VictorJuiz/thesis huggingface dataset:
Towards the development and evaluation of a transmission-blocking vaccine for Plasmodium falciparum malaria

Plasmodium falciparum malaria continues to evade control efforts in part through the complexity of its life cycle. While asexual parasites cause clinical illness in the human host, the highly specialized sexual stages transmit infection by uptake as intra-erythrocytic gametocytes from peripheral blood into a mosquito vector. Evidence from endemic settings suggests that naturally acquired immunity to sexual stage parasites may disrupt this cycle. Indeed in a vaccination model, antibodies to sexual stage antigens, ingested in the mosquito blood meal, can inhibit parasite growth in the insect midgut as judged by functional ex vivo experiments such as the standard membrane feeding assay (SMFA). To date, only a fraction of sexual stage antigens have been screened by this methodology; the list of proteins capable of eliciting the robust inhibitory responses required of a transmission-blocking vaccine (TBV) has changed little over the past 30 years. This thesis aims to strengthen the pre-clinical TBV pipeline by improving the characterization of known and novel candidate antigens. This study first establishes an independent and unbiased performance ranking of historical TBV antigens, and then uses this ranking as a benchmark to evaluate a diverse set of sexual stage proteins by heterologous expression and functional prioritization in SMFA. Finally, both known and novel proteins with exposure to human immunity are evaluated for seroreactivity in malaria-endemic Burkina Faso and Mali to better assess longitudinal antibody responses to potential TBVs. Proteins of little interest to vaccine development are considered as possible markers of gametocyte exposure in a Malian cohort with defined gametocyte positivity.

Advisor: Draper, S
Biswas, S
Long, C
Novel approaches to studying the role of the anterior cingulate cortex in cognition and Parkinson's disease

The motor symptoms of Parkinson's disease (PD) have been linked to the emergence of exaggerated oscillatory activity in the 13 - 35 Hz beta range in recordings of the basal ganglia (BG) thalamocortical circuit of PD patients and animal models. PD patients and animal models also express dopamine-dependent cognitive impairments, implying effects of dopamine loss on the function of the anterior cingulate cortex (ACC). This thesis examines the electrophysiological behavior of the BG thalamocortical circuit in PD and dopamine-normal states during cognitive and motor activity. In vivo recordings in the BG of PD and dystonic patients were used to study the influence of dopamine during a test of executive function. Normal executive function was also investigated in the dopamine-healthy ACC of chronic pain patients. Both the BG and ACC exhibited lateralized electrophysiological responses to feedback valence. The BG also exhibited dopamine-sensitive event-related behavior. In additional experiments, chronically implanted recording electrodes in awake, behaving hemiparkinsonian rats were used to examine the transmission of synchronized oscillatory activity from the BG, through the ventral medial (VM) thalamus, to the ACC. Modulation of subthalamic nucleus, VM thalamus, and ACC activity during a simple cognitive/movement task was also investigated in hemiparkinsonian rats. Findings in the rat model suggest that ACC-mediated executive function is dopamine-sensitive and is reflected in the region’s electrophysiology. These results may provide further insight into the significance of excessive oscillatory activity in PD and its influence on cognitive systems.

Keywords: Basal ganglia
Chronic pain
Parkinson's disease - animal models
Prefrontal cortex
Advisor: Aziz, T
Walters, J
The role of DNA methylation on transcription factor occupancy and transcriptional activity

DNA methylation is an epigenetic mark that is deposited throughout the genome of mammals and plays an important role in the maintenance of transcriptionally repressive states across cell divisions. There are two major mechanisms by which DNA methylation has been proposed to act: one involves the recognition of the mark by protein complexes containing histone deacetylases (HDACs) that can remodel the local chromatin. Alternatively, methylation has been suggested to directly affect the interaction between transcription factors and their cognate binding sequence. The aim of this research was to determine the contributions of these two mechanisms in cells.
The importance of HDAC activity in mediating DNA methylation-dependent transcriptional repression was assessed by comparing the genes and retrotransposons that are upregulated in response to DNA methylation loss or the disruption of HDAC activity. To this purpose, we performed whole-genome transcriptional analysis in wild type and DNA methylation-deficient mouse embryonic stem cells (DNMT.TKO mESCs) in the presence and absence of the HDAC inhibitor trichostatin A. Our data suggests that there are few genes whose repression is solely dependent on the recruitment of HDACs by DNA methylation in mESCs. Rather it appears that DNA methylation and HDAC-mediated silencing represent two independent layers of repression that converge at certain transcriptional elements.
To investigate the contribution of DNA methylation on the genome-wide occupancy of transcription factors, we compared the global chromatin accessibility landscape and the binding profile of candidate transcription factors in the absence or presence of DNA methylation. We found that loss of DNA methylation associates with localised gains in accessibility, some of which can be linked to the novel binding of transcription factors such as GABPA, MAX, NRF1 and YY1.
Altogether, our results present new insights into the interplay between DNA methylation and histone deacetylation and their impact on the localisation of transcription factors from different families.

