VictorJuiz/thesis huggingface dataset:
Investigating the effects of oxidative stress on extracellular vesicle function and RNA cargo loading

Extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed structures which have been suggested to play a critical role in maintaining intracellular homeostasis through the elimination of unnecessary biological material from EV-producing cells, and as a delivery system enabling intercellular communication between distant cells. Although extensive study has revealed many RNA biotypes that are associated with EVs, and has begun to elucidate the mechanisms of their packaging and delivery, little is currently known about how these processes are conserved in different species and under different cellular conditions. In this thesis, an in vitro Drosophila model in S2R+ cells was set up to investigate EV biology under normal and stress conditions, as a complement to an in vivo system being set up in Drosophila larvae. Under hydrogen peroxide-induced oxidative stress, an increase to EV number was seen, whilst no changes to size or protein marker composition were evident. Preliminary work indicated that these stress-cell- derived EVs acted to induce cell death in recipient cells. Characterisation of the total RNA content of cells and EV samples under control and oxidative stress conditions revealed that EV RNA was not representative of parental cells, but was instead enriched for ribosomal RNA, Copia retrotransposon, snoRNA, and RNAs relating to cytoskeletal and developmental functions. Investigation of potential loading motifs in mRNA 3’UTRs found no sequences which could differentiate mRNA packaging under stress conditions. Further exploration of mRNA loading in EVs found no preference for short mRNA transcripts, but an enrichment of intronic and untranslated regions, and 3’ end degradation, under stress. A striking increase in base mismatch in the RNA of EV preparations was seen under stress, possibly indicative of targeting of aberrant RNA to EVs, or of RNA modification. These results present strong evidence that the RNA content of Drosophila EVs is altered under oxidative stress and provides several avenues for further investigation of mechanisms by which it may occur. Furthermore, these data indicate the potential increased importance that EVs may play in metabolic and signalling functions under different cellular stress conditions, which has great relevance for disease pathology.

Keywords: exosomes
Drosophila
Extracellular vesicles
RNA
oxidative stress
EVs
Advisor: Baena Lopez, LA
Carter, D
Human cardiac 31p magnetic resonance spectroscopy at 7 tesla

Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) is unique in its ability to study high-energy phosphate metabolism noninvasively; when applied in the human heart, 31P-MRS is a sensitive marker of the occurrence and progression of heart failure. To date, 31P-MRS has been hindered by the inherent low signal-to-noise ratio (SNR) of acquisitions. In recent years, however, whole-body 7 T MRI scanners have brought a step change in the available SNR, increasing the precision of cardiac 31P-MRS measurements.
The work in this thesis quantifies how the increased SNR afforded by using a 7 T scanner translates into improved reproducibility of human 31P-MRS in the heart. A ‘short’ (6.5 minute) uttra-short echo chemical shift imaging (UTE-CSI) protocol is also established that is both sufficiently short and reproducible to allow multiple 7 T 31P-MRS spectra to be acquired in the same scanning session. This ‘short’ UTE-CSI scan is used in a proof-ofprinciple study testing the feasibility of a using a commercially available ketone ester drink as a treatment for heart failure in diabetic subjects.
Finally, a novel multiple spin-echo 31P CSI sequence is developed. The limitations of a low, varying transmit field are overcome by designing a novel composite refocusing pulse. While scanning restrictions due to the COVID-19 pandemic meant that this sequence is not yet tested in vivo, simulations are performed to explore the potential of this sequence to measure cardiac 31P transverse relaxation times and further improve SNR of cardiac 31P-MRS at 7 T.

