VictorJuiz/thesis huggingface dataset:
The mechanistic modelling and simulation of vaccine-adjuvant induced immune responses
Keywords: vaccine
adjuvants
modelling
vaccination
mathematical
mechanistic
AS01
simulation

Vaccination is one of the most successful public health interventions in human history. A key component of subunit-vaccines are adjuvants; immunostimulants that shape and enhance the immune response to antigens. Despite the importance of adjuvants, the mechanisms of how adjuvants promote immune responses are not fully understood, limiting detailed appli- cation of modelling and simulation to determine optimal vaccine formulations, dosing and timings of prime and boost. To rationally accelerate next-generation vaccines while promot- ing transparency, it is critical to foster a detailed understanding of the mechanism of action of efficacious adjuvants. AS01 is a patented adjuvant used in clinically approved Malaria (RTS,S/AS01) and Herpes-Zoster vaccines (Shingrix). In this thesis, the first detailed the- oretical model of AS01’s mechanism of action from injection site to generation of antibody response is presented. From this non-executable description of AS01 biology, mathematical models were developed. These mathematical models permitted analysis of the interplay of cytokines (IFNγ, IL12 and IL18) and cells (macrophages, dendritic cells and monocytes) in early events based on data from a murine iliac draining lymph node. Model analysis led to the novel hypothesis that dendritic cells are the predominate cell type responsible for early IL12 production. IL12 is known to synergise with macrophage-derived IL18 to initiate early IFNγ. We provide evidence that AS01-mediated loss of subcapsular macrophages has a role in regulating the duration of IFNγ production acting as an endogenous inhibitory mechanism. Model analysis suggests that this cell loss affects the minimal temporal spacing of AS01-based vaccination required to obtain canonical IFN responses. This mathematical model was extended to capture CD4+ T cell priming dynamics. By analysing two simula- tions that permit exploring different hypotheses of AS01-mediated CD4+ T cell priming, we observed that our hypothesis of how IFN regulates CD4+ T cell priming was likely to be incomplete, which led to a refined hypothesis for IFNγ’s role in this process. We observed that ‘inflammation-induced’ na ̈ıve CD4+ T cell recruitment may be a key factor regulating the magnitude of CD4+ T cell priming. Thus, physiological factors including time of the day and spacing of consecutive jabs may have a key role in AS01 vaccine efficacy.
The international movement of financial assets: a liberal egalitarian perspective
Keywords: culturalist theory of justice
John Rawls
anti-cosmopolitanism
cross-border movement of assets
tax avoidance
global justice
immigration
justice of international trade
internationalist conception of justice
international justice
public political culture

This thesis discusses how a liberal egalitarian society should respond to the international movement of financial assets. Specifically, it addresses what constraints can be legitimately imposed on the freedom of individuals and corporations to transfer their financial assets, which include cash, bonds, and other types of liquid assets, out of the country. The thesis consists of two parts. The first part lays out the theoretical framework. It argues that there are three liberal egalitarian justifications for constraining an agent’s claim and exercise of private property rights: the priority of the disadvantaged, the demand for fair contribution, and the requirement of membership. After that, it defends an internationalist interpretation of these constraints by defending a culturalist conception of justice under which two distinctive sets of principles of justice should apply to domestic liberal egalitarian societies and the international arena respectively. The justification for this two-tiered account of justice is that the public political culture that mediates the relation between the citizens of a liberal egalitarian society is fundamentally different from the one that mediates the relation between societies in the international arena. The second part of the thesis applies the theoretical framework developed in the first part to three different cases of international movement of financial assets: capital relocation, profit shifting, and personal asset migration. It argues that in each case a liberal egalitarian society has good reasons to impose constraints on the outflow of financial assets. The restrictions on capital outflow are justified because they prevent the interests of disadvantaged citizens from being sacrificed for the gains of the already advantaged. The ban on profit shifting is legitimate because it helps secure a fair financial contribution from the rich and multinationals. The constraints on emigrants’ freedom to leave the country with their personal property are justified because a society has the right to impose financial conditions on emigration. Together, the thesis offers a critique of a pillar of global capitalism as it is known today—the international free movement of financial assets.
MSH3 promotes back-up DNA end-joining pathways that sustain the survival of BRCA2- deficient cells
Keywords: Polθ
cancer
MSH3
alternative non-homologous end-joining
DSB repair
PARPi
BRCA2

