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.

Formative and summative assessment and the notion of constructive alignment

This paper discusses the different perceptions of first year accounting students about their tutorial activities and their engagements in assessment. As the literature suggests, unless participation in learning activities forms part of graded assessment, it is often difficult to engage students in these activities. Using an action research model, this paper reports the study of first year accounting students' responses to action-oriented learning tasks in tutorials. The paper focuses on the importance of aligning curriculum objectives, learning and teaching activities and assessment, i.e. the notion of constructive alignment. However, as the research findings indicate, without support at institutional level, applying constructive alignment to facilitate quality student learning outcomes is a difficult task. Thus, the impacts of policy constraints on curriculum issues are also discussed, focusing on the limitations faced by tutors and their lack of involvement in curriculum development.

Formative and Summative Assessment and the Notion of Constructive Allignment

This paper discusses perceptions of first year accounting students about their tutorial activities and their engagements in assessment. As the literature suggests, unless participation in learning activities forms part of graded assessment it is often difficult to engage students in these activities. Using an action research model, this paper reports the study of first year accounting students' responses to action-orientated learning tasks in tutorials. The paper focuses on the importance of aligning curriculum objectives, learning and teaching activities and assessment,i.e. the notion of constructive alignment. However, as the research findings indicate, without support at institutional level, applying constructive alignment to facilitate quality student learning outcomes is a difficult task. Thus, the impacts of policy constraints on curriculum issues are also discussed, focusing on the limitations faced by tutors and their lack of involvement in curriculum development.

Rethinking the notion of culture in the national history curriculum

Major global changes are placing new demands on the Australian education system. Recent statements by the Prime Minister, together with current education policy and national curriculum documents available in the public domain, look to education’s role in promoting economic prosperity and social cohesion. Collectively, they emphasise the need to equip young Australians with the knowledge, understandings and skills required to compete in the global economy and participate as engaged citizens in a culturally diverse world. However, the decision to prioritise discipline-based learning in the forthcoming Australian history curriculum without specifically encompassing culture as a referent, raises the following question. How will students acquire the cultural knowledge, understandings and skills necessary for this process? This paper addresses this question by situating the current push for a national history curriculum, with specific reference to the study of Indigenous history and the study of Asia in Australia.

L'étendue internationale des nouvelles firmes de hautes technologies: le rôle du capital humain et de l'intention stratégique des fondateurs

De récentes recherches ont mis l’accent sur l’importance pour les nouvelles entreprises internationales de l’existence de ressources et de compétences spécifiques. La présente recherche, qui s’inscrit dans ce courant, montre en particulier l’importance du capital humain acquis par les entrepreneurs sur base de leur expérience internationale passée. Mais nous montrons en même temps que ces organisations sont soutenues par une intention délibérée d’internationalisation dès l’origine. Notre recherche empirique est basée sur l’analyse d’un échantillon de 466 nouvelles entreprises de hautes technologies anglaises et allemandes. Nous montrons que ce capital humain est un actif qui facilite la pénétration rapide des marchés étrangers, et plus encore quand l’entreprise nouvelle est accompagnée d’une intention stratégique délibérée d’internationalisation. Des conclusions similaires peuvent être étendues au niveau des ressources que l’entrepreneur consacre à la start-up : plus ces ressources sont importantes, plus le processus d’internationalisation tend à se faire à grande échelle ; et là aussi, l’influence de ces ressources est augmenté par l’intention stratégique d’internationalisation. Dans le cadre des études empiriques sur les born-globals (entreprises qui démarrent sur un marché globalisé), cette recherche fournit une des premières études empiriques reliant l’influence des conditions initiales de création aux probabilités de croissance internationale rapide.

