Rural Health - Research Publications
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ItemNo Preview AvailableGeneration and analysis of Siah2 mutant mice(AMER SOC MICROBIOLOGY, 2003-12)Siah proteins function as E3 ubiquitin ligase enzymes to target the degradation of diverse protein substrates. To characterize the physiological roles of Siah2, we have generated and analyzed Siah2 mutant mice. In contrast to Siah1a knockout mice, which are growth retarded and exhibit defects in spermatogenesis, Siah2 mutant mice are fertile and largely phenotypically normal. While previous studies implicate Siah2 in the regulation of TRAF2, Vav1, OBF-1, and DCC, we find that a variety of responses mediated by these proteins are unaffected by loss of Siah2. However, we have identified an expansion of myeloid progenitor cells in the bone marrow of Siah2 mutant mice. Consistent with this, we show that Siah2 mutant bone marrow produces more osteoclasts in vitro than wild-type bone marrow. The observation that combined Siah2 and Siah1a mutation causes embryonic and neonatal lethality demonstrates that the highly homologous Siah proteins have partially overlapping functions in vivo.
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ItemNo Preview AvailableThe ubiquitin ligase component Siah1a is required for completion of meiosis I in male mice(AMER SOC MICROBIOLOGY, 2002-04)The mammalian Siah genes encode highly conserved proteins containing a RING domain. As components of E3 ubiquitin ligase complexes, Siah proteins facilitate the ubiquitination and degradation of diverse protein partners including beta-catenin, N-CoR, and DCC. We used gene targeting in mice to analyze the function of Siah1a during mammalian development and reveal novel roles in growth, viability, and fertility. Mutant animals have normal weights at term but are postnatally growth retarded, despite normal levels of pituitary growth hormone. Embryonic fibroblasts isolated from mutant animals grow normally. Most animals die before weaning, and few survive beyond 3 months. Serum gonadotropin levels are normal in Siah1a mutant mice; however, females are subfertile and males are sterile due to a block in spermatogenesis. Although spermatocytes in mutant mice display normal meiotic prophase and meiosis I spindle formation, they accumulate at metaphase to telophase of meiosis I and subsequently undergo apoptosis. The requirement of Siah1a for normal progression beyond metaphase I suggests that Siah1a may be part of a novel E3 complex acting late in the first meiotic division.
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ItemThe retinoid anticancer signal: mechanisms of target gene regulation(NATURE PUBLISHING GROUP, 2005-08-08)Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.
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ItemStatistical analysis of an RNA titration series evaluates microarray precision and sensitivity on a whole-array basis(BMC, 2006-11-22)BACKGROUND: Concerns are often raised about the accuracy of microarray technologies and the degree of cross-platform agreement, but there are yet no methods which can unambiguously evaluate precision and sensitivity for these technologies on a whole-array basis. RESULTS: A methodology is described for evaluating the precision and sensitivity of whole-genome gene expression technologies such as microarrays. The method consists of an easy-to-construct titration series of RNA samples and an associated statistical analysis using non-linear regression. The method evaluates the precision and responsiveness of each microarray platform on a whole-array basis, i.e., using all the probes, without the need to match probes across platforms. An experiment is conducted to assess and compare four widely used microarray platforms. All four platforms are shown to have satisfactory precision but the commercial platforms are superior for resolving differential expression for genes at lower expression levels. The effective precision of the two-color platforms is improved by allowing for probe-specific dye-effects in the statistical model. The methodology is used to compare three data extraction algorithms for the Affymetrix platforms, demonstrating poor performance for the commonly used proprietary algorithm relative to the other algorithms. For probes which can be matched across platforms, the cross-platform variability is decomposed into within-platform and between-platform components, showing that platform disagreement is almost entirely systematic rather than due to measurement variability. CONCLUSION: The results demonstrate good precision and sensitivity for all the platforms, but highlight the need for improved probe annotation. They quantify the extent to which cross-platform measures can be expected to be less accurate than within-platform comparisons for predicting disease progression or outcome.
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ItemEmpirical array quality weights in the analysis of microarray data(BMC, 2006-05-19)BACKGROUND: Assessment of array quality is an essential step in the analysis of data from microarray experiments. Once detected, less reliable arrays are typically excluded or "filtered" from further analysis to avoid misleading results. RESULTS: In this article, a graduated approach to array quality is considered based on empirical reproducibility of the gene expression measures from replicate arrays. Weights are assigned to each microarray by fitting a heteroscedastic linear model with shared array variance terms. A novel gene-by-gene update algorithm is used to efficiently estimate the array variances. The inverse variances are used as weights in the linear model analysis to identify differentially expressed genes. The method successfully assigns lower weights to less reproducible arrays from different experiments. Down-weighting the observations from suspect arrays increases the power to detect differential expression. In smaller experiments, this approach outperforms the usual method of filtering the data. The method is available in the limma software package which is implemented in the R software environment. CONCLUSION: This method complements existing normalisation and spot quality procedures, and allows poorer quality arrays, which would otherwise be discarded, to be included in an analysis. It is applicable to microarray data from experiments with some level of replication.
