VictorJuiz/thesis huggingface dataset:
Sons of Adam, daughters of Eve: original sin and the evolution of sexual difference
Keywords: evolution
sexual difference
gender
original sin

Since the publication of Charles Darwin’s On the Origin of Species in 1859, there has been much scholarly interest in developing a coherent synthesis between the doctrine of original sin and scientific accounts of human origins. Despite the significant interest in integrating theories of evolution with a doctrine of original sin, there has been comparatively little effort devoted to reexamining original sin in light of information about the evolution of Homo sapiens as sexually differentiated, even though the doctrine has carried implications for gendered relationships since its earliest formulations. This project fills this gap in scholarly literature by developing an interdisciplinary conversation between evolutionary biology, New Feminist Materialism, and theology in order to articulate a way of thinking about original sin that takes seriously the nature of Homo sapiens as continually evolving in sexually differentiated ways. By engaging with developments in evolutionary theory and biological information about sexual difference, the project aims to cultivate a sense of wonder at the diversity and explosive unpredictability of human biology, a value for the role of creativity in the human participation that partially shapes our ongoing evolution, and humility about the extent to which we can predict and control the future of the evolution of our species. The biological investigations in this project illuminate the interdependencies that define creaturely life, the persistent entanglement of nature and culture, the centrality of desire to human identity and behavior, and the role played by biology in the transmission of sin. These biological insights confirm some of Augustine’s anthropological intuitions. In the second half of the project, John Paul II’s Theology of the Body is juxtaposed with New Feminist Materialism in order to develop a framework for a Christian Feminist Materialism that sees material life as evolving, generative, and “imbued with activity;” but also as simultaneously infected with sin and saturated with the divine.
Investigating the neuroprotective function of TLDc proteins
Keywords: cerebellum
oxidative stress
neurodegeneration

A recent World Health Organisation Global Burden of Disease study reports a yearly increase in the prevalence of neurodegenerative diseases, with more than 100 million people worldwide expected to be living with dementia by 2050. These disorders represent a range of neurological conditions characterised by selective neuronal cell death; no effective treatments have been developed, with the available therapy only able to reduce the symptoms in some cases. Although etiology of neurodegenerative diseases is not well understood, some common pathological features are shared between them, including protein aggregation and oxidative stress. Identification of the molecular mechanisms underlying these processes would therefore deepen our understanding of the disease pathogenesis and help in the search for new therapeutic targets. Members of a conserved protein family (TLDc) have been shown in recent years to protect neurons from oxidative insults in vitro and in vivo and play a role in oxidative stress response regulation via unknown mechanism. In addition, TLDc mutations are causative in range of neurological disorders, some characterised by neurodegeneration. Therefore, further analysis of this particular protein family may provide new insights into fundamental protective mechanisms that could be harnessed in the future.
The aim of this thesis was to investigate the mechanism of action of the TLDc protein oxidation resistance 1 (Oxr1) in oxidative stress protection and in the maintenance of neural tissue homeostasis. Using a combination of in vitro assays and in animal models with disruption or overexpression of Oxr1, I have shown that Oxr1 interacts with the potent antioxidant enzyme peroxiredoxin-2 where it regulates its post-translational modifications and oligomerisation in a brain-region specific manner. I have also for the first time discovered a molecular function of Oxr1 by showing it possesses holdase chaperone activity in vitro, suggesting it acts as a putative chaperone. Next, to understand the cause of neurodegeneration in the Oxr1 knockout mouse, transcriptional profiling was carried out, revealing an induction of presymptomatic neuroinflammatory markers, suggesting Oxr1 is critical for the normal inflammatory response in the brain. I have also produced preliminary data suggesting a role for Oxr1 in autophagy. Finally, computational analysis of transcriptional activity and regulation of TLDc family members suggests high degree of functional conservation between TLDc genes and their involvement in processes throughout the body, proposing novel directions for future studies. Together, my results contribute to our understanding of the functions of TLDc genes in the CNS and the role of Oxr1 in oxidative stress protection and proteostasis.
Genomic analyses of polysaccharide capsules in Neisseria species
Keywords: bacteria
virulence
evolution
commensals
genomes

