Listening, sharing understanding and facilitating consumer, family and community empowerment through a priority driven partnership in Far North Queensland

Objectives: This paper provides an example of a mental health research partnership underpinned by empowerment principles that seeks to foster strength among community organizations to support better outcomes for consumers, families and communities. It aims to raise awareness among researchers and service providers that empowerment approaches to assist communities to address mental health problems are not too difficult to be practical but require long-term commitment and appropriate support. Methods: A collaborative research strategy that has become known as the Priority Driven Research (PDR) Partnership emerged through literature review,consultations, Family Wellbeing Program delivery with community groups and activities in two discrete Indigenous communities. Progress to date on three of the four components of the strategy is described. Results: The following key needs were identified in a pilot study and are now being addressed in a research-based implementation phase: (i) gaining two-way understanding of perspectives on mental health and promoting universal awareness; (ii) supporting the empowerment of carers, families, consumers and at-risk groups through existing community organizations to gain greater understanding and control of their situation; (iii) developing pathways of care at the primary health centre level to enable support of social and emotional wellbeing as well as more integrated mental health care; (iv) accessing data to enable an ongoing process of analysis/sharing/planning and monitoring to inform future activity. Conclusion: One of the key learnings to emerge in this project so far is that empowerment through partnership becomes possible when there is a concerted effort to strengthen grassroots community organizations. These include social health teams and men’s and women’s groups that can engage local people in an action orientation. Key words: Aboriginal, empowerment, Indigenous, mental health.

Biochemical characterization of Aprataxin, the protein deficient in Ataxia with Oculomotor Apraxia type 1

