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Since their introduction in 2008, Community Treatment Orders (CTOs) have become an increasingly common feature of mental health treatment. Although compulsory community treatment is used in many countries, there is a lack of consistent evidence of its clinical effectiveness and a dearth of methodically robust studies. The international use of CTOs remains contentious based on the ethics of coercion and infringement of autonomy. Detailed understanding and interpretation of the experiential impact on service-users is necessary to inform the ongoing use and development of CTOs. Although some of the extant literature acknowledges the effect of historical and contextual influences on the implementation of CTOs, these influences have not been comprehensively evaluated. Existing exploratory studies reveal wide-ranging, often conflicting responses from service-users, describing mainly ambivalent reactions to a CTO. This indicates a need for rich detailed data and analysis of the service-users’ experience of CTOs. This study aimed to investigate how service-users make sense of their CTO experience. Ten active CTO service-users were purposefully recruited from an Assertive Outreach Team caseload in the north of England. Each participant undertook one or two semi-structured interviews facilitated with photo-journals and diaries. A total of 18 interviews were completed and the data subject to Interpretative Phenomenological Analysis. Themes were generated and organised into three clusters: Pained and Powerless; Alignment and Reconnection; and Consolation and Compensation. Some participants felt powerless to challenge the ‘sentence’ imposed as therapeutic intent. Many participants described feeling disadvantaged, different and labelled, but were also committed to recovery and reintegration into the community. Some participants perceived that small interactions could combine to leave them feeling more secure, less anxious and, paradoxically, more in control. The study proposes a theoretical framework that may unlock the therapeutic potential of CTOs, improving lived experience without compromising their social significance or effectiveness.

Chronic obstructive pulmonary disease (COPD) the third leading cause of death, with an estimated 65 million cases worldwide. Despite this, most research to date has focused on treating the symptoms of COPD rather than the underlying mechanisms. Recently, we have shown that exposure to cigarette smoke (CS), the leading cause of COPD, results in an increase in cytosolic calcium and the rapid internalization and insolublization of the cystic fibrosis transmembrane conductance regulator (CFTR). Normal ion transport is imperative for mucus hydration and clearance, and its dysfunction after CS exposure may be responsible for the mucus dehydration and accumulation seen in COPD patients. Thus, the primary aim of this thesis was to establish the mechanism(s) behind the CS-induced internalization of CFTR. Confocal imaging and Förster resonance energy transfer demonstrated that CFTR-CFTR interactions were reduced upon internalization of CFTR, and that CFTR was internalized with a T1/2 of 27.7 min. U0126, an inhibitor of MEK1 and MEK2, abolished the internalization of CFTR by CS. Furthermore, U0126 had no effect on CS-induced Ca2+ release. These data implicate the necessity of MAPK/ERK kinases in CS-induced internalization, and suggest that this kinase activity is downstream of Ca2+ release. Furthermore, CS caused dephosphorylation of plasma membrane CFTR, and CS-induced internalization of CFTR was prevented by forskolin, suggesting that dephosphorylation of CFTR by CS may lead to its internalization. CS-induced CFTR internalization was ablated by inhibitors of endocytosis, hypertonic sucrose and dynasore. Consistent with results demonstrating that CS-internalized colocalization CFTR with clathrin light chain, these data suggest that CS-induced internalization of CFTR is both clathrin- and dynamin-dependent. CS-internalized CFTR colocalized substantially with markers of the endoplasmic reticulum. Partial colocalization of CS-internalized CFTR with markers of the early endosomes, late endosomes, and the Golgi apparatus but not recycling endosomes, suggest that CFTR is trafficked in a retrograde pathway from the plasma membrane to the endoplasmic reticulum. This thesis provides new insights into the mechanism of CS-induced CFTR internalization, and may help in the development of new therapies for CFTR correction and airway surface liquid rehydration in patients with COPD.

The portfolio thesis is separated into three parts: a meta-synthesis of qualitative research, an empirical study and appendices. Part one is a meta-synthesis reviewing the published qualitative literature regarding the decision to remain childfree in women. The aim of the synthesis was to provide healthcare professionals with an in depth insight into the influences and consequences of the decision in order to inform aspects of their practice when working with childfree women, alongside infertile women and those contemplating the motherhood decision. Five broad themes were discovered from six papers eliciting that the childfree decision is multifaceted and individual. The findings are discussed in relation to clinical implications and potential future research. Part two is an empirical study that explores the experience of the motherhood decision in women diagnosed with Multiple Sclerosis. Eleven women were interviewed, and data was analysed using Interpretative Phenomenological Analysis (IPA). Though the study involved both women who had children and women who did not have children following diagnosis, several themes occurred across interviews with participants. Key implications for the aid of the decision making process within health care services are discussed. Part three consists of appendices supporting both the meta-synthesis and the empirical study. It also includes a reflective statement detailing the process of the research from beginning to end.

