Extrinsic factors regulate partial agonist efficacy of strychnine-sensitive glycine receptors

BACKGROUND: Strychnine-sensitive glycine receptors in many adult forebrain regions consist of alpha(2 )+ beta heteromeric channels. This subunit composition is distinct from the alpha(1 )+ beta channels found throughout the adult spinal cord. Unfortunately, the pharmacology of forebrain alpha(2)beta receptors are poorly defined compared to 'neonatal' alpha(2 )homomeric channels or 'spinal' alpha(1)beta heteromers. In addition, the pharmacologic properties of native alpha(2)beta glycine receptors have been generally distinct from receptors produced by heterologous expression. To identify subtype-specific pharmacologic tools for the forebrain alpha(2)beta receptors, it is important to identify a heterologous expression system that closely resembles these native glycine-gated chloride channels. RESULTS: While exploring pharmacological properties of alpha(2)beta glycine receptors compared to alpha(2)-homomers, we found that distinct heterologous expression systems appeared to differentially influence partial agonist pharmacology. The β-amino acid taurine possessed 30–50% efficacy for alpha(2)-containing receptor isoforms when expressed in HEK 293 cells. However, taurine efficacy was dramatically reduced in L-cell fibroblasts. Similar results were obtained for β-alanine. The efficacy of these partial agonists was also strongly reduced by the beta subunit. There were no significant differences in apparent strychnine affinity values calculated from concentration-response data between expression systems or subunit combinations. Nor did relative levels of expression correlate with partial agonist efficacy when compared within or between several different expression systems. Finally, disruption of the tubulin cytoskeleton reduced the efficacy of partial agonists in a subunit-dependent, but system-independent, fashion. CONCLUSIONS: Our results suggest that different heterologous expression systems can dramatically influence the agonist pharmacology of strychnine-sensitive glycine receptors. In the systems examine here, these effects are independent of both absolute expression level and any system-related alterations in the agonist binding site. We conclude that complex interactions between receptor composition and extrinsic factors may play a significant role in determining strychnine-sensitive glycine receptor partial agonist pharmacology

An examination of the association between seeing smoking in films and tobacco use in young adults in the west of Scotland: cross-sectional study

The objective is to examine the association between the amount of smoking seen in films and current smoking in young adults living in the west of Scotland in the UK. Cross-sectional analyses (using multivariable logistic regression) of data collected at age 19 (2002–04) from a longitudinal cohort originally surveyed at age 11 (1994–95) were conducted. The main outcome measure is smoking at age 19. No association was found between the number of occurrences of smoking estimated to have been seen in films (film smoking exposure) and current (or ever) smoking in young adults. This lack of association was unaffected by adjustment for predictors of smoking, including education, risk-taking orientation and smoking among peers. There was no association between film smoking exposure and smoking behaviour for any covariate-defined subgroup. Associations have been found between film smoking exposure and smoking initiation in younger adolescents in the United States. In this study, conducted in Scotland, no similar association was seen, suggesting that there may be age or cultural limitations on the effects of film smoking exposure on smoking. The lack of association could be due to methodological issues or greater sophistication of older adolescents and young adults in interpreting media images or the greater ubiquity of real-life smoking instances in Scotland. If the latter, film smoking exposure could become a more important risk factor for smoking uptake and maintenants in older adolescents following the recent ban on smoking in public places in Scotland

Multilevel Modeling of Interval-Contingent Data In Neuropsychology Research Using the \u3ci\u3eImerTest\u3c/i\u3e Package In R

Intensive longitudinal research designs are becoming more common in the field of neuropsychology. They are a powerful approach to studying development and change in naturally occurring phenomena. However, to fully capitalize on the wealth of data yielded by these designs, researchers have to understand the nature of multilevel data structures. The purpose of the present article is to describe some of the basic concepts and techniques involved in modeling multilevel data structures. In addition, this article serves as a step-by-step tutorial to demonstrate how neuropsychologists can implement basic multilevel modeling techniques with real data and the R package, lmerTest. R may be an ideal option for some empirical scientists, applied statisticians, and clinicians, because it is a free and open-source programming language for statistical computing and graphics that offers a flexible and powerful set of tools for analyzing data. All data and code described in the present article have been made publicly available

A well-separated pairs decomposition algorithm for k-d trees implemented on multi-core architectures

Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI.Variations of k-d trees represent a fundamental data structure used in Computational Geometry with numerous applications in science. For example particle track tting in the software of the LHC experiments, and in simulations of N-body systems in the study of dynamics of interacting galaxies, particle beam physics, and molecular dynamics in biochemistry. The many-body tree methods devised by Barnes and Hutt in the 1980s and the Fast Multipole Method introduced in 1987 by Greengard and Rokhlin use variants of k-d trees to reduce the computation time upper bounds to O(n log n) and even O(n) from O(n2). We present an algorithm that uses the principle of well-separated pairs decomposition to always produce compressed trees in O(n log n) work. We present and evaluate parallel implementations for the algorithm that can take advantage of multi-core architectures.The Science and Technology Facilities Council, UK