Neurodegenerative disorders are heterogenous in nature and include a range of ataxias with oculomotor apraxia, which are characterised by a wide variety of neurological and ophthalmological features. This family includes recessive and dominant disorders. A subfamily of autosomal recessive cerebellar ataxias are characterised by defects in the cellular response to DNA damage. These include the well characterised disorders Ataxia-Telangiectasia (A-T) and Ataxia-Telangiectasia Like Disorder (A-TLD) as well as the recently identified diseases Spinocerebellar ataxia with axonal neuropathy Type 1 (SCAN1), Ataxia with Oculomotor Apraxia Type 2 (AOA2), as well as the subject of this thesis, Ataxia with Oculomotor Apraxia Type 1 (AOA1). AOA1 is caused by mutations in the APTX gene, which is located at chromosomal locus 9p13. This gene codes for the 342 amino acid protein Aprataxin. Mutations in APTX cause destabilization of Aprataxin, thus AOA1 is a result of Aprataxin deficiency. Aprataxin has three functional domains, an N-terminal Forkhead Associated (FHA) phosphoprotein interaction domain, a central Histidine Triad (HIT) nucleotide hydrolase domain and a C-terminal C2H2 zinc finger. Aprataxins FHA domain has homology to FHA domain of the DNA repair protein 5’ polynucleotide kinase 3’ phosphatase (PNKP). PNKP interacts with a range of DNA repair proteins via its FHA domain and plays a critical role in processing damaged DNA termini. The presence of this domain with a nucleotide hydrolase domain and a DNA binding motif implicated that Aprataxin may be involved in DNA repair and that AOA1 may be caused by a DNA repair deficit. This was substantiated by the interaction of Aprataxin with proteins involved in the repair of both single and double strand DNA breaks (XRay Cross-Complementing 1, XRCC4 and Poly-ADP Ribose Polymerase-1) and the hypersensitivity of AOA1 patient cell lines to single and double strand break inducing agents. At the commencement of this study little was known about the in vitro and in vivo properties of Aprataxin. Initially this study focused on generation of recombinant Aprataxin proteins to facilitate examination of the in vitro properties of Aprataxin. Using recombinant Aprataxin proteins I found that Aprataxin binds to double stranded DNA. Consistent with a role for Aprataxin as a DNA repair enzyme, this binding is not sequence specific. I also report that the HIT domain of Aprataxin hydrolyses adenosine derivatives and interestingly found that this activity is competitively inhibited by DNA. This provided initial evidence that DNA binds to the HIT domain of Aprataxin. The interaction of DNA with the nucleotide hydrolase domain of Aprataxin provided initial evidence that Aprataxin may be a DNA-processing factor. Following these studies, Aprataxin was found to hydrolyse 5’adenylated DNA, which can be generated by unscheduled ligation at DNA breaks with non-standard termini. I found that cell extracts from AOA1 patients do not have DNA-adenylate hydrolase activity indicating that Aprataxin is the only DNA-adenylate hydrolase in mammalian cells. I further characterised this activity by examining the contribution of the zinc finger and FHA domains to DNA-adenylate hydrolysis by the HIT domain. I found that deletion of the zinc finger ablated the activity of the HIT domain against adenylated DNA, indicating that the zinc finger may be required for the formation of a stable enzyme-substrate complex. Deletion of the FHA domain stimulated DNA-adenylate hydrolysis, which indicated that the activity of the HIT domain may be regulated by the FHA domain. Given that the FHA domain is involved in protein-protein interactions I propose that the activity of Aprataxins HIT domain may be regulated by proteins which interact with its FHA domain. We examined this possibility by measuring the DNA-adenylate hydrolase activity of extracts from cells deficient for the Aprataxin-interacting DNA repair proteins XRCC1 and PARP-1. XRCC1 deficiency did not affect Aprataxin activity but I found that Aprataxin is destabilized in the absence of PARP-1, resulting in a deficiency of DNA-adenylate hydrolase activity in PARP-1 knockout cells. This implies a critical role for PARP-1 in the stabilization of Aprataxin. Conversely I found that PARP-1 is destabilized in the absence of Aprataxin. PARP-1 is a central player in a number of DNA repair mechanisms and this implies that not only do AOA1 cells lack Aprataxin, they may also have defects in PARP-1 dependant cellular functions. Based on this I identified a defect in a PARP-1 dependant DNA repair mechanism in AOA1 cells. Additionally, I identified elevated levels of oxidized DNA in AOA1 cells, which is indicative of a defect in Base Excision Repair (BER). I attribute this to the reduced level of the BER protein Apurinic Endonuclease 1 (APE1) I identified in Aprataxin deficient cells. This study has identified and characterised multiple DNA repair defects in AOA1 cells, indicating that Aprataxin deficiency has far-reaching cellular consequences. Consistent with the literature, I show that Aprataxin is a nuclear protein with nucleoplasmic and nucleolar distribution. Previous studies have shown that Aprataxin interacts with the nucleolar rRNA processing factor nucleolin and that AOA1 cells appear to have a mild defect in rRNA synthesis. Given the nucleolar localization of Aprataxin I examined the protein-protein interactions of Aprataxin and found that Aprataxin interacts with a number of rRNA transcription and processing factors. Based on this and the nucleolar localization of Aprataxin I proposed that Aprataxin may have an alternative role in the nucleolus. I therefore examined the transcriptional activity of Aprataxin deficient cells using nucleotide analogue incorporation. I found that AOA1 cells do not display a defect in basal levels of RNA synthesis, however they display defective transcriptional responses to DNA damage. In summary, this thesis demonstrates that Aprataxin is a DNA repair enzyme responsible for the repair of adenylated DNA termini and that it is required for stabilization of at least two other DNA repair proteins. Thus not only do AOA1 cells have no Aprataxin protein or activity, they have additional deficiencies in PolyADP Ribose Polymerase-1 and Apurinic Endonuclease 1 dependant DNA repair mechanisms. I additionally demonstrate DNA-damage inducible transcriptional defects in AOA1 cells, indicating that Aprataxin deficiency confers a broad range of cellular defects and highlighting the complexity of the cellular response to DNA damage and the multiple defects which result from Aprataxin deficiency. My detailed characterization of the cellular consequences of Aprataxin deficiency provides an important contribution to our understanding of interlinking DNA repair processes.

