VictorJuiz/thesis huggingface dataset:
How to build a bony vertebrate in evolutionary time

Jawed vertebrates (gnathostomes) account for over 99% of living vertebrate diversity, with origins that stretch back nearly half a billion years, and comprise two groups: Osteichthyes (fishes and land-dwelling vertebrates) and Chondrichthyes (sharks, rays and chimaeras). Osteichthyans are the dominant clade, with at least 60,000 species approximately evenly divided between two clades: the Actinopterygii and the Sarcopterygii. However, our understanding of early osteichthyan evolution is skewed in favour of sarcopterygians, leaving the origin of nearly half of all vertebrate diversity critically understudied. Furthermore, recent upheavals in the early gnathostome tree have destabilised relationships amongst fossil taxa and eroded our understanding of primitive anatomical conditions of key groups. Central to understanding early gnathostome evolution is the braincase, an anatomically complex structure that provides a wealth of morphological characters. However, braincases rarely fossilise, and their position inside the skull makes them difficult to attain. X-ray tomography allows a comprehensive description of the internal and external anatomy of fossils, including the braincase. This thesis sets out to target phylogenetically pivotal taxa and incorporate new anatomical data in building up a picture of character evolution in early jawed vertebrates. In particular, I target the gnathostome stem, describing a new taxon that helps bridge the morphological gap between placoderms and crown gnathostomes, allowing a more comprehensive understanding of both dermal and endoskeletal evolution. I also focus on early actinopterygians, describing the endoskeleton of the first members of the group in order to understand primitive anatomical conditions. I then investigate actinopterygian braincase anatomy in the context of a revised phylogenetic analysis, illuminating the early evolution of the actinopterygians. Finally, I present a synthetic review of braincase anatomy across the early gnathostome tree. These results provide a more accurate picture of braincase evolution across gnathostomes and actinopterygians, clarifying our understanding of their evolution while revealing new information about when key innovations arose in the brains of the very first ray-finned fishes.

Advisor: Friedman, M
Electrophysiological characterization of the human two-pore channel 2

The Two-pore channel (TPC1-3) family represents a recently identified class of endolysosomal ion channels. TPCs were originally proposed to be promising candidate channels for NAADP-induced Ca2+ release. However, subsequent studies have emerged to propose an alternative view where TPCs may be Na+-selective channels regulated by the lysosome-specific phosphoinositide PI(3,5)P2 or voltage in an isoform-dependent manner. This thesis asks the question of whether pharmacological and ion permeation properties of TPCs, in particular the human TPC2, may satisfy or may be consistent with the requirement of a potential NAADP-sensitive Ca2+-release channel. These fundamental properties of hTPC2 were approached using patch-clamp electrophysiology and confocal fluorescence microscopy, and were analysed quantitatively to extract relevant physical parameters important to our understanding of their physiological and functional significance.
Chapter 2 presents the basic electrophysiological characterisation of hTPC2. It follows a logical way by first determining the ion permeation properties, followed by the investigation of its physical relation with fractional Ca2+ current and Ca2+ nanodomains to rigorously prove that this Na+ selectivity is sufficient to ensure negligible Ca2+ leakage both experimentally and theoretically. This follows the logic that matter must not be created nor destroyed so that a Na+-selective channel that poses a physiologically significant energy barrier to Ca2+ permeation from one side would not lead to the creation of Ca2+ on the other
side.
Chapter 3 represents a natural progression from Chapter 2 and is aimed at investigating the underlying mechanisms responsible for the electrophysiological ion selectivity observed. This chapter also follows a logical way by first identifying spermine as a high valence intracellular blocker, its mutual antagonism with different external ionic species that allows the determination of ion-binding affinity, followed by the determination of the concentration dependence of ion conduction to identify possible lower affinity binding. By considering all the above qualities, the outcome is a coherent description and connection of ion binding selectivity, kinetic selectivity and ion binding configuration with the observed electrophysiological selectivity.
Chapter 4 discusses the missing puzzles and how these questions might be addressed.

Keywords: Intracellular channel blocker
Ion permeation mechanisms
Equilibrium ion selectivity
Fractional Ca2+ current
Ion transport selectivity
Two-pore channels
Advisor: Galione, A
Development of tools to provide prioritisation and guidance in the development of chemical probes and small molecule leads