DNA repair pathways that maintain genomic stability are essential in avoiding carcinogenesis. However, inactivation of these repair pathways frequently occurs during tumorigenesis and cancer cells become dependent on alternative mechanisms for DNA repair. Cancer cells with heterozygous germline mutations in BRCA1 and BRCA2 have abrogated HR function, hence they rely on alternative DSB repair pathways known to promote genomic instability, one of which is alternative non-homologous end-joining (A- NHEJ). This pathway requires the activity of error-prone DNA polymerase θ (Polθ) to anneal sequences with microhomology and utilise them as primers for DNA synthesis. Previous studies have shown that Polθ activity is critical for the survival of BRCA2- deficient cells and A-NHEJ has also been implicated in the resistance of BRCA2-deficient tumours to chemotherapy. Hence, factors of A-NHEJ represent potential targets for the elimination of BRCA-deficient tumours. The MSH2/MSH3 heterodimer has been canonically characterised in mismatch repair (MMR) in recognising long distortions in DNA structure. Notably, yeast and hamster MSH2/MSH3 displayed MMR-independent activity in repairing DNA lesions by joining DNA breaks with microhomologies, similar to A-NHEJ. The aim of this thesis was to investigate the potential role of MSH3 in the A- NHEJ pathway in BRCA2-deficient cells. We discovered that concurrent loss of MSH3 and BRCA2 reduced cell viability, thus indicating a role for MSH3 in the survival of BRCA2-deficient cells. Subsequently, we performed epistatic experiments with MSH3 and Polθ which indicated that MSH3 likely has a role in A-NHEJ. PARP-inhibitors are known to eliminate BRCA2-deficient cells. Interestingly, we observed that MSH3 loss in BRCA2-deficient cells led to their increased sensitivity to PARP inhibitor (PARPi) treatment. Thus, we have identified novel functions of MSH3 in the survival and response to treatment of human BRCA2-deficient cells.
Scaling-up of the electrochemical leaf system
Keywords: electrochemical leaf

This thesis presents an exploration of the Electrochemical Leaf (e-Leaf) with a novel application-oriented direction. The e-Leaf, a recent breakthrough made in the Armstrong group in the area of bio-electrochemical catalysis, is inspired by the natural leaf: enzyme cascade is immobilised in the nanopores of the electrode, allowing multi-step biotransformations to be energised, controlled, and monitored in real time. Ferredoxin NADP+ reductase (FNR) is the key enzyme in the e-Leaf, catalysing the interconversion of NADP+/NADP(H). Other co-entrapped NADP(H)-dependent enzyme(s) catalyse reactions coupled to this regeneration, achieving a fast conversion due to the very high effective concentration of enzymes and short distances for cofactor and reactants to diffuse between the enzymes in the nanopores. The e-Leaf is a powerful tool for the investigation of biocatalytic processes and potentially for the production of valuable chemicals.
In this work, the e-Leaf has been exploited for its versatility in application. First, the e-Leaf has been scaled up from a 4 mL lab-scale cell to a 500 mL pilot level reactor with new reactor designs, optimisations of the electrode construction and optimisation of reaction conditions. The productivity scales up linearly with the size of the reactor, showing the feasibility and potential of scaling up an electrochemical system.
The e-Leaf has also been explored to function as a biphasic reactor. The introduction of an organic layer containing substrate and(or) solvent has provided the electrochemical system with a sustainable substrate supply with simultaneous relief of product-inhibition. The final step in engineering the e-Leaf has been its transformation from an original batch design into a flow reactor in which the electrochemical reactions have been performed under flow as a proof of concept. The e-Leaf therefore has the potential to work in series continuously with high space-time-yield to accommodate complex requirements for industry-level syntheses.
In a separate branch of work, the e-Leaf has been exploited to achieve the deracemisation and stereoinversion of a secondary alcohol in a dually-controlled method, with the ability to switch the direction of the redox reaction and to change the enantioselectivity of the electrode. The reaction process is monitored in real-time to complete a one-pot, one-step deracemisation (or stereoinversion).
In situ diagnostics of damage accumulation in Ni-based superalloy
Keywords: creep
in situ X-ray computed tomography
void growth
acoustic emission
high temperature testing
superalloy

