VictorJuiz/thesis huggingface dataset:
Investigating the role of Oxr1 in mitochondria

Oxidative stress (OS) and mitochondrial dysfunction are common features of neurodegenerative disease, suggesting that antioxidant defence systems are critical for cell survival in the central nervous system (CNS). Oxidation resistance 1 (OXR1) has emerged as an essential antioxidant protein that controls the susceptibility of neurons to OS; however, the function of this novel protein is unknown. The overall goal of this thesis was to investigate the potential role of Oxr1 in mitochondria and to understand more regarding the function of the gene in the oxidative stress response in vitro and in vivo.
It was demonstrated that different isoforms of Oxr1 are expressed in specific sub-cellular compartments and certain mitochondrial Oxr1 isoforms are associated with mitochondrial membrane. In addition, it was shown that over-expression of the shortest isoform of Oxr1 in the cytoplasm is protective; both against oxidative stress-induced apoptosis and against mitochondrial morphological changes caused by disease-associated TDP-43 mutations. Analysis of mitochondrial metabolism and fusion and fission proteins in Oxr1 knockout (bella) tissue indicated that that Oxr1 deletion alone does not trigger overt mitochondrial dysfunction but it may influence aspects of mitochondrial morphology.
To ascertain whether loss of Oxr1 in specific neuronal populations would render them more susceptible to cell death, the conditional deletion of Oxr1 in mouse dopaminergic neurons was studied. Preliminary data showed that aged mice displayed no motor or pathological abnormalities in the midbrain, suggesting that this particular conditional deletion does not lead to significant neurodegeneration. Finally, ENU mutagenesis screening of Oxr1 identified a point mutation in the highly-conserved TLDc domain of Oxr1 (Y644H). In vitro analysis suggested that this mutant rendered cells more vulnerable to oxidative stress, demonstrating that this region of the protein is functionally important.
Taken together, these studies deepen the understanding of Oxr1 as a novel antioxidant protein and offer new and important insights into its role in the OS-response and its potential use in future antioxidant therapies.

Advisor: Davies, K
What we owe to future people: a contractualist account of intergenerational ethics

This thesis applies T.M. Scanlon's version of contractualism to the problem of future generations. I begin by analyzing Rawls' contractarian account of just savings and find that there is no plausible composition of the original position that can deal with the inclusion of future people. I then examine Scanlon's contractualism and some objections to it before moving on to applying it to future people. I argue that the disanalogies between the intra- and inter-generational contexts do not preclude including future people in the contractualist framework, and that the theory avoids the non-identity problem. Part II of the thesis applies contractualism to three intergenerational topics and develops principles governing them: resource conservation, procreation, and population size. To conclude, I address how to deal with the fact that, in the case of future generations, we often have imperfect knowledge of what they will need, how our actions will affect them, and how many of them there will be.

Advisor: Caney, S
The ethics of deception: secrecy, transparency and deceit in the origins of modern political thought

The purpose of this thesis is to reflect on the importance that deception has had on the efficient functioning of societies and the development of individuals. I attempt to do so by adopting an historical perspective, analysing the development of the notion of lawful deception during the Middle Ages and, mainly, the Early Modern Age through theological and political discourses.
The scope of my investigation is pan-European. I examine sources from the major Western territories, but I pay special attention to those produced in the Spanish-Habsburg Empire, which was a major political and cultural entity during this period.
My claim is that between the thirteenth and seventeenth centuries, the West witnessed the formation of what I call an "Ethics of Deception:" a trend of thought that, without challenging the Augustinian prohibition of lying, recognised deception as intrinsic to nature and mankind, thereby justifying its use from moral and political perspectives. I explain how this intellectual process was conducted, fostered by new social realities, and helped by the flourishing of casuistry, tacitism and neostoicism.
Furthermore, I argue that the acceptance of deception contributed to the creation of a new view of the world, language and human interaction. A view that is in the very basis of some of the most characteristic features of Baroque art and that opened the door to some of the most transcendental cultural changes of the period, such as the creation of politics governed by reason rather than faith, the secularisation of social behaviour, and the emergence of the notions of individualism, privacy and freedom of thought. For these reasons, I claim that deception played an important role in the shaping of Modernity.