Keywords: Transcription factors
Gene regulation
Chromatin accessibility
DNA methylation
Advisor: Kriaucionis, S
Synthesis of sulfur-containing organic compounds: sulfones, sulfonamides and benzoisothiazoles

This thesis documents the development of novel methodologies for access to sulfur-containing compounds, including sulfones, sulfonamides and benzoisothiazoles.
Chapter 1 provides an overview of the applications and the synthesis of sulfonyl-containing compounds. A comprehensive introduction to the development of sulfur dioxide surrogates and their applications in transition metal-catalysed organic chemistry is given.
Chapter 2 describes the development of a one-step copper(I)-catalysed sulfonylative Suzuki-Miyaura cross coupling reaction. A wide range of aryl and alkenyl boronic acids are coupled with aryl and alkenyl iodides to give the corresponding sulfones. A two-step one-pot sulfination/derivatisation method was also developed, allowing access to compounds including β-hydroxy sulfones, sulfonamides and sulfonyl fluorides.
Chapter 3 illustrates a one-step copper(II)-catalysed sulfonamide synthesis using boronic acids, amines and SO2. Various aryl and alkenyl boronic acids as well as amines and anilines are compatible, including active pharmaceutical ingredients such as amoxapine and desloratadine.
Chapter 4 details an aryne-based selective formation of substituted benzoisothiazoles. Different substitution pattern of the aryne precursor and the thiadiazole are employed, with the target heterocycles being obtained in good to excellent yields.
Chapter 5 summarises the research and the future work.
Chapter 6 documents the experimental procedures and data.

Keywords: Benzyne
Sulfonamide
Sulfone
DABSO
Advisor: Willis, M
Perinatal depression in refugee and labour migrant women on the Thai-Myanmar border: prevalence, risk factors and experiences

Background: Perinatal depression is a significant contributor to maternal morbidity and mortality worldwide. Left untreated, perinatal depression has severe and far-reaching consequences for women, their families and wider society. Migrant women, including labour migrants and refugees, may be particularly prone to developing perinatal depression as a result of multiple stressors associated with displacement. Despite the vast majority of global migration flows occurring within low- and middle-income countries, evidence from these regions is severely lacking. This research addresses this imbalance by examining perinatal depression in migrant women living on the Thai-Myanmar border: a resource-poor setting of political tension and socio-economic disadvantage.
Aims: This research aims to review the existing evidence around perinatal depression among migrant women from low- and middle-income settings; identify an appropriate tool to detect perinatal depression in migrant women on the Thai-Myanmar border; determine the prevalence of, and risk factors for, perinatal depression in this setting; explore women's experiences of perinatal depression; and develop recommendations for policy and practice.
Methods: A sequential-exploratory mixed-methods design was used. The research included the following five study components: a systematic literature review; a validation study to identify a culturally-acceptable and appropriate assessment tool; a prospective cohort study of migrant women on the Thai-Myanmar border followed-up from the first trimester of pregnancy to one month post-partum; in-depth interviews with a subgroup of women with severe perinatal depression; and an informal exploration of stakeholder views.
Findings: The systematic review found a wide range in prevalence of perinatal depression among migrant women and confirmed the absence of studies conducted in low-and middle-income destination countries. A total of 568 migrant women on the Thai-Myanmar border participated in the prospective cohort study, of whom 18.5% experienced moderate-severe depression and 39.8% experienced depression of any severity during the perinatal period. Almost a third (29%) of women reported suicidal ideation. Interpersonal violence (OR 4.5), experience of trauma (OR 2.4), a self-reported history of depression (OR 2.3) and perceived insufficiency of social support (OR 2.1) were significantly associated with perinatal depression. Lives of women with severe perinatal depression were characterised by difficult partner relationships, alcohol use among partners and interpersonal violence. A lack of mental health services currently limits the effective management of perinatal depression in this setting. Alongside training of health staff, primary, secondary and tertiary prevention efforts are required to effectively address perinatal depression on the Thai-Myanmar border.

