Regulation of striated muscle differentiation and development are complex processes coordinated by an array of transcription factors. MEF2 is a crucial transcription factor required for muscle differentiation, but the roles of the individual MEF2 family members, MEF2A-D, have not been extensively evaluated. Acute ablation of Mef2 expression in skeletal myoblasts revealed a required role for MEF2A activity in myoblast differentiation that was not shared with the other MEF2 factors. We hypothesized that a transcriptomic level analysis of Mef2-deficient skeletal myoblasts would reveal distinct regulatory roles for each MEF2 isoform. Comparative microarray analysis supported our hypothesis and we observed distinct gene programs preferentially-sensitive to individual MEF2 isoforms. While there was no variance in the consensus binding site associated with regulation by individual MEF2 isoforms, we did observe uniquely enriched binding sites for candidate co-regulatory proteins that mediate these complex regulatory patterns. Based on our observations in skeletal myoblasts, we performed a series of acute Mef2 knockdowns in neonatal cardiomyocytes and uncovered a requirement for MEF2A and -D, but not MEF2C in cardiomyocyte survival. Comparative microarray analysis confirmed that, similar to skeletal myoblasts, the MEF2 family regulated distinct but overlapping gene programs in cardiomyocytes. Additionally, this analysis uncovered a previously uncharacterized antagonistic regulation of a subset of cell cycle and sarcomere genes. Interestingly, Mef2a and -d knockdowns caused an upregulation of cell cycle markers and downregulation of sarcomere genes, with the opposite regulatory pattern in Mef2c knockdown. Further investigation of the proximal promoter region of these genes revealed enriched binding sites for transcription factors associated with key signaling pathways in the developing embryo, Hedgehog and Notch. Overexpression of constitutively active components of these signaling pathways revealed that Notch function requires the presence of MEF2A and -D, while Hedgehog does not appear to interact with these two isoforms. We have shown through our studies that MEF2, a core muscle transcription factor, takes part in complex regulatory interactions that are critical for the appropriate development of striated muscle tissues. / 2018-08-09T00:00:00Z

This thesis examines the role of the media in the Kurdistan Region focusing on developments since the fall of Saddam Hussein¿s regime in 2003 in order to identify the challenges which have faced journalists there, and the construction of national identity and the potential opportunities which this sector presents for shaping public opinion and strengthening the nascent democracy in the region. After tracing the history of the Kurdish media against the broader backdrop of Iraq, using an interdisciplinary approach, this thesis analyses the strengths and weaknesses of the Kurdish media, with particular reference to regulation, examining the Press Law (2008). It concludes with a series of recommendations regarding the growth and development of new opportunities in the Kurdish media. In addition, it will present arguments to support the urgent need to develop a legal and regulatory framework which is fit-for-purpose for the media in this style democracy.

Regulatory T cells (Treg) are essential for the induction and maintenance of immunological tolerance to self and foreign antigens. The development of allergic asthma is mediated by T helper cell type-2 (Th2) inflammatory mechanisms and may also involve, based on murine and human studies of allergic asthma, compromised Treg immune regulation. Our overall objective was to more thoroughly elucidate the biology of Treg in allergic asthma, and to better understand their potential as a treatment for the disease. Initially, we characterized three different Treg phenotypes based on frequency and functional capacity. We showed both quantitative and functional heterogeneity in circulating Treg. Quantitative variability was also observed in circulating, but not airway, Treg when comparisons were made between healthy controls and asthmatic subjects. These findings emphasize the need for clear definitions of Treg phenotypes, and that interpretation of their frequency and function in health and disease needs to be phenotype-specific. Next, we assessed the Treg response in mild allergic asthmatic isolated early responders and dual responders after allergen inhalation challenge. We observed a reduced frequency of airway Treg after allergen challenge in DR, but not IER, associated with a smaller ratio of Treg to CD4+ cells. These data suggest that Treg to T effector cell (Teff) balance is important in the regulation of late asthmatic responses. Lastly, we evaluated the effects of two novel monoclonal anti-asthma therapies on circulating Treg after allergen inhalation challenge. We demonstrated that neither anti-OX40L nor anti-TSLP therapy altered circulating Treg frequency, while anti-TSLP, but not anti-OX40L, was effective in attenuating allergen-induced airway responses. These observations demonstrate the need for further investigation into the effects of anti-asthma therapies on Treg as well as the development of novel therapies aimed at manipulating Treg in order to better control immune responses. The findings of this thesis enhance our understanding of Treg in allergic asthma. Treg, utilized as stand-alone or adjunct therapy, may provide a novel therapy in the treatment of allergic asthma. / Thesis / Doctor of Philosophy (PhD)

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