VictorJuiz/thesis huggingface dataset:
Brain neurokinin-1 receptors in depression and interactions with the serotonin system
Keywords: serotonin
brain
neurokinin-1 receptor
depression
positron emission tomography
immunohistochemistry

Emerging evidence suggests neurokinin-1 receptors (NK1Rs) may be altered in depression and NK1R antagonists may have antidepressant properties. In addition, blockade or deletion of NK1Rs has been shown to increase neuronal firing in the dorsal raphe nucleus suggestive of an interaction with the serotonin (5-HT) system. Against this background, one main aim of this thesis was to investigate anatomical interactions in the rat brain between NK1Rs and the 5-HT system. The second main aim was to use the positron emission tomography (PET) radioligand [18F] SPA-RQ to study NK1Rs in vivo in normal human volunteers and in patients with depression.
In the animal studies, immunofluorescence experiments found NK1Rs colocalised with 5-HT1A receptors to a high degree in many forebrain regions, in particular in the medial septum and hippocampus. Colocalisation was also present in the prefrontal cortex, frontal cortex and lateral/basolateral amygdala, but to a lesser degree. NK1Rs were found to mostly colocalise with 5-HT2A receptors in hippocampus only. Colocalisation between NK1Rs and 5-HT1A receptors was much greater than that between NK1Rs and 5-HT2A receptors. In separate experiments, using retrograde tracing combined with immunohistochemistry and light and electron microscopy, NK1Rs were found on the cell bodies of some of the neurons within the lateral habenula and locus coeruleus that project to the dorsal raphe nucleus, but were not found on the cell bodies of afferent neurons in the prefrontal cortex.
In the human studies, a comparison of a reversible two-tissue, four rate constants compartment model using plasma input function was made with a transient equilibrium model for the in vivo quantification of NK1Rs in humans using the PET radioligand [18F]SPA-RQ. The regional brain uptake of [18F]SPA-RQ was found to be consistent with the known distribution of NK1Rs: highest in the striatum, moderate in cortex and thalamus and low in the cerebellum. Furthermore, using the transient equilibrium model and a simplified PET imaging protocol with [18F]SPA-RQ, there was no difference in binding potential in any of the brain regions studied between depressed patients, patients recovered from depression and controls. However, a negative correlation was found between age and binding potential for global and regional NK1Rs (in particular, anterior temporal lobe).
Collectively these data provide evidence for an interaction between NK1Rs and the 5-HT system at both the presynaptic and postsynaptic levels. In addition, they confirm the utility of the PET radioligand [18F] SPA-RQ for studying NK1Rs in vivo in humans. However, they do not support the idea of altered NK1R numbers in depression.
Politics and religion in later Stuart Cornwall and south-west Wales
Keywords: restoration
politics
identity
religion
Wales
Cornwall
early modern

This thesis adopts a comparative approach to provide the first full-length study of Cornwall and south-west Wales during the later Stuart period. It explores the extent to which these isolated regions possessed unique religious and political cultures during these tumultuous decades, but also how they faced challenges and responded to developments which were common to the entire kingdom. Recent local studies have tended to downplay the distinctiveness of regions in England and Wales – preferring to use them as case studies to assess broader national trends, rather than delineating unique regional experiences. Furthermore, our understanding of the later Stuart period has been skewed by a propensity for modern studies to focus on London or other major urban centres. This thesis seeks to redress the balance by revealing the unique characteristics of two rural regions, whilst also placing them within a broader contextual framework. In doing so, it offers a re-appreciation of the multiplicity of religious and political experiences within the British Isles.
While the gentry of Cornwall and south-west Wales were far from insular, this thesis argues that their locality nonetheless continued to shape their lives and relationships. In terms of religious life, unique structural challenges in these regions posed considerable problems for the Church of England and affected its ability to carry out pastoral care – but also inhibited the growth of nonconformity. In the aftermath of the Toleration Act of 1689, each region experienced a contrasting ‘Anglican revival’: Cornwall’s conservative approach kept dissent at bay, whilst a low-church revival in the diocese of St. Davids could not compensate for worsening structural challenges, and dissent flourished. With regards to political culture, Cornwall’s electoral importance imbued the region with political influence. Both regions were traditionally royalist, but, following James II’s attacks on Anglican hegemony, this loyalty was redeployed in defence of the Church and parliamentary authority. However, this thesis argues that proclamations of unanimous loyalty were used tactically, to mask growing partisan divisions. After the Glorious Revolution, the ‘rage of party’ came to dominate political life in both regions, but was conditioned by kinship, Jacobitism, and the inability of the lower orders to participate routinely in the political process.
Developing neuroimaging biomarkers for neurodegeneration and ageing using machine learning methods
Keywords: Ageing
Errors-in-variables
Neurodegeneration
Classification algorithms
Decomposition algorithms
Brain ageing
Magnetic Resonance Imaging
Biomarkers

