The neurokinin 1 receptor antagonist, ezlopitant, reduces appetitive responding for sucrose and ethanol

Abstract Background: The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7,8]. The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown. Methodology/Principal Findings: We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption. Conclusions/Significance: The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.

Prospective association between physical activity and falls in community-dwelling older women

Abstract Objective: To explore associations between physical activity and risk of falls and broken or fractured bones in community-dwelling older women. Design, setting and participants: This was a prospective observational survey with 3- and 6-year follow-ups. The sample included 8562 healthy, community-dwelling women, aged 70-75 years in 1996, who completed surveys as participants in the Australian Longitudinal Study on Women’s Health. Outcomes were reports of a fall to the ground, injury from a fall, and broken or fractured bones in 1999 and 2002. The main predictor variable was physical activity level in 1996, categorized based on weekly frequency as none/very low, low, moderate, high, and very high. Covariates were demographic and health-related variables. Logistic regression models were computed separately for each outcome in 1999 and 2002. Main results: In multivariable models, very high physical activity was associated with decreased risk of a fall in 1999 (odds ratio 0.67, 95% CI 0.48 to 0.93) and in 2002 (odds ratio 0.62, 95% CI 0.42 to 0.92). High/very high physical activity was associated with decreased risk of broken or fractured bones in 2002 (odds ratio 0.64, 95% CI 0.42 to 0.96). No significant association was found between physical activity and injury from a fall. Conclusions: The results suggest that at least daily moderate to vigorous physical activity is required for the primary prevention of falls to the ground and broken or fractured bones in women aged 70-75 years.

Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Abstract Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

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.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Heroes & harmony

The first practice-led research project 'Heroes of the Club', through collaboration with business and community, involved portraying the stories on canvas of heroes of the Australian Surf Life Saving movement. The second project 'Crossing the intersection… art and life' researched a post-modernist approach to a fusion of the aesthetics of Abstract Expressionism and Pop Art. This study resulted in a body of work 'Long Playing' which sought to harmoniously reconcile two apparent polarities of style and context between high and low art characteristics, through personal narrative and with reference to artistic tradition.

Clinical factors and technological barriers as determinants for the intention to use wireless handheld technology in healthcare environment: an Indian case study

Abstract]: Traditional technology adoption models identified ‘ease of use’ and ‘usefulness’ as the dominating factors for technology adoption. However, recent studies in healthcare have established that these two factors are not always reliable on their own and other factors may influence technology adoption. To establish the identity of these additional factors, a mixed method approach was used and data were collected through interviews and a survey. The survey instrument was specifically developed for this study so that it is relevant to the Indian healthcare setting. We identified clinical management and technological barriers as the dominant factors influencing the wireless handheld technology adoption in the Indian healthcare environment. The results of this study showed that new technology models will benefit by considering the clinical influences of wireless handheld technology, in addition to known factors. The scope of this study is restricted to wireless handheld devices such as PDAs, smart phones, and handheld PCs Gururajan, Raj and Hafeez-Baig, Abdul and Gururajan, Vijaya

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.

PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines

Deletions detected in cytogenetic and loss of heterozygosity (LOH) studies indicate that at least one tumour suppressor gene maps to the long arm of chromosome 10. Previous deletion mapping studies have observed LOH on 10q in about 30% of melanomas analysed. The PTEN gene, mapping to chromosome band 10q23.3, encodes a protein with both lipid and protein phosphatase activity. Somatic mutations and deletions in have been detected in a variety of cell lines and tumours, including melanoma samples. We performed mutation analyses and extensive allelic loss studies to investigate the role this gene plays in melanoma pathogenesis. We found that a total of 34 out of 57 (60%) melanoma cell lines carried hemizygous deletions of chromosome 10q encompassing the PTEN locus. A further three cell lines carried smaller deletions excluding PTEN. Inactivation of both PTEN alleles by exon-specific homozygous deletion or mutation was observed in 13 out of 57 (23%) melanoma cell lines. The mutation spectrum observed does not indicate an important role for ultraviolet radiation in the genesis of these mutations, and evidence from three cell lines supports the acquisition of PTEN aberrations in culture. Ten out of 49 (20%) matched melanoma tumour/normal samples harboured hemizygous deletions of either the whole chromosome or most of the long arm. Mutations within were detected in only one of the 10 tumours demonstrating LOH at 10q23 that were analysed. These results suggest that PTEN inactivation may be important for the propagation of melanoma cells in culture, and that another chromosome 10 tumour suppressor gene may be important for melanoma pathogenesis.