Keywords: perinatal depression
Myanmar
migrant
Thailand
refugee
Advisor: Fitzpatrick, R
McGready, R
Plugge, E
Fazel, M
Measuring poverty in the EU: Investigating and improving the empirical validity in deprivation scales of poverty

Non-monetary deprivation indicators are now widely used for studying and measuring poverty in Europe. However, despite their prevalence, the empirical performance of existing deprivation scales has rarely been examined. This thesis i) identifies possible conceptual problems of existing deprivation scales such as indexing, missing dimensions and threshold; ii) empirically assesses the extent of possible error in measurement related to these conceptual problems; and iii) offer an alternative way for constructing deprivation measures to mitigate the identified conceptual problems. The thesis consists of four stand-alone papers, accompanied by an overarching introduction and conclusion. The first three papers provide empirical evidence on the empirical consequences of the missing dimensions and threshold problems for the measurement and analysis of poverty, while the fourth paper exemplifies a concept-led multidimensional design that can reduce the error introduced by these conceptual problems. The analysis is generally held for 25 EU countries using European Survey of Income and Living Conditions (EU-SILC); only in the second paper, the analysis is done for the UK using British Household Panel Survey (BHPS).

Keywords: Deprivation threshold
needs for health
equivalization
out-of-pocket payments
Multidimensionality of poverty
social class gradient in deprivation
needs for care
Missing dimensions
unmet needs for health
deprivation risk vs. deprivation level
count data models
zero deprivation
conversion factors
measurement validity
Unmet needs
zeros vs. counts
determinants of deprivation
cost-related unmet needs
Multidimensional measurement of poverty
needs for education
Advisor: Walker, R
Bukodi, E
Evolution of bHLH transcription factors that control epidermal cell development in plants

The colonization of the arid continental surface by plants was one of the milestones in Earth's history. Morphological innovations, such as the origin of complex 3D tissues, allowed the successful colonization and radiation of plants on land. The epidermis is the outermost plant tissue that constitutes the interface between the plant and the environment. Thus, the evolution of epidermal cells was crucial for the adaptation of plants on the terrestrial arid environment. I undertook a combined approach that aims to understand the evolutionary trends that drove land plant colonization and the genetic mechanisms that underlie the development of the epidermis. This approach includes: 1) analyses of plant transcription factors (TFs) families distribution and diversification, with a particular focus on the basic Helix-Loop-Helix (bHLH) TF family, and 2) functional characterization of a putatively conserved bHLH TF subfamily involved in epidermal cell development in land plants. Here, I showed that there was a stepwise increase in the number of transcription factor (TF) families and bHLH subfamilies that predated the colonization of the terrestrial surface by plants. The subsequent increase in TF number on land was through duplication within pre-existing TF families and subfamilies. Moreover, a similar trend occurred in metazoan bHLH TF, suggesting that the majority of innovation in plant and metazoan TF families occurred in the Precambrian before the Phanerozoic radiation of land plants and metazoans. Furthermore, I demonstrated that the function of IIIf bHLH TFs in controlling the development of the epidermal cell layer is conserved between liverworts and angiosperms. This suggests that IIIf bHLH TFs are ancient and conserved regulators of epidermal cell development since the early colonization of the land by plants. Moreover, these bHLH TFs were recruited during the evolution of land plants to control the development of seemingly unrelated morphological characters in specific lineages of extant land plants. The recruitment of ancient developmental regulators to control distinct and unrelated developmental processes in land plants might underlie the huge morphological and taxonomic radiation of plants on land.

Keywords: Marchantia polymorpha
Transcription factors
Land Plants
Advisor: Dolan, L
Evaluating the impact of automation on labour markets in England and Wales

Robots are now able to complete many tasks with greater efficiency than humans. This is leading employers to demand different skills from their workforces. Simultaneously, there has been a notable decline in manufacturing employment in the UK. Using data at a local authority level, this thesis shows that industrial robot technology in the transportation manufacturing industry, an empirical proxy for automation, had a negative and statistically significant effect on employment across England and Wales between 1991 and 2001; a period of increasing industrial robot usage in the UK. Using structural parameter estimates for the UK economy, the empirical results suggest that one industrial robot in the transportation manufacturing industry reduced employment by 4.2 workers between 1991 and 2001. This is equivalent to approximately 21,000 job losses over the decade. Upon establishing the result for automation, the empirical analysis is extended to disentangle the impact of automation from trade. It is found that Chinese import exposure had a larger effect than automation between 1991-2001, accounting for approximately 27% of the decline in UK manufacturing employment over the period.

