VictorJuiz/thesis huggingface dataset:
The anxious body of modernism: Kafka, Hamsun, and Woolf

This thesis argues that psychological anxiety is a central narrative mechanism for modernist writing, and that this anxiety is expressed through the prominence of the body in texts. Through readings of Knut Hamsun’s Sult, Franz Kafka’s Der Verschollene, and Virginia Woolf’s Mrs Dalloway and its manuscript draft The Hours, I argue that anxiety as articulated in key modernist texts is more pervasive and differently distributed than previously thought.
This thesis counteracts the predominant phenomenological approaches to the body in literary studies, which see the body as constitutive of identity, and emphasize bodily agency in writing and thought. Instead, I make the case for a psychologically informed, critical reading of the body through the concept of body image, the study of which began in the modernist period.

Advisor: Robertson, R
Marcus, L
Modelling the impact of parenting on health, personality and socio-attitudinal outcomes

Previous literature in the field of social demography and psychology has extensively focused on the effect of parenting and other major life course events on a variety of attitudinal and health outcomes. In this thesis we build on the existing research by examining the role played by entering parenthood on gender role attitudes, psychological well-being and personality traits. In our final chapter, we also investigate entry into marriage, separation and divorce and unemployment as drivers of personality change. Finally, we attempt to answer some research questions previously neglected, in particular whether child’s sex affects our outcomes of choice around the transition to parenthood. By excluding births of higher orders from our analysis we avoid causality issues related to endogeneity in the children’s sex composition. Our empirical analysis, carried out on two samples of British and German men and women (as included in the British Household Panel Survey, Understanding Society and the German Socio-Economic Panel), finds support for four major conclusions. Firstly, we find that the life course events under analysis exercise an effect on the three outcomes, with such effect being significantly different between mothers and fathers in the case of gender role attitudes and psychological well-being. Secondly, we find evidence for an effect related to parenting a daughter relative to a son on gender role attitudes. Thirdly, our findings suggest that personality responds to life events through mechanisms of secondary socialisation, although these changes are not systematic and depend on the experience under analysis. Lastly, we find support for the existence of moderating factors, such as education, in the impact of life course events.

Advisor: Billari, F
A molecular toolkit for high-throughput identification of competitive and effective rhizobial strains

Legumes tend to become nodulated by highly competitive but not necessarily effective rhizobial strains, resulting in less optimal plant growth. Research focused on the identification of both competitive and highly effective nitrogen-fixing strains has been limited because, so far, the only way to test competitive rhizobial strains has been to isolate individual strains and compare them one at a time in large-scale plant growth assays.
We have developed a library of novel reporter plasmids (Plasmid IDs) compatible with Golden Gate cloning which consist of i) a promoter-probe vector (pOGG026) suitable for studies where antibiotic selection is not possible, ii) the maker gene sfGFP under the control of a synthetic consensus promoter (psNifH) to drive nodule-specific expression in biovars and strains of Rhizobium leguminosarum and which can be used as a proxy for nitrogenase activity assays, and iii) a 12-nucleotide specific sequence to mark R. leguminosarum strains.
Additionally, we developed reporter plasmids that express biomarkers, such as gusA, celB and mCherry suitable for rhizobial screening in the rhizosphere. The plasmid pOGG026 allowed us to develop a new plasmid-based system to mark Rhizobium strains with GusA/CelB and evaluate their competitiveness.
Results demonstrated the proof of concept of Plasmid IDs as a tool for high-throughput identification of competitive and effective rhizobial strains.
The application of this tool in a competition assay among eighty-four Tagged-strains, in non-sterilised agricultural soil containing indigenous rhizobia, allowed us to identify an effective and super competitive strain, in addition to mixed nodules occupied by up to four Tagged-strains. This tool has the potential to revolutionise the search for elite indigenous rhizobia, by reducing the costs involved in identifying competitive and effective rhizobial strains.

Keywords: Molecular biology
Sustainable agriculture
Microbiology
Environmental agriculture
Plant sciences
Advisor: Poole, P
Cancer cell killing using engineered intracellular antibody fragments