There has been a significant interest in capturing how the damage is initiated and accumulated in polycrystalline Ni-based superalloys while applying thermal and mechanical impact – tensile and creep loading at 800◦C. This is because the turbine component in jet propulsion or power generation these materials applied can experience such environments while in service and need to avoid unexpected degradation and failure causing severe accidents. In situ damage observation techniques required to be developed to understand the sequential mechanisms of damage growth even in such complicated environment.
In this work, for the first time in this field, a design and operation of laboratory-scale X-ray computed tomography (XCT) arrangement is developed for the purpose of in situ damage observation. The in situ XCT technique covers high-temperature mechanical testing and improvements of tomography image processing for high resolution enables to capture the sequential damage growth during tensile or creep loading at 800◦C, in examples of polycrystalline Ni-based superalloys, Inconel 718 and Nimonic 80A. Furthermore, laser-based Acoustic Emission (AE) techniques are combined with the system to determine whether the object is damaged to be captured by XCT.
The developed in situ observation technique was applied to high-temperature tensile and creep testing. Our results indicated that the damage growth could be captured with the resolution of 30 µm at 800◦C, and can be compared not only with strain rate and loading condition but with the stress state of the deformed testpiece, and that AE the technique can be the damage indicator of the object by observing the change in AE energy and frequency.
Serotonin transporters in depression
Keywords: 5-hydroxtryptamine
depression
serotonin transporter
major depressive disorder
5-HT
positron emission tomography
magnetic resonance imaging
DASB
serotonin
brain

Major depression is a common, recurrent and severe mental illness and is a leading cause of medical disability worldwide. The pathophysiology of depression is not well understood but evidence strongly suggests that dysfunction in brain serotonin (5-HT) neurons may play a significant role. The serotonin transporter (5-HTT) recycles released 5-HT back into neurons and is a key regulator of 5-HT neurotransmission. Abnormality in the 5-HTT has been proposed as an important mechanism in the etiopathophysiology and the treatment of depression. Using positron emission tomography (PET) in conjunction with [11C] DASB, a selective 5-HTT radiotracer, it is now possible to measure the 5-HTT in the living human brain. The aim of this thesis was to study 5-HTT binding in major depression and also to identify the effect of a 5-HTT genetic polymorphism on 5-HTT binding and brain morphology.
Unmedicated, acutely depressed patients had diminished availability of the 5-HTT in several brain regions including the brain stem, thalamus, caudate, putamen, anterior cingulate cortex and frontal cortex. However, there was no significant difference in 5-HTT availability between unmedicated recovered depressed patients and healthy comparison subjects in any of the brain regions studied. There was no significant difference in brain 5-HTT availability in healthy controls with different 5-HTT polymorphic variations. However, brain morphological analysis revealed reduced brain gray matter volume in S’ allele carriers vs L’L’ homozygotes in several brain regions including anterior cingulate cortex.
The results suggest at least in a subgroup of patients, acute depression is associated with decreased availability of the 5-HTT as measured by ligand PET. The results indicate that this abnormality is a state marker of depression but this needs to be confirmed by future studies following the same group of patients through depression, treatment and its resolution. The findings also suggest that if the 5-HTT promoter polymorphism exerts a reliable effect on the risk of depression it is not mediated through changes in the 5-HTT but more probably through modifications in brain morphology perhaps of neurodevelopmental origin.
Social bonding through processing fluency for interpersonal synchronisation
Keywords: evolution
processing fluency
entrainment
synchrony
social bonding

