Search

Within capitalist societies, active participation in paid employment is often considered an indicator of good mental health and wellbeing. Many support services for individuals with diagnoses of severe and enduring mental health conditions are focused around assisting these individuals to attain and retain paid employment. Despite this, in 2019 only 28.5% of individuals categorised as having a diagnosis of a 'mental illness or other nervous disorder' were in paid employment in the UK. This thesis explores the experiences of work and employment for individuals who have a diagnosis of a mental health condition and attended a 'working community' service in Scotland. This working community encourages its service users to participate in 'meaningful work' and prepare for entering paid employment in order for these individuals to achieve 'mental health recovery'. I explore the space of the working community as an alternative to other welfare-to-work and supported employment approaches. Enlisting an emancipatory epistemology that aims to privilege the voices of individuals with diagnoses of mental health conditions, in this thesis I present a detailed account of the space of the working community and the experiences of those working within it. Utilising a qualitative multi-method research approach, I collected data through a year-long, in-depth ethnography as an observant participant in conjunction with semi-structured interviews and documentary analysis. I engage with literature from the geographies of mental health and beyond to conceptualise 'community' and 'care' and am informed by mad studies and critical disability studies to challenge exclusionary narratives of 'mental health recovery' which infer that obtaining paid employment inevitably improves mental wellbeing. This thesis offers a careful consideration of both the positive and negative aspects of work and employment for individuals with diagnoses of mental health conditions and examines the issues faced by these individuals in finding and keeping paid employment within a neoliberal society in which their potential productive capacity is undervalued. Through this, I contribute empirically to the geographies of mental health by adding a detailed ethnographic account of a space of work for individuals diagnosed with mental health conditions, and conceptually through providing a critical consideration of the term 'recovery'.

NHERF1 is a PDZ domain containing scaffold protein which facilitates the formation of a number of important protein complexes. PDZ domains are globular protein recognition modules which bind to short linear motifs, generally found at the extreme C-termini of integral membrane proteins. Via its two PDZ domains, NHERF1 is able to bind to the C-termini of a range of membrane receptors and channels, including that of the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a chloride ion channel, loss of function mutations of which cause the autosomal recessive disease cystic fibrosis. The most common cystic fibrosis causing mutation is the deletion of phenylalanine at position 508 (F508del), which causes protein-misfolding and subsequent targeting of CFTR for degradation. NHERF1 overexpression has been shown to increase both the plasma membrane localisation and activity of F508del CFTR and, as such, the interaction between these two proteins is of particular therapeutic interest. The structure the extended PDZ2 domain of NHERF1 in complex with the PDZ binding motif of CFTR was determined using X-ray crystallography. This structure provided a new insight into the structural determinants of this interaction. In particular, the structure revealed that specific side chain mediated interactions within the binding pocket enable the recognition of the arginine at the -2 position of the PDZ binding motif. This contradicts previous studies, which have suggested that the loss of this interaction is the sole determinant for the lower binding affinity exhibited NHERF1 PDZ2 as compared to PDZ1. As such, this work suggests that instead a variety of dynamic and allosteric effects dictate the specificity and affinity of the PDZ domain motif interaction. Further to this, this study employed a range of novel techniques to further characterise the interaction between NHERF1 and CFTR. iBox PAK4cat in-cellulo crystallisation is based on the phenomenon that serine/threonine kinase PAK4 and its endogenous inhibitor, iBox, form cytoplasmic rod-type protein crystals when transfected into mammalian cells. The in-cellulo crystal structure of PAK4cat bound to iBox revealed that iBox-PAK4cat molecules form a hexagonal array within the crystal lattice, with channels 80 Å in diameter that run the length of the crystal. The work presented in this study sought to explore whether it is possible to incorporate other proteins into this cavity and, as such, determine whether iBox PAK4cat crystals can be utilised for other experimental purposes. A novel in cellulo iBox PAK4cat protein protein interaction screening assay was developed. This assay enabled further characterisation of the NHERF1 CFTR PDZ domain motif interaction in a cellular context. The results from this study corroborated the finding from the crystal structure, indicating that the arginine at the -2 position of the CFTR PDZ binding motif is specifically recognised by the binding pocket of NHERF1 PDZ2. Finally, the PDZ domains of NHERF1 were employed in a proof of concept study into the use of iBox PAK4cat crystals as the basis for the development of a novel in-cellulo platform for the crystallisation of guest proteins. While ultimately this work did not enable determination of the in-cellulo structures of the NHERF1 PDZ domains, the results generated from this study have given a useful insight into the iBox-PAK4cat system and will inform future optimisation studies.