Keywords: tacitism
privacy
secrecy
reason of state
statecraft
deception
history
dissimulation
transparency
political thought
Advisor: Conde, J
Anion-induced molecular motion within interlocked structures

This thesis describes the construction and exploration of a variety of interlocked structures that exhibit anion-induced molecular motion of their constituent parts.
Chapter One provides a brief overview of the field of supramolecular chemistry; in particular anion recognition and the concept of mechanically interlocked molecules and their applications in the fields of nanotechnology.
Chapter Two describes the preparation of a series of bistable [2]rotaxanes followed by thorough investigation of their dynamic properties. Specifically, the success of an iodo-triazolium–naphthalene-diimide-based two-station axle component to facilitate halide-stimulated large-amplitude translational motion of the macrocyclic wheel in a [2]rotaxane is demonstrated.
Chapter Three expands on the design principles established in the previous chapter with the synthesis of exotic higher-order structures including the first halogen bonding [3]rotaxane. These systems are capable of the recognition and colorimetric sensing of oxoanions via a novel dynamic pincer-like motion of the macrocycle components.
Chapter Four further highlights the capabilities of controlled co-conformational switching in interlocked structures, resulting in a unique mechanism to accomplish anion sensing. The incorporation of C60 fullerene- and ferrocenyl-reporter groups into a four-station [3]rotaxane enables sensing of chloride to be realised by a dual fluorescence response.
Chapter Five presents the synthesis of novel interlocked structures containing a substituted perylene diimide motif that functions as a recognition site for macrocycles. Chloride binding stimulates translational motion in a [3]rotaxane and unprecedented rotary motion in a [3]catenane, with co-conformational changes in both systems resulting in a colorimetric response for this anion.
Chapter Six describes experimental procedures used throughout this work and details the characterisation of novel compounds.
Chapter Seven provides a summary of the major conclusions from the research described in this thesis.
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Keywords: Molecular machines
Advisor: Beer, P
Structural studies of signal transduction in bacterial chemotaxis and a metabolism-related cancer target

Transmission electron microscopy (TEM) has had a growing impact on the life sciences as both technological and methodological developments have allowed for cells and macromolecules to be resolved at increasingly higher resolutions. Variations of TEM can be used to visualize cellular ultrastructure as well as to determine macromolecular structure in a near-native state.
In this work, a number of TEM-based methods were utilized to structurally characterize proteins from different biological systems. The areas of study were the chemotaxis systems of Escherichia coli and Rhodobacter sphaeroides as well as human cancer metabolism. In each system, a key protein of interest was selected for investigation.
Bacteria use their chemotaxis systems to dynamically sense and respond to their environment by biasing their movements towards favorable directions. The E. coli serine chemotaxis receptor (Tsr) was studied using cryo-electron tomography of arrays formed by overexpressed Tsr in a thin E. coli cell strain and in membrane isolates. Subsequent sub-volume averaging yielded structures of the full-length receptor which showed that serine binding is accompanied by expansion of the signaling domain.
The protein selected for study in the R. sphaeroides chemotaxis systems, PpfA, is an ATPase responsible for segregating the cluster of cytoplasmic chemosensory proteins. Immuno-gold labeling of cryo-sections showed that both wild-type and mutant PpfA demonstrated some degree of clustering into foci.
The enzyme pyruvate kinase M2 (PKM2) plays an important role in various cancers by regulating metabolism to promote cell survival and propagation. Single particle cryo-electron microscopy was used to perform a structural comparison of wild-type PKM2 with a patient-derived mutant form of the protein. At the resolution of the structures solved, the molecular architecture of the patient and mutant forms of the protein were the same, except for the mutated residue. The structures revealed the potential presence of a stabilizing stacking interaction in the mutant that may explain differences in its biochemical behavior.
These studies illustrate the range of biological questions and systems to which TEM- based techniques can be applied with the goal of gaining structure-based mechanistic insights. For macromolecular targets of clinical relevance such as PKM2, such information can be used for rational drug design.

