Membrane associated transporter protein gene (SLC45A2) and the genetic basis of normal human pigmentation variation

This work is concerned with the genetic basis of normal human pigmentation variation. Specifically, the role of polymorphisms within the solute carrier family 45 member 2 (SLC45A2 or membrane associated transporter protein; MATP) gene were investigated with respect to variation in hair, skin and eye colour ― both between and within populations. SLC45A2 is an important regulator of melanin production and mutations in the gene underly the most recently identified form of oculocutaneous albinism. There is evidence to suggest that non-synonymous polymorphisms in SLC45A2 are associated with normal pigmentation variation between populations. Therefore, the underlying hypothesis of this thesis is that polymorphisms in SLC45A2 will alter the function or regulation of the protein, thereby altering the important role it plays in melanogenesis and providing a mechanism for normal pigmentation variation. In order to investigate the role that SLC45A2 polymorphisms play in human pigmentation variation, a DNA database was established which collected pigmentation phenotypic information and blood samples of more than 700 individuals. This database was used as the foundation for two association studies outlined in this thesis, the first of which involved genotyping two previously-described non-synonymous polymorphisms, p.Glu272Lys and p.Phe374Leu, in four different population groups. For both polymorphisms, allele frequencies were significantly different between population groups and the 272Lys and 374Leu alleles were strongly associated with black hair, brown eyes and olive skin colour in Caucasians. This was the first report to show that SLC45A2 polymorphisms were associated with normal human intra-population pigmentation variation. The second association study involved genotyping several SLC45A2 promoter polymorphisms to determine if they also played a role in pigmentation variation. Firstly, the transcription start site (TSS), and hence putative proximal promoter region, was identified using 5' RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE). Two alternate TSSs were identified and the putative promoter region was screened for novel polymorphisms using denaturing high performance liquid chromatography (dHPLC). A novel duplication (c.–1176_–1174dupAAT) was identified along with other previously described single nucleotide polymorphisms (c.–1721C>G and c.–1169G>A). Strong linkage disequilibrium ensured that all three polymorphisms were associated with skin colour such that the –1721G, +dup and –1169A alleles were associated with olive skin in Caucasians. No linkage disequilibrium was observed between the promoter and coding region polymorphisms, suggesting independent effects. The association analyses were complemented with functional data, showing that the –1721G, +dup and –1169A alleles significantly decreased SLC45A2 transcriptional activity. Based on in silico bioinformatic analysis that showed these alleles remove a microphthalmia-associated transcription factor (MITF) binding site, and that MITF is a known regulator of SLC45A2 (Baxter and Pavan, 2002; Du and Fisher, 2002), it was postulated that SLC45A2 promoter polymorphisms could contribute to the regulation of pigmentation by altering MITF binding affinity. Further characterisation of the SLC45A2 promoter was carried out using luciferase reporter assays to determine the transcriptional activity of different regions of the promoter. Five constructs were designed of increasing length and their promoter activity evaluated. Constitutive promoter activity was observed within the first ~200 bp and promoter activity increased as the construct size increased. The functional impact of the –1721G, +dup and –1169A alleles, which removed a MITF consensus binding site, were assessed using electrophoretic mobility shift assays (EMSA) and expression analysis of genotyped melanoblast and melanocyte cell lines. EMSA results confirmed that the promoter polymorphisms affected DNA-protein binding. Interestingly, however, the protein/s involved were not MITF, or at least MITF was not the protein directly binding to the DNA. In an effort to more thoroughly characterise the functional consequences of SLC45A2 promoter polymorphisms, the mRNA expression levels of SLC45A2 and MITF were determined in melanocyte/melanoblast cell lines. Based on SLC45A2’s role in processing and trafficking TYRP1 from the trans-Golgi network to stage 2 melanosmes, the mRNA expression of TYRP1 was also investigated. Expression results suggested a coordinated expression of pigmentation genes. This thesis has substantially contributed to the field of pigmentation by showing that SLC45A2 polymorphisms not only show allele frequency differences between population groups, but also contribute to normal pigmentation variation within a Caucasian population. In addition, promoter polymorphisms have been shown to have functional consequences for SLC45A2 transcription and the expression of other pigmentation genes. Combined, the data presented in this work supports the notion that SLC45A2 is an important contributor to normal pigmentation variation and should be the target of further research to elucidate its role in determining pigmentation phenotypes. Understanding SLC45A2’s function may lead to the development of therapeutic interventions for oculocutaneous albinism and other disorders of pigmentation. It may also help in our understanding of skin cancer susceptibility and evolutionary adaptation to different UV environments, and contribute to the forensic application of pigmentation phenotype prediction.

