VictorJuiz/thesis huggingface dataset:
Characterisation of DNA polymerase δ exonuclease domain mutations associated with cancer predisposition using fission yeast
Keywords: polymerase δ
fission yeast
colon cancer

Heterozygous germline exonuclease/proofreading domain mutations (EDMs) in DNA polymerase delta (Pol δ) are linked predominantly to colorectal and endometrial cancers with microsatellite stability (MSS), such as POLD1 S478N. Pol δ synthesises the lagging strand during DNA replication and partakes in DNA repair.
To assess the pathogenicity of more cancer-associated EDMs that affect highly conserved residues, POLD1 P327L, G321S, L474P and D316N variants were constructed in Schizosaccharomyces pombe (S. pombe) pol3 and mutation rate assays were carried out. Pol3(d)D316N had the highest mutation rate, comparable to Pol3 with no 3'-5' exonuclease activity (exo-null). Pol3(d)L474P had a moderate mutator phenotype, and pol3(d)P327L and pol3(d)G321S did not have increased mutation rates compared to wild type but showed hydroxyurea (HU) sensitivity, suggesting that DNA replication under stressful conditions is defective.
Some Pol ε EDMs are hypermutating, but this is not seen with Pol δ EDMs. Interestingly, none of the variants had hyper-mutation rates in excess of Pol δ exo-null, unlike some Pol ε variants. To investigate this further, pol3(d)P327R, equivalent to the hypermutating pol2(e)P286R variant, was constructed but this had a low mutation rate.
The HU-sensitivity phenotype of pol3P327L and pol3G321S was further investigated. A significant proportion of cells expressing pol3P327L displayed mitotic abnormalities during HU treatment. Pol3G321S cells took longer to complete S phase compared to the other mutants after HU block and release and had reduced viability in hydroxyurea. Both strains were synthetically sick with Rad3 inactivation, suggesting dependence on the DNA replication or repair checkpoint.
Thirdly, a genome-wide systematic screen was carried out to identify any novel negative synthetic interactions with pol3L474P. The screen yielded 565 possible hits, of which 28 were designated for further characterisation. This identified fen1 and msh2, which have been previously reported as synthetically lethal with exo-null pol3.
Development and feasibility testing of an intervention to reduce salt intake in people with hypertension
Keywords: Dietary change
Hypertension
High blood pressure
App
Salt
Sodium

Reducing dietary salt intake plays an important role in the prevention and management of hypertension, yet the evidence for effective and scalable individual-level interventions is scarce. In this research I aimed to fill this gap by developing and testing an intervention to reduce salt intake in people with hypertension. Firstly, I investigated the impact of offering shoppers lower-salt alternatives when grocery shopping, in a randomised controlled trial using a simulated online supermarket platform. I found that shoppers were willing to swap to lower-salt alternatives, and that offering a wide range of products with greater reductions in salt (>20% less) significantly reduced the salt content of their shopping basket compared with offering alternatives which were more similar in nature and salt content (-0.09 g/100g, 95% C.I. -0.10 to -0.07 p<0.001). Secondary analysis showed that participants who had previously received advice to reduce their salt intake accepted more lower-salt swaps than those who had not. I then developed a primary care-led intervention, using a theoretical behaviour change framework, to motivate and support people with hypertension to reduce their salt intake, including an app to help them choose lower-salt food when grocery shopping. A feasibility randomised controlled trial showed that the intervention (‘SaltSwap’) could be delivered in routine primary care settings (intervention fidelity 81% and high acceptability among healthcare professionals), it successfully engaged individuals with high blood pressure (the intervention session was attended by all participants randomised to the intervention group and the SaltSwap app was used by 87% of intervention participants in the first month and in 75% of shopping trips overall) and encouraged participants to swap to lower-salt alternatives for foods which typically contribute most to salt intake. An in-depth qualitative study demonstrated that SaltSwap improved participants’ knowledge and motivation to reduce salt intake, and individuals engaged with the SaltSwap app in a meaningful way. Together these results suggest that offering shoppers lower-salt alternatives is a promising approach to reducing salt intake among people with hypertension and a future large-scale trial to test the effectiveness of the SaltSwap intervention for reducing blood pressure is warranted.
From legal object to legal subject: changing conceptions of criminal animals in fourteenth- and fifteenth-century France
Keywords: Medieval Law
Animals in Law
Medieval History