Advisor: Adams, A
Frey, C
Chilling effects in the internet age: three case studies

This thesis is an empirical legal investigation into regulatory chilling effects in online contexts. Internet censorship is on the rise globally and state surveillance and cyber-policing capabilities are rapidly evolving. Understanding regulatory "chilling effects"—the idea that laws, regulations, or state surveillance can deter people from exercising their freedoms or engaging in legal activities—has thus today taken on greater urgency and public importance. Yet, the notion is not uncontroversial; many commentators have questioned the existence and impact of regulatory chilling effects, particularly in online contexts. It does not help that previous studies on regulatory chilling effects are generally narrow in methodological and theoretical approach and concern traditional media contexts, shedding little light on how chilling effects may work online. Drawing on a theoretical framework that synthesizes traditional chilling effects theory—forged largely by legal theorists Frank Schauer and Daniel Solove—and informed by insights from both online privacy and computer mediated communications (CMC) research, this thesis addresses this gap in the literature with an innovative research design that explores regulatory chilling effects online, with case studies exploring its comparative, regulatory, and surveillance-related dimensions.
In concrete terms, this thesis provides empirical and theoretical foundations not only for the notion of regulatory chilling effects online but also factors that influence them. The first case study, a first-of-its-kind online survey with over 1200 respondents, provides general empirical support for the existence of regulatory chilling effects in online contexts, including comparative insights, that is, how some forms of regulation or surveillance may have more significant regulatory chilling effects than others, and why. The second case study examines whether widely covered revelations in June 2013 concerning NSA/PRISM online surveillance has had a chilling effect on Wikipedia users. The third case study is an investigation of the United States Digital Millennium Copyright Act (DMCA)’s controversial notice and takedown copyright enforcement system, a scheme often criticized for creating chilling effects online. This DMCA study is carried with a sample of 500 Google Blogs and 500 Twitter accounts and offers insights into how regulatory chilling effects work in practice, along with insights and implications of automated or "robotized" legal enforcement and the DMCA's international impact.
Ultimately, this thesis addresses substantial gaps in existing research and literature concerning the existence, scope, impact, and permanence of regulatory chilling effects, and factors that influence them, while helping lay the foundation for a theory of regulatory chilling effects for online contexts. It also has substantial methodological contributions, offering unique and innovative methods for measuring and exploring regulatory chilling effects that can be re-deployed or built upon in future research

Advisor: Nash, V
The effects of hypomorphic STAT3 on lymphocyte function and intestinal immune regulation

Dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3) underlie the human primary immunodeficiency autosomal dominant hyper IgE syndrome (HIES). A number of aspects of this disease, including the eponymous elevated serum IgE, remain poorly understood. Additionally, work from numerous animal models has suggested STAT3 plays a critical role in the development, regulation and resolution of intestinal inflammation. Human genetic studies have associated this pleiotropic transcription factor with inflammatory bowel disease (IBD), but elucidation of the overall role of STAT3 in intestinal homeostasis has been hindered by the lethality associated with germline deletion. To better understand STAT3 function in both intestinal homeostasis and IgE regulation, we generated bacterial artificial chromosome (BAC)-transgenic mice that expressed a HIES-associated STAT3 allele. Transgenic cells exhibited normal tyrosine phosphorylation of STAT3 following acute cytokine stimuli, but marked inhibition in DNA-binding activity. The mice recapitulated important aspects of HIES, including elevated serum IgE. We identified an intrinsic bias towards IgE class switch recombination (CSR) in transgenic B cells, and a possible role for STAT3 in directly regulating both the immunoglobulin heavy chain locus and key regulators of CSR, such as Id2, an inhibitor of μ-ε switching. The partial loss of STAT3 signaling also led to important changes in intestinal responses, with transgenic mice showing enhanced susceptibility to both dextran sodium sulfate (DSS) and Citrobacter rodentium induced colitis. Following C. rodentium infection, we observed defects in both the early production of certain antimicrobial peptides such as RegIIIγ and resolution of inflammation in late infection, where the bacterial burden was decreasing. Transgenic myeloid cells were hyporesponsive to IL-10, suggesting that hypomorphic STAT3 activity within the intestine destabilizes the system: predisposing to infection and hindering the IL-10 regulatory pathway’s ability to keep inflammatory responses in check. Therefore, our data suggest that STAT3 plays key roles in both CSR and the maintenance of intestinal homeostasis.