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排序方式: 共有2031条查询结果,搜索用时 15 毫秒
1.
Viktoria M. S. Kjær Loukas Ieremias Dr. Viktorija Daugvilaite Dr. Michael Lückmann Prof. Thomas M. Frimurer Prof. Trond Ulven Prof. Mette M. Rosenkilde Dr. Jon Våbenø 《ChemMedChem》2021,16(17):2623-2627
The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch. 相似文献
2.
Dr. Yahu A. Liu Dr. Qihui Jin Qiang Ding Dr. Xueshi Hao Tingting Mo Shanshan Yan Dr. Yefen Zou Dr. Zhihong Huang Xiaoyue Zhang Wenqi Gao Dr. Tom Y.-H. Wu Chun Li Dr. Badry Bursalaya Dr. Michael Di Donato Dr. You-Qing Zhang Lisa Deaton Dr. Weijun Shen Dr. Brandon Taylor Anwesh Kamireddy Dr. George Harb Dr. Jing Li Dr. Yong Jia Dr. Andrew M. Schumacher Dr. Bryan Laffitte Dr. Richard Glynne Dr. Shifeng Pan Dr. Peter McNamara Dr. Valentina Molteni Dr. Jon Loren 《ChemMedChem》2020,15(16):1562-1570
Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation. 相似文献
3.
Sheldon H. Jacobson Julie L. Virta Jon M. Bowman John E. Kobza John J. Nestor 《IIE Transactions》2003,35(3):259-269
Aviation security protects vital national interests, as well as passengers and aircraft. Key components of an aviation security system include baggage and passenger screening devices and operations. Determining how and where to assign (deploy) such devices can be quite challenging. Moreover, even after such systems are in place, it can be difficult to measure their effectiveness. This paper describes how discrete optimization models can be used to address these questions, based on three performance measures that quantify the effectiveness of airport baggage screening security device systems. These models are used to solve for optimal airport baggage screening security device deployments considering the number of passengers on a set of flights who have not been cleared using a security risk assessment system in use by the Federal Aviation Administration (i.e., passengers whose baggage is subjected to screening), the number of flights in this set, and the size of the aircraft for such flights. Several examples are provided to illustrate these results, including an example that uses data available from the Official Airline Guide. 相似文献
4.
Jon T. Carter Paul E. Krajewski Ravi Verma 《JOM Journal of the Minerals, Metals and Materials Society》2008,60(11):77-81
The hot blow forming of magnesium sheet offers significant opportunity for forming complex, lightweight parts for automotive
applications. This paper characterizes the elevated-temperature formability of AZ31 magnesium sheet materials and the effect
of processing conditions on the performance of these materials. In addition, magnesium sheet application development at General
Motors Corporation is reviewed. 相似文献
5.
Jon David 《Computers & Security》2002,21(8):696
The flow of information, within organizations, between networks, and from single users to other individuals and networks, is commonly at rates that only a few years ago were dreams. Earlier methods for the detection and prevention of malicious activities are anywhere from inefficient to unworkable with transmissions at the giga speeds that are prevalent today. This writing sets forth the problems and threats associated with these new high speed transmissions, and presents methodologies and systems for treating them. 相似文献
6.
Numerical Modeling of Silicon Photodiodes for High-Accuracy Applications Part I. Simulation Programs
Jon Geist Deane Chandler-Horowitz A. M. Robinson C. R. James 《Journal of research of the National Institute of Standards and Technology》1991,96(4):463-469
The suitability of the semiconductor-device modeling program PC-1D for high-accuracy simulation of silicon photodiodes is discussed. A set of user interface programs optimized to support high-accuracy batch-mode operation of PC-1D for modeling the internal quantum efficiency of photodiodes is also described. The optimization includes correction for the dark current under reverse- and forward-bias conditions before calculating the quantum efficiency, and easy access to the highest numerical accuracy available from PC-1D, neither of which is conveniently available with PC-1D’s standard user interface. 相似文献
7.
