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On the anatomy and phylogeny of Tetraclaenodon (Mammalia, Placentalia) and implications for the evolution of Palaeocene phenacodontid ‘condylarths’

During their 200 million-year long evolutionary history, mammals evolved all the adaptations that have made them one of the most successful groups of vertebrates on Earth today. Nevertheless, the mode and tempo of some of the major macro-evolutionary trends in mammals are still poorly understood. One crucial moment in the history of Mammalia was the Cretaceous-Paleogene (K-Pg) mass extinction, 66 million years ago. After the disappearance of circa 75% of life on land and in the oceans, the surviving mammals diversified and thrived. Survivors of the K-Pg mass extinction included members of the monotreme, marsupial and placental mammals lineages. In the first few million years of the Palaeocene, new groups of placental mammals emerged, diversified and dispersed. However, gaps in our knowledge of these earliest Cenozoic mammals has thus far hindered understanding of the precise timing and dynamics of eutherian mammal evolution. These first pioneers of the Palaeocene included a plethora of ‘archaic’ mammal groups. One such group, the ‘condylarths’ were extremely successful during the Palaeocene and Eocene epochs. Although now considered an informal group, the ‘condylarths’ embrace fossil placental mammals that presented a medium body size and generalized diets and locomotory styles. They are also referred to as ‘archaic ungulates’ and various extant mammal lineages are postulated to have arisen from them. Of these, probably one of the more abundant and successful ‘condylarth’ families were phenacodontids. The phenacodontids are best known for their inferred close relationship to the modern odd-toed hoofed mammals, the perissodactyls. Although phenacodontids are considered by many workers to be a monophyletic grouping, their in-group relationships and those to other mammalian groups, including perissodactyls, are highly debated. For these reasons, a clearer understanding of their anatomy, paleobiology and phylogenetic position is sorely needed. The main aim of this doctoral thesis has been to create the most up to date, comprehensive higher-level phylogenetic analysis of phenacodontid taxa. The goal was to shed light on the species level interrelationships of phenacodontid taxa and between them and other Palaeocene, Eocene and crown groups. A core element of this work was also to understand the morphological adaptations that characterized phenacodontids. To that end, this thesis incorporates the most detailed description, to date, of the anatomy of Tetraclaenodon, the basal-most phenacodontid. In order to describe the anatomy of this taxon, new dental, cranial and postcranial material of Tetraclaenodon from the San Juan Basin of New Mexico was studied in depth. In doing so, both traditional and innovative methods were employed to gather the most anatomical detail possible. My results indicate that Tetraclaenodon was characterized by a medium body size (5-10 Kg) and was a terrestrial, generalized mammal. The basic early placental body plan is combined with bunodont dentition, pentadactyl manus and pes that bore small hoof-like unguals and a long, heavy tail. From the statistical multivariate analyses of the lower m1 of Tetraclaenodon throughout the Torrejonian North American Land Mammal Age (NALMA) of the San Juan Basin, it emerges that two size groups existed between the earlier Tetraclaenodon populations (Tj1-3) and the later (Tj4-6). This confirms a trend also seen in other Palaeocene mammals, such as Periptychus. Apart from the size differential, these two populations overlap stratigraphically, to an extent, but are not distinguished by significant morphological differences. It is thus plausible that these represent a single evolutionary line characterized by increase in body size over time, and not two separate species like reported by some (Kondrashov and Lucas, 2012). The phylogenetic dataset incorporated 19 species of phenacodontids, alongside additional Palaeocene, Eocene and extant exemplars. The total number of taxa, 136, were then scored for 687 morphological characters. Of these, 70 were novel characters added to better define the phenacodontid and perissodactyl groups. The results of the cladistic analyses confirms that Tetraclaenodon is basal to Phenacodus and together form a monophyletic clade. My findings indicate that although Phenacodontidae are on the evolutionary stem of perissodactyls, they are most likely not monophyletic. In my analyses Meniscotherium results as sister to a clade composed of phenacodontids and perissodactyls and their closest relatives (‘panperissodactyls’). Phenacodontids together form the sister clade to perissodactyls and relatives. The more lophodont phenacodontids are closer to perissodactyls than Meniscotherium. The Eurasian pleuraspidotheriid taxa form a clade with the afrothere Ocepeia, whereas Radinskya is resolved as a stem perissodactyl. The robusticity of the tree topology is however somewhat fragile and the strict consensus tree of 8 most parsimonious trees was obtained by removing taxa and characters both a priori and a posteriori. It is, however, judicious to point out that the possibility of homoplasy is high in these taxa and further broader spectrum studies incorporating molecular data will undoubtably be crucial in clarifying these results. It remains clear that during the Palaeocene and early Eocene, ‘phenacodontids’ were extremely diverse and displayed a multitude of successful adaptations. Their position on the perissodactyl stem confirms the initial observations of previous authors. Whether or not directly ancestral to modern rhinos, horses and tapirs, these early placental mammals were important protagonists in the Palaeocene revolution that ushered in the ‘Age of Mammals’