Experimental methodological developments in measuring protein-ligand interactions for small molecule (<900 Da) drug discovery have led to an influx of data. In some instances this data overload has been overwhelming and can complicate rather than inform decision-making during drug discovery. The focus of this thesis is thus to develop novel methods to contextualise and extract useful information that helps medicinal and computational chemists make sense of available data and improve the productivity of drug discovery. Specifically I have developed computational tools to structure and analyse protein-ligand interaction data.
I generated 48 novel ligand-bound protein structures for the bromodomain of BAZ2B and the JmjC domain of KDM4 using experimental fragment soaking. This quantity of structures required time consuming and subjective analysis. A 3D interactive visualisation tool, WONKA, was therefore developed. WONKA displays interesting and unusual features (e.g. residue motions) within ensembles of protein-ligand structures and allows for sharing of observations between scientists. WONKA does not consider protein-ligand activity data, so I developed OOMMPPAA. OOMMPPAA is an interactive 3D visualisation tool that incorporates protein-ligand activity data with protein-ligand structural data using 3D matched molecular pairs. OOMMPPAA highlights nuanced structure activity relationships (SAR) and summarises available protein-ligand activity data in the protein context.
WONKA and OOMMPPAA form a data model and platform to analyse structural and activity data. The extensibility and utility of this data model are demonstrated by the development of two further tools. The first, GLOOP, suggests ligand modifications from large datasets, and provides quantification of the importance of putatively important moieties. The second, LLOOMMPPAA, designs synthetically tractable molecules that explore a diverse range of protein-ligand interactions. LLOOMMPPAA has been shown experimentally to provide useful SAR. The tools described in this thesis provide novel analyses of and a framework for investigating protein-ligand interaction data.

Advisor: Deane, C
Marsden, B
Delegation beyond the nation-state

This research investigates support for delegation to international organisations using a framework derived from post-functionalist theory in the EU literature. This theory is extended such that economic interests and cosmopolitan identity are not only determinants of support for delegation, but also vary in importance, depending on the type of international organisation in question (i.e. peace-keeping vs. economic). Hypotheses are tested using data collected by the Chicago Council of Global Affairs (2007) and the 5th wave of the World Values Survey. The former also allows for a test of endogeneity - a persistent issue in the literature - using instrumental variables for an Indian sample.

Keywords: delegation
public opinion
cosmopolitanism
international organisations
instrumental variables
Advisor: Vries, C
A rebellion in the Korean medicine community: an ethnography of healthcare politics in contemporary South Korea

This thesis explores South Korean healthcare politics based on a series of inter-generational conflicts that occurred in a medical community in 2012. The conflicts broke out among 'doctors of Korean medicine', a medical profession unique to Korea practicing a form of medicine of East Asian origin that has recently undergone significant 'bio-medicalization'. Doctors of Korean medicine have the same status as doctors of Western medicine in the country's mainstream healthcare system, although the purview of their practice is legally demarcated. Government policies aimed at the industrialization of pharmaceuticals and the promotion of health among Korea's elderly population were the source of the conflicts that escalated into a group of junior doctors leading to what could be considered a 'rebellion' against the community leaders.
The thesis investigates first the socioeconomic and political backgrounds of the conflict. It proposes that elements of intra- and inter-professional politics and the aftermath of the country's re-democratization, economic shock and demographic transition were all important factors. Second, it explores the nature of the rebellion itself by focusing on the emergence of a set of norms and values and on the 'ritual-like' interactions observed during the event. The analysis reveals that during the conflicts the actors referenced certain values and ideologies underpinning their everyday lives and, in doing so, were effectively engaged in the strengthening, rather than the weakening, of existing social structures.
This thesis contributes to the study of Korean medicine by revealing the features of its integration into the country’s healthcare system and the effects of its bio-medicalization. By describing the process by which new online-based agents of a social movement emerged, it also contributes to the study of hyper-connectivity in Korean society. Finally, the ethnography contributes to the anthropological study of East Asian medicine by illustrating the importance of institutional factors such as politics and the economy in capturing the modes of its contemporary presence.

Keywords: East Asian (Chinese) medicine
medical professionalization
generational conflicts
contemporary Korean society
digital sociality
Korean Medicine
Korean healthcare politics
rituals of rebellion
Essays on time-inconsistency and revealed preference

This thesis concerns three important issues related to the problem of time-inconsistency in decision-making and revealed preference analysis. The first chapter focuses on the welfare properties of equilibria in exchange economies with time-dependent preferences. We reintroduce the notion of time-consistent overall Pareto efficiency proposed by Herings and Rohde (2006) and show that, whenever the agents are sophisticated, any equilibrium allocation is efficient in this sense. Thereby, we present a version of the First Fundamental Welfare Theorem for this class of economies. Moreover, we present a social welfare function with maximisers that coincide with the efficient allocations and prove that every equilibrium can be represented by a solution to the social welfare optimisation problem.
In the second chapter we concentrate on the observable implications of various models of time-preference. We consider a framework in which subjects are asked to choose between pairs consisting of a monetary payment and a time-delay at which the payment is delivered. Given a finite set of observations, we are interested under what conditions the choices of an individual agent can be rationalised by a discounted utility function. We develop an axiomatic characterisation of time-preference with various forms of discounting, including weakly present-biased, quasi-hyperbolic, and exponential, and determine the testable restrictions for each specification. Moreover, we discuss possible identification issues that may arise in this class of tests.
Finally, in the third chapter, we discuss the testable restrictions for production technologies that exhibit complementarities. Suppose that we observe a finite number of choices of input factors made by a single firm, as well as the prices at which they were acquired. Under what conditionsimposed on the set of observations is it possible to justify the decisions of the firm by profit-maximisation with production complementarities? In this chapter, we develop an axiomatic characterisation of such behaviour and provide an easy-to-apply test for the hypothesis which can be employed in an empirical analysis.

