Theses (M.S.)--Marshall University, 2007. / Title from document title page. Includes abstract. Document formatted into pages: contains vii, 96 p. Includes vitae. Bibliography: p. 87-92.

Thesis (Ph. D.)--Texas State University-San Marcos, 2006. / Vita. Appendices: leaves 343-357. Includes bibliographical references (leaves 358-370).

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Thesis submitted in fulfillment of the requirements for the degree of Masters in Technology: Biomedical Sciences in the Faculty of Health and Wellness Sciences at the Cape Peninsula University of Technology 2015 / Background: The Mixed Ancestry population of South Africa has recently been reported to have a higher prevalence of type 2 diabetes (T2DM). However, the genetic risk factors that may contribute to the development of T2DM are currently unknown. We investigated the association of fat mass and obesity-associated gene (FTO), ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) and transcription factor 7-like 2 gene (TCF7L2) with T2DM risk in a community residing in Bellville South, Cape Town. Methods: Five hundred and sixty six participants (11.7% males) who consented to genetic analyses were genotyped for six single nucleotide polymorphisms (SNPs): ENPP1-rs997509 and -rs1044498, FTO-9941349 and -rs3751812, TCF7L2-rs12255372 and -rs7903146. The SNPs were genotyped using their corresponding Taqman genotyping assays, and validated by automated sequencing. Allele and genotype frequencies were determined and regression analyses was conducted to assess the association of the polymorphisms with T2DM and its related,traits. Results: Overall and in subgroups defined by diabetes and obesity statuses, there were present no significant differences in the distribution of alleles and genotypes, except for the polymorphisms observed in the FTO and ENPP1 genes. In logistic regression models adjusted for age, sex, body mass index (BMI) and insulin resistance, minor alleles of ENPP1-rs997509 and ENPP1-rs1044498 were associated with risk for T2DM respectively, 4.55 (1.06-19.49) (p=0.041) and 1.81 (1.09-2.98) (p=0.021) assuming a recessive genetic model. Furthermore, the FTO rs9941349 minor allele was associated with the prevalent T2DM under the log-additive model: 1.40 (1.00 to 1.96) (0.049). The TCF7L2 polymorphisms showed no evidence of association with T2DM and/or insulin sensitivity/resistance indicators. Conclusion: Our results demonstrate that ENPP1 and FTO polymorphisms may contribute to T2DM susceptibility in this population, confirming previous findings that insulin resistance may mediate the development of the disease in the Mixed Ancestry population group of South Africa.

The present study was designed to explore the mind-body connection within a psychosocial-cultural context. More specifically, the current investigator hoped to examine how various dimensions of the mind and body interact with psychosocial-environmental factors, which are significantly influenced by cultural processes and reference group membership A cross-sectional study was designed to examine the relationship between health beliefs and health behaviors in sample of 419 adults with Type II diabetes with a focus on the moderating effects of social support, emotional reactions, and experiences of unfair treatment. A self-report questionnaire comprised of 90-items obtained from previously established measures of health beliefs, psychosocial-cultural factors, and health behaviors was administered online via Qualtrics.com. Results of testing a series of measurement and structural models using confirmatory factor analysis (CFA) showed poor fit across all models specified. While these results indicated that the expanded Health Belief Model (eHBM) specified for this study did not adequately describe the diabetes-related thoughts, attitudes, and behaviors for the current sample of participants, findings may have provided preliminary evidence of a three-factor structure reflecting participants’ worries and concerns about their health & perceptions involving challenges or obstacles to successful behavior change, which could interfere with daily life. Although it is unclear whether these results were related to limitations in the measurement instruments and study design, or to differences in the nature of the constructs and the ways in which participants interpreted and responded to the scales, the overall findings of this study suggest a need for research that examines the equivalence of health belief and health behavior measures and greater empirical evidence to ensure that the theories and models used in health research are generalizable across groups of people with varying world-views, identities and lived experiences. Implications for the Health Belief Model (HBM) and ideas for future research are discussed.