De la reconstruction a l’augmentation du corps humain en medecine restaurative et en cybernetique

Aux confluences historiques et conceptuelles de la modernité, de la technologie, et de l’« humain », les textes de notre corpus négocient et interrogent de façon critique les possibilités matérielles et symboliques de la prothèse, ses aspects phénoménologiques et spéculatifs : du côté subjectiviste et conceptualiste avec une philosophie de la conscience, avec Merleau-Ponty ; et de l’autre avec les épistémologues du corps et historiens de la connaissance Canguilhem et Foucault. Le trope prometteur de la prothèse impacte sur les formations discursives et non-discursives concernant la reconstruction des corps, là où la technologie devient le corrélat de l’identité. La technologie s’humanise au contact de l’homme, et, en révélant une hybridité supérieure, elle phagocyte l’humain du même coup. Ce travail de sociologie des sciences (Latour, 1989), ou encore d’anthropologie des sciences (Hakken, 2001) ou d’anthropologie bioculturelle (Andrieu, 1993; Andrieu, 2006; Andrieu, 2007a) se propose en tant qu’exemple de la contribution potentielle que l’anthropologie biologique et culturelle peut rendre à la médecine reconstructrice et que la médecine reconstructrice peut rendre à la plastique de l’homme ; l’anthropologie biologique nous concerne dans la transformation biologique du corps humain, par l’outil de la technologie, tant dans son histoire de la reconstruction mécanique et plastique, que dans son projet d’augmentation bionique. Nous établirons une continuité archéologique, d’une terminologie foucaldienne, entre les deux pratiques. Nous questionnons les postulats au sujet des relations nature/culture, biologie/contexte social, et nous présentons une approche définitionnelle de la technologie, pierre angulaire de notre travail théorique. Le trope de la technologie, en tant qu’outil adaptatif de la culture au service de la nature, opère un glissement sémantique en se plaçant au service d’une biologie à améliorer. Une des clés de notre recherche sur l’augmentation des fonctions et de l’esthétique du corps humain réside dans la redéfinition même de ces relations ; et dans l’impact de l’interpénétration entre réalité et imaginaire dans la construction de l’objet scientifique, dans la transformation du corps humain. Afin de cerner les enjeux du discours au sujet de l’« autoévolution » des corps, les théories évolutionnistes sont abordées, bien que ne représentant pas notre spécialité. Dans le cadre de l’autoévolution, et de l’augmentation bionique de l’homme, la somation culturelle du corps s’exerce par l’usage des biotechnologies, en rupture épistémologique de la pensée darwinienne, bien que l’acte d’hybridation évolutionnaire soit toujours inscrit dans un dessein de maximisation bionique/génétique du corps humain. Nous explorons les courants de la pensée cybernétique dans leurs actions de transformation biologique du corps humain, de la performativité des mutilations. Ainsi technologie et techniques apparaissent-elles indissociables de la science, et de son constructionnisme social.

Resurrecting the notion of journalistic objectivity : a discussion of journalistic objectivity in one-on-one interviews

A number of recent books on ethics (Hirst and Patching 2005, Tanner et al, 2005, Ward, 2006)have indicated that traditional understandings of journalism "objectivity" are in need of renovation if they are to sustain the claim as a guide to ethical action. Ward argues for the recasting of the notions of traditional objectivity to offer a "pragmatic objectivity" as an alternative and plausible underpinning to ethical journalism practice. He argues that a recast or "pragmatic objectivity" should respond to the changing rhetorical relationship between journalists and their audiences; and, in so doing, should take inspiration from attempts to be objective in other domains---professions such as law and public relations in seeking models. This paper seeks to take a step in that direction through illustrating how journalism interviews do "objectivity" through an adaptation of the principles of the "Fourth Estate" to political interviews. It turns such analysis to the ends of establishing the particular "pragmatic ethic" underpinning such practices and how journalism interviewing techniques has allowed for proactive journalists to strike a workable balance between pursuing the public interest and observing the restraining protocols of modern journalistic practice.

Expert science teacher's notion of scientific literacy

This paper will report on the way expert science teachers’ conceive of scientific literacy in their classrooms, the values related to scientific literacy they hold and how this conception and the underpinning values affect their teaching practice. Three perceived expert science teachers who teach both at senior and middle school levels and across the range of sub-disciplines (one senior biology, one senior chemistry and one senior physics) were interviewed about their understanding of scientific literacy and how this influenced their teaching practice. The three teachers were video recorded teaching a junior science class and a senior science class. The data were analysed to identify values that underpin their conceptions of science and science education. The analysis focussed on the matching of the verbalised conceptions and values with their practice of teaching science. This paper will report on these data.

