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Diabetes is a complex group of metabolic disorders with genetic, immunological, and environmental etiologies. Decades of diabetes research have elucidated many genetic drivers of normal islet function and dysfunction. Furthermore, genome wide associated studies (GWAS) have discovered that most diabetes susceptibility loci fall outside of coding regions, which suggests a role for noncoding elements in the development of disease. This highlights our incomplete understanding of the islet regulome and suggests the need for detailed functional analyses of noncoding genes to precisely determine their contribution to diabetes susceptibility and disease progression. Transcriptome analyses have revealed that the eukaryotic genome is pervasively transcribed. Strikingly, only a small proportion of the transcriptome is subsequently translated into protein; the majority is made up non-protein coding RNAs (ncRNAs). The most abundant class of these ncRNAs are called long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides that lack protein-coding potential. The establishment of lncRNAs, once dismissed as genomic dark matter, as essential gene regulators in many biological processes has redefined the central role for RNA in cells. While evidence suggests a role for lncRNAs in islets and diabetes, in vivo functional characterization of islet lncRNAs is lacking. For my thesis project, I sought to understand the lncRNA regulatory mechanisms that promote pancreas development and function. We conducted comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets and identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors. One of the candidate lncRNAs, Pax6 Upstream Antisense RNA (Paupar), mapped near Pax6, a gene encoding an essential pancreatic regulatory protein. We demonstrate Paupar is enriched in glucagon-producing alpha cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential alpha cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of Pax6 alpha cell target genes and corresponding alpha cell dysfunction. These findings illustrate a distinct mechanism by which lncRNAs can contribute to cell-specific regulation of broadly expressed transcription factors to coordinate critical functions within a cell.

CpG islands (CGIs) are short GC rich sequences with a high frequency of CpGs that are associated with the active chromatin mark H3K4me3. Most occur at gene promoters and are often free of cytosine methylation. Recent work has begun to clarify the functional significance of CGIs with respect to chromatin structure and transcription. In particular, proteins associated with histone-modifying activities, such as Cfp1 and Kdm2a, bind specifically to non-methylated CGIs via their CxxC domains. For example, artificial promoterless CpG-rich sequences integrated at the 3’ UTR of genes recruit Cfp1 and generate novel peaks of H3K4me3 in mouse ES cells without apparent RNA polymerase recruitment. There is also evidence that G+C-rich DNA recruits H3K27me3, a gene silencing mark. In this thesis I am exploring the constraints on DNA sequence and genomic location that are required to impose both H3K4me3 and H3K27me3 at CGI sequences. Showing that the generation of novel peaks of H3K4me3 and H3K27me3 over a promoter-less CpG rich sequence in a gene desert region is independent of it’s location in the genome extends earlier findings. These findings suggest that shared features of the primary DNA sequence at CGIs directly influence chromatin modification. Thus CGIs are not passive footprints of other cellular mechanisms, but play an active role in setting up local chromatin structure. However, the relative contribution of CpG frequency versus G+C content remains unclear. Therefore a sequence was generated that contains low levels of CpGs, comparable to the bulk genome, but has a G+C content similar to that of CGIs (Low CpG / High G+C). When this sequence was inserted into a gene desert neither marks of H3K4me3 or H3K27me3 were formed, indicating the importance of CpGs. Surprisingly, the reverse sequence with a high CpG frequency similar to that of CGIs and a low G+C content similar to that of the bulk genome (High CpG / Low G+C) did not establish H3K4me3 or H3K27me3 either. However, it was found that this sequence becomes heavily methylated in contrast to CGI-like sequences that remained unmethylated when introduced into a gene desert. This finding suggests that a high G+C content is important for keeping CGI-like sequences methylation free. Upon insertion of this High CpG / Low G+C sequence into mouse ES cells that were devoid of the de-novo DNA methyltransferases 3a and 3b (Dnmt3a/3b -/-) both H3K4me3 and H3K27me3 marks were established at the inserted sequence. This discovery confirms the importance of CpGs for setting up local chromatin structure.

Metabolic syndrome defines a cluster of related comorbidities including obesity, Type 2 diabetes, fatty liver disease, and cardiovascular diseases. Increasingly prevalent in Western countries, metabolic syndrome diseases are a major focus of efforts to understand the complex genetics that underlie disease risk and severity. Immunoglobulin domain-containing receptor 2 (ILDR2) is an ER transmembrane protein first identified as a candidate genetic modifier of diabetes susceptibility in the context of obesity. Obese, leptin-deficient mice with hypomorphic Ildr2 expression had hypoinsulinemic hyperglycemia with reduced beta cell mass, suggesting that ILDR2 plays a role in maintain beta cell mass and function. Further studies proposed a role for ILDR2 in hepatic lipid metabolism as Ildr2 shRNA-mediated knockdown (KD) caused hepatic steatosis in mice. The goal of this thesis work is to clarify the role of ILDR2 in diabetes and hepatic steatosis in an effort to elucidate the specific mechanism of ILDR2. We developed a conditional Ildr2 knockout (KO) allele, enabling tissue-specific ablation in mice. Liver-specific and hepatocyte-specific KO mice did not develop hepatic steatosis. However, liver-specific KO mice treated with adenoviral Ildr2 shRNA accumulated hepatic triglycerides, suggesting off-target effects of the shRNA. Using RNA sequencing and sequence alignment, several gene candidates for shRNA off-targeting effect were identified. Future studies are proposed to elucidate role(s) of these genes in the previously described phenotype of Ildr2 KD mice. I conclude that Ildr2 ablation may contribute to the development of hepatic steatosis, but does not play a major role in hepatic lipid metabolism. We also developed beta cell-specific (RIP2-cre) and pancreas-specific (Pdx-cre) Ildr2 KO mice and characterized them for diabetic phenotypes. Pancreas-specific KO mice displayed impaired glucose tolerance, reduced insulin secretion and decreased calcium signaling in islets. These results confirm a role for ILDR2 in islet cell function. Experiments performed in RIP2-cre beta cell-specific KO mice were confounded by effects of the Cre construct, prohibiting definitive conclusions about the role of ILDR2 in the beta cell. Additionally, because Ildr2 is expressed at low levels in beta cells, we propose that ILDR2 may function in islet macrophages. Overall, this work defines the metabolic functions of ILDR2, clarifying its role in hepatic lipid metabolism, and confirming its role in islet cell function. In addition, I discuss preliminary evidence suggesting that ILDR2 may function in the brain to regulate body weight and metabolism.

