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31.
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
32.
Fresh and frozen-thawed (F-T) pork meats were classified by Vis–NIR hyperspectral imaging. Eight optimal wavelengths (624, 673, 460, 588, 583, 448, 552 and 609 nm) were selected by successive projections algorithm (SPA). The first three principal components (PCs) obtained by principal component analysis (PCA) accounted for over 99.98% of variance. Gray-level-gradient co-occurrence matrix (GLGCM) was applied to extract 45 textural features from the PC images. The correct classification rate (CCR) was employed to evaluate the performance of the partial least squares-discriminate analysis (PLS-DA) models, by using (A) the reflected spectra at full wavelengths and (B) those at the optimal wavelengths, (C) the extracted textures based on the PC images, and (D) the fused variables combining spectra at the optimal wavelengths and textures. The results showed that the best CCR of 97.73% was achieved by applying (D), confirming the high potential of textures for fresh and F-T meat discrimination. 相似文献
33.
This article presents a new approach for solving the Optimal Control Problem (OCP) of linear time-delay systems with a quadratic cost functional. The proposed method can also be used for designing optimal control time-delay systems with disturbance. In this study, the Variational Iteration Method (VIM) is employed to convert the original Time-Delay Optimal Control Problem (TDOCP) into a sequence of nonhomogeneous linear two-point boundary value problems (TPBVPs). The optimal control law obtained consists of an accurate linear feedback term and a nonlinear compensation term which is the limit of an adjoint vector sequence. The feedback term is determined by solving Riccati matrix differential equation. By using the finite-step iteration of a nonlinear compensation sequence, we can obtain a suboptimal control law. Finally, Illustrative examples are included to demonstrate the validity and applicability of the technique. 相似文献
34.
Barbara M. Johnston Peter R. Johnston 《International journal for numerical methods in engineering》2003,56(4):589-607
Accurate numerical evaluation of integrals arising in the boundary element method is fundamental to achieving useful results via this solution technique. In this paper, a number of techniques are considered to evaluate the weakly singular integrals which arise in the solution of Laplace's equation in three dimensions and Poisson's equation in two dimensions. Both are two‐dimensional weakly singular integrals and are evaluated using (in a product fashion) methods which have recently been used for evaluating one‐dimensional weakly singular integrals arising in the boundary element method. The methods used are based on various polynomial transformations of conventional Gaussian quadrature points where the transformation polynomial has zero Jacobian at the singular point. Methods which split the region of integration into sub‐regions are considered as well as non‐splitting methods. In particular, the newly introduced and highly accurate generalized composite subtraction of singularity and non‐linear transformation approach (GSSNT) is applied to various two‐dimensional weakly singular integrals. A study of the different methods reveals complex relationships between transformation orders, position of the singular point, integration kernel and basis function. It is concluded that the GSSNT method gives the best overall results for the two‐dimensional weakly singular integrals studied. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
35.
声波测井换能器的激发响应由换能器振动时所表现出来的动态阻抗和激发电路参数决定。而换能器的动态(阻抗)参数随压电晶体及其装配方式(力学边界条件)改变。为了测量换能器动态参数的影响,采用声波测井仪器常用的压电晶体和升压变压器,通过改变激发脉冲宽度和直流电压进行了实验,结果发现:在换能器两端的瞬态响应中,一共有三个二阶网络响应,分别对应于不同的频率。最低的一个影响声波测井波形的基线、与换能器主频接近的一个决定激发效率以及电路与压电晶体之间的匹配关系,是激发电路设计中比较关键的,其参数可以通过导纳圆测量仪器得到。 相似文献
36.
37.
目前需求预测在整个印制电路板产业的生产活动控制中正扮演着越来越重要的角色。分析了影响印制电路板需求的因素和现有的预测方法,提出了一种适用于PCB产业需求预测的有效方法——遗传/BP—神经网络。实验表明该方法能够进一步改善印制电路板预测的准确度和减少生产成本的消耗。 相似文献
38.
硬件教学实验必须由验证性向设计性转变,才能达到培养学生设计能力和处理问题的能力。而逻辑分析仪是数字系统设计的常用工具.对于实验和教学都起着不可忽视的作用。 相似文献
39.
40.
The Intellectual Development of Science and Engineering Students. Part 2: Teaching to Promote Growth
As college students experience the challenges of their classes and extracurricular activities, they undergo a developmental progression in which they gradually relinquish their belief in the certainty of knowledge and the omniscience of authorities and take increasing responsibility for their own learning. At the highest developmental level normally seen in college students (which few attain before graduation), they display attitudes and thinking patterns resembling those of expert scientists and engineers, including habitually and skillfully gathering and analyzing evidence to support their judgments. This paper proposes an instructional model designed to provide a suitable balance of challenge and support to advance students to that level. The model components are (1) variety and choice of learning tasks; (2) explicit communication and explanation of expectations; (3) modeling, practice, and constructive feedback on high‐level tasks; (4) a student‐centered instructional environment; and (5) respect for students at all levels of development. 相似文献