Advisor: Armitage, J
Subramaniam, S
Development of early predictors of cerebral ischaemia after subarachnoid haemorrhage

Aneurysmal subarachnoid haemorrhage (SAH) is a severe disease often leading to profound disability and death. There has been increasing interest in nitric oxide (NO) signalling after brain injury, as it appears to influence many of the cellular metabolic pathways that eventually result in apoptosis and neuronal dysfunction.
Many animal studies have shown exogenous cerebral NO donation appears to confer neuroprotective effects. It has shown to particularly affect many of the pathophysiological processes that occur after SAH.
The work presented here describes two studies. The first study correlates changes in quantitative electroencephalography (qEEG) with the infusion of a cerebral NO donor, sodium nitrite after severe (World Federation of Neurosurgeon’s grades 3, 4 and 5) SAH. There is a need for better cerebral function assessment tools in this patient cohort as the usefulness of neurological examination is limited.
The second study investigates magnetic resonance imaging (MRI) methods of evaluating acute tissue blood flow changes that occur after severe SAH, namely vessel encoded pseudo-continuous arterial spin labelling (VEPCASL).
The results from the first study demonstrate that qEEG changes in response to an NO donor correlate with the subsequent development of delayed cerebral ischaemia (DCI) and poor clinical outcomes. The results from the second study show that VEPCASL can be used to obtain measures of regional cerebral blood flow changes that occur over time in the acute stages of severe SAH.
This thesis demonstrates that bedside EEG monitoring is an extremely useful tool to give additional information regarding neuronal health after severe SAH. We have offered a new insight into the mechanisms behind therapeutic repletion of NO, aiding its development as a potential new therapy. We have also shown that VEPCASL MRI is a useful tool in assessing cerebral perfusion in the acute stages of injury.

Advisor: Pattinson, K
Residual stresses, cracking and stress intensity factors for vickers indentations in ceramics

Vickers hardness indentations on AI2O3 were studied comprehensively. Beneath indentation, there is a well-defined interface between the plastic zone and the elastic region and the radius of the plastic zone is close to half the indentation diagonal length. The residual stress field around the indentations has been measured by optical fluorescence microscope (FLM) scans. Yoffe's stress model predicted higher stresses than the experimental stress results. the radial crack lengths were measured by FLM scans, and the optical microscope (OM) and SEM methods for crack length measurements were found to significantly underestimate the crack lengths. Post indentation slow crack growth was found on the radial cracks were determined. The radial-median crack system was found for alumina indentations. Lateral cracks were also found for all the indentations, and their depths were close to the half diagonal lengths. the lateral cracks joined the tips of the radial cracks and had the similar growth rates to the radial cracks.
The indentation parameters of SiC and 3Y-TZP indentations were also measured. Lateral cracking was observed beneath in SiC indentations but not in case of £Y-TZP. The depth of the lateral crack of the SiC indentation was found to be close to the half diagonal length. the residual stresses and surface profiles around SiC and 3Y-TZP indentations were measured. the lateral crack lengths of the SiC determined from the surface profiles were close to the radial crack lengths. For TZP indentations, the highest volume fraction of the monoclinic zirconia phase was found near the edge of the indentations. Surface uplifts around indentations were found to have the profiles matching with distributions of the volume fraction of the monoclinic phase.
A new Vickers indentation residual stress model has been presented using assumptions based on the experimental findings on alumina indentations. The main novelty of the model is that it predicts the stresses in the presence of cracking, and is therefore testable. The residual stress model has successfully predicted the stress fields around the polycrystalline alumina and SiC indentations but failed on TZP indentations because of the lack of lateral cracking and the tetragonal-to-monoclinic phase transformation. From the residual stress model, a new formula for the indentation stress intensity factor K was derived, which provided good results for threshold stress intensity factor, K10, on alumina, and fracture toughness, KIC, for SiC, and Si3N4. Three adjustable parameters can be added to strengthen existing model.