Children's Fiction About 9/11: Ethnic, Heroic and National Identities

In this study, Lampert examines how cultural identities are constructed within fictional texts for young people written about the attacks on the Twin Towers. It identifi es three significant identity categories encoded in 9/11 books for children:ethnic identities, national identities, and heroic identities,arguing that the identities formed within the selected children’s texts are in flux, privileging performances of identities that are contingent on post-9/11 politics. Looking at texts including picture books, young adult fiction, and a selection of DC Comics, Lampert finds in post-9/11 children’s literature a co-mingling of xenophobia and tolerance; a binaried competition between good and evil and global harmony and national insularity; and a lauding of both the commonplace hero and the super-human. The shifting identities evident in texts that are being produced for children about 9/11 offer implicit and explicit accounts of what constitutes good citizenship, loyalty to nation and community, and desirable attributes in a Western post-9/11 context. This book makes an original contribution to the field of children’s literature by providing a focused and sustained analysis of how texts for children about 9/11 contribute to formations of identity in these complex times of cultural unease and global unrest.

The critical competences needed for innovative organizational inter-firm and intra-firm integration

In today's highly challenging business environment, an innovative and systemic approach is imperative to survival and growth. Organisational integration and technological integration, are often seen as a catalyst of change that could lead to significant improvements in organisations. The levels of improvement in inter and intra firm integration should arise from a detailed understanding and development of competences within and between organisations. Preliminary findings suggest that lack of trust across organisational cultures within the firms has a negative influence on the development of the capabilities to integrate and align technological innovations and hinders implementation and the effectiveness of the operations. Additionally, poor communication and conflict effects customer satisfaction. Firms need to transfer the competences that support cooperative integration, developed through interaction with supply chain partners, to their relationship arrangements with other supply chain partners, as these are key to ensuring low operational costs.

Using self-referencing to explain the effectiveness of ethnic minority models in advertising

Advertising research has generally not gone beyond offering support for a positive effect where ethnic models in advertising are viewed by consumers of the same ethnicity. This study offers an explanation behind this phenomenon that can be useful to marketers using self-reference theory. Our experiment reveals a strong self-referencing effect for ethnic minority individuals. Specifically, Asian subjects (the ethnic minority group) self-referenced ads with Asian models more than white subjects (the ethnic majority group). However, this result was not evident for white subjects. Implications for academics and advertisers are discussed.

Ethnic differences in the BMI-%BF relationships between young Japanese and Australian-Caucasian males living in Australia using dual-energy X-ray absorptiometry

The Body Mass Index (BMI) has been used worldwide as an indicator of fatness. However, the universal cut-off points by the World Health Organisation (WHO) classification may not be appropriate for every ethnic group when consider the relationship with their actual total body fatness(%BF). The application of population-specific classifications to assess BMI may be more relevant to public health. Ethnic differences in the BMI%BF relationship between 45 Japanese and 42 Australian-Caucasian males were assessed using whole body dual-energy X-ray absorptiometry (DXA) scan and anthropometry using a standard protocol. Japanese males had significantly (p<0.05) greater %BF at given BMI values than Australian males. When this is taken into account the newly proposed Asia-Pacific BMI classification of BMI 23 as overweight and 25 as obese may better assess the level of obesity that is associated increased health risks for this population. To clarify the current findings, further studies that compare the relationships across other Japanese populations are recommended.