Elements pour adapter les systemes de recherche d'information aux dyslexiques [Elements to adapt information retrieval systems to dyslexic users]

RÉSUMÉ. La prise en compte des troubles de la communication dans l’utilisation des systèmes de recherche d’information tels qu’on peut en trouver sur le Web est généralement réalisée par des interfaces utilisant des modalités n’impliquant pas la lecture et l’écriture. Peu d’applications existent pour aider l’utilisateur en difficulté dans la modalité textuelle. Nous proposons la prise en compte de la conscience phonologique pour assister l’utilisateur en difficulté d’écriture de requêtes (dysorthographie) ou de lecture de documents (dyslexie). En premier lieu un système de réécriture et d’interprétation des requêtes entrées au clavier par l’utilisateur est proposé : en s’appuyant sur les causes de la dysorthographie et sur les exemples à notre disposition, il est apparu qu’un système combinant une approche éditoriale (type correcteur orthographique) et une approche orale (système de transcription automatique) était plus approprié. En second lieu une méthode d’apprentissage automatique utilise des critères spécifiques , tels que la cohésion grapho-phonémique, pour estimer la lisibilité d’une phrase, puis d’un texte. ABSTRACT. Most applications intend to help disabled users in the information retrieval process by proposing non-textual modalities. This paper introduces specific parameters linked to phonological awareness in the textual modality. This will enhance the ability of systems to deal with orthographic issues and with the adaptation of results to the reader when for example the reader is dyslexic. We propose a phonology based sentence level rewriting system that combines spelling correction, speech synthesis and automatic speech recognition. This has been evaluated on a corpus of questions we get from dyslexic children. We propose a specific sentence readability measure that involves phonetic parameters such as grapho-phonemic cohesion. This has been learned on a corpus of reading time of sentences read by dyslexic children.

Stochastic regularization method for backward Cauchy problem in Banach spaces

We consider a stochastic regularization method for solving the backward Cauchy problem in Banach spaces. An order of convergence is obtained on sourcewise representative elements.

Entry into Valhalla : contextualising the learning of legal ethics through the use of Second Life machinima

An ability to recognise and resolve ethical dilemmas was identified by the Australian Law Reform Commission as one of the ten fundamental lawyering skills. While the ‘Priestley 11’ list of areas of law required to qualify for legal practice includes ethics and professional responsibility, the commitment to ethics learning in Australian law schools has been far from uniform. The obligation imposed by the Priestley 11 is frequently discharged by a traditional teaching and learning approach involving lectures and/or tutorials and focusing on the content of the formal rules of professional responsibility. However, the effectiveness of such an approach is open to question. Instead, a practical rather than a theoretical approach to the teaching of legal ethics is required. Effective final-year student learning of ethics may be achieved by an approach which engages students, enabling them to appreciate the relevance of what they are learning to the real world and facilitating their transition from study to their working lives. Entry into Valhalla comprises a suite of modules featuring ‘machinima’ (computer-generated imagery) created using the Second Life virtual environment to contextualise otherwise abstract concepts. It provides an engaging learning environment which enables students to obtain an appreciation of ethical responsibility in a real-world context and facilitates understanding and problem-solving ability.

A traffic simulation standard based on data marts

Traffic Simulation models tend to have their own data input and output formats. In an effort to standardise the input for traffic simulations, we introduce in this paper a set of data marts that aim to serve as a common interface between the necessaary data, stored in dedicated databases, and the swoftware packages, that require the input in a certain format. The data marts are developed based on real world objects (e.g. roads, traffic lights, controllers) rather than abstract models and hence contain all necessary information that can be transformed by the importing software package to their needs. The paper contains a full description of the data marts for network coding, simulation results, and scenario management, which have been discussed with industry partners to ensure sustainability.