Discovery,Synthesis and Characterization of a Highly Muscarinic Acetylcholine Receptor (mAChR)‐Selective M5‐Orthosteric Antagonist,VU0488130 (ML381): A Novel Molecular Probe

Of the five G‐protein‐coupled muscarinic acetylcholine receptors (mAChRs; M₁–M₅), M₅ is the least explored and understood due to a lack of mAChR subtype‐selective ligands. We recently performed a high‐throughput functional screen and identified a number of weak antagonist hits that are selective for the M₅ receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)‐penetrant M₅‐orthosteric antagonist, with sub‐micromolar potency (hM₅ IC₅₀=450 nM , hM₅ K_i=340 nM , M₁–M₄ IC₅₀ >30 μM ), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M₅ in addiction and other diseases.     

On the documentation of statistical analyses in the "clicky-box" era.

The proliferation of user-friendly computer packages that perform statistical analyses has led to what we call the "clicky-box" era in statistics: It is now possible to run complicated statistical analyses by clicking on menu options and reading the output. Although the advent of such technology has had a profoundly positive impact on psychological research (think of doing a factor analysis or fitting a structural equation model without such software!), it has also led to a greater opportunity for confusion. This article provides some essential procedures for the documentation and safe handling of data. The procedures outlined serve as a guide to help avoid the problems and confusions that can easily arise in the clicky-box era of highly automated data analysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of social context and gender on drinking patterns of young adults.

The social context of alcohol use involves both motivational and situational factors that influence drinking behavior among young adults. In this study, a significant multivariate interaction involving gender and alcohol use intensity was found on 6 social context factors. Among women, the social context of Emotional Pain most clearly separated lower intensity from higher intensity drinkers, whereas for men, the clearest separating factor was the context of Social Facilitation. Higher intensity drinkers were more likely than lower intensity drinkers to use alcohol in these contexts. Significant interaction effects involving gender were not found for driving under the influence or riding with an impaired driver; however, significant main effects for these 2 factors were discovered. The implications of the findings for counseling alcohol-abusing young adults are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Perceptual salience of acoustic features of Japanese monkey coo calls.

Smooth early high (SEH) and smooth late high (SLH) coo calls differ in the temporal location of a frequency inflection and are generally used in different situations. Coo quality is also influenced by additional features, such as relative harmonic level, which may have communicative significance. The authors used multidimensional scaling to analyze the perceptual similarity of SEH and SLH coos. Neither the temporal position of the frequency inflection nor caller identity could explain the coo groupings. Only the temporal relationships of the relative harmonic levels consistently differed between stimulus clusters. Relative level manipulations were conducted on synthetic coo replicas, resulting in substantial stimulus space reorganization. Although temporal position of the frequency inflection may provide the basis for coo classification, the authors suggest that relative harmonic amplitude can also influence response properties. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

When expertise reduces age differences in performance.

Examined whether aviation expertise reduces age differences in a laboratory task that was similar to routine air traffic control (ATC) communication. In Exp 1, older (mean age 66.6 yrs) and younger (mean age 29.0 yrs) pilots and age-matched nonpilots read typical ATC messages (e.g., commands to change aircraft heading). After each message, they read back (repeated) the commands, which is a routine ATC procedure requiring short-term memory. Ss also performed less domain-relevant tasks. Expertise eliminated age differences in repeating heading commands but did not reduce age differences for the less relevant tasks. In Exp 2, expertise reduced but did not eliminate age differences in repeating heading commands from spoken messages. Results suggest that expertise compensates age declines in resources when the task is highly domain relevant. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sources of the continued influence effect: When misinformation in memory affects later inferences.

Several lines of research have found that information previously encoded into memory can influence inferences and judgments, even when more recent information discredits it. Previous theories have attributed this to difficulties in editing memory: failing to successfully trace out and alter inferences or explanations generated before a correction. However, in Exps 1A and 1B, Ss who had received an immediate correction made as many inferences based on misinformation as Ss who had received the correction later in the account (despite presumably having made more inferences requiring editing). In a 2nd experiment, the availability of the misinformation within the comprehension context was tested. Results showed that Ss continued to make inferences involving discredited information when it afforded causal structure, but not when only incidentally mentioned or primed during an intervening task. Exps 3A and 3B found that providing a plausible causal alternative, rather than simply negating misinformation, mitigated 1 effect. The findings suggest that misinformation can still influence inferences one generates after a correction has occurred; however, providing an alternative that replaces the causal structure it affords can reduce the effects of misinformation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Patient attitudes and behavior regarding hygiene and replacement of soft contact lenses and storage cases

Purpose

To review important aspects of contact lens compliance and to survey contact lens replacement frequency, steps in lens care and hygiene and replacement of the lens storage case via online surveys.

