VictorJuiz/thesis huggingface dataset:
Identification and characterisation of the type VI secretion system in rhodobacter sphaeroides

The type VI secretion system (T6SS) is a versatile multi-component nanomachine found in 25% of Gram-negative bacteria. It translocates effector proteins into neighbouring eukaryotic or prokaryotic cells, and therefore it is important for bacterial virulence, as well as interbacterial competition. Although initially T6SSs were considered to be primarily contact-dependent weapons de- ployed during bacterial warfare, recently T6SSs that secrete effector proteins to sequester common goods from the environment have also been identified. Characterised examples of such systems play a role in the uptake of zinc, manganese, iron, copper and molybdate ions. The mechanism behind T6SS- dependent metal ion acquisition involves secretion of a metal-binding protein which sequesters metal ions from the extracellular milieu. The subsequent steps by which cells uptake the sequestered metal ions remain largely elusive, nonetheless it it is known that, in some cases, interaction of the secreted protein with a TonB-dependent outer membrane transporter is required.
Here we report the previously uncharacterised T6SS of Rhodobacter sphaeroides WS8N. By performing bioinformatic analyses on the putative T6SS cluster we find that it encodes all 13 core T6SS proteins along with four proteins known to be involved in T6SS regulation (TagE-H), the T6SS tip sharpening protein PAAR, the peptidoglycan-binding protein TagL and an additional seven hypothetical proteins. We also find the presence of a T6SS to be strain, and not species, specific in the Rhodobacteraceae family of proteobacteria.
Further, we investigated the conditions under which the the T6SS of R. sphaeroides WS8N is active and demonstrate that, its function is required for photoheterotrophic growth under iron-limited conditions. In particular, presence of this T6SS allows growth of R. sphaeroides WS8N in limited amounts of both Fe2+ and Fe3+, but does not support growth in iron-depleted media supplemented with heme. Finally, we performed preliminary biochemical studies of the C-terminal extension of VgrG, which showed the potential to bind iron. This suggests that VgrG might be the secreted protein facilitating the T6SS-dependent uptake of iron.
The data presented in this study represents the first characterisation of a T6SS from the Rhodobacteraceae family of proteobacteria, informing us on the role of this system in a class of organisms that heavily depend on the use of iron for their growth.

Keywords: T6SS
type VI secretion system
Rhodobacter sphaeroides
Advisor: Mavridou, D
Foster, K
Opposition strategy-formation in autocracies: a theory of coordination with evidence from Latin America


When and why do oppositions coordinate their actions against authoritarian regimes? This dissertation studies uneven patterns of opposition coordination in autocracies. By paying attention to the individual and collective dilemmas of opposition elites, this research challenges existing knowledge and the assumptions that scholars bring to the study of non-democratic regimes. In contrast to existing accounts that mostly focus on the behaviour and choices of the autocrat, my project provides insights into the micro-foundations of the decision-making and strategy-formation processes of opposition parties. This work also makes a conceptual contribution to the existing theories of non-democratic regimes explaining when and why coordination is more likely to happen.
Based on 239 semi-structured interviews with opposition elites, academics, journalists, regime defectors, civil society members, amongst others, collected during iterative field research trips between 2014 and 2019 to the US, Mexico and Venezuela, this study hones in on repression as an explanatory variable for opposition strategic choices in autocracies. I have found that what shapes opponents’ decision-making and strategy-formation is the amount of repression they are facing and how repression is applied (targeted or indiscriminate). This dissertation disaggregates the concept of repression into violent and non-violent and singles out that the rulers deliberately choose who to repress and how much to repress to divide their opponents into irreconcilable camps. In a nutshell, this research argues that opposition coordination is only possible under two conditions: When repression is both moderate and indiscriminate. When repression is either low/high and/or targeted towards specific parties, coordination is less likely to occur.