Jon Bryan Burley 《Landscape Research》1992,17(2):74-78
This paper describes the configuration and cultural context of the oldest known designed space in central America, Gheo-Shih, dating from 5,000 - 4,000 BC. This site may have been a ceremonial space, being employed in a similar fashion to ceremonial spaces of Native American cultures from the North American Great Basin. It contains physical features that set precedents and are similar to the geomantic features of later nearby Mesoamerican cultures. 相似文献
8.
In this article, we are combining minimization criteria in the colorant separation process for spectral color reproduction. The colorant separation is performed by inverting a spectral printer model: the spectral Yule‐Nielsen modified Neugebauer model. The inversion of the spectral printer model is an optimization operation in which a criterion is minimized at each iteration. The approach we proposed minimizes a criterion defined by the weighted sum of a spectral difference and a perceptual color difference. The weights can be tuned with a parameter α ∞ [0, 1]. Our goal is to decrease the spectral difference between the original data and its reproduction and also to consider perceptual color difference under different illuminant conditions. In order to find the best α value, we initially compare a pure colorimetric criterion and a pure spectral criterion for the reproduction, then we combine them. We perform four colorant separations: the first separation will minimize the 1976 CIELAB color difference where four illuminants are tested, the second separation will minimize an equally weighted summation of 1976 CIELAB color difference with the four illuminants tested independently, the third colorant separation will minimize a spectral difference, and the fourth colorant separation will combine a weighted sum of a spectral difference and one of the two first colorimetric differences previously introduced. This last colorant separation can be tuned with a parameter in order to emphasize on spectral or colorimetric difference. We use a six colorants printer with artificial inks for our experiments. The prints are simulated by the spectral Yule‐Nielsen modified Neugebauer model. Two groups of data are used for our experiments. The first group describes the data printed by our printing system, which is represented by a regular grid in colorant space of the printer and the second group describes the data which is not originally produced by our printing system but mapped to the spectral printer gamut. The Esser test chart and the Macbeth Color Checker test chart have been selected for the second group. Spectral gamut mapping of this data is carried out before performing colorant separation. Our results show improvement for the colorant separations combining a sum of 1976 CIELAB color difference for a set of illuminants and for the colorant separation combining a sum of 1976 CIELAB color difference and spectral difference, especially in the case of spectral data originally produced by the printer. © 2008 Wiley Periodicals, Inc. Col Res Appl, 33, 494–504, 2008 相似文献
9.
The recommendation of the CIE has been followed as closely as possible to evaluate the accuracy of five color gamut mapping algorithms (GMAs)—two nonspatial and three spatial algorithms—by psychophysical experiments with 20 test images, 20 observers, one test done on paper and a second one on display. Even though the results do not show any overall “winner,” one GMA is definitely perceived as not accurate. The importance of a high number of test images to obtain robust evaluation is underlined by the high variability of the results depending on the test images. Significant correlations between the percentage of out‐of‐gamut pixels, the number of distinguishable pairs of GMAs, and the perceived difficulty to distinguish them have been found. The type of observers is also important. The experts, who prefer a spatial GMA, show a stronger consensus and look especially for a good rendering of details, whereas the nonexperts hardly make a difference between the GMAs. © 2008 Wiley Periodicals, Inc. Col Res Appl, 33, 470–476, 2008 相似文献
10.
Blanchard Kimberly A.; Morgenstern Jon; Morgan Thomas J.; Lobouvie Erich W.; Bux Donald A. 《Canadian Metallurgical Quarterly》2003,17(4):328
Negative consequences are an important component of the substance use change process, yet no standardized measure exists to assess consequences of use. This study evaluated the psychometric properties of the Inventory of Drug Use Consequences, a self-report measure assessing drinking and drug use consequences. Participants (N=252) were assessed at entry into outpatient substance abuse treatment. Items loaded strongly on 1 factor, and internal consistency of the total scale was high. Fifteen items with the highest correlations with the total scale were chosen to represent the construct. The shortened measure exhibited good internal consistency, convergent and discriminant validity, and detected change over time and may be the measure of substance use consequences that is lacking in the field. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献