Advisor: Quah, J
The representation of women in early Christian literature: Armenian texts of the fifth century

In recent decades there has been a growing scholarly interest in the representation of women in early Christian texts, with the works of Greek and Latin authors being the primary focus. This dissertation makes an important contribution to the existing scholarship by examining the representation of Armenian women in the fifth-century Christian narratives, which have been instrumental in forging the Christian identity and worldview of the Armenian people. The texts that are discussed here were written exclusively by clerics whose way of thinking was considerably influenced by the religious teachings of the Greek and Syriac Church Fathers. However, as far as the representation of women is concerned, the Greek Fathers' largely misogynistic discourse did not have discernible effect on the Armenian authors. On the contrary, the approach developed in early Christian Armenian literature was congruous with the more liberal way of thinking of the Syriac clerics, with a marked tendency towards empowering women ideologically and providing them with prominent roles in the male-centred society. I argue that such a representation of women was primarily prompted by the ideology of the pre-Christian religion of the Armenians.
This research discusses the main historical and cultural factors that prompted a positive depiction of women, and highlights the rhetorical and moralising strategies that the authors deployed to construct an "ideal woman". It further explores the representation of women's agency, experience, discourse, and identity. In particular, women's pivotal role in Armenia's conversion to Christianity and female asceticism in fourth–fifth century Armenia are extensively investigated. It is also argued that women's status in the extended family determined the social spaces they could enter and the extent of power they could exercise. It appears that Iranian matrimonial practice, including polygyny and consanguineous marriages, was common among the Armenian elite, whereas the lower classes mainly practised marriage by bride purchase or abduction. Special attention is devoted to the institution of queenship in Arsacid Armenia and the position of the queen within the framework of power relationships. Finally, this study examines the instances of violence towards women during wars and how the female body was exploited to achieve desirable political goals.

Keywords: Church Fathers
Violence against Women
Female Asceticism
Persian
Marriage
Sassanian
Christianisation
Subintroductae
Women
Zoroastrianism
Conversion
Customary Law
Armenian Christianity
Iranian
Queenship
Advisor: van Lint, TM
The Hesiodic Aspis: introduction and commentary on vv. 139–237

This thesis is concerned with the pseudo-Hesiodic Aspis, also known as the Scutum or Shield of Herakles (Heracles). It is divided into two halves: the Introduction, consisting of four chapters, is followed by detailed line-by-line commentary on a portion of the Greek text.
Chapter I surveys the evidence for the poem's origins and dating before moving on to its scholarly reception since Wolf. It then argues that, for a proper understanding of the Aspis, the methodologies of oral poetics must be balanced with an awareness of its responses to fixed texts (in particular the Iliad).
Chapter II examines the author as a poet within the oral tradition, focussing on: narrative style and structuring; type-scenes; similes; poetic ethos; the poem’s position relative to the Hesiodic corpus; the use of formular language; and the growth of the poem in the author’s hands. These problems are most fruitfully approached by taking account of the interplay of tradition on the one hand and of allusion to specific texts on the other. Wider points about the advanced stages of the oral tradition also emerge; in particular, from an analysis of narrative inconsistencies in the Aspis it is suggested that writing played a role in the poem's composition.
Chapter III positions the poet within the literary tradition: his interactions with other songs and tales are sometimes sophisticated engagements of a kind more often detected in Hellenistic and Roman poetry. The presentation of the protagonist of the Aspis evinces the poet's skilful handling of myth, here manipulated for political purposes. Chapter III concludes with a survey of the poem’s reception in early art and in literature up to Byzantine times.
In Chapter IV the central section of the poem, the description of Herakles' shield (vv. 139–320), is examined in detail, both in relation to the Homeric Shield of Achilles and within the context of the Aspis.
The second half of the thesis comprises a critical edition of and lemmatic commentary on vv. 139–237.

