VictorJuiz/thesis huggingface dataset:
Genomic approaches to virus discovery and molecular epidemiology

Viral sequence data has great potential for answering questions about the epidemiological dynamics and evolution of viruses. Classical approaches have sought amino acid changes that alter pathogenesis or transmissibility by influencing a virus's ability to enter or replicate within cells. However, this approach rarely recognises the fundamental impact of heterogeneous host contact structures and existing immunological responses on viral transmission. This thesis draws heavily on ecological and immunological concepts to explore the epidemiological dynamics, diversity and evolution of viruses using molecular sequence data.
A number of different research approaches and study systems are used in this thesis. I begin by describing a novel polyomavirus in a European badger, and apply phylogenetic techniques to analyze the evolutionary history of the Polyomaviridae. I subsequently describe a large metaviromic study in a population of wild mute swans, for which host demographic data are available. I describe nine new viral species and test whether age and season are associated with differences in abundance and prevalence of different viral taxonomic groups. The study highlights the potential of metaviromics for investigating viral epidemiological dynamics in natural populations.
Influenza A viruses of avian origin (AIV) threaten human and animal health. Using phylogeographic methods, I reconstruct the spatial spread of an H5N8 virus at a regional scale, and investigate how bird density and migration shaped this dispersal. Despite the importance of acquisition of humoral immunity to different strains throughout the lifespan of wild birds for epidemiological dynamics, this topic is poorly understood. I assess the accumulation of immune responses to AIV with age in mute swans. I consider how ecological factors, including age-structured immunity, might have affected the epidemiology of an H5N8 outbreak in the population.

Keywords: Genetics
Avian influenza virus
Evolution
Metagenomics
Viruses
Genomics
Birds
Epidemiology
Metaviromics
Ecology
Virology
Phylodynamics
Advisor: Pybus, O
Use of optical imaging in brain slices from developing rats to evaluate spatio-temporal dynamics of large-scale neuronal coalitions: effects of physiological and pharmacological manipulations

Voltage-sensitive dye imaging (VSDI), is a relatively novel technique which enables the recording and observation of neuronal population activity at the meso-scale of brain organisation. This optical imaging technique is used here in combination with extracellular electrophysiology (field potentials) in order to investigate ‘Neuronal Assemblies’, i.e. the phenomenon of synchronous and dynamic activation of millions of inter-connected neurons, giving rise to detectable patterns of large-scale population activity. For the experiments presented here, VSDI and field potentials were used to characterise and compare assemblies evoked in 2 cortical and 2 sub-cortical preparations: for the former, the well-studied primary somatosensory cortex (S1BF) was chosen, in addition to the agranular insular cortex (AIC) which has been less extensively studied. For the latter sub-cortical areas, responses were evoked in ventroposteromedial (VPM) thalamic nucleus and basal forebrain (BF). These investigations suggested cortical tissue produced similar response dynamics regardless of location, meaning large neuronal assemblies may be a inherent property of cortical tissue, since these response types were not found in sub-cortical structures. In addition to this, comparisons of evoked assemblies highlighted clear differences between cortical, thalamocortical and sub-cortical activity patterns, with evoked responses appearing geared for their biological functions, and allowed for the selection of 3 preparations of interest, i.e. S1BF LIV, AIC LII/III and thalamocortical stimulations, for characterising more fully the impact of anaesthetics on the parameters of neuronal assemblies. All anaesthetics tested here induced dose-dependent inhibitions of cortical activity, which were significantly more pronounced when assemblies were triggered via thalamocortical (remote) activation and in BF. Comparison of anaesthetic effects seen here with those induced on target proteins (from the literature) highlighted GABAA and nicotinic acetylcholine (nACh) receptors as key effectors in anaesthetic-induced inhibition by group 1 anaesthetics, while experiments with ketamine highlighted NMDA and nACh receptors in addition to HCN channels. These data describe more fully the manner in which anaesthetics rely on multi-target mechanisms, as well as exemplifying the practicality of combining VSDI with field potentials in the investigation of drug action on neuronal assembly functioning and cerebral function.

Advisor: Greenfield, S
Mann, E
Refining a direct-to-user online treatment for recurrent binge eating

The aim of the research was to provide data to inform the refinement of a new direct-to-user online treatment for recurrent binge eating. Two studies were undertaken.
The first study had two parts. The first part comprised a systematic search of efficacious unsupported, direct-to-user, online treatments designed to treat adults with mental health disorders. Forty-three named, eligible interventions were found. The second part identified the design features of these interventions. It was found that the majority of interventions were similar in terms of aspects such as appearance, for instance the use of images, and interactive features such as comment boxes; however, there were differences for example the amount of interactive design features.
The second study investigated 34 users’ views of the new online treatment. It employed both an investigator-based interview and self-report questionnaires. It was found that overall, the treatment was positively viewed by participants. Potential improvements suggested by participants included increasing the accessibility of the treatment through developing a smartphone application, and adding more personalisation to the intervention. Based upon these findings, the beta version of the new treatment will be refined.

