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Organoid systems have revolutionised the study of adult stem cells and organ homeostasis. However, there have been limited attempts to use the technology to study human organ development. The work of this thesis established two novel hepatic organoid systems; one based upon the archetypal liver stem cell, the hepatoblast, whilst the other was based upon a hitherto undescribed biliary progenitor cell. The work continued with exploration of the development of the human intestine, characterising how intestinal organoids develop in vitro, and going on to assess human intestinal maturation in vivo at single cell resolution. First, the developing human liver was characterised during the first trimester and the cellular composition at this crucial developmental timepoint was investigated at single cell resolution. The hepatoblast organoids (HBO) were then demonstrated to retain their hepatoblast profile in culture and demonstrated the functional capacity of this fetal cell-type. Exploiting this new model, the molecular processes of differentiation were then explored as the HBO were demonstrated to have bipotential capacity to generate hepatocytes and cholangiocytes. Furthermore, these organoids were then transplanted into mice and were able to differentiate into complex functional tissues. Next, a newly discovered stem cell was characterised and termed the 'biliary progenitor cell'. This new cell type was able to generate three-dimensional organoids, fetal biliary organoids (FBO), that could be transplanted into mice and provide insight into biliary development. Next induced pluripotent stem cell (iPSC)-derived and primary fetal intestinal derived organoids were characterised against purified primary intestinal epithelial tissue, demonstrating a dynamic transcriptome of fetal organoids in vitro and a lack of tissue specificity of iPSC-derived organoids. The fetal and paediatric intestine were assessed at single cell level to assess the cell types and developmental pathways involved in the process of development, and this   information was then utilised to try to model development in vitro using small molecule stimulation of fetal intestinal organoids. The work described in this thesis develops our understanding of human endodermal organ development. The newly described organoid models present an exciting opportunity to model human liver development, generate cells for drug-screening, and offer the potential for cell-based therapies, whilst the exploration of the human intestine during development may aide our understanding of how such pathways may be abrogated in developmental defects, or reverted to during disease states.

For at least the past two decades, international Anglicanism has been gripped by a crisis of identity: what is to be the dynamic between autonomy and interdependence? Where is authority to be located? How might the local relate to the international? How are the variously diverse national churches to be held together 'in communion'? These questions have prompted an explosion of interest in Anglican ecclesiology within both the church and academy, with particular emphasis exploring the nature of episcopacy, synodical government, liturgy and belief, and common principles of canon law. However, one aspect of Anglican ecclesiology which has received little attention is the place of provincial polity and metropolitical authority across the Communion. Yet, this is a critical area of concern for Anglican ecclesiology as it directly addresses questions of authority, interdependence and catholicity. However, since at least the twentieth century, provincial polity has largely been eclipsed by, and confused with, the emergence of a dominant 'national church' polity. This confusion has become so prevalent that the word 'province' itself is used interchangeably and imprecisely to mean both an ecclesial province in its strict sense and one of the 39 'member- churches' which formally constitute the Anglican Communion, with a handful of 'extra-provincial' exceptions. The purpose of this research project is to untangle this confusion and to give a thorough account of the development of provincial polity and metropolitical authority within the Communion, tracing the historical origins of the contemporary status quo. The scope of this task is not in any way intended to be a comprehensive history of the emergence of international Anglicanism, but rather to narrowly chart the development of this particular unit of ecclesial polity, the province, through this broader narrative. The historical work of Part One in itself represents an important new contribution to Anglican Studies; however, the project aims to go further in Parts Two and Three to identify from this context key questions concerning the problems facing contemporary Anglican polity as the basis for further theological and ecclesiological reflection. Part Two examines how provincial polity has given way to an assumption of the 'national church' as the building block of the Communion. To what extent is it consonant with Anglican tradition? How is it problematic? What tensions exist with a more traditional understanding of the province? How might all this relate to wider political understandings and critiques of the 'nation- state' in an increasingly globalised world? Along with the emergence of a 'national church' ecclesiology, so too has the role of the 'Primates' been magnified. Part Three charts this development, culminating in a critique of the recent 2016 Primates' Meeting. What is the nature of primacy within Anglicanism and how does it relate to metropolitical authority? What is the right balance of honour and authority as it relates to primacy? How do Anglican understandings of primacy correspond to those of the Roman and Orthodox Communions? Finally, Part Four attempts to give some concrete focus to the preceding discussion through the illustrative example of the Anglican Church of Australia, which is frequently cited as being analogous to the Communion in having a loose federal system and resolutely autonomous dioceses. The prevalence of this 'diocesanism' has recently been criticised by the Royal Commission into Institutional Responses to Child Sexual Abuse. However, there has been a recent revival of provincial action within the Province of Victoria in response to these issues which will be evaluated to discern what the Australian example might offer toward a theologically robust and credible ecclesiology for Anglicanism into the twenty-first century.