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Abnormal regulation of growth hormone (GH) secretion has been reported in some patients with insulin-dependent diabetes (IDD). We compared the GH responses in 32 healthy subjects (age 25 ± 2 SE years) and in 23 IDD patients (28 ± 1.9 years old, diabetes duration 10.4 ± 2 years, and glycohemoglobin levels 9.3 ± 2.0%). During acute, severe hypoglycemia (glucose < 40 mg/dl), the mean GH levels were similar. When prolonged mild hypoglycemia was induced (58.0 ± 2.0 mg/dl in the controls and 54.0 ± 2.0 mg/dl in the IDD patients), the mean GH levels were similar, although the increase in GH was delayed in the latter group. During brief (30 min) exercise at 40-50% of VO2 max, GH rose comparably in both groups (IDD patients maintained euglycemia with basal insulin infusion). However, with more prolonged and intense exercise using a glucose clamp to maintain euglycemia, GH rose to 5.4 ± 2.2 ng/ml in controls and 26.4 ± 12.6 ng/ml in the diabetics (P < 0.05). When the combination of intense exercise and hypoglycemia (~ 55 mg/dl) was used, GH rose to a peak of 21.7 ± 2.7 ng/ml in the controls and to 33 ± 3.0 ng/ml in the diabetics (P = NS). Our data show that in insulin-infused IDD patients made euglycemic for these experiments: a) The GH response to acute, severe hypoglycemia was identical to that in the controls and the response to mild, prolonged hypoglycemia was delayed, but of similar magnitude compared with controls; b) Exercise-induced GH responses were observed in both groups, but exaggerated in the diabetics at a higher exercise intensity; c) Hypoglycemia during exercise produced an additive effect on GH secretion in the controls but not in the IDD patients. We conclude that the wide range of abnormal GH secretory responses in type I diabetes reflects a central, possibly hypothalamic, defect in GH regulation.

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廣泛的區域內和跨民族的轉錄變化反映了人類的適應和自然選擇。基因表達是轉化基因組信息為功能基因產品 - 蛋白質的主要機制。異常基因的表達和疾病的發病機制有關。基因組革命提供了獨特的機會為複雜的人類轉錄組進行全面的研究。轉錄分析需要複雜的生物信息學方法。在技術角度，一個實證模型用了哺乳動物基因組中內含子長度幾何尾分佈的定律準確地確定剪接交界處和非唯一映射讀取的位置。這種方法在處理非唯一映射讀取比BWA更好。這方法還比其他工具檢測出更多已經實驗證實的剪接交界處。核糖核酸測序首先用於北京漢人和西歐之間的表達表型與的轉錄變化的詳盡研究。民族的具體剪接交界處被發現。此外，民族的具體特點體現在相對異構體的豐度差。最後，這分子表型剪接頻譜的變化在不同種族之間的不同表明了另一個描繪種族多樣性的方法，核糖核酸測序還被用於探索的一種複雜的疾病：二型糖尿病的分子異常。二型糖尿病表現在廣泛不同的基因表達。（1）這研究證實先前公佈的全基因組關聯研究;（2）改善策劃不佳的位點和（3）發現新型2型糖尿病相關的基因。本研究通過整合各種改變的信號，並在一個高度可信的基因 - 基因相互作用網絡進行解釋，增強表達異常在2型糖尿病的認識。在更廣泛的69×79的情況下，對照組的結果進行了驗證。本研究增強表達異常在2型糖尿病的認識。 / Extensive intra- and inter- ethnic transcriptome variation reflects human adaptation and natural selection. Gene expression is the primary mechanism that translates genome information into functional gene product that lead to physiological phenotypes. Aberrant gene expression has been associated to the pathogenesis of diseases. The genome revolution has offered unique opportunity for a comprehensive interrogation of the complexity of human transcriptome. Analysis of transcriptome using RNA-Seq requires sophisticated bioinformatics approach. In a technical perspective, an empirical model based on the geometric-tail distribution of intron lengths in mammalian genome was developed to accurately determine splice junctions from junction reads and locations of non-uniquely mapped reads. Such method handles non-uniquely mapped reads better than BWA. The method can also detect more experimentally confirmed splice junction than other tools. Expressional phenotyping was employed to explore global transcriptomic variation between Beijing Han Chinese and Western European. In addition to inter-ethnic variations in gene expression, ethnic specific splice juctions were found. Further, ethnic