VictorJuiz/thesis huggingface dataset:
The molecular genetics of dupuytren disease

Dupuytren disease (DD) is a fibromatosis of the fascia of the hand. It affects around 4% of the population in the UK. Treatment for DD is dominated by surgery, but the recurrence rate after surgery is high. There are also no existing treatments to prevent progression of early disease, and reduce the need for surgery. At the cellular level, the fibrotic environment in DD is similar to that of other tissue specific fibrotic condition of other organs, such as lung and liver where myofibroblasts and some immune cells are found residing in a rich extracellular matrix. Although myofibroblast cells are thought to be the driving force in the development of DD, no effective biomarkers have been identified to date. Many different cell types have been suggested to be the origin of the myofibroblast cell population, but often without any solid evidence. As a result, the aetiology of DD remains poorly understood. The advent of high through put sequencing and genotyping techniques provided me with a new approach to the investigation of the pathophysiology of DD.
DD is a complex genetic disease, with a heritability of 80% - very similar to type I diabetes. Currently, the most effective method to interrogate a complex genetic disease is a GWAS. In the second chapter of my thesis, I report a total of 17 novel associated variants discovered with this approach. I prioritised variants for functional mechanistic studies through fine mapping and in silico analysis using epigenomic and transcriptomic public databases. Follow-up functional analysis on SFRP4 and DDR2, in chapters II and III respectively, assess transcriptomic expression and various fibrotic phenotypes such as cell migration in diseased myofibroblasts resected from patients with DD. These analyses have revealed the pro-fibrotic nature of these proteins, and suggest potential new therapeutic targets. In studying DDR2, I have also demonstrated that different collagen types can alter the myofibroblast cell function from pro-fibrotic to pro-inflammatory.

Advisor: Furniss, D
Dunford, J
Determining material properties using impact wave propagation method

Mechanically testing soft materials to identify dynamic material properties remains challenging in both theory and practice. Commonly used methods, the SHPB technique for example, have very limited capacity. One of the shortcomings is the impedance mismatch between bar and specimen: conventionally metal rods are employed, which generates a weak transmitted signal; also, the stress equilibrium assumption, on which traditional time domain analysis was built, is likely to be violated due to low wave speed in soft samples. Using low-impedance polymer bars is one of the promising solutions: it removes the obstacle of the weak signal. However, the problem of stress equilibrium is not yet resolved, and complexity increased: as viscosity is introduced, material behaviours become both time and frequency dependent. Therefore, applying polymeric bars in impact settings calls for rebuilding the analytical framework and testing it in simulation and experimental environments.
This work aims to answer the question: how material properties can be retrieved from an impact test? To realise this, three independent and integrated impact techniques were developed: the single rod direct impact method, the interface impact method, and the 3-rod impact method (modified SHPB). In each case, the frequency-dependent mechanical properties are derived from measurements of stress waves as they propagate in the system. The techniques were designed in a consecutive manner, but each can be used on its own. The first two techniques were fully deployed here, with complete theoretical, simulation and experimental investigations; the last technique was theoretically described, with some experimental phenomenon presented. Frequency domain analysis (FFT) was mainly adopted, important issues such as wave propagation, mechanical models, signal processing, dispersion, noise sensitivity, error analysis etc., were demonstrated throughout the journey. It is for the first time a comprehensive investigation of the single rod technique was performed combining previous and extended work; while the interface technique was brand new. The integrated framework demonstrates the robustness, accuracy, and effectiveness of utilizing wave propagation approach to identify dynamic material properties; and with proper calibration, these established works can be applied to a broad range of polymeric system-based equilibrium-free impact tests.

Keywords: impact
frequency domain analysis
wave propagation
material properties
Advisor: Siviour, C
Forming future citizens: emotion and the republic's colonias for evacuee children during the Spanish civil war (1936–1939)

