Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

Opioids are the drugs of choice in severe pain management. Unfortunately, their use involves serious, potentially lethal side effects. Therefore, efforts in opioid drug design turn toward safer and more effective mechanisms, including allosteric modulation. In this study, molecular dynamics simulations in silico and ‘writhing’ tests in vivo were used to characterize potential allosteric mechanism of two previously reported compounds. The results suggest that investigated compounds bind to μ opioid receptor in an allosteric site, augmenting action of morphine at subeffective doses, and exerting antinociceptive effect alone at higher doses. Detailed analysis of in silico calculations suggests that first of the compounds behaves more like allosteric agonist, while the second compound acts mainly as a positive allosteric modulator.     

Using hydroacoustics to relate fluctuations in fish abundance to river restoration efforts and environmental conditions in the Penobscot River,Maine

Quantifying change after large habitat restoration efforts is critical to assessing the effort's success. After river restoration activities, fish abundance is expected to increase and also fluctuates naturally by season and with environmental conditions. A side‐looking hydroacoustic system was used to estimate fish abundance in the Penobscot River, ME, from 2010 to 2016 during predam (2010–2013) and postdam (2014–2016) removal years during nonice periods. Automated data processing enabled continuous abundance estimates from fish tracks. A threefold increase in mean fish abundance was recorded after dam removal. A fourfold increase in median fish abundance occurred in the fall relative to spring and summer of the same year, regardless of dam presence. Interannual fish abundance in every season monitored increased at least twofold after dam removal. We related variability in fish abundance to tide, discharge, temperature, diurnal cycle, daylength, moon phase, and restoration activities (focusing on dam presence). Daylength corresponding to the fall and summer was the most important indicator for higher fish abundance. Fish abundance was generally greatest in the fall during outgoing tides at night, with lesser peaks occurring during the month of June at night. Before dam removal, fish abundance peaked when water temperature was less than 9.25°C, at night, during outgoing tides. After dam removal, fish abundance peaked when daylength was less than 11.3 hr, at night, during outgoing tides, when water temperature was above 4.56°C and no full moon was present. Peak fish abundance occurred during only 0.02–2.3% of the total time sampled. The threefold increase in fish abundance recorded after dam removal was observed despite yearly stocking efforts of adult alewife increasing 24% in postdam removal years. Finally, parallel studies of fish presence in the Penobscot River were used to compare the utility of this method as an indicator of fish abundance in response to dam removal.     

Functional Chromatography Reveals Three Natural Products that Target the Same Protein with Distinct Mechanisms of Action

Access to lead compounds with defined molecular targets continues to be a barrier to the translation of natural product resources. As a solution, we developed a system that uses discrete, recombinant proteins as the vehicles for natural product isolation. Here, we describe the use of this functional chromatographic method to identify natural products that bind to the AAA+ chaperone, p97, a promising cancer target. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1‐hydroxydehydroherbarin, and phomapyrrolidone A as distinct p97 modulators. Excitingly, each of these molecules displayed a unique mechanism of p97 modulation. This discovery provides strong support for the application of functional chromatography to the discovery of protein modulators that would likely escape traditional high‐throughput or phenotypic screening platforms.     

Assessment of contaminant diffusivities in building materials from porosimetry tests

Recent studies have shown that surface and gaseous contaminant interactions may play an important role in indoor air quality. Modeling is an important tool to improve our knowledge about the phenomena involved and define appropriate ventilation strategies. However, data for sorption isotherms and diffusion in building materials remain woefully lacking. This paper deals with the latter point. It aims at investigating a methodology based on an analysis of the material porosity first and then the application of Carniglia's mathematical model to determine the effective diffusivity of gaseous species in building materials. This methodology, whose main principles are presented in the first part of the paper, was applied to seven commonly found materials. Mercury intrusion porosimetry (MIP) tests, and the calculations using Carniglia's model, reveal typical total porosities and tortuosity factors for these materials. The analysis of pore size distributions (PSDs) also draws one's attention to the possible differences in the pore structures that may exist between two samples of the same type of material and the differences in the effective diffusivities of contaminants that may result from them. The computed effective diffusivities were subsequently compared to data from experiments carried out in the frame of the EC project MATHIS. An agreement was obtained, thus validating Carniglia's methodology - a methodology that offers many practical advantages compared to diffusion-cell methods.     