In this thesis, we present three novel methods based on machine learning for use with MRI-derived neuroimaging data, all with the aim of aiding biomarker development for neurodegeneration.

Resting-state functional MRI (rfMRI) can potentially detect early functional changes in disease. Therefore, the first method is a novel supervised learning algorithm for use in classifying rfMRI data into two groups. The main advantage over existing rfMRI-based classification approaches is that the entire voxel by time data is fed in without any prior decomposition or parcellation of the data into brain regions, and it does not require any prior knowledge of potential discriminatory networks. We show that the algorithm can give interpretable results for simulated data, performs better than two existing approaches for a Parkinson's disease dataset and gives results consistent with those reported previously for an anaesthesia dataset.

Ageing is strongly linked with neurodegeneration. Hence, the second method is an errors-in-variables model for estimating the brain age of individuals. It takes a fundamentally different approach compared to existing methods, which gives it the advantages of being able to capture inverted U-shaped brain ageing trajectories, provide visualisable trajectories and potentially model interactions with disease. Using simulated data, we show that it is effective at estimating brain age, and can match and in some cases outperform current approaches. Using the UK biobank dataset, we show that the difference between chronological age and predicted brain age for an individual correlates with variables that are consistent with those reported previously. We also show that it can potentially provide information that is complementary to existing methods.

The final method is a tool for decomposing multimodal neuroimaging data into spatial maps and associated trajectories. The main differences compared to existing methods are that the decomposition is driven by a variable of interest, which in our case was age, and each brain region is associated with only one trajectory as opposed to a mixture of different trajectories. This means that the components do not have to be associated with age post-hoc and the results are potentially more interpretable. Using simulated data, we show that, compared to two existing methods, our method can more accurately reproduce trajectories and associated spatial maps. Using the UK biobank dataset, we show that our method estimates trajectories and associated regions that are in agreement with previously published studies.
Searching over time: A study of attention using preview search
Keywords: Preview search
Preview benefit
Visual attention
Visual marking
Attention

Attention is the mechanism that enables us to process the sensory information most relevant to our current goals. As our most dominant sense, the way in which we attend to the visual environment is a highly important and highly researched topic (Sperling, 1960; Eriksen & Eriksen, 1974; Posner, 1980). One such method of examining visual attention is using a visual search task, where participants must locate a specified target amid distractors and their reaction times and accuracy are recorded (Treisman & Gelade, 1980; Duncan & Humphreys, 1989; Wolfe, Cave & Franzel, 1989) to gain an understanding of how attention can be guided through an array of items. Using a particular variant of the visual search task known as preview search (Watson & Humphreys, 1997), the purpose of this thesis is to extend our understanding of visual attention by examining how and if we can ignore stimuli known to be irrelevant, and if prior knowledge and expectation can guide attention effectively. Chapter 1 examines the effect of a concurrent task on performance, and suggests the timing of a concurrent task as well as the modality impact the efficiency of search. Chapters 2 and 3 examine the role of prior knowledge and expectation on search and show that the usefulness of expectation depends on the type of prior knowledge (e.g. a property or the location of the stimuli). Chapter 4 examines the role of emotion and whether a negative face can be ignored, with the results suggesting preferential selection of faces viewed face-on, rather than in profile. Results of the experiments are discussed in relation to theories of preview search.
Diarrhoeal disease in children under five years of age in an urban community in Viet Nam
Keywords: Diarrhoea
Antimicrobial resistance

