Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency

SummaryMost animal models of obesity and hyperinsulinemia are associated with increased vagal cholinergic activity. The M3 muscarinic acetylcholine receptor subtype is widely expressed in the brain and peripheral tissues and plays a key role in mediating the physiological effects of vagal activation. Here, we tested the hypothesis that the absence of M3 receptors in mice might protect against various forms of experimentally or genetically induced obesity and obesity-associated metabolic deficits. In all cases, the lack of M3 receptors greatly ameliorated impairments in glucose homeostasis and insulin sensitivity but had less robust effects on overall adiposity. Under all experimental conditions tested, M3 receptor-deficient mice showed a significant elevation in basal and total energy expenditure, most likely due to enhanced central sympathetic outflow and increased rate of fatty-acid oxidation. These findings suggest that the M3 receptor may represent a potential pharmacologic target for the treatment of obesity and associated metabolic disorders

Transduction of rat pancreatic islets with pseudotyped adeno-associated virus vectors

<p>Abstract</p> <p>Background</p> <p>Pancreatic islet transplantation is a promising treatment for type I diabetes mellitus, but current immunosuppressive strategies do not consistently provide long-term survival of transplanted islets. We are therefore investigating the use of adeno-associated viruses (AAVs) as gene therapy vectors to transduce rat islets with immunosuppressive genes prior to transplantation into diabetic mice.</p> <p>Results</p> <p>We compared the transduction efficiency of AAV2 vectors with an AAV2 capsid (AAV2/2) to AAV2 vectors pseudotyped with AAV5 (AAV2/5), AAV8 (AAV2/8) or bovine adeno-associated virus (BAAV) capsids, or an AAV2 capsid with an insertion of the low density lipoprotein receptor ligand from apolipoprotein E (AAV2apoE), on cultured islets, in the presence of helper adenovirus infection to speed expression of a GFP transgene. Confocal microscopy and flow cytometry were used. The AAV2/5 vector was superior to AAV2/2 and AAV2/8 in rat islets. Flow cytometry indicated AAV2/5-mediated gene expression in approximately 9% of rat islet cells and almost 12% of insulin-positive cells. The AAV2/8 vector had a higher dependence on the helper virus multiplicity of infection than the AAV 2/5 vector. In addition, the BAAV and AAV2apoE vectors were superior to AAV2/2 for transducing rat islets. Rat islets (300 per mouse) transduced with an AAV2/5 vector harboring the immunosuppressive transgene, <it>tgfβ1</it>, retain the ability to correct hyperglycemia when transplanted into immune-deficient diabetic mice.</p> <p>Conclusion</p> <p>AAV2/5 vectors may therefore be useful for pre-treating donor islets prior to transplantation.</p

Patterns of abundance across geographical ranges as a predictor for responses to climate change:Evidence from UK rocky shores

Aim: Understanding patterns in the abundance of species across thermal ranges can give useful insights into the potential impacts of climate change. The abundant-centre hypothesis suggests that species will reach peak abundance at the centre of their thermal range where conditions are optimal, but evidence in support of this hypothesis is mixed and limited in geographical and taxonomic scope. We tested the applicability of the abundant-centre hypothesis across a range of intertidal organisms using a large, citizen science-generated data set. Location: UK. Methods: Species' abundance records were matched with their location within their thermal range. Patterns in abundance distribution for individual species, and across aggregated species abundances, were analysed using Kruskal–Wallis tests and quantile general additive models. Results: Individually, invertebrate species showed increasing abundances in the cooler half of the thermal range and decreasing abundances in the warmer half of the thermal range. The overall shape for aggregated invertebrate species abundances reflected a broad peak, with a cool-skewed maximum abundance. Algal species showed little evidence for an abundant-centre distribution individually, but overall the aggregated species abundances suggested a hump-backed abundance distribution. Main Conclusions: Our study follows others in showing mixed support for the abundant-centre hypothesis at an individual species level, but demonstrates an increased predictability in species responses when an aggregated overall response is considered

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The post-war division of Berlin and its social effects, as illustrated by the translations of three short stories by Ingeborg Drewitz

This thesis examines three short stories by Ingeborg Drewitz, translated from German to English for this specific purpose. All three stories deal with a major concern of Drewitz, namely the effects the separation between East and West Germany had on the population. The introduction comments on the importance of the stories, their relevance to the chosen topic, and the author's writing techniques. A brief account of the historical events leading up to the establishment of the Berlin Wall will provide the necessary background information to set the stories into context. A further section is dedicated to Ingeborg Drewitz herself, including a look at her childhood, her literary accomplishments and awards. The central portion of the thesis is the presentation of the English translations of the stories, each followed by a brief analysis. The concluding comparison of these stories focuses on their contribution to the overall theme

The use of cooperative grouping in inclusive elementary classrooms.

With the advent of inclusion students with disabilities have been placed in settings that can maximize their opportunities to interact with their nondisabled peers. However, the inappropriate social behaviors of students with disabilities often prevented them from acceptance or classroom membership. Cooperative learning has been seen as one means of teaching all students in an inclusive classroom. Teacher support in the form of management systems and reward structures used in cooperative groupings are examined in this study. The use of qualitative research methods (observations, interviews, document analysis) in combination with a quantitative element (simple count) helped to determine the effectiveness of teacher supports for children in cooperative groupings. Teacher management systems and reward structures were examined to determine their effect on the social behaviors of children with disabilities who were placed in cooperative groupings. For the most part, children with disabilities exhibited more positive behaviors when teachers facilitated groups by instructing students in the appropriate group interactions, prior to placing students in cooperative groupings. This teacher facilitation in combination with positive verbalizations and points or tokens provided the greatest success. Teachers used cooperative groupings because they prevented children from alienation, and in many instances, promoted friendships between children with disabilities and nondisabled children. Many group interactions were positive in nature, with helping behaviors being displayed by all children

Non-Medical Use of Prescription Drugs in the Workplace

Background: University scholars and community members formed the Prescription Drug Abuse and Misuse Working Group in response to the prescription drug abuse/misuse epidemic plaguing the Appalachian region. Their collaboration has yielded no fewer than four funded and six volunteer service projects in the community. A concern voiced by key community stakeholders has been the non-medical use of prescription drugs (NMUPD) among the workforce. The team discovered that the relationship between NMUPD and workplace characteristics is understudied. This study aimed to show the overall and industry-specific prevalence of NMUPD, and to examine workplace characteristics associated with NMUPD. Methods: Data from the 2011-2012 National Survey on Drug Use and Health (NSDUH) were used. Multiple logistic regression assessed workplace characteristics on past-year NMUPD among employed adults 18 years and older, controlling for demographic variables. Results: The overall prevalence of NMUPD was 9.23% (95% CI: 8.98-9.48). The industries with the highest prevalence were: arts, entertainment, recreation, accommodation, and food services (14.48%; 95% CI: 13.70-15.27), construction (10.82%; 95% CI: 9.77-11.87), and retail trade (10.04%; 95% CI: 9.34-10.74). NMUPD was significantly associated with industry type (p Conclusions: Results suggest alcohol or drug use workplace policies and employee assistance or other counseling programs may protect against NMUPD. Workplace prevention efforts for NMUPD could benefit from incorporating these approaches