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.     

多样化的用户定制线缆

从电力与精确数字、模拟信号,到高压气态和液态介质,如今的用户定制电缆几乎无所不传。线缆制造商们现在可以提供的连接线缆材料可谓五花八门,从多种规格的传统铜线和光纤,到各类软管和导管,甚至包括碳纤维等半导体材料。在对一种专用电缆的设计作出最终决定前,要做一点“外形匹配”的工作。通常要回答的问题包括:“要传输些什么?”、“有什么限制条件?”、“完成任务应该采用何种连接物”。在进行优化的阶段,还要另外考虑使用环境,包括可能存在的电磁干扰、机械应力影响(如扭曲和/或摩擦)、化学和/或高温的损伤。细绞合铜导线在进行大功率…     

Context-Processing Deficits in Schizotypal Personality Disorder.

Research suggests that schizotypal personality disorder (SPD) is a part of the spectrum of schizophrenia-related illnesses. This article hypothesizes that a deficit in the representation and maintenance of context is a core cognitive disturbance in schizophrenia and that SPD individuals should demonstrate context-processing deficits. To test this hypothesis, the authors administered 3 versions of their AX-CPT task, designed to assess context processing, to 35 healthy controls and 26 individuals with DSM-IV SPD. They also administered working memory and selective attention tasks. SPD individuals displayed context representation deficits similar to those found in schizophrenia but did not show the same additional deficits in context maintenance. Context processing was strongly associated with working memory and selective attention performance in the SPD individuals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Quantum chemical studies of Li cation binding to polyalkyloxides

A quantum chemical study of the binding of Li⁺ cation to polyalkyloxides has been carried out. The lithium cation interaction with three polyalkyloxides (polyethylene oxide (PEO), polytrimethylene oxide (PTMO), and polypropylene oxide (PPO)) has been investigated using ab initio molecular orbital theory at the HF/6-31G^* level with molecular models for the polymers. Coordination by one to six oxygens was considered. In addition, higher level calculations were carried out using G3(MP2) theory for coordination of Li⁺ by one oxygen. For coordination of lithium by one oxygen, the binding energy ordering is PTMO>PPO>PEO, with PTMO having the largest lithium cation affinity. The same ordering is found for larger coordination numbers with the exception of coordination by six oxygens, where the ordering changes due to the steric interactions.     

THE DILEMMAS OF BUILDING A PROGRESSIVE URBAN COALITION: The Linked Development Debate in Chicago

ABSTRACT: In 1983 Chicago elected its first black mayor, Harold Washington. During Washington's first term of office, his administration not only reordered municipal priorities in such a fashion as to benefit his core, minority voting constituency, but also defined a municipal agenda emphasizing greater attention to neighborhood needs and more open government. In 1984 an important neighborhood coalition, the Save Our Neighborhoods/Save Our City Coalition (SON/SOC), proposed a linked development policy to tap downtown investment for neighborhood projects. Although SON/SOC's proposal was compatible with the Washington neighborhood agenda, this mainly white organization and the Washington administration experienced considerable difficulty in forging a mutually acceptable proposal The linked development debate in Chicago demonstrates the salience of race, class-cultural factors, and alternative approaches to neighborhood mobilization as barriers to the development of progressive coalitions in city politics.     

阻止抬升盆地原油生物降解的深埋灭菌作用

微生物活动造成的原油生物降解作用发生地球中大多数的油藏中，人们认为生物降解作用大大降低油藏中原油的质量，为成功寻找工业油藏，理解地质建造中生物降解作用发生的条件与过程是十分重要的，尽管最近的研究推测微生物活动在温度在150℃仍能有效地发生，但是人们普遍认为在地质时代，有效的石油生物降解作用通常发生在温度低于80℃的储层中，然而奇怪的是在温度低于80℃的储层中，还可发现未降解的原油，本文收集了一些油藏中有关生物降解程度的数据，发现未降角原油局限于埋藏浅的冷盆地，这些盆地曾是地球中更深，更热的部位，后经抬升作用形成的，我们认为这石油储层在深埋过程中，在温度为80－90℃时经历了灭菌作用，使得深部生物圈中降解烃类的生物停止活动，尽管这些储层后期抬升到较冷的部位并再次发生石油充注，也不会发生生物降解作用，表明灭菌后的沉积物不再适合降解烃类的细菌生长。     

Computerized conferencing for knowledge acquisition from multiple experts

The increasing complecity of many expert system application areas calls for the integration of the knowledge of multiple experts. The use of multiple experts introduces some interesting new problems during the process of knowledge acquisition. The problems are further complicated when the experts are geographically dispersed or unavailable for face-to-face interactions.

This article discusses the motivations for acquiring the knowledge of multiple experts, the problems related to knowledge acquisition, new issues that arise whens multiple experts interact, solutions that can be brought to bear in building multiple expert systems (particularly when experts are geographically dispersed), and new tools for knowledge engineers to use when dealing with multiple experts.     

Limitations on the uses of multimedia exposure measurements for multipathway exposure assessment--Part II: Effects of missing data and imprecision.

Multimedia data from two probability-based exposure studies were investigated in terms of how missing data and measurement-error imprecision affected estimation of population parameters and associations. Missing data resulted mainly from individuals'refusing to participate in certain measurement activities, rather than from field or laboratory problems; it suggests that future studies should focus on methods for maximizing participation rates. Measurement error variances computed from duplicate-sample data were small relative to the inherent variation in the populations; consequently, adjustments in nonparametric percentile estimates to account for measurement imprecision were small. Methods of adjustment based on lognormality assumptions, however, appeared to perform poorly.     

Determination of vitality from a non-invasive biomedical measurement for use in fingerprint scanners

Fingerprints are the oldest and most widely used biometrics for personal identification. Unfortunately, it is usually possible to deceive automatic fingerprint identification systems by presenting a well-duplicated synthetic or dismembered finger. This paper introduces one method to provide fingerprint vitality authentication in order to solve this problem. Detection of a perspiration pattern over the fingertip skin identifies the vitality of a fingerprint. Mapping the two-dimensional fingerprint images into one-dimensional signals, two ensembles of measures, namely static and dynamic measures, are derived for classification. Static patterns as well as temporal changes in dielectric mosaic structure of the skin, caused by perspiration, demonstrate themselves in these signals. Using these measures, this algorithm quantifies the sweating pattern and makes a final decision about vitality of the fingerprint by a neural network trained by examples.