VictorJuiz/thesis huggingface dataset:
Transcriptional control of phenotype in melanoma

Melanoma is the most aggressive and deadly type of skin cancer, mainly as a consequence of its high metastatic capacity and refractoriness to treatment. Over recent years increasing evidence suggests that the intra-tumour microenvironment can drive cells to adopt invasive and drug-resistant phenotypes that play a key role in disease progression. Understanding how phenotypic heterogeneity is generated, and the molecular mechanisms underpinning the acquisition of invasive or drug-resistant states is key to the development of more effective therapies. Current evidence suggests an important role for the micropththalmia-associated transcription factor MITF in the development of phenotypic heterogeneity in melanoma. Yet how MITF is regulated and how it controls melanoma biology remains poorly characterised.
Here we show that activating transcription factor 4 (ATF4), whose expression is induced via a translational switch that occurs under microenvironment stresses frequently found in tumours such as nutrient deprivation or hypoxia, has the potential to directly supress MITF expression and also directly target a repertoire of well-characterised and novel MITF target genes. In addition, ATF4 also directly binds and has the potential to activate expression of novel target genes linked to invasiveness/metastasis or with a cytoprotective role. Our results therefore suggest that in response to a stressful intra-tumour microenvironment the induction of ATF4 provides a potentially reversible mechanism for the generation of phenotype heterogeneity in melanoma leading to the acquisition of metastatic and/or drugresistant capacities in specific subpopulations of cells.

Advisor: Goding, C
Discovering genetic modifiers in Niemann-Pick Disease Type C

Niemann-Pick Disease, Type C (NPC) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and sphingolipids. These subcellular pathologies eventually cause phenotypes of hepatosplenomegaly and neurological degeneration leading to premature death. NPC is extremely heterogeneous in the timing of clinical presentation (prenatal to adulthood) and is associated with a wide spectrum of causative NPC1 mutations. Miglustat (Zavesca) is the only approved therapy for NPC, and while it has been shown to improve clinical outcomes it is not a cure. To study the genetic architecture of NPC, including the clinical and genetic heterogeneity seen in this patient population, we have generated a new mouse model (Npc1em1Pav). Using this model, we identified strain- specific quantitative trait loci (QTL) affecting lifespan and characterized a novel lung phenotype causing neonatal lethality. Interestingly, Npc1em1Pav mutants on a C57BL/6J (B6J) genetic background had a more severe visceral pathology of foam cell accumulation than Npc1em1Pav mutants on a BALB/cJ background. These underlying pathological changes translated into B6J mutants having a significantly shorter lifespan (70 + 4.30 days) than mutants on a BALB/cJ background (84 + 7.25; p<0.0001), suggesting strain- specific modifiers contribute to disease severity. QTL analysis of backcross N2 mutants detected significant linkage to markers on chromosomes 1 (LOD=5.57) and 7 (LOD=8.91). Analysis of predicted deleterious sequence variants between B6J and BALB/cJ strains at these two loci resulted in a short list of candidate genes that can now be evaluated as potential modifiers of NPC severity and progression. A significant reduction of viable Npc1em1Pav mice was also observed on the B6J background at Postnatal day 10 (P10) (10.5% vs. 25%, p<0.0001). Interestingly, the expected genotype frequency was observed at E18.5-E19.5 (26.5% % vs. 25%, p=0.034) indicating Npc1em1Pav mutants exhibit a previously uncharacterized lethal phenotype postnatally. C-sections accompanied by maternal fostering confirmed that the majority of Npc1em1Pav mutants died shortly after birth showing signs of respiratory insufficiency and abnormal surfactant pathology. A similar phenomenon reported in NPC patients with pre/perinatal onset indicates Npc1em1Pav may be the first valid animal model of this severely affected group.

Keywords: Genetic modifiers
Neonatal Lethality
Niemann-Pick Disease Type C
Mouse models
Advisor: Platt, F
Pavan, W
Scheduled at the margins: antecedents and consequences of nonstandard work schedules