Methods

Random US samples (n = 645 and 787) of frequent replacement contact lens wearers answered questions on contact lens wear in online, sponsor-masked surveys.

Results

Wearers of lenses prescribed by their practitioner for 2 weekly replacement reported that they replaced lenses as follows: within 2 weeks 45%, within 3 weeks (minor stretching) 68%, within 4 weeks 89%, ≥8 weeks (extreme stretching) 4%, compared to Monthly wearers who reported: within 4 weeks 37%, within 5 weeks (minor stretching) 57%, ≥8 weeks 23% (≥8 weeks extreme stretching, Chi-square p = 0.001). Median frequency for cleaning lens storage case was 2–3 times per week, while 33% reported cleaning monthly or less often. Median lens storage case replacement was every 4–6 months, while 48% reported annual replacement or less often. Most patients cleaned their lens case with hot or cold tap water (72%).

Conclusions

These internet surveys revealed significant non-compliance with lens care steps, case hygiene and lens replacement schedule. More than half of the contact lens wearers surveyed were not compliant with their 2-weekly or monthly schedule. Lenses prescribed for longer replacement intervals can lead to more extreme stretching of lens life. To encourage better patient habits, eye care providers should reinforce their recommended frequency of replacement of lenses and storage cases and should reinforce care and hygiene steps at each patient visit.     

Manure Management at Ohio Confined Animal Feeding Facilities in the Maumee River Watershed

In 2015, 48 permitted Confined Animal Feeding Operations (CAFOs) housed approximately 90% of poultry and 20% of swine and cattle within the Ohio portion of the Maumee River watershed. Recently, concerns about the impact CAFOs may have on nutrient loading in the watershed have been raised. In this study, we used manure management plans and inspection reports obtained from the Ohio Department of Agriculture Division of Livestock Environmental Permitting (ODA-DLEP) to assess how these CAFOs managed their manure for the years 2014 and 2015. A majority of liquid manure was applied between April and October, closely matching the amount of liquid manure planned to be applied during this period. Approximately 79% of the acres under control of the CAFOs that received manure had Bray P1 soil test phosphorus values below 50 ppm. The average distance between a swine CAFO’s livestock holding barn to the fields they control that can receive manure was 1.43 miles while for cattle CAFOs this distance was 1.91 miles. Approximately 78% of manure phosphorus generated on CAFOs was planned to be transferred through Distribution and Utilization, a process in which ownership of manure changes hands, including virtually all solid poultry manure phosphorus. While publicly available data show that, in general, CAFOs in the region are adhering to their state-approved permits, a knowledge gap regarding the management of approximately 80% of manure phosphorus exists due to manure transferred through Distribution and Utilization and manure produced from non-permitted livestock operations.     

In situ accelerated degradation of gas diffusion layer in proton exchange membrane fuel cell: Part I: Effect of elevated temperature and flow rate

Past studies have shown that both the substrate and microporous layer of the gas diffusion layer (GDL) significantly affect water balance and performance of a proton exchange membrane (PEM) fuel cell. However, little effort has been made to investigate the importance of GDL properties on the durability of PEM fuel cells. In this study, the in situ degradation behaviour of a commercial GDL carbon fiber paper with MPL was investigated under a combination of elevated temperature and elevated flow rate conditions. To avoid the possible impact of the catalyst layer during degradation test, different barriers without catalyst were utilized individually to isolate the anode and cathode GDLs. Three different barriers were evaluated on their ability to isolate GDL degradation and their similarity to a fuel cell environment, and finally a novel Nafion/MPL/polyimide barrier was chosen. Characterization of the degraded GDL samples was conducted through the use of various diagnostic methods, including through-plane electrical resistivity measurements, mercury porosimetry, relative humidity sensitivity, and single-cell performance curves. Noticeable decreases in electrical resistivity and the hydrophobic properties were detected for the degraded GDL samples. The experimental results suggested that material loss plays an important role in GDL degradation mechanisms, while excessive mechanical stress prior to degradation weakens the GDL structure and changes its physical property, which consequently accelerates the material loss of the GDL during aging.