Many multiplayer games feature teams, and whether they are pitted against each other or against the game itself it seems likely that the way these teams bond will affect the players' experience. What are the factors that influence the experience of being a team member in a game? To what extent can the game designer manipulate the cohesion of the teams by changing the game design? How does the satisfaction of the player with their team relate to their feeling of cohesion? How does cohesion differ between tabletop and online games? These issues become particularly important where the group dynamic is central to the desired outcome of the game e.g. educational games aiming to place the players in specific social situations. Four studies were conducted on four similar simulation games (two tabletop, two online) used for teaching in International Development Studies. These games explore farming in sub-Saharan Africa and require 12-30 players to play in small groups. The group dynamics are important for the learning outcomes. Similar groups of participants (all students of International Development Studies) played one game each. Each group played for 3 hours before completing a questionnaire about their experience and wrapping up with a full-group reflective discussion. Results from the two tabletop games suggested that, as expected, altering the rules of the game manipulated levels of team cohesion. However, the lack of significant result from the two online games suggests that careful design is required to achieve the same outcomes in the online environment. This suggests that seemingly small changes between tabletop and online implementations may impact the game play experience in unanticipated ways. The team cohesion reported by the players was found to correlate strongly with the team member satisfaction levels of the players. The gender composition of the teams was shown to have a large impact on both team cohesion and team member satisfaction: having one or more females in the group significantly increased both measures.

Investigations into the safety of diagnostic ultrasound and mechanisms of therapeutic ultrasound have provided evidence of a number of cellular responses to ultrasound. These studies have mainly concentrated on cells in culture, while work on intact tissue employed mainly kHz ultrasound fields, although diagnostic and many therapeutic procedures are performed using MHz ultrasound. Vascular tissue is known to respond to a variety of physical and chemical signals, and so arteries were used as a model system in this thesis to study the effects of MHz ultrasound in vitro. Rings of equine carotid and lateral cecal mesenteric artery exhibited reversible, repeatable contraction on exposure to both pulsed and continuous wave 3.2 MHz ultrasound at acoustic powers up to 145 mW. Wall stress increased by up to 1.5% in carotid arteries and up to 2% in mesenteric arteries during exposure, and returned to basal levels after approximately 10 minutes. Contraction was endothelium independent, and was not affected by changes in the pulsing regime. The magnitude of contraction was dependent on the acoustic power, and the change in wall stress increased with increasing acoustic power in a linear fashion. The acoustic power dependence suggested the response was thermally mediated and this was confirmed by investigation of the response of arteries to non ultrasound generated heating, which also induced contraction. The effects of ultrasound and heating were also investigated in 1st order branches of the lateral cecal artery, as a model of a small artery. No response was observed in either case. In order to determine the cellular basis of the response of carotid and mesenteric arteries, the involvement of potassium ion channels in the response was investigated using a potassium channel blocker. The response of arteries to ultrasound was increased by inhibition of inward-rectifier potassium channels, which would otherwise help to return the cell membrane potential to the normal level. The change in wall stress was increased by 42% on average, confirming the involvement of these channels in the response. Contraction of arteries is mediated by an increase in intracellular calcium. The ion channel activity during non ultrasound generated heating was examined further by observation of intracellular calcium concentration using a fluorescent calcium sensitive dye. Increases in intracellular calcium were observed in carotid and large mesenteric arteries, which confirmed the thermal influence on ion channel function in these vessels. No such effect was observed in the smaller vessels.