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排序方式: 共有769条查询结果,搜索用时 15 毫秒
1.
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
2.
Guangyan Li W. Ian Hamilton Ged Morrisroe Theresa Clarke 《Cognition, Technology & Work》2006,8(1):30-40
A study was carried out using simulation to investigate driver responses to lineside signals and signs at various approach
speeds. The objectives of the study were: (1) to find out whether train speed would significantly affect signal/sign reading;
(2) to examine at which point certain types of signs or signals could be detected or recognised, and (3) to determine a speed
cut-off level above which certain types of signs or signals are no longer recognisable or detectable. Fifty-seven train drivers
from 12 Train Operating Companies in the UK participated in the trials. Twenty different types of lineside signs and ten types
of signals were tested under six different approach speeds ranging from 100 to 350 km/h (62–218 mph). Driver performance measures
were ‘time remaining to the signal/sign’ at the point of detection or recognition, and reading error rate. The results showed
a significant influence of train speed on driver responses to lineside signals/signs and demonstrated a non-linear relationship
between driver responses to signals/signs and approach speed. This has been used to estimate a maximum approach speed limit
within which a specific signal or sign can be correctly detected or recognised. The findings and implications of the study
are discussed in the paper. 相似文献
3.
D. Dietrich ÖVE H. Reiter Th. Sauter H. -J. Schweinzer 《e & i Elektrotechnik und Informationstechnik》1997,114(5):225-230
The past decade may be regarded as the phase of the fundamental developments in fieldbus systems that were based on the OSI model. Today we are entering a second stage. It is the objective of this issue to present the current state and where the further developments will lead to. This introductory article is intended to give an overview on the subject. 相似文献
4.
5.
"Homeland security" is a major concern for governments worldwide, which must protect their populations and the critical infrastructures that support them. Information technology plays an important role in many homeland security initiatives. On one hand, it can help mitigate risk and enable effective responses to disasters of natural or human origin. Yet, its suitability for this role is plagued by questions ranging from dependability concerns to the risks that some technologies, such as surveillance, profiling and data aggregation, pose to privacy and civil liberties. On the other hand, information technology is itself an infrastructure to be protected. This includes not only the Internet and financial infrastructure but also the complex systems that control critical infrastructure such as energy, transportation, and manufacturing. 相似文献
6.
Various indexes have been proposed to mark when a child is on the verge of acquiring new knowledge. This article described a new method for indexing this point of transition, which is based on the specificity of children's verbal explanations. The degree to which children were specific in their verbal explanations was related to whether they benefited from instruction. In particular, children who were vague in their explanations (i.e., less specific) benefited from instruction more than children who were explicit in their explanations (i.e., more specific). This index provides insights into the child's mental state prior to acquiring new knowledge. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
7.
Comments on S. Harvey's (see record 1994-43015-001) article on using the Canadian Psychological Association's (CPA's) Code of Ethics for psychologists in an organizational case. T. J. Kline disputes the necessity of developing specific standards for particular areas of practice because she contends that the CPA code is meant to serve as a guide and a conceptual device, not a body of law. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
8.
Heriberto Cabezas Christopher W. Pawlowski Audrey L. Mayer N. Theresa Hoagland 《Clean Technologies and Environmental Policy》2003,5(3-4):167-180
Sustainability is generally associated with a definition by the World Commission on Environment and Development, 1987: "... development that meets the needs of the present without compromising the ability of future generations to meet their own needs ..." However, there is no mathematical theory embodying these concepts, although one would be immensely valuable in humanity's efforts to manage the environment. The concept of sustainability applies to integrated systems comprising humans and the rest of nature; the structures and operation of the human component (society, economy, law, etc.) must be such that they reinforce the persistence of the structures and operation of the natural component (ecosystem trophic linkages, biodiversity, biogeochemical cycles, etc.). One of the challenges of sustainability research lies in linking measures of ecosystem functioning to the structure and operation of the associated social system. We review the nature of this complex system including its ecological, social, economic, and technological aspects, and propose an approach to assessing sustainability based on Information Theory that bridges the natural and human systems. These principles are then illustrated using a model system with an ecological food web linked to a rudimentary social system. This work is part of the efforts of a larger multidisciplinary group at the U.S. Environmental Protection Agency's National Risk Management Research Laboratory. 相似文献
9.
Little is known of the current smoking cessation activities of practice nurses and their attitudes toward giving smoking cessation advice. This study aimed to (a) compare practice nurses' reports of giving smoking cessation advice as part of cervical screening with their reports of giving such advice in cardiovascular disease screening and diabetes care, (b) compare their beliefs about providing such advice in these three contexts, and (c) determine the strongest predictors of their reports of giving smoking cessation advice. A survey was completed by 152 practice nurses in the United Kingdom. The frequency with which they reported giving smoking cessation advice and their beliefs about giving such advice in three contexts are reported. Nurses reported being more likely to give smoking cessation advice and had more positive beliefs about giving it in the more traditional contexts of cardiovascular screening and diabetes care compared with cervical screening. Beliefs about the appropriateness and practicality of giving such advice in the latter context were the strongest predictors of nurses' reports of doing so. This study provides guidance on the potential barriers that need to be overcome to increase the frequency with which nurses give smoking cessation advice in the context of cervical screening. 相似文献
10.
The purpose of these experiments was to determine whether the exposure of rats at night to pulsed DC magnetic fields (MF) would influence the nocturnal production and secretion of melatonin, as indicated by pineal N-acetyltransferase (NAT) activity (the rate limiting enzyme in melatonin production) and pineal and serum melatonin levels. By using a computer-driven exposure system, 15 experiments were conducted. MF exposure onset was always during the night, with the duration of exposure varying from 15 to 120 min. A variety of field strengths, ranging from 50 to 500 microT (0.5 to 5.0 G) were used with the bulk of the studies being conducted using a 100 microT (1.0 G) field. During the interval of DC MF exposure, the field was turned on and off at 1-s intervals with a rise/fall time constant of 5 ms. Because the studies were performed during the night, all procedures were carried out under weak red light (intensity of <5 microW/cm2). At the conclusion of each study, a blood sample and the pineal gland were collected for analysis of serum melatonin titers and pineal NAT and melatonin levels. The outcome of individual studies varied. Of the 23 cases in which pineal NAT activity, pineal melatonin, and serum melatonin levels were measured, the following results were obtained; in 5 cases (21.7%) pineal NAT activity was depressed, in 2 cases (8.7%) studies pineal melatonin levels were lowered, and in 10 cases (43.5%) serum melatonin concentrations were reduced. Never was there a measured rise in any of the end points that were considered in this study. The magnitudes of the reductions were not correlated with field strength (i.e., no dose-response relationships were apparent), and likewise the reductions could not be correlated with the season of the year (experiments conducted at 12-month intervals under identical exposure conditions yielded different results). Duration of exposure also seemed not to be a factor in the degree of melatonin suppression. The inconsistency of the results does not permit the conclusion that pineal melatonin production or release are routinely influenced by pulsed DC MF exposure. In the current series of studies, a suppression of serum melatonin sometimes occurred in the absence of any apparent change in the synthesis of this indoleamine within the pineal gland (no alteration in either pineal NAT activity or pineal melatonin levels). Because melatonin is a direct free radical scavenger, the drop in serum melatonin could theoretically be explained by an increased uptake of melatonin by tissues that were experiencing augmented levels of free radicals as a consequence of MF exposure. This hypothetical possibly requires additional experimental documentation. 相似文献