Copper depletion down-regulates expression of the Alzheimer's Disease amyloid-ß precursor protein gene

Alzheimer's disease is characterized by the accumulation of amyloid-ß peptide, which is cleaved from the amyloid-ß precursor protein (APP). Reduction in levels of the potentially toxic amyloid-ß has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of the APP gene. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-ß in copper homeostasis. We hypothesized that metals and in particular copper might alter APP gene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein. MNK deletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulated APP gene expression. Furthermore, APP promoter deletion constructs identified the copper-regulatory region between -490 and +104 of the APP gene promoter in both basal MNK overexpressing cells and in copper-chelated MNK deletion cells. Overall these data support the hypothesis that copper can regulate APP expression and further support a role for APP to function in copper homeostasis. Copper-regulated APP expression may also provide a potential therapeutic target in Alzheimer's disease.

The role of Ca2+ in insulin-stimulated glucose transport in 3T3-L1 cells.

We have examined the requirement for Ca2+ in the signaling and trafficking pathways involved in insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Chelation of intracellular Ca2+, using 1,2-bis (o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra (acetoxy- methyl) ester (BAPTA-AM), resulted in >95% inhibition of insulin-stimulated glucose uptake. The calmodulin antagonist, W13, inhibited insulin-stimulated glucose uptake by 60%. Both BAPTA-AM and W13 inhibited Akt phosphorylation by 70-75%. However, analysis of insulin-dose response curves indicated that this inhibition was not sufficient to explain the effects of BAPTA-AM and W13 on glucose uptake. BAPTA-AM inhibited insulin-stimulated translocation of GLUT4 by 50%, as determined by plasma membrane lawn assay and subcellular fractionation. In contrast, the insulin-stimulated appearance of HA-tagged GLUT4 at the cell surface, as measured by surface binding, was blocked by BAPTA-AM. While the ionophores A23187 or ionomycin prevented the inhibition of Akt phosphorylation and GLUT4 translocation by BAPTA-AM, they did not overcome the inhibition of glucose transport. Moreover, glucose uptake of cells pretreated with insulin followed by rapid cooling to 4 °C, to promote cell surface expression of GLUT4 and prevent subsequent endocytosis, was inhibited specifically by BAPTA-AM. This indicates that inhibition of glucose uptake by BAPTA-AM is independent of both trafficking and signal transduction. These data indicate that Ca2+ is involved in at least two different steps of the insulin-dependent recruitment of GLUT4 to the plasma membrane. One involves the translocation step. The second involves the fusion of GLUT4 vesicles with the plasma membrane. These data are consistent with the hypothesis that Ca2+/calmodulin plays a fundamental role in eukaryotic vesicle docking and fusion. Finally, BAPTA-AM may inhibit the activity of the facilitative transporters by binding directly to the transporter itself.

A review of epidemiological studies on children`s health and wellbeing

New epidemiological studies on children's health and wellbeing are essential to guide policy development. To ensure that these studies are based on the current conceptualisation of health, they should have a theoretical rationale for the selection of their domains. The scales used to measure each domain must be psychometrically sound, and also reflect the current conceptualisation of the domain. When selecting scales for each domain, child questionnaires must be considered, in addition to adult proxy measures. Through following these recommendations, researchers can ensure that their studies have theoretical and practical relevance. (non-author abstract)

What do they think when we stack them in? A comparative analysis of student perceptions relating to large and small marketing subjects

University education is in a period of flux with emphasis being focused on quality education, competition for students both local and international as well as changes in governmental financial support and direction. It is with this scenario as a backdrop, that universities in an endeavour to obtain economies of scale offer subjects with large student enrolments. This study investigates marketing students’ perception of and participation in marketing subjects relating to teaching quality, staff availability and support, and individual student involvement in marketing education with large enrolments compared to subjects with small enrolments. This research builds on the investigations of effects of class size by Cuseo (2004) and Binney et al (2004). The study used a multi-method approach. Data from a sample of 621 students was analysed using Factor analysis, MANOVA and ANOVA. Students indicated that there was little difference in the quality of learning obtained in small or large classes. Of interest from a marketing perspective, however, is the perception by students that they are more likely to obtain practical assistance and support from tutors in smaller classes. Student perceptions generally show no major differences between large and small classes in relation to subject selection, ability to learn and lecture  attendance. Students expressed a preference for the opportunity to choose from a number of lecture streams available in subjects with large enrolments. Of interest, however is the student belief that they are less likely to actively participate in large lectures than in small lecture environments.