Efficient Monte Carlo methods for Bayesian state-space model inference

State-space models are widely used to model time series data where the observations depend on a latent process. The latent process consists of a sequence of latent states that evolve according to a specified system process. The observed time series data are then modelled as a function of the latent states via an observation process. Estimating the parameters of a state-space model within a Bayesian framework can be challenging. In this thesis, we consider these challenges and develop efficient Monte Carlo algorithms to aid inference. We propose two classes of method that, as a central theme, leverage approximate hidden Markov models for efficient inference. In the first part of this thesis, we propose that approximate hidden Markov models can be used to design efficient Markov chain Monte Carlo proposal distributions, defined such that the usual theoretical guarantees apply. We discuss how the hidden Markov models are constructed under the proposed approach, the associated generality arising from the tuning parameters, and how these tuning parameters can be chosen efficiently in practice. We demonstrate that this proposed algorithm provides an efficient and robust alternative method for fitting state-space models, even for those that exhibit near-chaotic behaviour. In the second part of this thesis, we develop an approximate hidden Markov model approach to designing efficient particle Markov chain Monte Carlo algorithms. In particular, we propose an approach to particle Gibbs with ancestor sampling that leverages approximate hidden Markov models to combat impoverishment within the sequential Monte Carlo steps of the original algorithm. We additionally propose that fixed approximations to the hidden Markov model can be used to substantially reduce the computational cost of the hidden Markov model and particle Gibbs with ancestor sampling algorithm. We demonstrate the efficiency of this proposed approach in several traditionally challenging examples, focusing on state-space models with regime switching

Lessons in anticipatory action: An operational pilot for flooding in Kenya

The Jameel Observatory for Food Security Early Action funded this research.From July 2021 to June 2024 Save the Children implemented a research programme in Somaliland and Kenya to find out how to make anticipatory action more effective at mitigating the impact of shocks to reduce food crises. The programme was implemented through the Jameel Observatory for Food Security Early Action. The research was implemented in north-eastern Kenya in the second half of 2023, where flooding was predicted. 13 villages were randomly assigned to receive anticipatory assistance ahead of the flooding or assistance after the flooding. The research found that project participants appreciated early warning information, but that flood impacts were severe. It also found that households had limited anticipatory strategies to protect livelihoods, and that expenditure on food was prioritised. Despite this, improvements in food security were temporary

