Identification of a BRCA1-mRNA splicing complex required for efficient DNA repair and maintenance of genomic stability

Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.

Establishing the conceptual and practical foundations of a new form of theatre for development: Theatre in conversations

This research was developed between Australia and Papua New Guinea (PNG) over two years investigating ways in which theatre for development could be held accountable for the claims it makes especially in PNG. The motivation to improve theatre for development (TfD) practice was triggered by the desire to enhance the democratic processes of collaboration and co–creativity often lacking in TfD activity in Papua New Guinea. Through creative practice as research and reflective processes, working with established and experienced local community theatre practitioners, a new form of theatre for development, Theatre in Conversations evolved. This form integrated three related genres of TfD including process drama, community theatre and community conversations. The suitability and impact of Theatre in Conversations was tested in three remote villages in PNG. Findings and outputs from the study have the potential to be used by theatre for development practitioners in other countries.

Destabilising Privilege: Disrupting Deficit Thinking in White Pre-service Teachers on Field Experience in Culturally Diverse, High Poverty Schools

This chapter examines the personal reflections and experiences of several pre-service and newly graduated teachers, including Kristie, who were involved in the NETDS program. Their documented professional journeys, which include descriptions of struggling when their privileged, taken-for-granted ways of being were destabilized, and grappling with tensions related to their own predispositions and values, are investigated in the context of Whiteness and privilege theory.

Evaluation of Interconnect Fabrics for an Embedded MPSoC in 28 nm FD-SOI

Embedded many-core architectures contain dozens to hundreds of CPU cores that are connected via a highly scalable NoC interconnect. Our Multiprocessor-System-on-Chip CoreVAMPSoC combines the advantages of tightly coupled bus-based communication with the scalability of NoC approaches by adding a CPU cluster as an additional level of hierarchy. In this work, we analyze different cluster interconnect implementations with 8 to 32 CPUs and compare them in terms of resource requirements and performance to hierarchical NoCs approaches. Using 28nm FD-SOI technology the area requirement for 32 CPUs and AXI crossbar is 5.59mm2 including 23.61% for the interconnect at a clock frequency of 830 MHz. In comparison, a hierarchical MPSoC with 4 CPU cluster and 8 CPUs in each cluster requires only 4.83mm2 including 11.61% for the interconnect. To evaluate the performance, we use a compiler for streaming applications to map programs to the different MPSoC configurations. We use this approach for a design-space exploration to find the most efficient architecture and partitioning for an application.

Unpacking director financial literacy

The social and economic effects of high profile governance scandals such as the National Safety Council, HIH and Centro have triggered much debate, reform and research into predicting and preventing future failures. While this has meant director financial literacy is now recognised as a core capability required of each individual director, there has been little guidance on what this capability involves other than the very general statement of being able to 'read and understand financial statements'. This thesis presents the results of a Delphi study aimed at identifying the core concepts a director needs to master to be financially literate. Thirty-five experts drawn from accounting, education and practice agreed that to be financially literate a director must have a conceptual understanding of 24 basic accounting concepts and be able to independently apply this understanding to a strategic evaluation of the finances of the organisation they serve.

Viewing systematic reviews and meta-analysis in social research through different lenses

Systematic reviews and meta-analyses are used to combine results across studies to determine an overall effect. Meta-analysis is especially useful for combining evidence to inform social policy, but meta-analyses of applied social science research may encounter practical issues arising from the nature of the research domain. The current paper identifies potential resolutions to four issues that may be encountered in systematic reviews and meta-analyses in social research. The four issues are: scoping and targeting research questions appropriate for meta-analysis; selecting eligibility criteria where primary studies vary in research design and choice of outcome measures; dealing with inconsistent reporting in primary studies; and identifying sources of heterogeneity with multiple confounded moderators. The paper presents an overview of each issue with a review of potential resolutions, identified from similar issues encountered in meta-analysis in medical and biological sciences. The discussion aims to share and improve methodology in systematic reviews and meta-analysis by promoting cross-disciplinary communication, that is, to encourage 'viewing through different lenses'.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Development of the dimensions of adult mastery motivation questionnaire

Mastery motivation is an important developmental construct that has implications for development across the lifespan. Research to date has focused predominantly on infants and children, with the Dimensions of Mastery Questionnaire (DMQ) being the most widely used measure of mastery motivation. This paper reports on the development and initial validation of an adult measure: the Dimensions of Adult Mastery Motivation Questionnaire (DAMMQ). Six hundred and twenty-eight adults (68 % female) aged 18 to 90 years completed the questionnaire. Factor analysis produced 24 items that represented five factors: task persistence, preference for challenge, task related pleasure, task absorption and competence/self-efficacy. The DAMMQ was found to have good internal consistency, test-retest reliability and concurrent validity. Within group differences for age, gender and education are reported. The development of the DAMMQ paves the way for future research about mastery motivation in adult populations.

Empowering PNG Women through Building Media Arts Production Capacity as Cultural Drivers: Showreel

The creative work comprises six short digital screen stories and emerges from a collaboration between the Discipline of Film Screen and Animation at Queensland University of Technology and the Centre for Social and Creative Media at University of Goroka, funded via the Department of Foreign Affairs and Trade's Australia Awards Fellowship. Six fellows traveled from Papua New Guinea to Brisbane for a two-week intensive course to learn the advanced skills necessary in order to create media that will empower women and girls to make more of their own economies in Papua New Guinea, and increase the representation of women and their well-being through leadership and decision-making. The resulting creative work is evidence of innovative media teaching-making methods designed to build human and cultural assets in PNG and address the increasing demand for media materials driven by the influx of mobile phones and internet services. The creative work provides a platform to directly address and positively impact gender issues in PNG and builds on the success of the Pawa Meri project, which trained six female directors to tell stories of women in leadership roles in PNG. One of the directors was a producer of this creative work. The creative work frames but problematises the complex issues influencing gender equity through the selection of content and narrative structures in ways which address the dynamics of male/female relationships and power in PNG society and will include strategies to illustrate transformed male and female behaviours. The creative work adopts a scaffolded approach, incorporating the findings of the Train the Trainer approach developed by UoG and QUT for the Life Drama research project. The creative work takes into account current developmental themes and approaches in the production of rich media products, and skills the key participants so that they are able to in turn train others in the wider community. The creative work was presented to partners and key stakeholders on 3 July 2015 at the Glasshouse, QUT Creative Industries Precinct and at the Dean’s Research Seminar Poster Exhibition 15 July 2015 at Room 212-213, Level 2, J Block, Gardens Point QUT and subsequent eBook. It has since returned to PNG to be showcased and distributed, and the skills and strategies disseminated.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.