Static Friction between Elastic Solids due to Random Asperities

Several workers have established that the Larkin domains for two three dimensional nonmetallic elastic solids in contact with each other at a disordered interface are enormously large. This implies that there should be negligible static friction per unit area in the macroscopic solid limit. The present work argues that the fluctuations in the heights of the random asperities at the interface that occur in the Greenwood-Williamson model can account for static friction.Comment: Contains some improvements in the treatment of the subjec

A High-Resolution Genetic Map of Yellow Monkeyflower Identifies Chemical Defense QTLs and Recombination Rate Variation

Genotyping-by-sequencing methods have vastly improved the resolution and accuracy of genetic linkage maps by increasing both the number of marker loci as well as the number of individuals genotyped at these loci. Using restriction-associated DNA sequencing, we construct a dense linkage map for a panel of recombinant inbred lines derived from a cross between divergent ecotypes of Mimulus guttatus. We used this map to estimate recombination rate across the genome and to identify quantitative trait loci for the production of several secondary compounds (PPGs) of the phenylpropanoid pathway implicated in defense against herbivores. Levels of different PPGs are correlated across recombinant inbred lines suggesting joint regulation of the phenylpropanoid pathway. However, the three quantitative trait loci identified in this study each act on a distinct PPG. Finally, we map three putative genomic inversions differentiating the two parental populations, including a previously characterized inversion that contributes to life-history differences between the annual/perennial ecotypes.We thank M. Montenero and K. Keefover-Ring for assistance in phytochemistry sample preparation and HPLC troubleshooting, respectively. The KU EEB Genetics group provided valuable comments on the manuscript. We also thank Emma Huang and two anonymous reviewers for their comments. Funding for this research was provided by National Science Foundation grants DEB-0841609 (to RLL) and IOS-0951254 (to J.K.K.), by NIH grant GM073990 (to J.K.K.), and funding from the University of Kansas Botany Endowment Funds (to P.J.M.)

An autonomous strawberry‐harvesting robot: Design, development, integration, and field evaluation

This paper presents an autonomous robot capable of picking strawberries continuously in polytunnels. Robotic harvesting in cluttered and unstructured environment remains a challenge. A novel obstacle‐separation algorithm was proposed to enable the harvesting system to pick strawberries that are located in clusters. The algorithm uses the gripper to push aside surrounding leaves, strawberries, and other obstacles. We present the theoretical method to generate pushing paths based on the surrounding obstacles. In addition to manipulation, an improved vision system is more resilient to lighting variations, which was developed based on the modeling of color against light intensity. Further, a low‐cost dual‐arm system was developed with an optimized harvesting sequence that increases its efficiency and minimizes the risk of collision. Improvements were also made to the existing gripper to enable the robot to pick directly into a market punnet, thereby eliminating the need for repacking. During tests on a strawberry farm, the robots first‐attempt success rate for picking partially surrounded or isolated strawberries ranged from 50% to 97.1%, depending on the growth situations. Upon an additional attempt, the pick success rate increased to a range of 75–100%. In the field tests, the system was not able to pick a target that was entirely surrounded by obstacles. This failure was attributed to limitations in the vision system as well as insufficient dexterity in the grippers. However, the picking speed improved upon previous systems, taking just 6.1 s for manipulation operation in the one‐arm mode and 4.6 s in the two‐arm mode

Optimization of a mega-ampere spherical tokamak for beta-limit and confinement studies

Recent favorable results on the START experiment have caused renewed interest in the potential of low aspect ratio tokamaks. To aid in designing a next-step spherical tokamak to study confinement scaling, high beta, and high normalized beta plasmas for minimal cost, the authors have developed a transport scaling and device optimization code. This code STOP, benchmarked against START, includes 10 empirical confinement scaling laws and essential tokamak physics such as stability limits. Parameters are optimized separately for each scaling law and physical goal. Using STOP the authors find for R/a = 1.2 to 2.0 one can achieve {beta}{sub N} = 5, ({beta}) = 31--44%, and easily study predicted confinement degradation with auxiliary heating with just two neutral beams (P{sub NB} < 3.5 MW) for I{sub p} {ge} 0.75 MA, and R{sub 0} {ge} 0.6 m. In contrast, if one insists on using the nominal device parameters, i.e. I{sub p} = 1 MA and R{sub 0} = 0.8 m, with each scaling law, achieving {beta}{sub N} = 5 requires typically P{sub NB} {approx} 7.5 MW. They also conclude that while running D{sup 0} {yields} D{sup +} increases {tau}{sub E} {approx} 25%, with {tau}{sub E} already uncertain by 2--3{times}, one incurs restricted machine access and compromised physics operation