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.

Reading Pitscottie's Cronicles: a case study on the history of literacy in Scotland, 1575-1814

This thesis addresses a range of research questions regarding literacy in early modern Scotland. Using the early modern manuscripts and printed editions of Robert Lindsay of Pitscottie’s late sixteenth-century 'Cronicles of Scotland' as a case study on literacy history, this thesis poses the complementary questions of how and why early modern Scottish reading communities were encountering Pitscottie’s 'Cronicles', and how features of the material page can be interpreted as indicators of contemporary literacy practices. The answers to these questions then provide the basis for the thesis to ask broader socio-cultural and theoretical questions regarding the overall literacy environment in Scotland between 1575 and 1814, and how theorists conceptualise the history of literacy. Positioned within the theoretical groundings of historical pragmatics and ‘new philology’ – and the related approach of pragmaphilology – this thesis returns to the earlier philological practice of close textual analysis, and engages with the theoretical concept of mouvance, in order to analyse how the changing ‘form’ of Pitscottie’s 'Cronicles', as it was reproduced in manuscript and print throughout the early modern period, indicates its changing ‘function’. More specifically, it suggests that the punctuation practices and paratextual features of individual witnesses of the text function to aid the highly-nuanced reading practices and purposes of the discrete reading communities for which they were produced. This thesis includes extensive descriptive material which presents previously unrecorded data regarding twenty manuscripts and printed witnesses of Pitscottie’s 'Cronicles', contributing to a gap in Scotland’s literary/historiographical canon. It then analyses this material using a transferable methodological framework which combines the quantitative analysis of micro-data with qualitative analysis of this data within its socio-cultural context, in order to conduct diachronic comparative analysis of copy-specific information. The principal findings of this thesis suggest that Pitscottie’s 'Cronicles' were being read for a combination of devotional and didactic purposes, and that multiple reading communities, employing highly nuanced reading practices, were encountering the text near-contemporaneously. This thesis further suggests that early modern literacy practices, and the specific reading communities which employ them, should be described as existing within a spectrum of available practices (i.e. more or less oral/aural or silent, and intensive or extensive in practice) rather than as dichotomous entities. As such, this thesis argues for the rejection of evolutionary theories of the history of literacy, suggesting that rather than being described antithetically, historical reading practices and purposes must be recognised as complex, coexisting socio-cultural practices, and the multiplicity of reading communities within a single society must be acknowledged and analysed as such, as opposed to being interpreted as universal entities.