VictorJuiz/thesis huggingface dataset:
Epicardial heterogeneity during zebrafish heart development

The epicardium, a cell layer enveloping the heart muscle, drives embryonic heart development and heart repair in the adult zebrafish. Previous studies found the epicardium to consist of multiple cell populations with distinct phenotypes and functions. Here, I investigated epicardial heterogeneity in the developing zebrafish heart, focusing on the developmental gene program that is also reactivated during adult heart regeneration. Transcription factor 21 (Tcf21), T-box 18 (Tbx18) and Wilms’ tumor suppressor 1b (Wt1b) are often used interchangeably to identify the zebrafish epicardium. Analyzing newly generated reporter lines and endogenous gene expression, I showed that the epicardial expression of tcf21, tbx18 and wt1b during development is heterogeneous. I then collected epicardial cells from newly generated reporter lines at 5 days-post-fertilization and performed single-cell RNA sequencing. I identified three distinct epicardial subpopulations with specific gene expression profiles. The first subpopulation expressed tcf21, tbx18 and wt1b and appeared to represent the main epicardial layer. The second subpopulation expressed tbx18, but not tcf21 or wt1b. Instead, it expressed smooth muscle markers and seemed restricted to the bulbus arteriosus. The third epicardial subpopulation only expressed tcf21 and resided within the epicardial layer. I compared the single-cell subpopulations with transcriptomic bulk data and visualized the expression of marker genes to investigate their spatial distribution. Using ATAC sequencing, I additionally identified open regulatory regions located in proximity to subpopulation-specific marker genes and showed subpopulation-specific activity in vivo. My results detail distinct cell populations in the developing zebrafish epicardium, likely to fulfil distinct and specific cellular functions. Future experiments will involve targeting signature genes enriched within each epicardial subpopulation, such as those encoding Adrenomedullin a (first subpopulation), Alpha Smooth Muscle Actin (second subpopulation) and Claudin 11a (third subpopulation), employing cell type-specific genome editing to test whether and how the identified heterogeneity underlies distinct epicardial cell fates and functions. Taken together, my work adds significantly to the understanding of the cellular and molecular basis of epicardial development and can offer novel insights in the context of heart regeneration.

Keywords: Single cell sequencing
Epicardium
Heart development
Heterogeneity
Zebrafish
Microscopy
Advisor: Simoes, F
Riley, P
Patient, R
Quantifying impaired metabolism following acute ischaemic stroke using chemical exchange saturation transfer magnetic resonance imaging

In ischaemic stroke a disruption of cerebral blood flow leads to impaired metabolism and the formation of an ischaemic penumbra in which tissue at risk of infarction is sought for clinical intervention. In stroke trials, therapeutic intervention has largely been based on perfusion-weighted measures, but these have not been shown to be good predictors of tissue outcome. The aim of this thesis was to develop analysis techniques for magnetic resonance imaging (MRI) of chemical exchange saturation transfer (CEST) in order to quantify metabolic signals associated with tissue fate in patients with acute ischaemic stroke. This included addressing robustness for clinical application, and developing quantitative tools that allow exploration of the in-vivo complexity.
Tissue-level analyses were performed on a dataset of 12 patients who had been admitted to the John Radcliffe Hospital in Oxford with acute ischaemic stroke and recruited into a clinical imaging study. Further characterisation of signals was performed on stroke models and tissue phantoms.
A comparative study of CEST analysis techniques established a model-based approach, Bloch-McConnell model analysis, as the most robust for measuring pH-weighted signals in a clinical setting. Repeatability was improved by isolating non-CEST effects which attenuate signals of interest. The Bloch-McConnell model was developed further to explore whether more biologically-precise quantification of CEST effects was both possible and necessary. The additional model complexity, whilst more reflective of tissue biology, diminished contrast that distinguishes tissue fate, implying the biology is more complex than pH alone. The same model complexity could be used reveal signal patterns associated with tissue outcome that were otherwise obscured by competing CEST processes when observed through simpler models.
Improved quantification techniques were demonstrated which were sufficiently robust to be used on clinical data, but also provided insight into the different biological processes at work in ischaemic tissue in the early stages of the disease. The complex array of competing processes in pathological tissue has underscored a need for analysis tools adequate for investigating these effects in the context of human imaging. The trends herein identified at the tissue level support the use of quantitative CEST MRI analysis as a clinical metabolic imaging tool in the investigation of ischaemic stroke.