Consumer loyalty versus propensity to switch between providers in mature IT markets (the case of mobile phone market)

The example of the youth mobile phone market is used for pilot empirical testing of a model of consumers’ decision making, based on common features of consumer behaviour in mature markets of information and high technology products. Firstly, we discuss the key properties of mature high technology markets which affect market behaviour and strategies. These properties include: established customer and provider bases; the elements of both oligopolistic and monopolistic competition; very short product life cycle; considerable product differentiation; and using product quality, versioning and price discrimination as planning and marketing tools. Secondly, a model of consumers’ decision making in such markets is suggested on the assumption that a choice is to be made between the following options: to continue using the existing version of the product, to upgrade it with the current provider or to switch to another provider. Product price, quality characteristics, switching costs and network effects are demonstrated to be the variables affecting consumers’ decisions and therefore, these variables should be considered by competing providers when they choose production and marketing strategies. In conclusion, the results of the empirical study are discussed in the context of their possible application to other information and high technology markets.

Cause-related marketing : an extension of the congruity concept

This paper considers the concept of congruity or 'fit' in a cause-related marketing (CRM) context. At present, there is a gap in the literature that explores how nonprofit-forprofit pairings affect a consumer's response to and evaluation of CRM campaigns. This paper develops the concept of 'fit' with particular attention being paid to three dimensions, namely, cognitive, emotional and behavioural congruity and the role these concepts play in determining consumers’ perception of the 'relatedness' of products and causes.

The mediating role of competitive advantage in the relationship between organisational capabilities and retail performance

This paper investigates the relationships between market, learning and brand orientation with competitive advantage and organisational performance in the context of the UK retail industry. The results indicate that competitive advantage contributes to strategic effectiveness and mediates the relationship between learning and brand orientation and strategic effectiveness. No significant relationship was found in relation to financial performance. Moreover, market orientation was not found to have a significant direct effect on competitive advantage or indirect affect on performance.

A strategic approach to target marketing-choosing the preferred generic customer : a model of shareholder value performance

In recent years the contribution of the marketing function has changed and interest now centres on its contribution to a firm’s financial performance. The Marketing Science Institute in the USA has stated that it is the number one marketing issue facing corporate America. The Australian Marketing Institute is promoting a set of marketing metrics that will help Australian firms measure the function’s contribution to shareholder value creation. Much of the literature relates notions such as customer satisfaction and other marketing activities with a firm’s profit. A missing link appears to be the choice firms make in terms of which customer groups to target and the resultant impact on shareholder value performance. The generic customer groups comprise: existing customers, former customers and prospects. A review of the literature reveals that marketing costs and benefits vary across these groups. The challenge for management is to determine which group represents the best target and to allocate scarce marketing resources accordingly. The task is made even more challenging because the economic value of members within each group also varies and some product lines may be unprofitable and therefore, may not be worth pursuing. To generate superior shareholder value it may not simply be the case of acquiring the maximum number of new customers from any source but to find the appropriate mix of the generic customer groups and manage the individual customer relationships accordingly. This paper seeks to firstly summarise and review the recent literature on marketing and its relationship to shareholder value and secondly to propose a model for allocating marketing resources across generic customer groups in order to generate improved shareholder value performance. Importantly, the model not only covers increasing business with customers but also shedding customers or shedding the extent of business conducted with customers as means of generating shareholder value.

Student's perceptions of compulsory asynchronous online discussion

Online discussion boards are increasingly being used by tertiary educators as tools for encouraging student interaction and for developing learning networks. In particular, educators who have adopted a socio-constructivist approach to teaching are keen to facilitate collaborative learning in which students share their experiences and perspectives, and construct knowledge together through shared meanings. In this paper, the findings from an electronic survey of 72 distance education students’ perceptions of an online discussion assessment item (ODAI) are presented. The study revealed that the majority of the respondents enjoyed the ODAI, and agreed that the online discussions had allowed them to achieve a range of cognitive and social learning outcomes, and to develop some important graduate skills.

Employer (dis)satisfaction With Australian marketing graduates: the development of a research framework

The gap between the skills and competencies of graduates on finishing their degrees and those required by employers is well documented in the literature with the development of educational curricula in business, and particularly marketing, being the subject of much research and debate over the past two decades. Nevertheless no comprehensive model appears to have been developed or tested within the Australian education sector to ensure the provision of adequate information on which to base decisions in this field. This paper attempts to contribute to this research area by presenting preliminary investigations into the needs of Australian businesses mainly in relation to marketing skills of graduates. Using a mail survey to collect data from 194 Australian businesses, a Wilcoxon signed-rank test was used to investigate the significant differences between the importance and satisfaction levels placed by employers on various graduate attributes. Findings of this research show that marketing skills appear to be valued at a lower level than general graduate attribute skills and that marketing programs may need to focus on basic marketing skills, more general skills and personal attributes rather than the higher level marketing skills that we currently teach at Australian universities.

Restitution law

Contains comprehensive extracts of the most significant cases from Australia and England. Explains the various academic views in areas where these are likely to be influential and incorporates a number of important new cases. Includes new sections dealing with practical questions such as pleading a claim in restitution.