Ectopic heterochromatin provides an alternative route to fungal resistance

Antifungal resistance in fungi, including the human pathogen Cryptococcus neoformans, commonly occurs via genetic mutations. However, the existence of unstable drug-resistant isolates suggests the possibility of epimutation-mediated resistance. Here, using the tractable model yeast fungus Schizosaccharomyces pombe (fission yeast) and the clinically relevant azole antifungal fluconazole, epigenetically mediated unstable drug resistance in fungi was investigated. S. pombe unstable fluconazole-resistant isolates displayed ectopic H3K9me-heterochromatin islands at various loci in the genome. Notable among these is the cup1 island, previously identified as a heterochromatin-dependent epimutation conferring caffeine resistance. To determine the relevance of heterochromatin-mediated antifungal resistance in human fungal infections, ectopic H3K9me-heterochromatin was investigated in unstable fluconazole-resistant C. neoformans isolates from HIV-AIDS patients. Novel heterochromatin islands were identified in several unstable resistant clinical isolates. Remarkably, isolates that lose resistance after continuous growth on non-selective media also lose about half of their ectopic H3K9me-heterochromatin islands, many of which harboured stress response-relevant genes. Mouse model experiments showed that in the absence of fluconazole treatment, lost islands do not reappear and isolates remain sensitive to fluconazole. In addition, previously resistant isolates lose both resistance and ectopic islands after passage in mice without fluconazole treatment. These observations suggest that ectopic H3K9me2 islands causing fluconazole resistance may not be influenced by animal host conditions. This study reveals that heterochromatin-mediated repression of specific genes may mediate transient resistance to antifungal therapy in clinical isolates of C. neoformans

Investigating the role of PAX6 during neurodevelopment using human stem cell-derived brain organoids

PAX6 is an evolutionarily conserved transcription factor which acts as a master regulator in the development of the eyes and brain. People with heterozygous mutations in PAX6 suffer from varying levels of optical defects (aniridia) and present with minor brain abnormalities, including thinning of parts of the cerebral cortex. In the few compound heterozygous cases recorded in humans, loss of functional PAX6 results in severe morphological brain defects, and only one patient survived into childhood. The role of PAX6 in human neurodevelopment remains understudied due to the practical and ethical limitations of studying human embryonic processes. To explore the function of PAX6 in the earliest stages of neurodevelopment, human stem cells (hiPSCs) were used to generate cortical organoids which are a powerful humans-specific method of studying developmental processes. The initial experiment compared PAX6⁻/⁻ and PAX6⁺/⁺ organoids in different extracellular matrix (ECM) conditions throughout the first 30 days of culture. This time course experiment revealed a significant impact of exogenous ECM addition (in the form of Matrigel) on growth. The Matrigel-free protocol resulted in significantly smaller PAX6⁺/⁺ organoids but did not impact the growth of PAX6⁻/⁻ organoids. PAX6 potentially suppressed growth in response to a lack of exogenous ECM. At the end of the standard Matrigel-supplemented protocol, there was no significant difference in the size of PAX6⁻/⁻ and PAX6⁺/⁺ organoids. Specific periods of development within the first 30 days of organoid growth were then investigated in more detail. At the neural induction-like period of organoid development, where organoids began forming neuroepithelium (day 10 of the protocol), bulk RNA sequencing was performed. Gene Ontology analysis revealed several dysregulated terms, including cerebral cortex regionalisation, axon guidance, fate specification and cell adhesion. In addition, differential gene expression analysis uncovered over 40 dysregulated cell adhesion-related genes including CDH8, CDH23, and CLDN11. Dysregulation of several neural tube closure-associated genes were also found, which included GHRL2, CDH1 and CLDN4. Building on Gene Ontology results, the potential link between PAX6 and neural tube closure was investigated histologically by analysing the transition of open neuroepithelial structures to closed rosettes. There was no difference in rosette formation between PAX6⁺/⁺ and PAX6⁻/⁻ organoids, both of which underwent efficient closure of rosettes within 24 hours of Matrigel embedding. Despite the dysregulation of neural tube closure-associated genes, defects relating to neural tube closure were not evident histologically. Finally, the impact of PAX6 and the extracellular matrix on dorsoventral regionalisation was investigated. Organoids were taken at days 20 and 30 of development when dorsal TBR2 and ventral DLX2 positive cells were present. At day 20, omitting embedding from the protocol had a significant negative impact on the capacity of PAX6⁺/⁺ organoids to form dorsal cells, in contrast to PAX6⁻/⁻ organoids which developed comparable levels of TBR2 regardless of embedding. This effect persisted to day 30 of culture. Ventralisation of PAX6⁻/⁻ organoids was evident at day 20 and increased at day 30. These results indicated that the reduced size of PAX6⁺/⁺ organoids in the initial time course experiment could be due to restricted development by PAX6 under low ECM conditions. These findings suggest that PAX6 may regulate several processes in the early stages of development, from neural induction to regionalisation. In addition, a new link between PAX6 and the ECM has been highlighted, which may contribute to regulation of development. Organoids are a powerful tool to investigate stages of human development which would otherwise be impossible, and this thesis raises interesting questions for future research