Keywords: quantitative imaging
CEST MRI
amide proton transfer, APT
ischemic stroke
acute ischaemic stroke
metabolic imaging
partial volume correction
clinical imaging
mathematical modelling
chemical exchange saturation transfer
nuclear Overhauser effect, NOE
biomedical image analysis
magnetisation transfer, MT
Advisor: Chappell, M
Effective judicial protection and damages in EU law: the case for the deterrent effect

The aim of the thesis is to examine whether the prohibition of overcompensation in the Antitrust Damages Directive is compatible with the EU legal and normative framework. To this end, the analysis is carried out on two levels. First, the rationale for damages in the selected jurisdictions (England, France and Germany) and in the EU is examined to test the main underpinning justification for the prohibition of overcompensation in the Antitrust Damages Directive, i.e. the “European legal tradition argument”. Second, the thesis addresses broader constitutional implications that underpin the debate on the desirability of the pursuit to prohibit overcompensation in the EU. These entail questions pertaining to the adoption of such measures and, thus, exploring whether the EU has the legitimacy to legislate and the related question of competence and the choice of the appropriate legal basis. The argument to be advanced in this thesis is that the aim of achieving a sufficient level of deterrence with awarding damages for EU competition law infringements stems from the very conceptual basis in which the right to damages is grounded – the principle of effective judicial protection and the principle of effectiveness. Thus, as the analysis reveals, the prohibition of overcompensation is inconsistent with the EU legal framework, since it has potential to jeopardise the deterrent or dissuasive function of antitrust damages actions. The prohibition of overcompensation has significantly contributed to the business- biased gist of the Directive, and thus to breaking the link between the rationale for the right to damages for EU competition law infringements, the legal basis and the content of the Directive. The thesis ultimately argues that the Directive’s prohibition is incompatible with the principles of conferral, subsidiarity and proportionality, and to a considerable extent inconsistent with the EU’s legal and normative framework.

Keywords: comparative law
damages
Antitrust Damages Directive
European Union law
EU competition law
effective judicial protection
Advisor: Weatherill, S
The costs and benefits of two exchange-rate regimes: the case of Ireland before and after entry to the E.M.S.

One of the central policy debates in the international monetry arena continues to be that of the relative merits of fixed exchange rates, floating exchange rates, and comprimises between them. This debate has proceeded at two levels. On the one hand, some of the arguments in the fixed/floating debate have concentrated on the purely international consequences of one or other exchange rate regime. Thus it has frequently been disputed, for example, whether or not flexible exchange rates have a built in inflationary bias...
English polyphonic style in transition: a study of the sacred music of Thomas Tallis

This study is concerned with the style (as opposed to the function) of English vocal polyphony during the period ca.1525 - ca.1575. It focusses on the sacred works of Thomas tallis (ca.1505 - 1585); but the aim is as much to come nearer to a full understanding of mid-Tudor stylistic evolution as it is to define the place of Tallis' music within the broad context. Tallis is therefore viewed both as an individual and as a representative of his time, and his music is assessed analytically rather than critically. The study takes as its premise the view that English music of the period is too often examined according to useful but unrealistic categories - sacred or secular, Catholic or Protestant, institutional or domestic, Henrician, Edwardian, Marian or Elizabethan - and that a sympathetic understanding of the evolution can only be reached when the period is considered in a broad, comprehensive and chronological sweep. It also argues that the evolution was largely stimulated by influence from abroad (the place of foreign music and musicians in mid-Tudor England is studied in detail), and that these influences can be sensed first and most deeply in secular music of the second half of Henry VIII's reign, rather than in contemporary liturgical music (the study includes a detailed discussion and full transcription of the late Henrician partsong repertory). The close stylistic identity between secular chamber style and that of Edwardian church music is emphasized, in particular their common reliance upon stretto lattices of declamatory imitation. Using Tallis' works as a touchstone, subsequent developments in musical substance and structure are investigated; and the study closes by demonstrating how Tallis' imitative practice changed rapidly and radically during the third quarter of the century, again almost certainly under the influence of foreign music.