It has often been observed that people like each other more after synchronising actions. This is referred to as the synchrony-bonding effect and it has been observed in a wide variety of settings – from dance to rowing. It has been suggested that music may have evolved alongside human rhythmic abilities in order to support synchronised action to promote social bonding and group cohesion. However, the precise cognitive mechanisms underpinning the synchrony-bonding effect remain opaque.
This thesis aims to bring new insights to the synchrony-bonding effect by testing a novel hypothesis: that the social bonding effects of synchrony arise from processing fluency. To do so, I bring together the general literature on processing fluency as it applies to perceptual preferences and aesthetic judgements, together with existing studies of interpersonal synchrony. I then conduct three empirical studies using novel experimental designs to test the fluency through synchrony hypothesis. Study 1 found that synchrony reduces processing load on a simple visual perception task, when compared with non-synchrony. Study 2 found that synchrony reduces processing load when participating in a rhythmic tapping task, when compared with non-synchrony. Study 3 built upon Study 2 and found that perceived difficulty of a rhythmic tapping task mediated the social bonding effects of synchrony.
These studies reframe synchrony as a means for reducing processing load, which could explain the synchrony-bonding effect as being an effect of processing fluency, rather than of synchrony per se. Thus, the act of synchronising may be considered an act of making oneself easier to process. I discuss these findings in the context of the broader synchrony-bonding literature, consider the implications for the evolution of rhythmic abilities, and attempt to highlight the importance of understanding synchrony in an increasingly de-synchronised world.
Theodor Adorno and Anglophone modernist literature 
Keywords: English Literature
Frankfurt School
James Joyce
Samuel Beckett
Charles Dickens
Modernist Literature
Modernism
Theodor Adorno
Critical Theory
Aldous Huxley
Anglophone Literature

Though studies of Adorno and literature have proliferated over the last 15 years, Adorno’s engagement with Anglophone literature continues to be overlooked. This thesis seeks to remedy such an omission by outlining the importance of four Anglophone writers - Dickens, Joyce, Beckett and Huxley - to Adorno’s wider philosophical project. I show how Adorno drew upon these writers’ works and interpreted them in his own specific way as modernist texts – in other words, as texts that had an especially critical, cognitive quality that would allow him to discuss and potentially counteract the false consciousness promoted by the different stages of capitalism. In the first chapter, I establish how Adorno uses Dickens’ novel The Old Curiosity Shop to propose a specific theory of allegory to resist reification in capitalist society. In the second chapter, I argue that Adorno should be understood as giving a powerful but tendentious reading of Joyce’s novels Ulysses and Finnegans Wake. In the third chapter, I uncover how Beckett’s The Unnamable and Endgame offer a paradoxical form of therapy for Adorno: their redemptive potential stems from their self-conscious failure to be consolatory texts. In the fourth and final chapter, I demonstrate how Adorno sees Huxley’s Brave New World as a tool for resisting the culture industry’s false consciousness because it promotes a kind of pleasure that opposes the false pleasures of capitalism. Overall, I aim to show the key role that Anglophone literature had in Adornian thought; it was both the source and object of his critical theory as well as a space that exposed the limits of its very place within his philosophy.
Genetic basis of immune-mediated susceptibility to infectious disease
Keywords: tuberculosis
Genomics
neutrophils
immunity
infectious diseases