Antimicrobial resistance (AMR) in infectious disease is a major global health issue. AMR is a particular problem in low to middle-income countries (LMICs), where infectious diseases, such as diarrhoea, remain common and are commonly treated haphazardly with antimicrobials. The aim of my thesis was to provide a comprehensive study of diarrhoeal disease in children under the age of five years in the community in Ho Chi Minh City (HCMC), Viet Nam. Additionally, I aimed to fill in a knowledge gap regarding antimicrobial usage for diarrhoea, the extent of AMR organisms in healthy children within the population, and investigate a potential solution for limiting AMR in the community. Active surveillance for diarrhoea in a prospective longitudinal cohort of 748 children followed for 24 months found a high incidence of diarrhoeal disease in the urban community (71.87/100 child-years of observation [95%CI: 65.68 -78.44]). Faecal samples were screened using conventional microbiology and multiplex molecular methods and found that the aetiology of this disease is highly variable. Pathogenic bacteria and viruses were detected at a high prevalence, but the most common were Salmonella and norovirus, respectively. Antimicrobials were commonly used for diarrhoeal treatment in hospital. Additionally, a mixed-methods approach in the community found an ease of access to antimicrobials for diarrhoeal management in the community through local pharmacies. However, despite antimicrobials being widely available in the community, antimicrobial usage was almost 10 times greater in the hospitals. Widespread antimicrobial access may induce the selection of antimicrobial resistant organisms (AROs) and antimicrobial resistance genes (ARGs). An assessment of the prevalence of and risk factors for carrying AROs and ARGs demonstrated a high prevalence of carriage antimicrobial resistant Escherichia coli (E. coli) and associated resistance genes to fluoroquinolones and third generation cephalosporins. Both these groups are commonly used to treat diarrhoea in this setting. Children of higher body weight and height z-score were more likely to carry fluoroquinolones resistance genes and younger children were more likely to carry either third generation cephalosporin resistance genes individually or in combination with fluoroquinolones resistance genes. Lastly, hypothesising that improved breastfeeding practices may reduce diarrhoeal disease and impact antimicrobial usage and consequently AMR, I investigated risk factors for suboptimal breastfeeding using data from a birth cohort conducted in both an urban and a semi-rural area. The study indicated that having a Caesarean section and neonatal complications prevented mothers from breastfeeding their infants during the hospital stay. Work from this thesis will contribute to the efforts of tackling AMR in a LMIC, specifically in Viet Nam where there is extensive exposure to antimicrobials and sustained exposure to enteric pathogens.
Discovery strategies for dark matter and Higgsinos at the LHC
Keywords: Sleptons
Supersymmetry
Higgsinos
ATLAS
LHC
Dark matter

New dynamics beyond the Standard Model is expected at scales probed by the Large Hadron Collider. In particular, weak scale supersymmetry can provide a dark matter candidate and stabilise the electroweak hierarchy. This thesis presents two studies investigating new strategies to discover such phenomena. First, a theoretical assessment uses six search strategies based on 3.2fb-1 of 13 TeV data to constrain a 19-parameter framework of supersymmetry. This identified the fermionic partners of Higgs bosons, called Higgsinos, as a key target for dark matter searches. Such scenarios are very difficult to discover at colliders in electroweak production, as produced states are one to tens of GeV heavier than the dark matter and leave little detector activity. The second part of this thesis presents a new experimental strategy targeting these so-called compressed scenarios, exploiting electrons and muons down to the lowest transverse momenta detectable by the ATLAS Experiment. Using 36.1fb-1 of 13 TeV data, this strategy opens hadron collider sensitivity to Higgsino dark matter down to mass splittings of 3 GeV, and coannihilation scenarios involving winos and sleptons down to mass splittings of 2.5 and 1 GeV respectively. While no statistically significant excesses are observed, this landmark LHC sensitivity surpasses lepton collider limits for the first time in nearly two decades.
Magnetic fields in and around galaxies
Keywords: Cosmology
Galaxy formation
Numerical methods: simulations
Magnetic fields: astrophysics