Advisor: Brown, D
Sternfeld, F
Harper, J
Prison to prison: the prison novels of Hagop Oshagan and Armenian penological literature

The prison novels (Haji Murat, Haji Abdullah and Süleyman Effendi) of Western Armenian writer Hagop Oshagan (1883 – 1948) articulate two unprecedented sociocultural critiques of Armenian experience. Like much of Oshagan’s works, these novels, comprising the cycle Haryur Mék Tarvan [101 Years’ Imprisonment] (1933), have scarcely been studied. The task of this study is to reveal the nature of Oshagan’s critique, and to revise two chief Armenian literary critical trends: that of either de-contextualizing or instrumentalizing these novels’ nationalist preoccupations; that is, either overlooking their contextual relevance as responses to contemporaneous nationalist dogmas, or distorting them to seem ideologically sympathetic. Oshagan’s novels rather deploy the prison trope to foreground and question the aesthetic and ideological influence of late 19th century Armenian nationalist-revolutionary movements. They moreover undermine the persisting paradigm borne of nationalist-revolutionary rhetoric that collectively represents Armenians and Turks as victims and victimizers respectively.
The present study reads Oshagan in the wider context of Armenian penological literature, and locates his engagement with nationalist-revolutionary ideology as an overtly critical, rather than sympathetic project. It provides an unprecedented appraisal of such political movements’ primarily negative impact upon late 19th and early 20th century Western Armenian literature, a tradition that has presented “Armenianness” through an almost exclusive narrative of subjection. This literary historical background allows Oshagan’s singularity to appear. He is the first to recognize the prison trope as the preferred nationalist-revolutionary literary convention, a trope he then reconfigures in order to formulate an alternative, a literary mode of nationalism – namely, mystic nationalism – informed by his readings of Dostoevsky’s novels. Oshagan imagines and articulates anew the Armenian-Turk relationship in terms that complicate, subvert and transcend the normative master/slave model instituted by nationalist-revolutionary rhetoric. In the process, he elaborates a conception of these movements as inadvertently complicit in the discursive – and, ultimately, also political – (self)-subjection of Armenians culminating as experiences of absolute subjection. After Oshagan, this study constitutes the first comprehensive analysis of literary renderings of both Armenian-Turk relations and nationalist-revolutionary ideology.

Advisor: Nichanian, M
Van Lint, T
Characterisation of novel cardiac and skeletal ion channels on intracellular Ca2+ stores.

Excitation-contraction (EC) coupling is the process by which Ca2+ is released from the sarcoplasmic reticulum (SR) and is fundamental to cardiac and skeletal muscle function. The SR contains many uncharacterised ion channels and proteins which may influence EC coupling and in this thesis I have investigated the biophysical properties of some of these channels.
I have demonstrated that the single-channel gating and conducting properties of SR K+ channels from various mammalian species (rabbit, sheep and mouse) are very similar. I investigated the actions of possible physiological regulators of these channels and demonstrated that luminal Ca2+ and Mg2+ can block K+ flux in a voltage-dependent manner, while luminal Ca2+, Ni2+, and alkaline pH can reduce Po by additional mechanisms. I also characterised the single-channel properties of the various SR anion channels that are observed after incorporating mammalian SR vesicles into artificial membranes.
The trimeric intracellular cation channels (TRIC-A and TRIC-B) and Mitsugumin 23 (MG23) are suggested to be SR cation channels. I have therefore utilised Tric-a KO and Mg23 KO mice to study SR membranes devoid of TRIC-A and MG23. Additionally, I have begun to investigate the single-channel properties of purified c. elegans TRIC-B1 and human TRIC-A. I found that SR K+ channel function was altered in SR from Tric-a KO or Mg23 KO tissue, however the underlying mechanisms for the observed changes appear to be complex. My initial studies of the purified TRIC-A and TRIC-B proteins show that they are permeable to K+, Ca2+, choline, and Cl-, properties which deviate from those of SR K+ channels from rabbit, mouse and sheep. This may reflect species differences or alterations to protein function caused during the purification process or that SR K+ channels remain an unidentified class of ion channel.