Keywords: Residual stresses
fluorescence
indentation
Raman
Advisor: Todd, R
Metaethical revisionism: a response to error theory

Error Theorists claim that there is a defect—an error—in our moral concepts. This error leads to their systematic reference failure, and the untruth of all substantive moral claims. I deny this and propose a Revisionist alternative. If the purported defect is present, then we should revise our moral concepts. Error Theorists claim that this is not possible, as the defect is a "non-negotiable" feature of the concepts. This final claim is, in my view, the most interesting part of their argument, and the focus of the thesis. Revisionist theories have been offered in a number of domains. Such views are sometimes claimed not to advance their respective debates because they succeed only in changing the subject. This objection is correct that revision is not always an option, but there are clearly some cases in which we can revise our concepts. A central task for the thesis is therefore to understand the conditions under which conceptual revision is possible. This means accounting for the phenomenon of conceptual "negotiability". If the view presented here is correct, it should be useful for Revisionists in any domain. Chapter 1 expounds the standard argument for Error Theory, clarifying three premises: Conceptual, Ontological, and Non-Negotiable. Conceptual and Ontological are granted for the sake of the argument. Chapter 2 offers my theory of conceptual negotiability. Chapter 3 applies that account, arguing against Non-Negotiable, the claim that moral concepts cannot be revised in the relevant way. Chapter 3 also discusses and defends Metaethical Revisionism as a plausible and appealing theoretical option. Finally, Chapter 4 offers my own (somewhat speculative) account of what is truly non-negotiable for moral concepts and considers some candidate metaethical revisions. The Conclusion presents a summary of the argument of the thesis (it might helpfully be read after the Introduction, and before Chapter 1).

Advisor: Kahane, G
Background independence in classical and quantum gravity

Background independence is sometimes claimed to be the defining characteristic of general relativity (GR), and a necessary feature of any candidate quantum extension. In this thesis, we appraise numerous definitions of background independence, before assessing whether various spacetime theories—both classical and quantum—manifest this quality. Our aims are threefold: (i) to clarify the best possible understanding of background independence; (ii) to assess the extent to which, at the level of classical spacetime theories, background independence is characteristic of GR alone; and (iii) to assess whether this quality is in fact manifest in some of our best candidate quantum gravity theories.

Keywords: Background independence
Spacetime theories
General relativity
Advisor: Pooley, O
Marlowe and monarchy

Focusing on the works of Christopher Marlowe (1564-93), this thesis explores the complex engagement of popular drama with the political and religious writing of the Elizabethan fin de siècle. It focuses on the five plays by Marlowe that feature royal protagonists: 1-2 Tamburlaine (1587), Dido, Queen of Carthage (1588), Edward II (1592), and The Massacre at Paris (1593). By interpreting each play in its immediate political context, it shows that Marlowe did not deal with monarchy in the abstract but responded to current affairs – from the incursions of the Ottoman Empire to the threat of the Spanish Armada, from the conspiracy claims of Catholic polemic to the debate surrounding England’s involvement in continental warfare.
The introduction situates the thesis in the critical and historiographical context relating to Marlowe and to the relationship between literature and politics in the early modern period; it provides the justification for reading Marlowe's plays as topical statements. Chapter One looks at 1-2 Tamburlaine in the light of contemporary attitudes to the Ottoman-Safavid War. Chapter Two shows that Dido, Queen of Carthage adapted the stories and tropes of polemic to reflect fears of Catholic conspiracy and Spanish invasion. Chapter Three reads Edward II as a creative response to the print war of 1591-2, which centred on the moral character of the queen's closest counsellors. Chapter Four proposes that Marlowe’s final play, The Massacre at Paris, employed arguments drawn from Reason of State to influence decisions at the 1593 Parliament. The thesis concludes by suggesting that despite Marlowe’s reputation as a radical overreacher, his drama displays considerable sympathy for the monarchs who must rule precariously and without the option of private happiness.

