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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by the selective degeneration of motor neurons in the brain and spinal cord, resulting in muscle wasting, paralysis and eventually death usually within 2-5 years of symptom onset. Despite decades of intense research to ultimately find a cure, there are still only a few treatments available to patients, none of which are effective in slowing disease progression. Therefore, novel therapeutic strategies will be increasingly important to alleviate this health burden. While the underlying pathogenic mechanisms remain unclear, increasing evidence suggests that oxidative stress (OS) is a key contributory factor early in ALS pathology. Therefore, understanding the role of proteins involved in antioxidant defence networks will facilitate the development of new therapeutic approaches. Oxidation resistance 1 (OXR1) has emerged as an essential antioxidant protein that regulates neuronal survival in response to OS, however its precise molecular functions remain unclear. Thus, the overall aim of this thesis was to investigate the neuroprotective function of Oxr1 in motor neurons, particularly focusing on its role in modulating disease-relevant phenotypes observed in ALS. To ascertain the importance of Oxr1 to motor neuron function and survival, mice in which Oxr1 was conditionally deleted in motor neurons were behaviourally and pathologically characterised. My data indicates that loss of Oxr1 specifically in motor neurons does not increase their susceptibility to degeneration or cause motor dysfunction in aged mice, but can induce a local neuroinflammatory response in the spinal cord. Next, to investigate the neuroprotective function of Oxr1 in ALS caused by mutations in TAR DNA-binding protein 43 (TDP-43), longitudinal behavioural and pathological analysis was carried out on a novel mutant TDP-43 mouse model of ALS in the presence or absence of increased Oxr1 expression. I demonstrate that neuronal overexpression of Oxr1 protects against motor dysfunction and neuromuscular defects in TDP-43 mutant mice. Furthermore, using primary motor neurons from TDP-43 mutant mice, I show that overexpression of Oxr1 can reduce the mislocalisation of TDP-43 protein, which is a characteristic feature in more than 95% of ALS cases. Finally, in order to begin to determine whether endogenous Oxr1 expression can be manipulated as a therapeutic strategy, I investigated its transcriptional regulation by characterizing Oxr1 promoter regions. I identified a highly conserved functional promoter region of Oxr1 that was subsequently used in establishing a new cell-based luciferase reporter assay that can be employed to identify compounds that upregulate Oxr1. Taken together, these studies deepen our understanding of Oxr1 as a neuroprotective antioxidant protein and offers new insights into its potential use as a future therapeutic target for the treatment of ALS.

This thesis explores the role played by the representation of hunger and appetite in the politics of the Renaissance stage. It adopts a Marxist approach, drawing on the work of theorists such as Raymond Williams, and emphasizing the significance of concepts such as class, the base/superstructure model, and lived experience. In order to understand the particular qualities which could be invested in hunger and appetite on the stage, the thesis situates the representation of these drives in the context of the material factors which defined the early modern theatre itself. The sale of food and the practicalities of staging both hunger and appetite are analysed as determining influences upon the content of specific dramatic works. The thesis demonstrates the extent to which hunger and appetite were deployed in the early modern theatre as a device by which playing companies interrogated the economic polarisation, urbanisation and imperialist expansion of the period. It argues that the depiction of hunger and appetite lent ideological form to underlying material differences between the period’s residual and emergent classes. The thesis builds upon existing criticism on a range of subjects, particularly poverty, hunger, and recent innovative work in food studies, but aims to synthesise the strengths of these relatively distinct critical areas by stressing the conceptual interrelation of hunger and appetite in the period. It explores the role played by hunger and appetite in the representation of service, gifts, sexual desire, imperialism and revolt. By rooting its understanding of hunger and appetite in the period’s politics, the thesis aims to demonstrate their significance as both a subject of political importance and a means by which wider political issues could be conceptualised.

The preparation and characterisation of novel biodegradable polymer fibres for application in tissue engineering and drug delivery are reported. Poly(e-caprolactone) (PCL) fibres were produced by wet spinning from solutions in acetone under low shear (gravity flow) conditions. The tensile strength and stiffness of as-spun fibres were highly dependent on the concentration of the spinning solution. Use of a 6% w/v solution resulted in fibres having strength and stiffness of 1.8 MPa and 0.01 GPa respectively, whereas these values increased to 9.9 MPa and 0.1 GPa when fibres were produced from 20% w/v solutions. Cold drawing to an extension of 500% resulted in further increases in fibre strength (up to 50 MPa) and stiffness (0.3 GPa). Hot drawing to 500% further increased the fibre strength (up to 81 MPa) and stiffness (0.5 GPa). The surface morphology of as-spun fibres was modified, to yield a directional grooved pattern by drying in contact with a mandrel having a machined topography characterised by a peak-peak separation of 91 mm and a peak height of 30 mm. Differential scanning calorimetery (DSC) analysis of as-spun fibres revealed the characteristic melting point of PCL at around 58°C and a % crystallinity of approximately 60%. The biocompatibility of as-spun fibres was assessed using cell culture. The number of attached 3T3 Swiss mouse fibroblasts, C2C12 mouse myoblasts and human umbilical vein endothelial cells (HUVECs) on as-spun, 500% cold drawn, and gelatin coated PCL fibres were observed. The results showed that the fibres promoted cell proliferation for 9 days in cell culture and was slightly lower than on tissue culture plastic. The morphology of all cell lines was assessed on the various PCL fibres using scanning electron microscopy. The cell function of HUVECs growing on the as-spun PCL fibres was evaluated.