The past 50 years have seen the erosion of working time regulations and transitions to service-based economies throughout most of Europe. This has led to, amongst other things, a growth in the proportion of the labour force employed in nonstandard work schedules. These are defined as work schedules falling outside of the traditional 9:00 am to 5:00 pm, Monday to Friday work week. Given that such work arrangements can overlap with – and, in many cases, monopolize – the hours traditionally reserved for family life, the aim of this thesis is to provide a comprehensive investigation into the ways in which families use and are affected by nonstandard schedules, focusing on the previously understudied but highly relevant context of the UK.
Over the course of four empirical chapters, I explore the composition and occupational characteristics of nonstandard schedule workers, the effects that these schedules take on work-family balance, and the ways in which preferences and endowed traits play a large role in shaping which individuals select into and stay in these arrangements. The thesis is unique in the extensive scope with which nonstandard work schedules are studied: I move all the way from the molecular level to the individual level and then up to the country level to showcase the antecedents, consequences, and institutions relevant to the study of nonstandard work schedules and families in the UK and beyond.
This thesis makes several contributions to the existing body of knowledge on nonstandard work schedules and family life. First, I show the many channels of self-, socioeconomic, and occupational selection underlying employment in nonstandard schedules, and present ways to account for these selection mechanisms when studying outcomes relating to work-family balance. Second, I highlight that the consequences of nonstandard schedules on family life are not necessarily universal, but instead depend partially on the country and institutional context in which they are studied. Third, I integrate molecular genetic data to show how the timing of one’s circadian rhythm influences preferences for nonstandard work hours, suggesting that such arrangements can be advantageous – and even optimal – for certain individuals.

Keywords: Work-family balance
Mahalanobis Distance Matching
Multilevel Modelling
Nonstandard work schedules
Mendelian Randomization
Advisor: Mills, M
The sexually selected ejaculate

The ejaculate is composed of many different parts: proteins, lipids, and much else travels alongside sperm. With so many elements comes the problem of composition. Does the mix matter for male reproductive success? To what extent is the composition fixed? What happens when males lose control over the composition? It is with these questions that this thesis is principally concerned.
I start by testing whether males alter ejaculate composition in relation to the intensity of male-male competition. I find that divergent allocation rules govern the transfer of sperm and seminal fluid proteins (‘SFPs’). While the allocation of both responds to competition, only SFP allocation responds to its intensity. I further show that variation between SFPs in their responsiveness leads to differentially-composed seminal fluid. The resulting ejaculate compositions are each accompanied by distinct costs and benefits for male reproductive performance, some of which appear specific to seminal fluid.
I next demonstrate that loss of BMP-regulated secretions from a seminal fluid-contributing cell-type (‘secondary cells’) imparts a syndrome of dysregulation on male and female reproductive performance. Within this, males lose the ability to reduce female receptivity to remating, but gain an advantage in defensive sperm competition. Through a systematic dissection of different episodes influencing sperm competition outcome, I find that loss of these secretions influences sperm entry into storage and potentially enhances their resistance to displacement.
In the following two chapters I show that loss of BMP-regulated secondary cell secretions and the keystone SFP sex peptide affects seminal fluid transfer to females. In both cases, I find clear signals of between-SFP dependencies in the regulation of SFP transfer, which collectively highlight novel mechanisms of seminal fluid organisation. I argue that these organising mechanisms may be used to a male’s advantage to exercise fine-scale, real-time control over the transfer of ready-made seminal fluid.

Advisor: Wigby, S
Pizzari, T
Sepil, I
Sample paths of some Gaussian processes via Malliavin calculus

In this thesis, we study the sample paths of some Gaussian processes using the methods from Malliavin calculus. To be more specific, we consider several interesting properties of fractional Brownian motion sample paths in the context of both probability measures and capacities. We are in particular interested in the non-differentiability, the modulus of continuity, the law of the iterated logarithm and self-avoiding properties. The capacities we use here are those induced by Brownian motions on the classical Wiener space, that is, we regard fractional Brownian motions with distinct Hurst parameters as a collection of Wiener functionals on the classical Wiener space and use the classical Wiener capacities as uniform measurements. We also formulate a capacity version of the large deviation principles for these functionals and determine the corresponding rate functions.