Advisor: Rodgers, C
Valkovič, L
Digital diplomatic crisis communication: diplomatic signalling and crisis narratives in an age of real – time governance

The practice of digital diplomatic signalling (DDS) and online crisis narratives (OCN) offers unexplored potential for analysing the creation and exercise of diplomatic communicative strategies during times of political crisis. Set within the global information space, the processes of DDS and OCN today carry the potential, to act as communicative tools for foreign policy power projection, and virtual powers of enlargement as the ‘battle for crisis narratives’ is now played out online. By developing a unique conceptual lens in which to view and analyse these communicative processes online, this research argues that digital signalling and online crisis narratives have become essential components of a Ministries of Foreign Affairs (MFAs) communicative toolbox, and worthy instruments in which they can seek to exert and extend their diplomatic influence both at home and abroad. Using DDS and OCN as conceptual lenses in which to view diplomatic crisis communication practices, we see that the power inherent in digital mediums becomes a communicative advantage during a crisis and a strategic instrument for the achievement of foreign policy goals. A new crop of studies which addresses the emergence of communicative power under the label ‘foreign policy in global information space’ adds substantial weight to these claims, supplying, new ways of extrapolating the power projections of digital diplomatic actors online. Through the exploration of two distinct case studies, the 2014 Israel-Gaza conflict, and 2013/4 Euromaidan crisis, this research therefore taps into the unexplored potential of the process of DDS, its power to create OCN’s, and ultimately expand a state's power and influence during times of crisis.

Keywords: Digital Diplomacy
Technology
Ukraine
Diplomacy
Israel
Facebook
Twitter
Crisis Communication
Palestine
Advisor: Bjola, C
Community and belief: the development of Anglo-Saxon Christian burial practice, AD 700-1066

The central aim of this thesis is to reveal patterns about burial practices over time and across the physical space of Anglo-Saxon England between 700 and 1066. This integration of geographical and chronological distribution analysis is achieved through bringing a breadth of unpublished Anglo-Saxon-period archaeological data to the fore that is now available due to advances in digitisation. It is argued that middle and Late Anglo-Saxon burial practice highlighted different levels of communities visible through burial practices: the family, who choose to overlap their graves to be together; the village community, which chooses to include the poor or ill and the dangerous in their midst; the region, in which the community travels or trades, and share the same custom of grave types; the religious community, which, in teaching about the Day of Judgement, leads the ‘little community,’ and fuses local practice, religious identity, and social rank. This is demonstrated through a combination of examination of the literary sources and both simple and statistical analysis of a broad sweep of new archaeological material. This thesis hopes to provide a typology and chronology for mid- to late Anglo-Saxon burial practice, creating a systematic, clear view of the consolidation, then diversification, of Christian burial practices in and across Anglo-Saxon England before the Conquest on a regional and national level.

Keywords: mortuary archaeology
Anglo-Saxon
burial practices
medieval history
archaeology
material culture
early medieval
cultural history
religious history
Advisor: Foot, S
Blair, J
The effects of prolonged hypoxia on respiration in man

This thesis is concerned with the effects of prolonged hypoxia on ventilatory control in humans.
Chapter 1 reviews some of the relevant studies in animals and humans relating to this thesis.
Chapter 2 describes the experimental apparatus and technique employed in dynamic endtidal forcing using a computer-controlled gas-mixing system. It also details some of the basic analytical procedures used.
Chapter 3 describes the construction of a chamber for the long-term control of end-tidal gases. Preliminary testing showed this technique to be successful.
Chapter 4 documents the ventilatory response to 8 hours of isocapnic and poikilocapnic hypoxia. Ventilation rose dramatically during isocapnic hypoxia, but not during poikilocapnic exposure. The next chapter investigated the mechanisms responsible for these changes.
Chapter 5 assessed the changes in the ventilatory response to acute changes in hypoxia during the isocapnic and poikilocapnic hypoxic exposures of Chapter 4. Hypoxic sensitivity and hypoxia-independent ventilation increased during both hypoxic exposures and the changes were not significantly different between protocols. It was, therefore, proposed that hypoxia per se was responsible for the changes in ventilation during isocapnic hypoxia. Hypoxic sensitivity was thought to rise as a result of increased carotid body function. However, the mechanism responsible for the rise in hypoxia-independent ventilation was not clear.
Chapter 6 repeated the experiments of Chapters 4 and 5, but over a 48-hour period of hypoxic exposure and over the 48 hours of deacclimatization subsequent to the exposure. In addition, measurements of the eupnoeic ventilation and hypercapnic response were made. Ventilation continued to rise in the isocapnic exposure after 8 hours and also showed a gradual, but smaller, increase during the poikilocapnic exposure. Eupnoeic ventilation rose during both exposures and fell during deacclimatization towards the pre-exposure levels. These changes were similar in both protocols. The changes in hypoxic sensitivity and hypoxia-independent ventilation suggested that hypoxia was the major factor in determining the changes in respiratory control during prolonged hypoxia, in both poikilocapnia and isocapnia. Hypoxia was proposed to be the principal factor in the early stages of altitude acclimatization, and not the associated acid-base changes.
Chapter 7 describes the attempt to find a protocol to measure the hypoxic response (ventilation vs. Po2). This initial attempt was not successful, but, with modifications, the basic form of this protocol may provide a suitable test of the hypoxic response.
Chapter 8 presents a brief summary of the findings of this thesis and suggestions for future work.