This thesis is a study of the discourse, practices and experience of the Republic's colonias—collective homes or family placements—created to protect and educate evacuee children during the Spanish Civil War (1936–1939). It contributes to our knowledge of state and rearguard civil institutions—unions, proletarian movements, revolutionary committees, and humanitarian organizations—which set up colonias and of the experience of parents, children, and teachers as they interacted with these authorities. Intersecting Spanish Civil War history with that of emotions and childhood, the thesis is shaped by a lexical framework of emotion words: fear, hope, (un)happiness, and disillusion. These provide an interpretive framework designed to retain the complexities and possibilities of the past and bring nuance to the ideologically cemented narrative of the war.
The thesis concludes, firstly, that the wartime colonias were a continuation of two very different prehistories: liberal Republican reform and proletarian labour conflict. As a result, whilst all authorities concurred with persuading parents to evacuate children, the utopian visions and practices of anarchist, communist, socialist, and liberal Republican authorities were incompatible. Authorities sought to form future citizens according to their particular ideology. Furthermore, the government's policy for control of all colonias was never entirely successful. Secondly, emotive propaganda and emotional practices developed around the colonia were an important part of dualist civil war rhetoric. They had a significant role in the cultural project of rebuilding Republican Spain and were useful to the state in securing international support. However, whilst evacuation to colonias removed children from the besieged capital to places of relative safety, in many cases the model colonias of propaganda were mere illusion and protection of children failed either through systemic failure; inadequate and disillusioned staff who did not align themselves with Republican ideology; or through the privations of war.

Keywords: Child evacuees
Colonias
Child displacement
War
Children and war
Children's colonies
Children
Emotion
Spanish Civil War (1936-1939)
Advisor: Lannon, F
Investigating reading comprehension in English as additional language learners: children's processing of metaphors and internal inconsistencies when reading text

English as an additional language (EAL) learners form a large group of students in UK schools and are known to differ from monolinguals, particularly in vocabulary and reading comprehension, but little is known about the way they process texts when reading. The three experiments presented in this thesis had three overarching objectives: first, to establish how children process different metaphors; second, to investigate how children monitor their comprehension; and third, to compare these reading processes between EAL learners and monolinguals. In Experiments 1 and 2, metaphor processing was compared across metaphor types (nominal and verbal) and between children with varying word knowledge. In Experiment 3, comprehension monitoring was associated with word knowledge and strategic awareness. Across all three experiments, language group differences were identified. Nominal metaphors were more challenging to understand for children than literal controls, a difficulty that stemmed from increased demands on post-lexical processing, as manifest in increased rereading. Children were able to monitor their comprehension on internal inconsistencies, which was demonstrated through selective rereading. Language group differences were evident relative to word knowledge. EAL learners were behind monolinguals in their metaphor processing relative to performance on standardised tests. Given sufficient word knowledge, EAL learners and monolinguals were, however, on a par in comprehension monitoring. For future research, the findings indicate that online tasks of reading processing hold valuable information about EAL learners’ reading comprehension. For teaching, results indicate the importance of supporting word knowledge to close language group differences and to support skilful reading processing.

Advisor: Nation, K
Murphy, V
Risk and resilience in cognitive ageing

Whilst advancing age is, on average, associated with declining cognitive abilities, the course of cognitive ageing is highly variable at the individual level. The overall aim of this thesis was to improve understanding of risk and protective factors associated with variability in cognitive ageing. I first explored the effect of Alzheimer’s risk gene ‘APOE’ on cognition in healthy adults, and by reviewing the extensive literature, I showed that APOE genotype can have diverse cognitive consequences via multiple neurobiological mechanisms, each with applications to distinct aspects of cognitive ageing and Alzheimer’s disease (AD). I also investigated subjective memory impairment (SMI), which like APOE is associated with increased AD risk, but is also commonly reported by healthy older adults. By presenting a clinical case of persistent SMI, and reviewing evidence for the long-term relevance of brain characteristics in SMI, I reported that MRI can detect early differences in brain structure that herald subsequent cognitive impairment, valuable in clinical settings to identify the most at-risk SMI cases.
I also investigated protective factors that preserve cognitive ability in some older adults, particularly whether the brain supports this superior cognitive ageing in multiple ways, via some older adults maintaining more ‘youthful’ brains, and others harnessing additional functional resources to ‘adapt’ to the challenge of brain ageing. Using structural and functional brain metrics alone, I identified multiple patterns of brain ageing predicted to be associated with superior cognitive ageing, and compared cross-sectional and longitudinal cognitive performance, as well as multi-modal MRI metrics acquired at multiple time points between groups. Across these analyses, I found convergent evidence that maintenance of more ‘youthful’ brain structure and function is associated with prior and continued superior cognitive and brain outcomes, particularly in grey and white matter structure, so promotion of this brain profile should be a goal of interventions. High frontal resting- state connectivity in older adults with poorer brain structure was not associated with the predicted cognitive performance benefit, when compared to those with lower structural and functional brain characteristics. Overall, this thesis provides novel insights into risk and protective factors related to variability in cognitive ageing, upon which further use of sensitive cognitive and imaging measures, and unique populations such as the oldest-old, can expand to inform markers and interventions to maximise cognitive abilities in later life.

