VictorJuiz/thesis huggingface dataset:
Serotonin transporters in depression

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.

Keywords: 5-hydroxtryptamine
depression
serotonin transporter
major depressive disorder
5-HT
positron emission tomography
magnetic resonance imaging
DASB
serotonin
brain
Advisor: Cowen, P
Social bonding through processing fluency for interpersonal synchronisation

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.

Keywords: evolution
processing fluency
entrainment
synchrony
social bonding
Advisor: Hathaway, E
Tarr, B
The evolution, molecular epidemiology and genomic sampling of emerging viruses

Emerging viruses represent a challenging threat to global health. Increasing human travel and global connectivity, changing climate patterns and incremental contact rates between human and animal populations contribute to the likelihood of emerging viral epidemics to occur at greater scales and higher frequencies. These pathogens have gained increased notoriety in recent years as emerging and re-emerging viruses such as Ebola virus, Zika Virus and SARS-CoV-2 caused large epidemics and pandemics of high consequence. The circulation and evolution of these viruses in regions like Africa and the Americas (where genomic surveillance remains limited) is key to their transmission dynamics, driven by environmental conditions combined with abundant biodiversity and complex human-animal interactions.
In this thesis, I apply genomic epidemiology tools to study the transmission and evolution of emerging viruses with limited sampling. The first study evaluates the evolution of Oropouche virus (OROV) since its emergence in the mid 20th century in South America. The second study describes the transmission dynamics of the first SARS-CoV-2 wave in Ecuador, where genomic sampling was limited. The third study investigates the emergence of a recombinant SARS-CoV-2 lineage in North America and describes its remarkable spread in early 2021. The fourth study compares the spatio-temporal spread of two arboviruses in Mexico, Dengue virus (DENV) and Chikungunya virus (CHIKV) and reveals similar trends in their importation and spread in the country. Finally, the fifth study derives from the investigation of a CHIKV outbreak in Kassala, Sudan, and explores the possible sources of the outbreak.

Advisor: Pybus, O
Theodor Adorno and Anglophone modernist 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.

Keywords: English Literature
Frankfurt School
James Joyce
Samuel Beckett
Charles Dickens
Modernist Literature
Modernism
Theodor Adorno
Critical Theory
Aldous Huxley
Anglophone Literature
Advisor: Dwan, D
Genetic basis of immune-mediated susceptibility to infectious disease

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.

Keywords: tuberculosis
Genomics
neutrophils
immunity
infectious diseases
Advisor: Hill, AVS
McShane, H
Morris, A
Pharmacological inhibition of the methyltransferases SUV4-20 in cellular models of Friedreich’s ataxia 

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.

Keywords: PSNs
Histone methyltransferase
iPSCs
Friedreich's ataxia
SUV4-20
Epigenetics
Advisor: Vilema-Enríquez , G
Wade-Martins, R
Characterising dynamical systems models of tumour-immune interactions

Despite clinical successes, data from trials of cancer immunotherapies continue to highlight non-responders. A better understanding of tumour-immune interactions is needed to explain outcome variability. In this thesis, we investigate whether tumour-immune interaction models can explain variation in mouse tumour volume time series data, focusing on a well-known mathematical model by Kuznetsov et al. (1994).
Exploiting a separation of timescales in the original model, and using matched asymptotics, we derive a new long-timescale approximation of the model, which differs from the quasi-steady-state approximation (QSSA) introduced by Kuznetsov et al. (1994), but is in good agreement with numerical solutions of the original model. As well as exhibiting the three stages of immunoediting – elimination, equilibrium and escape, together with complex bifurcations and bistability, our reduced model highlights excitability, a feature not traditionally associated with tumour-immune models. We also identify different biophysical parameters that could be targeted with immunotherapy in order to control tumour size.
As the QSSA model is simpler, but still exhibits immunoediting, we use it for case studies investigating parameter identifiability for complex bifurcating and bistable models using in silico data, generated from the model with variable parameters, observables and noise levels. Using profile likelihoods, we show that identifiability varies across dynamically different datasets. Parameters related to the immune system are highly correlated, and can result in large parameter confidence intervals and bimodal likelihood surfaces.
We then explore a population approach, where the model is simultaneously calibrated to dichotomous data from two individuals, noting that variation in tumour outcomes can arise from bistability or bifurcations, representing distinct hypotheses for heterogeneous tumour responses. We demonstrate the hypotheses can be distinguished for most synthetic datasets considered, except for highly noisy tumour data, by comparing Bayesian population fits under each hypothesis.
This thesis provides a new perspective on how qualitative differences between tumour growth dynamics of responders and non-responders may be explained by bifurcating and/or bistable models. At the same time, it illustrates how integration of mathematical and statistical methods can facilitate development of simplified models, their analysis and calibration.

