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排序方式: 共有441条查询结果,搜索用时 31 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.
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
4.
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
5.
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
6.
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
7.
This paper describes a database model based on the original rough sets theory. Its rough relations permit the representation of a rough set of tuples not definable in terms of the elementary classes, except through use of lower and upper approximations. The rough relational database model also incorporates indiscernibility in the representation and in all the operators of the rough relational algebra. This indiscernibility is based strictly on equivalence classes which must be defined for every attribute domain. There are several obvious applications for which the rough relational database model can more accurately model an enterprise than does the standard relational model. These include systems involving ambiguous, imprecise, or uncertain data. Retrieval over mismatched domains caused by the merging of one or more applications can be facilitated by the use of indiscernibility, and naive system users can achieve greater recall with the rough relational database. In addition, applications inherently “rough” could be more easily implemented and maintained in the rough relational database. 相似文献
8.
Michael Hausmann Martin Falk Charlotte Neitzel Andreas Hofmann Abin Biswas Theresa Gier Iva Falkova Dieter W. Heermann Georg Hildenbrand 《International journal of molecular sciences》2021,22(7)
In cancer therapy, the application of (fractionated) harsh radiation treatment is state of the art for many types of tumors. However, ionizing radiation is a “double-edged sword”—it can kill the tumor but can also promote the selection of radioresistant tumor cell clones or even initiate carcinogenesis in the normal irradiated tissue. Individualized radiotherapy would reduce these risks and boost the treatment, but its development requires a deep understanding of DNA damage and repair processes and the corresponding control mechanisms. DNA double strand breaks (DSBs) and their repair play a critical role in the cellular response to radiation. In previous years, it has become apparent that, beyond genetic and epigenetic determinants, the structural aspects of damaged chromatin (i.e., not only of DSBs themselves but also of the whole damage-surrounding chromatin domains) form another layer of complex DSB regulation. In the present article, we summarize the application of super-resolution single molecule localization microscopy (SMLM) for investigations of these structural aspects with emphasis on the relationship between the nano-architecture of radiation-induced repair foci (IRIFs), represented here by γH2AX foci, and their chromatin environment. Using irradiated HeLa cell cultures as an example, we show repair-dependent rearrangements of damaged chromatin and analyze the architecture of γH2AX repair clusters according to topological similarities. Although HeLa cells are known to have highly aberrant genomes, the topological similarity of γH2AX was high, indicating a functional, presumptively genome type-independent relevance of structural aspects in DSB repair. Remarkably, nano-scaled chromatin rearrangements during repair depended both on the chromatin domain type and the treatment. Based on these results, we demonstrate how the nano-architecture and topology of IRIFs and chromatin can be determined, point to the methodological relevance of SMLM, and discuss the consequences of the observed phenomena for the DSB repair network regulation or, for instance, radiation treatment outcomes. 相似文献
9.
Oliver Schmutzler Sebastian Graf Nils Behm Wael Y. Mansour Florian Blumendorf Theresa Staufer Christian Krnig Dina Salah Yanan Kang Jan N. Peters Yang Liu Neus Feliu Wolfgang J. Parak Anja Burkhardt Elisabetta Gargioni Sabrina Gennis Sharah Chandralingam Finn Heg Wolfgang Maison Kai Rothkamm Florian Schulz Florian Grüner 《International journal of molecular sciences》2021,22(7)
Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time. 相似文献
10.
Indentation-crack-length procedures were used to determine the critical fracture toughness (KIC ) and the sensitivity to environmentally enhanced crack growth in heavy-metal fluoride glasses of varying chemical composition. The data show that while KIC was more or less invariant with composition, some glasses were more susceptible to subcritical crack growth than others. The results are interpreted in terms of existing crack-growth models. A technique for predicting KIC from fundamental atomic bonding and crystal-structure data for these glasses is discussed. 相似文献