Correction of a mouse model of Menkes disease by the human Menkes gene

The brindled mouse is an accurate model of the fatal human X-linked copper deficiency disorder, Menkes disease. Males carrying the mutant allele of the Menkes gene orthologue Atp7a die in the second week of life. To determine whether the genetic defect in the brindled mice could be corrected by expression of the human Menkes gene, male transgenic mice expressing ATP7A from the chicken β-actin composite promoter (CAG) were mated with female carriers of the brindled mutation (Atp7aMo-br). Mutant males carrying the transgene survived and were fertile but the copper defect was not completely corrected. Unexpectedly males corrected with one transgenic line (T25#5) were mottled and resembled carrier females, this effect appeared to be caused by mosaic expression of the transgene. In contrast, males corrected with another line (T22#2) had agouti coats. Copper concentrations in tissues of the rescued mutants also resembled those of the heterozygous females, with high levels in kidney (84.6 ± 4.9 μg/g in corrected males vs. 137.0 ± 44.3 μg/g in heterozygotes) and small intestine (15.6 ± 2.5 μg/g in corrected males vs. 15.7 ± 2.8 μg/g in heterozygotes). The results show that the Menkes defect in mice is corrected by the human Menkes gene and that adequate correction is obtained even when the transgene expression does not match that of the endogenous gene.

The value of information in an agency model with moral hazard

I show that the principal and the agent may each prefer that the principal or the agent has imperfect information about the principal's technology in a principal-agent environment with moral hazard. Principals expend considerable resources on data cumulation and analysis. However, such investments in information acquisition are benecial only if the agent will know that the principal is not ignorant or it allows the principal to implement a dierent action. When the principal is perfectly informed about her technology, the agent prefers to be ignorant. In addition, the value of perfect information for the agency is negative if the principal would implement the same action with either possible technology. I also investigate the dierences between ex ante and ex post contracting, and the ramications of the principal being ignorant or potentially ignorant about the technology. Finally, I determine if the principal's utility varies continuously with the degree of informativeness of the agent about the principal's technology. In this vein, I determine whether the agent's uncertainty may make the principal better o if she has the less informative technology.

Development of a model of the antecedents and consequences of an inclusivie team climate

Exclusion due to the tendency of people to form subgroups based on perceived interpersonal similarities and dissimilarities still prevents many individuals and teams from reaching their full potential. Using research from the social psychology and organisational behaviour literature we examine the relationship between perceived dissimilarity, subgroup formation and team climate and individual team member's responses to the team and propose a model of the antecedents and consequences of individual team members propensity to perceive dissimilarity and an inclusive team climate.

Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Background and Aim: The toxic milk (tx) mouse is a non-fatal animal model for the metabolic liver disorder, Wilson's disease. The tx mouse has a mutated gene for a copper-transporting protein, causing early copper accumulation in the liver and late accumulation in other tissues. The present study investigated the efficacy of liver cell transplantation (LCT) to correct the tx mouse phenotype.

Methods: Congenic hepatocytes were isolated and intrasplenically transplanted into 3–4-month-old tx mice, which were then placed on various copper-loaded diets to examine its influence on repopulation by transplanted cells. The control animals were age-matched untransplanted tx mice. Liver repopulation was determined by comparisons of restriction fragment length polymorphism ratios (DNA and mRNA), and copper levels were measured by atomic absorption spectroscopy.

Results: Repopulation in recipient tx mice was detected in 11 of 25 animals (44%) at 4 months after LCT. Dietary copper loading (whether given before or after LCT, or both) provided no growth advantage for donor cells, with similar repopulation incidences in all copper treatment groups. Overall, liver copper levels were significantly lower in repopulated animals (538 ± 68 µg/g, n = 11) compared to non-repopulated animals (866 ± 62 µg/g, n = 14) and untreated controls (910 ± 103 µg/g, n = 6; P < 0.05). This effect was also seen in the kidney and spleen. Brain copper levels remained unchanged.

Conclusion: Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain.

A model to enable organisational cultural change using systemic strategic human resource management

Cultural change in organisations is both difficult to implement and hard to achieve. In this paper, theory from strategic human resource management, organisational cultural change, systemic thinking and practice, and punctuated equilibrium, is integrated in order to build a model for organisational culture change. Evidence is provided showing the capacity of the model to enable researchers and organisational change agents to improve the success of organisational cultural change programs.

Recognising behaviours of multiple people with hierarchical probabilistic model and statistical data association

Recognising behaviours of multiple people, especially high-level behaviours, is an important task in surveillance systems. When the reliable assignment of people to the set of observations is unavailable, this task becomes complicated. To solve this task, we present an approach, in which the hierarchical hidden Markov model (HHMM) is used for modeling the behaviour of each person and the joint probabilistic data association filters (JPDAF) is applied for data association. The main contributions of this paper lie in the integration of multiple HHMMs for recognising high-level behaviours of multiple people and the construction of the Rao-Blackwellised particle filters (RBPF) for approximate inference. Preliminary experimental results in a real environment show the robustness of our integrated method in behaviour recognition and its advantage over the use of Kalman filter in tracking people.