Shaping the 'at-risk' youth : risk, governmentality and the Finn Report

The category of the `at-risk youth' currently underpins a good deal of youth policy, and in particular, education policy. Primarily, the category is centred around a range of programmes associated with the need for state intervention, intervention which largely occurs `at a distance' within domains such as the school and the family. While it is argued that in some ways, the `at-risk youth' simply replaces older characterisations used in the policing of the young, it will also be argued that the preventative policies associated with `risk' are constituted in terms of factors rather than individuals; that prevention is no longer primarily based upon personal expertise, but rather upon the gathering and collation of statistical knowledge which identifies `risks' within given populations; and that `risk' permits a greater number of young people to be brought into the field of regulatory strategies. Importantly, the category of the `at-risk youth' underpins crucial sections of policy documents such as the Finn Report (into credentialling/ education and vocational competency). In this case, youth is deemed to be `at-risk' of not making the transition to adulthood successfully. It will be argued that not only is the Finn Report significant in the administrative and cultural shaping of the category of `youth', but also by employing the notion of `risk', the Report puts in place yet another element of an effective network of governmental intelligibility covering the young. Finally, it will be argued that young women, as a specific example of a `risk' group (vis-a-vis obtaining certain types of employment), require particular forms of intervention, primarily through changing the vocational aspirations of their parents.

The family attitude scale : reliability and validity of a new scale for measuring the emotional climate of families

Research on outcomes from psychiatric disorders has highlighted the importance of expressed emotion (EE), but its cost-effective measurement remains a challenge. This article describes development of the Family Attitude Scale (FAS), a 30-item instrument that can be completed by any informant. Its psychometric characteristics are reported in parents of undergraduate students and in 70 families with a schizophrenic member. The total FAS had high internal consistency in all samples, and reports of angry behaviour in FAS items showed acceptable inter-rater agreement. The FAS was associated with the reported anger, anger expression and anxiety of respondents. Substantial associations between the parents' FAS and the anger and anger expression of students was also observed. Parents of schizophrenic patients had higher FAS scores than parents of students, and the FAS was higher if disorder duration was longer or patient functioning was poorer. Hostility, high criticism and low warmth on the Camberwell Family Interview (CFI) were associated with a more negative FAS. The highest FAS in the family was a good predictor of a highly critical environment on the CFI. The FAS is a reliable and valid indicator of relationship stress and expressed anger that has wide applicability.

Entrepreneurship and family firms : growth and survival

Family businesses dominate in a majority of economies (Astrachan and Shanker, 2003; Chrisman, Chua, and Sharma, 2005; Morck and Yeung, 2004). As entrepreneurial activities have been shown to be central to economic growth it is essential that family businesses, irrespective of ownership patterns, not only survive but also grow thus growing the economy overall. While a great deal is known about entrepreneurial activities and a body of knowledge is being developed in relation to entrepreneurial processes in family firms, more needs to be understood in relation to the dynamics of entrepreneurial activities at the individual family firm level. One area of particular interest is the dynamics within the business and the family and how these dynamics impact upon entrepreneurial activities. Specifically how relationships between and among family members engaged in the business can interact with professional non-family member senior executives. The senior executives can actively use their positions in such ways that initiatives suggested by family members are less successful than they might be. This paper addresses how ‘family’ aspects of a business can assist or impede the entrepreneurial activities of individuals. It takes into account some of the unique features of family businesses – such as the importance of ‘familiness’ as a competitive advantage; the direct links between ownership and control of a business and the recognition (often implicit) that individuals in families do make a difference to how the business functions (Habbershon and Williams, 1999, Sharma, 2004; and Tokarczyk, Hansen Green, and Down, 2007). This emphasis on individuals in families fits well with the idea of entrepreneur as individual, as expressed by Schumpeter (1934), Baumol et al (2007). The theoretical approach that adopted to explore the dynamics of processes occurring within family firms is structuration theory combined with a theory of embeddeness (Dacin, Ventresca and Beal, 1999; Giddens, 1979, 1984, Jack and Anderson, 2002; and Sarason, Dean and Dillard, 2006).