This thesis concerns cases against harm-causing animals which occurred in France in the fourteenth and fifteenth centuries. I have focused on Eastern and Northern France, particularly Burgundy and areas around Paris. As a subject deemed at best a curiosity and at worst a remnant of a superstitious age, my purpose is to suggest how we might more effectively read, interpret, and understand cases where an animal that had killed a human became subject to the judicial process.
To this end, I put forward a study revealing practices and modes of thought that both reaffirmed and challenged the notion of animals as criminals. Specifically, I am interested in the ways criminal status was applied or denied after an animal had killed a human. In receipts of animal executions found in seigneurial financial registers, for example, criminality was applied through the use of particular legal terminology and the insistence on following standard criminal procedure. Here, the status of the animal was no longer that of mere property; it acquired a legal personality with which to operate within the confines of the law. This transformation from legal object to legal subject not only challenged the idea that humans, and only humans, could be subjects within the law, but it highlighted the flexibility and adaptability of the legal system.
By examining moments of criminalisation alongside sources in which harm-causing animals were denied a legal personality, such as within the customary tradition, I challenge the persistent historiography which portrays the treatment of such animals in medieval France as static or uniform. The records show that there was not a single ‘medieval’ attitude toward criminal animals, but rather multiple discourses that existed side by side. My sources thus range from customals and legal commentaries, to receipts and petitions relating to verifiable cases. Instead of one narrative, I will present here a multitude of views that engaged with as well as argued against the idea of criminal animals.
Management and mechanisms of severe eosinophilic asthma
Keywords: asthma
severe asthma
eosinophil
crth2

Severe asthma is a complex problem in which eosinophilic asthma is an over-represented phenotype compared to mild and moderate asthma. Asthma attacks, for which persistent eosinophilic inflammation is a major risk factor, are the most clinically concerning aspect of this disease as they result in high healthcare use and spending, treatment related morbidity due to oral corticosteroids, and reduced quality of life for patients.
I studied the response to monitored inhaled corticosteroids (ICS) in patients with severe eosinophilic asthma. Patients who suppressed FeNO, a marker of eosinophilic inflammation, had marked reduction in mediators of eosinophilic inflammation in the airways. This was in contrast to those who did not suppress FeNO, suggesting ICS-resistant pathways. Prostaglandin D2 (PGD2) was particularly non-responsive in this group with ICS-resistant eosinophilic inflammation.
I next studied the effect of timapiprant, an antagonist of the PGD2 receptor CRTH2, in a randomised, placebo-controlled trial in severe eosinophilic asthma. This study found a trend towards a clinically significant lowering of sputum eosinophils compared to placebo, but no changes in lung function or symptom scores. These findings are in keeping with trials of other targeted anti-inflammatory treatments in asthma.
Finally, the effects of mepolizumab, an anti-IL-5 antibody treatment, on exacerbations of severe eosinophilic asthma were investigated for the first time. In novel post hoc analyses I found that exacerbations that occur on mepolizumab are less severe in terms of changes in lung function and symptoms, are associated with less eosinophilic airway inflammation, and may be less steroid-responsive than those on placebo.
In combination, these findings suggest a role for CRTH2 antagonists in the management of severe, treatment-refractory eosinophilic asthma. Further, larger studies required to explore this. The effects of anti-inflammatory treatments on asthma exacerbations needs to be studied in more detail as my analyses have shown them to be different in nature to those on placebo. The underlying drivers of exacerbations occurring on type-2 targeted treatments need to be further understood. These exacerbations may require a different treatment approach tailored towards the underlying pathology.
Maritime metaphorics in modernist literature
Keywords: Ezra Pound
metaphor
maritime history
maritime ideology
Joseph Conrad
T.S. Eliot
Virginia Woolf
H.D.
modernism