Keywords: brain ageing
healthy ageing
dementia
neuroimaging
cognitive ageing
magnetic resonance imaging
Advisor: Mackay, C
Zamboni, G
The role of the small GTPase, arf-3, in seam cell development and secretion in C. elegans

The Caenorhabditis elegans seam cell lineage provides a useful model to study stem cell biology and the regulation of cellular division and differentiation. Seam cells are a population of stem-like cells that run along the length of the worm which divide both symmetrically, to expand the pool of progenitor cells, and asymmetrically to generate various differentiated cells including hypodermal and neuronal cells.
The seam cells also have a secretory function; giving rise to the cuticle and the alae. Seam cells do not retain their proliferative property through adult life, terminally differentiating at the end of development by undergoing homotypic fusion to produce the adult seam cells whose function is to secrete cuticle components. Thus the seam cells make an excellent model for studying the molecular basis of cell fate determination as well as more cell biological aspects of development, including the re-shaping of cells during differentiation, the polarity of cell fate allocation and cellular trafficking processes accompanying secretion.
In this thesis, I investigated the role of the small GTPase, arf-3, an ADPribosylation factor (ARF), in C. elegans seam cell development. I found that arf-3 knockout or overexpression causes severe developmental defects including embryonic lethality and seam cell defects. Furthermore, knockdown of arf-3 in a RNAi hypersensitive mutant causes defects in moulting and seam cell divisions. In a screen for genes interacting with arf-3 I identified agef-1 and dyn-1. I also show that their interaction with arf-3 is linked to moulting.
arf-3 expression in the seam is driven by a 3' intronic enhancer element that also drives the expression of the "Seam Cell Marker", scm::gfp, a transcriptional reporter which is used as a marker of seam cell fate. I identified two transcription factors, elt-1 and nhr-23 that bind the 3' enhancer to regulate arf-3 expression in the seam cells. ARF-3::mCherry localises with the golgi, early and late endosomes in the seam cells in concert with the moulting cycle. This, and the moulting defects observed in arf-3 knockdown suggests a role in regulating cuticle synthesis and moulting.
In summary, arf-3 function is crucial to ensure proper development of the C. elegans seam cells and the regulation of moulting.

Advisor: Woollard, A
Investigating novel progenitor cell populations in the fish heart

After cardiac injury, most mammals, including humans, cannot regenerate lost heart muscle with new, functioning cardiomyocytes. The cave-dwelling variant of A mexicanus, a species of teleost fish, is similar to humans and also cannot regenerate. Remarkably, the surface-dwelling variant of the same species can regrow damaged heart muscle, like its fellow teleost fish the zebrafish. Comparison of the surface and cave-dwelling A mexicanus fish is, therefore, a powerful method to identify new mechanisms behind the ability to regenerate, which could lead to therapeutic interventions for humans who have suffered a cardiac injury. Using this model system, comparison of cave and surface variants showed that there are variations in the levels of epicardial fat before and after cardiac injury between the fish, suggesting differential activity of a mesenchymal fat progenitor. Fat has been found to have a positive effect on injury outcome, but fatty fibrotic scar tissue is a symptom of a nonregenerative environment. Such a progenitor has not been found in the fish before, therefore efforts were made to identify it. Investigations using a mesenchymal stem cell marker, Pdgfrα, identified previously unknown populations positive for this marker in the fish heart, including one in the epicardium and another in the endocardium. Lineage tracing experiments showed that the epicardium, likely Pdgfrα-positive epicardial cells, is the source of the epicardial fat that arises during development and after injury, a process that has been previously reported in the mouse. Investigation of the identity of the endocardial population showed that some of these endocardial cells begin to express Runx1, a hematopoietic progenitor marker, after injury. The expression of hematopoietic markers in endothelial cells has been previously shown during development, where endocardial cells undergo an endothelial-to-hematopoietic transition (EHT) and detach, forming hematopoietic stem cells that give rise to the blood lineages. Transcriptomic analyses showed that the injured endocardium has upregulated expression of many key hematopoietic development genes. Live imaging experiments in cultured heart slices, a novel experimental method, show endocardial cells detaching from the myocardium after injury in a way that recapitulates the developmental EHT. These results strongly suggest that the injured fish endocardium produces hematopoietic stem cells after injury. In summary, through analysis of fish hearts, two novel injury-responsive progenitors have been identified: an epicardial fat progenitor and hematopoietic progenitors derived from the injured endocardium. These progenitors offer an exciting new avenue for investigations into the mechanisms behind the ability to repair damaged hearts.