Advisor: Kewes, P
Single-molecule imaging of electroporated chemotaxis proteins in live bacteria

Many species of motile bacteria use rotating extracellular filaments to propel themselves through liquid media. Each filament is driven by a membrane spanning rotary nano-machine called the bacterial flagellar motor. In Escherichia coli and Rhodobacter sphaeroides the motor is powered by a transmembrane flux of H+ and the chemical energy is converted into work through a ring of stator units pushing on a central rotor.
Chemotaxis is the biasing of movement towards regions that contain higher concentrations of beneficial, or lower concentrations of toxic, chemicals and is one of the most well-understood bacterial sensory pathways. Upon phosphorylation, the response regulator protein CheY transduces changes of environmental chemical gradients detected by specific transmembrane chemoreceptors to the flagellar motors: it binds to the N-terminus of the FliM proteins in the C-ring part of the motor inducing a cascade of conformational changes that modulate the direction of rotation (in E. coli) or the motor stopping (in R. sphaeroides).
In this project, a novel technique for protein internalisation in live bacteria based on electroporation and single-molecule imaging using a custom-built microscope are combined to perform an in-depth investigation of the interactions between wild type and mutant chemotaxis proteins, chemoreceptors and the motor complex in vivo.
Chemotaxis proteins are purified, labelled with organic dyes and inserted into live E.coli and R. sphaeroides cells by electroporation. In typical experiments exploiting this new capability, video fluorescence microscopy shows single molecules diffusing within cells, interacting with the sensory clusters and individual flagellar motors. The work described in this thesis allows for the first time imaging and tracking of single dye-labelled chemotaxis proteins performing their function as response regulators in real time. Diffusion as well as relevant binding constants and dwell times at each end of their journey are measured, providing also a comparison of such quantities across different protein mutants, genetic backgrounds and environmental conditions.

Keywords: Electroporation
Chemotaxis
Single-molecule microscopy
Bacterial flagellar motor
Advisor: Berry, R
Formal analysis of modern security protocols in current standards

While research has been done in the past on evaluating standardised security protocols, most notably TLS, there is still room for improvement. Modern security protocols need to be rigorously and thoroughly analysed, ideally before they are widely deployed, so as to minimise the impact of often creative, powerful adversaries. We explore the potential vulnerabilities of modern security protocols specified in current standards, including TLS 1.2, TLS 1.3, and SSH. We introduce and formalise the threat of Actor Key Compromise (AKC), and show how this threat can and cannot be avoided in the protocol design stage. We find AKC-related and other serious security flaws in protocols from the ISO/IEC 11770 standard, find realistic exploits, and harden the protocols to ensure strong security properties. Based on our work, the ISO/IEC 11770 working group is releasing an updated version of the standard that incorporates our suggested improvements. We analyse the unilaterally and mutually authenticated modes of the TLS 1.3 Handshake and Record protocols according to revision 06 of their specification draft. We verify session key secrecy and perfect forward secrecy in both modes with respect to a powerful symbolic attacker and an unbounded number of threads. Subsequently, we model and verify the standard authenticated key exchange requirements in revision 10. We analyse a proposal for its extension and uncover a flaw in it, which directly impacts the draft of revision 11.

Keywords: actor key compromise
KCI
AKC
IEC
TLS
security standards
security protocols
standardisation
ISO
IETF
Advisor: Cremers, C