This thesis explores the metaphoric role that the maritime world plays in modernist literature. Specifically, I make the case for a historically grounded modernist maritime metaphorics, by which authors draw on the material history of a pervasive maritime world in the late 19th and early 20th centuries in their engagements with signature topics such as the city (Joseph Conrad), perception (Virginia Woolf and H.D.), expatriation (T.S. Eliot), and right-wing politics (Ezra Pound). Combining perspectives from the New Modernist Studies and Oceanic Studies, my thesis focuses on a historicist turn in the critique of modernist literature's use of marine metaphors, tracing the ways in which naval competition, a global maritime economy, scientific innovation in marine biology, and maritime imperialism are reflected and interrogated in figurative language in the period. Reading the work of canonical authors such as Conrad, Woolf, H.D., Eliot, and Pound, I catalogue the ways in which differing and conflicting deployments of the sea, of the submarine, and of drowning are used, in their work, to reflect, interrogate, or advocate for a specifically maritime world order. This maritime world, I argue, constitutes an important and neglected context for the emergence and the development of Anglo-American modernism. This thesis thus offers a corrective to the occlusion of the maritime as a context for modernism, and provides an example of a historicist reading of maritime metaphors that have largely been dismissed as clichés or ahistorical flights of fancy.
In Chapter 1, I trace the maritime underpinnings of the modern imperial metropolis of London. Reading Joseph Conrad's city texts like The Return and The Secret Agent, I argue that metaphors describing the city as watery or oceanic register the maritime economy and colonial hinterland that shape an urban modernity.
Chapter 2 argues that the submarine metaphorics of Woolf and H.D. draws on the nexus of marine biology, visual culture, and optical science to interrogate the subjectivity and gendering of vision.
Chapter 3 contrasts the submarine metaphorics of the previous chapter with that of T.S. Eliot, tracing the horror and allure that he reads in images of drowning and watery ego-death.
Finally, in Chapter 5, I study the occluded world of maritime trade, focusing on the poetry and prose of Ezra Pound. I argue that the sea is a crucial economic exemplar in The Cantos and in Pound’s prose, ranging throughout his work in the ancient maritime economies of Venice, Rome, and Athens, in the maritime contestations of the American Revolution by US president John Adams with the British and the French, and finally in the imperialist ideology of Italian Fascism.
Taken together, these chapters constitute evidence that the modernist sea, in its historically grounded metaphorics, provides authors with a powerful lens through which to interrogate conceptions of the urban, of perception, of the transatlantic, and of empire.
The organisation and dynamics of Escherichia coli outer membrane proteins
Keywords: Superresolution Microscopy
Colicins
Microbiology
OmpF
OMPs
Membrane Biology
Microscopy
Bacteriocins
Outer Membrane Protein