Neisseria meningitidis is one of several Neisseria species that asymptomatically colonise the human nasopharynx. Occasionally, N. meningitidis invades the bloodstream, resulting in invasive meningococcal disease (IMD). In most settings, expression of a serogroup A, B, C, W, X or Y polysaccharide capsule is essential for IMD. Previously, capsules were considered unique to N. meningitidis, among the Neisseria, possibly acquired by horizontal genetic transfer (HGT). In this thesis, genomic analyses further investigate the distribution and evolution of capsules in Neisseria species.
Chapter 2 identifies orthologues of conserved capsule export genes in 13 nonpathogenic Neisseria species. Novel capsule synthesis genes are further characterised and found to resemble those present in other encapsulated bacteria including N. meningitidis, Actinobacillus and Haemophilus. Preliminary 1H NMR results are consistent with some of the structural predictions arising from these comparisons.
Phylogenetic analyses in Chapter 3 indicate that the meningococcal capsule has undergone HGT with other Neisseria species on at least two occasions. Sequence analyses are consistent with hypotheses postulating that the meningococcal capsule was acquired de novo through HGT, with Neisseria subflava identified as a potential donor, but are not sufficient to definitively prove that such an event occurred.
Finally, Chapter 4 explores a more contemporary example of HGT within the meningococcal capsule locus. Capsule switching from serogroup E to serogroup B is shown to be responsible for cases of IMD in clonal complexes cc60 and cc1157. This example is further explored to discuss the interaction between the capsule and the wider genetic profile of meningococci, and their association with IMD.
These analyses expand on previous understanding of the distribution and evolution of the polysaccharide capsule in the Neisseria, and the implications for the epidemiology of IMD. Discussions of this important virulence-associated factor address its enigmatic existence in organisms that principally colonise the nasopharynx without causing disease.
Sequelae of selected gastrointestinal infections: incidence, risk factors and economic impact on the National Health Service in England
Keywords: Sequelae
direct costs
Proton pump inhibitors
Salmonellosis
Campylobacter
Antibiotics
Campylobacteriosis

Background Sequelae of reactive arthritis (ReA), irritable bowel syndrome (IBS), Guillain-Barré syndrome (GBS), ulcerative colitis (UC), Crohn’s disease (CD) and Rheumatoid arthritis (RA) following gastrointestinal (GI) infections can occur. Evidence suggests proton pump inhibitors (PPI) or antibiotics can increase the risk of GI infections, but their role in sequelae onset is unclear. Further, the impact on the National Health Service (NHS) of GI infections sequelae is unknown.
Methods Four studies were conducted in this thesis. First, a systematic review (SR) to determine the association between prior use of PPI or treatment with antibiotics and the onset of ReA and IBS amongst patients with Campylobacter or non-typhoidal Salmonella (NTS) infections. Second, a population-based study of routinely collected linked primary care, hospital, deprivation and deaths data (2000-2015) to determine the incidence of ReA, IBS, GBS, UC, CD, and RA in the 12 months following Campylobacter or NTS infection. Third, a retrospective cohort study to assess the role of antibiotics or PPI in the onset of sequelae amongst patients with Campylobacter infection. Fourth, an economic assessment to determine the impact of sequelae of the selected GI infections on the volume, type and costs of all health care encounters in the periods’ pre- and post-infection.
Results In the SR, only one study reported an elevated risk in the onset of ReA amongst patients with the selected GI infections who had prior PPI prescription. There was no clear association between antibiotics and sequelae onset. In the population-based study, less than two per cent of the patients developed sequelae. Patients with sequelae were mainly females in comparison with those with GI infection only. Of all the sequelae considered, the incidence of IBS was highest in the 12 months post-infection (1.2%). Female Campylobacter patients on PPI were two and a half times more likely to develop IBS. There was no association with antibiotics and the onset of sequelae of campylobacteriosis. Sequelae significantly impacted the NHS with an additional £1.3 million in expenditure on average annually. Males, older people (65+), and those with underlying health conditions incurred the highest costs.
Conclusions The findings raise the need to emphasise the negative consequences of Campylobacter and NTS infections. It highlights the significant impact of sequelae on the NHS and the patient groups with excess expenditure. This is vital in the evaluation of public health interventions to reduce the overall burden of these GI infections. Further evidence to determine the existence of a dose-response relationship between PPI and Campylobacter infection in the onset of IBS is warranted.
Assessing early postoperative recovery following lower limb joint replacement
Keywords: Orthopaedic
Unicompartmental knee replacement
Psychometrics
Surgery
Research
Patient-reported outcome measure
Arthroplasty
Factor analysis
Hip replacement
Quantitative
Postoperative
Patient-reported change measure
Early recovery
Systematic review
Questionnaire development
Knee replacement
Health measurement scales
Joint replacement
Qualitative
Recovery