Advisor: Fairburn, C
Optimisation and applications of Raman plasma amplifiers

Laser pulses have the shortest duration, smallest spatial extent, highest power, longest range and highest electric field of any known physical probe. In just 5 decades, the laser has led to the detection of gravitational waves, quantum optics and computers, worldwide fibre-optic communications, innumerable manufacturing applications and a prime contender for replicating the sun's nuclear fusion on earth. Modern high power lasers achieve intensities exceeding 1021 W/cm-2.
Laser powers have increased without bound due to the method of chirped pulse amplification. However, continuing this trend may require new amplifier materials with higher damage thresholds. This work assesses the feasibility of laser amplification in a plasma. Energy is transferred from a long, low power pulse to a short, high power pulse. This is due to the coupling of the light with plasma electron waves, the so called Raman instability. The resulting pulses could ignite a nuclear fusion capsule under the fast ignition scheme, or generate electron positron plasmas.
The energy efficiency and coherence of the amplifier are greatly influenced by the plasma conditions, investigated here using large scale computer simulations. The existing analytical solution is then generalised to three dimensions. The simulations show effective amplification, even in non-uniform plasmas.
A method for seeding the amplifier was investigated experimentally at the Central Laser Facility. A second experiment at the Laboratory for Laser Energetics in New York, U.S.A., found features of the Raman light that show promise for testing the full scheme in 2019.

Advisor: Norreys, P
For God, Country, and Empire? New Zealand and Irish boys in elite secondary education, 1914-1918

This thesis compares adolescent engagement with the First World War in Ireland and New Zealand between 1914 and 1918. Twenty-five elite boys’ secondary schools are used as case studies, including Catholic and Protestant institutions. This approach not only captures a common adolescent cohort, but also brings transnational connections to the fore; Catholics comprised approximately 14 percent of New Zealand’s population, at least nine-tenths of whom were of Irish descent. In addition to differentiating student behaviour from adult-articulated expectations, boys’ responses to the war are juxtaposed against those of their teachers. Using school periodicals, newspapers, and memoirs, this thesis partially recovers the neglected history of adolescent wartime experiences in two under-researched regions of the British Empire. It also elucidates the ways in which hostilities disrupted age-specific concerns and practices in elite school settings.
Age was critical in shaping how male non-combatants were impacted by, and reacted to, the conflict. This argument is substantiated by in-depth analyses of several related themes, including ‘war enthusiasm’, death, dissent, and cultural ‘re-mobilization’. While the First World War was near-uniformly identified as a crucial event, staff responses were mediated by longstanding orientations and responsibilities. Teachers prioritised institutional concerns such as state funding and school status throughout. Irish and New Zealand adolescents also engaged with hostilities on their own terms; ‘boy culture’ and age-related interests provided a constant baseline against which external interventions into daily life were evaluated. These cross-national similarities were modulated by immediate contexts. Coercive measures implemented by the state did not always receive popular support, contributing to new political trajectories and visions of the future within particular communities. National parameters also had the final say as to when students could legally enlist. This intersection of age and place ultimately proved pivotal in determining civilian reactions to major global developments during the 1910s.

Keywords: New Zealand
History of Childhood and Youth
British Empire
History of Education
First World War
Ireland
Advisor: Belich, J
Paseta, S
Electronic communication in heterometallated porphyrin oligomers