Ethnic differences in body composition and anthropometric characteristics in Australian Caucasian and urban Indigenous children

The objective was to compare ethnic differences in anthropometry, including size, proportions and fat distribution, and body composition in a cohort of seventy Caucasian (forty-four boys, twenty-six girls) and seventy-four urban Indigenous (thirty-six boys, thirty-eight girls) children (aged 9–15 years). Anthropometric measures (stature, body mass, eight skinfolds, thirteen girths, six bone lengths and five bone breadths) and body composition assessment using dual-energy X-ray absorptiometry were conducted. Body composition variables including total body fat percentage and percentage abdominal fat were determined and together with anthropometric indices, including BMI (kg/m2), abdominal:height ratio (AHtR) and sum of skinfolds, ethnic differences were compared for each sex. After adjustment for age, Indigenous girls showed significantly (P < 0·05) greater trunk circumferences and proportion of overweight and obesity than their Caucasian counterparts. In addition, Indigenous children had a significantly greater proportion (P < 0·05) of trunk fat. The best model for total and android fat prediction included sum of skinfolds and age in both sexes (>93 % of variation). Ethnicity was only important in girls where abdominal circumference and AHtR were included and Indigenous girls showed significantly (P < 0·05) smaller total/android fat deposition than Caucasian girls at the given abdominal circumference or AHtR values. Differences in anthropometric and fat distribution patterns in Caucasian and Indigenous children may justify the need for more appropriate screening criteria for obesity in Australian children relevant to ethnic origin.

A method of lines approach for modelling saltwater intrusion in coastal aquifiers

The equations governing saltwater intrusion in coastal aquifers are complex. Backward Euler time stepping approaches are often used to advance the solution to these equations in time, which typically requires that small time steps be taken in order to ensure that an accurate solution is obtained. We show that a method of lines approach incorporating variable order backward differentiation formulas can greatly improve the efficiency of the time stepping process.

Granule-based knowledge representation for intra and inter transaction association mining

Abstract With the phenomenal growth of electronic data and information, there are many demands for the development of efficient and effective systems (tools) to perform the issue of data mining tasks on multidimensional databases. Association rules describe associations between items in the same transactions (intra) or in different transactions (inter). Association mining attempts to find interesting or useful association rules in databases: this is the crucial issue for the application of data mining in the real world. Association mining can be used in many application areas, such as the discovery of associations between customers’ locations and shopping behaviours in market basket analysis. Association mining includes two phases. The first phase, called pattern mining, is the discovery of frequent patterns. The second phase, called rule generation, is the discovery of interesting and useful association rules in the discovered patterns. The first phase, however, often takes a long time to find all frequent patterns; these also include much noise. The second phase is also a time consuming activity that can generate many redundant rules. To improve the quality of association mining in databases, this thesis provides an alternative technique, granule-based association mining, for knowledge discovery in databases, where a granule refers to a predicate that describes common features of a group of transactions. The new technique first transfers transaction databases into basic decision tables, then uses multi-tier structures to integrate pattern mining and rule generation in one phase for both intra and inter transaction association rule mining. To evaluate the proposed new technique, this research defines the concept of meaningless rules by considering the co-relations between data-dimensions for intratransaction-association rule mining. It also uses precision to evaluate the effectiveness of intertransaction association rules. The experimental results show that the proposed technique is promising.

Determination of optimal preventive maintenance strategy for serial production lines

A Split System Approach (SSA) based methodology is presented to assist in making optimal Preventive Maintenance decisions for serial production lines. The methodology treats a production line as a complex series system with multiple PM actions over multiple intervals. Both risk related cost and maintenance related cost are factored into the methodology as either deterministic or random variables. This SSA based methodology enables Asset Management (AM) decisions to be optimized considering a variety of factors including failure probability, failure cost, maintenance cost, PM performance, and the type of PM strategy. The application of this new methodology and an evaluation of the effects of these factors on PM decisions are demonstrated using an example. The results of this work show that the performance of a PM strategy can be measured by its Total Expected Cost Index (TECI). The optimal PM interval is dependent on TECI, PM performance and types of PM strategies. These factors are interrelated. Generally it was found that a trade-off between reliability and the number of PM actions needs to be made so that one can minimize Total Expected Cost (TEC) for asset maintenance.