Application of cognitive-behavioural family intervention for schizophrenia in multidisciplinary teams : what can the matter be?

Surveyed 45 therapists who had participated in a family intervention for schizophrenia training program to examine the difficulties they had encountered, their recall of the intervention strategies, and the extent that they thought the approach had become integrated in their everyday work. Between 6 mo and 3 yrs after the family training, Ss reported the number of families they had systematically treated, and the difficulties they had encountered. Allowance of time to undertake the intervention, afterhours scheduling, and illness or holidays presented particular difficulties. Only 4% reported that their knowledge of behavioral techniques was a problem, but in a written test most therapists did not display minimum recall of the material of cognitive therapy, social skills training, or behavioral strategies. The study demonstrated significant problems in disseminating cognitive-behavioral approaches to multidisciplinary settings.

Slice of Brisbane in family shadows

Review of 'The True Story of Butterfish', Brisbane Festival / Brisbane Powerhouse, published in The Australian, 6 October 2009.

Unsettling portrait of family strife

Review of 'The Wishing Well', Queensland Theatre Company, published in The Australian, 30 March 2009.

Kallikrein-related peptidase 4 activation of protease-activated receptor family members and association with prostate cancer

Two areas of particular importance in prostate cancer progression are primary tumour development and metastasis. These processes involve a number of physiological events, the mediators of which are still being discovered and characterised. Serine proteases have been shown to play a major role in cancer invasion and metastasis. The recently discovered phenomenon of their activation of a receptor family known as the protease activated receptors (PARs) has extended their physiological role to that of signaling molecule. Several serine proteases are expressed by malignant prostate cancer cells, including members of the kallikreinrelated peptidase (KLK) serine protease family, and increasingly these are being shown to be associated with prostate cancer progression. KLK4 is highly expressed in the prostate and expression levels increase during prostate cancer progression. Critically, recent studies have implicated KLK4 in processes associated with cancer. For example, the ectopic over-expression of KLK4 in prostate cancer cell lines results in an increased ability of these cells to form colonies, proliferate and migrate. In addition, it has been demonstrated that KLK4 is a potential mediator of cellular interactions between prostate cancer cells and osteoblasts (bone forming cells). The ability of KLK4 to influence cellular behaviour is believed to be through the selective cleavage of specific substrates. Identification of relevant in vivo substrates of KLK4 is critical to understanding the pathophysiological roles of this enzyme. Significantly, recent reports have demonstrated that several members of the KLK family are able to activate PARs. The PARs are relatively new members of the seven transmembrane domain containing G protein coupled receptor (GPCR) family. PARs are activated through proteolytic cleavage of their N-terminus by serine proteases, the resulting nascent N-terminal binds intramolecularly to initiate receptor activation. PARs are involved in a number of patho-physiological processes, including vascular repair and inflammation, and a growing body of evidence suggests roles in cancer. While expression of PAR family members has been documented in several types of cancers, including prostate, the role of these GPCRs in prostate cancer development and progression is yet to be examined. Interestingly, several studies have suggested potential roles in cellular invasion through the induction of cytoskeletal reorganisation and expression of basement membrane-degrading enzymes. Accordingly, this program of research focussed on the activation of the PARs by the prostate cancer associated enzyme KLK4, cellular processing of activated PARs and the expression pattern of receptor and agonist in prostate cancer. For these studies KLK4 was purified from the conditioned media of stably transfected Sf9 insect cells expressing a construct containing the complete human KLK4 coding sequence in frame with a V5 epitope and poly-histidine encoding sequences. The first aspect of this study was the further characterisation of this recombinant zymogen form of KLK4. The recombinant KLK4 zymogen was demonstrated to be activatable by the metalloendopeptidase thermolysin and amino terminal sequencing indicated that thermolysin activated KLK4 had the predicted N-terminus of mature active KLK4 (31IINED). Critically, removal of the pro-region successfully generated a catalytically active enzyme, with comparable activity to a previously published recombinant KLK4 produced from S2 insect cells. The second aspect of this study was the activation of the PARs by KLK4 and the initiation of signal transduction. This study demonstrated that KLK4 can activate PAR-1 and PAR-2 to mobilise intracellular Ca2+, but failed to activate PAR-4. Further, KLK4 activated PAR-1 and PAR-2 over distinct concentration ranges, with KLK4 activation and mobilisation of Ca2+ demonstrating higher efficacy through PAR-2. Thus, the remainder of this study focussed on PAR-2. KLK4 was demonstrated to directly cleave a synthetic peptide that mimicked the PAR-2 Nterminal activation sequence. Further, KLK4 mediated Ca2+ mobilisation through PAR-2 was accompanied by the initiation of the extra-cellular regulated kinase (ERK) cascade. The specificity of intracellular signaling mediated through PAR-2 by KLK4 activation was demonstrated by siRNA mediated protein depletion, with a reduction in PAR-2 protein levels correlating to a reduction in KLK4 mediated Ca2+mobilisation and ERK phosphorylation. The third aspect of this study examined cellular processing of KLK4 activated PAR- 2 in a prostate cancer cell line. PAR-2 was demonstrated to be expressed by five prostate derived cell lines including the prostate cancer cell line PC-3. It was also demonstrated by flow cytometry and confocal microscopy analyses that activation of PC-3 cell surface PAR-2 by KLK4 leads to internalisation of this receptor in a time dependent manner. Critically, in vivo relevance of the interaction between KLK4 and PAR-2 was established by the observation of the co-expression of receptor and agonist in primary prostate cancer and prostate cancer bone lesion samples by immunohistochemical analysis. Based on the results of this study a number of exciting future studies have been proposed, including, delineating differences in KLK4 cellular signaling via PAR-1 and PAR-2 and the role of PAR-1 and PAR-2 activation by KLK4 in prostate cancer cells and bone cells in prostate cancer progression.

