University General - Research Publications
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ItemNo Preview AvailableMof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture(AMER SOC MICROBIOLOGY, 2008-08)Acetylation of histone tails is a hallmark of transcriptionally active chromatin. Mof (males absent on the first; also called MYST1 or KAT8) is a member of the MYST family of histone acetyltransferases and was originally discovered as an essential component of the X chromosome dosage compensation system in Drosophila. In order to examine the role of Mof in mammals in vivo, we generated mice carrying a null mutation of the Mof gene. All Mof-deficient embryos fail to develop beyond the expanded blastocyst stage and die at implantation in vivo. Mof-deficient cell lines cannot be derived from Mof(-/-) embryos in vitro. Mof(-/-) embryos fail to acetylate histone 4 lysine 16 (H4K16) but have normal acetylation of other N-terminal histone lysine residues. Mof(-/-) cell nuclei exhibit abnormal chromatin aggregation preceding activation of caspase 3 and DNA fragmentation. We conclude that Mof is functionally nonredundant with the closely related MYST histone acetyltransferase Tip60. Our results show that Mof performs a different role in mammals from that in flies at the organism level, although the molecular function is conserved. We demonstrate that Mof is required specifically for the maintenance of H4K16 acetylation and normal chromatin architecture of all cells of early male and female embryos.
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ItemOsteoclast Inhibitory Lectin, an Immune Cell Product That Is Required for Normal Bone Physiology in Vivo(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2008-11-07)Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice. These mice appeared healthy and were fertile, with no apparent immune function defect, and phenotypic abnormalities were limited to bone. Histomorphometric analysis revealed a significantly lower tibial trabecular bone volume and trabecular number in the 10- and 16-week-old male ocil(-/-) mice compared with wild type mice. Furthermore, ocil(-/-) mice showed reduced bone formation rate in the 10-week-old females and 16-week-old males while Static markers of bone formation showed no significant changes in male or female ocil(-/-) mice. Examination of bone resorption markers in the long bones of ocil(-/-) mice indicated a transient increase in osteoclast number per unit bone perimeter. Enhanced osteoclast formation was also observed when either bone marrow or splenic cultures were generated in vitro from ocil(-/-) mice relative to wild type control cultures. Loss of ocil therefore resulted in osteopenia in adult mice primarily as a result of increased osteoclast formation and/or decreased bone formation. The enhanced osteoclastic activity led to elevated serum calcium levels, which resulted in the suppression of circulating parathyroid hormone in 10-week-old ocil(-/-) mice compared with wild type control mice. Collectively, our data suggest that OCIL is a physiological negative regulator of bone.
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ItemMacronuclear genome sequence of the ciliate Tetrahymena thermophila, a model eukaryote.(Public Library of Science (PLoS), 2006-09)The ciliate Tetrahymena thermophila is a model organism for molecular and cellular biology. Like other ciliates, this species has separate germline and soma functions that are embodied by distinct nuclei within a single cell. The germline-like micronucleus (MIC) has its genome held in reserve for sexual reproduction. The soma-like macronucleus (MAC), which possesses a genome processed from that of the MIC, is the center of gene expression and does not directly contribute DNA to sexual progeny. We report here the shotgun sequencing, assembly, and analysis of the MAC genome of T. thermophila, which is approximately 104 Mb in length and composed of approximately 225 chromosomes. Overall, the gene set is robust, with more than 27,000 predicted protein-coding genes, 15,000 of which have strong matches to genes in other organisms. The functional diversity encoded by these genes is substantial and reflects the complexity of processes required for a free-living, predatory, single-celled organism. This is highlighted by the abundance of lineage-specific duplications of genes with predicted roles in sensing and responding to environmental conditions (e.g., kinases), using diverse resources (e.g., proteases and transporters), and generating structural complexity (e.g., kinesins and dyneins). In contrast to the other lineages of alveolates (apicomplexans and dinoflagellates), no compelling evidence could be found for plastid-derived genes in the genome. UGA, the only T. thermophila stop codon, is used in some genes to encode selenocysteine, thus making this organism the first known with the potential to translate all 64 codons in nuclear genes into amino acids. We present genomic evidence supporting the hypothesis that the excision of DNA from the MIC to generate the MAC specifically targets foreign DNA as a form of genome self-defense. The combination of the genome sequence, the functional diversity encoded therein, and the presence of some pathways missing from other model organisms makes T. thermophila an ideal model for functional genomic studies to address biological, biomedical, and biotechnological questions of fundamental importance.