Advisor: Qian, Z
The development of electrochemical sensors based on the use of different forms of carbon materials

This thesis presents experimental work with the main aim of the development of chemical sensors using electroanalytical methods for applications in the food industry and for medical diagnosis. The first chapter introduces the principles and techniques of electrochemistry. Chapter 2 provides information on the experimental procedures and chemical/reagents used in the studies.
In this thesis, carbon based materials such as pyrolytic graphite; carbon nanotubes and carbon fibre have been used for a number of analytical and fundamental investigations. The first research aim of this thesis is to develop sensors for the detection of chemical compounds in ginger and turmeric. Chapter 3 and 4 demonstrate the capability of multiwalled carbon nanotubes modified electrodes for adsorptive stripping voltammetric determination of gingerol and curcumin along with the possibility for commercialisation. An extension of the first project to compare different types of carbon electrode materials including multiwalled carbon nanotubes, carbon black, graphene nanoplatelets, screen-printed carbon electrode and carbon paste electrode for the AdsSV technique is presented in Chapter 5. General principles to offer guidance in the optimal choice of carbon electrodes for AdsSV are established.
Chapter 6 investigates the reaction mechanism of atmospheric oxygen with an edge plane pyrolytic graphite electrode to generate surface quinone functionality. The results presented in Chapter 6 are evidenced as photochemical in nature and to likely involve singlet oxygen.
As a possible biomarker of salivary pH for diseases such as gingivitis and dental caries, the next aim of this thesis is to develop sensors for pH measurement in saliva. Chapter 7 reports the development of a micro-sized pH probe exploiting the pH dependence of surface quinones on micro carbon fibres for pH measurement of saliva. Applications in human saliva without any pre-treatment are highlighted.
In Chapter 8, amperometric pH sensing in samples of sheep’s blood is investigated. At the beginning, surface quinones on graphite electrode are used in the study. However, in terms of signal size and the lack of robustness of the developed electrodes, micro-disc carbon fibre electrodes appeared to be less than optimal to use for study in biological samples with complex matrices such as blood. The investigation and exploitation of metal/metal oxide specifically iridium oxide electrodes for amperometric pH sensing in sheep’s blood are carried out, shown to be superior, and are described in Chapter 8.
Finally, Chapter 9 presents overall conclusions.

Advisor: Compton, R
Care and control: an ethical analysis of parenting support within a UK prison mother and baby unit

This research is an empirical ethics study of parenting support delivered within a UK prison mother and baby unit (MBU).
In recent years, the idea of state provided ‘parenting support’ has gained prominence within the early intervention (EI) policy agenda. A central claim of EI policy is that poor parenting during the early years of life can lead to a range of bad outcomes for children, such as ill health, academic failure, poverty, and crime. These outcomes create substantial costs for both individuals and society. Therefore, EI often involves identifying babies and children who are at risk of being ‘poorly parented,’ and intervening upon these parents in order to help them provide better care to their children.
In the context of EI, parenting support gives rise to a number of complex ethical questions, both in policy and in practice. These concern what it means to be a good mother, the nature of a good childhood, the rights and responsibilities of parents, and the appropriate role of the state to intervene in family life. Prison MBUs provide an informative and challenging case study through which to consider how these ethical questions arise in practice for those involved in the delivery and receipt of parenting support.
In the UK, female prisoners who are pregnant or who have a small child are able to apply to serve their sentence within a prison MBU. The baby can remain within the unit up until the age of 18 months, and whilst the mother serves her sentence she is provided with various kinds of parenting support. Some of these forms of parenting support look very similar to that which is provided to women enrolled in EI programs in the community. However, prison policy is unclear as to the goals of parenting support in this environment and it is possible to anticipate a number of ethical challenges that may arise in practice: how can prison provide a good start in life for children? What is the relationship – if any – between crime and being a good mother? To what extent can and should women exercise parental autonomy in a prison environment?
Over a period of 7 months I conducted interviews, focus groups, and participant observation within the MBU of a women’s prison in the North of England. In this thesis I provide a rich ethical analysis of the practice of parenting support as it take place within the ‘moral world’ of the MBU. I elucidate the relevant ethical questions arising in this context, map out the values and normative commitments in play, identify where lack of clarity impedes the pursuit of goals, and analyse these concerns within a framework informed by relevant ethical theories. I situate these findings in the context of the EI policy literature in order to consider what this case study reveals about the ethical dimensions of parenting support both in prison and in EI policy more broadly. With this in mind, I offer some recommendations that may shape the provision of parenting support both inside and outside of prison.