Cancer is one of the leading causes of morbidity and death worldwide, with many either refractory to current therapy regimens or subsequently developing resistance. Novel targeted therapies are therefore needed. Acute T cell leukaemia (T-ALL) is an example of a malignancy without targeted therapies. It has a poor prognosis in adult patients and relapsed disease patients have only a 10% survival rate. T-ALL oncogenes include mutant RAS and aberrantly expressed LMO2, occurring in approximately 10-20% and 50% of cases respectively. There are currently no treatments specific for these oncogenes.
Intracellular expression of single domain VH antibodies raised against these targets has been shown to inhibit tumour growth in leukaemic models. These antibody fragments can target and disrupt the effect of oncogenic proteins and their downstream complexes. The aim of this thesis was to potentiate the effect of these antibodies by linking them to a cytotoxic domain to destroy tumour cells upon antibody-antigen interaction. This thesis describes a novel adaptation to a method of targeted cancer cell killing known as Antibody-antigen Interaction Dependent Apoptosis (AIDA). The results of this study show the ability of two single domain antibodies (VH and VL) linked to the inactive apoptotic enzyme proCaspase 3 to elicit RAS antigen-specific, antibody-mediated cancer cell death. This effect requires both antibody fragments to bind at close epitopes for proximity auto-activation of the caspase 3 enzyme. This thesis also describes the development of a mammalian screening strategy for isolation of VL antibody fragments complementary to antigenbinding VH, and a method of in vitro culture and testing of AIDA in T cell lines and primary tumours. Subject to further progress in therapeutic delivery methods, this approach is anticipated to be widely applicable to cancers caused by many different oncogenic proteins, following the development of synergistic antigen-specific antibody fragments.

Advisor: Rabbitts, T
Modelling and simulation of phenotypic variability in cardiac tissue and application to stem cell-derived cardiomyocytes

Prediction of the safety of a novel pharmaceutical compound at the earliest possible stage of development is of great importance for drug discovery. Cardiac side-effects are a particular cause for concern, with several drugs such as Terfenadine and Cisapride having being withdrawn from the market due to adverse events. Investigation of the properties of novel compounds can be facilitated by the use of in silico models, which can provide a high-throughput and low-cost method of translating the known effects of a novel compound on multiple ion channels to effects on tissue-level electrophysiology.
In this thesis, we examine the case of monolayers of human stem cell-derived cardiomyocytes (hSC-CMs). In recent years, experimental systems utilising such monolayers have become more widely used, especially following their inclusion in the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. In contrast to cells found in the adult heart, hSC-CMs beat spontaneously and are not necessarily spatially segregated by their subtype, or phenotype. These properties mean that the overall electrophysiological activity of a monolayer is sensitive to the spatial arrangement of the different types of cells. The simulation framework must therefore permit different spatial distributions of phenotypes.
The first part of this thesis is dedicated to the development of a simulation framework for modelling monolayers of hSC-CMs that incorporate phenotypic variability. While tissue containing regions of distinct cell types can be modelled using the bidomain equations, this approach is not computationally efficient when the cells are well-mixed. We test a novel approach, the homogenised phenotypes model, where the homogenisation process that underpins the bidomain equations is carried out over a small unit that contains two cell types.
In the second part of this thesis, we utilise the homogenised phenotypes model in simulations of the micro-electrode array, a device which is used to record extracellular field potentials from a monolayer of hSC-CMs, and compare our simulation predictions with experimental recordings. We investigate how variability in cellular phenotype and the distribution of these phenotypes throughout the monolayer affects the field potential, how this variability is manifest in simulations of drug block, and discuss the implications of our findings for the safety assessment process.

Keywords: Safety pharmacology
Computational biology
Bidomain equations
Cardiac electrophysiology
Advisor: Mirams, G
Gavaghan, D
Hypoxia and HIF signalling in the epicardium during development and regeneration

Heart failure is a major cause of death worldwide due to the inability of the mammalian heart to regenerate after injury. The neonatal mouse heart however mounts a substantial regenerative response; though this capacity is lost one week after birth. The epicardium, which is activated in response to injury, becomes quiescent during this time-frame and may, therefore, be involved in the loss of regenerative potential. Another key change that occurs in the heart after birth is the transition to a post-natal circulation, meaning it becomes less hypoxic. Hypoxia inducible factor (HIF) is a transcription factor, which is activated in response to hypoxia and significantly, activated HIF can directly bind to and upregulate expression of Wt1, the master regulator of epicardial activation via epithelial-to-mesenchymal transition (EMT). I, therefore, sought to investigate a functional requirement for hypoxia and HIF-signalling in the activation of the epicardium during murine heart development and neonatal cardiac regeneration.
In the developing heart, co-expression of WT1 with hypoxyprobe at embryonic stages (E)16.5 and E18.5 indicated the epicardium is hypoxic at later stages of embryogenesis. Epicardial-specific loss of Hif1-alpha or Hif2-alpha during development led to decreased epicardial activation and EMT which impacted on coronary vessel development and myocardial compaction. Furthermore, stabilisation of HIF in epicardial explant cultures, via genetic ablation of prolyl hydroxylase domain 2 gene (Phd2), or chemical inhibition of PHD enzymes via FG-4592 (also known as Roxadustat), resulted in enhanced EMT, implicating a role for HIF signalling in epicardial activation. Whilst the epicardium becomes quiescent within the first postnatal week, stabilisation of HIF signalling after birth through loss of Phd2 was sufficient to maintain activation of the epicardium. Moreover, genetic knock-down and pharmacological (treatment with FG-4592) inhibition of PHD2 to stabilise HIF augmented the epicardial response to injury and preliminary results suggested an improvement in the regenerative response.
Further analysis into the full impact on neonatal cardiac regeneration, and transition to the injured adult heart, is required. Nevertheless, FG-4592, which is already in clinical trials for patients with anaemia, presents a potential novel therapeutic approach to improve cardiac repair in human patients following myocardial infarction.