This thesis presents the synthesis and characterisation of a range of heterometallated porphyrin oligomers and other novel 3D π-conjugated porphyrin nanostructures. Subsequently, their physical organic properties were evaluated which revealed some fascinating electronic properties.
Chapter 1 summarises some of the work done in the Anderson group on porphyrin nanostructures and reviews the literature regarding heterometallated porphyrin oligomers. In addition it introduces the main concepts and techniques used in the remainder of the thesis.
In Chapter 2 the stabilities of a family of four linear porphyrin pentamer complexes are determined by UV-vis-NIR titrations and analysed using chemical double-mutant cycles which reveal that the binding energy of the copper centre to an axial pyridine ligand is –6.2 kJ mol–1. Subsequently, the Zn-Zn-Cu-Zn-Zn pentamer is used in the synthesis of a heterometallated 10-porphyrin nanoring.
Chapter 3 will describe the investigation of quantum interference phenomena in a bis-copper six-porphyrin nanoring by using EPR spectroscopy. We show that the exchange coupling between two spin centres is increased by a factor 4.5 in the ring structure with two parallel coupling pathways as compared to an otherwise identical system with just one coupling path.
In Chapter 4 the syntheses of three isomers of the bis-copper 6-porphyrin nanoring are described. DFT calculations have indicated potential destructive interference phenomena in one of the isomers which would allow for the formation of a molecular system with behaviour resembling that of a hypothetical molecular interferometer.
Chapter 5 reports on the template-directed synthesis of a π-conjugated 14-porphyrin nanoball. This bicyclic structure consists of two intersecting nanorings of 6 and 10 porphyrin units. Fluorescence up-conversion spectroscopy experiments demonstrate that electronic excitation delocalises over the whole 3D π-system within 0.3 ps if the nanoball is bound to its templates or within 5 ps if the nanoball is empty.
In Chapter 6 the synthesis and characterisation of a D4h symmetric analogue of the porphyrin nanoball is described. The structure consists of ten porphyrin units arranged as two perpendicular 6-porphyrin nanorings intersecting at two porphyrins. In the synthesis, a combination of magnesium and zinc porphyrins are used which allows for the introduction of a selective demetallation method crucial for accessing this novel structure.

Keywords: Electronic communication
Template
self-assembly
Nano
Porphyrin
heterometallated
Advisor: Anderson, H
Understanding pneumothorax: epidemiology, physiology and predicting outcome

Contrary to traditional teaching, patients with Primary Spontaneous Pneumothorax (PSP) do not have normal lungs. Emphysema-like change (ELC) and inflammation are common. However, the natural history of ELC and its significance in terms of future disease is not known. Current management of pneumothorax is generic and not personalised.
This thesis updates the UK epidemiology of pneumothorax, describes the use of two novel methods to examine the lungs, a method of predicting early treatment failure, the association of CT findings and recurrence, and a systematic review of chemical pleurodesis to reduce recurrence.
Analysis of fifty years’ data on ~150,000 admissions demonstrated that the incidence of pneumothorax is increasing, and established a method to identify primary from secondary pneumothoraces and their relative risk of recurrence.
Reduced ventilation of hyperpolarised Xenon on enhanced-Magnetic Resonance Imaging (MRI) was seen in those PSP patients with greater low attenuation areas on Computed Tomography (CT) and with reduced pulmonary function. A model of lung inhomogeneity found that metrics of lung ventilation distinguished pneumothorax patients from healthy volunteers and Chronic Obstructive Pulmonary Disease (COPD) patients. This may represent subtle or mild disease, not identified on standard testing, which may be exacerbated by smoking.
CT scanning found that mild emphysema and cystic airspaces were common in PSP patients. Ex- or current smokers had more (and larger) cysts. Emphysema was more common in smokers and patients with a history of previous pneumothorax: who were at higher risk of recurrence. However, variation in number and size of cysts were seen in both those patients with and without recurrence. As such, no single algorithm to predict recurrence was identified.
Airflow measurement early in the patient pathway has the potential to identify those likely to fail treatment, potentially allowing early triage to surgery. The addition of talc or minocycline as an adjunct to surgery provides the lowest recurrence rates, but physician-led talc poudrage may be similarly effective. Those in whom surgery is not suitable, chemical pleurodesis could be offered via chest drain.
Data presented in this thesis thus provides insights into the underlying abnormalities in PSP and lays the groundwork for strategies to fundamentally alter the management paradigm.

Keywords: Predicting outcomes
Epidemiology
Spontaneous
Pneumothorax
Advisor: Rahman, N
An autophagy-related single nucleotide polymorphism in artemisinin-resistant Plasmodium falciparum

Artemisinin-resistant Plasmodium falciparum parasites have been reported in the Greater Mekong Subregion since 2007. Artemisinin combination therapy (ACT) is the mainstay of antimalarial treatment and is responsible for decreases in malaria-related morbidity and mortality over the past fifteen years. The slowed parasite clearance rates following ACT indicates resistance to artemisinin derivatives. This resistance places increasing selective pressure for variants or traits that confer resistance to the partner drug used in combination and has led to the rapid failure of several partner drugs. While a single nucleotide polymorphism (SNP) in kelch13 has been shown to mediate some resistance phenotypes, the complete mechanism of artemisinin resistance is poorly understood. The known mechanisms of resistance hint at a connection to autophagy, an intracellular pathway that cells use to degrade waste molecules or organelles in response to stress and starvation, which is poorly characterized in Plasmodium. In this doctoral thesis project, I investigated the role of an autophagy-like mechanism in P. falciparum in the mechanism of artemisinin resistance. I found a SNP in autophagy-related gene 18 (atg18) that was associated with clinical delayed parasite clearance half-life following ACT. This gene encodes PfAtg18, a protein that I characterized as being similar to mammalian/yeast homologues in terms of structure, binding abilities, and ability to form puncta in response to stress. In order to investigate the contribution of the mutation in this protein, I edited the atg18 gene using CRISPR/Cas9 and screened the mutant and parent parasites against a drug library of over 6000 unique compounds. I discovered that while the SNP did not change the mutant parasite’s susceptibility to any of the antimalarial compounds using a 72-hour drug pulse, it did alter the susceptibility to 227 other compounds. Further, I found that the SNP offers parasites a fitness advantage by allowing them to grow better in nutrient-limited settings. Finally, I determined that neither this atg18 SNP nor several polymorphisms in kelch13 modulate a dormancy phenotype that appears to be involved in the artemisinin-resistance mechanism.