The neuromuscular junction (NMJ), the synapse formed between lower motor neuron and skeletal muscle fibre, is known to be a target in a number of neurodegenerative conditions, including motor neuron disease (MND). Located in an accessible part of the peripheral nervous system, the NMJ can be used as a ‘model synapse’ in the context of ‘connectomics’ – the study of synaptic connectivity throughout the nervous system as a whole. Although the NMJ has been studied in a number of species, relatively little is known about its structure in humans, complicating the translation of animal models of disease to the human condition. Described here is the first detailed cellular and molecular characterization of the human NMJ. A standardized methodology for comparative morphometric analysis of NMJs was developed and validated (‘NMJ-morph’). NMJ-morph was used to generate baseline data for 2160 NMJs from a single litter of wild type mice, representing 9 distinct muscles across 3 body regions. Principal components analysis (PCA) revealed synaptic size and fragmentation to be the key determinants of synaptic variability. Correlation data revealed the pre-synaptic cell (motor neuron) to be a stronger predictor of synaptic morphology than the post-synaptic cell (muscle fibre). Other factors influencing synaptic variability were in a clear hierarchy: muscle identity accounted for more variation in synaptic form than animal identity, with side having no effect. Human tissue was obtained from 20 patients (aged 34 to 92 years) undergoing lower limb amputation, primarily for the complications of peripheral vascular disease (PVD). Muscle samples were harvested from non-pathological regions of the surgical discard tissue. 2860 human NMJs were analyzed from 4 distinct muscles (extensor digitorum longus, soleus, peroneus longus and peroneus brevis), and compared with equivalent NMJs from wild type mice. Human NMJs displayed unique morphological characteristics, including small size, thin axons, rudimentary nerve terminals and distinctive ‘nummular’ endplates, all of which distinguished them from equivalent mouse NMJs. The previous notion of partial occupancy in human NMJs was disproved. As in mice, the pre-synaptic cell was shown to correlate more strongly with NMJ morphology; in contrast to mice, the human NMJ was found to be relatively stable throughout its 90+ year lifespan. In support of the tissue harvesting procedure, patient co-morbidities (diabetes mellitus and vascular disease) did not significantly impact NMJ morphology. Super-resolution imaging of the NMJ revealed significant differences in the functional architecture of human and mouse active zones. Despite the smaller synaptic size in humans, the total quantity of active zone material was conserved between the species, suggesting a homeostatic mechanism to preserve effective neurotransmission. Parallel proteomic profiling demonstrated further species-specific differences in the broader molecular composition of the NMJ. The cellular and molecular anatomy of the human NMJ is fundamentally different to that of other mammalian species. These differences must be taken into account when translating animal models of disease to the human condition.

Drainage systems which developed during the initiation of Large Igneous Provinces were subjected to dynamic volcanic and tectonic activity. However, even during periods of intense volcanic activity, terrestrial drainage systems had the capacity to recover and ingress into volcanic terrains which allowed for the re-establishment of ecological communities. This study compares and contrasts the Skye Lave Fields (Selandian, 61-59Ma) which were emplaced within an exhumed, extensional basin in the Sea of Hebridies [sic], NW Scotland; with the sediments intercalated with the Columbia River Basalts (Miocene, 16.6-6Ma) which were emplaced within a back-arc setting and prograded into an ancient drainage basin known as the Clearwater Embayment, Idaho, NW USA. Hyaloclastite sequences dominate the lower succession of the Skye Lava Fields. The Northern Skye region was deprived of large feeder catchments which restricted sedimentary interbeds, composed of fine grained, tuffaceous and carbonaceous sediment, to thicknesses of < 5m. Tabular sheet flows dominate the lower succession of the Columbia River Basalts. However on the margins of the province, thick (average 20m, up to 70m) fluvio-lacustrine sediments intercalated with lava flows. Eruption of high volume lavas caused ponding of the fluvial systems, which were supplied with coarse grained sediment by large, elevated drainage basins. Although very different from a sedimentological perspective, comparable palynological trends were observed in each case study. The lower most deposits in each case were dominated by mature, late successional swamp vegetation. Eruptive episodes resulted in destruction of these early forests, but then recovery of the drainage systems allowed for the establishment of riparian corridors with diverse floodplain communities. Due to the contrasting volcanic and depositional styles, the development of a generic model for LIP initiation which can be applied universally is challenging and individual models should be produced from the detailed understanding of local factors and processes.