Keywords: Hypoxia
HIF signalling
Myocardial infarction
Epicardium
Heart failure
Cardiovascular disease
Advisor: Riley, P
Vieira, J
Exploring TLR adaptor protein MyD88 as a sensitivity determinant to HDAC inhibitors

Carcinogenesis has shown to be a result of aberrant genetic as well as epigenetic processes. Histone Deacetylase (HDAC) inhibitors, a class of therapeutic agents developed against the latter, have been shown to be efficient against certain haematological malignancies. However, the underlying molecular mechanisms are still largely unknown. An unbiased loss-of-function screen was used to identify genes that govern cellular sensitivity to HDAC inhibitors (HDIs). Myeloid differentiation primary response 88 (MyD88), a Toll-like receptor (TLR) adaptor protein, was identified as a key regulator of the anti-proliferative effects of HDIs, whereas levels of MyD88 were found to govern cells response to HDI treatment through regulating cytokines levels. Furthermore, MyD88 L265P, its most abundant loss-of-function mutation, was associated with increased cell sensitivity to HDIs. It was also found that MyD88 acetylation status contributed to its regulation via an HDAC6-dependant interaction. These results suggested that through scrutinising the underlaying molecular pathways that become altered during tumourigenesis there could be important relative prognostic and diagnostic values for cancer treatment in clinical settings; whereas levels of MyD88, its acetylation status, or the expression of its L265P mutant; could represent a valuable set of indicators to identify subsets of patients who are more likely to respond positively to HDI treatment.

Advisor: La Thangue, N
Investigating the role of inhibition in healthy human motor system plasticity

Across our lifespan we encounter novel physical problems that must be overcome by learning to produce new movements, or to adapt the movements we already know. Learning or adaptation of these skills is the result of plastic changes occurring across a network of motor areas within the brain. The factors influencing these changes across the brain, and how they link to behaviour are not currently well understood. This multimodal thesis primarily focuses on elucidating the link between motor system inhibition, plasticity, and motor learning. It does so by using magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) to measure inhibition, and using a variety of tasks to assess motor learning.
Firstly, the neurochemical changes induced by the ‘plasticity enhancing’ intervention, transcranial direct current stimulation (tDCS), were investigated. We found that tDCS caused changes in inhibition across the motor network, and that these changes were related to individuals’ white matter microstructure. Next the effect of primary motor cortex (M1) tDCS on skill learning with the ipsilateral hand was probed. Here we found that anodal tDCS caused impairment of learning, but this may be offset, in part by decreases in inhibition occurring in the contralateral M1. Finally, we explored the effect of directly modulating inhibitory signalling on healthy human motor learning. We found that using a single, clinically-relevant, dose of baclofen to increase inhibitory signalling caused impairments in performance on an adaptation task. Behaviour changes in this task were related to the degree of inhibition change within the contralateral M1.
Taken together this work strengthens support for the theory that reducing inhibition within M1 is vitally important for allowing the normal plastic processes underpinning motor learning to occur. However, these results also highlight the importance of inhibition changes across the motor network. Investigating these changes, and how they affect network interactions is crucial if we are to understand how healthy motor learning occurs, and leverage this understanding to enhance learning in health and disease

Advisor: Stagg, C
Johansen-Berg, H
Religion, conflict and criminal justice in 13th and 14th century Siena