The effects of bereavement by drug-related death: a systematic review and grounded theory study

OBJECTIVE: The project aimed to explore the effects of bereavement by drug-related death (DRD). The systematic review aimed to synthesise studies exploring the experiences of drug death bereaved family members, friends, and staff providing a caring role. The empirical study aimed to explore the effects DRDs on staff members in substance use services and resulting support needs. METHODS: The review searched five databases to identify qualitative studies exploring DRD bereavement experiences of family, friends, or staff members. Results were analysed and brought together using thematic synthesis. For the empirical study grounded theory methodology was used. Eight practitioners employed in substance use services were interviewed and two provided feedback on emerging theory. RESULTS: Nineteen studies met eligibility criteria for the systematic review. One overarching concept of Omnipresent Stigma was found to frame and complicate all features of drug death bereavement. Bereavement entailed a significant burden in various domains and support was found to be inhibited. During the empirical study a theory emerged of ‘managing the contradictions of responsibility.’ This core process determined how staff experienced bereavement and provided insight into resulting support needs. DISCUSSION: Drug death bereavement itself is stigmatised and under recognised. Both studies emphasise significant unmet support needs. Strategies and interventions focussing above the level of the individual may be most productive in rectifying this situation

Power and law: asymmetric balancing between China, the US, and Southeast Asian claimants in the South China Sea and the subregional order, 2010-2021