Professionals' perceptions of a new model of sexual assault investigation adopted by Victoria Police

This article presents a qualitative evaluation of a new method of operation for sexual assault investigation developed by Victoria Police. The model is characterised by two core components: the establishment of specialist teams of investigators responsible for investigation and victim support; and the establishment of service sites, referred to as 'Multidisciplinary Centres', where all key services are located in a single building separate from police stations. The research approach consisted of in-depth interviews with 90 stakeholders (police, counsellors, medical officers, child protection workers and prosecutors). Collectively, these interviews revealed strong, unanimous support for the ideologies that underpinned the new reforms. Reported outcomes included the following: improved collaboration; increased victim satisfaction, referrals between professionals and reporting rates; reduced response and investigation times; better quality briefs; and higher prosecution and conviction rates. These findings, along with the stakeholders' suggestions for further improvements, are discussed.

The influence of job, team and organizational level resources on employee well-being, engagement, commitment and extra-role performance : test of a model

Purpose – Worker well-being continues to be fundamental to the study of work and a primary consideration for how organizations can achieve competitive advantage and sustainable and ethical work practices (Cartwright and Holmes; Harter, Schmidt and Keyes; Wright and Cropanzano). The science and practice of employee engagement, a key indicator of employee well-being, continues to evolve with ongoing incremental refinements to existing models and measures. This study aims to elaborate the Job Demands-Resources model of work engagement (Bakker and Demerouti) by examining how organizational, team and job level factors interrelate to influence engagement and well-being and downstream outcome variables such as affective commitment and extra-role behaviour.

Design/methodology/approach – Structural equations modelling of survey data obtained from 3,437 employees of a large multi-national mining company was used to test the important direct and indirect influence of organizational focused resources (a culture of fairness and support), team focused resources (team climate) and job level resources (career development, autonomy, supervisor support, and role clarity) on employee well-being, engagement, extra-role behaviour and organizational commitment.

Findings – The fit of the proposed measurement and structural models met criterion levels and the structural model accounted for sizable proportions of the variance in engagement/wellbeing (66 percent), extra-role-behaviour (52 percent) and commitment (69 percent).

Research limitations/implications – Study limitations (e.g. cross-sectional research design) and future opportunities are outlined.

Originality/value – The study demonstrates important extensions to the Job Demands-Resources model and provides researchers and practitioners with a simple but powerful motivational framework, a suite of measures, and a map of their inter-relationships which can be used to help understand, develop and manage employee well-being and engagement and their outcomes.

Predicting future purchases with the Poisson log-normal model

The negative binomial distribution (NBD) has been widely used in marketing for modeling purchase frequency counts, particularly in packaged goods contexts. A key managerially relevant use of this model is Conditional Trend Analysis (CTA)—a method of benchmarking future sales utilizing the NBD conditional expectation. CTA allows brand managers to identify whether the sales change in a second period is accounted for by previous non-, light, or heavy buyers of the brand. Although a useful tool, the conditional prediction of the NBD suffers from a bias: it under predicts what the period-one non-buyer class will do in period two and over predicts the sales contribution of existing buyers. In addition, the NBD's assumption of a gamma-distributed mean purchase rate lacks theoretical support—it is not possible to explain why a gamma distribution should hold. This paper therefore proposes an alternative model using a log-normal distribution in place of the gamma distribution, hence creating a Poisson log-normal (PLN) distribution. The PLN distribution has a stronger theoretical grounding than the NBD as it has a natural interpretation relying on the central limit theorem. Empirical analysis of brands in multiple categories shows that the PLN distribution gives better predictions than the NBD.

Non-homogeneous volatility correlations in the bivariate multifractal model

In this paper, we consider an extension of the recently proposed bivariate Markov-switching multifractal model of Calvet, Fisher, and Thompson [2006. "Volatility Comovement: A Multifrequency Approach." Journal of Econometrics {131}: 179-215]. In particular, we allow correlations between volatility components to be non-homogeneous with two different parameters governing the volatility correlations at high and low frequencies. Specification tests confirm the added explanatory value of this specification. In order to explore its practical performance, we apply the model for computing value-at-risk statistics for different classes of financial assets and compare the results with the baseline, homogeneous bivariate multifractal model and the bivariate DCC-GARCH of Engle [2002. "Dynamic Conditional Correlation: A Simple Class of Multivariate Generalized Autoregressive Conditional Heteroskedasticity Models." Journal of Business & Economic Statistics 20 (3): 339-350]. As it turns out, the multifractal model with heterogeneous volatility correlations provides more reliable results than both the homogeneous benchmark and the DCC-GARCH model. © 2014 Taylor & Francis.

N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.