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ItemTerminal osteoblast differentiation, mediated by runx2 and p27(KIP1), is disrupted in osteosarcoma(Rockefeller University Press, 2004-12-06)The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
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ItemAssessment of the structure of the Hospital Anxiety and Depression Scale in musculoskeletal patients.(Springer Science and Business Media LLC, 2005-12-19)BACKGROUND: Research suggests there is a high prevalence of anxiety and depression amongst patients with chronic musculoskeletal pain, which can influence the effectiveness of rehabilitation programs. It is therefore important for clinicians involved in musculoskeletal rehabilitation programs to consider screening patients for elevated levels of anxiety and depression and to provide appropriate counselling or treatment where necessary. The HADS has been used as a screening tool for assessment of anxiety and depression in a wide variety of clinical groups. Recent research however has questioned its suitability for use with some patient groups due to problems with dimensionality and the behaviour of individual items. The aim of this study is to assess the underlying structure and psychometric properties of the HADS among patients attending musculoskeletal rehabilitation. METHODS: Data was obtained from 296 patients attending an outpatient musculoskeletal pain clinic. The total sample was used to identify the proportion of patients with elevated levels of anxiety and depression. Half the sample (n = 142) was used for exploratory factor analysis (EFA), with the holdout sample (n = 154) used for confirmatory factor analysis (CFA) to explore the underlying structure of the scale. RESULTS: A substantial proportion of patients were classified as probable cases on the HADS Anxiety subscale (38.2%) and HADS Depression subscale (30.1%), with the sample recording higher mean HADS subscales scores than many other patient groups (breast cancer, end-stage renal disease, heart disease) reported in the literature. EFA supported a two factor structure (representing anxiety and depression) as proposed by the scale's authors, however item 7 (an anxiety item) failed to load appropriately. Removing Item 7 resulted in a clear two factor solution in both EFA and CFA. CONCLUSION: The high levels of anxiety and depression detected in this sample suggests that screening for psychological comorbidity is important in musculoskeletal rehabilitation settings. It is necessary for clinicians who are considering using the HADS as a screening tool to first assess its suitability with their particular patient group. Although EFA and CFA supported the presence of two subscales representing anxiety and depression, the results with this musculoskeletal sample suggest that item 7 should be removed from the anxiety subscale.
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ItemPerceptions of reconciliation and related indigenous issues among young residents of Shepparton(WILEY, 2007-01-01)It has been argued that reconciliation between Indigenous and non‐Indigenous Australians requires non‐Indigenous Australians to change their attitudes. Some suggest that this process is occurring and that younger people hold more positive attitudes towards Indigenous Australians. This paper explored the perspectives of 86 young people from Shepparton, Victoria in relation to reconciliation and related Indigenous issues. The study found that young participants' views of reconciliation varied, and while some supported reconciliation, many opposed a national apology and indicated that they were not very informed about or interested in Aboriginal issues. Many distinguished between ‘good’ and ‘bad’ Aboriginals based on behaviour. Their talk was embedded with notions of special privilege, ‘sameness’ and social hierarchy but excluded attention to cultural difference. Findings suggest that these young people have embraced discourses of sameness, individualism and ‘practical reconciliation’ and that they are reluctant to reflect on their position of White privilege.
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ItemShifting egalitarianisms and contemporary racism in rural Victorian football: The Rumbalara experience(WILEY, 2007-12)This article builds on our understanding of racism towards Aboriginal people in Australia through an examination of discriminatory belief structures pervasive in the mainstream community as evidenced through the important social field of country football in regional Victoria. It analyses the power and pervasiveness of the racial stereotyping that exists in some segments of the community by using Langton's (1997) notion of ‘iconic images' as well as discussing the importance of particular ideological motivations around values such as ‘egalitarianism’. This is achieved through analysing the views of players, supporters and officials of mainstream clubs towards the Aboriginal Rumbalara Football Netball Club. This analysis is structurally situated within a broader understanding of Australian national identity, in particular looking at the intersection of the powerful cultural domains of sport and evolving expressions of whiteness and egalitarianism.
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