Partial agonists of the [alpha]3[beta]4[ast] neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

Varenicline, an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

Labyrinthine literacies : navigating cultural agency in the arrival and requiem for a beast

The OED reminds us as surely as Ovid that a labyrinth is a “structure consisting of a number of intercommunicating passages arranged in bewildering complexity, through which it is it difficult or impossible to find one’s way without guidance”. Both Shaun Tan’s The Arrival (2006) and Matt Ottley’s Requiem for a Beast: A Work for Image, Word and Music (2007) mark a kind of labyrinthine watershed in Australian children’s literature. Deploying complex, intercommunicating logics of story and literacy, these books make high demands of their reader but also offer guidance for the successful navigation of their stories; for their protagonists as surely as for readers. That the shared logic of navigation in each book is literacy as privileged form of meaning-making is not surprising in the sense that within “a culture deeply invested in myths of individualism and self-sufficiency, it is easy to see why literacy is glorified as an attribute of individual control and achievement” (Williams and Zenger 166). The extent to which these books might be read as exemplifying desired norms of contemporary Australian culture seems to be affirmed by the fact of Tan and Ottley winning the Australian “Picture Book of the Year” prize awarded by the Children’s Book Council of Australia in 2007 and 2008 respectively. However, taking its cue from Ottley’s explicit intertextual use of the myth of Theseus and from Tan’s visual rhetoric of lostness and displacement, this paper reads these texts’ engagement with tropes of “literacy” in order to consider the ways in which norms of gender and culture seemingly circulated within these texts might be undermined by constructions of “nation” itself as a labyrinth that can only partly be negotiated by a literate subject. In doing so, I argue that these picture books, to varying degrees, reveal a perpetuation of the “literacy myth” (Graff 12) as a discourse of safety and agency but simultaneously bear traces of Ariadne’s story, wherein literacy alone is insufficient for safe navigation of the labyrinth of culture.

tert-Butylaminium 2-carboxy-4,5-dichlorobenzoate

In the structure of the title anhydrous salt C4H12N+ C8H3Cl2O4-, the 4,5-dichlorophthalate monoanions have the common 'planar' conformation with the carboxyl groups close to coplanar with the benzene ring and with a short intramolecular carboxylic acid O-H...O hydrogen bond. A two-dimensional sheet structure is formed through aminium N-H...O(carboxyl) hydrogen-bonding associations.

The association between playgroup participation, learning competence and social-emotional wellbeing for children aged 4-5 years in Australia

Data from Growing Up in Australia: The Longitudinal Study of Australian Children is used to examine the associations between playgroup participation and the outcomes for children aged 4 to 5 years. Controlling for a range of socio-economic and family characteristics, playgroup participation across the ages of 0-3 years was used to predict learning competence and social-emotional functioning outcomes at age 4-5 years. For learning competence, both boys and girls from disadvantaged families scored 3-4% higher if they attended playgroup when aged 0-1 and 2-3 years compared to boys and girls from disadvantaged families who did not attend playgroup. For social and emotional functioning, girls from disadvantaged families who attended playgroup when they were aged 0-1 and 2-3 years scored nearly 5% higher than those who did not attend. Demographic characteristics also showed that disadvantaged families were the families least likely to access these services. Despite data limitations, this study provides evidence that continued participation in playgroups is associated with better outcomes for children from disadvantaged families.

Investigating literacy years 4-9 : a pilot. Final report.

Investigating Literacy Years 4-9: A pilot acknowledges that the literacy required of students in the middle years of schooling changes as they begin to read and write to learn across the subject areas using various resources and media. Teachers begin to look for evidence of understanding of concepts, content details, appropriate genre uses and the capacity to work with extended and complex texts. Yet, in comparison to the early years, there has been relatively little research conducted during this period of schooling, especially Years 4-7 of primary schooling (Comber et al, 2002). However, evidence suggests that gaps between those who perform highly and those who perform poorly on standardised measures of literacy increase rather than decrease, and these gaps relate to social background. Hence there is a need to investigate how different school communities with diverse student populations design rich curriculum at these stages of schooling and explicitly teach young people to handle new and changing literacy demands.

4-Aminopyridinium cis-2-carboxycyclohexane-1-carboxylate

In the structure of the title compound, C5H7N2+ C8H11O4-, the cis-monoanions associate through short carboxylic acid-carboxyl O-H...O hydrogen bonds [graph set C(7)], forming zigzag chains which extend along c and are inter-linked through pyridinium and amine N-H...O(carboxyl) hydrogen bonds giving a three-dimensional network structure.

Ethane-1,2-diaminium 4,4'-sulfonyldibenzoate

In the title compound 2(C2H10N2+) C14H8O6S2-, both the ethylenediaminium cations and the 4,4'-sulfonyldibenzoate dianions have crystallographic two-fold rotational symmetry and are interlinked by aminium N-H...O(carboxyl) hydrogen-bonding associations giving sheets which extend along (101) and are further linked down b forming a three-dimensional structure.

Expert elicitation into Bayesian networks, Part 1 of 4 : understanding probability

An introduction to elicitation of experts' probabilities, which illustrates common problems with reasoning and how to circumvent them during elicitation.

Expert elicitation into Bayesian networks, part 2 of 4: designing elicitation

An introduction to design of eliciting knowledge from experts.

Expert elicitation into Bayesian networks, Part 4 of 4: eliciting a conditional probability table

An introduction to eliciting a conditional probability table in a Bayesian Network model, highlighting three efficient methods for populating a CPT.

O'Neill Building Nudgee College

This project involved the complete refurbishment and extension of a 1980’s two-storey domestic brick building, previously used as a Boarding House (Class 3), into Middle School facilities (Class 9b) on a heritage listed site at Nudgee College secondary school, Brisbane. The building now accommodates 12 technologically advanced classrooms, computer lab and learning support rooms, tuckshop, art room, mini library/reading/stage area, dedicated work areas for science and large projects with access to water on both floors, staff facilities and an undercover play area suitable for assemblies and presentations. The project was based on a Reggio Emilia approach, in which the organisation of the physical environment is referred to as the child’s third teacher, creating opportunities for complex, varied, sustained and changing relationships between people and ideas. Classrooms open to a communal centre piazza and are integrated with the rest of the school and the school with the surrounding community. In order to achieve this linkage of the building with the overall masterplan of the site, a key strategy of the internal planning was to orientate teaching areas around a well defined active circulation space that breaks out of the building form to legibly define the new access points to the building and connect up to the pathway network of the campus. The width of the building allowed for classrooms and a generous corridor that has become ‘breakout’ teaching areas for art, IT, and small group activities. Large sliding glass walls allow teachers to maintain supervision of students across all areas and allow maximum light penetration through small domestic window openings into the deep and low-height spaces. The building was also designed with an effort to uphold cultural characteristics from the Edmund Rice Education Charter (2004). Coherent planning is accompanied by a quality fit-out, creating a vibrant and memorable environment in which to deliver the upper primary curriculum. Consistent with the Reggio Emilia approach, materials, expressive of the school’s colours, are used in a contemporary, adventurous manner to create panels of colour useful for massing and defining the ‘breakout’ teaching areas and paths of travel, and storage elements are detailed and arranged to draw attention to their aesthetic features. Modifications were difficult due to the random placement of load bearing walls, minimum ceiling heights, the general standard of finishes and new fire and energy requirements, however the reuse of this building was assessed to be up to 30% cheaper than an equivalent new building, The fit out integrates information technology and services at a level not usually found in primary school facilities. This has been achieved within the existing building fabric through thoughtful detailing and co-ordination with allied disciplines.