Modernist 16-19 Business Education in a Postmodern world - critical evidence of business practice and business education in the cultural industries

This article examines the continued relevance of the 16-19 business education curriculum in the UK, stimulated by doubts expressed by Thomas (1996), over its continued relevance. We express a concern that business education needs, but is struggling, to respond to significant societal shifts in consumption and production strategies that do not sit easily within traditional theories of business practice currently underpinning 16-19 business education. We examine firstly, the extent to which a formal body of knowledge couched in a modernist discourse of facts and objectivity can cope with the changing and fluid developments in much current business practice that is rooted in the cultural and symbolic. Secondly, the extent to which both academic and vocational competences provide the means for students to develop a framework of critical understanding that can respond effectively to rapidly changing business environments.Findings are based on research conducted jointly by the University of Manchester and the Manchester Institute for Popular Culture at Manchester Metropolitan University. The growth of dynamism of the cultural industries sector - largely micro-businesses and small and medium sized enterprises (SMEs) -encapsulates forms of business knowledge, business language and business practice which may not immediately fit with the models provided within business education. Results suggest increasingly reflexive forms of consumption being met by similarly reflexive and flexible modes of production.Our evidence suggests that whilst modernist business knowledge is often the foundation for many 16-19 business education courses, these programmes of study/training do not usually reflect the activities of SME and micro-business practitioners in the cultural industries. Given the importance of cultural industries in terms of the production strategies required to meet increasingly reflexive markets, it is suggested that there may be a need to incorporate a postmodern approach to the current content and pedagogy; one that is contextual, cultural and discursive.