Keywords: bifurcations
cancer
modelling tumour-immune interactions
parameter estimation
dynamical systems
asymptotics
inverse problems
immuno-oncology
bistability
excitable systems
Advisor: Byrne, H
Gaffney, E
The world according to PEN and UNESCO: Makers of world literature, 1921-1996

This study charts for the first time the complex, always evolving relationship between PEN International (PEN) and the United Nations Educational, Scientific and Cultural Organization (UNESCO), including its precursor the International Committee on Intellectual Cooperation (ICIC), from 1921 to 1996, focusing on their joint translation policies. Over these 75 years, the three international organisations collaborated with each other to develop and implement literary translation programmes that would foster mutual understanding among peoples and nation-states, though the way they conceptualised ‘world literature’ diverged over time. Drawing on multiple archives and official publications, this study argues that their joint translation policies concretely shaped, and were shaped by, their official and informal partnerships as PEN championed the role of living writers, and UNESCO the role of literary books, in these programmes. Their collaboration during the 20th century succumbed to and resisted interventions from member states and the pressure of the international marketplace, yielding unexpected or mixed outcomes. Part 1 examines the interwar period when PEN and the ICIC, despite the brevity of their collaboration, set the terms for the prehistory of translation programmes, especially through their debates on national literary languages. Part 2 examines PEN and UNESCO’s collaborative projects that prompted each other to engage with Eastern and Western literatures, shaping their post-war world literary visions. Part 3 turns to the most controversial period for PEN and UNESCO when the two, goaded by international politics, began to actively intervene in each other’s policymaking while articulating their own independent understanding of world literature and literary rights. Investigating multiple institutional and individual crossings, this study overall reflects on the role of PEN and UNESCO as makers of world literature, tracing their tangled historical developments, fraught implementations of their translation programmes, and competing imperatives underlying their long-running collaboration.

Keywords: UNESCO
Book History
Sociology of Translation
PEN International
World Literature
ICIC
Advisor: McDonald, PD
Sociological applications of positive mental health

This thesis tests the conceptual relevance and empirical usefulness of the positive mental health (PMH) framework for quantitative sociological research. The PMH approach postulates mental health to be inherently multidimensional and to consist of the tripartite domains of hedonic (affective, emotional, and cognitive), psychological (eudaimonic) and social well-being. It stipulates that the presence of PMH does not merely mirror the absence of mental disorders and illnesses (dual continua model), and it proposes that eudaimonic well-being, in particular, can be meaningfully distinguished from other forms of mental health. Even though versions of the PMH approach have gained considerable popularity in academia and public policy, they are often still limited by a lack of longitudinal evidence and a shortage of advanced statistical modelling that would demonstrate their broader importance. In response, this thesis employs state-of-the-art PMH indicators, primarily the Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS), on high-quality nationally representative data and strategically contrasts the finding of PMH scales with more established NMH ones over a broad array of sociological conditions and outcomes.
The first empirical chapter tests the empirical prevalence, predictors and consequences of the dual continua model and sheds light on the psychometric and sociological differences between the SWEMWBS, the GHQ and life satisfaction and uses allostatic load measures as a physiological benchmark. The subsequent two empirical chapters analyse how neighbourhoods, as an important meso-level consideration, and how religiosity, as an eminent individual-level factor, distinctly affect PMH while jointly controlling for NMH, both cross-sectionally and over ten years (with four measurement occasions of the SWEMWBS). Finally, the fourth paper establishes the link between PMH and mortality risk over a 21-year span while controlling for the influences of other mental health and psychological measures.
Throughout the thesis, an extensive set of statistical techniques such as event history, fixed and random effects, and structural equation modelling are employed. While the thesis finds somewhat of an expected overlap between the PMH scales and the competing mental health measures, the dual continua model of mental health is supported, and striking differences emerge in reference to the SWEMWBS’ sub-dimensions of feeling optimistic and feeling usefulness. Each chapter also portrays meaningful differences in the relationships of the mental health variables with life course conditions. The thesis demonstrates that sociological researchers must deliberately choose the right psychological scale or sub-dimension with care and that, in certain applications, differentiating between negative and positive mental health according to the dual continua model of mental health can provide new insights.

Keywords: WEMWBS
dual-continua model of mental health
eudaimonia
well-being
positive mental health
mental health
Advisor: Monden, C
Billari, F
Host gene expression change during viral stress

Viral infection induces extensive changes in the host transcriptome. One crucial way in which the transcriptome is remodelled is via changes to host mRNA 3’-end processing, but how virus infection induces these changes, and to what extent, is poorly understood. Over 70% of human genes have the potential to be cleaved and polyadenylated at multiple sites, and differential usage of these sites can regulate gene expression by affecting transcript properties and by altering transcript coding capacity.
In this investigation, we used two strains of influenza A virus as models to study host alternative cleavage and polyadenylation (APA) changes induced by viral infection. Influenza A is an RNA virus that replicates in the nuclei of host cells, and has previously been reported to interact with host 3’-end processing factors. We utilised a powerful experimental approach, combining 3’RNA-sequencing with a custom-built bioinformatic pipeline, to analyse APA changes in the nuclei and cytoplasms of host cells during viral infections.
We identified widespread APA changes in the 3’-untranslated and coding regions of mRNAs in viral-infected cells. We also extracted many physiologically relevant APA changes which have the potential to influence viral replication, suggesting that APA is another layer of gene regulation defined by competition between the host and virus. Additionally, we examined the mechanistic basis for APA during viral infection by analysing cis-element sequences surrounding poly(A) sites and uncovered highly significant frequency biases, suggesting that cis-element differences play a critical role in viral-induced differential poly(A) site selection.
Overall, this thesis characterises host gene expression changes during influenza infection, with further exploration of differences in host poly(A) site usage. It identifies APA changes which are likely to be of physiological importance for viral propagation, and it examines the underlying mechanisms directing APA in an infection context.

Keywords: RNA biology
Bioinformatics
Influenza
APA
Viruses
Alternative cleave and polyadenylation
Advisor: Furger, A