The Identification of Genetic and Epigenetic Changes that Contribute to Type 1 Diabetes

Type 1 diabetes (T1D) results from an immune cell mediated destruction of insulin-producing pancreatic β cells. Currently there is no cure for T1D. The exact cause for T1D is unknown but growing evidence points to the contribution of both genetic and environmental factors, leading to a breakdown in immunological tolerance normally maintained by Regulatory T (Treg) cells. The exact environmental contributions to T1D progression are not well characterised but emerging studies suggest that they may alter the immune system via epigenetic modification. Recent data strongly link the breakdown in tolerance in T1D and other autoimmune diseases to alterations in the transcriptional program in CD4+ T cells, however, the molecular mechanisms are not well understood. This work proposes that in T1D causal genetic risk SNPs alter the gene expression patterns in CD4+ Treg and or T helper cells by either disrupting or creating new TF (transcription factor) binding sites in regulatory elements (enhancers) located in genetic susceptibility regions and this may combine with environmentally induced epigenetic change and alter chromatin accessibility. Current methods to identify the functional consequences and mechanisms of these changes are complex, time consuming and expensive as generally they can only examine one TF/binding site at a time, involve TF binding site prediction, which has a high degree of false positives/negatives and require large quantities of starting material making them challenging for application on limited clinical samples. To overcome these limitations, and to functionally annotate genetic risk of T1D, this study employs genome wide approaches including ATAC-seq and RNA-seq to compare the DNA accessibility and transcriptomes in CD4+ Treg and Th (Helper T)/Tconv (Conventional T) cells isolated from individuals with established T1D and sibling-matched healthy controls. By incorporating case-control ATAC-seq and TF footprints this study prioritises 111 and 96 T1D-associated SNPs in Treg and Tconv cells, respectively, that may play a role in mediating the disease susceptibility and subsequently contributing to the loss of tolerance in T1D. Using a bioinformatic pipeline to integrate case-control ATAC-seq differentially accessible peaks and RNA-seq differentially expressed genes with Hi-C 3D connectivity maps this study identifies 42 and 21 dysregulated gene targets in Treg and Tconv cells, respectively. Those targets include TIGIT, MAF and IL2 and the enhancers regulating those loci showed differential accessibility and are enriched for T1D SNPs and differential TF footprint signals. One theory to explain such observation is T1D SNPs and epigenetic alterations may alter or disrupt TF occupancy at these loci contributing to dysregulated target gene regulation. This study identifies changes in chromatin structure in T1D samples relative to healthy controls, enabling the identification of changes driven by both genetic and epigenetic variation that correlates with an altered transcriptional program in T1D. T1D associated SNPs at these regions can then be correlated with alterations in TF binding and putative epigenetically modified T1D regions can be validated in follow-up functional assays to demonstrate causality. This study captures chromatin and transcriptional changes between T1D and healthy individuals but it does not have the capability to distinguish if the changes are the driver or the consequence of the disease because the case cohort contains only established T1D from a single time point. In order to infer causality those changes would need to be tracked and validated over a timeline of disease progression in a longitudinal cohort. Nonetheless, this work provides a novel 3D genomic approach to functionally annotating the genetic risk and epigenetic changes that directly or indirectly result in altered gene expression, and promising preliminary data warranting further investigation on the causal functional role of the dysregulated gene targets in T1D.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 202

Remaining Competitive In China: a Case Study of Acic’s Business Model on Work-Integrated-Learning

This case study explores the strategy engaged by Australia China Investment Corporation (ACIC), taking into account the effects of globalization and the emerging-economy environment of the People’s Republic of China (PRC). Kes kajian ini menerokai strategi yang digunakan oleh Australia China Investment Corporation (ACIC), dengan mengambil kira kesan-kesan globalisasi and persekitaran ekonomi baru Republik Rakyat China (PRC)

Is text messaging a viable way to support parents? A systematic review, pilot study, and correlation study examining the feasibility, utility, and barriers to a parenting text messaging intervention