Improving perioperative recovery is critical to enhance patient care, ensure timely discharge from the patient, clinician and hospital perspective and improve short and long-term outcomes after surgery.
A systematic review was performed examining tools for early post-operative recovery after elective lower limb joint replacement. It showed that no fully-validated, patient-reported tools existed. Currently used measures included pain scores, opioid usage, length of stay and surgical satisfaction.
In order to address this need, a patient-reported outcome measure (PROM) and change measure for use in the first six weeks following surgery have been developed. A five-phased, best practice, iterative approach was used.
Planning Phase - Qualitative interviews (n=22) were performed with orthopaedic healthcare professionals, ascertaining if and how clinicians would use such a PROM. These helped determine the views of potential users, and guide structure and layout.
Phase One - Qualitative patient-interviews (n=30) from the day of surgery to nine weeks postoperatively were completed. Analysis of these interviews identified important patient-reported factors in early recovery.
Phase Two - The factors provided from Phase One interviews were used to find questionnaire themes. Items were then generated and pilot questionnaires developed. Items were tested and refined in the context of cognitive debrief interviews (n=34) for potential inclusion in the final tools.
Phase Three - Final testing of questionnaire properties with item reduction (n=168). The Oxford Arthroplasty Early Recovery Score (OARS) is a 14-item PROM measuring health status at the time of testing. The Oxford Arthroplasty Early Change Score (OACS) is a 14-item measure to assess change.
Phase Four - Validation: The OARS and OACS were administered to consecutive patients (n=155) in an independent cohort. Validity and reliability were assessed. Psychometric testing showed positive results, good validity and sensitivity to change.
The OARS and OACS were then utilised in a pilot study to assess the feasibility of day case treatment. Inpatient (n=29) and day-case (n=26) unicompartmental knee arthroplasty (UKA) patients completed the two measures, and the results confirmed that day case treatment and discharge is a valid option.
The work completed in this thesis will now enable these newly developed scores to be used to define and assess an optimal-recovery protocol for lower limb joint replacement.
Kernel-based hypothesis tests: large-scale approximations and Bayesian perspectives
Keywords: Bayes Factor
Hilbert Schmidt Independence Criterion
Kernel Methods
Large-Scale
Hypothesis Testing