The outer membrane of E. coli is a component of the cell envelope with significant physiological importance. This multifunctional membrane allows the influx of nutrients and simultaneously excludes toxic compounds, such as antibiotics, which must cross this membrane to elicit their cytotoxic effect. The composition and general structure of this membrane are well known, an asymmetric lipid bilayer containing LPS in the outer leaflet, phospholipids in the inner leaflet, densely populated by integral β-barrel outer membrane proteins and extensively linked to the underlying peptidoglycan through certain lipoylated inner leaflet outer membrane proteins. Little is known, however, about the lateral organisation and dynamics of the proteins in this membrane. In this thesis I investigate the organisation and dynamics of two highly abundant outer membrane proteins: the general porin, OmpF, and the lipoprotein, Pal.
OmpF distribution—visualised with Colicin N fluorescent fusion proteins—could be sorted into distinct categories related to the cell cycle, and these distributions arose due to the biased insertion of OmpF at mid-cell. This biased mid-cell insertion also caused old OmpF to localise to the cell poles during growth. Superresolution investigations showed that at fine resolutions, OmpF displayed a significant degree of clustering in the outer membrane and was highly restricted in its diffusion (Dapp: 0.0018 µm2s−1).
Pal, investigated by PALM-SPT, was shown to accumulate at the septum of dividing cells, revealing a key mechanism by which this protein stabilises the outer membrane during division. Pal diffusion was highly restricted (0.0042 µm2s−1) as a result of peptidoglycan binding, demonstrated by an almost 5 fold increase in diffusion coefficient (0.0205 µm2s−1) upon removal of the PG binding domain.
This work shows that integral β-barrel OMP distribution and dynamics are dictated by the subcellular biased assembly of these proteins into a membrane that does not permit lateral diffusion. In addition, analysis of Pal demonstrates the vastly different diffusive environment of the inner leaflet of the outer membrane and the contribution of underlying cell envelope components on protein diffusion.
Rhyme in Shakespeare's theatre
Keywords: Rhyme
Form
Shakespeare
Renaissance
Theatre

This thesis analyses, contextualises, and celebrates rhyme in Shakespeare’s plays. Taking a historical formalist methodology, it reads rhyme’s local and structural functions both in aesthetic terms and within the network of cultural, textual, and theatrical associations that nourish them. The audiences’ varied horizons of expectation regarding rhyme – from literary reading, earlier forms of theatre, previous encounters with Shakespeare and other early modern dramatists, and wider performance culture – provide a basis for examining rhyme’s effects and allusions. The thesis explores the fully rhyming drama that preceded and influenced Shakespeare’s theatre; the productive tension in early modern dramatic rhyme between the classical and the English; the self-reflexive humour of Shakespeare’s early comedies; the different ways in which two Henriads invoke the register of the Mirror for Magistrates; the development of the rhyming lover; the influence of clowns, fools, and their improvised rhyme performances on Shakespeare’s work, specifically King Lear; the ways in which Othello, Hamlet, and Macbeth subvert different established conventions of the early modern dramatic couplet; Shakespeare’s negotiation of the line and the line ending in his late work, and its relation to the human and the wild in Cymbeline; and finally the legacy of Shakespearean dramatic rhyme, with brief discussions of post-Restoration adaptations and contemporary hip-hop Shakespeare productions. The thesis aims to be holistic not only in its approach to the various agents of theatre experience, but also in the way it views rhyme within a play. Rather than focusing solely on specific instances in their local contexts, it considers these moments as parts of broader structural and tonal principles. The argument of this thesis is that Shakespeare’s dramatic rhyme is worthy of study, not only for its powerful place in individual moments, but as a device with far-reaching associations and engagements: structural, allusive, and cultural.
Mapping tissue magnetic susceptibility and its biological correlates in the human brain
Keywords: Quantitative Susceptibility Mapping
Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the brain visualises anatomical structures on the scale of millimetres, but is nevertheless sensitive to microscopic tissue features. One of the features that is intrinsically important to MRI is magnetic susceptibility (χ). In brain imaging, χ contrast between structures primarily arises from tissue iron, calcium and myelin content, all of which are important tissue constituents related to a variety of brain functions and diseases.
Interest in quantification of tissue χ distribution has thus led to quantitative susceptibility mapping (QSM), a technique that quantifies tissue χ distributions through sophisticated postprocessing of phase images. The past decade has witnessed great progress in QSM. The histological correlates of χ estimates have been established including an approximately linear relationship with iron concentration validated using post-mortem brain tissue, and in vivo studies have demonstrated QSM’s ability to detect disease-relevant changes, particularly iron accumulation in neurodegeneration.
The work presented in this thesis seeks to further investigate the biological correlates of tissue χ measures in previously unexplored settings. The first experimental chapter discusses the development of a QSM processing pipeline for fixed post-mortem, whole-brain data. Using this pipeline, we compared the resulting χ maps in brains from patients with amyotrophic lateral sclerosis and controls, with validation against iron and myelin histology. The second and third research chapters discuss implementing QSM in a large-cohort study. We developed a robust QSM processing pipeline to produce χ estimates in 35,885 subjects from the UK Biobank imaging study. We carried out phenotypic association studies and the first genome-wide association studies of χ estimates in the brain, identifying a broad range of associated phenotypes and genetic variants.
The results presented in this thesis demonstrate the richness of information provided by QSM and hopefully promote greater clinical take-up of QSM in the future.
Form unfollows function: subversions of functionality
Keywords: modern art
design of everyday things
art and design
design
contemporary art
Lygia Clark
modern sculpture
reader-response theory
reception aesthetics
Claes Oldenburg
Donald Norman
Wolfgang Kemp
Joseph Beuys