Tensions in the South China Sea (SCS) have significantly escalated since 2010. They have developed from territorial and maritime disputes among littoral states to complicated issues covering sovereignty, jurisdiction, resources, geopolitics, and international law. China has stepped up efforts to fulfil territorial claims in the SCS and made significant achievements. The United States has deepened its intervention in the SCS disputes and security. The Philippines initiated an international arbitration (2013–2016) against China, challenging China’s nine–dash line claim and maritime activities. China and the Association of Southeast Asian Nations (ASEAN) have endeavoured to negotiate a Code of Conduct (CoC) under international law to manage tensions in the SCS. Against this background, it is puzzling that weaker Southeast Asian claimants have not always deferred to/bandwagon with their powerful counterpart, China, despite the widened economic and military disparities, which would be inconsistent with Asymmetry theory’s expectation (Womack, 2006). Neither have they taken firm actions to balance China’s growing power in the SCS despite the enlarged system disequilibrium, which would be out of traditionally Western–centric theories’, notably realism’s anticipation (Hans J. Morgenthau, 1973; Waltz, 1979). This thesis aims to resolve the puzzle of why Southeast Asian claimants’ behaviours have not aligned with the expectations of certain elements of IR theories. Doing so requires examining how, and with what outcomes, the forces of power politics and international law have interacted to steer state interactions and order in the SCS since 2010. It further expands to three interrelated questions. First, how has China exerted its power to advance territorial claims in the SCS, and in what ways has it promoted an asymmetric subregional order? Second, how has the US penetrated its power in the SCS, and in what ways has it influenced asymmetric order in this subregional system? Third, how has international law contributed to solving the SCS disputes, and in what ways has it impacted asymmetric order in this subregional system? To carry out the investigation, this thesis adopts qualitative methods, using documentary research for data collection and content analysis for data analysis. The selected objects are China, the US, and Southeast Asian claimants: Vietnam, Malaysia, Indonesia, Brunei, and the Philippines. The timeline focuses on 2010–2021, from when both China and the US upgraded the strategic importance of the SCS to when it was approaching the end of US President Donald Trump’s term. Besides, it looks back to the time before 2010 and keeps an eye on the dynamics after 2021 until the completion of this thesis because the SCS problem is historical and ongoing. It adopts an interdisciplinary approach, incorporating International Relations (IR) and International Law (IL). This thesis combines Asymmetry and Regional Security Complex (RSC) theories and uses both political and legal analytical tools to build a composite theoretical framework for unravelling the relevant states’ interactions in the SCS and their influence on subregional order. Asymmetry (Womack, 2006) and RSC (Buzan & Wæver, 2003) theories shed different light on the problem under investigation, but neither is sufficient. The former is an Asian–driven theory assuming a hierarchical order. The latter is developed from traditionally Western–oriented realism, liberalism, and constructivism that take anarchy for granted. This thesis conciliates the two different perspectives about the structural nature of international systems, maintaining that the SCS subregional system is fundamentally asymmetric/hierarchical but anarchic to a certain degree. It argues that since 2010, power politics and international law have become two forces intertwined to form an “asymmetric balancing” model characterising the interactions between China, the US, and Southeast Asian claimants in the SCS subregional system. It has shaped a hybrid asymmetric order, essentially hierarchical but presenting some anarchic characters. It further argues that the rapidly enlarged power disparities between China and Southeast Asian claimants have prompted the SCS asymmetry, which is relatively peaceful and stable, crediting to normalcy management by littoral states. The US superpower penetration in the SCS has generated power–balancing effects on the system, weakening the base of the SCS asymmetry militarily. International law has brought legal–balancing effects on the system, weakening the normative base of the asymmetry. Power and legal balancing forces have prompted the SCS subregional system to morph into a hybrid one presenting not only hierarchical but also anarchic features, including alliance behaviours (between the US and Southeast Asian claimants), great power competition (between the US and China), sovereign equality principles. However, they have not fundamentally altered the asymmetric/hierarchical nature of the system’s order because the power gap and the inequalities between China and Southeast Asian claimants are profound. This thesis makes unique contributions to studying state interactions and order in the SCS and IR. First, it develops IR theories by combining multiple theories and different disciplinary perspectives to create a hybrid theoretical framework, in which it proposes three new concepts: “asymmetric balancing”, “legal balancing”, and “hybrid asymmetric order”. They advance the explanation of the hybridity in interactions between China, the US, and Southeast Asian claimants in the SCS and the subregional order, which presents both hierarchy and anarchy and is shaped by both power–political and legal forces. These concepts can also be applied beyond the SCS scenario, explaining state interactions in other cases that present hybridity. Second, this thesis advances the application of the RSC theory’s “superpower penetration” concept by applying it to examine US engagement in the SCS and its implications on subregional security and order. This extends the theoretical application of this notion in a new case and offers novel empirical experience to develop it. Third, this thesis adds new knowledge to the SCS study field and IR by exploring the historical asymmetry in Southeast Asia and the regional uniqueness, weighing more on Southeast Asian claimants’ approach to major powers and their role in shaping the SCS order, and incorporating scholarship in IL

Crustal properties and heat flow in Victoria Land and Wilkes subglacial basin, Antarctica: forward and inverse modelling of gravity and magnetic data coupled with petrological measurements