Keywords: bioethics
public health
prison
ethics
parenting
Advisor: Singh, I
Parker, M
Detecting mitophagy in mitochondrial disease: towards a new type of therapy

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signalling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. The aim of this thesis is to investigate mitophagy in several mitochondrial disease. Additionally, to test potential drug modulators of mitophagy with the view that they may provide an alternative therapy for certain kinds of mitochondrial diseases in the future.
Twenty-nine patient derived fibroblast lines were investigated. Most patient cells had dysregulated mitophagy, where mitochondrial turnover was often higher when compared to control cell lines. Amongst the potential drug modulators, Metformin, AICAR, Chlorodiazepoxide, and Duloxetine were sufficient at inducing mitophagy without a cytotoxic effect.
Altered mitophagy seems to be a hallmark of many mitochondrial diseases and the trigger might be crucial to the phenotype, therefore it offers a potential therapeutic target. Identifying potential drug modulators of mitophagy is the first step towards a novel therapy for not only mitochondrial disease but many neurodegenerative disorders as well. Monitoring mitophagy could also be useful for assessing the efficacy of certain treatments or even supplements on an individual level, as the effect of drugs that benefit patients can manifest in alleviation of the increased mitochondrial turnover.

Advisor: Poulton, J
Churchill, G
The role of cognitive biases and executive functions in adolescent worry

Worry is common in childhood and adolescence. In moderation, worry can serve as an adaptive response in anticipation to perceived threat. However, some young people experience excessive, uncontrollable, and persistent worries that cause significant distress and impairments to daily functioning. Research presented in this thesis investigated the role of cognitive biases and executive functions in adolescent worry. In Chapter Two, a systematic review examined the existing literature on child and adolescent worry and found that cognitive biases and executive functions were associated with worry in youth. The systematic review identified some of the gaps in the child and adolescent literature on worry, which provided a research framework for subsequent studies in this thesis. Chapters Three and Four presented data from the CogBias Longitudinal study and showed that interpretation and memory biases were closely interrelated cognitive processes associated with adolescent worry. Furthermore, Chapter Four found that negative biases played a causal role in the manifestation of worry from early to mid-adolescence. Chapters Five and Six, investigated the role of executive functions in adolescent worry. Findings in Chapter Five, indicated that attentional control and working memory were not associated with worry in adolescence. Moreover, these executive functions did not moderate the association between cognitive biases and worry. In Chapter Six, an experimental study was designed to assess the effect of active worry on working memory capacity using a worry induction paradigm in a community sample of adolescents. In line with the findings of Chapter Five, active worry did not impair working memory capacity in adolescents. The research presented in this thesis indicates that cognitive biases are mechanisms underlying worry in adolescence, however evidence that executive functions play a role in adolescent worry was not supported. Future research using longitudinal and experimental designs would provide further insight into the causal mechanisms underlying worry in adolescence and how these cognitive processes interact and develop over time.

Keywords: adolescents
longitudinal
cognitive biases
worry
executive functions
Advisor: Fox, E
Ehlers, A
New Techniques in wide-field interferometric imaging

With each new telescope that comes online, modern astronomy is ever moving towards a point where processing the resultant data deluge is arguably as much of a challenge as interpreting the science for which the instruments are designed. To this aim I have investigated the application of new processing techniques to two common problems in computationally intensive astronomical data reduction.
I present a comparative study of the CLEAN deconvolution algorithm applied to the spectral analysis of jet speed data from the microquasar SS 433 recorded over the last 26 years to investigate a claim made in the recent literature that there was a phase shift in one of the key periodicities observed. This investigation demonstrates how the CLEAN algorithm can be used to great effect for the spectral analysis of unevenly sampled time-series data, revealing characteristics that would otherwise be unattainable. While using this technique it was possible to rule out any strong evidence for a steady systematic phase variation in the jet speed periodicity, due to the well known relationship between frequency instability and phase variation. It was not possible with the current data set to definitively exclude the possibility that a variable frequency dependence of the jet speed on orbital period is at play in this microquasar.
Modern interferometric telescopes mandate innovative use of computers for data processing because (i) huge data rates and sensitive detectors require complex algorithms to optimally extract the valuable science results and (ii) the rising costs of electricity and the environmental impact of excessive power consumption means that simply allocating more and more computing resources to solve the problem is impractical. To this context I describe my implementation of the w-projection algorithm for imaging wide-field interferometric data on graphics processing units (GPU). In this study I identify the advantages and pitfalls of using GPUs for the processing of astronomical data and demonstrate that GPUs present a fast, cost effective and energy efficient solution to imaging for the next generation of radio interferometers where the value of FLOPS per watt is increasingly an important factor in developing new processing solutions. While investigating the application of imaging on the GPU, I have developed a modular, flexible testbed application for developing, studying and testing the deployment of GPU algorithms for interferometric imaging can I present this code.

Advisor: Blundell, K