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No description available.

In Louisiana, barrier islands are undergoing morphological change driven by high rates of relative sea-level rise and interior wetland loss. Previous works utilized historical region-scale bathymetry and shoreline change analyses to assess coastal evolution. However, more localized assessments considering the role of sediment transport processes in regional evolution are lacking. This is essential to predicting coastal change trajectories and allocating limited sand resources for nourishment. Using bathymetric and shoreline data, 100-m spaced shore-normal transects were created to track meter-scale elevation change for 1880s, 1930s, 1980s, 2006, and 2015. An automated framework was used to quantify and track parameters such as shoreline change, barrier island area and width, bathymetric isobath migration, and shoreface slope. Our results illustrate that monitoring subaerial island erosion rates are insufficient for evaluating regional sediment dynamics of transgressive coastal systems. Advances in understanding these processes will facilitate more informed planning, management, and mitigation of transgressive barrier islands.

This study is concerned with the representation of women in leadership positions in Solomon Islands. In particular, it explores the educational leadership experiences of women working in Solomon Islands' secondary schools. While much research to date has been carried out in the developed and developing countries, very little has been undertaken in Melanesian countries. As such, we know very little about women's experiences in educational leadership in Melanesia. Research data was gathered using qualitative methods. Specifically, interviews were conducted with eight women, five were deputy principals and three were Heads of Departments. All the participants were teaching in schools in an urban centre. Data gathered were analyzed using the thematic analysis approach. The data gathering was conducted in the Solomon Islands in October 2007. The key findings revealed a number of issues that impacted on the women's leadership in their respective schools. Findings include lack of self confidence, difficulties in balancing work and family, discriminatory attitudes and the influence of the cultural patriarchal norms on the attitudes towards women in leadership positions. Other key findings related to the nature of the organization, in this case, the school. This included a lack of initial preparatory and on - going professional development programmes and a lack of consultation in the decision making process. This study also found that while the women embraced the collaborative approach to leadership, the structural barriers through the hierarchical organization of the schools meant they could not lead the way they would like to.

This study used the qualitative semi-structured interview method to collect data to discover Solomon Islands parents' educational and career aspirations for their children and their perceptions of formal secondary education in the Solomon Islands with respect to their children's preparation for meeting these aspirations. In carrying out the research, four couples were selected as participants and categorized into two groups according to their educational attainment (well educated and less educated). What was found was that, although parents have educational and career aspirations for their children, not all parents were specific. The findings also suggested that the career aspirations parents have were mainly influenced by economic and social factors rather than internal factors. In relation to parents' perception of the formal secondary education system in terms of preparing students for work, the findings suggested parents have both a positive and low opinion of formal secondary education in the Solomon Islands. There was also a mixed feeling and point to the idea that there are other factors such as teachers and curriculum subjects that impacted on the perceptions of success or vice-versa of the secondary education system. The findings also suggested that while parents appreciate the vocational curriculum and education system as preparing students for work (than secondary education), preference however was given to secondary education first and foremost.

This thesis is concerned with the ways Imperialism (and consequently colonialism) has pervaded the indigenous �primitive� world. Protectorates and �the colonies� reflected imperialist ideals, expansion, territory, external revenue and power. Missionaries were the footmen of colonial policy. The relations forged between these evangelists and the indigene have been thoroughly studied and scrutinised. However, reported interaction has been about missionaries and the �native�, with less about that between the indigenes, individual and tribe, elder and young. The thesis intends to redress this imbalance in the Bay of Islands from 1814 to 1834. The following work is an examination of a process of social change in Aotearoa. In the early 19th century the physical, spiritual and intellectual contact made between Maori peoples and the European explorers, scientists, and missionaries involved a deliberate cultural entanglement. It is the processes of acculturation, assimilation, or simply misunderstanding that are of interest. The study will have several foci involving the reaction of peoples of the Bay of Islands to the missionary institution of religious education. Chapter One addresses the theoretical location of the peoples that interacted in the Bay, while the second chapter is a brief description of a Maori coastal society prior to the arrival of literate missionaries. Chapter Three is about the cultural and social engagements of Ruatara, Marsden, Kendall and Hongi. The final chapter is a biographical exploration in the life of Rawiri Tawhanga and his interactions with missionaries and Maori of the Bay. Fundamentally it is the indigenous interaction during the initial periods of external European contact and, therefore, the effects of internal societal change that the author wishes to examine.