Magnetic fields are an ubiquitous component of our Universe. They are expected to play an important role in the evolution of many astrophysical systems, from molecular clouds to galaxy clusters. In the case of galaxies, magnetic energy is measured to be in equipartition with thermal and turbulent energies of the interstellar medium. Despite this omnipresence, the origin of cosmic magnetic fields remains an open question, and the precise influence that magnetic fields have in shaping the formation and evolution of galaxies is uncertain.
Using magnetohydrodynamical numerical simulations of both cosmological volumes and high-resolution cosmic zoom-ins on individual galaxies, I explore in this thesis the main mechanisms likely to generate galactic magnetic fields similar to those observed and the role these latter play in shaping galaxies. I present various extensions to existing numerical techniques to account for magnetism in state-of-the-art software employed to simulate galaxies. These culminate in the introduction of a new algorithm that traces magnetic fields generated by different sources separately. In particular, I simulate the formation of a Milky Way-like galaxy, magnetised either through dynamo amplification, a strong primordial magnetic field, or magnetised stellar feedback, demonstrating that each mechanism is capable of producing realistic levels of magnetisation on its own. Jointly tracing primordial and stellar generated fields, I study how they compete to produce the total magnetic field. I find a large degree of interaction, both inside galaxies, where the two components contribute significantly to the magnetic energy budget, and around galaxies, where the magnetic fields pushed out by stellar feedback pollute the primordial magnetic field. In a final set of simulations, I explore how magnetic fields modify the global properties of a galaxy, finding evidence of morphological compression and braking of the rotation of the galaxy by strong magnetisation.
Moral worth and knowledge
Keywords: Moral Worth
Knowledge
Moral Luck
Epistemic Luck
Non-accidental Truth
Non-accidental Rightness

Actions can be morally right while lacking moral worth. Kant’s prudent shopkeeper, for example, treats his customers fairly only to maximise his long-term profit. Although he’s doing the right thing, his actions have no moral worth. It has been suggested that the shopkeeper’s actions lack moral worth because they are only accidentally right. Moral worth excludes luck. But how should we understand the relevant notion of non-accidental rightness?
To answer this question, this thesis utilises a striking analogy between moral worth and knowledge. Just as actions can be right without having moral worth, beliefs can be true without amounting to knowledge. For instance, guessing the correct outcome of a fair lottery makes for a true belief, but not knowledge. This lack of knowledge has often been explained by the fact that the belief is only accidentally true. Knowledge excludes luck.
The notion of epistemic luck has received much attention in the last decades. This thesis draws on the insights from the epistemic literature to clarify the relevant notion of non-accidental rightness in the moral domain. In doing so, two necessary conditions for non-accidental rightness are identified. An action is non-accidentally right only if (i) the action is reliably right; and (ii) the agent has control over the action’s rightness.
Selective vulnerability of the primary motor cortex in amyotrophic lateral sclerosis
Keywords: Neuropathology