This thesis contributes to the field of nonparametric hypothesis testing (i.e. two-sample and independence testing) by providing a large-scale framework and developing a Bayesian perspective. We focus on nonparametric measures of homogeneity and dependence by considering the Hilbert norms between the embeddings of probability distributions in the reproducing kernel Hilbert space (RKHS). The rich representation provided by the associated kernel feature map enables the use of multivariate or non-Euclidean observations (e.g. strings and graphs) and it leads to powerful tests that are able to solve challenging problems given enough observations. However, the cost of computing the kernel matrix scales at least quadratically in the number of samples and makes it prohibitive to use in modern large-scale datasets. First, we propose three estimators of the well-known kernel dependence measure, the Hilbert Schmidt Independence Criterion (HSIC), namely the block-based estimator, the Nystrom estimator and the random Fourier feature (RFF) estimator, and establish the corresponding linear time independence test for each of the estimators. Secondly, we consider a normalised version of HSIC, the NOrmalised Cross COvariance (NOCCO) statistic, and propose an RFF approximated NOCCO. This results in a distribution free test that is robust to the kernel bandwidth misspecification. Thirdly, we propose a two-step conditional independence test that extends the popular two-step approach REgression with Subsequent Independence Test (RESIT) through RKHS valued regressions. When used as a part of the classical PC algorithm for causal inference, the resulting algorithm is more robust to hidden variables that induce nonfunctional associations. Finally, we utilise the classical Bayes factor formalism for model comparison and propose a Bayesian two-sample test by modelling the witness function of the well-known kernel measure of homogeneity, the Maximum Mean Discrepancy (MMD), with a Gaussian Process.
Functional study of waist-hip ratio associated loci and the WARS2 gene as modulators of fat distribution.
Keywords: Epigenetics
TBX15
Obesity
Waist-hip ratio
GWAS
WARS2

Waist-hip ratio (WHR) is a risk factor for diabetes and cardiovascular disease. Genome-wide association studies identified 346 loci linked to increased WHR adjusted for Body Mass Index (WHRadjBMI) (Shungin et al., 2015; Pulit et al., 2018). To elucidate the genetic underpinning of WHRadjBMI, I aimed to identify causal SNPs in 4 of these loci and test the tryptophanyl-tRNA synthetase 2 (WARS2) gene, previously shown to severely affect adipose mass, as modulators of fat distribution and browning.
To prioritise real signals, with colleagues, I selected 3 SNPs in EMILIN2, VEGFA, C5orf67 loci with posterior probability analysis (PPA) scores > 0.95 for functional analysis. In the more complex TBX15-WARS2 locus, we filtered 61 SNPs and selected 5 SNPs with a PPA score > 0.2 and further 8 top-scoring SNPs according to the epi-Phylogenetic Module Complexity Analysis (epi-PMCA). Using electrophoretic mobility shift assays (EMSAs) and luciferase assays in a differentiating human white adipose cell line, I showed that rs3936510 in the C5orf67 locus and rs3810068 in the EMILIN2 affected DNA-protein binding and identified enhancer/promoter activities in these loci. I demonstrated that rs3810068 altered the binding of CCAAT/enhancer-binding protein beta (CEBP/β). In the TBX15-WARS2 locus, I used luciferase assays, RNA degradation analysis and allele-specific qPCR to show that the rs2645294, lead SNP in the 3’UTR of WARS2, did not impact RNA stability.
Wars2 (Wars2V117L/V117L) mice showed previously progressive tissue-specific pathologies including reduced adiposity and browning of white adipose tissue (GTEx-Consortium, 2013; Civelek et al., 2017; Agnew et al., 2018). I show that whilst heterozygous female mice (Wars2+/V117L and Wars2+/-) were unaffected, Wars2V117L/V117L mice failed to gain fat mass on a high-fat diet (HFD) in both sexes, had increased visceral:subcutaneous adipose ratio specifically in males on HFD and showed lower food intake in males. In both sexes, brown adipose tissue (BAT) showed loss of browning markers and mitochondrial dysfunction. In white adipose tissue (WAT), browning markers were upregulated, with a greater difference in the subcutaneous inguinal WAT compared to visceral gonadal WAT. In differentiated primary preadipocytes no difference in browning was observed. Plasma showed elevated levels of Fibroblast growth factor-21 (FGF21) and Growth/differentiation factor 15 (GDF15) In summary, a hypomorphic mutation in the mitochondrial gene WARS2 reduced fat mass irrespective of diet and altered fat distribution in a diet and sex-specific manner, likely due to differences in depot-specific browning and elevation of mitokines FGF21 and GDF15 from other affected tissues.
Exploring the role of the RNA-binding protein SRSF3 in the developing heart
Keywords: coronary vessel
proepicardium
epicardium