This thesis utilises inverse and forward modelling of geophysical data to investigate the subglacial geology and influences on geothermal heat flow in northern Victoria Land and in Wilkes Subglacial Basin, a region of East Antarctica adjacent to the Transantarctic Mountains (TAM) that is comprehensively covered by ice. The TAM separate the warmer lithosphere of the Cretaceous-Tertiary West Antarctic Rift System and the colder and older provinces of East Antarctica. Low velocity zones beneath the TAM imaged in recent seismological studies have been interpreted as warm low-density mantle material, suggesting a strong contribution of thermal support to the uplift of the TAM. For the first of the three main studies that comprise this thesis (Chapter 2), I present new Curie Point Depth (CPD) and geothermal heat flow (GHF) maps of the northern TAM and adjacent Wilkes Subglacial Basin (WSB) based exclusively on high resolution magnetic airborne measurements. I find shallow CPD and high GHF beneath the northern TAM, reinforcing the hypothesis of thermal support of the topography of the mountain range. Additionally, the study demonstrates that limiting spectral analysis to areas with a high density of aeromagnetic measurements increases the resolution of CPD estimates, revealing localised shallow CPD and associated high heat flow. The recovered CPD and GHF estimates show a good agreement to sparse in situ GHF measurements and the location of active volcanoes. Subglacial geology influences geothermal heat flow. However, due to the lack of geological information most GHF models do not account for a heterogeneous crust since direct geological information in Antarctica is limited to ice-free regions along the coast, high mountain ranges or isolated nunataks. Therefore, indirect methods are required to interpret subglacial geology and heterogeneities in crustal properties. In Chapter 3 I present a 3D crustal model of density and susceptibility distribution in WSB and TAM region based on joint inversion of airborne gravity and magnetic data. This model reveals a large body located in the interior of WSB interpreted as a batholithic structure, as well as a linear dense body at the margin of the adjacent Terre Adélie Craton. Density and susceptibility relationships are used to interpret petrophysical properties and permit the reconstruction of those crustal bodies. The petrophysical relationships indicate that the postulated batholith is granitic in composition. Emplacement of a large volume of granite batholiths can potentially elevate local geothermal heat flow significantly. Finally, I present a new conceptual tectonic model for this region based on the inversion results. Chapter 4 addresses the validation of geophysical modelling to constrain hidden subglacial geology. I present a new rock property catalogue containing density and susceptibility measurements on 320 rock samples from northern Victoria Land. This catalogue is used to assess the reliability of local and regional scale inverse results. I compare those measurements to the inverted values. The close correspondence between inverted and measured rock properties allows us to predict locations of rock types where currently such information is missing. The presented studies in this thesis demonstrate that subglacial geology matter for geothermal heat flow. Future heat flow models need to account for heterogeneities in subglacial geology and crustal properties in terms of radiogenic heat production and thermal conductivity. To obtain such information the broader geophysical community needs to increase their efforts of imaging geology hidden beneath the ice in Antarctica. This thesis provides evidence that joint inversion of gravity and magnetic airborne data is a powerful tool to infer subglacial geology and crustal properties. Furthermore, this thesis provides a workflow that can be followed for joint inversion studies in other areas of Antarctica where sufficient airborne data exists

Animation education in Scotland: a framework for training environments and individual growth

The Animation sector in Scotland relies on a successful collaboration between industry and the educational bodies who provide the training and background for the workforce. Over the past twenty years, this has often been strained due to changes in both sectors each facing their own challenges. A lack of consistency in this relationship has resulted in difficulty for students when identifying development pathways and contributes to potential ability gaps when graduating, making the transition into industry challenging. The purpose of this practice-based research is to scrutinise the ways in which industry and education have collaborated within Scottish animation and propose a framework for education which can develop a resilient, future facing, cohort. Exploring this research using a rhizomatic methodological approach, this research engaged with a number of interviews across industry and education perspectives and studied literature from sporting domains in order to work towards an appropriate solution. Through the sporting lens of a development environment, both industry and education will be established in macro and microenvironments to better understand their impact on individuals training within the medium. With an environment suitable for Scottish animation established, animation pedagogy will then be examined and a more holistic approach with emphasis on an animator’s mindset will be proposed. This thesis outlines infrastructural proposals in response to the research and discusses ways in which shared knowledge with sporting domains can impact positive change to development pathways in Scottish animation. Alongside the research, an animated documentary will be presented to act as provocation for discussion and also as an autoethnographic research on approaching practice. The overall aim of this doctorate will be to present a tangible method that will see a more cohesive network between industry and education, contributing original research to the pedagogical approaches to animation practice and theory