Effect of plasma treatment on the surface properties of polydimethylsiloxane

In this work, the analysis of the plasma modification of polydimethylsiloxane (PDMS) substrates was conducted. The influence of the modification onto the changes occurred within the geometrical structure and chemical composition of the surface was analyzed. Due to the study of the atomic force microscopy, it was possible to determine the relationships between the surface development and applied process parameters, defining the conditions facilitating to obtain isotropic or anisotropic orientations of wrinkles. A precise analysis of the chemical composition of the surface, executed before and after the modification processes, enabled to define the changes in their elementary composition. Moreover, the modification influence onto the changes of the contact angle and the surface free energy were also analyzed. So, based on the research it was stated that the increase of value of the surface free energy is proportional to the sp³ phase contents in the DLC coatings. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41635.     

Measuring errors and violations on the road: A bifactor modeling approach to the Driver Behavior Questionnaire

The Driver Behavior Questionnaire (DBQ) is a self-report measure of driving behavior that has been widely used over more than 20 years. Despite this wealth of evidence a number of questions remain, including understanding the correlation between its violations and errors sub-components, identifying how these components are related to crash involvement, and testing whether a DBQ based on a reduced number of items can be effective. We address these issues using a bifactor modeling approach to data drawn from the UK Cohort II longitudinal study of novice drivers. This dataset provides observations on 12,012 drivers with DBQ data collected at .5, 1, 2 and 3 years after passing their test. A bifactor model, including a general factor onto which all items loaded, and specific factors for ordinary violations, aggressive violations, slips and errors fitted the data better than correlated factors and second-order factor structures. A model based on only 12 items replicated this structure and produced factor scores that were highly correlated with the full model. The ordinary violations and general factor were significant independent predictors of crash involvement at 6 months after starting independent driving. The discussion considers the role of the general and specific factors in crash involvement.     

Using shear force,sarcomere length,particle size,collagen content,and protein solubility metrics to predict consumer acceptance of aged beef tenderness

In this study, the relationship between sensory evaluation and several objective metrics of beef tenderness was tested. Objective metrics included shear force, sarcomere length, collagen content, myofibrillar, and sarcoplasmic protein solubility and particle size analysis. These results were compared to consumer panel scores of tenderness for the same aged beef striploin (longissimus lumborum muscle) samples. There was found to be a significant relationship between sarcomere length, shear force, and particle size with tenderness scores. Collagen content and protein solubilities were not associated to tenderness scores (p > 0.05). Sarcomere length contributions for explaining tenderness variation were overlapped by the contributions of shear force (collinearity). Independent models demonstrated that the lower 95% confidence interval of the fitted regression line exceeded 50% acceptance of tenderness when shear force values <42.6 N and when particle size values <198 μm. We can recommend these as thresholds for consumer acceptance of beef tenderness, although considerations of sample type, analytical methodology, and consumer demographics should be made prior to their adoption. This provision was based on the variation in tenderness scores evident between individual panelists and experimental striploins.     

DNA Break Mapping Reveals Topoisomerase II Activity Genome-Wide

Genomic DNA is under constant assault by endogenous and exogenous DNA damaging agents. DNA breakage can represent a major threat to genome integrity but can also be necessary for genome function. Here we present approaches to map DNA double-strand breaks (DSBs) and single-strand breaks (SSBs) at the genome-wide scale by two methods called DSB- and SSB-Seq, respectively. We tested these methods in human colon cancer cells and validated the results using the Topoisomerase II (Top2)-poisoning agent etoposide (ETO). Our results show that the combination of ETO treatment with break-mapping techniques is a powerful method to elaborate the pattern of Top2 enzymatic activity across the genome.     

Physicochemical properties of ready‐to‐eat extruded nixtamalized maize‐based snacks enriched with grasshopper

The aim of this research was to prepare an extruded snack based on nixtamalized maize flour (Zea mays L.) (NMF) enriched with grasshopper meal (Sphenarium purpurascens Ch.) (GM) using a single screw extruder with a compression screw ratio of 3:1. A central experimental design comprising three independent variables, namely, extrusion temperature (T = 120–180 °C), feed moisture content (FMC = 18–22 g/100 g) and the grasshopper meal proportion (GMP = 0–40 g/100 g), was used. Increasing T decreased (P < 0.05) the expansion index (EI), bulk density (BD) and hardness (H). Increasing the FMC increased (P < 0.05) the EI. Increasing the GMP decreased (P < 0.05) the EI, H and water absorption index (WAI) and increased (P < 0.05) the BD and total colour difference (ΔE). The treatments that resulted in better general acceptability were those that contained a lower GMP. An extruded snack acceptable to the consumer can be obtained from a blend of NMF and GM, and up to 8.11 g/100 g of GM can be incorporated without affecting the physicochemical properties and acceptance of the snack.