Advisor: Robbins, P
The sedimentology, mineralogy and geochemistry of the ~1.4 ga Roper Superbasin Northern Australia

Eukaryotic life arose around 1.6 billion years ago, but for much of Earth history has been ecologically and biologically conservative. There is a gap of around a billion years between the first eukaryotic fossils and their rise to ecological prominence around 800 million years ago. The causes of this delay in eukaryote evolution are widely debated, but in recent years the role of oxygen, has been proposed as a major driver in the evolution of complex life. Oxygen drives metabolism for energy intensive organisms like eukaryotes, it is also a key component of eukaryotic biomolecules. Oxygen is also a key player in the cycling of essential bio-limiting nutrients such as phosphorus. Some have hypothesized that in the low oxygen Proterozoic world, phosphorus was scarce and thus limited primary productivity, slowing the oxygenation of the Earth and locking the planet into a billion-year long period of environmental stasis. Additionally, the iron rich oceans are proposed to have sequestered phosphorus in sediments as iron phosphate minerals. To date, neither of these hypotheses have been robustly tested against the sedimentary record.
To test these two hypotheses, I conducted a high-resolution study of exquisitely preserved ~1.4 - 1.3 Ga sedimentary rocks from the Roper Superbasin (RSB), northern Australia. I find no evidence of sedimentary sequestration of phosphorus as Fe-phosphate in the examined sediments. Additionally, I find that sediments were deposited under ferruginous and oxic conditions, contrary to published work. Also, in contrast to previous work, I find that the RSB is a restricted basin and underwent periods of disconnection from the global ocean. As an epicratonic basin enclosed on multiple sides, the RSB is unsuitable for investigating global ocean conditions in the Proterozoic. However, such locations appear to be commonnly preserved in this interval, and may have been important sites for phosphorus deposition. Regardless of ocean connection the RSB, and locations like it, are where we find eukaryote fossils, and so were obviously an important part of eukaryote evolution. The questions raised by this study highlight how much is left to learn about Earths distant past and the organisms that inhabited the planet at that time.

Keywords: precambrian
mesoproterozoic
McArthur Basin
Velkerri Formation
Sherwin Ironstone
Black Shale
Tijunna Group
Iron Formation
Roper Group
sedimentology
Geology
Advisor: Tosca, N
Tostevin, R
Robinson, S
Investigations into inflammation and nerve regeneration in a human model system of neuropathic pain