Advisor: Mommersteeg, M
Riley, P
Messaging migration: media agenda-setting, immigration attitudes, and the effects of evidence on perceptions and policy preferences

How do messages impact what people think? Although this broad question speaks to current debates about the role of information in politics, variations of it have appeared throughout political science. My approach draws upon political communication, psychology, and linguistics to demonstrate how information relates to attitudes, perceptions, and policy preferences.
Across four separate studies that use the issue of immigration in the British case, I address several sub-questions. First, how has the British press—itself a key messenger of political information—portrayed immigration and immigrants over several decades? Applying corpus linguistic methods, I find press coverage about immigration has both increased and been characterised by several sub-agendas. Second, how have these messages at the word-level related to changes in public concern about immigration? Using time series models, I show how specific dimensions of immigration—its sociocultural, geographic, and numerical aspects—and not overall levels of coverage are related to aggregate public concern. These two studies collectively demonstrate how the agenda-setting power of print media is likely more subtle and delimited than commonly expected.
In the third study, I focus on the individual-level impacts of messages. Which qualities of immigrants matter more for public attitudes? Findings from a nationally-representative conjoint survey experiment demonstrate how the British public places greater importance on skill level and language fluency when evaluating individual immigrants. Finally, I broaden my view of messages to include different types of supporting evidence. Do arguments citing numerical or narrative evidence impact public perceptions and policy preferences? A second nationally-representative survey experiment shows how positive messages about immigrants featuring numerical or narrative supporting evidence can positively change perceptions, especially among people who would be expected to hold more negative views. But, the presence of extra information neither raises perceptions more than similarly positive messages lacking evidence, nor influences policy preferences.

Keywords: media
text analysis
Great Britain
immigration
public attitudes
political communication
survey experiment
Advisor: Tilley, J
Learning to study the developing brain: characterising brain development with machine learning, image analysis and ex vivo culture

Brain development, and indeed development in general, is complex. Correct development requires tight regulation of cell numbers, movements and fates. However, decisions are taken by individual cells, integrating spatial and temporal cues. Understanding development, therefore, necessitates studying cells in the native tissue context. In this thesis, I focus on neurogenesis, studying neural stem cell division in cultured whole Drosophila brains. To facilitate this, I develop an approach based on live imaging, image analysis and the use of a novel software tool that is applicable to studying development in a range of systems. I start with optimised imaging, culture and image processing to study cell divisions in Drosophila brains. Building on previous work by L. Yang, I develop a pipeline allowing high resolution, medium-throughput imaging of multiple brains. Using patch-based denoising, and gradient-descent-based image registration, I follow divisions of stem cells and their daughters in an intact brain, in a way that was previously unachievable. This allowed me to record cell behaviours, such as cell cycle length, which I show are consistent with published results. However, analysing the resulting datasets was highly time-consuming, and impractical on larger scales. Existing automated analysis tools proved to be inadequate, likely due to signal-to-noise ratio and complex structures in these images. To overcome this, I developed CytoCensus, image analysis software for complex 4D data, in collaboration with D. Waithe. Unlike other software, which aims to identify whole cells and their boundaries, CytoCensus identifies only cell centres, allowing it to cope with neighbouring cells and low signal-to-noise. I show that CytoCensus identifies different cell types in the brain, performing better than competing approaches. Combining the aforementioned live imaging and culture methods with CytoCensus analysis, provided insights into normal and aberrant development. I characterise changes in the development mutant syp, in which both neuroblasts and daughter cells exhibit an increased division rate, accounting for the observed increase in brain size. I further demonstrate that this approach is generally applicable to studying developmental processes in other contexts by quantifying transcription factors in mouse embryos, counting organelles in spermatogenesis, and comparing cell distributions in zebrafish retinal organoids. Taken together, it is clear that this approach, and these tools can be used to study the development of different organisms, by studying the behaviour of cells in a relevant context.

Advisor: Davis, I
Parton, RM