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排序方式: 共有3536条查询结果,搜索用时 109 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
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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
4.
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
5.
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
6.
Chouping Luo Marek Klisinski 《International journal for numerical methods in engineering》2004,61(2):159-188
The present study is a continuation of our previous work with the aim to reduce problems caused by standard higher order elements in contact problems. The difficulties can be attributed to the inherent property of the Galerkin method which gives uneven distributions of nodal forces resulting in oscillating contact pressures. The proposed remedy is use of piece‐wise linear weight functions. The methods to establish stiffness and/or mass matrix for 8‐node quadrilateral element in 2D are presented, i.e. the condensing and direct procedures. The energy and nodal displacement error norms are also checked to establish the convergence ratio. Interpretation of calculated contact pressures is discussed. Two new 2D 8‐node quadrilateral elements, QUAD8C and QUAD8D, are derived and tested in many examples, which show their good performance in contact problems. Copyright © 2004 John Wiley & Sons, Ltd. 相似文献
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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
9.
Shiffman Saul; Paty Jean A.; Gnys Maryann; Kassel Jon D.; Elash Celeste 《Canadian Metallurgical Quarterly》1995,14(4):301
From previous studies, chippers (very light, long-time cigarette smokers) seem not to be nicotine dependent, despite decades of smoking. The effect of tobacco deprivation on chippers' withdrawal reactions was examined. Matched groups of 26 chippers and 25 regular smokers were studied while abstaining or smoking for 2-day blocks, with assessments administered 5 times daily by palm-top computers. As hypothesized, chippers showed no changes as a result of nicotine deprivation. In contrast, regular smokers demonstrated distinct changes in craving, mood, arousal, and sleep disturbance. The computers also tested participants' cognitive performance. Unlike chippers, regular smokers' performance on complex tasks was slower under deprivation; the effect could not be explained by changes in motor performance or simple reaction time. Results suggest performance may have been improved by nicotine rather than worsened by withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
10.
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