Keywords: Ion channel
TRIC channel
Excitation-contraction coupling
Advisor: Sitsapesan, R
Catullus: lyric poet, lyricist

There exists between lyric poetry and music a bond that is at once tangible and grounded in practice, and yet that is indeterminate, a matter of perception as much as theory. From Graeco-Roman antiquity to the modern day, lyrical forms have brought together music and text in equal partnership: in archaic Greece, music and lyric poetry were inextricably (now irrecoverably) coupled; when lyric poetry flowered in the eighteenth century, composers harnessed text to music in order to create the new and fully integrated genre of Lieder; and in our contemporary age, the connection between word and music is perhaps most keenly felt in pop music and song ‘lyrics’. In 2016, the conferral of the Nobel Prize for Literature on Bob Dylan brought to wider public attention the nature of lyric’s poetical-musical bond: can Dylan be considered a poet if the meaning, syntax and expression of his words are dependent upon music? Is music supplementary to the words or are the two so harnessed that the music is in fact a facet of the poetic expression?
The connection between music and poetry is perfectly clear in such integrated lyric forms as these, but a more indeterminate connection can also be felt in ‘purely’ musical or poetic works – or at least in the way that we perceive them – as our postRomantic, adjectival use of the word ‘lyrical’ shows. Describing music as lyrical often suggests that it carries an extra-musical significance, a deeply felt emotion, something akin to verbal expression, while a lyrical poem brings with it an emotive aurality and a certain musicality. Text and music of lyrical quality may, therefore, invoke the other for the purpose of expression and emotion so long as our understanding of lyric forms remains conditioned by the appreciation of an implied music-poetry relationship
This thesis works within the overlap of music and poetry in order to explore the particular lyric voice of Catullus in the context of his twentieth-century musical reception. Whilst some of Catullus’s poems may have been performed musically, what we know of poetry circulation, publication and recitation in first-century BCE Rome suggests that the corpus was essentially textual. Nevertheless, Catullus’s poetry was set to music centuries later, not in reconstruction of an ancient model, but in new expression, suggesting not only that composers of the twentieth century found themes in Catullus’s poetry that resonated in their own contemporary world but that they found a particular musicality, something in the poetry that lent itself to musical form. I argue that it is in these works of reception that we can most clearly identify the essence of Catullan lyricism. Moreover, by considering the process of reception, this thesis is able to take a broader view of lyric, identifying traits and characteristics that are common to both music and poetry, thus transcending the boundaries of individual art forms in order to consider the genre in larger, interdisciplinary terms.

Keywords: Ariadne
Carl Orff
Ned Rorem
Hugo von Hofmannsthal
Richard Strauss
Lyricism
Alan Rawsthorne
Advisor: Macintosh, F
Trimble, G
Tunbridge, L
Understanding the role of the SNM1B and EXD2 in DNA damage repair