Infectious diseases remain a major driver of morbidity and mortality globally. For example, Mycobacterium tuberculosis causes about 10 million cases of tuberculosis (TB) and 1.5 million deaths. In a series of studies I demonstrate that discovering the genetic underpinnings of how immune factors affect susceptibility to diseases such as TB reveal new insights into disease susceptibility. Previous transcriptome-wide studies suggested that the ratio of myeloid:lymphoid transcripts was elevated in infants who subsequently developed TB. These data were reminiscent of observations made 80 years ago where the ratio of monocytes:lymphocytes (ML) at time of challenge with mycobacteria, was predictive of survival in animal models. To establish the peripheral blood ML ratio as a novel intermediate phenotype for TB susceptibility, I demonstrated that the ML ratio predicts TB disease in three independent cohorts of adults (n=2207), infants (n=1336) and pregnant women (n=1202). Moreover, in collaboration with others, these findings were extended to other diseases including malaria. Turning attention to the pathophysiologic basis of this association, I found qualitative differences in monocytes according to ML ratio even amongst healthy individuals (n=136), both in functional response to mycobacteria and in transcriptomic profile at rest. Next, I found that the ML and neutrophil:lymphocyte (NL) ratio are highly phenotypically and genetically correlated, suggesting the presence of pleiotropic genetic regulators. I present formal estimates of heritability based on concordance and structural equation modeling of data from twin studies (1664 twin pairs), and amongst unrelated adults (n=5034). A meta-analysis of four genome-wide association studies (total n=5768) was performed as a resource to understand how the ML and NL ratios may be regulated, and to facilitate Mendelian randomization studies. Finally, in a more generalised approach I identified genetic regulators of gene expression in monocytes and neutrophils from healthy adults (n=101) and demonstrated how these give fundamental new insights into a wide array of infectious and non-infectious diseases. Taken together, these studies offer original contributions to the understanding of how genetic factors give rise to immune-mediated susceptibility to infectious disease.
Pharmacological inhibition of the methyltransferases SUV4-20 in cellular models of Friedreich’s ataxia 
Keywords: PSNs
Histone methyltransferase
iPSCs
Friedreich's ataxia
SUV4-20
Epigenetics

FRDA is the most common hereditary ataxia in the western world. The disorder is characterised by a pathological GAA trinucleotide repeat expansion in the FXN gene, resulting in a decrease in the expression of its encoded protein, frataxin. Symptoms commonly arise during adolescence, with patients exhibiting a clinical syndrome of progressive neurodegeneration, cardiomyopathy and endocrine dysfunction. FRDA remains without a cure, likely due to our incomplete understanding of disease pathology, coupled with limitations surrounding the in vitro models historically used for drug discovery. Recently, the methyltransferases SUV4-20 have been identified for their role in facilitating the partial silencing of FXN, through an increase in repressive H4K20 di- and trimethylation marks. Inhibition of SUV4-20 by the tool compound A-196 has been show to rescue FXN expression, implicating SUV4-20 as an exciting therapeutic target for FRDA. Working in collaboration with medicinal chemists, we were provided with 22 structural derivatives of A-196, in order to determine their effectiveness to increase FXN expression. We found that several analogues were capable of increasing FXN expression in our FXNLuciferase reporter model. Progression of the most promising analogues to testing in FRDA patient fibroblast lines, demonstrated one compound capable of significantly increasing FXN mRNA expression. Additionally, by adapting 2 previously published differentiation protocols we aimed to establish an iPSC-derived sensory neuronal model of FRDA. Utilising 2 control and 2 FRDA iPSC lines, we analysed the gene expression profiles and performed immunocytochemistry staining of derived cells, confirming the successful generation of an iPSC-derived sensory neuronal model. Further work is required to fully establish this model and determine the subpopulations of PSNs derived. Thus, overall this project contributes to accelerating drug development for FRDA, firstly by advancing our understanding of the epigenetic mechanisms underpinning FXN repression, and secondly by working towards developing a phenotypically relevant cellular model of the disease.