This practice-led doctoral thesis explores what happens when we consider works of art as designed objects (i.e., their process of production as a process of design) through two discrete yet mutually informing components: a series of original objects and a written dissertation.
This practice-led doctoral thesis explores what happens when we consider works of art as designed objects The objects, which play with the language of industrial design yet are presented in a traditional fine art exhibition setting, are intended to oscillate between a sense of utility and a sense of futility, thereby destabilising the ground on which they are presented and received. By straddling both registers, the objects resist neat subsumption either into the category of “art” or that of “design,” consequently urging their re-evaluation.
The dissertation, which draws on Donald Norman’s theory of the design of everyday things on the one hand and Wolfgang Kemp’s theory of reception aesthetics in the visual arts on the other, sets up a theoretical framework for considering the products of artistic production in design terms (namely, affordances, constraints, signifiers, feedback, mapping, and conceptual model). Through a close focus on three works of modern art—Claes Oldenburg’s "Saw," Joseph Beuys’s "Capri Battery," and Lygia Clark’s "Critter"—the dissertation offers keyhole comparisons of everyday products and the canonical sculptures, whereby the analyses of the former enable unexpected “functional” readings of the latter.
Through these two complementary forms of enquiry (the object-making and the writing), the thesis aims to challenge traditional distinctions between different modes of creative production, and it argues for a consideration of artistic production as a rational mode of visual and material production that does not follow means-end rationality.
Experimental and analytical investigations of non-skeletal carbonate production
Keywords: Limestone
Mg-calcite
Experimental
Geochemistry
Precamabrian
Carbonate
Magnesite
Neoproterozoic
Tonian
Phosphate

The overriding aim of this research is concerned with understanding the chemical controls on carbonate sedimentation in naturally occurring highly alkaline systems that produce enigmatic mineral assemblages. The main approach taken here is to characterize the kinetic pathways of Ca-Mg-carbonate precipitation and mineralization in systems lacking a biological carbonate factory and to understand the relationship between fluid chemistry and mineralogy in non-classical nucleation regimes. The first line of research explores the kinetics of Ca-Mg-carbonate nucleation and recrystallization in the presence of phosphate (PO4) as an inhibitor in high-alkalinity experiments. We identify and constrain new crystallization pathways to Mg-rich carbonates magnesite and disordered dolomite from amorphous precursors that overcome energy barriers under Earth surface conditions. The second line of research explores CaCO3 nucleation under Neoproterozoic seawater conditions. We identify and constrain saturation state thresholds required for nucleation in these settings that are influenced by micromolar concentrations of PO4. The third line of research explores geological carbonates to test our hypotheses that PO4 may have influenced the mid-Neoproterozoic CaCO3 factory. We reveal new P records that identify abundant and widespread P distribution at significantly elevated PO4 concentrations in Neoproterozoic Tonian-aged carbonate rocks. Together, this research indicates enhanced P-cycling in the Tonian that influenced the CaCO3 factory and may have resulted in enhanced concentrations of bioavailable P that was crucial for biological evolution.