Analysis and modelling of immune cell behaviour in lymph nodes based on multi-photon imaging

This thesis presents quantitative studies of T cell and dendritic cell (DC) behaviour in mouse lymph nodes (LNs) in the naive state and following immunisation. These processes are of importance and interest in basic immunology, and better understanding could improve both diagnostic capacity and therapeutic manipulations, potentially helping in producing more effective vaccines or developing treatments for autoimmune diseases. The problem is also interesting conceptually as it is relevant to other fields where 3D movement of objects is tracked with a discrete scanning interval. A general immunology introduction is presented in chapter 1. In chapter 2, I apply quantitative methods to multi-photon imaging data to measure how T cells and DCs are spatially arranged in LNs. This has been previously studied to describe differences between the naive and immunised state and as an indicator of the magnitude of the immune response in LNs, but previous analyses have been generally descriptive. The quantitative analysis shows that some of the previous conclusions may have been premature. In chapter 3, I use Bayesian state-space models to test some hypotheses about the mode of T cell search for DCs. A two-state mode of movement where T cells can be classified as either interacting to a DC or freely migrating is supported over a model where T cells would home in on DCs at distance through for example the action of chemokines. In chapter 4, I study whether T cell migration is linked to the geometric structure of the fibroblast reticular network (FRC). I find support for the hypothesis that the movement is constrained to the fibroblast reticular cell (FRC) network over an alternative 'random walk with persistence time' model where cells would move randomly, with a short-term persistence driven by a hypothetical T cell intrinsic 'clock'. I also present unexpected results on the FRC network geometry. Finally, a quantitative method is presented for addressing some measurement biases inherent to multi-photon imaging. In all three chapters, novel findings are made, and the methods developed have the potential for further use to address important problems in the field. In chapter 5, I present a summary and synthesis of results from chapters 3-4 and a more speculative discussion of these results and potential future directions.

Non-comital women of twelfth-century England: a charter based analysis

This thesis sets out to explore the place and agency of non-comital women in twelfth-century Anglo-Norman England. Until now, broad generalisations have been applied to all aristocratic women based on a long established scholarship on royal and comital women. Non-comital women have been overlooked, mainly because of an assumed lack of suitable sources from this time period. The first aim of this thesis is to demonstrate that there is a sufficient corpus of charters for a study of this social group of women. It is based on a database created from 5545 charters, of which 3046 were issued by non-comital women and men, taken from three case study counties, Oxfordshire, Suffolk and Yorkshire, and is also supported by other government records. This thesis demonstrates that non-comital women had significant social and economic agency in their own person. By means of a detailed analysis of charters and their clauses this thesis argues that scholarship on non-comital women must rethink the framework applied to the study of non-comital women to address the lifecycle as one of continuities and as active agents in a wider public society. Non-comital women’s agency and identity was not only based on land or in widowhood, which has been the one period in their life cycles where scholars have recognised some level of autonomy, and women had agency in all stages of their life cycle. Women’s agency and identity were drawn from and part of a wider framework that included their families, their kin, and broader local political, religious, and social networks. Natal families continued to be important sources of agency and identity to women long after they had married. Part A of the thesis applies modern charter diplomatic analysis methods to the corpus of charters to bring out and explore women’s presence therein. Part B contextualises these findings and explores women’s agency in their families, landholding, the gift-economy, and the wider religious and social networks of which they were a part.

Joseph McKeen and the soul of Bowdoin College: an analysis of the chapel sermons of Rev. Joseph McKeen, first president of Bowdoin College, as they relate to his call to serve the common good

The Reverend Joseph McKeen (1757-1807) was the first president of Bowdoin College, Brunswick, Maine, USA, (founded 1794). McKeen is famous for his inaugural address in which he calls students to serve the common good. His view of common good is a deeply theological view, coloured by the theological era in which he lived and worked. This study examines the idea of common in the light of McKeen’s college sermons, taking note of the following subjects: Scottish Common Sense Realism; The Nature of True Virtue; The Controversy with Unitarianism; and Science and Mathematics. McKeen’s view of common good is not simply a political view. He is not merely a republican, expressing his views on the future of the republic in a classical political way. He is also, indeed primarily, a pastor and theologian.

Negative symptoms of schizophrenia and psychosocial treatment: thematic analysis of stakeholders’ perspectives

Objectives. Recent literature indicates variance in psychosocial treatment preferences for negative symptoms of schizophrenia. Attempts at defining therapeutic aims and outcomes for negative symptoms to date have not included major stakeholder groups. The aim of the present study was to address this gap through qualitative methods. Design. Thematic Analysis was applied to qualitative semi-structured interview data to gather the opinions of people who experience negative symptoms, carers, and healthcare professionals. Participants were recruited from two mental health sites (inpatient/community) to increase generalisability of results. Ten people participated in the research. Methods. Semi-structured interview scripts were designed utilising evidence from the review in Chapter 1 of effective psychosocial intervention components for specific negative symptoms. Interviews were audio recorded and transcribed verbatim. Thematic analysis was employed to analyse data. Results. A common theme across groups was the need for a personalised approach to intervention for negative symptoms. Other themes indicated different opinions in relation to treatment targets and the need for a sensitive and graded approach to all aspects of therapy. This approach needs to be supported across systemic levels of organisation with specific training needs for staff addressed. Conclusions. There is disparity in treatment preferences for negative symptoms across major stakeholders. The findings suggest an individualised approach to intervention of negative symptoms that is consistent with recovery. Implementation barriers and facilitators were identified and discussed. There remains a need to develop a better understanding of treatment preferences for patients.