and contractors and that contractors who feel trusted perform both contractually mandated actions and actions external to the contract more diligently, resulting in the likelihood of improved outcomes for both parties.     

Comparative analysis on performance of vertical drain improved clay deposit under vacuum or surcharge loading

This paper presents two well-instrumented large-scale field tests of PVD-improved soft soil with vacuum and surcharge preloading, respectively. The two large-scale field tests were conducted adjacent to each other with the same preload. A comparative analysis was performed to investigate the performance of subsoil (i.e., the ground settlement, the layered settlement, the lateral displacement of subsoil and pore water pressure) under vacuum preloading and equivalent surcharge preloading. Some design methods were verified based on the field data. Cone Penetration Tests (CPT) and Vane Shear Tests (VST) were conducted to assess the improvement effects on subsoil after preloading. The results showed that as compared with surcharge preloading, vacuum preloading mitigated the differential settlement of the ground. The vacuum pressure transmitted into the soil with a minor loss through the PVD length. From a practical point of view, the improvement effects by vacuum preloading and surcharge preloading were similar in terms of influence depth and soil strength based on the in-situ tests.     

一种新的解映射算法的推导和实现

本文在一种16QAM,64QAM,256QAM的解映射算法启发下,提出了新的适合32QAM和128QAM的解映射算法,并在此基础上,给出了适合DVB-C接收机的多QAM解映射结构.然后在FPGA中实现和仿真.最后通过比较说明,相对于传统的查找表解映射方法,提出的解映射算法可以明显减少资源使用率.     

从频谱监测和国际协调探讨短波广播频段扩展的可行性

短波广播能够实现远距离和大范围的覆盖，至今仍是进行地区性、全国性及国际性广播覆盖的最好手段之一。ITU在2001年4月批准的1514建议书《30MHz以下广播频段的数字声音广播系统》，正式确定了DRM系统为全球统一的数字广播系统。在短波广播由模拟向数字化过渡的进程中，如何解决短波广播频谱短缺的问题，本文根据国家相关的频谱监测和国际短波频率协调的情况，对短波广播中4～10MHz频谱的扩展可行性进行初步分析。     

Microstructures and Phase Transition Points of As-Cast Mg-Zn-Y System Alloys

As-east mierostruetures and their distribution of Mg-Zn-Y ternary alloy with high magnesium, low zinc and yttrium were examined using Nikon Epiphot optical microscopy （OM）, RigakuD/max-3C X- ray diffraetion （XRD）, and JEOL JSM-6700F scanning electron microscopy （SEM） equipped with an energydispersive X-ray spectroscopy （EDS）. In the as-east mierostructures, Yttrium and zinc tend to segregate at grain boundaries,     

GIS在深圳市三防指挥信息系统中的应用

深圳市三防指挥信息系统利用GIS技术,结合水利(水务)、防汛、抗旱的具体业务,建立了水情遥测数据处 理分系统、工况监测数据处理分系统、水务行业三防信息管理分系统、决策支持分系统、水源优化调度分 系统,提高了现代化管理水平。     

一种改进型自适应加权模糊均值滤波算法

针对原有的自适应加权模糊均值AWFM滤波器对局部噪声幅度估计不足的缺点。提出了一种新的改进型自适应加权模糊均值MAWFM滤波算法。该算法采用了一种新的模糊检测方法，可以同时检测各个像素点的正负向噪声幅度，从而能够建立一种新的自适应的模糊信号空间，以适应噪声在各个图像局部的变化。实验结果表明，MAWFM滤波器比以前的AWFM滤波器及传统的中值滤波器均有较优越的性能。