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.

Estrogen receptor-Beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNF-alpha mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133+ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

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.

(Re)focusing the Lens to Make Diversity and Difference Visible : Teaching for Quality and Equity

Despite the evidence that Australia’s children are learning literacy, there is also significant evidence that the poorest and most disadvantaged children are being left behind. To date our understanding of the place of transitions in this has been limited, although there has been work on the fourth grade slump (Gee, 2000, 2008), the transition from primary years to secondary years (e.g. Bahr & Pendergast, 2007; Pendergast & Bahr, 2005, 2010), and transitions when changing schools (Henderson, 2008). In this chapter, we consider the notion of transitioning, as we unpack issues related to recognising and valuing student diversity and difference. We want to highlight ways of providing high quality and high equity literacy pedagogy and literacy outcomes for middle years students. We will also discuss the importance of recognising that students transit to schools and school learning from other significant contexts, each with their own combinations of literacy practices, rituals and values.

Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines

Mutations in exon 3 of the CTNNB1 gene encoding beta-catenin have been reported in colorectal cancer cell lines and tumours. Although one study reported mutations or deletions affecting beta-catenin in 20% of melanoma cell lines, subsequent reports detected a much lower frequency of aberrations in uncultured melanomas. To determine whether this difference in mutation frequency reflected an in vitro culturing artefact, exon 3 of CTNNB1 was screened in a panel of 62 melanoma cell lines. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect intragenic deletions affecting exon 3. One out of 62 (1.6%) cell lines was found to carry a mutation, indicating that aberration of the Wnt-1/wingless pathway through activation of beta-catenin is a rare event, even in melanoma cell lines.

Diversity in product familiarity across younger and older adults

This paper reports on the findings of a completed experiment examining levels of familiarity in younger and older adults. Research has shown that older adults use products less intuitively than younger adults, and that familiarity is an essential element of intuitive interaction. This finding influenced the decision to focus on familiarity and to investigate why older adults use products less intuitively than younger adults. By identifying and understanding the differences in familiarity, it is hypothesised that designers will be able to design more usable products for older adults. An empirical study was conducted, investigating the differences in familiarity between younger and older adults with contemporary products. Younger adults demonstrate significantly higher levels of familiarity compared to older adults, and the three groups of older adults demonstrated no significant differences between them. The implications of this finding is discussed.

Diversity interventions for a socially sustainable construction industry

Major construction sites in Australia have an above average presence of ethnic minorities. These groups and the interfaces between them require effective management in order to meet the social imperatives of sustainable design and construction. A survey of 1155 workers and 204 managers on Sydney construction sites respectively, found a significant level of normalisation of negative forms of cross cultural interaction. Yet it was also found that anti-racism programs are not currently a management priority and that they generally lack sophisticated community relations aspects. This paper presents the results of a desk-top study of leading global companies within and outside the construction sector which have won international awards and recognition for their cultural diversity strategies. A key insight is that the companies profiled see diversity as a key resource and as an opportunity rather than a risk which is best harnessed through long-term and on-going commitment of senior management. These leading companies also recognise that cultural diversity strategies operate at three levels - in terms of its relationship with its own workforce; its relationship with its clients and; its relationships with the communities in which it operates - and if properly managed it can be a source of competitive advantage.

Understanding the diversity of non-specialised units within Australian property degrees

Building on the recommendations of the Bradley Review (2008), the Australian Federal government intends to promote a higher level of penetration of tertiary qualification across the broader Australian community which is anticipated to result in increased levels of standardisation across university degrees. In the field of property, tertiary academic programs are very closely aligned to the needs of a range of built environment professions and there are well developed synergies between the relevant professional bodies and the educational institutions. The strong nexus between the academic and the professional content is characterised by ongoing industry accreditation which nominates a range of outcomes which the academic programs must maintain across a range of specified metrics. Commonly, the accrediting bodies focus on standard of minimum requirements especially in the area of specialised subject areas where they require property graduates to demonstrate appropriate learning and attitudes. In addition to nominated content fields, in every undergraduate degree program there are also many other subjects which provide a richer experience for the students beyond the merely professional. This study focuses on the nonspecialised knowledge field which varies across the universities offering property degree courses as every university has the freedom to pursue its own policy for these non-specialised units. With universities being sensitive to their role of in the appropriate socialisation of new entrants, first year units have been used as a vehicle to support students’ transition into university education and the final year units seek to support students’ integration into the professional world. Consequentially, many property programs have to squeeze their property-specific units to accommodate more generic units for both first year and final year units and the resulting diversity is a feature of the current range of property degrees across Australia which this research will investigate. The matrix of knowledge fields nominated by the Australian Property Institute for accreditation of degrees accepted for Certified Practising Valuer (CPV) educational requirement and the complementary requirements of the other major accrediting body (RICS) are used to classify and compare similarities and differences across property degrees in the light of the streamlining anticipated from the Bradley Review.