Pharmacologic evidence for a putative conserved allosteric site on opioid receptors

Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the μ-opioid receptor (μ-OR). BMS-986187 is a structurally distinct PAM for the δ-opioid receptor (δ-OR) that has been reported to exhibit 100-fold selectivity in promoting δ-OR over μ-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the μ-OR and at the κ-opioid receptor (κ-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for δ-ORs and κ-ORs is approximately 20- to 30-fold higher than for μ-ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types (μ-OR, δ-OR, and κ-OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics

Denitrification and N2O emission from forested and cultivated alluvial clay soil.

Restored forested wetlands reduce N loads in surface discharge through plant uptake and denitrification. While removal of reactive N reduces impact on receiving waters, it is unclear whether enhanced denitrification also enhances emissions of the greenhouse gas N2O, thus compromising the water-quality benefits of restoration. This study compares denitrification rates and N2O:N2 emission ratios from Sharkey clay soil in a mature bottomland forest to those from an adjacent cultivated site in the Lower Mississippi Alluvial Valley. Potential denitrification of forested soil was 2.4 times of cultivated soil. Using intact soil cores, denitrification rates of forested soil were 5.2, 6.6 and 2.0 times those of cultivated soil at 70, 85 and 100% water-filled pore space (WFPS), respectively. When NO3 was added, N2O emissions from forested soil were 2.2 times those of cultivated soil at 70% WFPS. At 85 and 100% WFPS, N2O emissions were not significantly different despite much greater denitrification rates in the forested soil because N2O:N2 emission ratios declined more rapidly in forested soil as WFPS increased. These findings suggest that restoration of forested wetlands to reduce NO3 in surface discharge will not contribute significantly to the atmospheric burden of N2O

Multi-Criteria Optimization in Friction Stir Welding Using a Thermal Model with Prescribed Material Flow

Friction stir welding (FSW) is an innovative solid-state joining process providing products with superior mechanical properties. It utilizes a rotating tool being submerged into the joint line and traversed while stirring the two pieces of metal together to form the weld. The temperature distribution in the weld zone, as a function of the heat generation, highly affects the evolution of the microstructure and the residual stresses, and also the performance of the weld. Therefore, thermal models play a crucial role in detailed analysis and improvement of this process. In this study, a three-dimensional steady state thermal model of FS welding of AA2024-T3 plates has been simulated. The effect of the tool rotation on the temperature distribution has been also taken into account. This thermal model has been integrated with the non-dominated sorting genetic algorithm (NSGA-II) to solve a common manufacturing problem having conflicting objectives, i.e., maximization of production rate and tool lifetime. The resulting multiple trade-off solutions are then investigated to unveil any design rules which have a strong potential in industrial use. © 2013 Taylor and Francis Group, LLC