Keywords: Artemisinin-resistance
Plasmodium falciparum
Autophagy-related protein 18
Advisor: Simon, A
Roberts, D
Thomas, C
Genotype and phenotype relationships in neurodevelopmental disorders

NeuroDevelopmental Disorders (NDDs) are a group of heterogeneous neuropsychiatric conditions, encompassing Developmental Delay (DD), Intellectual Disability (ID), Autism Spectrum Disorder (ASD) and Gilles de la Tourette Syndrome (GTS). NDDs often involve a life-long need of supportive services and represent a major economic and societal burden in Europe and the United States. Hitherto, no safe and effective treatment strategies are available, underpinning the urgency of deciphering their elusive aetiology.
NDDs have a strong genetic component. Accordingly, the mechanistic understanding of disease involves (1) the description of mutational landscapes, (2) the molecular and cellular of characterisation of genetic variants and (3) their integration at circuit and system levels. In this thesis, we tackled these theoretical underpinnings to provide insights into the genetics of NDDs and the onset of associated clinical abnormalities.
Firstly, aiming to shape the genetic architecture of GTS, a condition characterised by the presence of motor and vocal tics, we undertook a whole-genome CNV study of a cohort of Danish GTS cases and healthy controls. Using statistical and functional genomics approaches, we proposed novel potential candidate genes and implicated the disruption of early neurodevelopmental and late synaptic processes in the aetiology of GTS.
Secondly, to elucidate the vast phenotypic heterogeneity of NDDs, we conducted a systematic investigation of genotype and phenotype relationships in DD, ID and ASD. Taking advantage of extensive phenotypic and genetic data available for DD/ID and ASD patients, we grouped individuals based on their functional rare CNV and gene disruptions but did not to identify distinguishing clinical archetypes. Instead, we showed converging molecular perturbations underlie the onset of globally more similar clinical presentations and investigated the role of common variants in modulating their expressivity.
Lastly, we established the relevance of mouse models in the study of human disease. By applying comprehensive genomics approaches to over 1,000 mouse neuroanatomical knockouts, we implicated early neurodevelopmental and adult synaptic processes in the aetiology of ID and brain malformations. Furthermore, we showed that functionally converging genetic disturbances translate at the phenotypic level and proposed novel candidate ID genes.

Advisor: Webber, C
A comparative study of the lithic technology, subsistence and bioclimatic settlement patterns of neanderthals in the Iberian peninsula (Cantabrian and Betic regions)

This thesis investigates Neanderthal lithic technical, subsistence practices and bioclimatic settlement patterns behaviour comparison between two different bioclimatology and biogeografically regions of the Iberian Peninsula - the Cantabrian region to the north, and the Betic region to the south-, during the late Pleistocene Period. The principal aim is to test whether or not hominid groups of the same species (Homo neanderthalensis) behave, exploit and occupy their territory in similar or different ways under different environmental conditions.
Three different approaches were undertaken to test the proposition. The first was a technological study of eight lithic assemblages from the latest Mousterian levels in the Cantabrian region: Axlor, Esquilleu, Morin, El Castillo; and the Betic region: Abrigo 3, Carihuela, Zafarraya, Gorham´s Cave, in order to establish whether any distinctive patterns emerge in both areas of study.
Subsistence practices, through a study of faunal remains, was the second dataset for this comparative study. A faunal database was constructed from the literature pertaining to Middle Palaeolithic sites in both regions focusing on large and small game, cannibalism practices and evidence for the consumption of plants. The aim is to establish the variability in Neanderthal subsistence behaviour.
The third approach was an analysis of settlement patterns through bioclimatic mapping, created by temperature and rainfall climate data from weather stations in both regions. The aim of this work was to explore whether or not Neanderthals inhabited both Cantabrian and Betic regions in different or similar ways.
The result of this thesis suggests that Neanderthals reacted to changes in local ecology and climate in similar ways in both study regions, highlighting their great adaptive ability and commonality in their behavioural response

Advisor: Higham, T