The intra-aortic balloon pump in heart failure management : implications for nursing practice

Management of acute heart failure is an important consideration in critical care. Mechanical support of the failing heart is crucial for improving health outcomes. The most common Australasian application of intraaortic balloon counterpulsation (IABP) is in the setting of cardiogenic shock. High end users of IABP (>37/annum) demonstrate significantly lower mortality for cardiogenic shock managed with IABP (p <0.001) in contrast to hospitals which employ limited IABP (<4/annum). This underscores the importance of proficiency in managing patient receiving IABP support. Nurses play a crucial role in carding for patients with acute heart failure. This paper summarises care considerations for management of the IABP.

Inter- and intra- project knowledge transfer : analysis of knowledge transfer techniques

Many studies in the area of project management and social networks have identified the significance of project knowledge transfer within and between projects. However, only few studies have examined the intra- and inter-projects knowledge transfer activities. Knowledge in projects can be transferred via face-to-face interactions on the one hand, and via IT-based tools on the other. Although companies have allocated many resources to the IT tools, it has been found that they are not always effectively utilised, and people prefer to look for knowledge using social face-to-face interactions. This paper explores how to effectively leverage two alternative knowledge transfer techniques, face-to-face and IT-based tools to facilitate knowledge transfer and enhance knowledge creation for intra- and inter-project knowledge transfer. The paper extends the previous research on the relationships between and within teams by examining the project’s external and internal knowledge networks concurrently. Social network qualitative analysis, using a case study within a small-medium enterprise, was used to examine the knowledge transfer activities within and between projects, and to investigate knowledge transfer techniques. This paper demonstrates the significance of overlapping employees working simultaneously on two or more projects and their impact on facilitating knowledge transfer between projects within a small/medium organisation. This research is also crucial to gaining better understanding of different knowledge transfer techniques used for intra- and inter-project knowledge exchange. The research provides recommendations on how to achieve better knowledge transfer within and between projects in order to fully utilise a project’s knowledge and achieve better project performance.

Exponential asymptotics with multiple stokes lines

When asymptotic series methods are applied in order to solve problems that arise in applied mathematics in the limit that some parameter becomes small, they are unable to demonstrate behaviour that occurs on a scale that is exponentially small compared to the algebraic terms of the asymptotic series. There are many examples of physical systems where behaviour on this scale has important effects and, as such, a range of techniques known as exponential asymptotic techniques were developed that may be used to examinine behaviour on this exponentially small scale. Many problems in applied mathematics may be represented by behaviour within the complex plane, which may subsequently be examined using asymptotic methods. These problems frequently demonstrate behaviour known as Stokes phenomenon, which involves the rapid switches of behaviour on an exponentially small scale in the neighbourhood of some curve known as a Stokes line. Exponential asymptotic techniques have been applied in order to obtain an expression for this exponentially small switching behaviour in the solutions to orginary and partial differential equations. The problem of potential flow over a submerged obstacle has been previously considered in this manner by Chapman & Vanden-Broeck (2006). By representing the problem in the complex plane and applying an exponential asymptotic technique, they were able to detect the switching, and subsequent behaviour, of exponentially small waves on the free surface of the flow in the limit of small Froude number, specifically considering the case of flow over a step with one Stokes line present in the complex plane. We consider an extension of this work to flow configurations with multiple Stokes lines, such as flow over an inclined step, or flow over a bump or trench. The resultant expressions are analysed, and demonstrate interesting implications, such as the presence of exponentially sub-subdominant intermediate waves and the possibility of trapped surface waves for flow over a bump or trench. We then consider the effect of multiple Stokes lines in higher order equations, particu- larly investigating the behaviour of higher-order Stokes lines in the solutions to partial differential equations. These higher-order Stokes lines switch off the ordinary Stokes lines themselves, adding a layer of complexity to the overall Stokes structure of the solution. Specifically, we consider the different approaches taken by Howls et al. (2004) and Chap- man & Mortimer (2005) in applying exponential asymptotic techniques to determine the higher-order Stokes phenomenon behaviour in the solution to a particular partial differ- ential equation.