Many high school students, especially those from a low socioeconomic background, struggle with poor academic outcomes and school disengagement (Hopson & Lee, 2011; Lamb et al., 2015). Therefore, an easily accessible and affordable intervention would be useful to enhance teenagers’ academic performance and engagement. One way to enhance academic outcomes is through parenting, as parenting and parental involvement in teenagers’ education are associated with better students' academic performance (Boonk et al., 2018; Cheung & Pomerantz, 2012; Froiland et al., 2013; Hill & Tyson, 2009; Vasquez et al., 2016). To allow the intervention to be easily accessible with minimal cost for parents, I looked into delivering the intervention through text messages hosted by a smartphone application, as most families own a smartphone, and have internet access (e.g., Australian Bureau of Statistics, 2018). A systematic review was conducted to gain insight from studies which had previously utilised parenting text messages to improve students’ academic outcomes and engagement. The review suggested that text messaging interventions could feasibly deliver parenting interventions. Some studies showed that text messaging parenting interventions were effective in enhancing teenagers’ academic achievement and/or engagement. However, the effect sizes tended to be very small, and findings were not consistent across studies. Therefore, the present thesis proceeded with using text messages as an intervention-delivery medium to further investigate the effect of a text messaging parenting program. A text messaging intervention for parents was developed to improve their parenting practices and thereby enhance their high school teenagers’ academic achievement and engagement. To ensure the effectiveness of the program, I used the evidence-based Positive Parenting Program (Triple P) as the foundation of my intervention (Sanders & Mazzucchelli, 2018b). A pilot study was conducted to understand high school parents’ preferences on the intervention logistics and text message content. Results suggested that parents would like to receive parenting text messages once a day between 9:00 a.m. and 9:59 a.m., and at most five times per week, during weekdays. The Triple P messages were also well-received by parents (the average usefulness rating ranged from 3.80 to 4.35 out of 5, 5 being extremely useful, 1 being not at all useful). In addition, parents’ socioeconomic status was only somewhat associated with the perceived usefulness of the messages. This led to the next study which involved launching the Triple P text messaging intervention to high school parents. However, due to the impact of the Coronavirus Disease 2019 pandemic, recruitment became difficult, and therefore, the intervention study was redesigned to provide sufficient power for effect detection. Specifically, the study investigated the extent to which Triple P messages could add value to Triple P Online. Despite advertising the free parenting program to thousands of parents, the recruitment rate was low, resulting in an insufficient sample size to perform meaningful statistical analyses. Nevertheless, parents in the study found Triple P messages to be generally useful (average usefulness rating ranged from 3.10 to 4.29 out of 5, with 5 being very useful, 1 being not at all useful). The low recruitment rate of the Triple P messaging and Triple P Online intervention was surprising given the substantial adverting and the fact that Triple P Online was a well-established parenting program (Ralph & Sanders, 2013). Therefore, I conducted a follow-up study to investigate the barriers high school parents might face that hinder their participation in parenting programs, especially in online and text messaging parenting programs. The results revealed some factors (e.g., parenting style and parents' attitude in being involved in their teenagers’ education) that were associated with parents’ willingness to seek parental help from various sources (including from online resources), as well as parents’ intention to participate in online and/or text message parenting interventions. Factors such as parental self-efficacy, parenting style, and parents' attitude in being involved in their teenagers’ education also predicted whether parents found parenting help useful. Moreover, the study found evidence of parental help negation - parents who might benefit from help (e.g., parents with less positive parenting practices) were less likely to seek it. These results provided potential explanations for the low recruitment rate of the Triple P messaging and online study. Future studies should address these barriers and thereby better encourage parents to seek parenting help

Neurodevelopmental outcomes of children born preterm: analyses into the validity of data collection and outcome reports

Background and aims: Information on the neurodevelopmental outcomes of children born very preterm is required for multiple purposes. Reliable and up-to-date data sources are lacking. The overall aim of this thesis is to evaluate the validity and usability of the neurodevelopmental outcome data of very preterm children available from current data sources. The specific objectives were: 1) to examine the validity of outcome data recorded during routine follow-up assessment 2) to explore early childhood social-communication difficulties exhibited by very preterm children 3) to assess the stability over time of neurodevelopmental diagnoses made in early childhood. Methods: Three studies were conducted to meet the objectives. For studies 1 and 2, I recruited children born at <30 weeks’ gestation at 2 years corrected age (age corrected for prematurity) from 13 participating study sites. In study 1, I compared the agreement between the neurodevelopmental outcomes of 190 children recorded at their routine NHS assessments and data obtained by a research assessment using the Bayley Scales of Infant Development, 3rd edition. In study 2, the social-communication skills of 141 children were determined using the parent-completed Quantitative Checklist of Autism in Toddlers (Q-CHAT) questionnaire and compared to published results from the general population. In study 3, I conducted a systematic review and using meta-analytic methods, I calculated the pooled sensitivity and specificity of early developmental assessment in identifying school-age cognitive deficit from 24 studies. Conclusions: 1) Compared with research assessment, routine NHS follow-up assessment had a low sensitivity but high specificity for identifying children with neurodevelopmental impairment. 2) Very preterm children display greater early childhood social-communication difficulties and autistic behaviour than the general population as measured by their parents on the Q-CHAT. 3) Early neurodevelopmental assessment has high specificity but low sensitivity for identifying later school-age cognitive deficits.Open Acces