This doctoral thesis is an in-depth comparison of lay and religious sources produced in Siena (1260-1330) on the topics of criminal justice, conflict and violence. Two main trends have been highlighted in the development of criminal justice in late medieval Italy. Firstly, that the practice of revenge was still popular among members of all social classes. Secondly, that crime was increasingly perceived as a public matter that needed to be dealt with by the government, and not by private citizens. These two aspects are partly contradictory, and the extent to which these models reflect the reality of communal justice is still open to debate. This thesis aims to shed light on this question through the contribution of religious sources. Recent works have highlighted the need to associate the study of political and judicial practices of conflict to that of religious elaborations - something that scholars have started attempting only very recently. The argument underlying this research is that religious people were an effective pressure group with regards to criminal justice, thanks both to the literary works they produced and their direct intervention in political affairs, and their contributions have not received the attention they deserve. The thesis suggests that the dichotomy between theories and practices of ‘private justice’ (e.g. revenge) and of ‘public justice’ (trials) should be substituted by a framework in which three models, or discourses, of criminal justice are recognised as present in late medieval Italian communes: in addition to the trends described above, also a specifically religious approach to criminal justice based on penitential spirituality should be recognised as an influence on the policies of the communes. This case study shows that, although the models were competing, they also influenced each other; and none of them managed, in this period, to eliminate the others, but they coexisted.

Advisor: Wickham, C
Family and familiarity in flies

The concept of gene-centred evolution and subsequent inclusive fitness theory provided a formal framework in which to study the adaptation of social behaviours. It highlighted the role of relatedness between individuals in mediating both cooperation and conflict. However, social behaviours can be difficult to study, particularly among animals in the wild. Drosophila melanogaster has been studied as a model organism for over a century, and we have a deep understanding of its genetics, development and physiology. Furthermore, its short lifespan, small size and fast reproduction rate make it an ideal laboratory animal. Yet we currently know very little about how relatedness affects social behaviours in this species. In this thesis, I aim to contribute to our knowledge of kin selection and recognition in Drosophila melanogaster, developing its use as a model organism for studying inclusive fitness.
In Chapter 2, I examine the role of relatedness on adult sexual behaviours, namely how male-male relatedness mediates sexual harm to females. I distinguish the roles of genetic relatedness and larval social familiarity, and find that familiarity alone is not sufficient and genetic relatedness is required to reduce sexual conflict. However, male intrasexual interactions are important, as in Chapter 3, I find no effect of relatedness when males are presented to the female sequentially rather than simultaneously.
In Chapters 4 and 5, I consider the effect of relatedness on larval social behaviours, which have thus far been understudied compared to their adult counterparts. Contrary to predictions from inclusive fitness theory, in Chapter 4 I find that larvae benefit from developing in unrelated, rather than related, groups. This is possibly due to the increased genetic diversity and therefore behavioural diversity in unrelated groups, reducing direct competition. In Chapter 5, I additionally show that larvae prefer to cannibalise unrelated and unfamiliar conspecific victims, which may have strong fitness consequences for both adult and larval behaviour.
This thesis provides new evidence that relatedness, over and above social familiarity, mediates both adult and larval behaviours in Drosophila melanogaster, allowing us further to develop this species as a model organism for kin selection.

Keywords: Drosophila melanogaster
Kin selection
Sexual conflict
Kin discrimination
Advisor: Wigby, S
West, S
The reception of Homer in modern science fiction literature

This thesis explores the varying ways in which science fiction (SF) authors of the twentieth and twenty-first centuries have adapted, reworked, and pulled apart the Homeric poems. The thesis draws on both reception and SF theory to highlight not only individual points of interest in the texts at hand but also wider theoretical similarities between the two disciplines.
Chapter 1: Polyphony deals with polyphonic narratives in the Bakhtinian sense, demonstrating how SF authors pick up on the multivocal nature of the Odyssey and exploit it to their own ends. Chapter 2: Genre examines the intricacies of the term ‘genre’ in both SF and classical scholarship; it discusses SF texts that fall into various ‘subgenres’—feminist SF; military SF—and parallels them with similar concerns of classical scholarship. Chapter 3: Adaptation outlines patterns in how modern versions of the Homeric poems choose to preserve or alter their stories, and further discusses how a number of texts can in fact be read as dramatisations of certain theories of reception. Chapter 4: Megatext works with the theory of the SF megatext, demonstrating how this works as a reading strategy and paralleling it with wider theoretical discussions of the process of receiving a text. Chapter 5: Sense of Wonder analyses the wonder of the Odyssey and wonders if this is in fact a key reason why SF adaptations of the Odyssey are more prevalent than those of the Iliad. Chapter 6: Cognitive Estrangement discusses the major SF theory of cognitive estrangement, showing how the theory in fact has significant parallels with theories of reception and indeed perhaps with the process of scholarship in general.
The thesis demonstrates that SF receptions of the Homeric poems are a rich source of material for scholars, and argues that the productive interface between the two is one that is ripe for further study.

Advisor: Pitcher, L