Advisor: Rutherford, R
Total synthesis of rubriflordilactone A

Rubriflordilactones A and B are highly oxygenated nortriterpenoid natural products isolated from Schisandra rubriflora. The latter is of particular biological interest as it shows significant anti-HIV activity.
Two transition metal-catalysed cascade cyclisation approaches for the formation of the CDE rings of the rubriflordilactones were developed. Palladium-catalysed cyclisation of bromoenediynes and cobalt-catalysed triyne cyclotrimerisation both transform acyclic precursors into 7,6,5-bisannelated arenes in a single step.
Two enantioselective syntheses of the AB ring fragment common to both rubriflordilactones, with bromoene or alkyne functional groups required for the respective cyclisation methods, are described; along with the refinement of a route to the CDE diyne fragment of rubriflordilactone A.
From these fully functionalised bromoenediyne and triyne substrates, both metal-catalysed cyclisation methods were successful; these strategies converged on a late-stage intermediate bearing the ABCDE ring system of rubriflordilactone A. Construction of the F ring, followed by attachment of the G ring by an intriguing oxo-carbenium ion addition reaction completed two enantioselective total syntheses of (+)-rubriflordilactone A.

Keywords: Schisandra natural products
total synthesis
Advisor: Anderson, E
Investigating the pathophysiology of acute ischaemic stroke using magnetic resonance imaging

The original description of the ischaemic penumbra asserted that both cerebral blood flow and metabolism would be required to monitor therapeutic intervention in acute ischaemic stroke. However, imaging in stroke trials has predominantly used biomarkers of infarction or perfusion-weighted signal to identify the pathophysiological processes that occur. This approach has neither identified novel treatment targets, nor been shown to consistently select patients who might benefit from intervention. The aim of this thesis was to use magnetic resonance imaging (MRI) biomarkers to identify and describe the pathophysiology of acute ischaemic stroke in patients.
Patients admitted to the John Radcliffe Hospital in Oxford were recruited into a clinical imaging study. Serial imaging data were acquired, predominantly in the first hours after symptom onset, to capture the early dynamics of brain pathophysiology. Tissue status was meticulously defined over time to ensure robust interpretation of the novel imaging biomarkers: multiple post labeling delay arterial spin labeling to measure cerebral blood flow (CBF), and amide proton transfer to generate an intracellular pH-weighted signal.
At a group level, the regions with the most severe injury had the lowest mean CBF and the greatest acidosis at presentation. There was a gradient of mean CBF and pH-weighted signal from the most ischaemic tissue to healthy tissue, but at the level of the individual there was considerable overlap in both parameters. The dynamics of perfusion were not sufficient to explain tissue outcome. Both acidosis and alkalosis were observed up to 24 hours in tissue that infarcted, and the nature of the pH change correlated with the timing of infarction.
These data show that single imaging biomarkers cannot explain the pathophysiology of stroke and tissue fate. There is heterogeneity of pathophysiology both within and between patients, and the dynamics of these processes vary. Insight from pH-weighted imaging highlights the limitations of using perfusion imaging alone to assess tissue status, and supports the use of complementary metabolic imaging in the investigation of ischaemic stroke.

Keywords: Stroke
Magnetic Resonance Imaging
Advisor: Kennedy, J
Targeting ATM/ATR signalling in lung cancer

Cells respond to the induction of DNA damage with activation of the DNA damage response (DDR), a complex signalling network which orchestrates cell cycle arrest and DNA repair in order to maintain genomic stability and cell viability. Activation of these signalling pathways enables cancer cells to survive DNA damaging chemo- or radiotherapy and contributes to the development of therapy resistance. Therefore, components of the DDR have become attractive targets for chemo- or radiosensitisation. Furthermore, cancer cells frequently exhibit defects in certain DDR components and may, as a consequence, become highly dependent on remaining DDR pathways to survive DNA damage.
Two apical mediators of the DDR are the serine/threonine protein kinases ATM and ATR. ATM is frequently mutated in non-small cell lung cancer (NSCLC), and defects in ATM may render the tumour cells dependent on ATR signalling for survival. In this study, we characterised the functional consequences of ATM mutations in NSCLC cell lines and established an immunohistochemistry-based assay to identify patients with loss of ATM expression. As a single agent, pharmacological ATR inhibition (ATRi) was selectively cytotoxic for cells deficient in both ATM and p53. Furthermore, ATRi in combination with either ATM or PARP inhibition selectively killed tumour cells with mutant p53.
We show that following ATR inhibition, ATM and p53 perform critical cell cycle checkpoint functions, independently of each other. Our results suggest that while retained function in any of these pathways is sufficient to maintain cell viability, functional loss of ATM, ATR and p53 results in premature mitotic entry, chromosome fragmentation and mitotic catastrophe.
We conclude that in NSCLC the functional status of both ATM and p53 determines the cellular response to ATR inhibition, and propose that a combination of ATR inhibition with ATM or PARP inhibition may have broad utility for the treatment of p53-mutated NSCLC.

Advisor: Ryan, A