Creating 'saviour siblings' : the notion of harming by conceiving in the context of healthy children

Over the past decade there have been a number of families who have utilised assisted reproductive technologies (ARTs) to create a tissue-matched child, with the purpose of using the child’s tissue to cure an existing sick child. This inevitably brings such families a sense of hope as the ultimate aim is to overcome a family health crisis. However, this specific use of reproductive technologies has been the subject of significant criticism, most of which is levelled against the potential harm to the ‘saviour’ child. In Australia, families seeking to access reproductive technologies in this context are therefore required to justify their motives to an ethics committee in order to establish, amongst other things, whether the child will suffer harm once born. This paper explores the concept of harm in the context of conception, focusing on whether it is possible to ‘harm’ a healthy child who has been conceived to save another. To achieve this, the paper will evaluate the impact of the ‘non-identity’ principle in the ‘saviour sibling’ context, and assess the existing body of literature which addresses ‘harm’ in the context of conception. As will be established, the majority of such literature has focused on ‘wrongful life’ cases which seek to address whether an existing child who has been born with a disability, has been harmed. Finally, this paper will distinguish the harm arguments in the ‘saviour sibling’ context based on the fact that the harm evaluation concerns the ‘future-life’ assessment of a healthy child.

State of multilevel research perspective in the information systems discipline

Existing distinctions among macro and micro approaches have been jeopardising the advances of Information Systems (IS) research. Both approaches have been criticized for explaining one level while neglecting the other; thereby, the current situation necessitates the application of multilevel research for revealing the deficiencies. Instead of studying single level (macro or micro), multilevel research entails more than one level of conceptualization and analysis, simultaneously. As the notion of multilevel is borrowed from reference disciplines, there tends to be confusions and inconsistencies within the IS discipline, which hinders the adoption of multilevel research. This paper speaks for the potential value of multilevel research, by investigating the current application status of multilevel research within the IS domain. A content analysis of multilevel research articles from major IS conferences and journals is presented. Analysis results suggest that IS scholars have applied multilevel research to produce high quality work ranging from a variety of topics. However, researchers have not yet been consistently defining “multilevel”, leading to idiosyncratic meanings of multilevel research, most often, in authors’ own interpretations. We argue that a rigorous definition of “multilevel research” needs to be explicated for consistencies in research community.

International corporate entrepreneurship among SMEs : a test of Stevenson's notion of entrepreneurial management

Geographical market expansion is included in various definitions of entrepreneurship as it entails the opening up of new markets (for example, Davidsson 2003). Expansion into new international markets and launch of new products in international markets are also consistent with definitions of entrepreneurship which center on the pursuit of opportunities {e.g.\Stevenson, 1983 #922;Gartner, 1993 #931}. Accordingly, the decision by managers of small, internationally active businesses to continue to internationalize can be viewed as an entrepreneurial act. In spite of the fact that both start-ups and existing firms can behave entrepreneurially by expanding into new international markets, the attention of entrepreneurship researchers interested in international activities has largely focused on international new ventures (INVs); that is, business organizations that internationalize from inception (Oviatt, and McDougall 1994; Oviatt, and McDougall 1997). Consequently, pursuit of international opportunities by established small and medium-sized enterprises (SMEs) lacks theoretical understanding and empirical investigation through an entrepreneurship lens. This paper contributes to the body of knowledge at the entrepreneurship-internationalization interface by testing whether Stevenson’s opportunity-based conceptualization of entrepreneurial management (Stevenson 1983; Stevenson and Gumpert 1985; Stevenson and Jarillo 1990) can explain the attainment of continued entrepreneurial outcomes by SMEs operating in foreign markets. We choose Stevenson’s conceptualization as it gauges firm-level characteristics that are theorized to facilitate the pursuit of entrepreneurial opportunities, which arguably is at the heart of SMEs’ continued venturing into international markets.