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ItemNo Preview AvailableFecal colonization with vancomycin-resistant enterococci in Australia(CENTER DISEASE CONTROL, 2000)To assess the rate of fecal vancomycin-resistant enterococci (VRE) colon ization in Austalia, we examined specimens from 1,085 healthy volunteers. VRE was cultured from 2(0.2%) of 1,085 specimens; both were vanB Enter ococcus faecium, identical by pulsed-field gel electrophoresis, but with a pattern rare in Melbourne hospitals.
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ItemNo Preview AvailableA randomized, blinded, controlled trial investigating the gastrointestinal health effects of drinking water quality(US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE, 2001-08)A double-blinded, randomized, controlled trial was carried out in in Melbourne, Australia, to determine the contribution of drinking water to gastroenteritis. Melbourne is one of the few major cities in the world that draws drinking water from a protected forest catchment with minimal water treatment (chlorination only). Six hundred families were randomly allocated to receive either real or sham water treatment units (WTUs) installed in their kitchen. Real units were designed to remove viruses, bacteria, and protozoa. Study participants completed a weekly health diary reporting gastrointestinal symptoms during the 68-week observation period. There were 2,669 cases of highly credible gastroenteritis (HCG) during the study (0.80 cases/person/year). The ratio of HCG episode rates for the real WTU group compared to the sham WTU group was 0.99 (95% confidence interval, 0.85-1.15, p = 0.85). We collected 795 fecal specimens from participants with gastroenteritis, and pathogens were not more significantly common in the sham WTU group. We found no evidence of waterborne disease in Melbourne. The application of this methodology to other water supplies will provide a better understanding of the relationship between human health and water quality.
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ItemNo Preview AvailableFaces of integration.(Ubiquity Press, Ltd., 2009-12-22)THEME: Two central themes permeate this paper-the interplay between structure and agency in integration processes and the extent to which this is mediated through sensemaking by individual actors. CASE STUDY: The empirical base for the paper is provided by case study research from Wales which draws on examples of different types of integration in health and social care. The individual case studies highlight different interpretations of integration set against a background of the resources involved, processes employed and outcomes achieved. DISCUSSION: A wide ranging discussion exposes the complex interplay and dynamics between structural factors and the manner in which they enable or constrain integration, and individual actors realising their potential agency through leadership, professionalism and boundary spanning to influence outcomes. The importance of structure and agency complementing each other to determine effective integration is emphasised, together with the scope that is available for interpretation and meaning by individual actors within the contested discourse of integration.
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ItemNo Preview AvailableThe design of a valid and reliable questionnaire to measure osteoporosis knowledge in women: the Osteoporosis Knowledge Assessment Tool (OKAT)(BMC, 2003-07-24)BACKGROUND: Osteoporosis knowledge is an important contributor to improving exercise and calcium intake behaviour. However, there are few validated instruments for measuring osteoporosis knowledge levels. The aim of this study was to design a valid and reliable instrument to measure osteoporosis knowledge in Australian women. METHODS: A 20 item instrument with true, false and don't know responses was drafted, based on the Osteoporosis Australia Osteoporosis Prevention and Self-management course and the information leaflet "Understanding Osteoporosis". The scoring range was 1 to 20. This was administered to a 467 randomly-selected, healthy women aged 25-44 years. Questionnaire performance was assessed by Flesch reading ease, index of difficulty, Ferguson's sigma, inter-item and item-total correlations, Cronbach's alpha and principal component factor analysis. RESULTS: Flesch reading ease was higher than desirable at 45, but this was due to the use of the word osteoporosis in many items. Of the individual items 17 had an index of difficulty less than 0.75. The questionnaire had a Ferguson's sigma of 0.96, a Cronbach's alpha of 0.70 and factor analysis consistent with only one factor (osteoporosis knowledge) being measured. Levels of osteoporosis knowledge were low with a mean score of 8.8 out of 20 which suggests the OKAT may be sensitive to change. CONCLUSIONS: The OKAT for measuring osteoporosis knowledge has good psychometric properties in Australian 25-44 year old females. While it should be applicable to other Caucasian populations, this will require confirmation by further research.
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ItemNo Preview AvailableMembrane-bound Fas ligand only is essential for Fas-induced apoptosis(NATURE PUBLISHING GROUP, 2009-10-01)Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.
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ItemIn vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs(NATURE PUBLISHING GROUP, 2008-07-15)TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.
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ItemNo Preview AvailableRevealing the intricacies of cancer.(Springer Science and Business Media LLC, 2002)A report on the 14th Lorne Cancer Conference, Lorne, Victoria, Australia, 14-17 February 2002.