There has been an astonishing variety of sesqui- and diterpene metabolites isolated—mainly from Laurencia species, or their predators—which possess the enantiopure α,α-dimethylcyclohexyl bromide moiety. The key step in their biogenesis is generally considered to be an enzyme-mediated formation of an asymmetric bromonium ion which initiates a cation-π cyclisation. This diverse array of terpene natural products is explored in the introduction to this thesis and their biogenesis via cation-π cyclisations analysed. Synthetic sources of electrophilic bromine such as NBS, TBCO and BDSB have been shown to initiate brominative polyene cyclisations with excellent control of relative stereochemistry albeit as necessarily racemic products. At the start of this work no asymmetric bromonium ion-induced polyene cyclisations had been demonstrated. Studies on a model system for the key in situ enantiopure bromonium ion generation and intramolecular trapping are described. Sharpless asymmetric dihydroxylation provides access to enantiopure diols of a trisubstituted alkene which can be manipulated to enantiopure bromohydrins. These are activated as 2,3,4,5-tetrafluorobenzoate esters which cyclise cleanly under the action of catalytic triflic acid to give enantiopure bromo-bicycles without racemisation from bromonium ion to alkene transfer. The mechanism of this reaction is investigated, it is practically demonstrated and shorter routes are explored. The synthesis of high purity linear terpene: homogeranyl 4-methoxybenzene is discussed, from which the synthesis of enantiopure bromo-tetrafluorobenzoate esters is carried out. The use of Lewis acid, in this case dimethylaluminium triflate, was found to successfully enact the cyclisation of these alkene containing substrates. Full conversion to cyclic products was achieved and the desired tricyclic product was isolated as a mixture of enantiopure diastereomers. Absolute and relative configuration of both diastereomers were determined by radical dehalogenation and comparison of the sign of the optical rotation of the product to literature values. Finally, the synthesis of homofarnesyl 4-methoxybenzene derived substrates is detailed. The cyclisation of which has the potential to generate tetracyclic compounds. This forms the basis of future work to be carried out.

The production of chemical energy from light energy is arguably the most important reaction known. Nearly all life depends on energy derived from light and it is by this process that the atmosphere of our planet was oxygenated. Chlorophyll is the pigment that absorbs light and donates an electron initiating the process of photosynthesis. This highly complex molecule is the result of many chemical reactions collectively known as chlorophyll biosynthesis. Chlorophyll is a modified tetrapyrrole and shares a common synthetic pathway to vitamin B12, Siroheam and haem. Photosynthetic organisms need both chlorophyll and haem, and the branch point they share, committing to the production of either is thought to be highly regulated. The common precursor to both pigments is protoporphyrin IX and the fate of the macrocycle depends on which divalent metal ion is inserted into the tetrapyrrole. The insertion of Fe2+ by ferrochelatase commits to the production of haem whereas the insertion of Mg2+ by magnesium chelatase commits to the production of chlorophyll. The magnesium chelatase is comprised of three subunits that are all essential for activity and are known as ChlH (~150 kDa), ChlD (~75 kDa) and ChlI (~40 kDa). It is known that the H protein binds both the tetrapyrrole substrate and product of the reaction. The I and D subunits are thought to be the catalytic element of the enzyme and once a H•substrate complex is formed, this binds with an ID complex to initiate the reaction. This work will focus on the structural and functional characteristics of a thermophilic magnesium chelatase (from Thermosynechococcus elongatus) which have never been previously studied.

This thesis proposes that Northern Irish elegy is a distinctive genre of contemporary poetry, which has developed during the years of the Troubles, and has continued to be adapted and defined during the current peace process. It argues that the practice of writing elegy for the losses of the Troubles has established a poetic mode in which Northern Irish poets have continued to work through losses of a more universal kind. This thesis explores the contention that elegy has a clear social and political function, providing a way in which to explore some of the losses experienced by a community over the past half-century, and helping to suggest ideas of consolation. Part one focuses on three first generation Northern Irish elegists: Seamus Heaney, Michael Longley and Derek Mahon. Heaney is considered in a chapter which takes in a poetic career, through which might be traced the development of Northern Irish elegy. Following this are two highly focused studies of the elegies of Longley and Mahon. The place of artifice in elegy is considered in relation to Longley's Troubles elegies, while Mahon’s irony is discussed in relation to his elegiac need for community. Part two looks at a second generation, represented by Ciaran Carson and Paul Muldoon. Carson's elegies for Belfast are read in a discussion of the destruction and reconstruction that occurs during the process of remembering. This study explores the idea that elegies might also be written for places and temporal spaces. Carson's interest in poetic form is shown to be intricately related to his elegiac practice. The chapter on Muldoon surveys a career which has interrogated the connections between art and suffering. Muldoon raises questions of poetic responsibility, and also challenges poetry itself, on a formal and linguistic level. As his career develops, he includes not only the local threats of Troubles violence within his elegies, but also the global threats of disease, violence and terror. Part three starts with Medbh McGuckian, whose work is discussed in relation to the third generation poets Sinead Morrissey, Leontia Flynn and Colette Bryce. As McGuckian's poetry is perhaps the least immediately accessible of all the poetry covered here, the thesis considers ways in which her work might be read, before her poems are discussed as Northern Irish elegies. Following this are readings of poems from Morrissey, Flynn and Bryce, noting ways in which this generation works to develop the genre of elegy, working in the same broad themes that have been charted throughout this thesis.