specific trait manifests in differential relative isoform abundance. Lastly, such spectrum of variations was different between different ethnic groups, suggesting alternative splicing as another molecular phenotype that delineates ethnic diversity. Expressional phenotyping was then used in a case-control study to explore the molecular abnormalities of a complex disease: Type 2 Diabetes (T2DM). T2DM manifested in wide-spread repression of gene expression. The study (1) confirmed previously reported Genome-wide Association Study (GWAS) loci; (2) curated poorly characteriezed GWAS loci and (3) discovered novel T2DM associated genes. By integrating various alteration signals and interpretation performed in a highly confident gene-gene interaction network, this study augmented the understanding of expressed abnormalities in T2DM. The results were validated in a broader 69 x 79 case-control group. / Detailed summary in vernacular field only. / Li, Jing Woei. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 118-130). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.v / 中文擇要 --- p.vi / Thesis/Assessment Committee --- p.ix / Acknowledgement --- p.ix / List of figures --- p.x / List of tables --- p.xii / List of Abbreviations --- p.xiii / Scientific contributions --- p.xv / List of Publication(s) related to this thesis --- p.xvi / Conference presentations --- p.xvii / Chapter Chapter 1: --- Introduction and Literature Reviews --- p.1 / Chapter 1.1 --- The variable human transcriptome --- p.1 / Chapter 1.2 --- Significance of variation in gene expression and transcript variants --- p.2 / Chapter 1.3 --- Transcriptomic study in a technological perspective --- p.8 / Chapter 1.3.1 --- Microarray: Probing what was designed to be probed --- p.8 / Chapter 1.3.2 --- RNA-Seq: the ab initio decoder of biological sequences --- p.9 / Chapter 1.4 --- Analysis of RNA-Seq data --- p.10 / Chapter 1.4.1 --- The bioinformatics challenges prevail --- p.10 / Chapter 1.4.2 --- Identifying changes in gene expression --- p.16 / Chapter 1.4.3 --- Identifying splice site, quantification of isoform level expression --- p.17 / Chapter 1.5 --- Conclusion --- p.19 / Chapter 1.6 --- Aims of this study --- p.20 / Chapter 1.6.1 --- Splice junction determination --- p.20 / Chapter 1.6.2 --- Expressional phenotyping in ethnical context --- p.20 / Chapter 1.6.3 --- Expressional phenotyping in a disease context --- p.20 / Chapter Chapter 2: --- Detection of splicing events --- p.21 / Chapter 2.1 --- Abstract --- p.21 / Chapter 2.2 --- Introduction --- p.22 / Chapter 2.3 --- Methods and workflow --- p.25 / Chapter 2.4 --- Algorithm --- p.29 / Chapter 2.5 --- Geometric-tail distribution --- p.32 / Chapter 2.6 --- Insert-size distribution --- p.33 / Chapter 2.7 --- Multiread analysis --- p.34 / Chapter 2.7.1 --- GT model probably places multiread more accurately than BWA --- p.35 / Chapter 2.8 --- Splice-site comparison --- p.37 / Chapter 2.8.1 --- GT model discovers more experimentally confirmed splice junction --- p.37 / Chapter 2.8.2 --- GT model is highly accurate --- p.39 / Chapter 2.9 --- Discussion --- p.40 / Chapter 2.10 --- Limitation --- p.40 / Chapter Chapter 3: --- Transcriptomic variation in a ethnicity context --- p.41 / Chapter 3.1 --- Abstract --- p.41 / Chapter 3.2 --- Introduction --- p.42 / Chapter 3.3 --- Materials and Methods --- p.46 / Chapter 3.3.1 --- HapMap lymphoblastoid cell-lines --- p.46 / Chapter 3.3.2 --- Sequenced samples --- p.48 / Chapter 3.3.3 --- Paired-end RNA-Seq, dataset and reads processing --- p.48 / Chapter 3.3.4 --- Genome reference and annotation --- p.49 / Chapter 3.3.5 --- Strategies for reads mapping --- p.49 / Chapter 3.3.6 --- Pathway and Gene Ontology analysis --- p.50 / Chapter 3.3.7 --- Differential gene expression analysis --- p.50 / Chapter 3.3.8 --- Ethnic specific splice junction --- p.51 / Chapter 3.3.9 --- Junction sites saturation analysis --- p.51 / Chapter 3.3.10 --- Ethnical novel transcribed regions --- p.52 / Chapter 3.3.11 --- Isoform dynamics and meta-analysis --- p.53 / Chapter 3.4 --- Result --- p.54 / Chapter 3.4.1 --- Paired-end RNA-Seq --- p.54 / Chapter 3.4.2 --- Differential gene expression and meta-analysis --- p.56 / Chapter 3.4.3 --- Ethnic specific splice junction is rare --- p.58 / Chapter 3.4.4 --- Saturation of discovery of highly confident annotated junctions --- p.59 / Chapter 3.4.5 --- Novel transcribed regions --- p.62 / Chapter 3.4.6 --- Isoform dynamics and meta-analysis --- p.63 / Chapter 3.5 --- Discussion --- p.66 / Chapter 3.6 --- Limitations --- p.67 / Chapter 3.6.1 --- HapMap LCLs may not reflect the entire spectrum of natural variation --- p.67 / Chapter 3.6.2 --- Sequencing depth and the usefulness of published dataset --- p.67 / Chapter 3.6.3 --- Knowledge gap in understanding of the human genome --- p.69 / Chapter Chapter 4: --- Transcriptomic investigation of complex disease: Type 2 Diabetes --- p.70 / Chapter 4.1 --- Abstract --- p.70 / Chapter 4.2 --- Introduction --- p.72 / Chapter 4.3 --- Materials and Methods --- p.75 / Chapter 4.3.1 --- Subjects --- p.75 / Chapter 4.3.2 --- Strand-specific RNA-Seq Library Construction --- p.77 / Chapter 4.3.3 --- Genome annotation sequencing reads processing --- p.81 / Chapter 4.3.4 --- Reads mapping for expression analysis --- p.82 / Chapter 4.3.5 --- Differential Gene expression analysis --- p.82 / Chapter 4.3.6 --- GWAS candidate genes --- p.83 / Chapter 4.3.7 --- Individual network, pathway and Gene Ontology analysis --- p.83 / Chapter 4.3.8 --- Alternative Splicing Variation --- p.83 / Chapter 4.3.9 --- Reads mapping and processing for expressed genomic variants discovery --- p.84 / Chapter 4.3.10 --- Expressed and functional genomic variants --- p.85 / Chapter 4.3.11 --- Screening for gene fusion --- p.86 / Chapter 4.3.12 --- Sense and Antisense analysis --- p.86 / Chapter 4.3.13 --- Integrated multi-level T2DM alternations gene interaction network --- p.87 / Chapter 4.3.14 --- Validation of selected genes --- p.87 / Chapter 4.4 --- Results --- p.88 / Chapter 4.4.1 --- High quality strand-specific pair-ended RNA-Seq facilitated downstream analyses --- p.88 / Chapter 4.4.2 --- Definition of significance --- p.91 / Chapter 4.4.3 --- Wide-spread repressed gene expression in T2DM --- p.91 / Chapter 4.4.4 --- Confirmation and curation of T2DM GWAS loci by RNA-Seq --- p.92 / Chapter 4.4.5 --- Global expression alteration on T2DM associated genes --- p.97 / Chapter 4.4.6 --- Alteration of relative splicing isoforms variations and T2DM specific isoforms --- p.100 / Chapter 4.4.7 --- Rare and deleterious SNPs --- p.100 / Chapter 4.4.8 --- Absence of alteration in Sense/Antisense ratio and expressed fusion gene --- p.101 / Chapter 4.4.9 --- T2DM manifests a broad spectrum of expressed abnormalities --- p.101 / Chapter 4.4.10 --- Pathway-based integration of multiple levels of alteration expanded the T2DM network --- p.103 / Chapter 4.4.11 --- Validation of selected genes --- p.107 / Chapter 4.5 --- Discussion --- p.108 / Chapter Chapter 5: --- Conclusions and future perspectives --- p.115 / Chapter 5.1 --- Conclusions --- p.115 / Chapter 5.2 --- Future perspective --- p.115 / Chapter 5.2.1 --- Splicing detection --- p.115 / Chapter 5.2.2 --- Studies related to ethnicity --- p.116 / Chapter 5.2.3 --- Complex diseases --- p.116 / References --- p.118 / Appendix --- p.131