Keywords: Opposition Strategies
Latin America
Venezuela
Autocracy
Political Parties
Democratization
Mexico
Coordination
Oppositions
Advisor: Doyle, D
Bermeo, N
A history of gold mining in the Asante region of Ghana (1950-1972)

This doctoral research project addresses the significant lacunae in the inadequate inclusive understanding of Ghana’s gold mining history over the late colonial and early post-colonial period that encompass multiple socio-political actors in the industry’s encounters with state and society. The thesis examines the overarching contestations among multiple social and political actors over access to the potential benefits to be derived from mineral extraction within this changing socio-political landscape. It utilises a wide range of archival materials encompassing colonial and post-colonial state and mining companies’ records, combined with in-depth oral histories with diverse mining communities’ actors with lived experiences of these settings, dating to the mid-to-late twentieth century.
While the study period saw the dominance of industrialised gold mining with accompanied political-economic policies and socio-cultural norms that prevented artisanal mining operations in the study communities, access to the resultant industrially generated mineral wealth took multiple and diverse forms. It transcended the often-explored state-company-worker relations within the formal masculinised industrial extractive sector, and is here analysed in relation to a pluralist understanding of these mining communities. The thesis demonstrates the need to understand Ghana’s gold mining history during this period in an inclusive and nuanced way, emphasising the agency of diverse social and political actors ranging from elite political and economic actors from the colonial metropole to the national, and then to local subaltern members of mining communities, within a single analytical framework. Against the background that historical reality often defies the logic of rigid periodisation, the thesis provides an inclusive understanding of how these diverse actors navigated change and contested—albeit commonly in unequal ways—access to the benefits generated by mineral resources based on ideas that were both historically continuous and radically transforming during the period under analysis.

Keywords: decolonisation
Mining communities
gold mining
gender
contested wealth
colonial capitalism
Asante
Advisor: Larmer, M
Adaptive robust model predictive control

Model Predictive Control (MPC) repeatedly solves a finite horizon optimal control problem subject to input and state constraints. The performance of MPC algorithms depends crucially on the quality of the model that is used to optimize the predicted future performance. To reduce system model uncertainties, adaptive controllers have been proposed for MPC enabling model parameters to be identified online. Adaptive robust MPC, combining adaptive control and robust MPC, therefore has the potential to estimate system parameters while satisfying operating constraints and providing stability guarantees. However, although adaptive robust MPC algorithms have been considered for several decades, robust, computationally tractable adaptive MPC remains a topic under research.
This thesis proposes several adaptive robust Model Predictive Control strategies for linear and nonlinear systems with constant unknown model uncertainties and bounded additive disturbances. By combining set membership parameter identification with robust tube MPC, the proposed algorithms guarantee robust constraint satisfaction and recursive feasibility. Computational tractability is ensured by using polytopic sets of fixed complexity to bound parameter sets and predicted states. The closed-loop system is proven to be input-to-state stable under a nominal cost.
For parameter identification, the thesis proposes various approaches that incorporate persistence of excitation conditions as computationally tractable constraints with feasibility guarantees within adaptive MPC. Methods of ensuring persistence of excitation include augmenting the cost function, exploiting the random nature of disturbance inputs inherent in the model, introducing additional excitation into the control inputs, and including both disturbance and additional input excitation in the algorithm. The performance of various approaches is compared in terms of parameter convergence and tracking or regulation performance. In addition, the thesis relates the probabilistic rates of parameter set convergence to persistence of excitation conditions and proves convergence of the estimated parameter sets to the true parameter values using the proposed algorithms.

Keywords: uncertain linear systems
Adaptive control
System identification
Model Predictive Control
control of constrained systems
Robust control
Advisor: Cannon, M
Characterisation of DNA polymerase δ exonuclease domain mutations associated with cancer predisposition using fission yeast

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.

Keywords: polymerase δ
fission yeast
colon cancer
Advisor: Kearsey, S
Humphreys, S
Mellor, E
Development and feasibility testing of an intervention to reduce salt intake in people with hypertension

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.

Keywords: Dietary change
Hypertension
High blood pressure
App
Salt
Sodium
Advisor: Jebb, S
Piernas sanchez, C
Aveyard, P
From legal object to legal subject: changing conceptions of criminal animals in fourteenth- and fifteenth-century France

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.

Keywords: Medieval Law
Animals in Law
Medieval History
Advisor: Forrest, I
Management and mechanisms of severe eosinophilic asthma

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.

Keywords: asthma
severe asthma
eosinophil
crth2
Advisor: Pavord, I
Maritime metaphorics in modernist literature

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.

Keywords: Ezra Pound
metaphor
maritime history
maritime ideology
Joseph Conrad
T.S. Eliot
Virginia Woolf
H.D.
modernism
Advisor: Mackay, M