Neuropathic pain is a serious and debilitating disease affecting a large proportion of the population. The disease is caused by direct damage to the nervous system and is often chronic in nature. Neuropathic pain is typically poorly treated, with patients often experiencing inadequate relief from symptoms. Part of this issue stems from ineffective treatment options while a lack of understanding of the disease pathology also presents as a major issue.
Recent findings have emerged which implicate the immune system in the initiation and generation of neuropathic pain. These studies have highlighted the role of inflammatory mediators including cytokines and immune cells as being heavily involved in the development of neuropathic pain. The majority of this work has been conducted in pre-clinical animal models where severe nerve injury paradigms are used. These experiments have proven useful in identifying the role of inflammation in neuropathic pain but do not necessarily reflect the nerve injury present in humans. Furthermore, preclinical findings do not always translate to patients in the clinic, which has resulted in a deficit in novel, effective neuropathic pain therapies. The mechanisms of nerve regeneration that occur after nerve injury are also incompletely understood. Similar to neuropathic pain, much work has been done using animal model systems of nerve regeneration, however human nerve regeneration presents with unique challenges and is often incomplete. Further studies are therefore required in humans to elucidate the precise role and action of inflammation in patients with neuropathic pain and to determine the mechanisms that are driving nerve regeneration after injury.
Carpal tunnel syndrome is an entrapment neuropathy commonly occurring in patients which presents as a unique model system with which to study neuropathic pain. Due to the unparalleled opportunity to collect tissues from these patients, both inflammation and nerve regeneration can be explored in the context of neuropathic pain. This thesis will firstly endeavour to describe and characterise inflammatory associations with neuropathic pain in patients with carpal tunnel syndrome using both genetic and molecular approaches. Using these same approaches, I will also investigate nerve regeneration after injury to uncover mediators stimulating nerve growth and determine associations with inflammation in this process.

Keywords: Nerve Regeneration
Inflammation
Neuropathic Pain
Pain
Nerve Injury
Advisor: Schmid, A
Bennett, D
Blat, D
Network-dependent dynamics of innovation and production

Complex networks have been demonstrated to play an important role in many economic systems. This thesis aims at further integrating the science of complex networks with economic theory with a focus on dynamic aspects of two types of economic networks: technology/innovation and production networks.
Technological evolution is often described as a recursive process whereby the recombination of existing components leads to new or improved technological components. While this idea implies a network structure of technological interdependencies, very little has been done to establish empirically that these interrelations help predict future innovation dynamics. We propose a simple model of network-dependent knowledge creation that we calibrate to patent data. We find that simple time series models yield fairly good predictive performance and represent a good benchmark for alternative forecasting models. Incorporating information on the network of patent citations, however, can substantially improve patenting forecasts.
The second part of this thesis studies the dynamics of macroeconomic variables using production network models. We propose a macroeconomic model which we calibrate to the UK economy to quantify sectoral and aggregate impacts of the Covid-19 pandemic. Beside the production function assumption and the estimation of first-order shocks, we find that inventories and input bottlenecks are crucial in economic prediction. To better understand the driving forces behind these predictions, we study simpler dynamic input-output models. We suggest a simple mathematical optimization procedure that allows us to determine lower bounds of shock propagation. We find that the minimal shock propagation can be substantial, but much smaller than when compared to decentralized rationing behaviors of firms. In particular, the estimated economic impact strongly depends on the density of the underlying production network.

Advisor: Hepburn, C
Farmer, J
Lafond, F
Model-driven reconstruction in atom probe tomography

This thesis presents a new continuum model for predicting results from atom probe tomography (APT) experiments. Unlike previous atomic-scale approaches, this continuum approach makes realistic specimen simulation computationally tractable, enabling direct quantitative comparison with experiment. Here, specimen evaporation resembles a moving boundary problem, where the electrostatic field at the surface and in the surrounding vacuum must be solved throughout time. Tracking the surface implicitly as a contour in a scalar field ensures numerical stability of surface faceting and evaporation of voids (cavities). The electric field is efficiently solved by a boundary integral equation. Proof-of-concept submodels for laser-assisted evaporation, crystallographic faceting, and material dielectricity are also considered. Predictions are shown to agree well with experiment.
The application of the model to directly performing data reconstruction is also considered. A protocol is proposed where the specimen model for an APT analysis is calibrated against experimental data by solving a generalised image registration problem. Here, model parameters are constrained by maximising the similarity between the model and experimental data, measured using mutual information (MI). Through this proposed method, large-scale trajectory distortions are shown to be corrected for two experimental semiconductor devices: a multilayer structure and a fin field-effect transistor (FinFET) structure.

