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
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
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
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
A 10.6 μm scan laser has been constructed and operated with an off-axis cathode ray tube, high reflectance multilayer thin-film structures, and a tapered plasma discharge tube. Equations are given for the switching time of a high-reflectance spot on the VO2and for the relation of scan laser output power to cavity geometry, cavity losses, and the gain of the active CO2medium. A scan capability of2.1 times 10^{3}easily resolvable directions was demonstrated, and sequential and randomly addressed spot rates of 105/s were achieved. The equations relating output power and cavity mode size were experimentally verified using a nonscanned beam. 相似文献
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
The objective of this study was to examine the effects of hygrothermal aging on the durability of a graphite/epoxy woven composite material system. The study was part of a larger project in which the objective was to evaluate and model the effects of moisture, temperature, and combined hygrothermal conditions on the strength and life of a graphite/epoxy woven composite material system. The results presented here represent an extension of the work by Patel and Case (Int. J. Fatigue 22 (2000) 809).
The hygrothermal aging consisted of cyclical temperature and moisture variations which were meant to simulate mission conditions for an advanced subsonic aircraft. Durability studies were carried out on the aged material system in the form of fatigue and residual strength testing under humid and elevated temperature environments. Damage mechanisms and failure modes were determined through fatigue testing, residual strength testing, and nondestructive evaluation.
Changes in physical appearance, thermal analysis results, fracture surfaces, and moisture diffusion behavior all supported the idea that the material was affected by the aging process. However, experimental testing also showed that the initial and residual tensile properties of the aged material were virtually unaffected by the imposed environmental aging (as compared to unaged material testing results), except when tested at elevated temperature. At elevated temperature, both the dynamic stiffness and residual strength were noticeably reduced from that at room temperature. 相似文献
The interfacial microstructures of 96 and 98% polycrystalline alumina joined with single crystal sapphire have been investigated in relation to the joining parameters. Joining has been evaluated based on either using a thin spin-on silica interlayer or by placing the alumina and sapphire in direct contact. The materials were joined by placing the coated or uncoated surfaces in contact and heating in the range of 1340–1475 °C with minimum external load. With the aid of a silica interlayer, sapphire and 98% polycrystalline alumina were successfully joined in 180 min at 1400 °C and above, while samples without a silica interlayer failed to join under these conditions. However, sapphire and 96% polycrystalline alumina were joined both with and without the use of silica interlayer. A variety of interfacial morphologies have been observed, including amorphous regions, fine crystalline alumina, and intimate contact between the sapphire and polycrystalline alumina. 相似文献
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