Unrepaired, or misrepaired, DNA damage can be carcinogenic or mutagenic; thus functional DNA damage repair pathways are essential for the safeguarding of the genome.
SNM1B is a 5’ to 3’ exonuclease implicated in the repair of damaged DNA, particularly the repair of interstrand crosslinks. Genetic studies have identified SNPs in the SNM1B gene as related to cancer risk. One of these (rs11552449) encodes a single amino acid change, H61Y. This study shows that WT and H61Y SNM1B have comparable in vitro biochemical and biophysical characteristics. The structures of both WT and H61Y C-terminally truncated SNM1B (Δ-SNM1B) were solved to 2.8 and 3.1 Å, respectively, and reveal similar structural properties. The structure of WT Δ-SNM1B was also reported (to 1.8 Å) with two 2’-deoxy-5’- adenosine monophosphate molecules in the active site. The structure of SNM1B shows an accessible extended active site, which may facilitate the binding of a variety of non-canonical DNA substrates. Accordingly, in vitro, WT and H61Y SNM1B are able to exonucleolytically process a wide range of structurally diverse DNA substrates. By utilising SNM1B depleted cell lines, this study also shows that SNM1B is required for DNA repair in response to treatment with DNA-crosslinking genotoxic agents (including cisplatin and SJG-136).
This study also identifies the novel double strand break repair factor, EXD2, as having intrinsic 3’ to 5’ exonuclease activity. EXD2 was shown to have enzymatic activity on a variety of substrates in vitro, including replication fork intermediates, ‘nicked’ or ‘gapped’ DNA duplexes, and RNA based substrates. Together with the cellular data this suggests a role for EXD2 in nucleolytically processing RNA or DNA-based intermediates in damage repair pathways.

Keywords: DNA damage repair
Advisor: McHugh, P
Gileadi, O
Aristotle on the value of friends

In this dissertation, I argue that Aristotle’s account of friendship is egoistic. Focusing on the Nicomachean Ethics, I begin with VIII.2. Here Aristotle claims that in all friendships, friends love only because of the lovable (φιλητόν), which divides into the useful, pleasant, and good. I argue that “because of (διὰ)” refers to at least the final cause and that “the lovable” refers to what appears to contribute one’s own happiness (εὐδαιμονία); therefore Aristotle claims that in all friendships, friends love only for the sake of their own happiness. This result may seem incompatible with some types of concern Aristotle principally attributes to his normative paradigm of complete friendship: wishing goods for the sake of the other and loving the other for himself. One might argue that these types of concern are altruistic, and so it cannot be the case that in all friendships, friends love only for the sake of their own happiness. I argue that these types of concern ultimately hinge on one’s own happiness. The object is the lovable (what appears to contribute to one’s own happiness), specifically the good instantiated by the other’s virtue; further, what a virtuous person takes as valuable about another’s virtue is how it facilitates her own virtuous activity, that is, her own happiness. From here I turn to Aristotle’s notion of “another self.” One popular interpretation of other selfhood defies the altruism/egoism divide. Here the essential feature of other selfhood is virtue, which allows for no prioritization among virtuous people; there is no prioritization of the other over oneself (as in altruism) nor of oneself over the other (as in egoism), since the relevant parties are equal in moral standing (they are virtuous). Assessing the instances of “another self” in the Nicomachean Ethics VIII.12, IX.4, and IX.9, I argue for an egoistic interpretation of other selfhood; the essential feature of other selfhood is involvement in one’s own actualization. That is, what makes other selves valuable is how they facilitate one’s own virtuous activity, one’s own happiness. Finally, I address the doctrine of self-love in the Nicomachean Ethics IX.8. Again, some interpreters derive non-prioritization from the text; Aristotle claims that all virtuous people identify with the understanding (νοῦς), so, the non-prioritization interpretation goes, there can be no prioritization among virtuous agents, as they are identical in the relevant way. I argue for an egoistic interpretation of IX.8; Aristotle endorses praiseworthy self-love, which involves maximizing the superlatively valuable fine (καλὸν) for oneself over others. Moreover, such self-prioritization occurs precisely by gratifying the understanding, that which was supposed to ground non-prioritization.

Keywords: Friendship
Altruism
Aristotle
Egoism
Love
Advisor: Irwin, T
Nielsen, K