Keywords: atom probe tomography
boundary element methods
semiconductor imaging
FEM-BEM coupling
continuum modelling
image registration
level set methods
image reconstruction
Advisor: Moody, M
Haley, D
Atom probe tomography of irradiated zirconium alloys

Zirconium alloys are used for nuclear reactor fuel cladding and structural components, but aqueous corrosion of these components is a significant life-limiting factor. A mechanistic understanding of the corrosion of zirconium alloys is sought which could aid in alloy development, and explain the improved in-reactor corrosion performance of Zr-Nb alloys compared to Zircaloy (Zr-Sn-Fe-Cr). This project was carried out as part of the third Mechanistic Understanding of Zirconium Corrosion (MUZIC-3) programme, which was established to work towards this goal.
Zirconium alloy corrosion is highly sensitive to small differences in alloy chemistry, and the C4 model has shown that oxidation kinetics are determined by aliovalent dopants in the oxide from the alloying elements. This indicates the importance of the elements in the base metal, such as niobium and iron, which are in low concentration in α-Zr and challenging to quantify. This project was carried out using atom probe tomography (APT) to quantify the nanoscale changes to the alloy chemistry in a Zr-2.5Nb pressure tube alloy before and after irradiation. A key aim was to quantify the solute niobium and iron concentration left behind in the α-Zr matrix after irradiationinduced clustering.
This thesis contains three experimental chapters corresponding to the irradiation of the same Zr-2.5Nb alloy by neutrons, protons, and krypton ions. Irradiation-induced clusters were found to separate into two distinct categories with increasing dose; iron-rich clusters with a range of compositions consistent with the Zr(Nb,Fe)2 Laves phase, which reject iron with increasing dose and become niobium-rich clusters of β-Nb composition. The concentration of niobium and iron was significantly lower in the α-Zr matrix as a result of the clustering. Before irradiation, the β-Zr phase had decomposed into β-Nb and α-Zr, and the β-Nb phase was found to be highly stable under high temperature neutron irradiation, contributing to corrosion resistance.

Keywords: irradiation induced precipitation
corrosion
atom probe tomography
heavy ion irradiation
neutron irradiation
Zr-2.5Nb
proton irradiation
clusters
CANDU
zirconium alloys
irradiation
MUZIC-3
Advisor: Grovenor, C
Moody, M
The development of novel therapeutic vaccines for chronic hepatitis B infection

Chronic infection with Hepatitis B virus (HBV) remains a significant health problem, infecting millions of people worldwide. Cirrhosis and hepatocellular carcinoma, the sequalae of longstanding HBV infection, have a high mortality. Current therapy controls HBV replication but does not eradicate the virus, and therefore most people require life-long treatment. A robust adaptive immune response is required to control acute HBV but is dysfunctional in individuals that go onto develop chronic infection. The immune response is an attractive target for novel HBV therapies, which aim to induce functional cure of HBV in finite treatment courses by restoring HBV specific immunity. Therapeutic vaccination, which describes the process of delivering non-infective HBV antigen into the body in order to induce or boost cellular immune responses to HBV, is one strategy under investigation for chronic HBV treatment.
In this thesis I evaluate the novel vaccines ChAdOx1-HBV and MVA-HBV as candidates for HBV therapeutic vaccination. I investigate their immunogenicity in heterologous prime-boost strategies in healthy mice, describing in detail the fine specificity, functionality and phenotype of vaccine induced T cell responses in the blood and the liver. I also describe the safety and immunogenicity ChAdOx1-HBV in a phase-1 open label clinical trial in healthy volunteers and patients with chronic HBV infection. This work is important to inform the development of therapeutic strategies using ChAdOx1-HBV and MVA-HBV in patients with chronic HBV going forward.

Keywords: HBV
vaccine
ChAdOx1
hepatitis B
Advisor: Barnes, E
Klenerman, P