Understanding the molecular processes that govern cardiovascular development has the potential to inform regenerative strategies for disease states. Due to their versatile roles, epicardial cells are an attractive therapeutic target. However, using epicardial cells for therapy is hindered by our limited understanding of epicardial biology.
The embryonic epicardium is one of the main regulators of cardiovascular development, functioning to secrete essential growth factors and produce epicardium-derived cells (EPDCs) that contribute most coronary vascular smooth muscle cells and cardiac fibroblasts. Due to its complex biology, the molecular mechanisms that control epicardial formation and differentiation have not been fully elucidated.
SRSF3 is an RNA-binding protein that has essential roles in RNA processing, and it is highly expressed in the proepicardium and later in the epicardial layer during heart development. Deletion of Srsf3 from the murine proepicardium using the Tg(Gata5-Cre) or embryonic day (E) 8.5 induction of Wt1CreERT2 led to proliferative arrest and impaired epithelial-to-mesenchymal transition (EMT), which prevented proper formation and function of the epicardial layer. The epicardial requirement for SRSF3 was further assessed in a mouse epicardial cell line using RNA interference, which revealed that SRSF3 is required for production of Cyclin D1 and for EMT in response to TGFβ.
Induction of Srsf3 deletion with the Wt1CreERT2 after the proepicardial stage resulted in disrupted sprouting from the sinus venosus and elevated hypoxia at E13.5. Single-cell RNA-sequencing showed SRSF3-depleted epicardial cells were removed by E15.5. The remaining non-targeted cells became hyperproliferative and compensated for the loss, with normal epicardial contribution being detected at E17.5.
Due to the compensation mechanism, the existence of epicardial subpopulations was explored through assessment of published heterogeneous marker genes: Sema3d, Scx, Tcf21, Tbx18 and Wt1, using RNAscope, PrimeFlow and Single-cell RNA-Sequencing, in both wild-type and SRSF3 mutants. Complete overlap of the markers was detected, with no evidence of epicardial subpopulations, raising questions regarding the specificity of previously reported Cre lines.
This research supports a role for SRSF3 as a master regulator of RNA metabolism in epicardial cells, however, further studies are required to dissect the exact molecular mechanisms involved.
Figured funerary stelai from Roman-period Anatolia, 100 BC-AD 400: regional considerations of cultural, social, and economic expressions in funerary contexts
Keywords: Funerary archaeology
Roman Anatolia
Roman archaeology

This thesis presents a multi-faceted, case-study based examination of regionalism and use of figured funerary stelai from fifteen sites in Roman-period Asia Minor and Galatia, focusing on local patterns of iconography and epigraphy as well as broader regional comparison of these trends. These non-door stelai, a sample of 302 monuments, are flat-face stones decorated with relief figures from a narrow selection of iconographic-types. This study offers a synthesis of all aspects of figured-stele use in the case-study sites, encompassing constituent elements of the monuments and consideration of stele-use between city and countryside, taking into account local geo-political histories, and approaching stelai as simultaneously private and public monuments of self-display. Section I focuses on stelai in the sepulchral landscape of Roman-period Anatolia, the technical details of the stelai themselves, and situating stelai in the economics of commemoration. There follows in Section II a detailed assessment of the iconography and epigraphy of the case-study figured stelai. Questions of represented socio-economic levels, stele-use vis-à-vis settlement patterns, and regional customs of commemoration are the subject of Section III, exploring relationships between patrons, deceased, and stele components. Iconography and epigraphy on these monuments highlight the ‘standardization’ of motifs in the Roman period and local shifts in image emphases and patron priorities, including the development of more individualized iconography with the expanded socio-economic spectrum employing this monument to include not only some ‘elite’ but also gladiators and farmers among other occupations. Similar expansion appears in the geographic distribution of figured stelai, incorporating regions with limited pre-Roman traditions for the monument. The simultaneous broadening of both the socio-economic levels of patrons and the geographic regions of use represent distinguishing characteristics of Roman-period figured-stele patterns.