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.

Comparing the ethical predisposition of university students in five English-speaking countries : an examination of 14 questionable business practices

Recent years have seen intense scrutiny focused on the reported ethical breaches of enterprises across the globe. At the forefront of the accompanying criticism are the actions of giant American firms such as WorldCom, Arthur Anderson, and Enron. However, such deviations from acceptable standards of conduct have not been confined to the American market. Australia endured its era of “corporate excess” in the 1980s [Milton-Smith, 1997]. As a result, a spate of ethics-based research was undertaken in the early 1990s. More recently, China has been identified as a major venue for behavior deemed to be unacceptable, even unsafe. Issues such as counterfeit fashion items, software, and automobile parts have been a concern for several years [Gonzalez, 2007]. Perhaps more disconcerting are the recent recalls of children’s products, many of which were produced for leading toy companies such as Mattel and Fisher-Price, because of the use of dangerous lead-based paint. As one might anticipate, news reports and consumer protection agencies have been quick to condemn any action that falls within the “controversial” category. Indeed, many segments of society characterize such actions as unethical behavior. One result of this increased level of concern is the higher level of attention given to ethics in higher education programs. Even accreditation bodies such as AACSB have virtually mandated the integration of ethics into the curriculum. As a consequence, academicians have ramped up their ethics-based research agendas.

Discourse practice gaps in work life balance : comparative case studies in the Australian construction industry

Perspectives on work-life balance (WLB) reflected in political, media and organisational discourse, would maintain that WLB is on the agenda because of broad social, economic and political factors (Fleetwood 2007). In contrast, critical scholarship which examines work-life balance (WLB) and its associated practices maintains that workplace flexibility is more than a quasi-functionalist response to contemporary problems faced by individuals, families or organisations. For example, the literature identifies where flexible work arrangements have not lived up to expectations of a panacea for work-home conflicts, being characterised as much by employer-driven working conditions that disadvantage workers and constrain balance, as they are by employee friendly practices that enable it (Charlesworth 1997). Further, even where generous organisational work-life balance policies exist, under-utilisation is an issue (Schaefer et al, 2007). Compounding these issues is that many employees perceive their paid work as becoming more intense, pressured and demanding (Townsend et al 2003).

Students’ perceptions of a blended web-based learning environment

The enhanced accessibility, affordability and capability of the Internet has created enormous possibilities in terms of designing, developing and implementing innovative teaching methods in the classroom. As existing pedagogies are revamped and new ones are added, there is a need to assess the effectiveness of these approaches from the students’ perspective. For more than three decades, proven qualitative and quantitative research methods associated with learning environments research have yielded productive results for educators. This article presents the findings of a study in which Getsmart, a teacher-designed website, was blended into science and physics lessons at an Australian high school. Students’ perceptions of this environment were investigated, together with differences in the perceptions of students in junior and senior years of schooling. The article also explores the impact of teachers in such an environment. The investigation undertaken in this study also gave an indication of how effective Getsmart was as a teaching model in such environments.

Blur limits for defocus, astigmatism and trefoil

We investigated the limits at which blur due to defocus, crossed-cylinder astigmatism, and trefoil became noticeable, troublesome or objectionable. Black letter targets (0.1, 0.35 and 0.6 logMAR) were presented on white backgrounds. Subjects were cyclopleged and had effectively 5 mm pupils. Blur was induced with a deformable, adaptive-optics mirror operating under open-loop conditions. Mean defocus blur limits of six subjects with uncorrected intrinsic higher-order ocular aberrations ranged from 0.18 ± 0.08 D (noticeable blur criterion, 0.1 logMAR) to 1.01 ± 0.27 D (objectionable blur criterion, 0.6 logMAR. Crossed-cylinder astigmatic blur limits were approximately 90% of those for defocus, but with considerable meridional influences. In two of the subjects, the intrinsic aberrations of the eye were subsequently corrected before the defocus and astigmatic blur were added. This resulted in only minor reductions in their blur limits. When assessed with trefoil blur and corrected intrinsic ocular aberrations, the ratio of objectionable to noticeable blur limits in these two subjects was much higher for trefoil (3.5) than for defocus (2.5) and astigmatism (2.2).

Limits of spherical blur determined with an adaptive optics mirror

We extended an earlier study (Vision Research, 45, 1967–1974, 2005) in which we investigated limits at which induced blur of letter targets becomes noticeable, troublesome and objectionable. Here we used a deformable adaptive optics mirror to vary spherical defocus for conditions of a white background with correction of astigmatism; a white background with reduction of all aberrations other than defocus; and a monochromatic background with reduction of all aberrations other than defocus. We used seven cyclopleged subjects, lines of three high-contrast letters as targets, 3–6 mm artificial pupils, and 0.1–0.6 logMAR letter sizes. Subjects used a method of adjustment to control the defocus component of the mirror to set the 'just noticeable', 'just troublesome' and 'just objectionable' defocus levels. For the white-no adaptive optics condition combined with 0.1 logMAR letter size, mean 'noticeable' blur limits were ±0.30, ±0.24 and ±0.23 D at 3, 4 and 6 mm pupils, respectively. White-adaptive optics and monochromatic-adaptive optics conditions reduced blur limits by 8% and 20%, respectively. Increasing pupil size from 3–6 mm decreased blur limits by 29%, and increasing letter size increased blur limits by 79%. Ratios of troublesome to noticeable, and of objectionable to noticeable, blur limits were 1.9 and 2.7 times, respectively. The study shows that the deformable mirror can be used to vary defocus in vision experiments. Overall, the results of noticeable, troublesome and objectionable blur agreed well with those of the previous study. Attempting to reduce higher-order aberrations or chromatic aberrations, reduced blur limits to only a small extent.