The ‘selective vulnerability’ of cells and systems to disease pathomechanisms is a defining feature of amyotrophic lateral sclerosis (ALS), where the relative clinical and pathological involvement of cortical motor neurons varies between patients. Mislocalisation and aggregation of hyperphosphorylated TDP-43 (pTDP-43) is the major neuropathological finding in the majority of ALS cases (ALS-TDP), however the relationship between TDP-43 aggregation and neurodegeneration remains unclear. Here, we sought to reconcile the selective vulnerability of specific cell types within the human primary motor cortex to the pathological hallmarks of ALS, and define commonalities and differences of neurodegenerative phenotypes across the genetic spectrum of the disease. We analysed human post-mortem tissue from a large cohort of genetically defined ALS/FTD (n = 78), and mean age-matched control cases (n = 15) using a combination of quantitative immunohistochemical techniques and multi-level generalized linear modelling. The utility of novel methods such as CLARITY, imaging mass cytometry, combined RNA-ISH/IHC and multiplexed immunofluorescence is also explored. Additionally, two monogenic forms of the disease which exhibit striking UMN/LMN predominance, ALS-FUS and ALS-OPTN, are discussed and compared in the context of a novel BAC transgenic mouse and a unique human index case.
We show that there is considerable variance in neuropathology within the ALS primary motor cortex both within and across the genetic spectrum of disease, including in pTDP-43 aggregation, microglial activation, and inhibitory interneuron number. We also assess the extent of this pathology across the corticospinal neuraxis, and begin to examine the interactive relationship of pathologies using multiplexed immunofluorescence. Using RNA-ISH, we also show that while FUS is significantly more highly expressed in the primary motor cortex, TARDBP demonstrates a higher retention of transcripts localised to the nucleus. We also begin to assess the expression of transcription factors associated with projection neuron diversity including CTIP2, SATB2 and TBR1 in the primary motor cortex. Broadly, this thesis refines the concept of selective vulnerability within the ALS motor cortex across genetic subtypes, whilst highlighting the distinction between cellular vulnerability to proteinopathy and vulnerability to degeneration itself. These findings have implications for our understanding of disease pathogenesis and the development of genotype-specific therapies.
The impact of sequence diversity on the glycan shield of HIV-1 immunogens
Keywords: mass spectrometry
immunogens
N-glycosylation
HIV-1
vaccine

Vaccine strategies for the human immunodeficiency virus type 1 (HIV-1) focus on the mimicry of its envelope spike (Env), due to its exposed location on the viral membrane and role in mediating infection. However, the virus has evolved to minimise the immunogenicity of Env, notably through extremely high sequence variability and the shielding of conserved protein epitopes by an extensive array of host-derived, immunologically ‘self’ N-linked glycans. Despite this, a subset of infected individuals eventually develop broadly neutralising antibodies that can recognise these glycans. Defining the composition of glycan epitopes on both viral Env and candidate immunogens is therefore a major research focus for HIV-1 vaccine design.
Using recombinant, soluble mimics of Env, this thesis sought to determine the impact of protein sequence on the processing of the glycan shield. This was addressed on three levels: the impact of virally-encoded sequence diversity, the impact of engineered stabilising mutations, and the impact of mutations affecting glycosylation sites. Despite the extensive diversity displayed by the Env sequence, many features of the glycan shield were remarkably conserved. Mutations affecting glycosylation sites, however, did impact the fine processing of nearby sites. Additionally, the glycan composition of Env mimics could be subtly altered using glycan-dependent broadly neutralising antibodies, either during the expression or purification stages. The latter effect appeared to be sequence-specific.
Although recombinant, soluble Env proteins are good structural and antigenic mimics of native, viral Env, the extent to which their glycan shields resemble that of infectious viruses is unknown. To that end, the glycosylation of a candidate immunogen was compared to that of sequence-matched Env derived from infectious virions. The glycan processing of key broadly neutralising antibody epitopes was largely conserved between virus and immunogen. However, there were subtle differences at some sites, with the viral material typically displaying elevated glycan processing. Given that recombinant Env constructs are good mimics of the viral glycan shield, they are likely also inherently immunoquiescent. Accordingly, this thesis also explored a strategy to boost the immunogenicity of the glycan shield, using yeast to decorate a soluble Env immunogen with ‘non-self’ glycan structures.
Overall, features of the Env glycan shield are largely conserved between virus and immunogens, and across multiple genotypes, supporting it as a suitable target for HIV-1 vaccine design.