Stochastic modelling of financial time series with memory and multifractal scaling

Financial processes may possess long memory and their probability densities may display heavy tails. Many models have been developed to deal with this tail behaviour, which reflects the jumps in the sample paths. On the other hand, the presence of long memory, which contradicts the efficient market hypothesis, is still an issue for further debates. These difficulties present challenges with the problems of memory detection and modelling the co-presence of long memory and heavy tails. This PhD project aims to respond to these challenges. The first part aims to detect memory in a large number of financial time series on stock prices and exchange rates using their scaling properties. Since financial time series often exhibit stochastic trends, a common form of nonstationarity, strong trends in the data can lead to false detection of memory. We will take advantage of a technique known as multifractal detrended fluctuation analysis (MF-DFA) that can systematically eliminate trends of different orders. This method is based on the identification of scaling of the q-th-order moments and is a generalisation of the standard detrended fluctuation analysis (DFA) which uses only the second moment; that is, q = 2. We also consider the rescaled range R/S analysis and the periodogram method to detect memory in financial time series and compare their results with the MF-DFA. An interesting finding is that short memory is detected for stock prices of the American Stock Exchange (AMEX) and long memory is found present in the time series of two exchange rates, namely the French franc and the Deutsche mark. Electricity price series of the five states of Australia are also found to possess long memory. For these electricity price series, heavy tails are also pronounced in their probability densities. The second part of the thesis develops models to represent short-memory and longmemory financial processes as detected in Part I. These models take the form of continuous-time AR(∞) -type equations whose kernel is the Laplace transform of a finite Borel measure. By imposing appropriate conditions on this measure, short memory or long memory in the dynamics of the solution will result. A specific form of the models, which has a good MA(∞) -type representation, is presented for the short memory case. Parameter estimation of this type of models is performed via least squares, and the models are applied to the stock prices in the AMEX, which have been established in Part I to possess short memory. By selecting the kernel in the continuous-time AR(∞) -type equations to have the form of Riemann-Liouville fractional derivative, we obtain a fractional stochastic differential equation driven by Brownian motion. This type of equations is used to represent financial processes with long memory, whose dynamics is described by the fractional derivative in the equation. These models are estimated via quasi-likelihood, namely via a continuoustime version of the Gauss-Whittle method. The models are applied to the exchange rates and the electricity prices of Part I with the aim of confirming their possible long-range dependence established by MF-DFA. The third part of the thesis provides an application of the results established in Parts I and II to characterise and classify financial markets. We will pay attention to the New York Stock Exchange (NYSE), the American Stock Exchange (AMEX), the NASDAQ Stock Exchange (NASDAQ) and the Toronto Stock Exchange (TSX). The parameters from MF-DFA and those of the short-memory AR(∞) -type models will be employed in this classification. We propose the Fisher discriminant algorithm to find a classifier in the two and three-dimensional spaces of data sets and then provide cross-validation to verify discriminant accuracies. This classification is useful for understanding and predicting the behaviour of different processes within the same market. The fourth part of the thesis investigates the heavy-tailed behaviour of financial processes which may also possess long memory. We consider fractional stochastic differential equations driven by stable noise to model financial processes such as electricity prices. The long memory of electricity prices is represented by a fractional derivative, while the stable noise input models their non-Gaussianity via the tails of their probability density. A method using the empirical densities and MF-DFA will be provided to estimate all the parameters of the model and simulate sample paths of the equation. The method is then applied to analyse daily spot prices for five states of Australia. Comparison with the results obtained from the R/S analysis, periodogram method and MF-DFA are provided. The results from fractional SDEs agree with those from MF-DFA, which are based on multifractal scaling, while those from the periodograms, which are based on the second order, seem to underestimate the long memory dynamics of the process. This highlights the need and usefulness of fractal methods in modelling non-Gaussian financial processes with long memory.

Econometric analysis of stuctural systems with permanent and transitory shocks

This paper considers the implications of the permanent/transitory decomposition of shocks for identification of structural models in the general case where the model might contain more than one permanent structural shock. It provides a simple and intuitive generalization of the influential work of Blanchard and Quah [1989. The dynamic effects of aggregate demand and supply disturbances. The American Economic Review 79, 655–673], and shows that structural equations with known permanent shocks cannot contain error correction terms, thereby freeing up the latter to be used as instruments in estimating their parameters. The approach is illustrated by a re-examination of the identification schemes used by Wickens and Motto [2001. Estimating shocks and impulse response functions. Journal of Applied Econometrics 16, 371–387], Shapiro and Watson [1988. Sources of business cycle fluctuations. NBER Macroeconomics Annual 3, 111–148], King et al. [1991. Stochastic trends and economic fluctuations. American Economic Review 81, 819–840], Gali [1992. How well does the ISLM model fit postwar US data? Quarterly Journal of Economics 107, 709–735; 1999. Technology, employment, and the business cycle: Do technology shocks explain aggregate fluctuations? American Economic Review 89, 249–271] and Fisher [2006. The dynamic effects of neutral and investment-specific technology shocks. Journal of Political Economy 114, 413–451].

Closing the cultural distance gap: managing value-based knowledge in MNC by using MEP

Today more than ever, generating and managing knowledge is an essential source of competitive advantage for every organization, and particularly for Multinational corporations (MNC). However, despite the undisputed agreement about the importance of creating and managing knowledge, there are still a large number of corporations that act unethically or illegally. Clearly, there is a lack of attention in gaining more knowledge about the management of ethical knowledge in organizations. This paper refers to value-based knowledge, as the process of recognise and manage those values that stand at the heart of decision-making and action in organizations. In order to support MNCs in implementing value-based knowledge process, the managerial ethical profile (MEP) has been presented as a valuable tool to facilitate knowledge management process at both the intra-organizational network level and at the inter-organizational network level.